CA2392979A1 - 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline crystal - Google Patents
4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline crystal Download PDFInfo
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- CA2392979A1 CA2392979A1 CA002392979A CA2392979A CA2392979A1 CA 2392979 A1 CA2392979 A1 CA 2392979A1 CA 002392979 A CA002392979 A CA 002392979A CA 2392979 A CA2392979 A CA 2392979A CA 2392979 A1 CA2392979 A1 CA 2392979A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
Crystalline forms of a CETP inhibitor of formula (I), methods of making the crystals, methods of using the crystals and pharmaceutically compositions containing the crystals are disclosed.
Description
4-CARBOXYAMINO-2-ETHYL-1,2,3,4-TETRAHYDROQUINOLINE CRYSTAL AS CETP INHIBITOR
Background Of The Invention This invention relates to cholesteryl ester transfer protein (CETP) inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans.
More particularly, this invention relates to CETP inhibitor crystals, pharmaceutical compositions comprising these crystals, a process for preparing these crystals and to methods of treating atherosclerosis, obesity, and related diseases and/or conditions with the crystals.
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-cholesterol 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
Background Of The Invention This invention relates to cholesteryl ester transfer protein (CETP) inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans.
More particularly, this invention relates to CETP inhibitor crystals, pharmaceutical compositions comprising these crystals, a process for preparing these crystals and to methods of treating atherosclerosis, obesity, and related diseases and/or conditions with the crystals.
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-cholesterol 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
-2-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 (--10-12%). 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 September 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:
O
R3 ~
\N- _ R
Rs R I O a 4~
6 ~~ 3 1~
N- _R
R z R8 R~
Specifically, the compound [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is described.
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 alternative therapies.
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 (--10-12%). 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 September 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:
O
R3 ~
\N- _ R
Rs R I O a 4~
6 ~~ 3 1~
N- _R
R z R8 R~
Specifically, the compound [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is described.
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 alternative therapies.
-3-Summary Of The Invention This invention is directed to a Formula I crystal r~
O
~N
Et Alternatively, a crystal of the above Formula I is named as [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
Another aspect of this invention is directed to an anhydrous crystal of Formula Another aspect of this invention is directed to the corresponding anhydrous crystal having the X-ray powder diffraction pattern as shown in Figure 1.
Another aspect of this invention is directed to an ethanolate crystal of Formula Another aspect of this invention is directed to the corresponding ethanolate crystal having the X-ray powder diffraction pattern as shown in Figure 2.
A preferred dosage is about 0.01 to 100 mg/kg/day of a Formula I crystal. An especially preferred dosage is about 0.1 to 10 mg/kg/day of a Formula I
crystal.
In the text herein including the following methods, pharmaceutical compositions, combinations and kits reference is made to a crystal of Formula I.
While it is understood that if the crystal is in solution, the crystal form is not present (in contrast to e.g., a dry tablet formulation), the following methods pharmaceutical compositions combinations and kits are intended to include a method or formulation IV
O' \
OEt
O
~N
Et Alternatively, a crystal of the above Formula I is named as [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
Another aspect of this invention is directed to an anhydrous crystal of Formula Another aspect of this invention is directed to the corresponding anhydrous crystal having the X-ray powder diffraction pattern as shown in Figure 1.
Another aspect of this invention is directed to an ethanolate crystal of Formula Another aspect of this invention is directed to the corresponding ethanolate crystal having the X-ray powder diffraction pattern as shown in Figure 2.
A preferred dosage is about 0.01 to 100 mg/kg/day of a Formula I crystal. An especially preferred dosage is about 0.1 to 10 mg/kg/day of a Formula I
crystal.
In the text herein including the following methods, pharmaceutical compositions, combinations and kits reference is made to a crystal of Formula I.
While it is understood that if the crystal is in solution, the crystal form is not present (in contrast to e.g., a dry tablet formulation), the following methods pharmaceutical compositions combinations and kits are intended to include a method or formulation IV
O' \
OEt
-4-resulting from a use of such crystal (e.g., administering a gelatin capsule including an oil formulation solution of the crystal).
Yet another aspect of this invention is directed to methods for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being either male or female) by administering to a mammal in need of such treatment an atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating atherosclerosis in a mammal (including a human being) by administering to a mammal in need of such treatment an atherosclerosis treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating peripheral vascular disease in a mammal (including a human being) by administering to a mammal in need of such treatment a peripheral vascular disease treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating dyslipidemia in a mammal (including a human being) by administering to a mammal in need of such treatment a dyslipidemia treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating hyperbetalipoproteinemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hyperbetalipoproteinemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating hypoalphalipoproteinemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypoalphalipoproteinemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to methods for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being either male or female) by administering to a mammal in need of such treatment an atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating atherosclerosis in a mammal (including a human being) by administering to a mammal in need of such treatment an atherosclerosis treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating peripheral vascular disease in a mammal (including a human being) by administering to a mammal in need of such treatment a peripheral vascular disease treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating dyslipidemia in a mammal (including a human being) by administering to a mammal in need of such treatment a dyslipidemia treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating hyperbetalipoproteinemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hyperbetalipoproteinemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating hypoalphalipoproteinemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypoalphalipoproteinemia treating amount of a Formula I crystal.
-5-Yet another aspect of this invention is directed to a method for treating hypercholesterolemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypercholesterolemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating hypertriglyceridemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypertriglyceridemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating familial-hypercholesterolemia in a mammal (including a human being) by administering to a mammal in need of such treatment a familial-hypercholesterolemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating cardiovascular disorders in a mammal (including a human being) by administering to a mammal in need of such treatment a cardiovascular disorder treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating angina in a mammal (including a human being) by administering to a mammal in need of such treatment an angina treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating ischemia in a mammal (including a human being) by administering to a mammal in need of such treatment an ischemic disease treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating cardiac ischemia in a mammal (including a human being) by administering to a mammal in need of such treatment a cardiac ischemic treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating stroke in a mammal (including a human being) by administering to a mammal in need of such treatment a stroke treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating a myocardial infarction in a mammal (including a human being) by administering to a mammal in need of such treatment a myocardial infarction treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating hypertriglyceridemia in a mammal (including a human being) by administering to a mammal in need of such treatment a hypertriglyceridemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating familial-hypercholesterolemia in a mammal (including a human being) by administering to a mammal in need of such treatment a familial-hypercholesterolemia treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating cardiovascular disorders in a mammal (including a human being) by administering to a mammal in need of such treatment a cardiovascular disorder treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating angina in a mammal (including a human being) by administering to a mammal in need of such treatment an angina treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating ischemia in a mammal (including a human being) by administering to a mammal in need of such treatment an ischemic disease treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating cardiac ischemia in a mammal (including a human being) by administering to a mammal in need of such treatment a cardiac ischemic treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating stroke in a mammal (including a human being) by administering to a mammal in need of such treatment a stroke treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating a myocardial infarction in a mammal (including a human being) by administering to a mammal in need of such treatment a myocardial infarction treating amount of a Formula I crystal.
-6-Yet another aspect of this invention is directed to a method for treating reperfusion injury in a mammal (including a human being) by administering to a mammal in need of such treatment a reperfusion injury treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating angioplastic restenosis in a mammal (including a human being) by administering to a mammal in need of such treatment an angioplastic restenosis treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating hypertension in a mammal (including a human being) by administering to a mammal in need of such treatment a hypertension treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating the vascular complications of diabetes in a mammal (including a human being) by administering to a mammal in need of such treatment a vascular complications of diabetes treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating obesity in a mammal (including a human being) by administering to a mammal in need of such treatment an obesity treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating endotoxemia in a mammal (including a human being) by administering to a mammal in need of such treatment an endotoxemia treating amount of a Formula I
crystal.
This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being) which comprise a therapeutically effective amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis in a mammal (including a human being) which comprise an atherosclerosis treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of peripheral vascular disease in a mammal (including a human being) which comprise a peripheral vascular disease treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of dyslipidemia in a mammal (including a human being) which comprise a dyslipidemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hyperbetalipoproteinemia in a mammal (including a human being) which comprise a hyperbetalipoproteinemia treating amount of a crystal of Formula I
and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypoalphalipoproteinemia in a mammal (including a human being) which comprise a hypoalphalipoproteinemia treating amount of a crystal of Formula I
and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammal (including a human being) which comprise a hypercholesterolemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypertriglyceridemia in a mammal (including a human being) which comprise a hypertriglyceridemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of familial-hypercholesterolemia in a mammal (including a human being) which comprise a familial-hypercholesterolemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of angina in a mammal (including a human being) which comprise an _g_ angina treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of ischemia in a mammal (including a human being) which comprise an ischemic treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of cardiac ischemia in a mammal (including a human being) which comprise a cardiac ischemic treating amount of a crystal of Formula 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of stroke in a mammal (including a human being) which comprise a stroke treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of a myocardial infarction in a mammal (including a human being) which comprise a myocardial infarction treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of reperfusion injury in a mammal (including a human being) which comprise a reperfusion injury treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent..
This invention is also directed to pharmaceutical compositions for the treatment of angioplastic restenosis in a mammal (including a human being) which comprise an angioplastic restenosis treating amount of a crystal of Formula I
and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypertension in a mammal (including a human being) which comprise a hypertension treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of the vascular complications of diabetes in a mammal (including a human being) which comprise a vascular complications of diabetes treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
_g_ This invention is also directed to pharmaceutical compositions for the treatment of obesity in a mammal (including a human being) which comprise an obesity treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of endotoxemia in a mammal (including a human being) which comprise an endotoxemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula I crystal;
a second compound, said second compound being an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/Apo B secretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and/or optionally a pharmaceutical carrier, vehicle or diluent.
Preferred among the second compounds are an HMG-CoA reductase inhibitor and a MTP/Apo B secretion inhibitor.
A particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
Another aspect of this invention is a method for treating atherosclerosis in a mammal comprising administering to a mammal suffering from atherosclerosis a first compound, said first compound being a Formula I crystal; and a second compound, said second compound being an HMG-CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant wherein the amounts of the first and second compounds result in a therapeutic effect.
A preferred aspect of the above method is wherein the second compound is an HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor.
A particularly preferred aspect of the above method is wherein the HMG-CoA
reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
Yet another aspect of this invention is a kit comprising:
a. a first compound, said first compound being a Formula I crystal, and a pharmaceutically acceptable carrier in a first in a unit dosage form;
b. a second compound, said second compound being an HMG CoA
reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier in a second unit dosage form; and c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
A preferred second compound is an HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor.
A particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
The present invention is also directed to processes for preparing crystalline anhydrous [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in the presence of a suitable organic solvent, preferably hexanes.
Another aspect of this invention is directed to a process for preparing crystalline ethanolate [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in ethanol/water at ambient temperature for about 0.5 to about 18 hours.
Preferably ethanol is used without water.
