# Patent

## Title
Glucagon receptor antagonist compounds

## Abstract

Glucagon receptor antagonist compounds are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.

## Background
BACKGROUND OF THE INVENTION
The present invention relates to glucagon receptor antagonist compounds, compositions containing such compounds and various methods of treatment relating to type 2 diabetes mellitus and related conditions.
Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or following glucose administration during an oral glucose tolerance test. Frank diabetes mellitus (e.g., a blood glucose level >126 mg/dL in a fasting state) is associated with increased and premature cardiovascular morbidity and mortality, and is related directly and indirectly to various metabolic conditions, including alterations of lipid, lipoprotein and apolipoprotein metabolism.
Patients with non-insulin dependent diabetes mellitus (type 2 diabetes mellitus), approximately 95% of patients with diabetes mellitus, frequently display elevated levels of serum lipids, such as cholesterol and triglycerides, and have poor blood-lipid profiles, with high levels of LDLcholesterol and low levels of HDL-cholesterol. Those suffering from Type 2 diabetes mellitus are thus at an increased risk of developing macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension (for example, blood pressure >130/80 mmHg in a resting state), nephropathy, neuropathy and retinopathy.
Patients having type 2 diabetes mellitus characteristically exhibit elevated plasma insulin levels compared with nondiabetic patients; these patients have developed a resistance to insulin stimulation of glucose and lipid metabolism in the main insulin-sensitive tissues (muscle, liver and adipose tissues). Thus, Type 2 diabetes, at least early in the natural progression of the disease is characterized primarily by insulin resistance rather than by a decrease in insulin production, resulting in insufficient uptake, oxidation and storage of glucose in muscle, inadequate repression of lipolysis in adipose tissue, and excess glucose production and secretion by the liver. The net effect of decreased sensitivity to insulin is high levels of insulin circulating in the blood without appropriate reduction in plasma glucose (hyperglycemia). Hyperinsulinemia is a risk factor for developing hypertension and may also contribute to vascular disease.
Glucagon serves as the major regulatory hormone attenuating the effect of insulin in its inhibition of liver gluconeogenesis and is normally secreted by alpha cells in pancreatic islets in response to falling blood glucose levels. The hormone binds to specific receptors in liver cells that trigger glycogenolysis and an increase in gluconeogenesis through cAMP-mediated events. These responses generate glucose (e.g. hepatic glucose production) to help maintain euglycemia by preventing blood glucose levels from falling significantly. In addition to elevated levels of circulating insulin, type 2 diabetics have elevated levels of plasma glucagon and increased rates of hepatic glucose production. Antagonists of the glucagon receptor are useful in improving insulin responsiveness in the liver, decreasing the rate of gluconeogenesis and glycogenolysis, and lowering the rate of hepatic glucose output resulting in a decrease in the levels of plasma glucose.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented by formula I:




or a pharmaceutically acceptable salt or solvate thereof wherein:

each R1 represents H or is selected from the group consisting of halo, CN, OH, NO2, CO2Ra, NRaRb, S(O)pRa, C1-10alkyl, C2-10alkenyl or C1-10alkoxy, the alkyl and alkenyl portions of, C1-10alkyl, C2-10alkenyl and C1-10alkoxy being optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
p represents 0, 1 or 2;
each Ra and Rb independently represents H or C1-4alkyl optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
R2 represents C1-6alkyl or C2-6alkenyl, each optionally substituted with 1-5 halo atoms up to perhalo, and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
R3 represents H or is selected from the group consisting of halo, CN, OH, NO2, CO2Ra, NRaRb, S(O)pRa, C1-10alkyl, C2-10alkenyl and C1-10alkoxy, the alkyl and alkenyl portions of, C1-10alkyl, C2-10alkenyl and C1-10alkoxy being optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo, NRaRb, and C1-6alkoxy;
each R4 independently represents H or is selected from the group consisting of halo, OH, C1-4alkyl, OC1-4alkyl, haloC1-4alkyl and haloOC1-4alkyl;
m represents 0, 1 or 2; when m represents 0, Z represents tetrazolyl; when m represents 1, Z represents a member selected from the group consisting of CO2H, SO3H, C(O)NH2 and tetrazolyl; and when m represents 2, Z represents a member selected from the group consisting of CO2H, SO3H and C(O)NH2.


DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched, or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-10 carbon atoms are intended for linear or branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like. Cycloalkyl is a subset of alkyl; if no number of atoms is specified, 3-10 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl and the like.
“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. Cycloalkenyl is a subset of alkenyl. If no number is specified, 4-8 carbon atoms are included. Examples include cyclopentenyl, cyclohexenyl and the like.
“Aryl” (Ar) means mono- and bicyclic aromatic rings containing 6-12 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like. “Aryl” also includes monocyclic rings fused to an aryl group. Examples include tetrahydronaphthyl, indanyl and the like.
“Heteroaryl” (HAR) means a mono- or bicyclic aromatic ring or ring system containing at least one heteroatom selected from O, S and N, with each ring containing 5 to 6 atoms. Examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl and the like. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium.
“Halogen” (Halo) includes fluorine, chlorine, bromine and iodine.
One aspect of the invention relates to a compound represented by formula I:




or a pharmaceutically acceptable salt or solvate thereof wherein:

each R1 represents H or is selected from the group consisting of halo, CN, OH, NO2, CO2Ra, NRaRb, S(O)pRa, C1-10alkyl, C2-10alkenyl or C1-10alkoxy, the alkyl and alkenyl portions of, C1-10alkyl, C2-10alkenyl and C1-10alkoxy being optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
p represents 0, 1 or 2;
each Ra and Rb independently represents H or C1-4alkyl optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
R2 represents C1-6alkyl or C2-6alkenyl, each optionally substituted with 1-5 halo atoms up to perhalo, and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
R3 represents H or is selected from the group consisting of halo, CN, OH, NO2, CO2Ra, NRaRb, S(O)pRa, C1-10alkyl, C2-10alkenyl and C1-10alkoxy, the alkyl and alkenyl portions of, C1-10alkyl, C2-10alkenyl and C1-10alkoxy being optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo, NRaRb, and C1-6alkoxy;
each R4 independently represents H or is selected from the group consisting of halo, OH, C1-4alkyl, haloC1-4alkyl and haloOC1-4alkyl;
m represents 0, 1 or 2; when m represents 0, Z represents tetrazolyl; when m represents 1, Z represents a member selected from the group consisting of CO2H, SO3H, C(O)NH2 and tetrazolyl; and when m represents 2, Z represents a member selected from the group consisting of CO2H, SO3H and C(O)NH2.
Another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R1 represents H or is selected from the group consisting of halo, CN, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy.
In particular, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R1 represents H or is selected from the group consisting of: halo selected from fluoro and, chloro; CN, CH3; OCH3; CF3; and OCF3.
Another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein R2 represents a member selected from the group consisting of: C1-4alkyl and C3-4alkyenyl, each optionally substituted with 1-3 halo atoms.
In particular, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein R2 represents C2-4alkyl optionally substituted with 1-3 halo atoms.
Even more particularly, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein R2 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, each optionally substituted with 1-3 halo atoms selected from fluoro and chloro.
Even more particularly, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein R2 is selected from the group consisting of n-propyl, n-butyl, CH2CH(CH3)2 and CH2CH2CF3.
Another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R3 represents H or is selected from the group consisting of halo, CN, OH, SCH3, SO2CH3, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy.
More particularly, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R3 represents H or is selected from the group consisting of halo which is selected from F, Cl and Br, CN, OH, SCH3, SO2CH3, C1-2alkoxy, haloC1-2alkyl and haloC1-2alkoxy wherein the halo portion of haloC1-2alkyl and haloC1-2alkoxy is selected from F and Cl.
Even more particularly, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R3 represents H, F, Cl, Br, CN, OH, CH3, OCH3, OCH2CH3, CHF2, CF3, SCH3, SO2CH3, OCHF2, and OCF3.
Another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R4 represents H, halo selected from F and Cl, OH, C1-2alkyl, C1-2alkoxy, haloC1-2alkyl and haloC1-2alkoxy wherein the halo portion of haloC1-2alkyl and haloC1-2alkoxy is selected from F and Cl.
In particular, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R4 represents H, F, Cl, OH, CH3, OCH3, CF3, and OCF3.
More particularly, another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein each R4 represents H, F, CH3 or OH.
Another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein m represents 0 and Z represents tetrazolyl.
Another aspect of the invention that is of interest relates to compounds in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein m is 2 and Z represents CO2H.
Another aspect of the invention that is of interest relates to compound in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof wherein:
each R1 represents H or is selected from the group consisting of halo, CN, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy;
R2 represents a member selected from the group consisting of: C1-4alkyl and C3-4alkyenyl, each optionally substituted with 1-3 halo atoms;
each R3 represents H or is selected from the group consisting of halo, CN, OH, C1-6alkyl, SCH3, SO2CH3, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy;
each R4 represents H, halo selected from F and Cl, OH, C1-2alkyl, C1-2alkoxy, haloC1-2alkyl and haloC1-2alkoxy wherein the halo portion of haloC1-2alkyl and haloC1-2alkoxy is selected from F and Cl;
m is 0 and Z is tetrazolyl, or m is 2 and Z represents CO2H.
Examples of compounds that fall within the invention described herein are in the tables and examples contained herein. Pharmaceutically acceptable salts and solvates of the compounds disclosed in the tables are included as well.
Another aspect of the invention that is of interest relates to a pharmaceutical composition comprising a compound as described above with respect to formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.
Another aspect of the invention that is of interest relates to a method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound as described above with respect to formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat type 2 diabetes mellitus.
Another aspect of the invention that is of interest relates to a method of delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to the patient a compound as described above in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to delay the onset of type 2 diabetes mellitus.
Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound as described above in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.
Another aspect of the invention that is of interest relates to a method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with formula I or a pharmaceutically acceptable salt or solvate thereof as described above.
Another aspect of the invention that is of interest relates to a method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with formula I as described above or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat obesity.
Another aspect of the invention that is of interest relates to a method of treating Syndrome X in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with formula I as described above or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat Syndrome X.
Another aspect of the invention that is of interest relates to a method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment, comprising administering to said patient a compound as described above with respect to formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat said lipid disorder.
Another aspect of the invention that is of interest relates to a method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with formula I as described above or a pharmaceutically acceptable salt or solvate thereof in an amount effective to treat atherosclerosis.
Another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient a compound in accordance with formula I as described above or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat said condition.
Another aspect of the invention that is of interest relates to a method of delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment, comprising administering to the patient a compound in accordance with formula I as described above or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to delay the onset of said condition.
Another aspect of the invention that is of interest relates to a method of reducing the risk of developing a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment, comprising administering to the patient a compound of formula I as described above or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to reduce the risk of developing said condition.
Another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of:
(1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment,
comprising administering to the patient effective amounts of a compound of formula I as described above, or a pharmaceutically acceptable salt or solvate thereof, and a another compound that is selected from the list provided below.
(1) growth hormone secretagogues, growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, and L-163,255, and such as those disclosed in U.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB1 receptor antagonists or inverse agonists, such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer), and those disclosed in U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01164634, WO02/076949, WO 03/007887, WO 04/048317, and WO 05/000809; and EPO Application No. EP-658546, EP-656354, EP-576357; (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such as those disclosed in U.S. Pat. No. 5,705,515, and U.S. Pat. No. 5,451,677 and PCT Patent Publications WO94/18161, WO95/29159, WO97/46556, WO98/04526 and WO98/32753, WO 01/74782, and WO 02/32897; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), cetilistat, Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No. 6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8) neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354; 6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332; 6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and 6,723,847, hereby incorporated by reference in their entirety; European Patent Nos. EP-01010691, and EP-01044970; and PCT International Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO 99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO 02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO 04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists, such as those disclosed in WO 01/21577 and WO 01/21169; (10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027, and Japanese Patent Application Nos. JP 13226269, and JP 2004-139909; (11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin-1 receptor antagonists, such as SB-334867-A, and those disclosed in PCT Patent Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838; (13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, and sertraline, and those disclosed in U.S. Pat. No. 6,365,633, and PCT Patent Application Nos. WO 01/27060 and WO 01/162341; (14) melanocortin agonists, such as Melanotan II, CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin); (15) other MC4R (melanocortin 4 receptor) agonists, such as those disclosed in: U.S. Pat. Nos. 6,410,548; 6,294,534; 6,350,760; 6,458,790; 6,472,398; 6,376,509; and 6,818,658; US Patent Publication No. US2002/0137664; US2003/0236262; US2004/009751; US2004/0092501; and PCT Application Nos. WO 99/64002; WO 00/74679; WO 01/70708; WO 01/70337; WO 01/74844; WO 01/91752; WO 01/991752; WO 02/15909; WO 02/059095; WO 02/059107; WO 02/059108; WO 02/059117; WO 02/067869; WO 02/068387; WO 02/068388; WO 02/067869; WO 02/11715; WO 02/12166; WO 02/12178; WO 03/007949; WO 03/009847; WO 04/024720; WO 04/078716; WO 04/078717; WO 04/087159; WO 04/089307; and WO 05/009950; (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and those disclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19) CCK agonists; (20) CCK-1 agonists (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131, and those described in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described and disclosed in PCT Application No. WO 02/15905, and O-[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzophenone derivatives and related compounds (Sasse, A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43 (2000)); (25) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (29) ghrelin receptor antagonists, such as those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT International Publication Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; (32) other BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed in Pept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron), and those disclosed in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813; (35) monoamine reuptake inhibitors, such as sibutramine, and those disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570, and 5,436,272, U.S. Patent Publication No. 2002/0006964 and PCT Application Nos. WO 01/27068, and WO 01/62341; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123; (37) thyroid hormone β agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190; (38) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444 and sitagliptin; and the compounds disclosed in U.S. Pat. No. 6,699,871, which is incorporated herein by reference; and International Patent Application Nos. WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181; (45) dicarboxylate transporter inhibitors; (46) glucose transporter inhibitors; (47) phosphate transporter inhibitors; (48) Metformin (Glucophage®); (49) Topiramate (Topimax®); (50) peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)), and those disclosed in U.S. Pat. No. 5,026,685, U.S. Pat. No. 5,604,203, U.S. Pat. No. 5,574,010, U.S. Pat. No. 5,696,093, U.S. Pat. No. 5,936,092, U.S. Pat. No. 6,046,162, U.S. Pat. No. 6,046,167, U.S. Pat. No. 6,093,692, U.S. Pat. No. 6,225,445, U.S. Pat. No. 5,604,203, U.S. Pat. No. 4,002,531, U.S. Pat. No. 4,179,337, U.S. Pat. No. 5,122,614, U.S. Pat. No. 5,349,052, U.S. Pat. No. 5,552,520, U.S. Pat. No. 6,127,355, WO 95/06058, WO 98/32466, WO 03/026591, WO 03/057235, WO 03/027637, and WO 2004/066966; (51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP) as described in Batterham et al., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4 agonists such as 1229U91; (53) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381, and pharmaceutically acceptable salts thereof; (54) Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A and those disclosed in U.S. Pat. No. 6,001,836; and PCT Application Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (55) Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, naltrexone, and those disclosed in: PCT Application No. WO 00/21509; (57) 11β HSD-1 (11-beta hydroxy steroid dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and those disclosed in WO 01/90091, WO 01/90090, WO 01/90092, and U.S. Pat. No. 6,730,690 and US Publication No. US 2004-0133011, which are incorporated by reference herein in their entirety; (56) aminorex; (57) amphechloral; (58) amphetamine; (59) benzphetamine; (60) chlorphentermine; (61) clobenzorex; (62) cloforex; (63) clominorex; (64) clortermine; (65) cyclexedrine; (66) dextroamphetamine; (67) diphemethoxidine, (68) N-ethylamphetamine; (69) fenbutrazate; (70) fenisorex; (71) fenproporex; (72) fludorex; (73) fluminorex; (74) furfurylmethylamphetamine; (75) levamfetamine; (76) levophacetoperane; (77) mefenorex; (78) metamfepramone; (79) methamphetamine; (80) norpseudoephedrine; (81) pentorex; (82) phendimetrazine; (83) phenmetrazine; (84) picilorex; (85) phytopharm 57; (86) zonisamide, (87) neuromedin U and analogs or derivatives thereof, (88) oxyntomodulin and analogs or derivatives thereof, (89) Neurokinin-1 receptor antagonists (NK-1 antagonists) such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and 5,637,699; (90) Qnexa; (91) smoking cessation agents, such as nicotine agonists, partial nicotine agonists, such as varenicline, monoamine oxidase inhibitors (MAOIs), antidepressants such as bupropion, doxepine, and nortriptyline; and anxiolytic agents such as buspirone or clonidine.
Specific compounds of use in combination with a compound of the present invention include: simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, and losartan, losartan with hydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO03/077847, including: N-[3-(4-chlorophenyl)-2(S)-phenyl-1(8)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, and pharmaceutically acceptable salts thereof; as well as those in WO05/000809, which includes the following: 3-{1-[bis(4-chlorophenypmethyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile, 1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol. 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((4-chlorophenyl) {3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, and 5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile, and pharmaceutically acceptable salts thereof; as well as: 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile, 3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile, 3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole, 3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one, 5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one, 4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile, and pharmaceutically acceptable salts thereof.
Specific NPY5 antagonists of use in combination with a compound of the present invention include: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide, trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N4-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexanc]-4′-carboxamide, trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, and pharmaceutically acceptable salts and esters thereof.
Specific ACC-1/2 inhibitors of use in combination with a compound of the present invention include: 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one; (5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methyl pivalate; 5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid; 1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one; and 1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one; and pharmaceutically acceptable salts and esters thereof. Specific MCH1R antagonist compounds of use in combination with a compound of the present invention include: 1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one, 4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one, 1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one, 4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one, 4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one, and 4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof.
Specific DP-IV inhibitors of use in combination with a compound of the present invention are selected from 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine. In particular, the compound of formula I is favorably combined with 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, and pharmaceutically acceptable salts thereof.
Specific H3 (histamine H3) antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO05/077905, including: 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpylido[2,3-d]-pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H-one 2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxyl}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclopentyl-4-piperidinypoxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyppropoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H-one, 2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone, 5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, and pharmaceutically acceptable salts thereof.
Specific CCK1R agonists of use in combination with a compound of the present invention include: 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; 3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; 3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; 3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; and 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; and pharmaceutically acceptable salts thereof.
Specific MC4R agonists of use in combination with a compound of the present invention include: 1) (5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]; 2) (5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]; 3) 2-(1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile; 4) 1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]; 5) N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine; 6) 2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile; and pharmaceutically acceptable salts thereof. Still further, neurokinin-1 (NK-1) receptor antagonists may be favorably employed in combination with a compound of the present invention. NK-1 receptor antagonists of use in the present invention are fully described in the art. Specific neurokinin-1 receptor antagonists of use in the present invention include: (±)-(2R3R,2S3S)—N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; aperpitant; C317493; GW597599; GW679769; R673; R067319; R1124; R1204; SSR146977; SSR240600; T-2328; and T2763.; or a pharmaceutically acceptable salts thereof. Examples of other anti-obesity agents that can be employed in combination with a compound of formula I are disclosed in “Patent focus on new anti-obesity agents,” Exp. Opin. Ther. Patents, 10: 819-831 (2000); “Novel anti-obesity drugs,” Exp. Opin. Invest. Drugs, 9: 1317-1326 (2000); and “Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity, Exp. Opin. Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y in obesity is discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346 (2000). Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs, 9; 1553-1571 (2000).
Another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor.
More particularly, another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin.
Even more particularly, another aspect of the invention that is of interest relates to a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor, wherein the HMG CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin and rivastatin.
Another aspect of the invention that is of interest relates to a method of reducing the risk of developing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelae of such conditions, delaying the onset or reducing the risk of developing said condition, comprising administering to a mammalian patient in need of such treatment therapeutically effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor.
More particularly, another aspect of the invention that is of interest relates to a method for delaying the onset of, or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin, and even more particularly, a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin and rivastatin.
Yet even more particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is simvastatin, atorvastatin or rosuvastatin.
Another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and a cholesterol absorption inhibitor. More particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above and a cholesterol absorption inhibitor wherein the cholesterol absorption inhibitor is ezetimibe.
Another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing the other diseases and conditions mentioned above, in a mammalian patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above, and a cholesterol absorption inhibitor.
More particularly, another aspect of the invention that is of interest relates to a method for delaying the onset or reducing the risk of developing the other diseases and conditions mentioned above, in a human patient in need of such treatment comprising administering to said patient effective amounts of a compound of formula I as described above, and a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor is ezetimibe.
Another aspect of the invention that is of interest relates to a method of treating, delaying the onset, or preventing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a CETP inhibiting compound.
More particularly, an aspect of the invention that is of interest relates to a method of treating, delaying the onset, or preventing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, comprising administering to the patient therapeutically effective amounts of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a CETP inhibiting compound selected from torcetrapib and anacetrapib.
Another aspect of the invention that is of interest relates to a pharmaceutical composition comprising (1) a compound of formula I as described above; (2) a compound selected from the list provide above in combination with a pharmaceutically acceptable carrier.
One pharmaceutical composition that is of interest is comprised of a compound of formula I as described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with a DPP-IV inhibitor selected from the group consisting of:




or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Many of the compounds of formula I contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all such isomeric forms of the compounds, in pure form as well as in mixtures.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with the compounds of Formula I.
Salts and Solvates
Salts and solvates of compounds of formula I are included in the present invention. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable substantially non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, as well as salts that can be converted into pharmaceutically acceptable salts. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glutamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
Solvates as used herein refers to the compound of formula I or a salt thereof, in association with a solvent, such as water. Representative examples include hydrates, hemihydrates, trihydrates and the like.
References to the compounds of Formula I are intended to include the pharmaceutically acceptable salts and solvates.
This invention relates to a method of inhibiting the activity of glucagon by antagonizing the glucagon receptor, thereby reducing the rate of gluconeogenesis and glycogenolysis, and the concentration of glucose in plasma.
The compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals associated with elevated levels of glucose, comprised of combining the compound of formula I with the carrier materials to provide the medicament.
Dose Ranges
The prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature or severity of the condition to be treated, the particular compound selected and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lies within the range of from about 0.001 mg to about 100 mg per kg body weight, preferably about 0.01 mg to about 50 mg per kg, and more preferably 0.1 to 10 mg per kg, in single or divided doses. It may be necessary to use dosages outside of these limits in some cases. The terms “effective amount”, “anti-diabetic effective amount” and the other terms appearing throughout the application addressing the amount of the compound to be used refer to the dosage ranges provided, taking into account any necessary variation outside of these ranges, as determined by the skilled physician.
Representative dosages of compounds of formula I, as well as the pharmaceutically acceptable salts and solvates thereof, for adults range from about 0.1 mg to about 1.0 g per day, preferably about 1 mg to about 500 mg, in single or divided doses. Examples of suitable dosages include 0.1 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 1000 mg and similar such doses. Representative dosages of compounds used in combination with the compounds of formula I are known, or the determination thereof is within the level of skill in the art, taking into account the description provided herein.
When intravenous or oral administration is employed, a representative dosage range is from about 0.001 mg to about 100 mg (preferably from 0.01 mg to about 10 mg) of a compound of Formula I per kg of body weight per day, and more preferably, about 0.1 mg to about 10 mg of a compound of formula I per kg of body weight per day.
Pharmaceutical Compositions
As mentioned above, the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. The term “composition” encompasses a product comprising the active and inert ingredient(s), (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions between ingredients. Preferably the composition is comprised of a compound of formula I in an amount that is effective to treat, prevent or delay the onset of type 2 diabetes mellitus, in combination with the pharmaceutically acceptable carrier.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Examples of dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like, with oral tablets being preferred.
In preparing oral compositions, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, in the case of oral liquids, e.g., suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solids, e.g., powders, capsules and tablets. Solid oral preparations are preferred. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any acceptable pharmaceutical process. All such methods include the step of combining the active ingredient(s) with the carrier components. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with a liquid or finely divided solid carrier component, and then, if necessary, manipulating the blend into the desired product form. For example, a tablet may be prepared by compression or molding. Compressed tablets may be prepared by compressing free-flowing powder or granules, containing the active(s) optionally mixed with one or more excipients, e.g., binders, lubricants, diluents, surfactants and dispersants. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid. Desirably, each tablet may contain, for example, from about 0.1 mg to about 1.0 g of the active ingredient and each cachet or capsule contains from about 0.1 mg to about 500 mg of the active ingredient.
The following are examples of pharmaceutical dosage forms containing a compound of Formula I:













Injectable





Suspension (im.)
mg/mL
Tablet
Mg/tablet


















Compound of
10.0
Compound of
25.0


Formula 1

Formula 1


Methylcellulose
5.0
Microcrystalline
415




Cellulose


Tween 80
0.5
Povidone
14.0


Benzyl alcohol
9.0
Pregelatinized Starch
4.0


Benzalkonium chloride
1.0
Magnesium Stearate
2.5


Water for injection
t.d. 1.0 mL
Total (approx.)
460 mg






















Capsule
mg/capsule
Aerosol
Per Canister



















Compound of
25.0
Compound of Formula 1
250
mg


Formula 1


Lactose
735
Lecithin, NF Liq. Conc.
1.2
mg


Mg Stearate
1.5
Trichloromethane, NF
4.025
g


Total (approx.)
761.5 mg
Dichloro-
12.15
g




difluoromethane, NF









Combination Therapy

As previously described, the compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/delaying the onset of type 2 diabetes mellitus, as well as other diseases and conditions described herein, for which compounds of Formula I are useful. Other drugs may be administered, by a route and in an amount commonly used, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a combination pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that alternatively contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) biguanides (e.g., buformin, metformin, phenformin), (b) PPAR agonists (e.g., troglitazone, pioglitazone, rosiglitazone), (c) insulin, (d) somatostatin, (e) alpha-glucosidase inhibitors (e.g., voglibose, miglitol, acarbose), (f) DPP-IV inhibitors, such as sitagliptin, vildagliptin, saxagliptin, and the like, such as those disclosed in U.S. Pat. No. 6,699,871B1 granted on Mar. 2, 2004 (g) LXR modulators and (h) insulin secretagogues (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide and repaglinide), and CB1 inhibitors, such as rimonabant and those compounds disclosed in WO03/077847A2 published on Sep. 25, 2003 and in WO05/000809 A1 published on Jan. 6, 2005.
An aspect of the invention that is particular interest relates to a pharmaceutical composition that is comprised of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a member selected from the group consisting of: simvastatin, mevastatin, ezetimibe, atorvastatin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, losartan, hydrochlorothiazide, buformin, phenformin, troglitazone, pioglitazone, rosiglitazone, insulin, somatostatin, voglibose, miglitol, acarbose, sitagliptin, vildagliptin, saxagliptin, alogliptin, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide and repaglinide, rimonabant and taranabant, in combination with a pharmaceutically acceptable carrier.
The weight ratio of the compound of the Formula I to the second active ingredient may be varied within wide limits and depends upon the effective dose of each active ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a PPAR agonist the weight ratio of the compound of the Formula I to the PPAR agonist will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
When used in combination with other agents, the dosages noted above for the glucagon antagonist are provided along with the usual dose for the other medication. For example, when a DPP-IV inhibitor such as those disclosed in U.S. Pat. No. 6,699,871B1, is included, the DPP-IV inhibitor can be used in an amount ranging from about 1.0 mg to as high as about 1000 mg, preferably about 2.5 mg to about 250 mg, and in particular, about 50 mg or about 100 mg administered in single daily doses or in divided doses as appropriate. Similarly, when the glucagon receptor antagonist is used in combination with a CB1 antagonist/inverse agonist, the CB1 antagonist/inverse agonist can be used in an amount ranging from as low as about 0.1 mg to as high as about 1000 mg, more particularly, in an amount ranging from about 1.0 mg to about 100 mg, and even more particularly, in an amount from about 1.0 mg to about 10 mg, administered in single daily doses or in divided doses as appropriate. Examples of doses of CB1 antagonist/inverse agonist include 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg and 20 mg.
Methods of Synthesis:
Compounds of the present invention can be prepared according to the Schemes provided below as well as the procedures provided in the Examples. The substituents are the same as in the above Formulas except where defined otherwise or otherwise apparent to the ordinary skilled artisan.
The novel compounds of the present invention can be readily synthesized using techniques known to those skilled in the art, such as those described, for example, in Advanced Organic Chemistry, March, 5th Ed., John Wiley and Sons, New York, N.Y., 2001; Advanced Organic Chemistry, Carey and Sundberg, Vol. A and B, 3rd Ed., Plenum Press, Inc., New York, N.Y., 1990; Protective groups in Organic Synthesis, Green and Wuts, 2nd Ed., John Wiley and Sons, New York, N.Y., 1991; Comprehensive Organic Transformations, Larock, VCH Publishers, Inc., New York, N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky and Pozharskii, 2nd Ed., Pergamon, New York, N.Y., 2000 and references cited therein. The starting materials for the present compounds may be prepared using standard synthetic transformations of chemical precursors that are readily available from commercial sources, including Aldrich Chemical Co. (Milwaukee, Wis.); Sigma Chemical Co. (St. Louis, Mo.); Lancaster Synthesis (Windham, N.H.); Ryan Scientific (Columbia, S.C.); Maybridge (Cornwall, UK); Matrix Scientific (Columbia, S.C.); Acros, (Pittsburgh, Pa.); BioBlocks, Inc. (San Diego, Calif.); and Trans World Chemicals (Rockville, Md.).
The procedures described herein for synthesizing the compounds may include one or more steps of protecting group manipulations and of purification, such as, re-crystallization, distillation, column chromatography, flash chromatography, thin-layer chromatography (TLC), and high-pressure chromatography (HPLC). The products can be characterized using various techniques well known in the chemical arts, including proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis and HPLC and mass spectrometry (HPLC-MS). Methods of protecting group manipulation, purification, structure identification and quantification are well known to one skilled in the art of chemical synthesis.
Appropriate solvents are those which will at least partially dissolve one or all of the reactants and will not adversely interact with either the reactants or the product. Suitable solvents are aromatic hydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g, methylene chloride, chloroform, carbontetrachloride, chlorobenzenes), ethers (e.g, diethyl ether, diisopropylether, tert-butyl methyl ether, diglyme, tetrahydrofuran, dioxane, anisole), nitriles (e.g, acetonitrile, propionitrile), ketones (e.g, 2-butanone, dithyl ketone, tert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol, iso-propanol, n-butanol, t-butanol), N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO) and water. Mixtures of two or more solvents can also be used. Suitable bases are, generally, alkali metal hydroxides, alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal amides such as lithium amide, sodium amide and potassium amide; alkali metal carbonates and alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and cesium hydrogen carbonate; alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metal alkyls such as methyllithium, n-butyllithium, sec-butyllithium, t-bultyllithium, phenyllithium, alkyl magnaesium halides, organic bases such as trimethylamine, triethylamine, triisopropylamine, N,N-diisopropylethyl amine, piperidine, N-methyl piperidine, morpholine, N-methyl morpholine, pyridine, collidines, lutidines, and 4-dimethylaminopyridine; and bicyclic amines such as DBU and DABCO.
It is understood that the functional groups present in compounds described in the Schemes below can be further manipulated, when appropriate, using the standard functional group transformation techniques available to those skilled in the art, to provide desired compounds described in this invention.
Throughout the synthesis schemes, abbreviations are used with the following meanings unless otherwise indicated:













AIBN = azobisisobutyronitrile
aq = aqueous


BINAP = 2,2′-bis(diphenylphosphino)-
Bn = benzyl


1,1′-binaphthalene


BOC, Boc = t-butyloxycarbonyl
BOP = benzotriazol-1-yloxy-



tris(dimethylamino)-phosphonium



hexafluorophosphate


Bu = butyl, t-Bu = t-butyl
BuLi, n-BuLi = n-butyllithium


CBZ, Cbz = Benzyloxycarbonyl
CDI = 1,1′-carbonyldiimidazole


(S)-DAIPEN = (S)-1,1-di(4-anisyl)-2-
dba = dibenzylideneacetone = trans,trans-


isopropyl-1,2-ethylenediamine = (S)-1,1-
1,5-diphenyl-1,4-pentadien-3-one


bis(4-methoxyphenyl)-3-methylbutane-


1,2-diamine


DCM = dichloromethane
2,4-diClPh = 2,4-dichlorophenyl


DIEA = diisopropylethylamine
DMAP = 4-Dimethylaminopyridine


DMF = N,N-dimethylformamide
DMS = dimethyl sulfide


DMSO = dimethyl sulfoxide
EDC = 1-ethyl-3-(3-dimethylaminopropyl)-



carbodiimide


eq. = equivalent(s)
Et = ethyl


EtOAc = ethyl acetate
EtOH = ethanol


g = gram(s)
HOBT, HOBt = Hydroxybenztriazole


HPLC = High pressure liquid
IPA = isopropanol


chromatography


iPr = isopropyl
KHMDS = potassium



bis(trimethylsilyl)amide


KOtBu = potassium tert-butoxide
LC/MS = liquid chromatography - mass



spectroscopy


LDA = lithium diisopropylamide
LHMDS = lithium bis(trimethylsilyl)amide


M = molar
mCPBA = 3-chloroperoxybenzoic acid


Me = methyl
MeCN, CH3CN = acetonitrile


MeOH = methanol
mg = milligram(s)


mL = milliliter(s)
mmol = millimole(s)


N = normal
NaOtBu = sodium tert-butoxide


NBS = N-bromosuccinimide
NCS = N-chlorosuccinimide


n-Pr = n-propyl
PCC = pyridinium chlorochromate


Pd/C = palladium on activated carbon
Ph = phenyl


PyBOP = Benzotriazol-1-
RT, rt = room temperature


yloxytripyrrolidinophosphonium


hexafluorophosphate


TBAF = tetrabutylammonium fluoride
Tf = triflate = trifluoromethanesulfonate


TFA = Trifluoroacetic acid
THF = tetrahydrofuran


TMS = trimethylsilyl
Tr = trityl = triphenylmethyl


(S)-xyl-SEGPHOS = (S)-5,5′-Bis[di(3,5-


xylyl)phosphino]-4,4′-bi-1,3-benzodioxole









Compounds of the present invention may be prepared according to the methodology outlined in the following general synthetic schemes.
In one embodiment of the present invention, compound Ia may be prepared from the acid 1 by the sequence depicted in Scheme 1. The carboxylic acid intermediate 1 is coupled with substituted or unsubstituted beta alanine ester (either methyl, ethyl or t-butyl ester) or glycine ester (either methyl, ethyl or t-butyl ester) using benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) and a base, generally N,N-diisopropylethylamine (DIEA), in a solvent such as N,N-dimethylformamide (DMF) or acetonitrile at ambient temperature to yield compound 2. Alternatively, the conversion of 1 to 2 may be carried out with EDC, HOBt, and a base such as DIEA in similar solvents as those used with BOP and DIEA. Many additional peptide coupling conditions are known and may also be used. Saponification of ester 2 (methyl, ethyl) to give compound Ia is achieved with a base such as aqueous lithium hydroxide (LiOH) or aqueous sodium hydroxide in a polar solvent such as tetrahydrofuran, methanol, ethanol or a mixture of similar solvents. In addition, compound 2, containing a t-butyl ester, can be converted to compound Ia using acid such as acetic acid or trifluoroacetic acid (TFA). The beta alanine or glycine moiety may also be incorporated at an earlier stage in the preparation of compound Ia. This is most commonly performed on hydroxyl acid intermediate 3 to give the beta alanine or glycine ester intermediate 4.




In additional embodiments of the invention, compounds Ib, Ic, and Id may also be prepared from the acid 1 as depicted in Scheme 2. Compounds Ib and Ic may be prepared directly by coupling acid 1 using the appropriately substituted amine and the peptide coupling methods described in the previous paragraph. Additionally, using the same conditions acid 1 may be coupled with substituted or unsubstituted 1-(1-trityl-1H-tetrazole-5-yl)-methylamine, which affords compound Id following deprotection of the trityl moiety with an acid such as acetic acid or trifluoroacetic acid (TFA).




Conversion of alcohols 4 to compound Ia can be achieved by the sequences depicted in Scheme 3. Treatment of 4 with a naphthalene ring in dichloromethane solvent at ambient temperature or 60° C. followed by the addition of a Bronsted acid such as trifluoroacetic acid (TFA) or a Lewis acid such as boron trifluoride-diethyl etherate may be conducted by analogy to the procedure described in Organic Letters, Chung, et. al., 2008, 10, 3037-3040. In the case of alcohol 4a, the t-butyl ester is deprotected under these conditions to afford Ia directly. In the case of alcohols 4b, containing a methyl or ethyl ester, the reaction with naphthalenes affords compound 2. In this case, the ester is subsequently saponified to afford Ia as described previously.