This invention is also directed to a process for preparing crystalline anhydrous [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 dissolving or mixing [2R,4S] 4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in ethanol at ambient temperature for about 2 to about 24 hours.
It is noted that as the anhydrous and ethanolate crystals are of different energy levels seeding with either anhydrous or ethanolate may determine the resulting isolated crystalline form. As is known in the art the presence of seed crystals in the air in a lab may be sufficient "seeding." In one embodiment anhydrous crystals may be obtained using hexanes and the resulting anhydrous crystals may be used to seed the production of further anhydrous crystals from ethanol.
As used herein the term mammals is meant to refer to all mammals which contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans. Certain other mammals e.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and so are not included herein.
The term ethanolate refers to an ethanol of solvation.
The term "treating", "treat" or "treatment" as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By "pharmaceutically acceptable" it is meant the carrier, vehicle, 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.
It will be recognized that the compound of this invention can exist in radiolabelled form, i.e., said compound may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include 3H,'4C, 32P, 355,'8F and 36C1, respectively. The compound of this invention which contains those radioisotopes and/or other radioisotopes of other atoms is within the scope of this invention. Tritiated, i.e., 3H, and carbon-14, i.e., '4C, radioisotopes are particularly preferred for their ease of preparation and detectability.
A radiolabelled compound of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by carrying out the procedures disclosed in the Examples below by substituting a readily available radiolabelled reagent for a non-radiolabelled reagent.
Other features and advantages will be apparent from the specification and claims which describe the invention.
Brief Description of the Drawings FIG. 1 is a characteristic x-ray powder diffraction pattern showing that anhydrous [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is crystalline. (Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)) FIG. 2 is the characteristic x-ray powder diffraction pattern of the ethanolate [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as crystalline Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)) Detailed Description Of The Invention In general the compound of this invention can be made by processes which include analogous processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compound of this invention are provided as further features of the invention and are described below including in the Examples.
The amorphous form of the compound of this invention [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is prepared as disclosed below (see Example 1 ).
An anhydrous crystalline form of the above compound may be prepared from the amorphous compound by recrystallization from hexanes (solvent comprised of hexane isomers (e.g., n-hexane, cyclohexane, methyl pentane, etc.)) at a temperature of about 40°C to about 80°C, preferably 60°
followed typically by granulating, for about 2 to about 24 hours, then filtering the material and subsequent air drying.
Alternatively, the anhydrous crystal may be prepared from the ethanolate crystalline form (described below) utilizing analogous procedures to the immediately preceding procedure. In addition, the yield in this procedure may be enhanced by azeotroping the ethanol from the hexanes.
An ethanolate crystalline form of the above compound may be prepared from the amorphous compound by recrystallization from ethanol/water at a temperature of about 20°C to about 25°C, preferably ambient temperature for about 0.5 hour to about 18 hours. Typically the range is about 3% to about 10% ethanol and about 90% to about 97% water. Preferably the ratio is about 10% to about 90%
ethanol/water.
Alternatively, the ethanolate crystalline form may be prepared utilizing procedures analogous to those described above but using ethanol alone. The filtered materials are typically granulated for about 2 hours to about 24 hours followed by air drying.
The following Table 1 details important properties for three forms of [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: the amorphous (A); and the two crystalline forms ethanolate (B) and crystalline anhydrous (C).
Thermal Stability Crvstallinitv Solubility Stability Amorphous M.P. 21 C Non- Most solublehygrocopic ' A crystallinein aqueous 'EthanolateMelt onset CrystallineHigher non-hygroscopic B 45C solubility C~ 90% relative in (Fig. 2) aqueous thanhumidity over 24 Anhydrous hours C
Anhydrous M.P. 89-90C CrystallineLeast solublenon-hygroscopic C in water at 80% &
100%
(Fig. 1 relative ) humidity over 3 da s.
'Loses thanol at some e closed bottle ambient conditions but remains crystalline The compound of the instant invention is orally administrable and is accordingly used in combination with a pharmaceutically acceptable vehicle, carrier or diluent suitable to oral dosage forms. Suitable pharmaceutically-acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described below. Thus, for oral administration the compound may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, for example a gel capsule, it may contain, in addition to or instead of materials of the above type, a liquid carrier such as a fatty glyceride or mixtures of fatty glycerides, such as olive oil, or MigIyoITM or CapmuITM glycerides. Dosage forms may also include orral suspensions.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The compound of the instant invention may also be administered parenterally.
For parenteral administration the compound may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly.
The pharmaceutical forms suitable for injectable use include sterile solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, or by irradiating or heating the compositions where such irradiating or heating is both appropriate and compatible with the drug formulation.
Additional pharmaceutical formulations may include, inter alia, suppositories, sublingual tablets, topical dosage forms and the like and these may be prepared according to methods which are commonly accepted in the art.
Controlled release, sustained release, and delayed release oral or parenteral compositions may be used.
The dosage of the compound of the instant invention which is administered will generally be varied according to principles well known in the art taking into account the severity of the condition being treated and the route of administration.
In general, the compound will be administered to a warm blooded animal (such as a human, livestock or pet) so that an effective dose, usually a daily dose administered in unitary or divided portions, is received, for example a dose in the range of about 0.01 to about 100 mg/kg/day body weight, preferably about 0.1 to about 10 mg/kg/day body weight. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such deviations are within the scope of this invention.
EXAMPLES
Melting points were determined with a Thomas Hoover melting point apparatus or a DSC apparatus. Unless otherwise stated, CD3C13 was used for NMR
spectra. Microanalysis was performed by Schwarzkopf Microanalytical Laboratory.
All reagents and solvents were obtained commercially and used without purification.
Example 1 cis-4-((3 5-Bis-trifluoromethVl-benzyl)-methoxycarbonyl-aminol-2-ethyl-6-trifluoromethyl-3 4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an ice/water bath as methyl chloroformate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight at room temperature, the reaction mixture was washed twice with a 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 5-10%
ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS mfz 601 (M+
+ 1 );
'H NMR (coalescing mixture of conformers, CDC13) 8 0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1 H), 2.1-2.3 (bm, 1 H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1 H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H).
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was prepared in optically enriched form by resolution of the corresponding racemate, or an intermediate in its synthesis, using standard methods.
Example 2 (1-Benzotriazol-1-yl-propel)-(4-trifluoromethyl-phenyl)-amine A two liter, four neck flask under nitrogen atmosphere was charged with benzotriazole (36.96 g, 310 mmol, 1.0 equiv) and dry toluene (400 mL). A room temperature solution of 4-(trifluoromethyl)aniline (39.1 mL, 310 mmol, 1.0 equiv) and 50 mL toluene was added over one minute. A room temperature solution of propionaldehyde (24.6 mL, 341 mmol, 1.1 equiv) and 50 mL toluene was then added over 20 minutes. There was an exotherm from 23°C to 30°C during this addition.
After stirring 24 h, n-heptane (500 mL) was added, and the slurry stirred an additional 1 h. The suspension was filtered, the solids were washed with n-heptane (1 x mL, then 1 x 200 mL, and dried. (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine was isolated as shiny white needles (81.3 g, 82%). After 24 h, a second crop was isolated from the filtrate (8.7 g, 9%). mp 130-132 °C;
'H NMR
-17_ (DMSO-d6, 400 MHz) 8 0.82 (t, 3H, J=7.5 Hz), 2.25 (m, 2H), 6.49 (m, 1 H), 6.80 (d, 2H, J=8.7 Hz), 7.35 (m, 3H), 7.50 (m, 1 H), 7.88 (d, 1 H, J=8.3 Hz), 7.99 (m, 1 H), 8.09 (d, 1H, J=8.5 Hz);'3C NMR (DMSO-d6, 100 MHz) 8 149.32, 146.19, 131.46, 127.73, 126.8, 125.33 (q, J=270 Hz), 124.44, 119.88, 118.27 (q, J=31.7 Hz), 112.91, 111.56, 71.03, 28.08, 10.29; DEPT spectrum: quaternary carbons 8 149.32, 146.19, 131.46, 125.33, 118.27; CH carbons 8 127.73, 126.8, 124.44, 119.88, 112.91, 111.56, 71.03;
CH2 carbon 8 28.08; CH3 carbon 8 10.29; IR (drifts) 3292 (s), 3038 (m), 2975 (m), 1621 (s), 1331 (s), 1320 (s), 1114 (vs); Anal. Calcd for C,6H,SN4F3: C, 59.99;
H, 4.72;
N, 17.49. Found (first crop): C, 60.16; H, 4.74; N, 17.86. Found (second crop): C, 59.97; H, 4.66; N, 17.63.
Example 3 cis-(2-Ethyl-6-trifluoromethyl-1 2 3 4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester A one liter, four neck flask under nitrogen atmosphere was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 mL).
(1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added, and the mixture heated to 70°C. After 2 h, the mixture was cooled to room temperature and transfered to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1 x 200 mL 1 N NaOH, 1 x 200 mL H20, 1 x 200 mL
brine, and dried (MgS04). The mixture was filtered and the solids washed 1 x 50 mL
ethyl acetate: The filtrate was concentrated to approximately 250 mL. 500 mL
toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL
n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157 °C; ' H
NMR (DMSO-d6, 400 MHz) b 0.92 (t, 3H, J=7.5 Hz), 1.5 (m, 3H), 2.00 (m, 1 H), 3.35 (m, 1 H), 4.77 (m, 1 H), 5.07 (d, 1 H, J=12.5 Hz), 5.15 (d, 1 H, J=12.5 Hz), 6.35 (s, 1 H), 6.61 (d, 1 H, J=8.5 Hz), 7.12 (s, 1 H), 7.18 (dd, 1 H, J=1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1 H, J=9.1 Hz);'3C NMR (DMSO-d6, 100 MHz) cS 157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J=270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J=31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbons 8 157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons 8 128.82, _18_ 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons b 65.85, 34.02, 28.68; CH3 carbon 8 9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), (vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100);
Anal.
Calcd for C2oH2,N202F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06, N,
Yet another aspect of this invention is directed to a method for treating angioplastic restenosis in a mammal (including a human being) by administering to a mammal in need of such treatment an angioplastic restenosis treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating hypertension in a mammal (including a human being) by administering to a mammal in need of such treatment a hypertension treating amount of a Formula I
crystal.
Yet another aspect of this invention is directed to a method for treating the vascular complications of diabetes in a mammal (including a human being) by administering to a mammal in need of such treatment a vascular complications of diabetes treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating obesity in a mammal (including a human being) by administering to a mammal in need of such treatment an obesity treating amount of a Formula I crystal.
Yet another aspect of this invention is directed to a method for treating endotoxemia in a mammal (including a human being) by administering to a mammal in need of such treatment an endotoxemia treating amount of a Formula I
crystal.