Scheme 4 summarizes the preparation of acid intermediates 1 and 3 using procedures adapted from Organic Letters, Chung, et. al., 2008, 10, 3037-3040. Coupling of aryl alkyl ketones 5 and aryl bromide 6 may be achieved under transition-metal mediated conditions such as those described in J. Am. Chem. Soc., Buchwald, S. L., et. al., 2000, 122, 13604370. Ketone 7 may be prepared, for instance, by heating 5 and 6 in the presence of a palladium source such as Pd2(dba)3, a ligand such as BINAP, a base such as NaOtBu, and a solvent such as THF. Reduction of ketone 7 to alcohol 8 can be accomplished with various achiral reductants, for instance NaBH4. Alternatively, dynamic kinetic resolution of ketone 7 can afford highly enantio- and diastereoenriched alcohol 8 using catalysts such as those reviewed extensively in Angew. Chem., Int. Ed., Noyori, R., et. al., 2001, 40, 40-73. This reaction can be performed using a ruthenium catalyst such as RuCl2[(S)-xyl-SEGPHOS][(S)-DAIPEN] and a base such as KOtBu in a solvent such as 2-propanol under an atmosphere of hydrogen. Deprotection of the t-butyl ester of alcohol 8 with an acid such as phosphoric acid in acetonitrile solvent gives the acid 3, which can be converted to 1 under the conditions described for converting 4 to 2 (Scheme 3). A wide range of substituents may be introduced at R1, R2, and R3 on acids 1 and 3 due to the functional group tolerance of the reactions employed in their preparation and the wide variety of starting naphthalenes and ketones 5 which are either commercially available or readily prepared by methods known to those skilled in the art.




An alternative preparation of acid intermediate 1, also proceeding from ketone 7, is shown in Scheme 5. Racemic ketone 7 is accessed as described in the preceeding paragraph. Alternatively, enantioenriched ketone 7 may be prepared by oxidation of diastereo- and enantioenriched alcohol 8 with a variety of oxidants, for instance PCC or Dess-Martin periodinane, in solvents such as dichloromethane. Naphthyl halides 9 can be metalated with an organometallic reagent, such as nBuLi, in an aprotic solvent such as THF at −78° C. The resulting metalated naphthyl intermediate can then add to ketone 7 to afford tertiary alcohol 10. Tertiary alcohol 10 may be converted to intermediate 1 by treatment with a hydride source such as triethylsilane with a Lewis acid such as boron trifluoride-diethyl etherate in a solvent such as dichloromethane at temperatures between −78° C. and ambient temperature.




While the R3 substituents are typically present in the starting naphthyl ring (Schemes 3-5), it is also possible to alter the R3 substituents on advanced intermediates as shown in Scheme 6. For instance, the methoxy substituent of intermediate 2a can be demethylated with a Lewis acid such as boron tribromide in a solvent such as dichloromethane to afford naphthol 2b. The hydroxyl group of this intermediate may then be alkylated with, for instance, a difluoromethyl substituent to afford compound la directly using chlorodifluoroacetophenone, a base such as potassium hydroxide, in a solvent such as acetonitrile, at a temperature of 80° C. Another possible functionalization is to convert the resulting naphthol intermediate 2b to the triflate 2c using a reagent such as trifluoromethanesulfonic anhydride and a base such as triethylamine. The resulting triflate 2c can be functionalized using a variety of metal-mediated cross-coupling reactions obvious to those skilled in the art. For instance, the triflate may be converted to nitrile 2d in the presence of a palladium catalyst such as Pd(PPh3)4 and a cyanide source such as Zn(CN)2, in a polar aprotic solvent such as DMF, at a temperature of 120° C. based on the chemistry described by Kubota and Rice, Tetrahedron Letters, 1998, 39, 2907-2910. Alternatively, using the same procedure the bromide substituent of intermediate 2e may be directly converted to nitrile 2d. Bromide 2e could also be functionalized using a variety of other metal-mediated cross-coupling reactions.




Similarly, while the R1 substituents are typically present in the starting alcohols 3 and 5 (Schemes 1-5), it is also possible to alter the R1 substituents on advanced intermediates as shown in Scheme 7. For instance, the 4-chloro substituent of intermediate 2f can be functionalized using a variety of metal-mediated cross-coupling reactions obvious to those skilled in the art. For instance, it may be converted to nitrile 2g in the presence of a nickel catalyst such as NiBr2 and a cyanide source such as NaCN, in a polar aprotic solvent such as N-methylpyrollidine, at a temperature of 200° C. under microwave irradiation.




Separation of diastereomers can be carried out at various stages in the preparation of compounds I, however, it is typically carried out on the ester 2 using silica gel chromatography and EtOAc/hexane eluent or on compound I using reverse phase HPLC.
Analytical HPLC Mass Spectrometry Conditions:


    LC1: Column: Waters Xterra MS C-18, 3.5μ, 2.1×20 mm


Temperature: 50° C.
Eluent: 5:95 to 98:2 v/v acetonitrile/water+0.05% TFA over 1.25 min.
Flow Rate: 1.5 mL/min, Injection 5 μL
Detection: PDA, 200-600 nm
MS: mass range 150-750 amu; positive ion electrospray ionization

    LC2: Column: Waters Xterra IS C-18, 3.5μ, 2.1×20 mm


Temperature: 50° C.
Eluent: 5:95 to 95:5 v/v acetonitrile/water+0.05% TFA over 3.00 min.
Flow Rate: 1.5 mL/min, Injection 5 μL
Detection: PDA, 200-600 nm
MS: mass range 150-750 amu; positive and negative ion electrospray ionization

    LC3: Column: Waters Xterra MS C-18, 3.5μ, 3.0×50 mm


Temperature: 50° C.
Eluent: 10:90 to 98:2 v/v acetonitrile/water+0.05% TFA over 3.75 min.
Flow Rate: 1.0 mL/min, Injection 10 μL
Detection: PDA, 200-600 nm
MS: mass range 150-750 amu; positive ion electrospray ionization
General chiral semi-preparative conditions: 2 cm×25 cm chiral column available from Daicel Chemical Industries, LTD, 9 mL/min isocratic EtOH or IPA/heptane eluent.


    Preparative reverse phase HPLC (RP-HPLC) conditions:


Column: Atlantis dC18, 5 μm, 19×150 mm
Flow Rate: 20.0 mL/min
Eluent: 10:90 to 100:0 v/v acetonitrile/water+0.1% TFA over 10.0 min.
Temperature: ambient
Detection: PDA, 254 nm
Preparative thin layer chromatography (PTLC) was performed on 20×20 cm plates (500 μm thick silica gel). Silica gel chromatography was done on a Biotage Horizon flash chromatography system.
The following examples are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way.
INTERMEDIATE 1
4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoic acid




Step A. tert-Butyl 4-[2-(4-chlorophenyl)-1-propylethan-2-one-1-yl]benzoate




A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl (aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC1 1.35 min. [M-tBu+H]+ 317.
Step B. tert-Butyl 4-[(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate




To degassed 2-propanol (5.0 mL) was added RuCl2[(S)-xyl-SEGPHOS][(5)-DAIPEN] (16.2 mg, 0.0134 mmol) and potassium t-butoxide (300 mg, 2.67 mmol). After this mixture was stirred at room temperature for 2 hours, the material obtained in Step A was added in 2-propanol (25 mL). This mixture was then treated with hydrogen (100 psi) at room temperature for 18 hours. The mixture was concentrated, then the residue was recrystallized from 2-propanol/water to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H), 7.32 (m, 2H), 7.26 (m, 2H), 7.22 (m, 2H), 4.76 (dd, J=7.7, 2.9 Hz, 1H), 2.89 (ddd, J=11.5, 7.7, 4.2 Hz, 1H), 1.84 (d, J=2.9 Hz, 1H), 1.62 (s, 9H), 1.61 (m, 1H), 1.41 (m, 1H), 1.05 (m, 2H), 0.76 (t, J=7.3 Hz, 3H); LC3 2.38 min. [M−H2O-tBu+H]+ 301; Chiral SFC Method: Chiralpak AD-H (250×4.6 mm), isocratic 15% MeOH/CO2, 1.5 mL/min, 200 bar, 35° C., 215 nm, 15 minutes: desired alcohol retention time=9.8 min; enantiomeric alcohol, retention time=10.6 min; diastereomeric alcohols: retention time=5.2 and 6.3 min.
Step C. 4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoic acid




Orthophosphoric acid (85 wt %, 11.4 g, 99 mmol) was added to a slurry of tert-butyl 4-[(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate (7.42 g, 19.8 mmol) in acetonitrile (75 mL). The mixture was purged with nitrogen, then heated at 65° C. for 3.5 hours. The mixture was allowed to cool to 40° C., then water (25 mL) was added dropwise. Once crystallization began, additional water (50 mL) was added and the mixture was allowed to cool to room temperature. The precipitate was collected by vacuum filtration, washed with 3:1 water:acetonitrile (35 mL), then dried in vacuo at 65° C. overnight to afford the title compound as a light green solid. 1H NMR (400 MHz, DMSO-d6) δ 12.71 (br s, 1H); 7.79 (d, J=8.3 Hz, 2H); 7.29 (d, J=8.4 Hz, 2H); 7.19-7.25 (m, 4H); 5.32 (br s, 1H); 4.76 (d, J=6.3 Hz, 1H); 2.85 (dt, J=10.7, 5.4 Hz, 1H); 1.61 (m, 1H); 1.44 (m, 1H); 1.00 (m, 2H); 0.73 (t, J=7.3 Hz, 3H)); LC1 1.13 min. [M−H2O+H]+ 301.
INTERMEDIATE 2
4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoic acid




Trifluoroacetic acid (40 mL) was added to INTERMEDIATE 1 (6.70 g, 21.0 mmol) and 1-fluoronaphthalene (3.07 g, 21.0 mmol), then the resulting mixture was stirred overnight at RT. The solvent was concentrated, then the residue was purified by preparative reverse phase HPLC, eluting with water/MeCN+0.1% TFA to afford the two diastereomers of the title compound.
Major diastereomer: 1H NMR (500 MHz, CD3OD): δ 8.38 (d, J=8.8 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.69-7.64 (m, 3H); 7.56 (d, J=8.0 Hz, 2H); 7.52 (m, 1H); 7.45-7.41 (m, 1H); 7.36 (d, J=7.8 Hz, 2H); 7.28 (d, J=8.3 Hz, 2H); 6.99 (dd, J=10.4, 8.2 Hz, 1H); 5.17 (d, J=11.5 Hz, 1H); 3.74 (m, 1H); 1.65-1.57 (m, 2H); 1.08-1.01 (m, 2H); 0.78 (t, J=7.2 Hz, 3H); LC2 2.65 min. [M+H]+446.
Minor diastereomer: 1H NMR (500 MHz, CD3OD): δ 8.46 (d, J=8.7 Hz, 1H); 8.11 (d, J=8.3 Hz, 1H); 7.85 (dd, J=8.0, 4.5 Hz, 3H); 7.65-7.61 (m, 1H); 7.59-7.54 (m, 1H); 7.39 (d, J=7.8 Hz, 2H); 7.31-7.26 (m, 1H); 7.17 (d, J=8.3 Hz, 2H); 6.96 (d, J 8.4 Hz, 2H); 5.07 (d, J=11.5 Hz, 1H); 3.77-3.72 (m, 1H); 1.61 (m, 2H); 1.13-1.03 (m, 2H); 0.73 (t, J=7.2 Hz, 3H); LC2 2.67 min. [M+H]+ 446.
INTERMEDIATE 3
4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoic acid




Trifluoroacetic acid (40 mL) was added to INTERMEDIATE 1 (6.70 g, 21.0 mmol) and 2-methoxynaphthalene (3.32 g, 21.0 mmol), then the resulting mixture was stirred overnight at RT. The solvent was concentrated, then the residue was purified by preparative reverse phase HPLC, eluting with water/MeCN+0.1% TFA to afford the two diastereomers of the title compound.
Major diastereomer: 1H NMR (499 MHz, CD3OD): δ 7.76-7.71 (m, 2H); 7.55-7.50 (m, 4H); 7.48-7.36 (m, 1H); 7.36-7.28 (m, 5H); 7.00-6.95 (m, 2H); 4.34 (d, J=11.7 Hz, 1H); 3.87 (s, 3H); 3.74-3.65 (m, 1H); 1.57 (d, J=8.7 Hz, 2H); 1.09-1.01 (m, 2H); 0.78 (t, J=7.3 Hz, 3H); LC2 2.60 min. [M−H]+ 457.
Minor diastereomer: 1H NMR (499 MHz, CD3OD): δ 7.87-7.80 (m, 3H); 7.77-7.72 (m, 2H); 7.57 (d, J=8.4 Hz, 1H); 7.35 (d, J=7.7 Hz, 2H); 7.26-7.18 (m, 3H); 7.14-7.09 (m, 1H); 7.02 (d, J=7.9 Hz, 2H); 4.34 (d, J=11.7 Hz, 1H); 3.89 (s, 3H); 3.74-3.66 (m, 1H); 1.58 (m, 2H); 1.03 (m, 2H); 0.74 (t, J=7.3 Hz, 3H); LC2 2.61 min. [M−H]+ 457.
INTERMEDIATE 4
tert-butyl (R)-4-[2-(4-chlorophenyl)-1-propylethan-2-one-1-yl]benzoate




Pyridinium chlorochromate (4.9 g, 23 mmol) was added to a solution of t-Butyl 4-(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate (7.1 g, 19 mmol) in CH2Cl2 (200 mL), and the mixture was stirred at room temperature until reaction was complete as monitored by LC/MS. The mixture was diluted with 200 mL of Et2O, filtered, and washed with Et2O. The combined filtrate and washings were concentrated then purified by silica gel chromatography with 0-5% EtOAc/hexanes to afford the title compound as a colorless oil which solidified upon standing. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC3: 1.35 min. [M−tBu+H]+317.
EXAMPLE 1
N-(4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alanine




Step A. Ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate




To a solution of INTERMEDIATE 1 (5.00 g, 15.7 mmol) in THF (100 mL) was added CDI (3.05 g, 18.82 mmol). After stirring at room temperature for one hour, β-alanine ethyl ester hydrochloride (3.61 mg, 23.53 mmol) was added, then the mixture was stirred at room temperature for two days. The mixture was diluted with EtOAc then washed with 1N NaOH, then water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used without further purification. 1H NMR (499 MHz, CDCl3): δ 7.74 (d, J=7.9 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 7.28 (t, J=4.0 Hz, 2H); 7.25-7.15 (m, 2H); 6.88 (brs, 1H); 4.77 (d, J=7.7 Hz, 1H); 4.20 (q, J=7.1 Hz, 2H); 3.75 (q, J=5.9 Hz, 2H); 2.89 (ddd, J=11.1, 7.7, 4.1 Hz, 1H); 2.66 (t, J=5.8 Hz, 2H); 1.47-1.37 (m, 2H); 1.30 (t, J=7.1 Hz, 3H); 1.11 (m, 2H); 0.76 (t, J=7.3 Hz, 3H). LC-MS: LC1 1.14 min. [M+H]+ 418.
Step B. Ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate




Method (a):
Trifluoroacetic acid (3 mL) was added to ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate (200 mg, 0.479 mmol) and 1-fluoronaphthalene (69.9 mg, 0.479 mmol). The solution was stirred overnight at RT, then the solvent was evaporated and the residue was purified by HPLC (ChiralPak IB column) eluting with 15% isopropanol/heptane to afford the major diastereomer of the title compound.
Method (b):
To a solution of INTERMEDIATE 2 (200 mg, 0.447 mmol) in THF (5 mL) was added CDI (109 mg, 0.671 mmol). After stirring at room temperature for one hour, β-alanine ethyl ester hydrochloride (137 mg, 0.895 mmol) was added, then the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc then washed with water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by HPLC (ChiralPak IB column) eluting with 15% isopropanol/heptane to afford the major diastereomer of the title compound.
Major diastereomer: 1H NMR (499 MHz, CDCl3): δ 8.17 (d, J=8.7 Hz, 1H); 7.97 (d, J=8.3 Hz, 1H); 7.50-7.43 (m, 4H); 7.40 (t, J=8.1 Hz, 3H); 7.24 (t, J=8.5 Hz, 4H) 6.95 (dd, J=10.0, 8.1 Hz, 1H); 6.81 (s, 1H); 4.99 (d, J=11.3 Hz, 1H); 4.12-4.06 (m, 2H); 3.57 (t, J=8.6 Hz, 2H); 3.42-3.36 (m, 1H); 2.53 (brs, 2H); 1.46-1.64 (m, 2H); 1.08-0.95 (m, 2H); 0.88 (t, J=6.9 Hz, 3H); 0.73 (t, J=7.3 Hz, 3H). LC1 1.21 min. [M+H]+ 546.
Step C. N-(4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alanine




To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (160 mg, 0.293 mmol) in ethanol (2 mL) and THF (2 mL) was added LiOH (2.0 N in water, 2.93 mL, 5.86 mmol), then the mixture was stirred for one hour. The mixture was diluted with DCM, then acidified with 2.0 N HCl (aq). The layers were separated, then the organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to obtain the title compound as a white solid. 1H NMR (499 MHz, CD3OD): δ 8.40 (d, J=8.8 Hz, 1H); 7.92 (d, J=8.3 Hz, 1H); 7.70 (dd, J=8.2, 5.3 Hz, 1H); 7.60 (d, J=8.3 Hz, 2H); 7.55 (t, J=7.6 Hz, 1H); 7.50 (d, J=8.1 Hz, 2H); 7.45 (t, J=7.6 Hz, 1H); 7.39 (d, J=8.1 Hz, 2H); 7.30 (d, J=8.3 Hz, 2H); 7.00 (dd, J=10.4, 8.2 Hz, 1H); 5.19 (d, J=11.5 Hz, 1H); 3.52 (t, J=6.9 Hz, 2H); 3.36-330 (m, 1H); 2.53 (t, J=7.0 Hz, 2H); 1.62 (d, J=10.4 Hz, 2H); 1.11-1.05 (m, 2H); 0.78 (t, J=7.3 Hz, 3H). LC3 4.01 min. [M+H]+ 518.
EXAMPLE 2
N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alanine




Step A. Ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methy]butyl}benzoyl)-β-alaninate




Trifluoroacetic acid (5 mL) was added to ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 1, Step A, 600 mg, 1.436 mmol) and 2-methoxynaphthalene (341 mg, 2.15 mmol). The solution was stirred overnight at RT, then the solvent was evaporated and the residue was purified by PTLC to afford the major diastereomer of the title compound. LC2 2.85 min. [M+H]+ 558.
Step B. N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alanine




To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (4.0 mg, 0.0072 mmol) in ethanol (1 mL) was added LiOH (2.0 N in water, 0.1 mL, 0.2 mmol), then the mixture was stirred for one hour The mixture was diluted with DCM, then acidified with 2.0 N HCl (aq). The layers were separated, then the organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to obtain the title compound as a white solid. 1H NMR (600 MHz, CD3OD): δ 7.53-7.48 (m, 6H); 7.42 (d, J=8.5 Hz, 1H); 7.33-7.28 (m, 5H); 6.98-6.94 (m, 2H); 5.47 (s, 1H); 4.32 (d, J=11.7 Hz, 1H); 3.79 (s, 3H); 3.51-3.47 (m, 2H); 2.50 (s, 2H); 1.56 (t, J=7.6 Hz, 2H); 1.04 (d, J=9.5 Hz, 2H); 0.73 (t, J=7.3 Hz, 3H); LC3 2.61 min. [M+H]+ 531.
EXAMPLE 3
N-[4-((1S)-1-{(4-chlorophenyl)[6-(difluoromethoxy)-2-naphthyl]methyl}butyl)benzoyl]-β-alanine




Step A. Ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-hydroxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate




To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 300 mg, 0.538 mmol) in DCM (10 mL) at 0° C. was slowly added BBr3 (1.0 M in DCM, 2.69 mL, 2.69 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 6 hours. After diluting with DCM, the mixture was washed with water, then saturated NaCl (aq). The organic layer was dried over MgSO4, filtered, then concentrated to afford the title product. LC2 2.65 min. [M+H]+ 544.
Step B. N-[4-((1S)-1-{(4-chlorophenyl)[6-(difluoromethoxy)-2-naphthyl]methyl}butyl)benzoyl]-β-alanine




Chlorodifluroacetophenone (294 mg, 1.54 mmol) was added to a mixture of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-hydroxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (140 mg, 0.257 mmol), KOH (303 mg, 5.40 mmol), and acetonitrile (3.0 mL) at −78° C., then the resulting mixture was warmed to 80° C. and stirred for 3 hours. The mixture was cooled to RT, quenched with 2.0 N HCl (aq), then diluted with EtOAc. The organic layer was washed twice with water then concentrated. The residue was purified by preparative reverse phase HPLC, eluting with water/MeCN+0.1% TFA to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.68 (d, J=9.0 Hz, 1H), 7.64 (s, 1H), 7.58-7.49 (m, 5H), 7.42 (d, J=8.7 Hz, 1H), 7.37-7.29 (m, 5H), 7.16-7.12 (m, 1H), 6.82 (t, J 7.4 Hz, 1H), 4.39 (d, J=11.8 Hz, 1H), 3.76-3.67 (m, 1H), 3.53-3.47 (m, 2H), 2.56-2.50 (m, 2H), 1.59 (d, J=8.9 Hz, 2H), 1.07 (d, J=10.2 Hz, 2H), 0.79 (t, J=7.2 Hz, 3H); LC2 2.49 min. [M+H]+ 566.
EXAMPLE 4
N-<4-{(1S)-1-[(4-chlorophenyl)(6-cyano-2-naphthyl)methyl]butyl}benzoyl)-β-alanine




Step A. Ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-{[(trifluoromethyl)sulfonyl]oxy}-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate




To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-hydroxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 3, Step A, 65 mg, 0.119 mmol) in DCM (5 mL) at 0° C. was added TEA (0.050 mL, 0.358 mmol), and the resulting solution was allowed to stir for 15 minutes. Trifluoromethanesulfonic anhydride (93 mg, 0.239 mmol) was added, then the solution was allowed to warm to RT and stirred overnight. The mixture was concentrated, then the residue was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to provide the title compound. LC2 3.00 min. [M+H]+ 676.
Step B. N-(4-{(1S)-1-[(4-chlorophenyl)(6-cyano-2-naphthyl)methyl]butyl}benzoyl)-β-alanine




A mixture of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-{[(trifluoromethyl)sulfonyl]oxy}-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (55 mg, 0.081 mmol), Pd(Ph3P)4 (19 mg, 0.016 mmol), and zinc cyanide (11.5 mg, 0.098 mmol) in DMF (3 mL) was stirred at 120° C. overnight. After cooling to RT, the mixture was partitioned between EtOAc and water. The (aq) layer was extracted with additional EtOAc, then the combined organic fractions were concentrated. The resulting greenish residue was purified by preparative reverse phase HPLC eluting with 40-100% acetonitrile/water+0.1% TFA. The resulting material was used directly for the next step.
The product of the previous step was dissolved in 2:1 THF/MeOH (3 mL), then LiOH (2.0 N in water, 1 mL, 2.0 mmol) was added and the mixture was stirred at RT for one hour. The mixture was acidified with 2.0 N HCl (aq), diluted with EtOAc, then the organic layer was washed twice with water. The organic layer was dried over MgSO4, filtered, then concentrated to afford the title compound as a white solid. 1H NMR (499 MHz, CD3OD): δ 8.10 (s, 1H); 7.78 (d, J=8.6 Hz, 1H); 7.75 (s, 1H); 7.66 (d, J=8.6 Hz, 1H); 7.60-7.50 (m, 5H); 7.48 (d, J=8.8 Hz, 1H); 7.35 (dd, J=12.1, 8.0 Hz, 4H); 4.47 (d, J=11.8 Hz, 1H); 3.80-3.72 (m, 1H); 3.55-3.46 (m, 2H); 2.58-2.50 (m, 2H); 1.60 (d, J=8.3 Hz, 2H); 1.20-1.02 (m, 2H); 0.76 (t, J=7.3 Hz, 3H). LC2 2.52 min. [M+H]+ 525.
EXAMPLE 5
N-(4-{(1S)-1-[(4-cyanophenyl)(4-fluoro-1-naphthyl)methyl]butyl}benzoyl)-β-alanine




Ethyl N-({4-[(2S)-1-(4-chlorophenyl)-1-(4-fluoronaphthalen-1-yl)pentan-2-yl]phenyl}carbonyl)-β-alaninate (EXAMPLE 1, Step B, 50 mg, 0.092 mmol), nickel (II) bromide (20.0 mg, 0.092 mmol), and sodium cyanide (9.0 mg, 0.18 mmol), were stirred in N-methylpyrollidine (1 mL) under microwave irradiation at 200° C. for 15 minutes. After cooling to room temperature, the mixture was diluted with diethyl ether and the organic layer was washed twice with water. The organic layer was concentrated, then the resulting residue was purified by preparative TLC eluting with 40% EtOAc/hexanes. The resulting material was used directly in the next step. LC2 2.46 min. [M+H]+ 536.
The product of the previous step (7 mg, 0.013 mmol) was dissolved in THF (2 mL), then LiOH (2.0 N in water, 0.061 mL, 0.123 mmol) was added and the reaction mixture was stirred for one hour at room temperature. The mixture was acidified with 2.0 N HCl (aq) and diluted with EtOAc. The organic layer was washed twice with water, dried over sodium sulfate, filtered, then concentrated to afford the title product as a white solid. 1H NMR (499 MHz, CD3OD) δ 8.42 (d, J=8.8 Hz, 1H); 7.93 (d, J=8.4 Hz, 1H); 7.84 (d, J=8.1 Hz, 2H); 7.75 (dd, J=8.2, 5.2 Hz, 1H); 7.67 (d, J=8.0 Hz, 2H); 7.59-7.54 (m, 1H); 7.51 (d, J=8.0 Hz, 2H); 7.49-7.42 (m, 1H); 7.41 (d, J=8.0 Hz, 2H); 7.02 (dd, J=10.3, 8.2 Hz, 1H); 5.31 (d, J=11.6 Hz, 1H); 3.86-3.79 (m, 1H); 3.54-3.49 (m, 2H); 2.56-2.52 (m, 2H); 1.11-1.03 (m, 2H); 0.95-0.89 (m, 2H); 0.77 (t, J=7.2 Hz, 3H). LC1 1.45 min. [M+H]+ 508.
EXAMPLE 6
N-(4-{(1S)-1-[(4-chlorophenyl)(5-cyano-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alanine




Step A: Ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-bromo-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate




Trifluoroacetic acid (50 mL) was added to ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 1, Step A, 2.00 g, 4.79 mmol) and 1-bromo-3-methylnaphthalene (1.16 g, 5.26 mmol). The solution was stirred overnight at RT, then the solvent was evaporated and the residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to afford the title compound. LC3 4.49 min. [M+H]+ 622.
Step B: Ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-cyano-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate




To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-bromo-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (40 mg, 0.064 mmol) in DMF (3 mL) was added zinc cyanide (8.3 mg, 0.071 mmol) and Pd(Ph3P)4 (22.3 mg, 0.019 mmol). The resulting reaction mixture was stirred at 110° C. for 24 hours, then concentrated. The resulting residue was purified by preparative TLC eluting with 40% EtOAc/hexanes afforded a 9:1 mixture of naphthyl regioisomers. The residue was purified by preparative HPLC (Chiralcel OD column) eluting with 5% EtOH/heptane to afford the major diastereomer of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.65 (d, J=7.5 Hz, 1H); 7.63 (s, 1H); 7.48 (d, J=8.5 Hz, 2H); 7.42 (m, 1H); 7.36 (d, J=8.5 Hz, 2H); 7.26 (d, J=8.0 Hz, 2H); 7.20 (d, J=8.5 Hz, 2H); 6.66 (m, 1H); 5.00 (d, J=11.5 Hz, 1H); 4.13 (q, J=7.2 Hz, 2H); 3.62 (q, J=11.8 Hz, 2H); 3.56 (m, 1H); 2.54 (q, 14.5 Hz, 2H); 2.54 (s, 3H); 1.62-1.51 (m, 2H); 1.25 (t, J=7.3 Hz, 3H), 1.06-1.00 (m, 2H); 0.74 (t, J=7.2 Hz, 3H). LC3 4.06 min. [M+H]+ 567.
Step C: N-4-{(1S)-1-[4-chlorophenyl)(5-cyano-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alanine




To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-cyano-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (18 mg, 0.032 mmol) in 2:1 THF/MeOH (3 mL) at room temperature was added LiOH (2.0 N in water, 0.265 mL, 0.530 mmol). The mixture was stirred at room temperature for one hour. The mixture was acidified with 2.0 N HCl (aq) and diluted with EtOAc. The organic layer was washed twice with water, dried over sodium sulfate, filtered, then concentrated to afford the title product as a white solid. LC1 1.59 min. [M+H]+ 538.
EXAMPLE 7
(2S)-3-[(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)amino]-2-hydroxypropanoic acid




To a solution of INTERMEDIATE 3 (50.0 mg, 0.109 mmol) in DMF (2 mL) was added CDI (53.0 mg, 0.327 mmol) and the resulting mixture was stirred for 30 minutes at room temperature. Methyl (2S)-3-amino-2-hydroxypropanoate (22.9 mg, 0.218 mmol) was added, then the resulting mixture was stirred at 65° C. for 12 hours. After cooling to room temperature, LiOH (2.0 N in water, 0.545 mL, 1.09 mmol) was added, then the mixture was stirred for 30 minutes at room temperature. The mixture was acidified with 2.0 N HCl (aq) and diluted with EtOAc. The organic layer was washed twice with water, then concentrated. The resulting yellow residue was purified by reverse phase HPLC eluting with 50-100% acetonitrile/water+0.1% TFA to provide the title compound. 1H NMR (499 MHz, CD3OD): δ 7.57-7.50 (m, 6H); 7.47-7.39 (m, 1H); 7.35 (d, J=8.0 Hz, 2H); 7.31 (d, J=8.2 Hz, 3H); 7.00-6.92 (m, 2H); 4.34 (d, J=11.7 Hz, 1H); 4.28 (dd, J=7.1, 4.3 Hz, 1H); 3.80 (s, 3H); 3.74-3.69 (m, 1H); 3.69-3.63 (m, 1H); 3.51 (dd, J=13.8, 7.1 Hz, 1H); 1.61-1.50 (m, 2H); 1.11-1.02 (m, 2H); 0.75 (t, J=7.3 Hz, 3H). LC1 1.27 min. [M+H]+ 546.
Using the chemistry described for the preparation of INTERMEDIATES 1-4 and EXAMPLES 1-7, the compounds in TABLES 1 and 2 were prepared as enantiopure compounds. The data listed is for the most active stereoisomer. Most compounds in TABLES 3 and 4 were also prepared as single stereoisomers, with the data listed being that for the most active stereoisomer. The only exceptions are examples 50, 51, 60, and 61, in which the compounds are a mixture of the two possible diastereomers at the stereocenter on the substituent labeled “Y” in the general structure. The R1 and R3 groups that are shown in TABLES 1 and 2 are specified when they represent a value other than a hydrogen atom. The remaining R1 and R3 groups that are unspecified are hydrogen atoms.







TABLE 1













 











Exam-






ple
R1
R2
R3
LC-MS Data














8
4-OCF3
n-Pr
4-F
LC1: 1.57 min.






(M + H) 568


9
3-F, 4-Cl
n-Pr
4-F
LC3: 3.73 min.






(M + H) 536


10
4-Cl
—CH2CH(CH3)2
4-F
LC3: 3.76 min.






(M + H) 532


11
4-Cl
n-Bu
4-F
LC3: 4.10 min.






(M + H) 532


12
4-Me
n-Pr
4-F
LC3: 3.68 min.






(M + H) 498









1H NMR (499 MHz, CDCl3): δ 8.26 (d, J = 8.7 Hz, 1 H);



7.99 (d, J = 8.3 Hz, 1 H); 7.60-7.52 (m, 1 H);



7.50 (d, J = 7.9 Hz, 2 H); 7.47-7.40 (m, 1 H);



7.37 (d, J = 7.7 Hz, 2 H); 7.24 (d, J = 8.2 Hz, 3 H); 



7.14-7.07 (m, 2 H); 7.00-6.93 (m, 1 H); 6.61 (s, 1 H); 



5.00 (d, J = 11.3 Hz, 1 H); 4.30-4.21 (m, 2 H);



3.69-3.62 (m, 1 H); 2.72-2.64 (m, 2 H); 2.31 (s, 3 H);



1.35 (m, 2 H); 0.97-0.87 (m, 2 H); 0.76 (t, J = 7.2 Hz, 3 H).











13
3,4-diCl
n-Pr
4-F
LC2: 2.76 min.






(M + H) 552


14
3-Cl, 4-CN
n-Pr
4-F
LC2: 2.23 min.






(M + H) 543


15
3,4-diCN
n-Pr
4-F
LC2: 2.21 min.






(M + H) 533


16
4-F
n-Pr
4-F
LC3: 3.78 min.






(M + H) 502


17
4-Cl
—CH2CH2CF3
4-F
LC2: 2.53 min.






(M + H) 572


18
2,4-diCl
n-Pr
4-F
LC1: 1.26 min.






(M + H) 552


19
2-Cl, 4-CN
n-Pr
4-F
LC1: 1.22 min.






(M + H) 543


20
4-Cl
n-Pr
2-Cl, 4-CN,
LC1: 1.59 min. 





5-F
(M + H) 576


21
4-Cl
n-Pr
4,7-diOMe
LC2: 2.28 min.






(M + H) 560









1H NMR (499 MHz, CD3OD): δ 8.16 (d, J = 9.2 Hz, 1 H);



7.73 (d, J = 8.1 Hz, 1 H); 7.63 (d, J = 7.9 Hz, 2 H);



7.48 (s, 1 H); 7.34 (d, J = 7.9 Hz, 2 H); 7.10 (d, J = 6.6



Hz, 2 H); 7.06 (d, J = 2.5 Hz, 1 H); 6.92 (d, J = 8.1 Hz,



2 H); 6.88 (d, J = 8.1 Hz, 1 H); 4.81 (d, J = 11.6 Hz,



1 H); 4.00 (s, 3 H); 3.92 (s, 3 H); 3.73-3.63 (m,



1 H); 3.63-3.57 (m, 2 H); 2.65-2.59 (m, 2 H); 



1.61 (d, J = 13.6 Hz, 2 H); 1.18-1.00 (m, 2 H); 



0.75 (t, J = 7.3 Hz, 3 H).











22
4-Cl
n-Pr
2,5-diOMe
LC2: 2.31 min.






(M + H) 560


23
4-Cl
n-Pr
4-Cl
LC3: 3.89 min.






(M + H) 534









1H NMR (500 MHz, CD3OD): δ 7.99 (s, 1 H); 7.60 



(dd, J = 8.4, 4.9 Hz, 2 H); 7.55 (dd, J = 8.3, 6.6 Hz, 4 H); 



7.48 (dd, J = 8.6, 1.7 Hz, 1 H); 7.45 (d, J = 7.4 Hz, 1 H);



7.35 (dd, J = 13.7, 8.1 Hz, 4 H); 7.28-7.22 (m, 1 H);



4.49 (d, J = 11.7 Hz, 1 H); 3.64-3.58 (m, 1 H);



3.54-3.48 (m, 2 H); 2.57-2.51 (m, 2 H); 1.65-1.58



(m, 2 H); 1.14-1.01 (m, 2 H); 0.76 (t, J = 7.2 Hz, 3 H).











24
4-Cl
n-Pr
5-Cl
LC2: 3.92 min.






(M + H) 534


25
4-Cl
n-Pr
5-F, 6-Me
LC1: 1.25 min.






(M + H) 532


26
4-Cl
n-Pr
5-F, 8-Me
LC1: 1.25 min.






(M + H) 532


27
4-Cl
n-Pr
5-CN, 6-Me
LC1: 1.26 min.






(M + H) 540


28
4-Cl
n-Pr
5-CN, 8-Me
LC1: 1.26 min.






(M + H) 540


29
4-Cl
n-Pr
2-Cl, 4-OH,
LC1: 1.27 min.





5-F
(M + H) 568


30
4-Cl
n-Pr
2-Cl, 4-OMe,
LC1: 1.30 min.





5-F
(M + H) 582


31
4-Cl
n-Pr
2-Cl, 4-OH
LC1: 1.21 min.






(M + H) 550


32
4-Cl
n-Pr
5,7-diMe
LC3: 4.15 min.






(M + H) 528
















TABLE 2













 











Example
R1
R2
R3
LC-MS Data





33
4-Cl
n-Pr
6,8-diMe
LC1: 2.47 min.






(M + H) 528


34
4-Cl
n-Pr
6-Me, 8-CN
LC1: 1.56 min.






(M + H) 539









1H NMR (499 MHz, CD3OD): δ 7.82 (s, 1 H); 7.70 (s, 1 H); 



7.68 (s, 1 H); 7.60 (d, J = 8.3 Hz, 1 H); 7.55 (dd,



J = 8.7, 2.7 Hz, 4 H); 7.52 (s, 1 H); 7.36 (dd, J = 14.9, 8.0 Hz,



4 H); 4.50 (d, J = 11.7 Hz, 1 H); 3.77-3.69 (m, 1 H); 3.54-3.48 



(m, 2 H); 2.55-2.50 (m, 2 H); 2.37 (s, 3 H); 1.61 (m, 2 H);



1.14-0.99 (m, 2 H); 0.76 (t, J = 7.3 Hz, 3 H).











35
4-Cl
n-Pr
6-OEt
LC1: 1.67 min.






(M + H) 544


36
4-Cl
n-Pr
6-SMe
LC2: 2.68 min.






(M + H) 546









1H NMR (499 MHz, CDCl3): δ 7.55-7.51 (m, 2 H); 7.47-7.40 



(m, 3 H); 7.39 (d, J = 8.1 Hz, 2 H); 7.31 (d, J = 8.3 Hz, 2 H);



7.28 (m, 3H); 7.23 (m, 2H); 6.67 (s, 1 H); 4.25 (d, J = 11.5 Hz,



1 H); 3.65 (dd, J = 11.7, 5.8 Hz, 2 H); 3.60-3.53 (m, 1 H);



2.61-2.56 (m, 2 H); 2.52 (s, 3 H); 1.26 (t, J = 7.1 Hz,



2 H); 1.09-1.01 (m, 2 H); 0.77 (t, J = 7.3 Hz, 3 H).











37
4-Cl
n-Pr
6-SO2CH3
LC2: 2.45 min.






(M + H) 578


38
4-Cl
n-Pr
6-Me
LC1: 1.25 min.






(M + H) 514


39
4-Cl
n-Pr
5-CN, 6-OMe
LC1: 0.48 min.






(M + H) 555


40
4-Cl
n-Pr
4-F, 6-OMe
LC1: 1.25 min.






(M + H) 549


41
4-Cl
n-Pr
4-F, 6-CN
LC1: 2.31 min.






(M + H) 543


42
4-Cl
n-Pr
5-F, 6-Me
LC1: 1.30 min.






(M + H) 532


43
4-Cl
n-Pr
5-CN, 8-Me
LC1: 1.21 min.






(M + H) 539


44
4-Cl
n-Pr
5-CN, 6-Me
LC1: 1.21 min.






(M + H) 539


45
4-Cl
n-Pr
1-F
LC1: 1.29 min.






(M + H) 518


46
4-Cl
n-Pr
6-Me, 8-F
LC1: 1.31 min.






(M + H) 532


47
4-Cl
n-Pr
1-OH, 3-Cl
LC1: 1.21 min.






(M + H) 550


48
4-OMe
n-Pr
6-MeO
LC1: 1.23 min






(M + H) 526
















TABLE 3













 











EXAMPLE
Y
LC-MS data







49




LC1: 1.27 min. (M + H) 534



 











1H NMR (499 MHz, CD3OD): δ 8.39




(d, J = 8.8 Hz, 1 H); 7.91 (d, J = 8.4 Hz,




1 H); 7.69 (dd, J = 8.2, 5.6 Hz, 1 H); 




7.57 (d, J = 8.2 Hz, 2 H); 7.52 (d, J =




7.7 Hz, 2 H); 7.43 (t, J = 7.7 Hz, 1 H); 7.38




(d, J = 7.9 Hz, 3 H); 7.31-7.24 (m, 2 H);




6.98 (dd, J = 10.4, 8.1 Hz, 1 H); 




5.17 (d, J = 11.5 Hz, 1 H); 




4.27 (dd, J = 6.9, 4.4 Hz, 1 H);




3.77-3.70 (m, 1 H); 3.70-3.56




(m, 1 H); 3.51 (dd, J = 13.8, 7.1 Hz,




1 H); 1.68-1.55 (m, 2 H); 1.10-0.99




(m, 2 H); 0.75 (t, J = 7.3 Hz, 3 H).



 











50




LC1: 1.31 min. (M + H) 532



 



51




LC1: 1.25 min. (M + H) 532



 



52




LC2: 2.42 min. (M + H) 554



 



53




LC1: 1.26 min. (M + H) 554



 



54




LC1: 1.21 min. (M + H) 540



 











1H NMR (500 MHz, CD3OD): δ 8.40 




(d, J = 8.7 Hz, 1 H); 7.91 (d, J = 8.3 Hz,




1 H); 7.70 (dd, J = 8.2, 5.3 Hz, 1 H); 




7.60 (d, J = 8.1 Hz, 4 H); 7.58-7.52 (m, 1 H);




7.44 (t, J = 7.7 Hz, 1 H); 7.40 (d, J = 7.8 Hz,




2 H); 7.29 (d, J = 8.2 Hz, 2 H); 




7.00 (dd, J = 10.4, 8.1 Hz, 1 H);




5.19 (d, J = 11.5 Hz, 1 H); 4.42 (s, 2 H);




3.80-3.72 (m, 1 H); 1.68-1.56 (m, 2 H);




(m, 2 H); 0.76 (t, J = 7.2 Hz, 3 H).



 











55




LC1: 1.21 min. (M + H) 528



 



56




LC1: 1.23 min. (M + H) 514



 



57




LC2: 1.83 min. (M + H) 517



 



58




LC1: 1.28 min. (M + H) 503



 



59




LC2: 3.22 min. (M + H) 504



 











1H NMR (499 MHz, CD3OD): δ 8.39




(d, J = 8.7 Hz, 1 H); 7.91 (d, J = 8.3 Hz,




1 H); 7.72-7.67 (m, 1 H); 7.59 (d,




J = 8.2 Hz, 2 H); 7.54 (t, J = 8.2 Hz,




3 H); 7.43 (t, J = 7.6 Hz, 1 H);




7.39 (d, J = 7.9 Hz, 2 H); 7.28




(d, J = 8.2 Hz, 2 H); 7.01-6.95 (m, 1 H);




5.18 (d, J = 11.5 Hz, 1 H); 3.95 (s, 2 H);




3.79-3.71 (m, 1 H); 1.67-1.56 (m, 2 H);




0.92-0.88 (m, 2 H); 0.79-0.72 (m, 3 H).

















TABLE 4













 









EXAMPLE
Y
LC-MS data





60




LC1: 1.33 min. (M + H) 544


 


61




LC1: 1.33 min. (M + H) 544


 


62




LC3: 3.28 min. (M + H) 515


 









1H NMR (499 MHz, CD3OD): δ 7.61 (d,



J = 8.0 Hz, 2 H); 7.54 (d, J = 8.0 Hz, 2 H);



7.52 (d, J = 8.0 Hz, 2 H); 7.44 (d, J = 9.0 Hz, 1 H);



7.37 (d, J = 8.5 Hz, 2 H); 7.32 (m, 3 H);



6.99 (s, 1 H); 6.96 (dd, J = 9.0, 2.5 Hz, 1 H); 



4.36 (d, J = 11.5 Hz, 1 H); 3.91 (s, 2 H);



3.80 (s, 3 H); 3.72 (m, 1 H); 1.32 (m, 2 H);



1.10-1.03 (m, 2 H); 0.76 (t, J = 7.2 Hz, 3 H).









EXAMPLE 63
N-(4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoyl)-β-alanine




Step A. tert-butyl 4-{(1R)-1-[(4-fluoro-1-naphthyl)(hydroxy)(4-methoxyphenyl)methyl]butyl}benzoate




To a solution of 1-bromo-4-fluoronaphthalene (229 mg, 1.02 mmol) in THF (6 mL) at −78° C. was added BuLi (2.5 M in hexanes, 0.434 mL, 1.086 mmol), then the solution was stirred for one hour. A solution of t-butyl (R)-4-[2-(4-methoxyphenyl)-1-propylethan-2-one-1-yl]benzoate (prepared using the procedure for INTERMEDIATE 4, 250 mg, 0.678 mmol) in THF (2 mL) was added and the solution was stirred for an additional hour. The solution was quenched with saturated NH4Cl (aq), then diluted with EtOAc (50 mL). The organic layer was separated, washed with water then brine, dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound. LC1 1.30 min. [M+H−H2O]+ 497.
Step B. 4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoic acid




Boron trifluoride diethyl etherate (0.074 mL, 0.583 mmol) was added dropwise to a solution of tert-butyl 4-{(1R)-1-[(4-fluoro-1-naphthyl)(hydroxy)(4-methoxyphenyl)methyl]butyl}benzoate (150 mg, 0.291 mmol) in DCM (2 mL) at 0° C. The solution was allowed to warm to RT and stirred overnight. The solution was diluted with EtOAc (30 mL) then washed with water and brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used directly in the next step without further purification. LC1 1.20 min. [M+H]+ 442.
Step C. Ethyl N-(4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoyl)-β-alaninate




To a solution of 4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoic acid in THF (5 mL) was added CDI (150 mg, 0.925 mmol) After stirring at room temperature for 30 minutes, β-alanine ethyl ester hydrochloride (150 mg, 0.977 mmol) was added, then the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc then washed with water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by preparative reverse phase HPLC eluting with acetonitrile/water+0.1% TFA to afford the two diastereomers of the title compound.
Faster-eluting diastereomer: 1H NMR (499 MHz, CDCl3): δ 8.23 (d, J=8.7 Hz, 1H); 8.01 (d, J=8.7 Hz, 1H); 7.54 (m, 6H); 7.40 (d, J=7.9 Hz, 2H); 7.20 (d, J=7.9 Hz, 2H); 6.97 (t, J=9.3 Hz, 1H); 6.84 (d, J=7.9 Hz, 2H); 4.97 (d, J=11.2 Hz, 1H); 4.15 (q, J=7.2 Hz, 2H); 3.76 (s, 3H); 3.67-3.55 (m, 3H); 2.58 (t, J=5.8 Hz, 2H); 1.30-1.22 (m, 5H); 1.05 (m, 2H); 0.76 (t, J=7.3 Hz, 3H). LC1 1.33 min. [M+H]+ 542.
Slower-eluting diastereomer: 1H NMR (500 MHz, CDCl3): δ 8.26 (d, J=8.6 Hz, 1H); 8.13 (d, J=8.2 Hz, 1H); 7.63 (dd, J=8.1, 5.2 Hz, 1H); 7.58 (d, J=7.8 Hz, 2H); 7.57-7.49 (m, 1H); 7.43 (d, J=8.2 Hz, 4H); 7.27-7.21 (m, 2H); 7.23-7.04 (m, 1H); 6.95 (d, J=8.4 Hz, 1H); 6.52 (d, J=8.5 Hz, 1H); 4.86 (d, J=11.3 Hz, 1H); 4.19 (q, J=7.1 Hz, 2H); 3.84-3.77 (m, 1H); 3.76 (s, 3H); 3.77-3.39 (m, 2H); 2.70-2.63 (m, 2H); 1.48-1.71 (m, 2H); 1.23 (t, J=7.3 Hz, 3H); 1.10 (m, 2H); 0.76- (t, J=7.2 Hz, 3H). LC1 1.33 min. [M+H]+ 542.
Step D. N-(4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoyl)-β-alanine




To a solution of ethyl N-(4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoyl)-β-alaninate (slower-eluting diastereomer, 10 mg, 0.018 mmol) in ethanol (2 mL) was added LiOH (2.0 N in water, 0.5 mL, 1.0 mmol), then the reaction mixture was stirred for one hour. The mixture was diluted with DCM (20 mL) acidified with 2.0 N HCl (aq). The organic layer was dried over MgSO4, concentrated, then the residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to afford the title compound. 1H NMR (499 MHz, CDCl3): δ 8.27 (d, J=8.5 Hz, 1H); 8.13 (d, J=8.2 Hz, 1H); 7.67-7.49 (m, 5H); 7.20 (m, 3H); 6.95 (dd, J=8.3, 2.5 Hz, 2H); 6.76 (m, 1H); 6.51 (d, J=8.3 Hz, 2H); 4.86 (d, J=11.3 Hz, 1H); 3.76 (m, 2H); 3.60 (s, 3H); 3.58 (m, 1H); 2.65 (t, J=5.8 Hz, 2H); 1.70 (m, 2H); 1.07 (m, 2H); 0.76 (t, J=7.2 Hz, 3H). LC1 1.19 min. [M+]+ 514.
EXAMPLE 64
N-(4-{(1S)-1-[(4-chlorophenyl)(1-naphthyl)methyl]butyl}benzoyl)-β-alanine




Using the procedures from EXAMPLE 63, 1-bromonaphthalene and INTERMEDIATE 4 were converted to the title compound. 1H NMR (499 MHz, CD3OD): δ 8.35 (d, J=8.7 Hz, 1H); 7.72 (d, J=7.4 Hz, 1H); 7.66 (d, J=8.2 Hz, 1H); 7.58 (t, J=9.6 Hz, 2H); 7.52-7.41 (m, 4H); 7.38 (d, J=8.0 Hz, 2H); 7.36-7.29 (m, 1H); 7.31-7.24 (m, 3H); 5.22 (d, J=11.5 Hz, 1H); 3.80-3.74 (m, 1H); 3.52-3.46 (m, 2H); 2.55-2.49 (m, 2H); 1.65-1.56 (m, 2H); 1.10-1.00 (m, 2H); 0.77 (t, J=7.2 Hz, 3H). LC1 1.54 min. [M+H]+ 500.
EXAMPLE 65
N-(4-{(1S)-1-[(4-bromo-1-naphthyl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alanine




Using the procedures from EXAMPLE 63, 1,4-dibromonaphthalene and INTERMEDIATE 4 were converted to the title compound. 1H NMR (499 MHz, CDCl3): δ 8.32 (d, J=8.0 Hz, 1H); 8.26 (d, J=8.0 Hz, 1H); 7.89 (d, J=7.8 Hz, 1H); 7.65-7.54 (m, 5H); 7.22 (d, J=7.9 Hz, 2H), 7.02 (m, 4H); 6.81 (t, J=6.2 Hz, 1H); 4.94 (d, J=11.3 Hz, 1H); 3.75 (m, 2H); 3.57 (t, J=11.4 Hz, 1H); 2.74 (t, J=5.8 Hz, 2H); 1.53-1.78 (m, 2H); 1.08-1.01 (m, 2H); 0.72 (t, J=7.3 Hz, 3H). LC1 1.34 min. [M+H]+ 580.
BIOLOGICAL ASSAYS
The ability of the compounds of the present invention to inhibit the binding of glucagon and their utility in treating or preventing type 2 diabetes mellitus and the related conditions can be demonstrated by the following in vitro assays.
Glucagon Receptor Binding Assay
A stable CHO (Chinese hamster ovary) cell line expressing cloned human glucagon receptor was maintained as described (Chicchi, et. al. J Biol Chem 272, 7765-9 (1997); Cascieri, et. al. J Biol Chem 274, 8694-7 (1999)). To determine antagonistic binding affinity of compounds, 0.001-0.003 mg of cell membranes from these cells were pre-incubated with 0.100 mg WGA-coated PVT SPA beads (Amersham) for 20 minutes at room temperature in 25 μL of a buffer containing 50 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 2 mM EDTA, 0.1% BSA and 3% glycerol in Costar 384 well plates with clear bottoms (#3706). Next, 25 μL of 125I-Glucagon (New England Nuclear, Mass.) (1×10−14 mol per well) and either 1 μL solutions of test compounds or 0.001 mM unlabeled glucagon or DMSO were added and mixed. After 4-12 hours incubation at room temperature, the radioactivity bound to the cell membranes was determined in a radioactive emission detection counter (Wallac-Microbeta). Data were analyzed using the Data Analyzer software program of Merck & Co., Inc. The IC50 values were calculated using non-linear regression analysis assuming single-site competition. IC50 values for the compounds of the invention are generally in the range of as low as about 1 nM to as high as about 500 nM, and thus have utility as glucagon antagonists. The IC50 values are shown below in TABLE 5 for the more active isomer of indicated compounds.










TABLE 5







Example
IC50 (nM)



















1
3.3



2
0.85



3
0.37



4
1.5



5
2.1



7
1.7



12
4.3



21
14.2



23
1.8



30
53



36
0.83



37
2.9



52
98



53
3.4



55
4.0



56
7.6










Inhibition of Glucagon-Stimulated Intracellular cAMP Formation

Exponentially growing CHO cells expressing human glucagon receptor were harvested with the aid of enzyme-free dissociation media (Specialty Media), pelleted at low speed, and re-suspended in the Cell Stimulation Buffer included in the Flash Plate cAMP kit (New England Nuclear, SMP0004A). The adenylate cyclase assay was conducted as per manufacturer instructions. Briefly, compounds were diluted from stocks in DMSO and added to cells at a final DMSO concentration of 5%. Cells prepared as above were preincubated in flash plates coated with anti-cAMP antibodies (NEN) in the presence of compounds or DMSO controls for 30 minutes, then stimulated with glucagon (250 pM) for an additional 30 minutes. The cell stimulation was stopped by addition of equal amounts of a detection buffer containing lysis buffer as well as 125I-labeled cAMP tracer (NEN). After 3 hours of incubation at room temperature the bound radioactivity was determined in a liquid scintillation counter (TopCount-Packard Instruments). Basal activity (100% inhibition) was determined using the DMSO control while 0% inhibition was defined at the amount of pmol cAMP produced by 250 pM glucagon. The resulting amount of cAMP generated per compound dose was back-calculated from a cAMP standard curve based on the percent inhibition achieved at each dose. The calculated cAMP levels were plotted versus compound dose to obtain IC50 values using non-linear four-parameter curve fitting with Assay Data Analyzer software (Merck & Co., Inc.).
Certain embodiments of the invention have been described in detail; however, numerous other embodiments are contemplated as falling within the invention. Thus, the claims are not limited to the specific embodiments described herein. All patents, patent applications and publications that are cited herein are hereby incorporated by reference in their entirety.

## Claims

1. A compound represented by formula I:




or a pharmaceutically acceptable salt thereof wherein:
each R1 represents H or is selected from the group consisting of halo, CN, OH, NO2, CO2Ra, NRaRb, S(O)pRa, C1-10alkyl, C2-10alkenyl or C1-10alkoxy, the alkyl and alkenyl portions of, C1-10alkyl, C2-10alkenyl and C1-10alkoxy being optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
p represents 0, 1 or 2;
each Ra and Rb independently represents H or C1-4alkyl optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
R2 represents C1-6alkyl or C2-6alkenyl, each optionally substituted with 1-5 halo atoms up to perhalo, and further optionally substituted with 1 group selected from OH, oxo and C1-6alkoxy;
R3 represents H or is selected from the group consisting of halo, CN, OH, NO2, CO2Ra, NRaRb, S(O)pRa, C1-10alkyl, C2-10alkenyl and C1-10alkoxy, the alkyl and alkenyl portions of, C1-10alkyl, C2-10alkenyl and C1-10alkoxy being optionally substituted with 1-5 halo atoms up to perhalo; and further optionally substituted with 1 group selected from OH, oxo, NRaRb, and C1-6alkoxy;
each R4 independently represents H or is selected from the group consisting of halo, OH, C1-4alkyl, OC1-4alkyl, haloC1-4alkyl and haloOC1-4alkyl;
m represents 0, 1 or 2; when m represents 0, Z represents tetrazolyl;

when m represents 1, Z represents a member selected from the group consisting of CO2H, SO3H, C(O)NH2 and tetrazolyl; and when m represents 2, Z represents a member selected from the group consisting of CO2H, SO3H and C(O)NH2.

2. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R1 represents H or is selected from the group consisting of halo, CN, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy.

3. A compound in accordance with claim 2 or a pharmaceutically acceptable salt thereof wherein each R1 represents H or is selected from the group consisting of: halo selected from fluoro and, chloro; CN, CH3; OCH3; CF3; and OCF3.

4. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein R2 represents a member selected from the group consisting of: C1-4alkyl and C3-4alkyenyl, each optionally substituted with 1-3 halo atoms.

5. A compound in accordance with claim 4 or a pharmaceutically acceptable salt thereof wherein R2 represents C2-4alkyl optionally substituted with 1-3 halo atoms.

6. A compound in accordance with claim 5 or a pharmaceutically acceptable salt thereof wherein R2 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, each optionally substituted with 1-3 halo atoms selected from fluoro and chloro.

7. A compound in accordance with claim 6 or a pharmaceutically acceptable salt thereof wherein R2 is selected from the group consisting of n-propyl, n-butyl, CH2CH(CH3)2 and CH2CH2CF3.

8. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R3 represents H or is selected from the group consisting of halo, CN, OH, SCH3, SO2CH3, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy.

9. A compound in accordance with claim 8 or a pharmaceutically acceptable salt thereof wherein each R3 represents H or is selected from the group consisting of halo which is selected from F, Cl and Br, CN, OH, SCH3, SO2CH3, C1-2alkyl, C1-2alkoxy, haloC1-2alkyl and haloC1-2alkoxy wherein the halo portion of haloC1-2alkyl and haloC1-2alkoxy is selected from F and Cl.

10. A compound in accordance with claim 9 or a pharmaceutically acceptable salt thereof wherein each R3 represents H, F, Cl, Br, CN, OH, CH3, OCH3, OCH2CH3, CHF2, CF3, SCH3, SO2CH3, OCHF2, and OCF3.

11. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R4 represents H, halo selected from F and Cl, OH, C1-2alkyl, C1-2alkoxy, haloC1-2alkyl and haloC1-2alkoxy wherein the halo portion of haloC1-2alkyl and haloC1-2alkoxy is selected from F and Cl.

12. A compound in accordance with claim 11 or a pharmaceutically acceptable salt thereof wherein each R4 represents H, F, Cl, OH, CH3, OCH3, CF3, and OCF3.

13. A compound in accordance with claim 12 or a pharmaceutically acceptable salt thereof wherein each R4 represents H, F, CH3 or OH.

14. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein m represents 0 and Z represents tetrazolyl.

15. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein m is 2 and Z represents CO2H.

16. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein:
each R1 represents H or is selected from the group consisting of halo, CN, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy;
R2 represents a member selected from the group consisting of: C1-4-alkyl and C3-4alkyenyl, each optionally substituted with 1-3 halo atoms;
each R3 represents H or is selected from the group consisting of halo, CN, OH, C1-6alkyl, SCH3, SO2CH3, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy;
each R4 represents H, halo selected from F and Cl, OH, C1-2alkyl, C1-2alkoxy, haloC1-2alkyl and haloC1-2alkoxy wherein the halo portion of haloC1-2alkyl and haloC1-2alkoxy is selected from F and Cl;
m is 0 and Z is tetrazolyl, or m is 2 and Z represents CO2H.

17. A compound in accordance with claim 1 selected from the group consisting of:














TABLE 1













 










Example 
R1
R2
R3





 8
4-OCF3
n-Pr
4-F


 9
3-F, 4-Cl
n-Pr
4-F


10
4-Cl
—CH2CH(CH3)2
4-F


11
4-Cl
n-Bu
4-F


12
4-Me
n-Pr
4-F


13
3,4-diCl
n-Pr
4-F


14
3-Cl, 4-CN
n-Pr
4-F


15
3,4-diCN
n-Pr
4-F


16
4-F
n-Pr
4-F


17
4-Cl
—CH2CH2CF3
4-F


18
2,4-diCl
n-Pr
4-F


19
2-Cl, 4-CN
n-Pr
4-F


20
4-Cl
n-Pr
2-Cl, 4-CN, 5-F


21
4-Cl
n-Pr
4,7-diOMe


22
4-Cl
n-Pr
2,5-diOMe


23
4-Cl
n-Pr
4-Cl


24
4-Cl
n-Pr
5-Cl


25
4-Cl
n-Pr
5-F, 6-Me


26
4-Cl
n-Pr
5-F, 8-Me


27
4-Cl
n-Pr
5-CN, 6-Me


28
4-Cl
n-Pr
5-CN, 8-Me


29
4-Cl
n-Pr
2-Cl, 4-OH, 5-F


30
4-Cl
n-Pr
2-Cl, 4-OMe, 5-F


31
4-Cl
n-Pr
2-Cl, 4-OH


32
4-Cl
n-Pr
5,7-diMe
















TABLE 2













 










Example
R1
R2
R3





33
4-Cl
n-Pr
6,8-diMe


34
4-Cl
n-Pr
6-Me, 8-CN


35
4-Cl
n-Pr
6-OEt


36
4-Cl
n-Pr
6-SMe


37
4-Cl
n-Pr
6-SO2CH3


38
4-Cl
n-Pr
6-Me


39
4-Cl
n-Pr
5-CN, 6-OMe


40
4-Cl
n-Pr
4-F, 6-OMe


41
4-Cl
n-Pr
4-F, 6-CN


42
4-Cl
n-Pr
5-F, 6-Me


43
4-Cl
n-Pr
5-CN, 8-Me


44
4-Cl
n-Pr
5-CN, 6-Me


45
4-Cl
n-Pr
1-F


46
4-Cl
n-Pr
6-Me, 8-F


47
4-Cl
n-Pr
1-OH, 3-Cl


48
4-OMe
n-Pr
6-MeO
















TABLE 3













 










EXAMPLE
Y







49







 



50







 



51







 



52







 



53







 



54







 



55







 



56







 



57







 



58







 



59





















TABLE 4













 








EXAMPLE
Y





60






 


61






 


62









Example
Compound





63






 


64






 


65













or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

19. A pharmaceutical composition in accordance with claim 18 further comprised of a member selected from the group consisting of: simvastatin, mevastatin, ezetimibe, atorvastatin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, losartan, hydrochlorothiazide, buformin, phenformin, troglitazone, pioglitazone, rosiglitazone, insulin, somatostatin, voglibose, miglitol, acarbose, sitagliptin, vildagliptin, saxagliptin, alogliptin, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide, repaglinide, rimonabant and taranabant.

20. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in an amount that is effective to treat said type 2 diabetes mellitus.