This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being) which comprise a therapeutically effective amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis in a mammal (including a human being) which comprise an atherosclerosis treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of peripheral vascular disease in a mammal (including a human being) which comprise a peripheral vascular disease treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of dyslipidemia in a mammal (including a human being) which comprise a dyslipidemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hyperbetalipoproteinemia in a mammal (including a human being) which comprise a hyperbetalipoproteinemia treating amount of a crystal of Formula I
and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypoalphalipoproteinemia in a mammal (including a human being) which comprise a hypoalphalipoproteinemia treating amount of a crystal of Formula I
and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammal (including a human being) which comprise a hypercholesterolemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypertriglyceridemia in a mammal (including a human being) which comprise a hypertriglyceridemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of familial-hypercholesterolemia in a mammal (including a human being) which comprise a familial-hypercholesterolemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of angina in a mammal (including a human being) which comprise an _g_ angina treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of ischemia in a mammal (including a human being) which comprise an ischemic treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of cardiac ischemia in a mammal (including a human being) which comprise a cardiac ischemic treating amount of a crystal of Formula 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of stroke in a mammal (including a human being) which comprise a stroke treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of a myocardial infarction in a mammal (including a human being) which comprise a myocardial infarction treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of reperfusion injury in a mammal (including a human being) which comprise a reperfusion injury treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent..
This invention is also directed to pharmaceutical compositions for the treatment of angioplastic restenosis in a mammal (including a human being) which comprise an angioplastic restenosis treating amount of a crystal of Formula I
and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hypertension in a mammal (including a human being) which comprise a hypertension treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of the vascular complications of diabetes in a mammal (including a human being) which comprise a vascular complications of diabetes treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
_g_ This invention is also directed to pharmaceutical compositions for the treatment of obesity in a mammal (including a human being) which comprise an obesity treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of endotoxemia in a mammal (including a human being) which comprise an endotoxemia treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula I crystal;
a second compound, said second compound being an HMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein (MTP)/Apo B secretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and/or optionally a pharmaceutical carrier, vehicle or diluent.
Preferred among the second compounds are an HMG-CoA reductase inhibitor and a MTP/Apo B secretion inhibitor.
A particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
Another aspect of this invention is a method for treating atherosclerosis in a mammal comprising administering to a mammal suffering from atherosclerosis a first compound, said first compound being a Formula I crystal; and a second compound, said second compound being an HMG-CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant wherein the amounts of the first and second compounds result in a therapeutic effect.
A preferred aspect of the above method is wherein the second compound is an HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor.
A particularly preferred aspect of the above method is wherein the HMG-CoA
reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
Yet another aspect of this invention is a kit comprising:
a. a first compound, said first compound being a Formula I crystal, and a pharmaceutically acceptable carrier in a first in a unit dosage form;
b. a second compound, said second compound being an HMG CoA
reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier in a second unit dosage form; and c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
A preferred second compound is an HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor.
A particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
The present invention is also directed to processes for preparing crystalline anhydrous [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in the presence of a suitable organic solvent, preferably hexanes.
Another aspect of this invention is directed to a process for preparing crystalline ethanolate [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester by dissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in ethanol/water at ambient temperature for about 0.5 to about 18 hours.
Preferably ethanol is used without water.
This invention is also directed to a process for preparing crystalline anhydrous [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 dissolving or mixing [2R,4S] 4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in ethanol at ambient temperature for about 2 to about 24 hours.
It is noted that as the anhydrous and ethanolate crystals are of different energy levels seeding with either anhydrous or ethanolate may determine the resulting isolated crystalline form. As is known in the art the presence of seed crystals in the air in a lab may be sufficient "seeding." In one embodiment anhydrous crystals may be obtained using hexanes and the resulting anhydrous crystals may be used to seed the production of further anhydrous crystals from ethanol.
As used herein the term mammals is meant to refer to all mammals which contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans. Certain other mammals e.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and so are not included herein.
The term ethanolate refers to an ethanol of solvation.
The term "treating", "treat" or "treatment" as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By "pharmaceutically acceptable" it is meant the carrier, vehicle, 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.
It will be recognized that the compound of this invention can exist in radiolabelled form, i.e., said compound may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include 3H,'4C, 32P, 355,'8F and 36C1, respectively. The compound of this invention which contains those radioisotopes and/or other radioisotopes of other atoms is within the scope of this invention. Tritiated, i.e., 3H, and carbon-14, i.e., '4C, radioisotopes are particularly preferred for their ease of preparation and detectability.
A radiolabelled compound of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by carrying out the procedures disclosed in the Examples below by substituting a readily available radiolabelled reagent for a non-radiolabelled reagent.
Other features and advantages will be apparent from the specification and claims which describe the invention.
Brief Description of the Drawings FIG. 1 is a characteristic x-ray powder diffraction pattern showing that anhydrous [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is crystalline. (Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)) FIG. 2 is the characteristic x-ray powder diffraction pattern of the ethanolate [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as crystalline Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)) Detailed Description Of The Invention In general the compound of this invention can be made by processes which include analogous processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compound of this invention are provided as further features of the invention and are described below including in the Examples.
The amorphous form of the compound of this invention [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester is prepared as disclosed below (see Example 1 ).
An anhydrous crystalline form of the above compound may be prepared from the amorphous compound by recrystallization from hexanes (solvent comprised of hexane isomers (e.g., n-hexane, cyclohexane, methyl pentane, etc.)) at a temperature of about 40°C to about 80°C, preferably 60°
followed typically by granulating, for about 2 to about 24 hours, then filtering the material and subsequent air drying.
Alternatively, the anhydrous crystal may be prepared from the ethanolate crystalline form (described below) utilizing analogous procedures to the immediately preceding procedure. In addition, the yield in this procedure may be enhanced by azeotroping the ethanol from the hexanes.
An ethanolate crystalline form of the above compound may be prepared from the amorphous compound by recrystallization from ethanol/water at a temperature of about 20°C to about 25°C, preferably ambient temperature for about 0.5 hour to about 18 hours. Typically the range is about 3% to about 10% ethanol and about 90% to about 97% water. Preferably the ratio is about 10% to about 90%
ethanol/water.
Alternatively, the ethanolate crystalline form may be prepared utilizing procedures analogous to those described above but using ethanol alone. The filtered materials are typically granulated for about 2 hours to about 24 hours followed by air drying.
The following Table 1 details important properties for three forms of [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: the amorphous (A); and the two crystalline forms ethanolate (B) and crystalline anhydrous (C).
Thermal Stability Crvstallinitv Solubility Stability Amorphous M.P. 21 C Non- Most solublehygrocopic ' A crystallinein aqueous 'EthanolateMelt onset CrystallineHigher non-hygroscopic B 45C solubility C~ 90% relative in (Fig. 2) aqueous thanhumidity over 24 Anhydrous hours C
Anhydrous M.P. 89-90C CrystallineLeast solublenon-hygroscopic C in water at 80% &
100%
(Fig. 1 relative ) humidity over 3 da s.
'Loses thanol at some e closed bottle ambient conditions but remains crystalline The compound of the instant invention is orally administrable and is accordingly used in combination with a pharmaceutically acceptable vehicle, carrier or diluent suitable to oral dosage forms. Suitable pharmaceutically-acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described below. Thus, for oral administration the compound may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, for example a gel capsule, it may contain, in addition to or instead of materials of the above type, a liquid carrier such as a fatty glyceride or mixtures of fatty glycerides, such as olive oil, or MigIyoITM or CapmuITM glycerides. Dosage forms may also include orral suspensions.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The compound of the instant invention may also be administered parenterally.
For parenteral administration the compound may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly.
The pharmaceutical forms suitable for injectable use include sterile solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, or by irradiating or heating the compositions where such irradiating or heating is both appropriate and compatible with the drug formulation.
Additional pharmaceutical formulations may include, inter alia, suppositories, sublingual tablets, topical dosage forms and the like and these may be prepared according to methods which are commonly accepted in the art.
Controlled release, sustained release, and delayed release oral or parenteral compositions may be used.
The dosage of the compound of the instant invention which is administered will generally be varied according to principles well known in the art taking into account the severity of the condition being treated and the route of administration.
In general, the compound will be administered to a warm blooded animal (such as a human, livestock or pet) so that an effective dose, usually a daily dose administered in unitary or divided portions, is received, for example a dose in the range of about 0.01 to about 100 mg/kg/day body weight, preferably about 0.1 to about 10 mg/kg/day body weight. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such deviations are within the scope of this invention.
EXAMPLES
Melting points were determined with a Thomas Hoover melting point apparatus or a DSC apparatus. Unless otherwise stated, CD3C13 was used for NMR
spectra. Microanalysis was performed by Schwarzkopf Microanalytical Laboratory.
All reagents and solvents were obtained commercially and used without purification.
Example 1 cis-4-((3 5-Bis-trifluoromethVl-benzyl)-methoxycarbonyl-aminol-2-ethyl-6-trifluoromethyl-3 4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an ice/water bath as methyl chloroformate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight at room temperature, the reaction mixture was washed twice with a 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 5-10%
ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS mfz 601 (M+
+ 1 );
'H NMR (coalescing mixture of conformers, CDC13) 8 0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1 H), 2.1-2.3 (bm, 1 H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1 H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H).
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was prepared in optically enriched form by resolution of the corresponding racemate, or an intermediate in its synthesis, using standard methods.
Example 2 (1-Benzotriazol-1-yl-propel)-(4-trifluoromethyl-phenyl)-amine A two liter, four neck flask under nitrogen atmosphere was charged with benzotriazole (36.96 g, 310 mmol, 1.0 equiv) and dry toluene (400 mL). A room temperature solution of 4-(trifluoromethyl)aniline (39.1 mL, 310 mmol, 1.0 equiv) and 50 mL toluene was added over one minute. A room temperature solution of propionaldehyde (24.6 mL, 341 mmol, 1.1 equiv) and 50 mL toluene was then added over 20 minutes. There was an exotherm from 23°C to 30°C during this addition.
After stirring 24 h, n-heptane (500 mL) was added, and the slurry stirred an additional 1 h. The suspension was filtered, the solids were washed with n-heptane (1 x mL, then 1 x 200 mL, and dried. (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine was isolated as shiny white needles (81.3 g, 82%). After 24 h, a second crop was isolated from the filtrate (8.7 g, 9%). mp 130-132 °C;
'H NMR
-17_ (DMSO-d6, 400 MHz) 8 0.82 (t, 3H, J=7.5 Hz), 2.25 (m, 2H), 6.49 (m, 1 H), 6.80 (d, 2H, J=8.7 Hz), 7.35 (m, 3H), 7.50 (m, 1 H), 7.88 (d, 1 H, J=8.3 Hz), 7.99 (m, 1 H), 8.09 (d, 1H, J=8.5 Hz);'3C NMR (DMSO-d6, 100 MHz) 8 149.32, 146.19, 131.46, 127.73, 126.8, 125.33 (q, J=270 Hz), 124.44, 119.88, 118.27 (q, J=31.7 Hz), 112.91, 111.56, 71.03, 28.08, 10.29; DEPT spectrum: quaternary carbons 8 149.32, 146.19, 131.46, 125.33, 118.27; CH carbons 8 127.73, 126.8, 124.44, 119.88, 112.91, 111.56, 71.03;
CH2 carbon 8 28.08; CH3 carbon 8 10.29; IR (drifts) 3292 (s), 3038 (m), 2975 (m), 1621 (s), 1331 (s), 1320 (s), 1114 (vs); Anal. Calcd for C,6H,SN4F3: C, 59.99;
H, 4.72;
N, 17.49. Found (first crop): C, 60.16; H, 4.74; N, 17.86. Found (second crop): C, 59.97; H, 4.66; N, 17.63.
Example 3 cis-(2-Ethyl-6-trifluoromethyl-1 2 3 4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester A one liter, four neck flask under nitrogen atmosphere was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 mL).
(1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added, and the mixture heated to 70°C. After 2 h, the mixture was cooled to room temperature and transfered to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1 x 200 mL 1 N NaOH, 1 x 200 mL H20, 1 x 200 mL
brine, and dried (MgS04). The mixture was filtered and the solids washed 1 x 50 mL
ethyl acetate: The filtrate was concentrated to approximately 250 mL. 500 mL
toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL
n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157 °C; ' H
NMR (DMSO-d6, 400 MHz) b 0.92 (t, 3H, J=7.5 Hz), 1.5 (m, 3H), 2.00 (m, 1 H), 3.35 (m, 1 H), 4.77 (m, 1 H), 5.07 (d, 1 H, J=12.5 Hz), 5.15 (d, 1 H, J=12.5 Hz), 6.35 (s, 1 H), 6.61 (d, 1 H, J=8.5 Hz), 7.12 (s, 1 H), 7.18 (dd, 1 H, J=1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1 H, J=9.1 Hz);'3C NMR (DMSO-d6, 100 MHz) cS 157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J=270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J=31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbons 8 157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons 8 128.82, _18_ 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons b 65.85, 34.02, 28.68; CH3 carbon 8 9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), (vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100);
Anal.
Calcd for C2oH2,N202F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06, N,
7.36.
Example 4 cis-4-Benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A three liter, four neck flask under nitrogen atmosphere was charged with cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (96.0 g, 254 mmol, 1.0 equiv), dry dichloromethane (720 mL), and dry pyridine (103 mL, 1.27 mol, 5.0 equiv). A solution of ethyl chloroformate (121 mL, 1.27 mol, 5.0 equiv), in dry dichloromethane (240 mL), was added slowly over 4 h. The addition was exothermic and required a reflux condenser. Once the chloroformate addition was complete, the reaction was cooled in an ice bath and 1350 mL 1 N NaOH were added. The mixture was stirred 15 min, then transferred to a separatory funnel. The layers were separated and the aqueous extracted 1 x 1 L dichloromethane. The combined dichloromethane layers were washed 1 x 1350 mL 1 N HCI, 1 x 1 L
saturated aq. NaHC03, 1 x 1 L brine, and dried (Na2SOa). The mixture was filtered, and the filtrate concentrated to an orange oil. 570 mL abs. ethanol were added, and the solution was concentrated. The solids were dissolved in 1370 mL abs.
ethanol.
570 mL H20 were added dropwise over 45 min. The resultant thick slurry was stirred 18 h and filtered. The solids were washed with cold 7:3 abs. ethanol/water (1 x 250 mL, then 1 x 100 mL) and dried (vac oven, 45°C) to give cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white, crystalline solid (94.54 g, 83%): mp 92-96°C;
'H NMR (CDC13, 400 MHz) 8 0.84 (t, 3H, J=7.4 Hz), 1.28 (t, 3H, J=7.0 Hz), 1.4 (m, 2H), 1.62 (m, 1 H), 2.53 (m, 1 H), 4.23 (m, 2H), 4.47 (m, 1 H), 4.79 (m, 1 H), 5.01 (d, 1 H, J=9.2 Hz), 5.18 (m, 2H), 7.4 (m, 5H), 7.5 (m, 2H), 7.57 (m, 1 H);'3C NMR
(CDCI3, 100 MHz) 8 155.97, 154.43, 139.44, 136.21, 134.33, 128.61, 128.33, 128.22, 126.32 (q, J=31.7 Hz), 126.18, 124.22, 124.19, 124.12 (q, J=273 Hz), 120.74, 120.70, 67.22, 62.24, 53.47, 46.79, 37.75, 28.25, 14.38, 9.78; DEPT spectrum: quaternary carbons
Example 4 cis-4-Benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A three liter, four neck flask under nitrogen atmosphere was charged with cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (96.0 g, 254 mmol, 1.0 equiv), dry dichloromethane (720 mL), and dry pyridine (103 mL, 1.27 mol, 5.0 equiv). A solution of ethyl chloroformate (121 mL, 1.27 mol, 5.0 equiv), in dry dichloromethane (240 mL), was added slowly over 4 h. The addition was exothermic and required a reflux condenser. Once the chloroformate addition was complete, the reaction was cooled in an ice bath and 1350 mL 1 N NaOH were added. The mixture was stirred 15 min, then transferred to a separatory funnel. The layers were separated and the aqueous extracted 1 x 1 L dichloromethane. The combined dichloromethane layers were washed 1 x 1350 mL 1 N HCI, 1 x 1 L
saturated aq. NaHC03, 1 x 1 L brine, and dried (Na2SOa). The mixture was filtered, and the filtrate concentrated to an orange oil. 570 mL abs. ethanol were added, and the solution was concentrated. The solids were dissolved in 1370 mL abs.
ethanol.
570 mL H20 were added dropwise over 45 min. The resultant thick slurry was stirred 18 h and filtered. The solids were washed with cold 7:3 abs. ethanol/water (1 x 250 mL, then 1 x 100 mL) and dried (vac oven, 45°C) to give cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white, crystalline solid (94.54 g, 83%): mp 92-96°C;
'H NMR (CDC13, 400 MHz) 8 0.84 (t, 3H, J=7.4 Hz), 1.28 (t, 3H, J=7.0 Hz), 1.4 (m, 2H), 1.62 (m, 1 H), 2.53 (m, 1 H), 4.23 (m, 2H), 4.47 (m, 1 H), 4.79 (m, 1 H), 5.01 (d, 1 H, J=9.2 Hz), 5.18 (m, 2H), 7.4 (m, 5H), 7.5 (m, 2H), 7.57 (m, 1 H);'3C NMR
(CDCI3, 100 MHz) 8 155.97, 154.43, 139.44, 136.21, 134.33, 128.61, 128.33, 128.22, 126.32 (q, J=31.7 Hz), 126.18, 124.22, 124.19, 124.12 (q, J=273 Hz), 120.74, 120.70, 67.22, 62.24, 53.47, 46.79, 37.75, 28.25, 14.38, 9.78; DEPT spectrum: quaternary carbons
8 155.97, 154.43, 139.44, 136.21, 134.33, 126.32, 124.12; CH carbons 8 128.61, _19_ 128.33, 128.22, 126.18, 124.22, 124.19, 120.74, 120.70, 53.47, 46.79; CH2 carbons ~
67.22, 62.24, 37.75, 28.25; CH3 carbons 8 14.38, 9.78; IR (drifts) 3304 (s), 3067 (m), 3033 (m), 2982 (m), 2932 (m), 1723 (s), 1693 (s), 1545 (s); MS (APCI+) m/z (rel.
intensity) 451 (M+H+, 2), 300 (100); Anal. Calcd for C23H2sN20aF3: C, 61.33;
H, 5.60;
N, 6.22. Found: C, 61.07; H, 5.69; N, 6.22.
Example 5 cis-4-Amino-2-ethyl-6-trifluoromethyl-3 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A one liter, four neck flask under nitrogen atmosphere was charged with cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1 g, 89 mmol, 1.0 equiv), methanol (400 mL), and ammonium formate (14.0 g, 223 mmol, 2.5 equiv). 10% Pd/C, 50% water wet (4.0 g) was added, and the slurry heated to 40° C over 1 h. After 1.5 h, the mixture was cooled to room temperature and filtered through Celite~. The cake was washed 2 x 100 mL methanol. The filtrate was concentrated to approximately 75 mL, transferred to a separatory funnel, and diluted with 400 mL ethyl acetate. The mixture was washed 1 x 125 mL saturated aq. NaHC03, 1 x 100 mL brine, and dried (Na2S04).
The mixture was filtered and the filtrate concentrated to a clear oil. The oil was crystallized from 100 mL n-heptane to give cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white crystalline solid (26.05 g, 93%): mp 61.5-63.5° C;'H NMR (CDC13, 400 MHz) 8 0.79 (t, 3H, J=7.5 Hz), 1.24 (m, 4H), 1.42 (m, 1 H), 1.51 (br s, 2H), 1.62 (m, 1 H), 2.46 (m, 1 H), 3.73 (m, 1 H), 4.17 (m, 2H), 4.36 (m, 1 H), 7.44 (m, 2H), 7.66 (m, 1 H); '3C NMR (CDC13, 100 MHz) 8 154.6, 139.3, 138.9, 126.3 (q, J=32 Hz), 125.7, 124.3 (q, J=271 Hz), 123.5, 119.8, 61.96, 54.16, 46.91, 41.50, 28.85, 14.38, 9.60; DEPT spectrum: quaternary carbons 8 154.6, 139.3, 138.9, 126.3, 124.3; CH carbons b 125.7, 123.5, 119.8, 54.16, 46.91;
CHz carbons 8 61.96, 41.50, 28.85; CH3 carbons 8 14.38, 9.60; IR (drifts) 3350 (s), 3293 (m), 2972 (s), 1697 (vs); MS (ES+) m/z (rel. intensity) 358 (M+H+CH3CN+, 55), 317 (M+H+, 7), 300 (100); Anal. Calcd for C,SH,gN202F3: C, 56.96; H, 6.06; N, 8.86.
Found: C, 56.86; H, 6.28; N, 8.82.
Example 6 (-) (2R 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt A one liter flask under nitrogen atmosphere was charged with cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (24.0 g, 75.9 mmol, 1.0 equiv) and (-) dibenzoyl-L-tartaric acid (anhydrous) (27.19 g, 75.9 mmol, 1.0 equiv). 300 mL of approximately 97%
ethanol (prepared by adding 10.5 mL H20 to 500 mL absolute ethanol, mixing, and measuring out 300 mL) was added. The mixture was stirred at room temperature for 18 h, then filtered. The solids were washed 1 x 48 mL approximately 97%
ethanol, and dried to give (-) (2R, 4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt as a white crystalline solid (14.77 g, 39%): mp 189.5-191.5 °C (dec);'H NMR (DMSO-d6, 400 MHz) 8 0.62 (t, 3H, J=7.3 Hz), 1.16 (t, 3H, J=7.1 Hz), 1.3 (m, 3H), 2.5 (m, 1 H), 4.1 (m, 4H), 5.63 (s, 1 H, methine proton in DBTA), 7.47 (m, 2H, DBTA aromatic H's), 7.6 (m, 3H, DBTA aromatic H's), 7.68 (s, 1 H), 7.95 (m, 2H), 8.2 (br s, NH3+, did not integrate);'3C NMR (DMSO-d6, 100 MHz) 8 169.85, 165.53, 154.10, 140.14, 134.59, 133.51, 130.74, 129.69, 128.98, 126.74, 124.82 (q, J=31.7 Hz), 124.69 (q, J=271 Hz), 124.50, 120.90, 74.49, 62.14, 53.51, 45.94, 38.81, 28.23, 14.63, 9.58;
DEPT
spectrum: quaternary carbons 8 169.85, 165.53, 154.10, 140.14, 134.59, 130.74, 124.82, 124.69; CH carbons 8 133.51, 129.69, 128.98, 126.74, 124.50, 120.90, 74.49, 53.51, 45.94; CH2 carbons 8 62.14, 38.81, 28.23; CH3 carbons 8 14.63,
67.22, 62.24, 37.75, 28.25; CH3 carbons 8 14.38, 9.78; IR (drifts) 3304 (s), 3067 (m), 3033 (m), 2982 (m), 2932 (m), 1723 (s), 1693 (s), 1545 (s); MS (APCI+) m/z (rel.
intensity) 451 (M+H+, 2), 300 (100); Anal. Calcd for C23H2sN20aF3: C, 61.33;
H, 5.60;
N, 6.22. Found: C, 61.07; H, 5.69; N, 6.22.
Example 5 cis-4-Amino-2-ethyl-6-trifluoromethyl-3 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A one liter, four neck flask under nitrogen atmosphere was charged with cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1 g, 89 mmol, 1.0 equiv), methanol (400 mL), and ammonium formate (14.0 g, 223 mmol, 2.5 equiv). 10% Pd/C, 50% water wet (4.0 g) was added, and the slurry heated to 40° C over 1 h. After 1.5 h, the mixture was cooled to room temperature and filtered through Celite~. The cake was washed 2 x 100 mL methanol. The filtrate was concentrated to approximately 75 mL, transferred to a separatory funnel, and diluted with 400 mL ethyl acetate. The mixture was washed 1 x 125 mL saturated aq. NaHC03, 1 x 100 mL brine, and dried (Na2S04).
The mixture was filtered and the filtrate concentrated to a clear oil. The oil was crystallized from 100 mL n-heptane to give cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white crystalline solid (26.05 g, 93%): mp 61.5-63.5° C;'H NMR (CDC13, 400 MHz) 8 0.79 (t, 3H, J=7.5 Hz), 1.24 (m, 4H), 1.42 (m, 1 H), 1.51 (br s, 2H), 1.62 (m, 1 H), 2.46 (m, 1 H), 3.73 (m, 1 H), 4.17 (m, 2H), 4.36 (m, 1 H), 7.44 (m, 2H), 7.66 (m, 1 H); '3C NMR (CDC13, 100 MHz) 8 154.6, 139.3, 138.9, 126.3 (q, J=32 Hz), 125.7, 124.3 (q, J=271 Hz), 123.5, 119.8, 61.96, 54.16, 46.91, 41.50, 28.85, 14.38, 9.60; DEPT spectrum: quaternary carbons 8 154.6, 139.3, 138.9, 126.3, 124.3; CH carbons b 125.7, 123.5, 119.8, 54.16, 46.91;
CHz carbons 8 61.96, 41.50, 28.85; CH3 carbons 8 14.38, 9.60; IR (drifts) 3350 (s), 3293 (m), 2972 (s), 1697 (vs); MS (ES+) m/z (rel. intensity) 358 (M+H+CH3CN+, 55), 317 (M+H+, 7), 300 (100); Anal. Calcd for C,SH,gN202F3: C, 56.96; H, 6.06; N, 8.86.
Found: C, 56.86; H, 6.28; N, 8.82.
Example 6 (-) (2R 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt A one liter flask under nitrogen atmosphere was charged with cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (24.0 g, 75.9 mmol, 1.0 equiv) and (-) dibenzoyl-L-tartaric acid (anhydrous) (27.19 g, 75.9 mmol, 1.0 equiv). 300 mL of approximately 97%
ethanol (prepared by adding 10.5 mL H20 to 500 mL absolute ethanol, mixing, and measuring out 300 mL) was added. The mixture was stirred at room temperature for 18 h, then filtered. The solids were washed 1 x 48 mL approximately 97%
ethanol, and dried to give (-) (2R, 4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt as a white crystalline solid (14.77 g, 39%): mp 189.5-191.5 °C (dec);'H NMR (DMSO-d6, 400 MHz) 8 0.62 (t, 3H, J=7.3 Hz), 1.16 (t, 3H, J=7.1 Hz), 1.3 (m, 3H), 2.5 (m, 1 H), 4.1 (m, 4H), 5.63 (s, 1 H, methine proton in DBTA), 7.47 (m, 2H, DBTA aromatic H's), 7.6 (m, 3H, DBTA aromatic H's), 7.68 (s, 1 H), 7.95 (m, 2H), 8.2 (br s, NH3+, did not integrate);'3C NMR (DMSO-d6, 100 MHz) 8 169.85, 165.53, 154.10, 140.14, 134.59, 133.51, 130.74, 129.69, 128.98, 126.74, 124.82 (q, J=31.7 Hz), 124.69 (q, J=271 Hz), 124.50, 120.90, 74.49, 62.14, 53.51, 45.94, 38.81, 28.23, 14.63, 9.58;
DEPT
spectrum: quaternary carbons 8 169.85, 165.53, 154.10, 140.14, 134.59, 130.74, 124.82, 124.69; CH carbons 8 133.51, 129.69, 128.98, 126.74, 124.50, 120.90, 74.49, 53.51, 45.94; CH2 carbons 8 62.14, 38.81, 28.23; CH3 carbons 8 14.63,
9.58;
IR (drifts) 3278 (m), 2400-3100 (broad), 1703 (vs); MS (ES+) m/z (rel.
intensity) 358 (M+H+CH3CN+, 55), 317 (M+H+, 7), 300 (100); Anal. Calcd for C,5H,9N202F3.C9H,04:
C, 58.18; H, 5.29; N, 5.65. Found: C, 57.99; H, 5.15; N, 5.64; Chiral HPLC:
mobile phase 950:50:2 n-hexane:2-propanoI:HOAc, flow rate 1.50 mUmin, column temp 40°C, chiralpakTM AD 4.6 x 250 mm, sample concentration approximately 0.5 mg/mL
in approximately 1:1 n-hexane:2-propanol. Authentic racemate shows retention times of 7.5 min and 10.0 min. (-) (2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt:
IR (drifts) 3278 (m), 2400-3100 (broad), 1703 (vs); MS (ES+) m/z (rel.
intensity) 358 (M+H+CH3CN+, 55), 317 (M+H+, 7), 300 (100); Anal. Calcd for C,5H,9N202F3.C9H,04:
C, 58.18; H, 5.29; N, 5.65. Found: C, 57.99; H, 5.15; N, 5.64; Chiral HPLC:
mobile phase 950:50:2 n-hexane:2-propanoI:HOAc, flow rate 1.50 mUmin, column temp 40°C, chiralpakTM AD 4.6 x 250 mm, sample concentration approximately 0.5 mg/mL
in approximately 1:1 n-hexane:2-propanol. Authentic racemate shows retention times of 7.5 min and 10.0 min. (-) (2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt:
10.0 min, 88.9%, 7.5 min «1 %, 2.0 min (solvent front) 11.1 %; [a]p = -153 (c=1.07, CH30H).
Example 7 (-)-(2R, 4S)-4-(3,5-Bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-guinoline-1-carboxylic acid ethyl ester tosylate salt (-) (2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt (13.0 g, 26.2 mmol, 1.0 equiv) was suspended in 1,2-dichloroethane (260 mL) in a 500 mL separatory funnel. The mixture was washed 1 x 65 mL 1 N NaOH, 1 x 65 mL brine, and dried (MgS04). The mixture was filtered, concentrated to approximately approximately 80 mL, and transferred to a 250 mL three neck flask. 3,5-Bis(trifluoromethyl)benzaldehyde (4.53 mL, 27.5 mmol, 1.05 equiv) was added, and the mixture stirred 1 h at room temperature under nitrogen atmosphere. Sodium triacetoxyborohydride (11.1 g, 52.4 mmol, 2.0 equiv) was added in one portion, and the white slurry was stirred 18 h. 50 mL 1,2-dichloroethane and 50 mL 2N NaOH were added, and the aqueous layer extracted 2 x 50 mL 1,2-dichloroethane. The combined organic extracts were washed 1 x 31 mL 1 N HCI, 1 x 50 mL saturated aq. NaHC03, 1 x 50 mL brine, and dried (Na2S04). The mixture was filtered and concentrated to a clear oil. The oil was dissolved in methanol (71 mL). p-Toluenesulfonic acid monohydrate (5.23 g, 27.5 mmol, 1.05 equiv) was added. After 5 min, 284 mL isopropyl ether was added.
The solution was concentrtated to approximately 35mL, transferred to a 500 mL
three neck flask (mech. stirrer), and diluted with 284 mL isopropyl ether. A thick white slurry formed in 10 minutes. After stirring 3 h, the slurry was filtered and the cake washed 2 x 70 mL isopropyl ether. After drying, (-)-(2R, 4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate salt was isolated as a white powder (16.18 g, 86%
overall): mp 191-192°C; ' H NMR (DMSO-d6, 400 MHz) 8 0.78 (t, 3H, J=7.5 Hz), 1.21 (t, 3H, J=7.0 Hz), 1.5 (m, 3H), 2.24 (s, 3H), 3.08 (m, 1 H), 4.17 (m, 2H), 4.41 (m, 1 H), 4.50 (m, 2H), 4.79 (m, 1 H), 7.04 (d, 2H, J=7.9 Hz), 7.42 (d, 2H, J=7.9 Hz), 7.7 (m, 2H), 7.81 (s, 1 H), 8.21 (s, 1 H), 8.35 (s, 2H), 9.58 (br s, 1 H), 9.83 (br s, 1 H);'3C NMR
(DMSO-d6, 100 MHz) 8 154.00, 145.46, 140.21, 138.39, 135.33, 132.51, 131.62, 130.79 (q, J=33.2 Hz), 128.49, 127.40, 125.82, 125.36, 124.99 (q, J=31.7 Hz), 124.59 (q, J=271 Hz), 123.69 (q, J=273 Hz), 123.44, 120.33, 62.32, 53.99, 53.79, 47.98, 33.30, 28.61, 21.13, 14.63, 9.58; DEPT spectrum: quaternary carbons b 154.00, 145.46, 140.21, 138.39, 135.33, 130.79, 124.99, 124.59, 123.69; CH
carbons 8 132.51, 131.62, 128.49, 127.40, 125.82, 125.36, 123.44, 120.33, 53.99, 53.79; CH2 carbons 8 62.32, 47.98, 33.30. 28.61; CH3 carbons S 21.13, 14.63, 9.58: IR
(drifts) 2300-3100 (broad), 2974 (m), 2731 (m), 2620 (m), 2455 (m), 1714 (s), 1621 (m), 1283 (vs), 1169 (vs), 1126 (vs); MS (ES+) m/z (rel. intensity) 584 (M+H+CH3CN+, 100), 543 (M+H+, 80); Anal. Calcd for C24H23N202F9.C~Ha03S: C, 52.11; H, 4.37;
N, 3.92. Found: C, 52.15; H, 4.22; N, 3.69; [a]o = -77.9 (c = 1.05, CH30H).
Example 8 (-)-(2R 4S)-4-f(3 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-aminol-2-ethyl-trifluoromethyl-3 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate Na2C03 (s) (6.75 g, 63.7 mmol, 3.5 equiv) was added to a room temperature solution of (-)-(2R, 4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate salt (13.0 g, 18.2 mmol, 1.0 equiv) in dry THF (130 mL). Methyl chloroformate (3.51 mL, 45.5 mmol, 2.5 equiv) was added neat, dropwise over 2 min. After 24 h, the mixture was concentrated to 65 mL, diluted with 260 mL ethyl acetate, and transferred to a separatory funnel. The mixture was washed 1 x 90 mL 1 N HCI (C02 evolution), 1 x 90 mL saturated aq. NaHC03, 1 x 90 mL brine, and dried (MgS04). Filtration and concentration of filtrate afforded a clear oil, which was costripped 3 x 33 mL
ethanol. The oil was dissolved in 33 mL 2B ethanol and seeded with a few milligrams of (-)-(2R, 4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate. After stirring 18 h at room temperature, the slurry was filtered and dried to give (-)-(2R, 4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate as a white crystalline powder (8.66 g, 74%): mp 54-58 °C;'H
NMR
(CDCI3, 400 MHz, 55°C) 8 0.73 (t, 3H, J=7.0 Hz), 1.20 (t, EtOH), 1.27 (t, 3H, J=7.1 Hz), 1.42 (m, 2H), 1.66 (m, 1 H), 2.25 (br s, 1 H), 3.67 (q, EtOH), 3.79 (s, 3H), 4.2 (m, 3H), 4.33 (m, 1 H), 5.2 (br s, 2H), 7.12 (s, 1 H), 7.49 (d, 1 H, J=8.3 Hz), 7.57 (d, 1 H, J=8.5 Hz), 7.73 (s, 2H), 7.78 (s, 1 H);'3C NMR (CDC13, 400 MHz) S 157.74, 154.37, 141.73, 140.05, 133.83, 132.14 (q, J=33 Hz), 126.94, 124.49, 123.96 (q, J=273 Hz), 123.13 (q, J=273 Hz), 121.31, 119.17, 62.29, 58.28, 54.42, 53.71, 53.08, 46.67, 37.01, 29.02, 18.29, 14.32, 9.22, (note: the fourth quartet appears to be buried under the 8 126.94 peak, with J approximately 32 Hz); DEPT spectrum: quaternary carbons 8 157.74, 154.37, 141.73, 140.05, 133.83, 132.14, 123.96, 123.13; CH carbons 8 126.94, 124.49, 121.31, 119.17, 54.42, 53.08; CH2 carbons 8 62.29, 58.28, 46.67, 37.01, 29.02; CH3 carbons 8 53.71, 18.29, 14.32, 9.22; IR (drifts) 3489 (s), 2974 (s), 2884 (m), 1701 (vs), 1280 (vs), 1131 (vs); MS (ES+) m/z (rel. intensity) 601 (M+H+, 100); Anal. Calcd for C26H2sN20aFs.C2H60: C, 52.01; H, 4.83; N, 4.33. Found:
C, 51.84; H, 4.54; N, 4.33; chiral HPLC: mobile phase 950:50:2 n-hexane:2-propanoI:HOAc, flow rate 1.0 mUmin, 254 nm, chiralpak AD 4.6 x 250 mm, column temp 40°C, sample concentration approximately 0.5 mg/mL in 90:10 n-hexane:2-propanol, authentic racemate retention times 3.6 and 4.6 min. (-)-(2R, 4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate shows 4.6 min, 99.1 and 3.6 min, not detected; [a]p = -93.3 (c = 1.08, CH30H).
Example 9 Anhydrous (-)-(2R 4S)-4-f(3 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-aminol-2-ethyl-6-trifluoromethyl-3 4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester.
A 2.6g portion of 4(S)-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (a mixture of predominantly amorphous material with traces of ethanolate crystalline form; the title compound was also prepared in an analogous manner starting from pure amorphous or pure ethanolate material) was charged to 13 milliliters of hexanes and heated to effect a solution at about 60°C. The heat was removed and the reaction was allowed to cool to ambient over a one hour period. The reaction was seeded with anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and granulated for eighteen hours under ambient conditions. Alternately, the anhydrous crystals may be prepared from hexanes without seeding. The product was collected by filtration and air dried. The isolated product X-ray pattern matched the calculated powder pattern.
Density: 1.406 Crystal System: Trigonal Microscopy: Well formed rods and equant (fractured rods) crystals demonstrating high birefringence when viewed across the C axis. Being in the Trigonal crystal system the crystals do not demonstrate birefringence when viewed down the C
axis.
The crystals demonstrate a cleavage plane perpendicular to the C axis.
Fusion Microsocopy: In Type A oil--------dissolution at 50°C.
Dry-------------------clear melt at 86°C.
NMR: No trace of ethanolate Degree of crystallinity: Highly crystalline Hygroscopicity: Non-hygroscopic at 100% relative humidity over 48 hours.
Appearance: Free flowing white powder.
The X-Ray diffraction d-spacing is provided in Table 2.
Anode: CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d A 1 rel d A I rel d A I rel
Example 7 (-)-(2R, 4S)-4-(3,5-Bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-guinoline-1-carboxylic acid ethyl ester tosylate salt (-) (2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester hemi-(-)-dibenzoyl-L-tartrate salt (13.0 g, 26.2 mmol, 1.0 equiv) was suspended in 1,2-dichloroethane (260 mL) in a 500 mL separatory funnel. The mixture was washed 1 x 65 mL 1 N NaOH, 1 x 65 mL brine, and dried (MgS04). The mixture was filtered, concentrated to approximately approximately 80 mL, and transferred to a 250 mL three neck flask. 3,5-Bis(trifluoromethyl)benzaldehyde (4.53 mL, 27.5 mmol, 1.05 equiv) was added, and the mixture stirred 1 h at room temperature under nitrogen atmosphere. Sodium triacetoxyborohydride (11.1 g, 52.4 mmol, 2.0 equiv) was added in one portion, and the white slurry was stirred 18 h. 50 mL 1,2-dichloroethane and 50 mL 2N NaOH were added, and the aqueous layer extracted 2 x 50 mL 1,2-dichloroethane. The combined organic extracts were washed 1 x 31 mL 1 N HCI, 1 x 50 mL saturated aq. NaHC03, 1 x 50 mL brine, and dried (Na2S04). The mixture was filtered and concentrated to a clear oil. The oil was dissolved in methanol (71 mL). p-Toluenesulfonic acid monohydrate (5.23 g, 27.5 mmol, 1.05 equiv) was added. After 5 min, 284 mL isopropyl ether was added.
The solution was concentrtated to approximately 35mL, transferred to a 500 mL
three neck flask (mech. stirrer), and diluted with 284 mL isopropyl ether. A thick white slurry formed in 10 minutes. After stirring 3 h, the slurry was filtered and the cake washed 2 x 70 mL isopropyl ether. After drying, (-)-(2R, 4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate salt was isolated as a white powder (16.18 g, 86%
overall): mp 191-192°C; ' H NMR (DMSO-d6, 400 MHz) 8 0.78 (t, 3H, J=7.5 Hz), 1.21 (t, 3H, J=7.0 Hz), 1.5 (m, 3H), 2.24 (s, 3H), 3.08 (m, 1 H), 4.17 (m, 2H), 4.41 (m, 1 H), 4.50 (m, 2H), 4.79 (m, 1 H), 7.04 (d, 2H, J=7.9 Hz), 7.42 (d, 2H, J=7.9 Hz), 7.7 (m, 2H), 7.81 (s, 1 H), 8.21 (s, 1 H), 8.35 (s, 2H), 9.58 (br s, 1 H), 9.83 (br s, 1 H);'3C NMR
(DMSO-d6, 100 MHz) 8 154.00, 145.46, 140.21, 138.39, 135.33, 132.51, 131.62, 130.79 (q, J=33.2 Hz), 128.49, 127.40, 125.82, 125.36, 124.99 (q, J=31.7 Hz), 124.59 (q, J=271 Hz), 123.69 (q, J=273 Hz), 123.44, 120.33, 62.32, 53.99, 53.79, 47.98, 33.30, 28.61, 21.13, 14.63, 9.58; DEPT spectrum: quaternary carbons b 154.00, 145.46, 140.21, 138.39, 135.33, 130.79, 124.99, 124.59, 123.69; CH
carbons 8 132.51, 131.62, 128.49, 127.40, 125.82, 125.36, 123.44, 120.33, 53.99, 53.79; CH2 carbons 8 62.32, 47.98, 33.30. 28.61; CH3 carbons S 21.13, 14.63, 9.58: IR
(drifts) 2300-3100 (broad), 2974 (m), 2731 (m), 2620 (m), 2455 (m), 1714 (s), 1621 (m), 1283 (vs), 1169 (vs), 1126 (vs); MS (ES+) m/z (rel. intensity) 584 (M+H+CH3CN+, 100), 543 (M+H+, 80); Anal. Calcd for C24H23N202F9.C~Ha03S: C, 52.11; H, 4.37;
N, 3.92. Found: C, 52.15; H, 4.22; N, 3.69; [a]o = -77.9 (c = 1.05, CH30H).
Example 8 (-)-(2R 4S)-4-f(3 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-aminol-2-ethyl-trifluoromethyl-3 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate Na2C03 (s) (6.75 g, 63.7 mmol, 3.5 equiv) was added to a room temperature solution of (-)-(2R, 4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester tosylate salt (13.0 g, 18.2 mmol, 1.0 equiv) in dry THF (130 mL). Methyl chloroformate (3.51 mL, 45.5 mmol, 2.5 equiv) was added neat, dropwise over 2 min. After 24 h, the mixture was concentrated to 65 mL, diluted with 260 mL ethyl acetate, and transferred to a separatory funnel. The mixture was washed 1 x 90 mL 1 N HCI (C02 evolution), 1 x 90 mL saturated aq. NaHC03, 1 x 90 mL brine, and dried (MgS04). Filtration and concentration of filtrate afforded a clear oil, which was costripped 3 x 33 mL
ethanol. The oil was dissolved in 33 mL 2B ethanol and seeded with a few milligrams of (-)-(2R, 4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate. After stirring 18 h at room temperature, the slurry was filtered and dried to give (-)-(2R, 4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate as a white crystalline powder (8.66 g, 74%): mp 54-58 °C;'H
NMR
(CDCI3, 400 MHz, 55°C) 8 0.73 (t, 3H, J=7.0 Hz), 1.20 (t, EtOH), 1.27 (t, 3H, J=7.1 Hz), 1.42 (m, 2H), 1.66 (m, 1 H), 2.25 (br s, 1 H), 3.67 (q, EtOH), 3.79 (s, 3H), 4.2 (m, 3H), 4.33 (m, 1 H), 5.2 (br s, 2H), 7.12 (s, 1 H), 7.49 (d, 1 H, J=8.3 Hz), 7.57 (d, 1 H, J=8.5 Hz), 7.73 (s, 2H), 7.78 (s, 1 H);'3C NMR (CDC13, 400 MHz) S 157.74, 154.37, 141.73, 140.05, 133.83, 132.14 (q, J=33 Hz), 126.94, 124.49, 123.96 (q, J=273 Hz), 123.13 (q, J=273 Hz), 121.31, 119.17, 62.29, 58.28, 54.42, 53.71, 53.08, 46.67, 37.01, 29.02, 18.29, 14.32, 9.22, (note: the fourth quartet appears to be buried under the 8 126.94 peak, with J approximately 32 Hz); DEPT spectrum: quaternary carbons 8 157.74, 154.37, 141.73, 140.05, 133.83, 132.14, 123.96, 123.13; CH carbons 8 126.94, 124.49, 121.31, 119.17, 54.42, 53.08; CH2 carbons 8 62.29, 58.28, 46.67, 37.01, 29.02; CH3 carbons 8 53.71, 18.29, 14.32, 9.22; IR (drifts) 3489 (s), 2974 (s), 2884 (m), 1701 (vs), 1280 (vs), 1131 (vs); MS (ES+) m/z (rel. intensity) 601 (M+H+, 100); Anal. Calcd for C26H2sN20aFs.C2H60: C, 52.01; H, 4.83; N, 4.33. Found:
C, 51.84; H, 4.54; N, 4.33; chiral HPLC: mobile phase 950:50:2 n-hexane:2-propanoI:HOAc, flow rate 1.0 mUmin, 254 nm, chiralpak AD 4.6 x 250 mm, column temp 40°C, sample concentration approximately 0.5 mg/mL in 90:10 n-hexane:2-propanol, authentic racemate retention times 3.6 and 4.6 min. (-)-(2R, 4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro 2H-quinoline-1-carboxylic acid ethyl ester mono ethanolate shows 4.6 min, 99.1 and 3.6 min, not detected; [a]p = -93.3 (c = 1.08, CH30H).
Example 9 Anhydrous (-)-(2R 4S)-4-f(3 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-aminol-2-ethyl-6-trifluoromethyl-3 4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester.
A 2.6g portion of 4(S)-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (a mixture of predominantly amorphous material with traces of ethanolate crystalline form; the title compound was also prepared in an analogous manner starting from pure amorphous or pure ethanolate material) was charged to 13 milliliters of hexanes and heated to effect a solution at about 60°C. The heat was removed and the reaction was allowed to cool to ambient over a one hour period. The reaction was seeded with anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and granulated for eighteen hours under ambient conditions. Alternately, the anhydrous crystals may be prepared from hexanes without seeding. The product was collected by filtration and air dried. The isolated product X-ray pattern matched the calculated powder pattern.
Density: 1.406 Crystal System: Trigonal Microscopy: Well formed rods and equant (fractured rods) crystals demonstrating high birefringence when viewed across the C axis. Being in the Trigonal crystal system the crystals do not demonstrate birefringence when viewed down the C
axis.
The crystals demonstrate a cleavage plane perpendicular to the C axis.
Fusion Microsocopy: In Type A oil--------dissolution at 50°C.
Dry-------------------clear melt at 86°C.
NMR: No trace of ethanolate Degree of crystallinity: Highly crystalline Hygroscopicity: Non-hygroscopic at 100% relative humidity over 48 hours.
Appearance: Free flowing white powder.
The X-Ray diffraction d-spacing is provided in Table 2.
Anode: CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d A 1 rel d A I rel d A I rel
11.21659 34.8 5.52958 60.0 4.04469 36.6 10.50618 12.0 5.39152 75.7 3.89345 39.6 9.66890 11.0 5.24818 80.5 3.72038 80.7 8.88669 4.1 4.84992 13.2 3.64330 15.0 7.31083 3.7 4.44170 100.0 3.49463 5.9 6.34185 56.4 4.32558 16.8 3.44831 7.2 6.09484 5.9 4.25150 31.0 3.33_631 14.7 5.92806 38.4 4.08413 42.7 3.22157 6.7 ~
d A I rel d A I rel 3.16983 8.3 2.57207 8.5 3.11970 14.0 2.49503 3.6 2.96985 16.3 2.44562 2.87051 8.7 2.42250 2.81002 6.8 2.38844 2.75539 6.8 2.36135 2.70226 3.6 2.32612 2.64524 8.9 Example 10 Monoethanolate, (-)-(2R,4S)-4-f(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester.
4.0 grams of (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester-were dissolved in 3.5 ml ethanol and sonicated for two minutes to complete dissolution. A
white solid formed to which 10 ml ethanol was added and stirred at ambient temperature overnight. A white powder was filtered and collected on 0.22 ~m LS
filter paper followed by washing with about 15 ml. ethanol. The isolated product X-ray pattern matched the calculated powder pattern.
Density: 1.402 Crystal System: orthorhombic Microscopy: crystalline needles with moderate birefringence.
Fusion Microsocopy: In Type A oil-----melt and dissolution at 43°C with loss of water Dry----------------clear melt at 43°C
NMR: shows ethanol of solvation Degree of crystallinity: highly crystalline Hygroscopicity: non-hygroscopic Appearance: free-flowing white power The X-Ray diffraction d-spacing is provided in Table 3.
Anode' CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d A 1 rel d A I rel d A I rel 22.15759 37.6 5.69284 6.9 4.18443 23.3 8.61222 15.1 5.45839 5.8 4.03073 30.9 8.15185 9.5 5.19975 19.0 3.96396 33.9 7.83462 47.0 4.90695 53.6 3.83314 35.0 7.47295 100.0 4.68527 42.1 3.77447 40.8 7.00403 9.6 4.80453 18.9 3.72125 33.1 6.46476 17.2 4.38780 16.3 3.62106 26.6 6.23035 14.8 4.30354 19.7 3.52462 17.1 5.90921 7.9 d A I rel d A I rel 3.44170 12.6 2.77147 5.0 3.35282 6.7 2.70399 7.5 3.25110 11.7 2.63859 4.6 3.12884 5.7 2.53872 6.4 3.03164 4.4 2.49493 5.3 2.94892 5.8 2.47186 5.0 2.86853 4.2 2.34837 4.7 4.3 2.26951 4.1 2.79318 Example 11 Anhydrous (-)-(2R 4S)-4-((3 5-bis-trifluromethylbenzyl)-methoxycarbonyl-aminol-ethvl-6-trifluoromethvl-3,4-dihvdro-2H-quinoline-1-carboxylic acid ethyl ester.
A crude solution of approximately 42 g of (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in 500 ml of ethyl acetate (obtained via the process described in Example 8) was concentrated under vacuum to a volume of 100-135 ml.
The remaining ethyl acetate was displaced with 3 X 220 ml 2B EtOH to a final volume of 100-135 ml. This solution was seeded with a crystal of anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. After stirring 18 hr at room temperature the slurry was filtered and vacuum dried to give 19.81 g of anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. The melting point behaviour was the same as the material prepared via Example 9 confirming the anhydrous nature of the material.
d A I rel d A I rel 3.16983 8.3 2.57207 8.5 3.11970 14.0 2.49503 3.6 2.96985 16.3 2.44562 2.87051 8.7 2.42250 2.81002 6.8 2.38844 2.75539 6.8 2.36135 2.70226 3.6 2.32612 2.64524 8.9 Example 10 Monoethanolate, (-)-(2R,4S)-4-f(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester.
4.0 grams of (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester-were dissolved in 3.5 ml ethanol and sonicated for two minutes to complete dissolution. A
white solid formed to which 10 ml ethanol was added and stirred at ambient temperature overnight. A white powder was filtered and collected on 0.22 ~m LS
filter paper followed by washing with about 15 ml. ethanol. The isolated product X-ray pattern matched the calculated powder pattern.
Density: 1.402 Crystal System: orthorhombic Microscopy: crystalline needles with moderate birefringence.
Fusion Microsocopy: In Type A oil-----melt and dissolution at 43°C with loss of water Dry----------------clear melt at 43°C
NMR: shows ethanol of solvation Degree of crystallinity: highly crystalline Hygroscopicity: non-hygroscopic Appearance: free-flowing white power The X-Ray diffraction d-spacing is provided in Table 3.
Anode' CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d A 1 rel d A I rel d A I rel 22.15759 37.6 5.69284 6.9 4.18443 23.3 8.61222 15.1 5.45839 5.8 4.03073 30.9 8.15185 9.5 5.19975 19.0 3.96396 33.9 7.83462 47.0 4.90695 53.6 3.83314 35.0 7.47295 100.0 4.68527 42.1 3.77447 40.8 7.00403 9.6 4.80453 18.9 3.72125 33.1 6.46476 17.2 4.38780 16.3 3.62106 26.6 6.23035 14.8 4.30354 19.7 3.52462 17.1 5.90921 7.9 d A I rel d A I rel 3.44170 12.6 2.77147 5.0 3.35282 6.7 2.70399 7.5 3.25110 11.7 2.63859 4.6 3.12884 5.7 2.53872 6.4 3.03164 4.4 2.49493 5.3 2.94892 5.8 2.47186 5.0 2.86853 4.2 2.34837 4.7 4.3 2.26951 4.1 2.79318 Example 11 Anhydrous (-)-(2R 4S)-4-((3 5-bis-trifluromethylbenzyl)-methoxycarbonyl-aminol-ethvl-6-trifluoromethvl-3,4-dihvdro-2H-quinoline-1-carboxylic acid ethyl ester.
A crude solution of approximately 42 g of (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in 500 ml of ethyl acetate (obtained via the process described in Example 8) was concentrated under vacuum to a volume of 100-135 ml.
The remaining ethyl acetate was displaced with 3 X 220 ml 2B EtOH to a final volume of 100-135 ml. This solution was seeded with a crystal of anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. After stirring 18 hr at room temperature the slurry was filtered and vacuum dried to give 19.81 g of anhydrous (-)-(2R,4S)-4-[(3,5-bis-trifluromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. The melting point behaviour was the same as the material prepared via Example 9 confirming the anhydrous nature of the material.
Claims (21)
- -28- A crystalline form of the compound of formula I
- 2. A crystal which is anhydrous [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
- 3. A crystal which is the ethanolate of [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
- 4. A crystal of claim 1 which is the anhydrous crystal having the x-ray powder diffraction d-spacing Anode: CU - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d(A) 1(rel) d(A) I(rel) d(A) I(rel) 11.21659 34.8 5.52958 60.0 4.04469 36.6 10.50618 12.0 5.39152 75.7 3.89345 39.6 9.66890 11.0 5.24818 80.5 3.72038 80.7 8.88669 4.1 4.84992 13.2 3.64330 15.0 7.31083 3.7 4.44170 100.0 3.49463 5.9 6.34185 56.4 4.32558 16.8 3.44831 7.2 6.09484 5.9 4.25150 31.0 3.33631 14.7 5.92806 38.4 4.08413 42.7 3.22157 6.7 d(A) I(rel) d(A) I(rel) 3.16983 8.3 2.57207 8.5 3.11970 14.0 2.49503 3.6 2.96985 16.3 2.44562 2.87051 8.7 2.42250 2.81002 6.8 2.38844 2.75539 6.8 2.36135 2.70226 3.6 2.32612 2.64524 8.9
- 5. A crystal of claim 1 which is the ethanolate crystal having the x-ray powder diffraction d-spacing Anode: CU - Wavelength 1:1.54056 Wavelength 2:1.54439 (Rel Intensity: 0.500) Range #1 - Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00 Smoothing Width: 0.300 Threshold: 1.0 d(A) 1(rel) d(A) I(rel) d(A) I(rel) 22.15759 37.6 5.69284 6.9 4.18443 23.3 8.61222 15.1 5.45839 5.8 4.03073 30.9 8.15185 9.5 5.19975 19.0 3.96396 33.9 7.83462 47.0 4.90695 53.6 3.83314 35.0 7.47295 100.0 4.68527 42.1 3.77447 40.8 7.00403 9.6 4.80453 18.9 3.72125 33.1 6.46476 17.2 4.38780 16.3 3.62106 26.6 6.23035 14.8 4.30354 19.7 3.52462 17.1 5.90921 7.9 d(A) I(rel) d(A) I(rel) 3.44170 12.6 2.77147 5.0 3.35282 6.7 2.70399 7.5 3.25110 11.7 2.63859 4.6 3.12884 5.7 2.53872 6.4 3.03164 4.4 2.49493 5.3 2.94892 5.8 2.47186 5.0 2.86853 4.2 2.34837 4.7 4.3 2.26951 4.1 2.79318
- 6. A pharmaceutical composition which comprises a therapeutically effective amount of a crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
- 7. The pharmaceutical composition as recited in claim 6 wherein the pharmaceutical composition comprises an atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia treating amount of the crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent.
- 8. The pharmaceutical composition as recited in claim 6 for the treatment of atherosclerosis which comprises an atherosclerosis treating amount of a crystal of Formula I and a pharmaceutically acceptable carrier, vehicle or diluent.
- 9. The pharmaceutical composition as recited in claim 8 wherein the atherosclerosis treating amount of the Formula I crystal is about 0.1 to 10 mg/kg/day, and the pharmaceutical composition was prepared by dissolving the crystal of claim 1 in a fatty oil.
- 10. The pharmaceutical composition as recited in claim 8 wherein the Formula I
crystal is anhydrous. - 11. The pharmaceutical composition as recited in claim 8 wherein the Formula I
crystal is the ethanolate crystal. - 12. A method of inhibiting CETP in a mammal in need thereof which comprises the administration of a CETP inhibiting amount of the Formula I crystal as recited in claim 1.
- 13. The method as recited in claim 12 comprising treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia by administering to a mammal, in need of such treatment a therapeutically effective amount of the Formula I crystal.
- 14. The method as recited in claim 13 wherein atherosclerosis is treated with an atherosclerosis treating amount of the Formula I crystal.
- 15. The method as recited in claim 14 wherein the atherosclerosis treating amount of the Formula I crystal is about 0.1 to 10 mg/kg/day and the Formula I
crystal was dissolved in a fatty oil. - 16. The method as recited in claim 15 wherein the Formula I crystal is anhydrous.
- 17. The method as recited in claim 15 wherein the Formula I salt is the ethanolate.
- 18. A process for preparing crystalline anhydrous [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 dissolving or mixing [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in hexanes at ambient temperature for about 2 to about 24 hours wherein said precursor is not an anhydrous crystalline form.
- 19. A process for preparing crystalline ethanolate [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester by dissolving or mixing (2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in ethanol/water at ambient temperature for about 0.5 to about 18 hours wherein said precursor is not a crystalline ethanolate form.
- 20. The process as recited in claim 19 wherein ethanol is used without water.
- 21. A process for preparing crystalline anhydrous [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 dissolving or mixing [2R,4S] 4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in ethanol at ambient temperature for about 2 to about 24 hours wherein said precursor is not an anhydrous crystalline form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16805199P | 1999-11-30 | 1999-11-30 | |
| US60/168,051 | 1999-11-30 | ||
| PCT/IB2000/001650 WO2001040190A1 (en) | 1999-11-30 | 2000-11-14 | 4-carboxyamino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as cetp inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2392979A1 true CA2392979A1 (en) | 2001-06-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002392979A Abandoned CA2392979A1 (en) | 1999-11-30 | 2000-11-14 | 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline crystal |
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| JP (1) | JP2003515592A (en) |
| KR (1) | KR20020058057A (en) |
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| US7115279B2 (en) | 2000-08-03 | 2006-10-03 | Curatolo William J | Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors |
| CZ20033341A3 (en) * | 2001-06-21 | 2004-10-13 | Pfizeráproductsáinc | Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors |
| GT200200170A (en) * | 2001-09-28 | 2003-05-23 | PREPARATION OF INHIBITOR OF CETP ANHIDRO | |
| JP2005523262A (en) | 2002-02-01 | 2005-08-04 | ファイザー・プロダクツ・インク | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming substances |
| CA2472028C (en) * | 2002-02-01 | 2010-03-30 | Pfizer Products Inc. | Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus |
| EP1920766B1 (en) * | 2002-02-01 | 2017-08-23 | Bend Research, Inc | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials |
| SK2332004A3 (en) | 2002-08-30 | 2004-12-01 | Japan Tobacco Inc | Dibenzylamine compound and medicinal use thereof |
| MXPA05003456A (en) | 2002-10-04 | 2005-07-05 | Millennium Pharm Inc | Pgd2 receptor antagonists for the treatment of inflammatory diseases. |
| US7504508B2 (en) | 2002-10-04 | 2009-03-17 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| DE60323536D1 (en) | 2002-12-20 | 2008-10-23 | Pfizer Prod Inc | DOSAGE FORM CONTAINING A CETP INHIBITOR AND AN HMG-COA REDUCTASE HEMMER |
| US20040132771A1 (en) * | 2002-12-20 | 2004-07-08 | Pfizer Inc | Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors |
| CN1795177A (en) * | 2003-03-28 | 2006-06-28 | 辉瑞产品公司 | 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity |
| JP2007501218A (en) | 2003-08-04 | 2007-01-25 | ファイザー・プロダクツ・インク | Pharmaceutical composition of adsorbate of amorphous drug and lipophilic microphase-forming substance |
| JP4773969B2 (en) | 2003-10-08 | 2011-09-14 | イーライ リリー アンド カンパニー | Compounds and methods for the treatment of dyslipidemia |
| JP4922924B2 (en) * | 2004-04-13 | 2012-04-25 | メルク・シャープ・エンド・ドーム・コーポレイション | CETP inhibitor |
| US20080269284A1 (en) * | 2004-06-24 | 2008-10-30 | Eli Lilly And Company | Compounds and Methods for Treating Dyslipidemia |
| WO2006033001A1 (en) * | 2004-09-23 | 2006-03-30 | Pfizer Products Inc. | Quinoline compounds |
| WO2006033004A1 (en) * | 2004-09-23 | 2006-03-30 | Pfizer Products Inc. | Quinoline compounds as cetp inhibitors |
| JP2008543726A (en) | 2005-02-24 | 2008-12-04 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | PGD2 receptor antagonist for the treatment of inflammatory diseases |
| WO2006098394A1 (en) * | 2005-03-14 | 2006-09-21 | Japan Tobacco Inc. | Method for inhibiting lipid absorption and lipid absorption inhibitor |
| US7737155B2 (en) | 2005-05-17 | 2010-06-15 | Schering Corporation | Nitrogen-containing heterocyclic compounds and methods of use thereof |
| CL2008000684A1 (en) | 2007-03-09 | 2008-08-01 | Indigene Pharmaceuticals Inc | PHARMACEUTICAL COMPOSITION THAT INCLUDES METFORMIN R - (+) LIPOATE AND A HMG-COA REDUCTASE INHIBITOR; UNIT DOSE FORMULATION; AND USE IN THE TREATMENT OF A DIABETIC COMPLICATION. |
| EP2379547A1 (en) | 2008-12-16 | 2011-10-26 | Schering Corporation | Pyridopyrimidine derivatives and methods of use thereof |
| EP2379562A1 (en) | 2008-12-16 | 2011-10-26 | Schering Corporation | Bicyclic pyranone derivatives as nicotinic acid receptor agonists |
| TWI450896B (en) | 2009-06-30 | 2014-09-01 | Lilly Co Eli | Trans-4-[[(5s)-5-[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2h-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-7,9-dimethyl-1h-1-benzazepin-1-yl]methyl]-cyclohexanecarboxylic acid |
| JP6854752B2 (en) | 2014-07-30 | 2021-04-07 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Genetic markers for predicting responsiveness to treatment with HDL-elevating agents or HDL mimetics |
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| US5231102A (en) * | 1989-03-08 | 1993-07-27 | Merck Sharp & Dohme, Ltd. | Tetrahydroquinoline derivatives useful for neurodegenerative disorders |
| AU5731098A (en) * | 1997-02-03 | 1998-08-25 | American Home Products Corporation | 2-substituted-1-acyl-1,2-dihydroquinoline derivatives to increase hdl-cholesterol level |
| US6197786B1 (en) * | 1998-09-17 | 2001-03-06 | Pfizer Inc | 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines |
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|---|---|
| AP2002002531A0 (en) | 2002-06-30 |
| PE20010904A1 (en) | 2001-09-10 |
| AU1048801A (en) | 2001-06-12 |
| HUP0203521A2 (en) | 2003-02-28 |
| IS6338A (en) | 2002-04-12 |
| CO5271716A1 (en) | 2003-04-30 |
| EA200200510A1 (en) | 2002-10-31 |
| EE200200277A (en) | 2003-10-15 |
| OA12099A (en) | 2006-05-04 |
| BG106854A (en) | 2002-12-29 |
| MA26845A1 (en) | 2004-12-20 |
| UY26454A1 (en) | 2001-07-31 |
| ECSP003792A (en) | 2002-04-23 |
| MXPA02005354A (en) | 2002-12-11 |
| TNSN00231A1 (en) | 2002-05-30 |
| GT200000199A (en) | 2002-05-23 |
| WO2001040190A1 (en) | 2001-06-07 |
| EP1246804A1 (en) | 2002-10-09 |
| NO20022558L (en) | 2002-05-29 |
| KR20020058057A (en) | 2002-07-12 |
| BR0015836A (en) | 2002-08-06 |
| JP2003515592A (en) | 2003-05-07 |
| TR200201446T2 (en) | 2002-11-21 |
| CN1402711A (en) | 2003-03-12 |
| PL355892A1 (en) | 2004-05-31 |
| IL149097A0 (en) | 2002-11-10 |
| NO20022558D0 (en) | 2002-05-29 |
| PA8506301A1 (en) | 2002-08-26 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |