Malonamic acids and derivatives thereof as thyroid receptor ligands

专利摘要:
The present invention relates to a novel thyroid receptor ligand, and more particularly to a novel thyroid receptor ligand which is useful for the treatment of obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, thyroid cancer, Which is useful for treating diabetes, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis. Formula I In this formula, All substituents are as defined in claim 1 of the claims. The present invention also provides a method, a pharmaceutical composition and a kit for treating the above diseases and disorders.
公开号:KR20020089420A
申请号:KR1020027013044
申请日:2001-03-07
公开日:2002-11-29
发明作者:아스프네스게리에릭；치앙유안-칭포비；에스텝킴벌리게일
申请人:화이자 프로덕츠 인코포레이티드；
IPC主号:

专利说明:

[0001] MALONAMIC ACIDS AND DERIVATIVES THEREOF AS THYROID RECEPTOR LIGANDS AS THYROID RECEPTOR LIGANDS [0002]
[2] Thyroid hormones are important for normal progression and maintenance of metabolic homeostasis. For example, thyroid hormone promotes the metabolism of cholesterol into bile acids and promotes the lipolysis of adipocytes against other hormones.
[3] In addition, thyroid hormones directly and indirectly affect cardiac function, for example by increasing the metabolic rate. For example, tachycardia, increased output, increased cardiac output, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure are observed in patients with hyperthyroidism.
[4] Thyroid disorders are usually treated by administering a naturally occurring thyroid hormone, or an analog that mimics the effect of the thyroid gland. Such analogs are referred to as thyroid-like drugs or thyroid receptor ligands.
[5] Two types of naturally occurring thyroid hormones, 3,5,3 ', 5'-tetraiodo-L-thyronine (also referred to as "T ₄ " or thyroxine) and 3,5,3'- -L-Thyronine (also " T ₃ ") is shown below:
[6]
[7] T ₃ is more biologically active than T _4, 5 'to the position in that iodine differs from T _4. T ₃ can be produced directly in the thyroid or peripheral tissues by removing iodine at the 5 'position of T ₄ by deiodinase enzyme. The thyroid receptor ligand can be designed to be structurally similar to T ₃ . In addition, naturally occurring metabolites of T ₃ are known.
[8] As discussed above, thyroid hormones affect cardiac function, for example by increasing heart rate and increasing consumption of oxygen. Increasing the consumption of oxygen may cause additional adverse effects in some situations by adding additional burden to the heart, despite causing certain desirable metabolic effects. Therefore, as described in AH Underwood et al., Nature , 324 , 425-429, 1986, thyroid hormone analogs functioning to lower lipid and serum cholesterol without causing the adverse effects of the above-mentioned heart are synthesized Efforts have been made to
[9] U.S. Patent No. 4,766,121; 4,826,876; 4,910, 305; And 5,061,798 disclose thyroid hormone analogues, namely 3,5-dibromo-3 '- [6-oxo-3 (1H) -pyridazinylmethyl] -thyronine.
[10] U.S. Patent No. 5,284,971 discloses a cholesterol lowering agent of the thyroid-like drug, namely 4- (3-cyclohexyl-4-hydroxy or -methoxyphenylsulfonyl) -3,5-dibromo-phenylacetic acid compound .
[11] U.S. Patent No. 5,401,772 (also published European Patent Application No. 0 580 550); 5,654,468; And the 5,569,674 discloses depressant certain lipids to compete with the T ₃ the cover in the binding analysis with a radioactive isotope using nuclear and plasma membrane preparations liver of rat (rat), i.e., the heteroaryl acetic acid derivatives, more specifically are octanoic acid derivatives Lt; / RTI >
[12] Certain oxo acids and their derivatives are known in the art, for example, U.S. Patent No. 4,069,343 discloses the use of certain oxo acids to prevent immediate type of hypersensitivity reactions; U.S. Patent No. 4,554,290 describes the use of specific oxalic acids to control pest for animals and plants; U.S. Pat. No. 5,232,947 discloses the use of certain oxalic acids to improve damaged cerebral function in the brain.
[13] In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. See, for example, N. Yokoyama et al., Journal of Medicinal Chemistry , 38 (4) , 695-707, 1995 ) discloses a method for producing -HNCOCO ₂ H by replacing a -CH ₂ group with an -NH group in a naturally occurring metabolite of T ₃ . In addition, an unfavorable heart has been described in RE Steele et al., International Congressional Service ( Atherosclerosis X ), 106 , 321-324, 1995 and ZF Stephan et al., Atherosclerosis , 126 , 53-63, Lt; RTI ID = 0.0 > lipid-lowering thyrotropic < / RTI >
[14] The commonly assigned International Patent Publication No. WO 00/51971, published September 8, 200 and the commonly assigned European Patent EP 1 033 364, published September 6, 2000, disclose a thyroid receptor ligand Specific oxo acids and derivatives thereof are disclosed. A commonly assigned US Non-Application Ser. No. 09/671668, filed on September 27, 1999, discloses certain 6-azauracil derivatives as thyroid receptor ligands. U.S. Provisional Application Serial No. 60 / 177,987, filed January 25, 2000, discloses certain tetrazole compounds as thyroid receptor ligands.
[15] DMT Chan et al., Tetrahedron Letters , 39 , 2933-2936, 1998 discloses novel N- and O-arylation reactions involving phenyl boronic acid and copper acetate.
[16] International Patent Publication No. WO 00/58279, published October 5, 2000, discloses glucocorticoids and thyroid hormone receptor ligands for the treatment of metabolic disorders.
[17] International Patent Publication No. WO 00/39077, published July 6, 2000, discloses novel thyroid receptor ligands.
[18] AH Taylor et al., &Quot; Beneficial Effect of a Novel Thyromimetic on Lipoprotein Metabolism ", Molecular Pharmacology , 52 , 542-547, 1997 discloses the beneficial effect of a novel thyroid-like drug on lipoprotein metabolism.
[19] Thienonine related to L-thyronine is described in JL Stanton et al., "Synthesis and Biological Activity of Phenoxyphenyl Oxamic Acid Derivatives Related to L-Thyronine", Bioorganic & Medicinal Chemistry Letters , 10 , 1661-1663, The synthesis and biological activity of the oxalic acid derivatives are disclosed.
[20] WO 00/72810, published December 7, 2000, discloses a method of treating alopecia using certain sulfonyl thyroid analogues. WO 00/72811, published December 7, 2000, discloses a method of treating alopecia using certain compounds described herein. International Patent Publication No. WO 00/72812, published on December 7, 2000, discloses a method of treating alopecia using certain diphenyl ether derivatives. International Patent Publication No. WO 00/72813, published December 7, 2000, discloses a method of treating alopecia using a specific diphenylmethane derivative. International Patent Publication No. WO 00/72920, published December 7, 2000, discloses certain substituted biaryl ether compounds and compositions for treating alopecia. International Patent Publication No. WO 00/73292, published December 7, 2000, discloses certain biaryl compounds and compositions for treating alopecia.
[21] Obesity is a major health risk factor that increases the mortality and rate of invention of type 2 diabetes, hypertension and dyslipidemia. In the United States, over 50% of the adult population is overweight and about one-quarter of the adult population is considered obesity (BMI 30 or greater). The incidence of obesity is increasing at an annual rate of 3% cumulative in the United States. Most of these massive obesity occur in the United States and Europe, and the prevalence of obesity is also rising in Japan. The adult prevalence rate is 10 to 25% in most countries in Western Europe.
[22] Obesity is a devastating disease. In addition to compromising physical health, obesity can harm mental health because it affects self-esteem and ultimately affects individuals' ability to interact socially with others. Unfortunately, obesity is poorly understood and social myths and estimates, which are considered to be only obesity, tend to exacerbate the psychological effects of the disease. Due to the impact of obesity on individuals and society, much effort has been made to find a way to treat obesity, but no achievement in the long-term treatment and / or prevention of obesity has been achieved. The present invention provides a method of treating obesity by administering a therapeutically effective amount of the thyroid-like drug of the present invention to an obesity patient or a patient at risk of obesity.
[23] The thyroid-like drug of the present invention may also be used for the treatment of diabetes, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmia, congestive heart failure and osteoporosis Lt; / RTI >
[24] Despite the recent discovery and use of sulfonylureas, biguanides, and thiazolidinediones such as rosiglitazone or pioglitazone as an oral insulin hypoglycemic agent, and the widespread use in the early detection and subsequent treatment of diabetes mellitus, the treatment of diabetes Still not satisfied.
[25] Excess doses of insulin cause hypoglycaemia, which affects mild to moderate blood glucose levels to coma or even death. Non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) is generally treated by the combination of diet, exercise, oral hypoglycemic agents such as thiazolidinediones, and, in more severe cases, insulin. However, clinically available hypoglycemic agents may have side effects that limit their use, or the hypoglycemic agents may be ineffective in certain patients. In the case of insulin-dependent diabetes mellitus (type I) It is a trend of treatment. An effective hypoglycemic agent is also needed if the side effects are less or other hypoglycemic agents are not effective.
[26] Atherosclerosis, an arterial disease, is recognized as the leading cause of death in the United States and Europe. A pathological chain reaction that causes atherosclerosis and obstructive heart disease is well known. The earliest stage of this chain action is the formation of " local ancestors " in the corticoids, coronary arteries, cerebral arteries and the aorta. This disorder is yellow due to the finding of lipid deposits in smooth muscle cells and macrophages of the intimal layer of arteries and aorta. In addition, most of the cholesterol found in the local ancestors is composed of lipid-rich accumulated endothelial smooth muscle cells and causes the development of "fibrous plaques" surrounded by extracellular lipids, collagen, elastin and proteoglycans Is assumed. Cells and matrices form fibrous caps that cover debris and deeper deposition of extracellular lipids. Lipids are mainly free and esterified cholesterol. Fibrous plaques are slowly formed and soon become calcified and become gangrenous and progress to a "complex disorder," which causes a tendency for arterial muscle spasms characterized by arteriosclerosis and wall thrombosis and progressive atherosclerosis.
[27] Epidemiologic evidence has firmly demonstrated hyperlipidemia as a major risk factor for cardiovascular disease (CVD) due to atherosclerosis. In recent years, medical profession leaders have re-discussed the importance of lowering plasma cholesterol levels and LDL cholesterol, especially as an essential step in preventing CVD. The upper limit of " normal " is known to be significantly lower than currently known. As a result, the population of many western regions is now particularly at high risk. These independent risk factors include myitability, left ventricular hypertrophy, hypertension, and men of man. Mounting vascular disease is particularly prevalent among diabetics, in part because of the combined presence of independent risk factors in the population. Thus, the successful treatment of hyperlipidemia in general population and diabetic patients is exceptionally medically important.
[28] Hypertension is a secondary symptom in the human population that causes various other disorders such as renal artery stenosis, chromium cell-mediated tumor or endocrine disorders. However, hypertension is also evidenced in numerous patients with known pathogens or disorders. While this " essential " hypertension is associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been elucidated. In addition, numerous patients exhibit hypertensive symptoms in the absence of any other indication of disease or disorder.
[29] Hypertension can directly cause heart failure and renal failure and stroke (cerebral hemorrhage). Such symptoms can lead to death of the patient. In addition, hypertension can contribute to the development of atherosclerosis and coronary artery disease. These symptoms can gradually weaken the patient and lead to death.
[30] The exact cause of essential hypertension is not known, although a number of factors are believed to contribute to the onset of the disease. These factors include stress, non-suppressed emotions, non-regulated hormone release (renin, angiotensin and aldosterone systems), excessive salt and water due to renal insufficiency, wall growth and hypertrophy of the vasculature that constricts blood vessels, There are factors.
[31] Treatment of essential hypertension was undertaken with the above factors in mind. Therefore, a wide range of beta-blockers, vasoconstrictor agents, and angiotensin converting enzyme inhibitors have been developed and marketed as antihypertensive agents. It has been demonstrated that the treatment of hypertension using these compounds is beneficial in preventing common deaths such as heart failure, renal failure and cerebral hemorrhage.
[32] Hypertension is associated with an increase in blood insulin levels, such as those known as hyperinsulinemia. In addition, insulin, a peptide hormone whose main action promotes glucose utilization, protein synthesis and formation and storage of neutral lipids, promotes vascular cell growth and promotes renal sodium retention. This latter function can be performed without affecting the glucose level and is known to be the cause of hypertension. For example, peripheral vasculature growth can constrict peripheral capillaries while sodium retention increases blood volume. Thus, a decrease in insulin levels in hyperinsulinemia may alleviate hypertension by preventing abnormal blood vessel growth and sodium retention caused by high levels of insulin.
[33] Alopecia is a common problem that is often promoted chemically, for example, due to congenital action, or due to the use of certain therapeutic drugs designed to alleviate symptoms such as cancer. The alopecia are often caused by a lack of regrowth of hair causing partial or complete baldness.
[34] As is well known in the art, hair growth occurs by an activity cycle involving a crossing period of growth and rest. This cycle is mainly divided into three major stages known as anagen, catagen and telogen. Anagen is a growth phase of the cycle and can be characterized by deep penetration into the dermis with rapid cell proliferation in which hair follicles differentiate and form hair. The next step is the catagen, a metastatic stage characterized by the arrest of cell division and regression of the hair follicle through the dermis and the stop of hair growth. The next step, telogen, is characterized by a dormant phase, while the degenerated hair follicle contains embryos with densely packed dermal papilla cells. In the telogen, the onset of the novel anagen phase occurs by rapid cell proliferation in the embryo, expansion of the dermal papilla, and synthesis of basement membrane components. When hair growth ceases, most hair follicles are present in the telogen and anagen is not involved, resulting in complete or partial baldness.
[35] Interestingly, it is known that thyroid hormone known as thyroxine (" T4 ") is converted to tyrosine (" T3 ") by deiodinase I, selenium protein in human skin. In the absence of selenium, the level of T3 is decreased by a decrease in the activity of the daiodinase I, and this decrease in T3 levels is closely related to hair loss. Consistent with these observations, hair growth is a reported side effect of T4 administration. Also, T3 and T4 are described, for example, in International Patent Publication No. WO 00/72810, published December 7, 2000, which is hereby incorporated by reference, International Patent Publication No. WO 00/72811, International Patent Publication No. WO 00/72812, published December 7, 2000, WO 00/72813, published December 7, 2000, December 2000 WO 00/72920, published on July 7, 2000, and WO 00/73292, published on December 7, 2000, which were the subject of several patent publications relating to hair loss treatment .
[36] SUMMARY OF THE INVENTION
[37] The present invention provides compounds of formula (I), isomers thereof, prodrugs of such compounds or isomers, or pharmaceutically acceptable salts of such compounds, isomers or prodrugs:
[38]
[39] In this formula,
[40] W is (a) -O-, (b) -S-, (c) -SO-, (d) -SO 2 -, (e) -CH 2 -, (f) -CF 2 -, (g) -CHF-, (h) -C (O ) -, (i) -CH (OH) -, (j) -NR a or (k) ego;
[41] R < ⁰ > is (a) hydrogen; (b) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, (ii) halogen, ₃ and (iv) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 substituent selected from the group consisting of phenyl substituted with 0 or 1 substituent selected from the group consisting of -OCF ₃ ; (c) -C (O) R ^h ; (d) -S (O) ₂ R ^h ; Or (e) halogen;
[42] R ^1, R ^2, R ³ and R ⁶ are each independently (a) hydrogen, (b) _{halogen, (c) - (C 1} -C 8) _{alkyl, (d) -CF 3, (} e) -OCF ₃ , (f) -O (C ₁ -C ₈ ) alkyl or (g) -CN;
[43] R ⁴ is selected from the group consisting of: (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0-3 substituents independently selected from the following group V, (c) - (C ₂ -C ₁₂ ) _{(d) - (c 2 -C} 12) alkynyl, (e) halogen, (f) -CN, (g ) -OR b, (h) -SR c, (i) -S (O) R c, (O) ₂ R ^c , (k) aryl, (l) heteroaryl, (m) - (C ₃ -C ₁₀ ) cycloalkyl, (n) heterocycloalkyl, ^{_{O) 2 NR c r d,}} (p) -C (O) NR c r d, (q) -C (O) OR c, (r) -NR a c (O) r d, (s) -NR ^{a c (O) NR c R} d, (t) -NR a S (O) 2 R d, (u) -NR a R d , or (v) -C (O) R c , or; Or R ³ and R ⁴ has the formula together with the carbon atom to which they are attached - (CH _{2) i} - tan forming the summons ring, or the formula of (wherein, i is 3, 4, 5 or 6 a) - (CH _{2) k} -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ;
[44] R ⁵ is (a) -OH, (b) -O (C 1 -C 6) alkyl, (c) -OC (O) R f, (d) F , or (e) -C (O) OR c , or ; Or R ⁴ and R ⁵ together with the carbon atoms to which they are attached form -CR ^c = CR ^a -NH-, -N = CR ^a -NH, -CR ^c = CR ^a -O-, -CR ^c = CR ^a -S -, -CR ^c = N-NH- and -CR ^a = CR ^a -CR ^a = N-;
[45] R ⁷ is (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl;
[46] R ⁸ and R ⁹ are each independently (a) hydrogen, (b) - (C ₁ -C ₆ ) alkyl, (c) aryl or (d) halogen;
[47] R ¹⁰ is _{(a) - (C 0 -C} 1) alkyl, -C (O) OH, (b ) - (C 0 -C 1) alkyl, ^{-C (O) OR f, (} c) - (C 0 - C ₁ ) alkyl-C (O) NR ^c R ^d or (d) - (C ₀ -C ₁ ) alkyl-OH;
[48] In each case R ^a is independently - (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 - (C ₃ -C ₆ ) cycloalkyl or methoxy;
[49] A R ^b is independently in each occurrence (a) hydrogen, (b) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₂₎ alkyl, (c) aryl, (d) (E) - (C ₃ -C ₁₀ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) NR ^c R ^d or (h) -C (O) R ^f ;
[50] R ^c and R ^d in each occurrence are each independently selected from the group consisting of (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0 to 3 substituents independently selected from the following group VI, (c) (C ₂ -C _{12) alkenyl, (d) - (C 2} -C 12) alkynyl, (e) aryl, (f) _{heteroaryl, (g) - (C 3} -C 10) cycloalkyl or ( h) heterocycloalkyl; Provided that when R ⁴ is a residue -SR ^c , -S (O) R ^c or -S (O) ₂ R ^c , then R ^c is not hydrogen; Or R ^c and R ^d are the atom they are attached (s) and with -O-, -NR ^e -, and 3-to 10-which may or may not include a heteroaryl of claim 2, selected from the group consisting of -S- (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , (c) oxo, (d) -CN, (e) phenyl and (f ) -NR &^lt; ^a &^gt; R &^lt; ^g &^gt;;
[51] R ^e is (a) hydrogen, (b) -CN, (c ) to the optionally substituted with 0 to 3 substituents independently selected from Group V in each occurrence - (C ₁ -C ₁₀₎ alkyl, (d) - (C ₂ -C _{10) alkenyl, (e) - (C 2} -C 10) _{alkoxy, (f) - (C 3} -C 10) cycloalkyl, (g) aryl, (h) heteroaryl, (i ) -C (O) R ^f , (j) -C (O) OR ^f , (k) -C (O) NR ^a R ^f or (l) -S (O) ₂ R ^f ;
[52] In each case R ^f is independently - (a) - (C ₁ -C ₁₀ ) alkyl, (b) - (C ₂ -C ₁₀ ) alkenyl substituted by 0 to 3 substituents independently selected from the following group VI , (c) - (C ₂ -C ₁₀ ) alkynyl, (d) - (C ₃ -C ₁₀ ) cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl;
[53] To R ^g are independently in each occurrence (a) _{hydrogen, (b) - (C 1} -C 6) _{alkyl, (c) - (C 2} -C 6) alkenyl, (d) aryl, (e) - ^{C (O) R f, (} f) -C (O) oR f, (g) -C (O) NR a R f, (h) -S (O) 2 R f , or (i) - (C ₃ -C ₈₎ cycloalkyl;
[54] R ^h is selected from the group ^consisting of (a) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, ) -CF _3, and (iv) substituted from the group consisting of -OCF ₃ to 0 or 1 substituent selected from the group consisting of phenyl substituted by 0 or 1 substituent selected - (C ₁ -C ₆₎ alkyl; (b) (1) - ( C 1 -C 4) alkyl, (2) halogen, ₍₃₎ -CF 3, and (4) phenyl substituted from the group consisting of -OCF ₃ to selected from 0 to 2 substituents independently ; _{(c) - (C 3 -C} 6) cycloalkyl; Or (d) heterocycloalkyl;
[55] Group V is (a) _{halogen, (b) -CF 3, (} c) -OCF 3, (d) -OH, (e) _{oxo, (f) - (C 1} -C 6) alkoxy, (g) - CN, (h) aryl, (i) _{heteroaryl, (j) - (C 3} -C 10) cycloalkyl, (k) ^{heterocycloalkyl, (l) -SR f, (} m) -S (O) R ^{f, (n) -S (o} ) 2 R f, (o) -S (o) 2 NR a R f, (p) -NR a R g , or (q)
[56] -C (O) NR < ^a > R <^f;
[57] Group VI is (a) halogen, (b) hydroxy, (c) _{oxo, (d) - (C 1} -C 6) alkoxy, (e) aryl, (f) heteroaryl, (g) - (C ₃ -C ₈₎ cycloalkyl, (h) heterocycloalkyl, (i) -CN, or (j) -OCF _3, and;
[58] However, the substituent R ⁴ is substituted with 0 to 3 substituents independently selected from the Group V - and (C ₁ -C ₁₂₎ alkyl, wherein if V is a substituent group of oxo, oxo groups - (C ₁ -C ₁₂ ) Alkyl at a carbon atom other than the C ₁ carbon atom;
[59] In each case, the aryl is independently (a) _{halogen, (b) - (C 1} -C 6) alkyl, (c) -CN, (d ) -SR f, (e) -S (O) R f, _{(f) -S (O) 2} R f, (g) - (C 3 -C 6) cycloalkyl, (h) -S (O) 2 NR a R f, (i) -NR a R g, ( ^{j) -C (O) NR a} R f, (k) -OR b, (l) - perfluoro - (C ₁ -C ₄₎ alkyl, and (m) independently selected from the group consisting of -COOR ^f 0 Phenyl or naphthyl substituted with up to four substituents;
[60] However, the substituent (s) on the aryl ^{-SR f, -S (O) R} f, -S (O) 2 R f, -S (O) 2 NR a R f, -NR a R g, -C ( O) NR ^a R ^f , -OR ^b or -COOR ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
[61] (A) halogen, (b) - (C ₁ -C ₄ ) alkyl, (c) - (C ₁ -C ₄ ) alkyl, ^{_{CF 3, (d) -OR b}} , (e) -NR a R g , and (f) -CO ₂ R 5 a circle having the ^f 0 to 3 substituents independently selected from the group consisting of, 6-, 7 membered, 8-membered, 9-membered or 10-membered ring or heterocyclic ring wherein the monocyclic heteroaryl ring is condensed to a benzene ring or another heteroaryl ring;
[62] Provided that when the substituent (s) on the heteroaryl is -OR ^b , -NR ^a R ^g or -CO ₂ R ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
[63] Heterocycloalkyl in each occurrence is independently O, NR ^e and having from 1 to 3 heteroatoms selected from the group consisting of S, (a) - (C 1 -C 4) alkyl, ^(b) -OR b, (c) oxo, (d) -CN, (e) phenyl and (f) -NR ^a R ^g , 8-membered, 9-membered or 10-membered ring or a dicyclic alkyl ring.
[64] The present invention also provides a method of using a compound of formula I for the treatment of alopecia.
[65] More specifically, the invention W is (a) -O-, (b) -S-, (c) -SO-, (d) -SO 2 -, (e) -CH 2 -, (f) - _{CF 2 -, (g) -CHF-} , (h) -C (O) -, (i) -CH (OH) -, (j) -NR a or (k) ego; R < ⁰ > is (a) hydrogen; (b) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, (ii) halogen, ₃ and (iv) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 substituent selected from the group consisting of phenyl substituted with 0 or 1 substituent selected from the group consisting of -OCF ₃ ; (c) -C (O) R ^h ; (d) -S (O) ₂ R ^h ; Or (e) halogen; R ^1, R ^2, R ³ and R ⁶ are each independently (a) hydrogen, (b) _{halogen, (c) - (C 1} -C 8) _{alkyl, (d) -CF 3, (} e) -OCF ₃ , (f) -O (C ₁ -C ₈ ) alkyl or (g) -CN; R ⁴ is selected from the group consisting of: (a) - (C ₁ -C ₁₂ ) alkyl, (b) - (C ₂ -C ₁₂ ) alkenyl substituted with 0 to 3 substituents independently selected from the following group V, C ₂ -C ₁₂₎ alkynyl, (d) halogen, (e) -CN, (f ) -OR b, (g) aryl, (h) _{heteroaryl, (i) - (C 3} -C 10) cycloalkyl Alkyl, (j) heterocycloalkyl, (k) -C (O) OR ^c , (1) -NR ^a C (O) R ^d , (m) -NR ^a C (O) NR ^c R ^d , ) -NR ^a S (O) ₂ R ^d , (o) -NR ^a R ^d or (p) -C (O) R ^c ; Or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, 4, 5 or 6, or - (CH ₂ ) _k -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ; R ⁵ is (a) -OH, (b) -O (C 1 -C 6) alkyl, (c) -OC (O) R f, (d) F , or (e) -C (O) OR c , or ; Or R ⁴ and R ⁵ together with the carbon atom to which they are attached form -CR ^c = CR ^a -NH-, -N = CR ^a -NH, -CR ^c = CR ^a -O-, -CR ^c = CR ^a -S -, -CR ^c = N-NH- and -CR ^a = CR ^a -CR ^a = N-; R ⁷ is (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl; R ⁸ and R ⁹ are each independently (a) hydrogen, (b) - (C ₁ -C ₆ ) alkyl, (c) aryl or (d) halogen; R ¹⁰ is _{(a) - (C 0 -C} 1) alkyl, -C (O) OH, (b ) - (C 0 -C 1) alkyl, ^{-C (O) OR f, (} c) - (C 0 - C ₁ ) alkyl-C (O) NR ^c R ^d or (d) - (C ₀ -C ₁ ) alkyl-OH; In each case R ^a is - (C ₁ -C ₆ ) alkyl, which is independently substituted with (a) hydrogen or (b) 0 or 1 - (C ₃ -C ₆ ) cycloalkyl or methoxy; A R ^b is independently in each occurrence (a) hydrogen, (b) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₂₎ alkyl, (c) aryl, (d) (E) - (C ₃ -C ₁₀ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) NR ^c R ^d or (h) -C (O) R ^f ; In each case R ^c and R ^d are each independently selected from the group consisting of (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0 to 3 substituents independently selected from the following group VI, (c) (C ₂ -C _{12) alkenyl, (d) - (C 2} -C 12) alkynyl, (e) aryl, (f) _{heteroaryl, (g) - (C 3} -C 10) cycloalkyl or ( h) heterocycloalkyl; Or R ^c and R ^d are the atom they are attached (s) and with -O-, -NR ^e -, and 3-to 10-which may or may not include a heteroaryl of claim 2, selected from the group consisting of -S- (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , (c) oxo, (d) -CN, (e) phenyl and (f ) -NR &^lt; ^a &^gt; R &^lt; ^g &^gt;; R ^e is in each occurrence (a) hydrogen, (b) -CN, (c ) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₀₎ alkyl, (d) - (C ₂ -C _{10) alkenyl, (e) - (C 2} -C 10) _{alkoxy, (f) - (C 3} -C 10) cycloalkyl, (g) aryl, (h) heteroaryl, (i ) -C (O) R ^f , (j) -C (O) OR ^f , (k) -C (O) NR ^a R ^f or (l) -S (O) ₂ R ^f ; In each case R ^f is independently - (a) - (C ₁ -C ₁₀ ) alkyl, (b) - (C ₂ -C ₁₀ ) alkenyl substituted by 0 to 3 substituents independently selected from the following group VI , (c) - (C ₂ -C ₁₀ ) alkynyl, (d) - (C ₃ -C ₁₀ ) cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl; With a R ^g in each case independently (a) _{hydrogen, (b) - (C 1} -C 6) _{alkyl, (c) - (C 2} -C 6) alkenyl, (d) aryl, (e) - ^{C (O) R f, (} f) -C (O) oR f, (g) -C (O) NR a R f, (h) -S (O) 2 R f , or (i) - (C ₃ -C ₈₎ cycloalkyl; R ^h is selected from the group ^consisting of (a) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, ) -CF _3, and (iv) substituted from the group consisting of -OCF ₃ to 0 or 1 substituent selected from the group consisting of phenyl substituted by 0 or 1 substituent selected - (C ₁ -C ₆₎ alkyl; (b) (1) - ( C 1 -C 4) alkyl, (2) halogen, ₍₃₎ -CF 3, and (4) phenyl substituted from the group consisting of -OCF ₃ to selected from 0 to 2 substituents independently _{; (c) - (C 3} -C 6) cycloalkyl; Or (d) heterocycloalkyl; A Group V (a) _{halogen, (b) -CF 3, (} c) -OCF 3, (d) -OH, (e) _{oxo, (f) - (C 1} -C 6) alkoxy, (g) - CN, (h) aryl, (i) _{heteroaryl, (j) - (C 3} -C 10) cycloalkyl, (k) ^{heterocycloalkyl, (l) -SR f, (} m) -S (O) R ^{f, (n) -S (O} ) 2 R f, (o) -S (O) 2 NR a R f, (p) -NR a R g , or (q) -C (O) NR a R f , and ; Group VI is (a) halogen, (b) hydroxy, (c) _{oxo, (d) - (C 1} -C 6) alkoxy, (e) aryl, (f) heteroaryl, (g) - (C ₃ -C ₈₎ cycloalkyl, (h) heterocycloalkyl, (i) -CN, or (j) -OCF _3, and; However, the substituent R ⁴ is substituted with 0 to 3 substituents independently selected from the Group V - and (C ₁ -C ₁₂₎ alkyl, wherein if V is a substituent group of oxo, oxo groups - (C ₁ -C ₁₂ ) Alkyl at a carbon atom other than the C ₁ carbon atom; (B) - (C ₁ -C ₆ ) alkyl, (c) -CN, (d) -SR ^f , (e) -S (O) R ^f , _{(f) -S (O) 2} R f, (g) - (C 3 -C 6) cycloalkyl, (h) -S (O) 2 NR a R f, (i) -NR a R g, ( ^{j) -C (O) NR a} R f, (k) -OR b, (l) - perfluoro - (C ₁ -C ₄₎ alkyl, and (m) independently selected from the group consisting of -COOR ^f 0 Phenyl or naphthyl substituted with up to four substituents; However, the substituent (s) on the aryl ^{-SR f, -S (O) R} f, -S (O) 2 R f, -S (O) 2 NR a R f, -NR a R g, -C ( O) NR ^a R ^f , -OR ^b or -COOR ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl; (A) halogen, (b) - (C ₁ -C ₄ ) alkyl, (c) - (C ₁ -C ₄ ) alkyl, ^{_{CF 3, (d) -OR b}} , (e) -NR a R g , and (f) -CO ₂ R 5 a circle having the ^f 0 to 3 substituents independently selected from the group consisting of, 6-, 7 membered, 8-membered, 9-membered or 10-membered ring or heterocyclic ring wherein the monocyclic heteroaryl ring is condensed to a benzene ring or another heteroaryl ring; Provided that when the substituent (s) on the heteroaryl is -OR ^b , -NR ^a R ^g or -CO ₂ R ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl; (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , or -OR ^b , wherein the heterocycloalkyl group in each case independently has 1 to 3 heteroatoms selected from the group consisting of O, NR ^e , (c) oxo, (d) -CN, (e) phenyl and (f) -NR ^a R ^g , Isomer, prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, wherein said compound is an 8, 9, or 10 membered ring or bicyclic ring.
[66] More particularly, the present invention provides a compound of formula I wherein W is O.
[67] More specifically, the present invention provides a compound of formula I wherein R < ^{1 >} is located at position 5 and R < ² >
[68] More specifically, the present invention provides a compound of formula I wherein R ⁰ is hydrogen and R ¹ and R ² are each independently hydrogen, - (C ₁ -C ₆ ) alkyl, halogen or CN.
[69] More specifically, the present invention R ³ is hydrogen, - (C ₁ -C ₄₎ alkyl or halogen; R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ substituted by cycloalkyl, and heterocycloalkyl 0 to 3 substituents independently selected from the group consisting of - (C ₁ -C ₁₀₎ alkyl, (b) -S (O) 2 NR c R d, (c) -C (O) NR c R d, (d) -S (O) 2 R c, (e) - (c ₃ -C ₈₎ cycloalkyl, (f) heterocycloalkyl, (g) -C (O) R c, (h) -OR b, (i) -SR c, (j) -S (O) ^{R c, (k) -NR a} c (O) R d, (l) -NR a c (O) NR c R d , or ^{(m) -NR a S (O} ) 2 R d , or; Or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, 4, 5 or 6, or - (CH ₂ ) _k -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ; However, the substituent R ⁴ is 0 to 3 substituted with a substituent - if the (C ₁ -C ₁₀₎ alkyl, oxo groups - a (C ₁ -C ₁₀₎ substituted at carbon atoms other than the C ₁ carbon atom in the alkyl To provide a compound of formula (I).
[70] More specifically, the present invention R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ cycloalkyl and heterocycloalkyl with 0-3 independently selected from the group consisting of substituted with a substituent - (c ₁ -C _{10) alkyl, (b) - (c 3} -C 8) cycloalkyl, (c) heterocycloalkyl, (d) -C (O) R c, (e) - oR ^b, the compound of ^{(f) -NR a C (O} ) R d, (g) -NR a C (O) NR c R d , or ^{(h) -NR a S (O} ) ₂ R ^d of the formula I to provide.
[71] More specifically, R ⁵ is -OH, -OC (O) R ^f or -F; It provides a (C ₁ -C ₁₀₎ alkyl Compounds of formula I - R ^f is substituted with 0 to 3 substituents independently selected from the Group VI.
[72] More specifically, the present invention R ⁶ is hydrogen, halogen, or - (C ₁ -C ₄₎ alkyl; R < ⁷ > is hydrogen or methyl; R ⁸ and R ⁹ are each independently hydrogen, - (C ₁ -C ₆ ) alkyl or halogen. Even more particularly, the invention relates to compounds of formula I wherein R < ⁶ > is hydrogen, R < ⁷ > R ⁸ and R ⁹ are each independently hydrogen, methyl or -F.
[73] More particularly, the invention relates to compounds of formula I wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ , or a pharmaceutically acceptable salt or solvate thereof Provide medication.
[74] More specifically, the present invention R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ cycloalkyl and heterocycloalkyl with 0-3 independently selected from the group consisting of substituted with a substituent - (c ₁ -C ₁₀₎ alkyl, (b) -S (O) 2 NR c R d, (c) -C (O) NR c R d, (d) -S (O) 2 R ^c, (e) - it provides a compound of (C ₃ -C ₈₎ cycloalkyl, (f) the formula (I) heterocycloalkyl or (g) -C (O) R c.
[75] Still more particularly, the present invention R ⁴ is ^{_{-S (O) 2 NR c R}} d and; R ^c is hydrogen or - (C ₁ -C ₆ ) alkyl; R ^d is - (C ₃ -C ₈ ) cycloalkyl, - (C ₁ -C ₁₀ ) alkyl, aryl or heteroaryl; Or R ^c and R ^d together with the nitrogen atom that they are attached are an -O-, -NR ^e -, and 3-to 8-membered heterocyclic ring which may or may not include a heteroaryl selected the second from the group consisting of -S- Lt; RTI ID = 0.0 > I < / RTI > forming a ring. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ₃ > is hydrogen; R < ₅ > is -OH; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . Most particularly, the invention relates to compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclopropyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclobutyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclobutyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclobutyl and R ¹⁰ is -C (O) OH; R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclopropyl, and R ¹⁰ is -C (O) OH; And R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclopropyl, and R ¹⁰ is -C (O) OH.
[76] Still more particularly, the present invention R ⁴ is -C (O) NR ^c R ^d and; R ^c is hydrogen or - (C ₁ -C ₆ ) alkyl; R ^d is _{(a) - (C 3 -C} 8) cycloalkyl, (b) substituted with 0 to 3 substituents independently selected from the Group VI - (C ₁ -C ₁₀₎ alkyl, (c) aryl, or (d) heteroaryl; Or R ^c and R ^d together with the nitrogen atom that they are attached are an -O-, -NR ^e -, and 3-to 8-membered heterocyclic ring which may or may not include a heteroaryl selected the second from the group consisting of -S- Lt; RTI ID = 0.0 > I < / RTI > forming a ring. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ₃ > is hydrogen; R < ₅ > is -OH; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . More particularly, the invention relates to compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl and R ¹⁰ is -C (O) OH; A compound wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -C (O) NH-CH (CH (CH ₃ ) ₂ ) ₂ and R ¹⁰ is -C (O) OH; And R ¹ is Cl, R ² is Cl, R ⁴ is -C (O) NH- (1S) -CH (CH ₃ ) -cyclohexyl and R ¹⁰ is -C (O) OH.
[77] In still more particularly, the present invention R ⁴ is -S (O) ₂ R ^c, and, R ^c is - (C ₀ -C ₂₎ alkyl, - (C ₃ -C ₆₎ cycloalkyl, - (C ₁ -C ₁₀ ) alkyl, aryl or - (C ₀ -C ₂ ) alkyl-heterocycloalkyl. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ₃ > is hydrogen; R < ₅ > is -OH; R ⁶ , R ⁷ and R ⁹ are each hydrogen; R < ⁸ > is hydrogen or methyl; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . Most particularly, the invention relates to compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OCH ₃ ; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OCH ₂ CH ₃ ; R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopropyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclopropyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OCH ₂ CH ₃ ; R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OCH ₃ ; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopentyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is methyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclohexyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is methyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopentyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclohexyl, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -phenyl-4-F, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH; And compounds wherein R ¹ is CH ₃ , R ² is Cl, R ⁴ is -SO ₂ -phenyl-4-F, R ⁸ is hydrogen and R ¹⁰ is -C (O) OH .
[78] In still more particularly, the present invention R ⁴ is - (C ₀ -C ₂₎ alkyl, - (C ₃ -C ₆₎ cycloalkyl, - (C ₁ -C ₁₀₎ alkyl or - (C ₀ -C ₂₎ alkyl, ≪ / RTI > aryl. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ³ > is hydrogen; R < ⁵ > is -OH; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . Most particularly, the invention provides such compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -CH ₂ -phenyl-4-F and R ¹⁰ is -C (O) OH.
[79] In still more particularly, the present invention R ⁴ is -CH (OH) - aryl, -CH (OH) - heteroaryl, -CH (OH) - (C ₀ -C ₂₎ alkyl, - (C ₃ -C ₈₎ Cycloalkyl or -CH (OH) - (C ₀ -C ₂ ) alkyl-heterocycloalkyl. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ³ > is hydrogen; R < ⁵ > is -OH; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . More particularly, the present invention relates to compounds of formula I wherein R ¹ is CH ₃ , R ² is CH ₃ and R ⁴ is -CH (OH) -phenyl-4-F and R ¹⁰ is -C (O) OH or -C ₃ ; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ and R ⁴ is -CH (OH) CH ₂ -cyclopentyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -CH (OH) CH ₂ -cyclobutyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -CH (OH) -phenyl-4-F and R ¹⁰ is -C (O) OH; R ¹ is Cl, R ² is CH ₃ , R ⁴ is -CH (OH) -cyclopentyl and R ¹⁰ is -C (O) OH; And compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -CH (OH) -cyclobutyl and R ¹⁰ is -C (O) OH.
[80] Still more particularly, the present invention R ⁴ is -C (O) - aryl, -C (O) - heteroaryl, -C (O) - (C ₀ -C ₂₎ alkyl, - (C ₃ -C ₈₎ Cycloalkyl or -C (O) - (C ₀ -C ₂ ) alkyl-heterocycloalkyl. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ³ > is hydrogen; R < ⁵ > is -OH; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . More particularly, the present invention relates to compounds of formula I wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) -phenyl-4-F and R ¹⁰ is -C (O) OH or -C ₃ ; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) -CH ₂ -cyclopentyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) -CH ₂ -cyclobutyl and R ¹⁰ is -C (O) OH; R ¹ is Cl, R ² is CH ₃ , R ⁴ is -C (O) -cyclobutyl and R ¹⁰ is -C (O) OH; R ¹ is Cl, R ² is CH ₃ , R ⁴ is -C (O) -cyclopentyl and R ¹⁰ is -C (O) OH; And R ¹ is Cl, R ² is CH ₃ and R ⁴ is -C (O) -phenyl-4-F and R ¹⁰ is -C (O) OH.
[81] Even more particularly, the invention relates to compounds of formula I wherein R < ³ > and R < ⁴ > together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, Optionally substituted with from 0 to 3 substituents independently selected from the group consisting of: Or ^a heterocyclic ring of the formula - (CH ₂ ) _k -Q- (CH ₂ ) _l - wherein Q is -NR ^a and R ^a is hydrogen or - (C ₁ -C ₆ ) alkyl, k is 1 and l is 1 , Wherein the heterocyclic ring is optionally substituted with one or two substituents independently selected from the group consisting of oxo and methyl. Even more particularly, the invention relates to compounds of formula (I) wherein R ¹ and R ² are each independently -CH ₃ or -Cl; R < ³ > is hydrogen; R < ⁵ > is -OH; R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ . Most particularly, the invention relates to compounds wherein R ¹ is CH ₃ , R ² is CH ₃ and R ³ and R ⁴ together with the carbon atom to which they are attached form indanyl and R ¹⁰ is -C (O) OH; R ¹ is Cl, R ² is CH ₃ and R ³ and R ⁴ together with the carbon atom to which they are attached form indanyl and R ¹⁰ is -C (O) OH; R ¹ is Cl, R ² is CH ₃ and R ³ and R ⁴ together with the carbon atom to which they are attached form 2-methyl-1-oxo-2,3-dihydro-1H-isoindolyl and R ¹⁰ is -C (O) OH; R ¹ is CH ₃ and R ² is CH ₃ and R ³ and R ⁴ is and R ¹⁰ to form a 2-methyl-1-oxo-2,3-dihydro -1H- isopropyl turn together with the carbon atom to which they are attached Is -C (O) OH; R ¹ is CH ₃ , R ² is CH ₃ and R ³ and R ⁴ together with the carbon atom to which they are attached form 2-methyl-1-oxo-indanyl and R ¹⁰ is -C (O) OH; And R ¹ is CH ₃ and R ² is CH ₃ and R ³ and R ⁴ are taken together with the carbon atom they are attached a 2,2-dimethyl-1-oxo-indanyl, and R ¹⁰ form the two -C (O) OH Phosphorus compounds.
[82] In a more specific embodiment, the present invention provides a compound of formula I wherein W is O and R < ⁰ > is hydrogen; R ¹ and R ² are each independently hydrogen, - (C ₁ -C ₆ ) alkyl or halogen; R ³ and R ⁶ are each independently hydrogen or halogen; R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ substituted by cycloalkyl, and heterocycloalkyl 0 to 3 substituents independently selected from the group consisting of - (C ₁ -C ₁₀₎ alkyl, (b) -S (O) 2 NR c R d, (c) -C (O) NR c R d, (d) -S (O) 2 R c, (e) - (C ₃ -C ₈ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) R ^c ; Or R ³ and R ⁴ is of the formula I are together with the carbon atom to which they are attached form a 3 - (CH _{2) i} - form a carbocyclic ring, or a; Or a heterocyclic ring of the formula - (CH ₂ ) _k -Q- (CH ₂ ) _l - wherein Q is -NR ^e and R ^e is hydrogen or methyl, k is 1 and l is 1, wherein the heterocyclic ring Is unsubstituted or substituted with one or two substituents independently selected from the group consisting of oxo and methyl; - (C ₁ -C ₁₀ ) alkyl wherein R ⁴ is substituted with 0 to 3 substituents, the oxo group is substituted at a carbon atom other than the C ₁ carbon atom in - (C ₁ -C ₁₀ ) alkyl; R < ⁵ > is -OH; R ⁷ , R ⁸ and R ⁹ are each independently hydrogen or methyl; R ¹⁰ is -C (O) OH or -C (O) O (C ₁ -C ₆ ) alkyl; In each case, R ^c is selected from the group consisting of: (a) hydrogen, (b) - (C ₁ -C ₁₀ ) alkyl, (c) - (C ₀ -C ₂ ) alkyl- (C ₃ -C ₈ ) cycloalkyl, ) Aryl, (e) - (C ₀ -C ₂ ) alkyl-heterocycloalkyl or (f) heteroaryl; R ^d is _{(a) - (C 3 -C} 8) cycloalkyl, (b) substituted with 0 to 3 substituents independently selected from the Group VI - (C ₁ -C ₁₂₎ alkyl, (c) aryl, or (d) heteroaryl; Or R ^c and R ^d together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycle which may or may not contain a second hetero group selected from the group consisting of -O-, -NR ^e - and -S-. Or a prodrug thereof, or a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof.
[83] The present invention also provides a compound of formula (A), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug:
[84]
[85] In this formula,
[86] R ¹ and R ² are each independently -CH ₃ or -Cl;
[87] R ⁴ is -SO ₂ -NH-cyclopropyl, -SO ₂ -NH-cyclobutyl, -SO ₂ -NH-cyclopentyl, -SO ₂ -NH-cyclohexyl, -SO ₂ -NH- (C ₁ -C ₈₎ unsubstituted or substituted by alkyl, or -SO ₂ -NH--fluoro phenyl;
[88] R ⁸ and R ⁹ are each independently hydrogen or methyl;
[89] R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[90] More specifically, the present invention provides compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclopropyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclopropyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclopropyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-CH (CH ₃ ) ₂ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -SO ₂ -NH- (CH ₂ ) ₃ -CH ₃ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -SO ₂ -NH- (CH ₂ ) ₆ -CH ₃ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH- (4-fluoro-phenyl), R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclohexyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; And compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -SO ₂ -NH-cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH. ≪ / RTI >
[91] The present invention also provides a compound of formula (A), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug:
[92] A
[93]
[94] In this formula,
[95] R ¹ and R ² are each independently -CH ₃ or -Cl;
[96] R ⁴ is _{-C (O) N (CH 3} ) - (C 3 -C 8) cycloalkyl, -C (O) NH-CH (CH (CH 3) 2) 2, -C (O) N (CH _{3) -CH (CH (CH 3} ) 2) 2, -C (O) N (CH 3) -CH (CH 3) 2, -C (O) NH-CH (CH 3) - cyclohexyl, -C (O) NH-CH ₂ - cyclohexyl, -C (O) N (CH 3) -CH 2 - cyclohexyl, -C (O) N (CH 3) -CH (CH 3) - cyclohexyl, or fluoro -C (O) NH-phenyl unsubstituted or substituted with halo;
[97] R ⁸ and R ⁹ are each independently hydrogen or methyl;
[98] R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[99] More particularly, the invention relates to compounds of formula I wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Wherein R ¹ is CH ₃ , R ² is CH ₃ and R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OCH ₃ ; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Wherein R ¹ is Cl, R ² is CH ₃ and R ⁴ is -C (O) NH-CH (CH (CH ₃ ) ₂ ) ₂ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C Phosphorus compounds; Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) NH-CH (CH (CH ₃ ) ₂ ) ₂ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C compound; A compound wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) NH-CH (CH ₃ ) -cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ and R ⁴ is -C (O) N (CH ₃ ) -cyclopentyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -CH (CH ₃ ) ₂ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C OH; Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) NH- (4-fluoro-phenyl) and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -C (O) NH-CH ₂ -cyclohexyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -CH ₂ -cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH. ; A compound wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -C (O) N (CH ₃ ) -cyclopentyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -cycloheptyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -CH (CH (CH ₃ ) ₂ ) ₂ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C O) OH; And R ¹ is Cl and R ² is Cl and R ⁴ is _{-C (O) N (CH 3} ) -CH (CH 3) - cyclohexyl, and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O ) OH. ≪ / RTI >
[100] The present invention also provides a compound of formula (A), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug:
[101] A
[102]
[103] In this formula,
[104] R ¹ and R ² are each independently -CH ₃ or -Cl;
[105] R ⁴ is selected from the group consisting of -SO ₂ -CH ₂ -cyclopropyl, -SO ₂ -CH ₂ -cyclobutyl, -SO ₂ -CH ₂ -cyclopentyl, -SO ₂ -CH ₂ -cyclohexyl, -SO ₂ -cyclopentyl or -SO ₂ -cyclohexyl;
[106] R ⁸ and R ⁹ are each independently hydrogen or methyl;
[107] R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[108] More particularly, the present invention relates to compounds of formula (I) wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen and R ⁹ is hydrogen and R ¹⁰ is -C ₃ ; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is methyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is H, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₂ CH ₃ ; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopropyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclopropyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₂ CH ₃ ; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₃ ; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is methyl and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is methyl, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclohexyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is methyl, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclohexyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; And compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -cyclopentyl, R ⁸ is hydrogen and R ⁹ is hydrogen and R ¹⁰ is -C (O) OH. ≪ / RTI >
[109] The present invention also relates to a method of treating a mammal comprising administering to a mammal a therapeutically effective amount of a compound of Formula I, an isomer thereof, a prodrug of such an or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug The use of a compound of formula I in the manufacture of a medicament for treating obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, hypothyroidism, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, And alopecia. ≪ / RTI > More specifically, the present invention provides a method wherein the condition is obesity. More specifically, the present invention provides a method wherein the condition is diabetes.
[110] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, Thereby providing a method of causing weight loss in a mammal.
[111] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, Thereby providing a method for increasing energy consumption in a mammal.
[112] The present invention also relates to the use of a compound of formula I in the treatment of obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, (1) a therapeutically effective amount of a compound of formula (I), an isomer thereof, such a compound or isomer thereof, as defined in claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, Or a pharmaceutically acceptable salt of such compound, isomer or prodrug; And (2) a method of treating obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, Obesity, hyperlipidemia, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, hypothyroidism, thyroid disease, osteoporosis, osteoporosis, osteoporosis, osteoporosis and alopecia, comprising administering a therapeutically effective amount of an additional compound useful for treating selected symptoms. The present invention provides a method for treating a symptom selected from the group consisting of cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, osteoporosis and alopecia. More specifically, the present invention provides a method wherein the additional compound is a lipase inhibitor. More particularly, the present invention relates to the use of lipase inhibitors in combination with a lipase inhibitor selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valyllactone, esterastin, everactone A, RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of these compounds and stereoisomers. Also, and more particularly, the present invention provides a method wherein the additional compound is an anorectic agent. Most particularly, the invention provides a method wherein the anorectic agent is selected from the group consisting of pentamine, sibutramine, penfluramine, dexfenfluramine and bromocriptine.
[113] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug.
[114] In another aspect,
[115] (a) a first pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug Composition;
[116] (b) a method of treating a condition selected from the group consisting of obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, A second pharmaceutical composition comprising additional compounds useful for treating selected conditions selected from the group consisting of osteoporosis and alopecia; And
[117] (c)
[118] Thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, , Osteoporosis, and alopecia are provided.
[119] In another aspect, the invention provides a compound of formula (I) as defined in claim 1, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug; And a method for the treatment and prevention of obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, The invention provides a pharmaceutical composition comprising additional compounds useful for treating selected conditions selected from the group consisting of alopecia. More particularly, the present invention provides such compositions wherein the condition is obesity.
[120] More specifically, the present invention provides such compositions wherein the additional compound is a lipase inhibitor. More particularly, the present invention relates to the use of lipase inhibitors in combination with a lipase inhibitor selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valyllactone, esterastin, everactone A, RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of these compounds and stereoisomers. Furthermore, and more particularly, the present invention provides such compositions wherein the further compound is an anorectic agent. Most specifically, the present invention provides such compositions wherein the anorectic agent is selected from the group consisting of pentamine, sibutramine, fenfluramine, dexfenfluramine, and bromocriptine.
[121] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, Or a pharmaceutically acceptable salt thereof.
[122] As a preferred embodiment of treating diabetes, diabetes is Type I diabetes.
[123] As another preferred embodiment of treating diabetes, diabetes is type II diabetes.
[124] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, Comprising administering to a patient a therapeutically effective amount of a compound of formula (I).
[125] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the manufacture of a medicament for the treatment or prevention of hypertension Or a pharmaceutically acceptable salt thereof.
[126] The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, The method comprising administering to a patient a therapeutically effective amount of a compound of the present invention.
[127] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the manufacture of a medicament for the treatment or prevention of hypercholesterolemia The method comprising administering to a patient a therapeutically effective amount of a compound of formula (I).
[128] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the manufacture of a medicament for the treatment of a patient suffering from or at risk of hyperlipidemia A method of treating hyperlipidemia.
[129] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, Comprising administering to a patient a therapeutically effective amount of a compound of the invention.
[130] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, isomers thereof, prodrugs of such compounds or isomers, or a pharmaceutically acceptable salt of such compounds, isomers or prodrugs, Comprising administering to a patient a therapeutically effective amount of a compound of the invention.
[131] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the manufacture of a medicament for the treatment of a patient suffering from or at risk of depression Or a pharmaceutically acceptable salt thereof.
[132] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the treatment of obesity or a patient at risk A method of treating obesity.
[133] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, to a patient suffering from or at risk of osteoporosis Or a pharmaceutically acceptable salt thereof.
[134] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, , ≪ / RTI > and a method of treating thyroid cancer.
[135] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the manufacture of a medicament for the treatment or prevention of glaucoma A method of treating glaucoma.
[136] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, In a patient in need of such treatment.
[137] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the treatment or prevention of congestive heart failure Comprising administering to a patient a therapeutically effective amount of a compound of the present invention.
[138] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug for the treatment of a patient suffering from or at risk of alopecia A method of treating alopecia.
[139] (A) acylating aniline with the corresponding ester of the following formula IC, and (c) reducing the ester to the corresponding aniline of formula (D) converting said acid to the corresponding acid chloride of formula IE, and e) reacting the acid chloride with an amine of formula NHR &^lt; ^c &^gt; R &^lt; ^{d &} a compound of the following, which is suitably protected during the reaction step formula I if a further comprises the step of obtaining the amide of formula IF, and, R ⁴ contains a primary or secondary amine, an isomer thereof, such compound or isomer Or a pharmaceutically acceptable salt of such a compound, isomer or prodrug thereof.
[140] Formula I
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148] In the above equations,
[149] W is (a) -O-, (b) -S-, (c) -SO-, (d) -SO 2 -, (e) -CH 2 -, (f) -CF 2 -, (g) -CHF -, (h) -C ( O) -, (i) -CH (OH) -, (j) -NR a or (k) ego;
[150] R < ⁰ > is (a) hydrogen; (b) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, (ii) halogen, ₃ and (iv) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 substituent selected from the group consisting of phenyl substituted with 0 or 1 substituent selected from the group consisting of -OCF ₃ ; (c) -C (O) R ^h ; (d) -S (O) ₂ R ^h ; Or (e) halogen;
[151] R ^1, R ^2, R ³ and R ⁶ are each independently (a) hydrogen, (b) _{halogen, (c) - (C 1} -C 8) _{alkyl, (d) -CF 3, (} e) -OCF ₃ , (f) -O (C ₁ -C ₈ ) alkyl or (g) -CN;
[152] R ⁴ is selected from the group consisting of: (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0-3 substituents independently selected from the following group V, (c) - (C ₂ -C ₁₂ ) _{(d) - (c 2 -C} 12) alkynyl, (e) halogen, (f) -CN, (g ) -OR b, (h) -SR c, (i) -S (O) R c, (O) ₂ R ^c , (k) aryl, (l) heteroaryl, (m) - (C ₃ -C ₁₀ ) cycloalkyl, (n) heterocycloalkyl, ^{_{O) 2 NR c R d,}} (p) -C (O) NR c R d, (q) -C (O) OR c, (r) -NR a c (O) R d, (s) -NR ^{a c (O) NR c R} d, (t) -NR a S (O) 2 R d, (u) -NR a R d , or (v) -C (O) R c , or; Or R ³ and R ⁴ has the formula together with the carbon atom to which they are attached - (CH _{2) i} - tan forming the summons ring, or the formula of (wherein, i is 3, 4, 5 or 6 a) - (CH _{2) k} -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ;
[153] R ⁵ is (a) -OH, (b) -O (C 1 -C 6) alkyl, (c) -OC (O) R f, (d) F , or (e) -C (O) OR c , or ; Or R ⁴ and R ⁵ together with the carbon atoms to which they are attached form -CR ^c = CR ^a -NH-, -N = CR ^a -NH, -CR ^c = CR ^a -O-, -CR ^c = CR ^a -S -, -CR ^c = N-NH- and -CR ^a = CR ^a -CR ^a = N-;
[154] R < ⁷ > is hydrogen;
[155] R ⁸ and R ⁹ are each independently (a) hydrogen, (b) - (C ₁ -C ₆ ) alkyl, (c) aryl or (d) halogen;
[156] R ¹⁰ is _{(a) - (C 0 -C} 1) alkyl, -C (O) OH, (b ) - (C 0 -C 1) alkyl, -C (O) OR ^f, or (c) - (C ₀ - C ₁ ) alkyl-C (O) NR ^c R ^d ;
[157] In each case R ^a is independently - (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 - (C ₃ -C ₆ ) cycloalkyl or methoxy;
[158] A R ^b is independently in each occurrence (a) hydrogen, (b) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₂₎ alkyl, (c) aryl, (d) (E) - (C ₃ -C ₁₀ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) NR ^c R ^d or (h) -C (O) R ^f ;
[159] R ^c and R ^d in each occurrence are each independently selected from the group consisting of (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0 to 3 substituents independently selected from the following group VI, (c) (C ₂ -C _{12) alkenyl, (d) - (C 2} -C 12) alkynyl, (e) aryl, (f) _{heteroaryl, (g) - (C 3} -C 10) cycloalkyl or ( h) heterocycloalkyl; Provided that when R ⁴ is a residue -SR ^c , -S (O) R ^c or -S (O) ₂ R ^c , then R ^c is not hydrogen; Or R ^c and R ^d are the atom they are attached (s) and with -O-, -NR ^e -, and 3-to 10-which may or may not include a heteroaryl of claim 2, selected from the group consisting of -S- (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , (c) oxo, (d) -CN, (e) phenyl and (f ) -NR &^lt; ^a &^gt; R &^lt; ^g &^gt;;
[160] R ^e is (a) hydrogen, (b) -CN, (c ) to the optionally substituted with 0 to 3 substituents independently selected from Group V in each occurrence - (C ₁ -C ₁₀₎ alkyl, (d) - (C ₂ -C _{10) alkenyl, (e) - (C 2} -C 10) _{alkoxy, (f) - (C 3} -C 10) cycloalkyl, (g) aryl, (h) heteroaryl, (i ) -C (O) R ^f , (j) -C (O) OR ^f , (k) -C (O) NR ^a R ^f or (l) -S (O) ₂ R ^f ;
[161] In each case R ^f is independently - (a) - (C ₁ -C ₁₀ ) alkyl, (b) - (C ₂ -C ₁₀ ) alkenyl substituted by 0 to 3 substituents independently selected from the following group VI , (c) - (C ₂ -C ₁₀ ) alkynyl, (d) - (C ₃ -C ₁₀ ) cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl;
[162] To R ^g are independently in each occurrence (a) _{hydrogen, (b) - (C 1} -C 6) _{alkyl, (c) - (C 2} -C 6) alkenyl, (d) aryl, (e) - ^{C (O) R f, (} f) -C (O) oR f, (g) -C (O) NR a R f, (h) -S (O) 2 R f , or (i) - (C ₃ -C ₈₎ cycloalkyl;
[163] R ^h is selected from the group ^consisting of (a) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, ) -CF _3, and (iv) substituted from the group consisting of -OCF ₃ to 0 or 1 substituent selected from the group consisting of phenyl substituted by 0 or 1 substituent selected - (C ₁ -C ₆₎ alkyl; (b) (1) - ( C 1 -C 4) alkyl, (2) halogen, ₍₃₎ -CF 3, and (4) phenyl substituted from the group consisting of -OCF ₃ to selected from 0 to 2 substituents independently ; _{(c) - (C 3 -C} 6) cycloalkyl; Or (d) heterocycloalkyl;
[164] Group V is (a) _{halogen, (b) -CF 3, (} c) -OCF 3, (d) -OH, (e) _{oxo, (f) - (C 1} -C 6) alkoxy, (g) - CN, (h) aryl, (i) _{heteroaryl, (j) - (C 3} -C 10) cycloalkyl, (k) ^{heterocycloalkyl, (l) -SR f, (} m) -S (O) R ^{f, (n) -S (O} ) 2 R f, (o) -S (O) 2 NR a R f, (p) -NR a R g , or (q)
[165] -C (O) NR < ^a > R <^f;
[166] Group VI is (a) halogen, (b) hydroxy, (c) _{oxo, (d) - (C 1} -C 6) alkoxy, (e) aryl, (f) heteroaryl, (g) - (C ₃ -C ₈₎ cycloalkyl, (h) heterocycloalkyl, (i) -CN, or (j) -OCF _3, and;
[167] However, the substituent R ⁴ is substituted with 0 to 3 substituents independently selected from the Group V - and (C ₁ -C ₁₂₎ alkyl, wherein if V is a substituent group of oxo, oxo groups - (C ₁ -C ₁₂ ) Alkyl at a carbon atom other than the C ₁ carbon atom;
[168] In each case, the aryl is independently (a) _{halogen, (b) - (C 1} -C 6) alkyl, (c) -CN, (d ) -SR f, (e) -S (O) R f, _{(f) -S (O) 2} R f, (g) - (C 3 -C 6) cycloalkyl, (h) -S (O) 2 NR a R f, (i) -NR a R g, ( ^{j) -C (O) NR a} R f, (k) -OR b, (l) - perfluoro - (C ₁ -C ₄₎ alkyl, and (m) independently selected from the group consisting of -COOR ^f 0 Phenyl or naphthyl substituted with up to four substituents;
[169] However, the substituent (s) on the aryl ^{-SR f, -S (O) R} f, -S (O) 2 R f, -S (O) 2 NR a R f, -NR a R g, -C ( O) NR ^a R ^f , -OR ^b or -COOR ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
[170] (A) halogen, (b) - (C ₁ -C ₄ ) alkyl, (c) - (C ₁ -C ₄ ) alkyl, ^{_{CF 3, (d) -OR b}} , (e) -NR a R g , and (f) -CO ₂ R 5 a circle having the ^f 0 to 3 substituents independently selected from the group consisting of, 6-, 7 membered, 8-membered, 9-membered or 10-membered ring or heterocyclic ring wherein the monocyclic heteroaryl ring is condensed to a benzene ring or another heteroaryl ring;
[171] Provided that when the substituent (s) on the heteroaryl is -OR ^b , -NR ^a R ^g or -CO ₂ R ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
[172] Heterocycloalkyl in each occurrence is independently O, NR ^e and having from 1 to 3 heteroatoms selected from the group consisting of S, (a) - (C 1 -C 4) alkyl, ^(b) -OR b, (c) oxo, (d) -CN, (e) phenyl and (f) -NR ^a R ^g , 8-membered, 9-membered or 10-membered ring or a dicyclic alkyl ring.
[173] More specifically, the invention W is (a) -O-, (b) -S-, (c) -SO-, (d) -SO 2 -, (e) -CH 2 -, (f) - _{CF 2 -, (g) -CHF-} , (h) -C (O) -, (i) -CH (OH) -, (j) -NR a or (k) ego; R < ⁰ > is (a) hydrogen; (b) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, (ii) halogen, ₃ and (iv) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 substituent selected from the group consisting of phenyl substituted with 0 or 1 substituent selected from the group consisting of -OCF ₃ ; (c) -C (O) R ^h ; (d) -S (O) ₂ R ^h ; Or (e) halogen; R ^1, R ^2, R ³ and R ⁶ are each independently (a) hydrogen, (b) _{halogen, (c) - (C 1} -C 8) _{alkyl, (d) -CF 3, (} e) -OCF ₃ , (f) -O (C ₁ -C ₈ ) alkyl or (g) -CN; R ⁴ is selected from the group consisting of: (a) - (C ₁ -C ₁₂ ) alkyl, (b) - (C ₂ -C ₁₂ ) alkenyl substituted with 0 to 3 substituents independently selected from the following group V, C ₂ -C ₁₂₎ alkynyl, (d) halogen, (e) -CN, (f ) -OR b, (g) aryl, (h) _{heteroaryl, (i) - (C 3} -C 10) cycloalkyl Alkyl, (j) heterocycloalkyl, (k) -C (O) OR ^c , (1) -NR ^a C (O) R ^d , (m) -NR ^a C (O) NR ^c R ^d , ) -NR ^a S (O) ₂ R ^d , (o) -NR ^a R ^d or (p) -C (O) R ^c ; Or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, 4, 5 or 6, or - (CH ₂ ) _k -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ; R ⁵ is (a) -OH, (b) -O (C 1 -C 6) alkyl, (c) -OC (O) R f, (d) F , or (e) -C (O) OR c , or ; Or R ⁴ and R ⁵ together with the carbon atom to which they are attached form -CR ^c = CR ^a -NH-, -N = CR ^a -NH, -CR ^c = CR ^a -O-, -CR ^c = CR ^a -S -, -CR ^c = N-NH- and -CR ^a = CR ^a -CR ^a = N-; R < ⁷ > is hydrogen; R ⁸ and R ⁹ are each independently (a) hydrogen, (b) - (C ₁ -C ₆ ) alkyl, (c) aryl or (d) halogen; R ¹⁰ is _{(a) - (C 0 -C} 1) alkyl, -C (O) OH, (b ) - (C 0 -C 1) alkyl, -C (O) OR ^f, or (c) - (C ₀ - C ₁ ) alkyl-C (O) NR ^c R ^d ; In each case R ^a is - (C ₁ -C ₆ ) alkyl, which is independently substituted with (a) hydrogen or (b) 0 or 1 - (C ₃ -C ₆ ) cycloalkyl or methoxy; A R ^b is independently in each occurrence (a) hydrogen, (b) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₂₎ alkyl, (c) aryl, (d) (E) - (C ₃ -C ₁₀ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) NR ^c R ^d or (h) -C (O) R ^f ; In each case R ^c and R ^d are each independently selected from the group consisting of (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0 to 3 substituents independently selected from the following group VI, (c) (C ₂ -C _{12) alkenyl, (d) - (C 2} -C 12) alkynyl, (e) aryl, (f) _{heteroaryl, (g) - (C 3} -C 10) cycloalkyl or ( h) heterocycloalkyl; Or R ^c and R ^d are the atom they are attached (s) and with -O-, -NR ^e -, and 3-to 10-which may or may not include a heteroaryl of claim 2, selected from the group consisting of -S- (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , (c) oxo, (d) -CN, (e) phenyl and (f ) -NR &^lt; ^a &^gt; R &^lt; ^g &^gt;; R ^e is in each occurrence (a) hydrogen, (b) -CN, (c ) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₀₎ alkyl, (d) - (C ₂ -C _{10) alkenyl, (e) - (C 2} -C 10) _{alkoxy, (f) - (C 3} -C 10) cycloalkyl, (g) aryl, (h) heteroaryl, (i ) -C (O) R ^f , (j) -C (O) OR ^f , (k) -C (O) NR ^a R ^f or (l) -S (O) ₂ R ^f ; In each case R ^f is independently - (a) - (C ₁ -C ₁₀ ) alkyl, (b) - (C ₂ -C ₁₀ ) alkenyl substituted by 0 to 3 substituents independently selected from the following group VI , (c) - (C ₂ -C ₁₀ ) alkynyl, (d) - (C ₃ -C ₁₀ ) cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl; With a R ^g in each case independently (a) _{hydrogen, (b) - (C 1} -C 6) _{alkyl, (c) - (C 2} -C 6) alkenyl, (d) aryl, (e) - ^{C (O) R f, (} f) -C (O) oR f, (g) -C (O) NR a R f, (h) -S (O) 2 R f , or (i) - (C ₃ -C ₈₎ cycloalkyl; R ^h is selected from the group ^consisting of (a) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, ) -CF _3, and (iv) substituted from the group consisting of -OCF ₃ to 0 or 1 substituent selected from the group consisting of phenyl substituted by 0 or 1 substituent selected - (C ₁ -C ₆₎ alkyl; (b) (1) - ( C 1 -C 4) alkyl, (2) halogen, ₍₃₎ -CF 3, and (4) phenyl substituted from the group consisting of -OCF ₃ to selected from 0 to 2 substituents independently ; _{(c) - (C 3 -C} 6) cycloalkyl; Or (d) heterocycloalkyl; A Group V (a) _{halogen, (b) -CF 3, (} c) -OCF 3, (d) -OH, (e) _{oxo, (f) - (C 1} -C 6) alkoxy, (g) - CN, (h) aryl, (i) _{heteroaryl, (j) - (C 3} -C 10) cycloalkyl, (k) ^{heterocycloalkyl, (l) -SR f, (} m) -S (O) R ^{f, (n) -S (O} ) 2 R f, (o) -S (O) 2 NR a R f, (p) -NR a R g , or (q) -C (O) NR a R f , and ; Group VI is (a) halogen, (b) hydroxy, (c) _{oxo, (d) - (C 1} -C 6) alkoxy, (e) aryl, (f) heteroaryl, (g) - (C ₃ -C ₈₎ cycloalkyl, (h) heterocycloalkyl, (i) -CN, or (j) -OCF _3, and; However, the substituent R ⁴ is substituted with 0 to 3 substituents independently selected from the Group V - and (C ₁ -C ₁₂₎ alkyl, wherein if V is a substituent group of oxo, oxo groups - (C ₁ -C ₁₂ ) Alkyl at a carbon atom other than the C ₁ carbon atom; (B) - (C ₁ -C ₆ ) alkyl, (c) -CN, (d) -SR ^f , (e) -S (O) R ^f , _{(f) -S (O) 2} R f, (g) - (C 3 -C 6) cycloalkyl, (h) -S (O) 2 NR a R f, (i) -NR a R g, ( ^{j) -C (O) NR a} R f, (k) -OR b, (l) - perfluoro - (C ₁ -C ₄₎ alkyl, and (m) independently selected from the group consisting of -COOR ^f 0 Phenyl or naphthyl substituted with up to four substituents; However, the substituent (s) on the aryl ^{-SR f, -S (O) R} f, -S (O) 2 R f, -S (O) 2 NR a R f, -NR a R g, -C ( O) NR ^a R ^f , -OR ^b or -COOR ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl; (A) halogen, (b) - (C ₁ -C ₄ ) alkyl, (c) - (C ₁ -C ₄ ) alkyl, ^{_{CF 3, (d) -OR b}} , (e) -NR a R g , and (f) -CO ₂ R 5 a circle having the ^f 0 to 3 substituents independently selected from the group consisting of, 6-, 7 membered, 8-membered, 9-membered or 10-membered ring or heterocyclic ring wherein the monocyclic heteroaryl ring is condensed to a benzene ring or another heteroaryl ring; Provided that when the substituent (s) on the heteroaryl is -OR ^b , -NR ^a R ^g or -CO ₂ R ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl; (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , or -OR ^b , wherein the heterocycloalkyl group in each case independently has 1 to 3 heteroatoms selected from the group consisting of O, NR ^e , (c) oxo, (d) -CN, (e) phenyl and (f) -NR ^a R ^g , 8-membered, 9-membered or 10-membered ring or heterocyclic ring; Comprising the reaction steps described above; When R ⁴ is a primary or secondary amine, a compound of formula (I), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug, is suitably protected during the reaction step And a method for producing the same.
[174] More specifically, the present invention provides a process wherein R ¹ is located at position 5 and R ² is located at position 3.
[175] More specifically, the present invention provides a process for preparing R ⁰ is hydrogen and R ¹ and R ² are each independently hydrogen, - (C ₁ -C ₆ ) alkyl, halogen or CN.
[176] More specifically, the present invention R ³ is hydrogen, - (C ₁ -C ₄₎ alkyl or halogen; R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ substituted by cycloalkyl, and heterocycloalkyl 0 to 3 substituents independently selected from the group consisting of - (C ₁ -C ₁₀₎ alkyl, (b) -S (O) 2 NR c R d, (c) -C (O) NR c R d, (d) -S (O) 2 R c, (e) - (c ₃ -C ₈₎ cycloalkyl, (f) heterocycloalkyl, (g) -C (O) R c, (h) -OR b, (i) -SR c, (j) -S (O) ^{R c, (k) -NR a} c (O) R d, (l) -NR a c (O) NR c R d , or ^{(m) -NR a S (O} ) 2 R d , or; Or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, 4, 5 or 6, or - (CH ₂ ) _k -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ; However, the substituent R ⁴ is 0 to 3 substituted with a substituent - if the (C ₁ -C ₁₀₎ alkyl, oxo groups - a (C ₁ -C ₁₀₎ substituted at carbon atoms other than the C ₁ carbon atom in the alkyl And a manufacturing method thereof.
[177] More specifically, the present invention R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ cycloalkyl and heterocycloalkyl with 0-3 independently selected from the group consisting of substituted with a substituent - (c ₁ -C _{10) alkyl, (b) - (c 3} -C 8) cycloalkyl, (c) heterocycloalkyl, (d) -C (O) R c, (e) - It provides a ^{oR b, (f) -NR a} C (O) R d, (g) -NR a C (O) NR c R d , or (h) a method for producing _{^{-NR a S (O) 2 R}} d .
[178] More specifically, R ⁵ is -OH, -OC (O) R ^f or -F; It provides a (C ₁ -C ₁₀₎ alkyl manufacturing method - R ^f is substituted with 0 to 3 substituents independently selected from the Group VI.
[179] More specifically, the present invention R ⁶ is hydrogen, halogen, or - (C ₁ -C ₄₎ alkyl; R < ⁷ > is hydrogen or methyl; R ⁸ and R ⁹ are each independently hydrogen, - (C ₁ -C ₆ ) alkyl or halogen.
[180] More particularly, the present invention relates to compounds of formula I wherein R < ⁶ > is hydrogen; R < ⁷ > is hydrogen; R ⁸ and R ⁹ are each independently hydrogen, methyl or -F.
[181] More particularly, the present invention relates to a process for the preparation of a compound of formula (I) wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ , or a pharmaceutically acceptable salt or prodrug thereof to provide.
[182] (A) acylating an aniline with the corresponding ester of formula A-4, and (b) reducing the compound of formula A-2 with a corresponding aniline of formula A- c) hydrolyzing said ester with a corresponding acid of formula A-5.
[183] R ¹ and R ² are each independently -CH ₃ or -Cl; R ⁴ is -SO ₂ -NH-cyclopropyl, -SO ₂ -NH-cyclobutyl, -SO ₂ -NH-cyclopentyl, -SO ₂ -NH-cyclohexyl, -SO ₂ -NH- (C ₁ -C ₈₎ unsubstituted or substituted by alkyl, or -SO ₂ -NH--fluoro phenyl; R ⁸ and R ⁹ are each independently hydrogen or methyl; Compounds of formula A wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ , isomers thereof, prodrugs of such compounds or isomers, Or a pharmaceutically acceptable salt of a prodrug;
[184] R ¹ and R ² are each independently -CH ₃ or -Cl; R ⁴ is _{-C (O) N (CH 3} ) - (C 3 -C 8) cycloalkyl, -C (O) NH-CH (CH (CH 3) 2) 2, -C (O) N (CH _{3) -CH (CH (CH 3} ) 2) 2, -C (O) N (CH 3) -CH (CH 3) 2, -C (O) NH-CH (CH 3) - cyclohexyl, -C (O) NH-CH ₂ - cyclohexyl, -C (O) N (CH 3) -CH 2 - cyclohexyl, -C (O) N (CH 3) -CH (CH 3) - cyclohexyl, or fluoro -C (O) NH-phenyl unsubstituted or substituted with halo; R ⁸ and R ⁹ are each independently hydrogen or methyl; Compounds of formula A wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ , isomers thereof, prodrugs of such compounds or isomers, Or a pharmaceutically acceptable salt of a prodrug; or
[185] R ¹ and R ² are each independently -CH ₃ or -Cl; R ⁴ is selected from the group consisting of -SO ₂ -CH ₂ -cyclopropyl, -SO ₂ -CH ₂ -cyclobutyl, -SO ₂ -CH ₂ -cyclopentyl, -SO ₂ -CH ₂ -cyclohexyl, -SO ₂ -cyclopentyl or -SO ₂ -cyclohexyl; R ⁸ and R ⁹ are each independently hydrogen or methyl; Compounds of formula A wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ , isomers thereof, prodrugs of such compounds or isomers, Or a pharmaceutically acceptable salt of a prodrug thereof.
[186] A
[187]
[188]
[189]
[190]
[191]
[1] The present invention relates to a novel thyroid receptor ligand, and more particularly to a novel thyroid receptor ligand which is useful for the treatment of obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, thyroid cancer, , Diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, osteoporosis and alopecia). The present invention also provides methods, pharmaceutical compositions and kits for the treatment of the above diseases and disorders.
[192] The present invention provides a compound of formula (I), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug. In addition,
[193] The use of compounds of formula (I), isomers thereof, prodrugs of such compounds or isomers, or pharmaceutically acceptable salts of such compounds, isomers or prodrugs to treat obesity, overweight, hyperlipidemia, glaucoma, cardiac arrhythmia Thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis. The present invention also relates to pharmaceutical compositions and kits.
[194] Also encompassed by the compounds of formula I, isomers thereof, prodrugs of such compounds or isomers, or the prodrugs of such compounds, isomers, and prodrugs thereof, for the treatment of symptoms such as alopecia in mammals, including stopping and / or reversing hair loss and promoting hair growth. Or a pharmaceutically acceptable salt of the prodrug may be used. Such symptoms may manifest themselves in alopecia, including, for example, male baldness and female baldness.
[195] The compounds of the invention are named according to the IUPAC or CAS nomenclature. In one way of naming the compounds of the present invention, the carbon atoms of the rings may be numbered as shown in the compounds of formula II:
[196]
[197] The carbon atom content of the various hydrocarbon-containing moieties is represented by the prefix designation of the minimum and maximum number of carbon atoms in the moiety, _i. E. The prefix (C _i -C _j ), together with the residues of the integer "i" . Thus, for example, (C ₁ -C ₃ ) alkyl together represent alkyl of 0 to 3 carbon atoms, ie methyl, ethyl, propyl and isopropyl, and all isomeric forms thereof and their straight and branched forms .
[198] The term " alkyl " means straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl. A preferred alkyl group is (C ₁ -C ₁₂ ) alkyl.
[199] The term " alkoxy " means an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. A preferred alkoxy group is (C ₁ -C ₁₂ ) alkoxy.
[200] The term " halogen " or " halo " means a radical derived from a chlorine, fluorine, bromine or iodine element.
[201] The term " alkenyl " means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds.
[202] The term " alkynyl " means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds.
[203] The term " cycloalkyl " refers to cyclic hydrocarbons. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred cycloalkyl groups are (C ₃ -C ₁₀₎ it is cycloalkyl. In addition, the cycloalkyl group may have one or more double bonds or triple bonds, or a combination of double bonds and triple bonds, but is not aromatic. Examples of cycloalkyl groups having double or triple bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like. It is also to be noted that the term cycloalkyl includes polycyclic compounds such as bicyclic or tricyclic compounds. The cycloalkyl group may be unsubstituted or substituted with 1 to 4 substituents.
[204] The term " perfluoroalkyl " means an alkyl group in which all oxygen atoms are replaced by fluorine atoms.
[205] The term " acyl " means a group derived from an organic acid (-COOH) by removal of the hydroxyl group (-OH).
[206] The term " aryl " means a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl and biphenyl. The aryl group may be unsubstituted or substituted.
[207] The term " heteroatom " includes oxygen, nitrogen, sulfur and phosphorus.
[208] The term " heteroaryl " means a cyclic aromatic hydrocarbon substituted with one or more carbon atoms by a heteroatom. When the heteroaryl group contains one or more heteroatoms, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, Indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo [b] thienyl . Preferred heteroaryl groups are 5-membered and 6-membered rings and include 1 to 3 heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group containing each heteroatom may be unsubstituted or substituted with 1 to 4 substituents, if chemically possible. For example, the heteroatom S may be substituted with one or two oxo groups, which may be represented by = O.
[209] The term " heterocycloalkyl " means a cycloalkyl group substituted by one or more carbon atoms with a heteroatom. When the heterocycloalkyl group contains one or more heteroatoms, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidyl and pyrrolidinyl. Preferred heterocycloalkyl groups are 5-membered and 6-membered rings and include 1 to 3 heteroatoms independently selected from the group consisting of O, N and S. In addition, the heterocycloalkyl group may have one or more double bonds or triple bonds, or a combination of double bonds and triple bonds, but is not aromatic. Examples of the heterocycloalkyl group containing a double or triple bond include dihydrofuran and the like. The heterocycloalkyl group containing each heteroatom may be unsubstituted or substituted with 1 to 4 substituents, if chemically possible. For example, the heteroatom S may be substituted with one or two oxo groups, which may be represented by = O. It is to be noted that cyclic ring groups, i. E., Aryl, heteroaryl, cycloalkyl, heterocycloalkyl, may comprise one or more rings. For example, the naphthyl group is a fused bicyclic ring system. The present invention also includes a ring group having a crosslinkable atom, or a ring group having a spiro orientation. For example, " spirocycloalkyl " refers to a cycloalkyl ring having a spiro compound (a compound formed by a single atom that is the only common member of the ring). Also, unless otherwise indicated, all suitable isomers of cyclic groups are understood to be included herein.
[210] Representative examples of 5 or 6 membered aromatic rings with or without one or two heteroatoms are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, iso Thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
[211] Representative examples of partially saturated, nuclear, saturated or fully unsaturated 5 to 8 membered rings with or without 1 to 3 heteroatoms include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further examples of the five-membered ring include furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H Imidazolidinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, Oligo, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, Triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxa 1,3-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, and 1,3-oxathiol.
[212] Further examples of 6-membered rings include 2-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, Thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2 , 3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H- 4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p- Isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl and 1,4,2-oxadiazinyl.
[213] Further examples of 7-membered rings include azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.
[214] Further examples of 8-membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
[215] Examples of bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated 5-membered and / or 6-membered rings, independently or with 1 to 4 heteroatoms independently selected from indolizinyl, indolyl, (B) thienyl, benzo (c) thienyl, lH-indazolyl, indolinyl, cyclopenta (b) pyridinyl, pyrano (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, Benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, Pyridyl (3,4-b) pyridinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, (3,2-b) pyridinyl, pyrido (4,3-b) pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl, and 4H-1 , 4-benzoxazinyl.
[216] The cyclic ring group may be bonded to another ring in more than one way. Although the binding arrangement is not specifically described, all possible arrangements are expected. For example, the term "pyridyl" includes 2-, 3- or 4-pyridyl, and the term "thienyl" includes 2- or 3-thienyl.
[217] The term " substituted " means that the hydrogen atom on the molecule is replaced by another atom or molecule. An atom or a molecule substituting a hydrogen atom is referred to as a substituent.
[218] The symbol " - " represents a covalent bond.
[219] The term " radical " refers to a group of atoms that behaves as a single atom in a chemical reaction, for example, an organic radical is an atomic group that characterizes a compound containing it or does not change during a series of reactions.
[220] The term " hydrate " is a compound of formula (I) or a salt thereof, including water in the form of a crystalline form or a salt thereof, e.g.
[221] The term " pharmaceutically acceptable salts " means that the salts of the compounds of the present invention may be formed into the compounds themselves, prodrugs, such as acids, esters, isomers and the like, ≪ / RTI > Pharmaceutically acceptable salts, esters, amides or prodrugs include, for example, carboxylate salts, amino acid addition salts, esters, amides, and toxins, irritants, allergic reactions, etc. that are not within normal medical judgment This includes prodrugs of compounds that are suitable for use in patients without a disease, where possible, with a reasonable benefit / risk ratio balanced and effective for the intended use, as well as amphoteric forms.
[222] The term " salt " means inorganic and organic salts of the compounds of the present invention. Such salts may be prepared in situ during final isolation and purification of the compound, or may be prepared by separately reacting the compound with a suitable organic acid, inorganic acid or salt and isolating the salt thus formed. It is preferred to use a base suitable for preparing the salt of the compound of the present invention. Representative salts include hydrobromides, hydrochlorides, sulfates, bisulfates, nitrates, acetates, hydroxides, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates , Fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate and the like. These include not only cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like but also non-toxic ammonium, quaternary ammonium and ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, (See, for example, SM Berge, et al., &Quot; Pharmaceutical Salts, " J. Pharm. Sci. , 66 , 1-19, 1977).
[223] More particularly, representative salts of the compounds of the present invention include sodium salts and potassium salts.
[224] Examples of pharmaceutically acceptable non-toxic esters of the compounds of the present invention include, depending on the application, (C ₁ -C ₈ ) alkyl esters. It is also an acceptable esters are (C ₅ -C ₇₎ cycloalkyl esters, as well as, contain aryl esters such as benzyl. Preferably a (C ₁ -C ₄ ) alkyl ester. Esters of the compounds of the present invention may be prepared according to methods well known in the art.
[225] Examples of pharmaceutically acceptable amphiphilic amides of the compounds of the present invention include amines derived from ammonia, (C ₁ -C ₈ ) alkyl primary amines and (C ₁ -C ₈ ) dialkyl secondary amines. In the case of a secondary amine, the amine may also be in the form of a 5-or 6-membered heterocycloalkyl group containing one or more nitrogen atoms. Preferably amides derived from ammonia, (C ₁ -C ₃ ) alkyl primary amines and (C ₁ -C ₂ ) dialkyl secondary amines. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art in view of the teachings of the present invention.
[226] The term " polymorph " means a compound, isomer, prodrug or salt thereof, such as a compound, isomer, prodrug or salt thereof of formula (I) produced in two or more forms.
[227] The term " prodrug " is a drug prodrug that, after administration, releases a drug (e. G., A compound of the invention) in vivo by a specific chemical or physiological method. For example, a prodrug is converted to the desired drug form by faced physiological pH or by enzymatic action. Such transformation may occur by various mechanisms, for example by hydrolysis in blood. A discussion of the use of prodrugs is provided in T. Higuchi and W. Stella, " Pro-drugs as Novel Delivery Systems ", ACS Symposium Series , Vol. 14 ] and [Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987).
[228] For example, when the compound of the present invention comprises a carboxylic acid functional group, the prodrug can be prepared by reacting the hydrogen atom of the acid group with (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, (Alkanoyloxy) ethyl having 1 to 10 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having 1 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyl (Alkoxy-carbonyloxy) ethyl, C 1-8 alkoxy-carbonyloxy, C 1-6 alkoxycarbonylaminomethyl, (C ₁ -C ₂ ) alkylamino (C ₂ -C ₆ ) alkylamino, such as methyl, ethyl, propyl, isopropyl, C ₃₎ alkyl (e. g., β- dimethylaminoethyl) carbamoyl - (C ₁ -C ₂₎ alkyl, N, N- di (C ₁ -C ₂₎ alkyl, carbamoyl - (C ₁ -C ₂ ) alkyl and piperidino-, pyrrolidino-or morpholino (C ₂ -C ₃₎ alkyl group such as It can comprise an ester formed by ring.
[229] Similarly, if a compound comprises the alcohol functionality of the present invention the prodrug is a hydrogen atom of the alcohol group (C ₁ -C _{6) alkanoyloxy-methyl, 1 - ((C 1 -C} 6) alkanoyloxy) ethyl (C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl, aryl acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl (O) (OH) ₂ , -P (O) (O (C ₁ -C ₆ ) alkyl) ₂ and glycosyl (which is produced by removing hydroxyl groups in the form of hemiacetals of carbohydrates Radicals)) with a group such as < RTI ID = 0.0 >
[230] If the compounds of the present invention comprise amine groups Prodrugs R- hydrogen atoms of the amine group-carbonyl, RO- carbonyl or carbonyl NRR'- [wherein, R and R 'are independently selected from (C ₁ respectively C ₁₀₎ alkyl, (C ₃ -C ₇₎ cycloalkyl or benzyl; R-carbonyl is natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, -C (OH) C (O) OY where Y is H, (C ₁ -C ₆ ) _{), -C (OY 0) Y} 1 ( wherein, Y ₀ is (C ₁ -C ₄₎ alkyl and Y ₁ is (C ₁ -C ₆₎ alkyl, carboxy (C ₁ -C ₆₎ alkyl, amino (C ₁ -C ₄₎ alkyl, or mono- or di -N- _{-N, N- (C 1 -C 6} ) _{alkyl-amino-alkyl), -C (Y 2) Y} 3) (Y 2 is H or methyl and Y ₃ is mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, morpholino, piperidin-1-yl or pyrrolidin- .
[231] The term " solvent " is a molecule or ion of a solvent and a molecule or ionic complex of a molecule or ion of a solute, and the " solvent ", in which the solvent is water, forms a hydrate or a hydrate ion.
[232] The phrase " therapeutically effective amount " means a compound amount or combination of compounds that ameliorates, decreases or eliminates a particular disease or condition, or prevents or delays the onset of a particular disease or condition.
[233] The term " patient " refers to animals such as dogs, cats, cows, horses, sheep, and humans. Particularly preferred patients are mammals, including both males and females.
[234] The phrase " pharmaceutically acceptable " means that the substance or composition must be compatible with the other ingredients of the formulation and not deleterious to the patient.
[235] The phrases " compounds of the present invention, compounds of formula (I) or compounds according to formula (I) ", and the like are to be understood to include, for example, their free forms (e.g., free acids or bases), all prodrugs, It should always be understood to include all active forms of the compounds, including hydrates, solvates, stereoisomers (e. G., Diastereoisomers and enantiomers), and all pharmaceutically acceptable salts as described above . In addition, suitable active metabolites of the compounds within the scope of Formula I of any suitable form will be recognized as being included herein.
[236] By " reaction-inert solvent " or " inert solvent " is meant a solvent or solvent mixture that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the desired product.
[237] The terms " treating ", " treating ", or " treating "
[238] The compounds of the present invention can exist in different stereoisomeric forms since they contain asymmetric or chiral centers. It is anticipated that all stereoisomeric forms of compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, when compounds contain double bonds, mixtures as well as cis and trans forms are expected.
[239] The diastereomeric mixtures can be separated into individual diastereomers based on physico-chemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization.
[240] Enantiomers are prepared by reacting an enantiomeric mixture with an appropriate, optional active compound (e. G., An alcohol) to convert to a diastereomeric mixture, separating into diastereomers and converting each diastereomer to the corresponding pure enantiomer For example, by hydrolysis). In addition, some of the compounds of the present invention may be rotationally disordered isomers (e. G., Substituted biaryls) and are considered part of the present invention.
[241] The compounds of the present invention may exist in solvated forms as well as unsolvated forms including pharmaceutically acceptable solvents such as water, ethanol, and the like. The present invention contemplates and encompasses both solvated and unsolvated forms.
[242] The compounds of the present invention may exist in different tautomeric forms. All tautomers of the compounds of the present invention are expected. For example, all tautomeric forms of imidazole residues are encompassed by the present invention. Also, all keto-enols or imine-enamines of, for example, compounds are included in the present invention.
[243] Those skilled in the art will recognize that the name of the compound included in the present invention may be based on the specific tautomer of the compound. While only names for certain tautomers can be used, all tautomers are included by the name of a particular tautomer and all tautomers are considered part of the invention.
[244] The presently disclosed subject matter also includes compounds synthesized in vitro using laboratory techniques, such as methods well known to synthetic chemists, or compounds synthesized using in vivo techniques such as metabolism, fermentation, digestion, and the like.
[245] It is also anticipated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
[246] The present invention also includes isotopically-labeled compounds, which are identical to the compounds described herein but differ from the fact that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature . Examples of isotopes that can be included in the compounds of the invention and each ^{2 H, 3 H, 13 C} , 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and ³⁶ Cl Such as hydrogen, carbon, nitrogen, oxygen, sulfur, phosphorus, fluorine and chlorine isotopes. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of these compounds or prodrugs, including the isotopes and / or other isotopes of other atoms, are within the scope of the present invention. The isotopes of triple deuterium ( ³ H) and carbon-14 ( ¹⁴ C) are particularly preferred because of their ease of preparation and detection sensitivity. In addition, certain therapeutic advantages may be obtained when substitution with a larger isotope such as deuterium ( ² H), for example, increases metabolic stability with an increase in half-life in vivo or a decrease in the required dosage, Which may be desirable. Isotopically-labeled compounds of the invention and prodrugs thereof are generally prepared by performing the methods described in the following scheme and / or examples and using isotope-labeled reagents that are readily available in place of non-isotope-labeled reagents .
[247] Compounds of formula I of the present invention are prepared as described in the following Schemes and Examples, or prepared by methods analogous to those readily known and available to those skilled in the art in view of this disclosure. The reaction schemes herein illustrate the preparation of compounds of the present invention and, unless otherwise indicated, the substituents in the schemes are as described above. In addition, the examples provided herein illustrate the preparation of the compounds of the present invention. The starting materials for each of the reaction schemes and examples provided herein are either commercially available or prepared according to methods known to those skilled in the art. It should be understood that the following schemes are provided for illustration only and are not intended to limit the invention as defined by the claims. Changes in the order of the reaction steps, and changes in the reactants and conditions used, will be readily apparent to those skilled in the art in light of the present disclosure. In some of the schemes, certain reagents and conditions are given for illustration purposes, but this is not intended to limit the disclosure.
[248]
[249]
[250]
[251] Scheme A
[252] Diphenyl ether A-1, a key intermediate for the preparation of the malonic acid of the present invention, can be synthesized by methods analogous to those known in the art. For example, diphenyl ether A-1 is 4-nitrophenol A-1a, wherein R ¹ is methyl and R ² is methyl; or R ¹ is chloro and R ² is chloro, all of which are commercially available. (See for example J. Med. Chem . 38 , 695-707, 1995) in a suitable organic solvent (e. G. Dichloromethane) with a copper catalyst (e. G. Copper bronze) and a suitable base )) With bis-aryl iodonium tetrafluoroborate A-1b at room temperature. Bis-aryl iodonium tetrafluoroborate A-1b is described in J. Med. Chem. , 38 , 695-707, 1995).
[253] In addition, diphenyl ether A-1 can be obtained by reacting commercially available phenol A-1c with 4- (2-methoxyphenyl) propane in the presence of a suitable base such as potassium carbonate or potassium t-butoxide in a polar inert solvent such as DMSO or N-methylpyrrolidone at 130 & Such as iodo nitrobenzene (where X is Idl), 4-bromonitrobenzene (where X is Br), 4-chloronitrobenzene (where X is Cl) or 4-fluoronitrobenzene With commercially available 4-halonitrobenzene A-1d.
[254] Another third method for the preparation of diphenyl ether A-1 is the coupling of copper (II) acetate and a suitable base (for example TEA, pyridine or a mixture of TEA and pyridine) in dichloromethane ( Tetrahedron Lett , 39 , 2933- 296, 2937-2940, 1998), at room temperature, is coupled with phenylboronic acid A-1e, which may be prepared commercially or according to literature methods.
[255]
[256]
[257] Scheme B
[258] The preparation of 3'-substituted or unsubstituted malonic acid B-5 is shown in Scheme B above. Phenol B-2 is obtained by demethylating A-1 of Scheme A using a suitable boron trichloride such as boron trichloride or boron tribromide in a suitable organic solvent such as dichloromethane or chloroform. Aniline B-3 is obtained by hydrogenating nitrophenol B-2 in MeOH or EtOH in the presence of 10% Pd / C. B-3 is acylated with malonyl chloride in THF as shown in step (a) to give ester B-4. Alternatively, an ester B-4 is obtained by heating aniline B-3 with an excess of dimethyl malonate at 140 占 폚, as shown in step (b). Hydrolysis of B-4 with a suitable base (e.g., NaOH or KOH) at room temperature in an aqueous MeOH solution produces Malonamic acid B-5, wherein the substituent is as defined above.
[259] In addition, ester B-6 is prepared by acylating B-3 with succinyl chloride in THF. 6 is hydrolyzed with a suitable base (e.g., NaOH or KOH) in MeOH aqueous solution at room temperature to produce malonic acid B-7 wherein the substituent is as defined above.
[260]
[261] Scheme C
[262] The 3'-sulfonamide of the present invention is prepared as shown in Scheme C above. The 3'-chlorosulfonyl compound C-2 is obtained by reacting compound C-1 of Scheme A wherein R ⁰ , R ³ , R ⁴ and R ⁶ are each hydrogen with pure chlorosulfonic acid at 0 ° C to room temperature. Compound C-3 is obtained by reacting compound C-2 with a primary amine in the presence of a suitable base such as TEA or diisopropylethylamine in a suitable solvent such as dichloromethane, THF, MeOH, EtOH or acetonitrile. Likewise, compound C-4 can be prepared by reacting compound C-2 with a secondary amine under similar conditions. Alternatively, by alkylation of the compound C-3 in a suitable organic solvent, such as compound C-4 uses a suitable alkylating agent such as (R ^d X) halogenated alkyl and X is halogen and THF under jonje of a suitable base such as sodium hydride Can be manufactured.
[263] Compound C-3 is demethylated with boron tribromide in chloroform. Phenol which is then demethylated by hydrogenation, acylation and basic hydrolysis according to a method analogous to that described in Scheme B, is converted to malonic acid C-5 as defined above. Likewise, malonic acid C-6, wherein the substituents are as defined above, can be prepared from the nitro compound C-4 by demethylation, hydrogenation, acylation and alkali hydrolysis according to methods analogous to those described in Scheme B.
[264]
[265] Scheme D
[266] The 3'-carboxamides of the present invention are prepared as described in Scheme D above. Compound C-1 of Scheme C is reacted with hexamethylenetetramine at 65 < 0 > C in TFA to give 3'-aldehyde D-1. Carboxylic acid D-2 is obtained by oxidation of formula D-1. Preferred oxidation methods include the Jones oxidation method (chromic acid / aqueous sulfuric acid) and sodium chlorite (NaClO ₂ , KH ₂ PO ₄ , 2-methyl-2-butene, t-butanol in THF) do. Carboxylic acid D-2 can be converted to carboxamide D-3 or D-4 according to methods analogous to those known in the art. For example, by reacting the acid chloride or mixed anhydride of the compound D-2 with a primary amine in the presence of a base such as TEA, dimethylaminopyridine or pyridine in a suitable aprotic organic solvent such as dichloromethane, THF, DME or DEE Compound D-3 is obtained. Likewise, compound D-4 can be prepared by reacting carboxylic acid D-2 with a secondary amine under similar conditions.
[267] The carboxylic acid D-2 may also be prepared by reaction with N-hydroxysuccinimide, dicyclohexylcarbodiimide and a primary or secondary amine in 1,2-dimethoxyethane in the presence of a suitable base such as TEA to give carboxamide D-3 or D-4, respectively. Alternatively, compound D-3 can be prepared from
[268] May be converted to compound D-4 by alkylation in a suitable organic solvent such as DMF in the presence of a suitable base such as sodium hydride, using a suitable alkylating agent such as a halogenated alkyl (R ^d X) wherein X is halogen.
[269] Compound D-3 can be converted to malonic acid D-5 as described above by substitution by demethylation, hydrogenation, acylation, and basic hydrolysis according to methods analogous to those described in Scheme B. Likewise, compound D-6, wherein the substituents are as defined above, can be prepared from compound D-4 by demethylation, hydrogenation, acylation and alkaline hydrolysis according to methods analogous to those described in Scheme B.
[270]
[271]
[272] Scheme E
[273] The preparation of the 3'-arylsulfone of the present invention is outlined in Synthetic Scheme 1 and 2 as shown in Scheme E above. In Synthetic Scheme 1, the dehydrating agent, preferably methanesulfonic acid (Eaton's reagent (Eaton's reagent)) or poly-aryl compound C-1 of Scheme C at about 110 ℃ from phosphoric acid, or aryl in the presence of P ₂ O ₅ Sulfonyl chloride gives Sulfone E-1, wherein X and Y are substituents in the phenyl ring. Nitro compound E-1 can be converted to malonamic acid E-2 as defined above by demethylation, hydrogenation, acylation and hydrolysis, analogously to the method described in Scheme B,
[274] Alternatively, the 3'-arylsulfone of the present invention can be preferably prepared as described above in Synthetic Scheme 2. Reduction of the commercially available arylsulfonyl chloride E-3 in H ₂ O to sodium sulfite in the presence of a base such as sodium bicarbonate or NaOH gives the arylsulfinic acid E-4. The dihydroxyaryl-arylsulfone E-5 is obtained by adding compound E-4 to the benzoquinone in a mixture of ethanol and water. Reacted with potassium bis (trimethylsilyl) amide in N-methylpyrrolidinone in the presence of 18-crown-6 and molecular sieves and then reacted with 4-halonitrobenzene A-1d of Scheme A to give dihydroxyaryl- E-5 can be selectively arylated to yield the hydroxy-nitro compound E-6. Hydroxy-nitro compound E-6 can be converted to malonamic acid E-2 by hydrogenation, acylation and hydrolysis according to methods analogous to those described in scheme B.
[275]
[276] Scheme F
[277] The preparation of the 3'-alkyl sulfone of the present invention is illustrated in Scheme F above. Compound C-1 of Scheme C is reacted with chlorosulfonic acid to give the 3'-chlorosulfonyl compound as shown as compound C-2 in Scheme C. Sulfinic acid F-1 is obtained by reducing the 3-chlorosulfonyl compound to sodium sulfite in H ₂ O in the presence of a base such as sodium bicarbonate or NaOH. Sodium bicarbonate, NaOH, sodium hydride and an alkyl, by alkylation with sodium methoxide or potassium t- butoxide X is halogen in the halogenated alkyl sulfonic acid F-1 in the presence of a base, such as a side (R ^c X) R ^c is an alkyl sulfone F-2 is obtained. The nitro compound F-2 can be converted to malonic acid F-3 by R < ^c > alkyl and other substituents as defined above by dimerization, hydrogenation, acylation and hydrolysis according to methods analogous to those described in Scheme B have. Reduction can also be performed in ethanol using SnCl ₂ as a reducing agent.
[278]
[279] Scheme G
[280] The 3'-keto and 3'-hydroxy derivatives of the present invention are prepared as shown in Scheme G above. Dichloro titanium tetrachloride at room temperature in methanesulfonic acid chloride with the compound C-1 of Scheme C - to prepare a Craft (Friedel-Crafts) acylated by a compound R ^c G-1 as defined above-catalysed Friedel. The malonic acid ester G-2, wherein the substituent is as defined above, is prepared from the nitro compound G-1 by demethylation, hydrogenation and acylation according to a method analogous to that described in Scheme B. Alkali hydrolysis of compound G-2 with a suitable solvent such as NaOH yields malonic acid G-3 in which the substituent is as defined above. Reduction of compound G-2 with sodium borohydride in MeOH affords alcohol G-4, wherein the substituent is as defined above. The reduction can also be carried out by hydrogenation using a Raney nickel catalyst. Alkali hydrolysis of compound G-4 with a suitable base such as NaOH affords the acid G-5 in which the substituent is as defined above.
[281]
[282] Scheme H
[283] 3'-tertiary alcohols and 3'-methylene derivatives are prepared according to the process shown in Scheme H above. Compound H-1 is obtained by reducing G-1 ketone carbonyl group with R < ^c > as defined above in Scheme G to triethylsilane and trifluoroacetic acid in dichloromethane. Malonamic acid H-3, wherein the substituent is as defined above, may be prepared from the nitro compound H-1 by demethylation, hydrogenation, acylation and hydrolysis according to methods analogous to those described in Scheme B.
[284] Diethyl ether to give a Grignard or with (Grignard) reagent alcohol or H-2 by reaction with an organolithium compound such as a ketone G-1 of Scheme G in an aprotic solvent, such as R ^d is as defined above THF. The nitro compound H-2 is converted to malonic acid H-4 as described above by substitution by demethylation, hydrogenation, acylation and hydrolysis according to a method analogous to that described in Scheme B.
[285]
[286] Scheme I
[287] The preparation of the 3'-methylamino derivatives of the present invention is shown in Scheme I above. Compound C-1 of Scheme C can be converted to malonic acid ester I-1 by demethylation, hydrogenation, and acylation according to methods analogous to those described in Scheme B. Compound I-1 is reacted with hexamethylenetetramine in TFA at 65 < 0 > C to give the 3'-aldehyde I-2. Aldehyde I-2 can be converted to the methylamino derivative I-3 as defined above wherein the substituent is as defined above by methods known in the art. In a preferred method, reductive amination is used. For example, reductive amination can be carried out by reacting the aldehyde I-2 with an amine and a reducing agent, R ^c and R ^d as defined above, in a suitable solvent in the presence of a 3 A molecular sieve. Preferred reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride. Preferred organic solvents include EtOH, MeOH and 1,2-dichloromethane. Hydrolysis of compound I-3 with a suitable base such as NaOH and acidification yields HCl salt I-4, wherein the substituent is as defined above.
[288]
[289] Scheme J
[290] 3'-aryl ethers are prepared as shown in Scheme J above. The commercially available compound J-1 is reacted with hydrogen peroxide in MeOH and phenol J-2 is obtained by adding concentrated H ₂ SO ₄ . Coupling ether J-3 is obtained by coupling phenol J-2 with 4-chloronitrobenzene in DMSO in the presence of potassium t-butoxide. Compound J-3 is debenzylated with thioanisole at room temperature in TFA to prepare 3'-hydroxy compound J-4. 4 with aryl boronic acid in dichloromethane in the presence of copper (II) acetate and a suitable base (e.g., TEA, pyridine, or a mixture of TEA and pyridine) to give the aryl ether J- 5 can be switched to. Alternatively, the aryl ether J-5 can also be obtained by coupling compound J-4 with aryl iodonium tetrafluoroborate in dichloromethane in the presence of copper bronze and TEA. Malonamic acid J-6, wherein X and Y are substituents on the < RTI ID = 0.0 > phenethyl < / RTI > ring and the other substituents are as defined above, is deprotected, hydrogenated, acylated and hydrolyzed to yield the nitro compound J-5 .
[291]
[292] Scheme K
[293] The preparation of the indole analog is shown in Scheme K above. Compound C-1 commercially available in N-methylpyrrolidone in the presence of potassium carbonate is reacted with commercially available p-halonitrobenzene K-2 such as 4-iodonitrobenzene (also Compound A-1d of Scheme A ) To obtain an ether compound K-3. Subsequently, the nitrobenzene compound K-3 is converted to malonic acid K-4 as defined above by hydrogenation, acylation and hydrolysis according to a method analogous to that described in Scheme B.
[294]
[295] Reaction formula L
[296] The preparation of C1-2-hydroxyacetamide is shown in Scheme L above. Benzyloxyacetamide L-2 is obtained by acylating aniline L-1, prepared as described in Scheme B, in THF in the presence of TEA with benzyloxyacetyl chloride. Hydrogenation of compound L-2 in the presence of 10% Pd / C gives the debenzylated product L-3, wherein the substituent is as defined above.
[297]
[298] Scheme M
[299] The C1-malonamide is prepared as shown in Scheme M above. Acid M-1, prepared as described in Scheme B above, is reacted with thionyl chloride in THF to afford acid chloride M-2. Reaction of the acid chloride M-2 with an amine in a suitable solvent such as methylene chloride gives the malonamide M-3 in which the substituent is as defined above.
[300]
[301] Scheme N
[302] Compound N-1, prepared as described in Scheme A, is brominated in chloroform using, for example, N-bromosuccinimide and trifluoroacetic acid under reflux to yield compound N-2. For example, compound N-2 is reduced to the corresponding aniline N-3 by hydrogenation (palladium / carbon catalyst in ethyl acetate) by catalysis. For example, compound N-3 can be reacted with a resin-bound aryl aldehyde, such as indole resin N-4, in dichloroethane and methanol using reductive amino conditions such as tetramethylammonium triacetoxyborohydride and sodium cyanoborohydride To give resin-bound aniline N-5 (resin B).
[303]
[304] Scheme O
[305] The resin N-5 (resin B) functionalized in the presence of a suitable base such as N, N-diisopropylethylamine, using a suitable coupling agent such as tetramethylfluoroformamidinium hexafluorophosphate, Coupling with a carboxylic acid such as t-butylmalonate gives the resin-bound amide O-1 (Resin C).
[306]
[307] Scheme P
[308] The functionalized resin O-1 (Resin C) can be reacted with DMF or 1,2 (1,2-dimethoxyethane) in the presence of a palladium catalyst (for example, tetrakis (triphenylphosphine) palladium (0)) and a base (Resin D) in which aryl is substituted or unsubstituted phenyl by coupling to an organoboronic acid, for example 4-methoxyphenylboronic acid, in a suitable organic solvent such as dichloroethane. The resin bound amide P-1 (resin D) is demethylated and a suitable boron trichloride (e.g., boron trichloride or boron tribromide) is reacted with a suitable organic solvent (e.g., 1,2- Dichloromethane), followed by esterification with aqueous methanol to obtain compound P-2, wherein aryl is phenyl unsubstituted or substituted with aryl. Resin O-1 (Resin C) is cleaved in dichloromethane with trifluoroacetic acid to give malonic acid P-3.
[309] Demethylation of the functionalized resin O-1 (resin C) and the appropriate boron trichloride (e.g., boron trichloride or boron tribromide) in a suitable organic solvent (e.g., 1,2-dichloroethane or 1,2 -Dichloromethane), followed by esterification with aqueous methanol to obtain compound P-4.
[310]
[311] Reaction formula Q
[312] The preparation of indan-malonamic acid Q-10 is shown in Scheme Q. The commercial 2,5-dimethoxycinnamic acid Q-1 is hydrated to obtain propionic acid Q-2. Indanone Q-3 is obtained by reacting compound Q-2 with P ₂ O ₅ in TFA. By selectively demethylating the compound Q-3 with BCl ₃ in CH ₂ Cl ₂ to afford the phenol Q-4.
[313] Reduction of compound Q-4 to triethylsilane in the presence of methanesulfonic acid gives indane Q-5. Coupling of indan-Q-5 with chloronitrobenzene A-1d in Scheme A in DMSO using potassium carbonate as base gives diaryl ether Q-6. Compound Q-6 is demethylated with methionine in methanesulfonic acid to give phenol Q-7. Compound Q-7 can be converted to malonic acid Q-10 by hydrogenation, acylation and alkaline hydrolysis according to methods analogous to those described in Scheme B.
[314]
[315] Scheme R
[316] Isoindol-1-one The preparation of compounds R-5 and R-7 is shown in Scheme R above. The 4,7-dihydroxy-isoindole-1,3-dione R-2 was prepared by reacting commercially available 3,6-dihydroxy-phthalonitrile R-1 in the presence of aqueous H ₂ SO ₄ at 100 & (See Chem. Europ. J. , EN; 2; 1; 31-44, 1996). Isoindole-1,3-dione R-2 is reduced with zinc in glacial acetic acid at 100 < 0 > C for 13 hours to obtain compound R-3 (see J. Med. Chem. , 243-246, 1983). Isoindol-1-one R-3 is reacted with potassium bis (trimethylsilyl) amide in N-methylpyrrolidinone in the presence of 18-crown-6 and molecular sieves, Lt; RTI ID = 0.0 > A-1d. ≪ / RTI > The hydroxy-nitro compound R-4 can be converted to malonamic acid R-5 by hydrogenation, acylation and hydrolysis according to methods analogous to those described in scheme B. Also, isoindol-1one R-4 is selectively methylated in the presence of a base such as potassium bis (trimethylsilyl) amide to give an O-methylated compound R-6. The N-alkylated compound is obtained by reacting methoxy-isoindol-1-one R-6 with an alkyl halide using a base such as sodium hydride. The methoxy-nitro compound R-7 can be converted to malonamic acid R-8 by demethylation, hydrogenation, acylation and hydrolysis according to methods analogous to those described in Scheme B.
[317] The present invention has aspects related to the treatment of the diseases / conditions described herein using a combination of active ingredients. In combination therapy therapies, the compounds of the invention and other drug therapies are used in mammals (e.g., man, male or female) by conventional formulations and methods as described above. As will be appreciated by those skilled in the art, therapeutically effective amounts of the compounds of the invention and other pharmacological therapies used in patients with combination therapy therapy will depend on a number of factors, including the desired biological activity, patient ' But it is not limited thereto. Dosages and methods of using other drug therapies useful in the present invention are known in the art, as described, for example, in the following patents, patent applications, and patent publications, the entirety of which is incorporated herein by reference.
[318] For example, the characteristics of a patient at risk for atherosclerosis are well known to those of skill in the art and include, but are not limited to, hypertension and atherosclerosis, non-renal disease patients, rarely exercise patients, hypercholesterolemia, hyperlipidemia and / Patients with a family history of cardiovascular disease, including those with hemophilia, patients with high levels of LDL or Lp (a), patients with low levels of HDL, and the like.
[319] In one aspect, the present invention is directed to the treatment of diabetes mellitus including tolerance to insulin resistance, insulin resistance, insulin dependent diabetes (type I) and non-insulin dependent diabetes mellitus (NIDDM or type II). Also, the treatment of diabetes includes diabetic complications such as neuropathy, nephropathy, retinopathy and cataract.
[320] A preferred type of diabetes mellitus to be treated with the compounds of the present invention is also non-insulin dependent diabetes mellitus known as type II diabetes or NIDDM.
[321] By administering a therapeutically effective amount of a compound of the invention to a patient suffering from diabetes (Type I or Type II), insulin resistance, impaired glucose tolerance or any diabetic complication (e.g., neuropathy, nephropathy, retinopathy or cataract) Diabetes can be treated. It is also intended to treat diabetes by administering a compound of the invention in combination with other drugs that may be used to treat diabetes.
[322] Representative drugs that can be used in combination with the compounds of the present invention to treat diabetes include insulin and insulin analogs (e.g., LysPro insulin); GLP-1 (7-37) (Insulated Reno Trojan pin) and _{GLP-1 (7-36) -NH 2} ; Sulfonylureas and analogs; Chlorpromamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide (R), glymepyrid, repaglinide, meglitinide and biguanide; Metformin, phenformin and < RTI ID = 0.0 > alpha 2-antagonists and imidazolines; Mydaglizole, isoglitol, derglyldol, dodozan, eparoxan and fluparoxan; Other insulin secretagogues; Linoglyories and A-4166; Glitazones; Cyclitazone; Actos (registered trademark) (pioglitazone), anglitazone, troglitazone, dalguritazon and Avandia (registered trademark) (BRL 49653); Fatty acid oxidation inhibitors; Clomipramine and clomipramine; alpha -glucosidase inhibitors; Acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose and MDL-73,945; β-antagonists; BRL 35135, BRL 37344, RO 16-8714, ICI D7114 and CL 316,243; Phosphodiesterase inhibitors; L-386,398; Lipid lowering agent: benfluorescein; Anti-aircraft agents: fenfluramine; Vanadium complexes with vanadium complexes (e.g., Naglivan (R)) and peroxovanadium complexes; Amylin antagonists; Glucagon antagonists; Glucagon antagonists; You biosynthesis inhibitors; Somatostatin analogs; Release of lipid lipids; And nicotinic acid, acipimox and wag (WAG) 994. In addition, pramine tide (Symlin (trademark)), AC 2993 and nateglinide are used in combination with the compound of the present invention. Any drug or mixture of drugs may be administered as described above.
[323] In addition, the compounds of the invention may be used in admixture with one or more of the aldose reductase inhibitors, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, NHE-I inhibitors and / or glucocorticoid receptor antagonists.
[324] The compounds of the present invention can be used in combination with an aldose reductase inhibitor. Aldose reductase inhibitors are a component of a class of compounds well known for their use in the treatment of symptoms resulting from diabetic complications such as diabetic neuropathy and nephropathy. Such compounds are well known to those skilled in the art and are readily identified by standard biological tests. For example, the aldose reductase inhibitor zolpolestate, 1-phthalazinic acetic acid, 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2- benzothiazolyl] methyl] - and related compounds are described in US Patent 4,939,140 to Larson et al.
[325] Aldose reductase inhibitors are taught for use in lowering lipid levels in mammals (see, for example, Kallai-sanfacon U.S. Pat. No. 4,492,706 and European Patent EP 0 310 931 A2 (Ethyl Corporation)).
[326] U.S. Patent No. 5,064,830 to Going discloses the use of certain oxoptalazinyl acetic acid aldose reductase inhibitors, including Joplorestat, to lower serum uric acid.
[327] The commonly assigned U.S. Patent No. 5,391,551 discloses the use of certain aldose reductase inhibitors, including Joplorestat, to lower blood lipid levels in the human body. The disclosure teaches that the therapeutic use is induced by the treatment of a disease caused by an increase in blood triglyceride levels, such as cardiovascular disorders (thrombosis), atherosclerosis, myocardial infarction and angina pectoris. A preferred aldose reductase inhibitor is Zoopholestat.
[328] The term aldose reductase inhibitor refers to a compound that is promoted by the enzyme aldose reductase and inhibits the biotransformation of glucose to sorbitol. Any aldose reductase inhibitor may be used in admixture with the compounds and mixtures of the present invention. Aldose reductase inhibitors are readily measured by those skilled in the art according to standard assays (see Red Cell Sorbitol, J. Malone , Diabetes , 29 , 861-864, 1980) do. While various aldose reductase inhibitors are described herein, other aldose reductase inhibitors useful in the compositions and methods of the present invention will be known to those skilled in the art.
[329] The activity of the aldose reductase inhibitor in the tissue can be reduced by either reducing the tissue sorbitol (i.e., by blocking aldose reductase as a result of further inhibition of sorbitol production) or by reducing tissue fructose (inhibiting the production of sorbitol By blocking the resultant aldose reductase and consequently inhibiting the production of fructose). ≪ / RTI >
[330] Thus, additional examples of aldosyldoduct inhibitors useful in the compositions, mixtures and methods of the present invention include,
[331] 1. 3- (4-Bromo-2-fluorobenzyl) -3,4-dihydro-4-oxo-1-phthalazineacetic acid (phonalesate, U.S. Patent No. 4,251,528);
[332] 2. N [[(5-Trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine (Tolestert, U.S. Patent No. 4,600,724);
[333] 3. 5 - [(Z, E) - - methylcinnamylidene] -4-oxo-2-thioxo-3-thiazolidene acetic acid (epalrestat, U.S. Patent Nos. 4,464,382, 4,791,126 and 4,831,045);
[334] 4. Preparation of 3- (4-bromo-2-fluorobenzyl) -7-chloro-3,4-dihydro-2,4-dioxo-1 (2H) -quinazoline acetic acid 4,734,419 and 4,883,800);
[335] 5. 2R, 4R-6,7-Dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Patent No. 4,883,410);
[336] 6. 2R, 4R-6,7-Dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Patent No. 4,883,410);
[337] 7. 3,4-Dihydro-2,8-diisopropyl-3-oxo-2H-l, 4-benzoxazine-4-acetic acid (U.S. Patent No. 4,771,050);
[338] 8. Preparation of 3,4-dihydro-3-oxo-4 - [(4,5,7-trifluoro-2-benzothiazolyl) methyl] -2H-1,4-benzothiazin- SPR-210, U.S. Patent No. 5,252,572);
[339] 9. N- [3,5-Dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -2-methylbenzeneacetamide (ZD5522, U.S. Patent Nos. 5,270,342 and 5,430,060);
[340] 10. (S) -6-Fluorospiro [chroman-4,4'-imidazolidine] -2,5'-dione (sorbinyl, U.S. Patent No. 4,130,714);
[341] 11. d-2-Methyl-6-fluorospiro (chroman-4 ', 4'-imidazolidine) -2', 5'-dione (US Pat. No. 4,540,704);
[342] 12. 2-Fluorospiro (9H-fluorene-9,4'-imidazolidine) -2 ', 5'-dione (U.S. Patent No. 4,438,272);
[343] 13. 2,7-difluorospiro (9H-fluorene-9,4'-imidazolidine) -2 ', 5'-dione (U.S. Patents 4,436,745 and 4,438,272);
[344] 14. 2,7-Difluoro-5-methoxy spiro (9H-fluorene-9,4'-imidazolidine) -2 ', 5'-dione (U.S. Patents 4,436,745 and 4,438,272) ;
[345] 15. 7-Fluorospiro (5H-indol [l, 2-b] pyridine-5,3'-pyrrolidine) -2 ', 5'-dione (U.S. Patents 4,436,745 and 4,438,272);
[346] 16. A compound according to claim 1 which is selected from the group consisting of d-cis-6'-chloro-2 ', 3'-dihydro-2'-methyl spiro (imidazolidin-4,4'- Pyridine) -2,5-dione (U.S. Patent No. 4,980,357);
[347] 17. Spiro [imidazolidin-4,5 '(6H) -quinoline] -2,5-dione-3'-chloro-7', 8'-dihydro-7'- ) (U.S. Patent No. 5,066,659);
[348] 18. (2S, 4S) -6-fluoro-2 ', 5'-dioxospiro (chroman-4,4'-imidazolidine) -2-carboxamide (U.S. Patent No. 5,447,946); And
[349] 19. A process for the preparation of 2 - [(4-bromo-2-fluorophenyl) methyl] -6-fluorospiro [isoquinolin- '(2H) -tetrone (ARI-509, U.S. Patent No. 5,037,831).
[350] Other aldose reductase inhibitors include compounds having the formula < RTI ID = 0.0 > (Ia) < / RTI &
[351]
[352] In this formula,
[353] Z is O or S;
[354] R ¹ is hydroxy or a group that is capable of generating a compound of formula I wherein R ¹ is OH in vivo;
[355] X and Y are the same or different and are selected from the group consisting of hydrogen, trifluoromethyl, fluoro and chloro.
[356] Preferred subgroups of aldose reductase inhibitors in this group include compounds No. 1, 2, 3, 4, 5, 6, 9, 10 and 17,
[357] 20. 3,4-dihydro-3- (5-fluoro-2-yl) -4-octanoic soft ride-triazine-1-yl acetic acid [R ¹ is hydroxy and X is F and Y is H;
[358] 21. A process for the preparation of 3- (5,7-difluorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R ¹ is hydroxy and X and Y Is F;
[359] 22. 3- (5-chloro-benzothiazol-2-ylmethyl) -3,4-dihydro-4-oxide Soap de-triazine-1-yl acetic acid [R ¹ is hydroxy and X is Cl and Y is H to be];
[360] 23. A compound according to claim 1, wherein R ¹ is hydroxy and X and Y are Cl or Cl. 3. A compound according to claim 1, to be];
[361] 24. A process for the preparation of 3,4-dihydro-4-oxo-3- (5-trifluoromethylbenzoxazol-2-ylmethyl) phthalazin-1-ylacetic acid, wherein R ¹ is hydroxy and X is CF ₃ Y is H;
[362] 25. A process for the preparation of 3,4-dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxopthalazin-1-yl acetic acid, wherein R ¹ is hydroxy, X is F and Y is H;
[363] 26. 3- (5,7-difluoro-benzoxazol-2-ylmethyl) -3,4-dihydro-4-oxide Soap de-triazine-1-yl acetic acid [R ¹ is hydroxy and X and Y Is F;
[364] 27. 3- (5-Chlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl acetic acid [R ¹ is hydroxy, X is Cl and Y is H to be];
[365] 28. 3- (5,7-Dichlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl acetic acid [R ¹ is hydroxy and X and Y are Cl to be];
[366] 29. Joplorestat; Dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] - [R ¹ is hydroxy and X is trifluoro Lt; / RTI > is H;
[367] In the above compounds 20 to 23 and 29, Z is S. In the above compounds 24 to 28, Z is O.
[368] Among the subgroups, compounds 20 to 29 are more preferable, and 29 is particularly preferable. Methods for preparing the aldose reductase inhibitors of formula (Ia) can be found in International Patent Publication No. WO 99/26659.
[369] In addition, the compounds of the invention may be used in admixture with glucocorticoid receptor modulators, or more specifically with glucocorticoid receptor antagonists. The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells in cytosol in an inactive state until stimulated by an agonist. Upon stimulation, the glucocorticoid receptor specifically interacts with DNA and / or protein (s) and transfers to the cell nucleus, which regulates transcription by the glucocorticoid response method. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NF [ _{kappa] -B} . As a result of the interaction, it is believed that the inhibition of API- and NF _{< [kappa] &gt}; -mediated transcription and the glucocorticoid-induced glucocorticoid have anti-inflammatory activity. In addition, glucocorticoids can exert a physiological effect independent of nuclear transfer. Biochemically suitable glucocorticoid receptor agonists include cortisol and corticosterone. There are numerous synthetic glucocorticoid receptor agonists including dexamethasone, prednisone, and prednisilone. By definition, glucocorticoid receptor antagonists bind to receptors and prevent the glucocorticoid receptor agonist, including transcription, from binding and inducing GR mediated events. RU486 is an example of a non-selective glucocorticoid receptor antagonist. GR antagonists can be used to treat diseases associated with an excess or deficiency of glucocorticoid in the body. Thus, GR antagonists are useful in the treatment of obesity, diabetes, cardiovascular disease, hypertension, X syndrome, depression, anxiety, glaucoma, HIV or AIDS, neurodegeneration (e.g. Alzheimer ' Alzheimer ' s disease and Parkinson ' s disease), cognitive impairment, Cushing's syndrome, Addison's disease, osteoporosis, weakness of the wills, inflammatory diseases (osteoarthritis, rheumatoid arthritis, asthma and rhinitis ), Adrenal function test, viral infection, immunodeficiency, immune control, autoimmune disease, allergy, wound healing, obsessive-compulsive behavior, multidrug resistance, drug addiction, psychosis, anorexia, cachexia, post- traumatic stress syndrome, Can be used to treat medicinal decomposition and prevention of muscle twitching. Examples of GR antagonists that can be used in admixture with the compounds of the present invention include the compounds disclosed in commonly assigned International Patent Publication No. WO 00/66522, incorporated herein by reference.
[370] In addition, the compounds of the present invention can be used in admixture with a sorbitol dehydrogenase inhibitor. Sorbitol dehydrogenase inhibitors can lower the fructose level and can be used to treat or prevent diabetic complications such as neuropathy, retinopathy, nephropathy, cardiomyopathy, microangiopathy and macrovascular disease. U.S. Patent Nos. 5,728,704 and 5,866,578 disclose compounds and methods for treating or preventing diabetic complications by inhibiting enzyme sorbitol dehydrogenase.
[371] The compounds of the present invention may also be used in admixture with sodium-hydrogen exchanger type 1 (NHE-1) inhibitors. Examples of NHE-I inhibitors include those compounds disclosed in International Patent Publication No. WO 99/43663, which is incorporated herein by reference.
[372] In addition, the compound of the present invention can be used in combination with a glycogen phosphorylase inhibitor. Examples of glycogen phosphorylase inhibitors include those described in commonly assigned U.S. patent application Ser. No. 09 / 670,759, filed September 27, 2000; And in commonly assigned International Patent Publications WO 96/39384 and WO 96/39385, which are incorporated herein by reference.
[373] Any glycogen phosphorylase inhibitor may be used in admixture with the compounds of the present invention. Glycogen phosphorylase inhibitors are readily determined by those skilled in the art according to standard assays (see, for example, Pesce, et al., Clinical Chemistry , 23 , 1711-1717, 1977). Although a variety of glycogen phosphorylase inhibitors are described above, other glycogen phosphorylase inhibitors will be known to those skilled in the art (see, for example, International Patent Publication No. WO 95/24391-A and US Pat. Patent No. 5,952,363). In addition, glycogen phosphorylase inhibitors that can be used in the present invention are described in U.S. Patent Nos. 5,998,463; In particular, the compound 3-isopropyl-4- (2-chlorophenyl) -1,4-dihydro-1-ethyl-2-methyl-pyridine is disclosed literature [Oikanomakos et al., Protein Science , 8 (10) , 1930-1945, 1999]; International Patent Application Publication Nos. WO 9524391, WO 9709040, WO 9840353, WO 9850359 and WO 9731901; European Patent EP 884050; And Hoover et al., J. Med. Chem ., 41 , 2934-2938, 1998.
[374] The compounds of the present invention may also be used as cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors, in particular HMG-CoA reductase inhibitors, HMG-CoA synthetase inhibitors, HMG-CoA reductase or synthase gene expression inhibitors, CETP inhibitors, May be administered in combination with other pharmaceutical agents such as fibrate, ACAT inhibitor, squalene synthetase inhibitor, antioxidant or niacin. In addition, the compounds of the present invention can be administered in admixture with a naturally occurring compound that serves to lower plasma cholesterol levels. The naturally occurring compounds are generally designated nutraceuticals, including, for example, garlic extract and niacin.
[375] In addition, the compounds of the present invention can be used in combination with an apolipoprotein B secretion inhibitor and / or a microcrystalline triglyceride transport protein (MTP) inhibitor. Some preferred apolipoprotein B secretion inhibitors and / or MTP inhibitors are described in commonly assigned U.S. Patent No. 5,919,795.
[376] A variety of apolipoprotein B secretion / MTP inhibitors are known to those skilled in the art. Any apolipoprotein B secretion / MTP inhibitor may be used in the practice of the methods and pharmaceutical compositions of the present invention, and generally preferred apolipoprotein B secretion / MTP inhibitors include, for example, EP 643057, EP 719763 , EP 753517, EP 764647, EP 765878, EP 779276, EP 779279, EP 799828, EP 799829, EP 802186, EP 802188, EP 802192 And EP 802197; In WO 96/13499, WO 96/33193, WO 96/40640, WO 97/26240, WO 97/43255, WO 97/43257, WO 98 / 16526 and WO 98/23593; And compounds disclosed in U.S. Patent Nos. 5,595,872, 5,646,162, 5,684,014, 5,712,279, 5,739,135, and 5,789,197.
[377] Particularly preferred apolipoprotein B secretion / MTP inhibitors include biphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-ylamide derivatives disclosed in WO 96/40640 and WO 98/23593 have. Particularly preferred apolipoprotein B secretion / MTP inhibitors disclosed in International Patent Publication Nos. WO 96/40640 and WO 98/23593 and useful in the methods and pharmaceutical compositions of the present invention include 4 ' -trifluoromethyl-bis 2-carboxylic acid- [2- (lH- [l, 2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydroisoquinolin- Trifluoromethyl-biphenyl-2-carboxylic acid- [2- (acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] amide.
[378] Another particularly preferred type of apolipoprotein B secretion / MTP inhibitor is disclosed in U.S. Patent Nos. 5,595,872, 5,721,279, 5,739,135 and 5,789,197.
[379] Particularly preferred apolipoprotein B secretion / MTP inhibitors disclosed in U.S. Patent Nos. 5,595,872, 5,721,279, 5,739,135 and 5,789,197 and useful in the methods and pharmaceutical compositions of the present invention include 9- {4- [4- ( (Trifluoromethyl) biphenyl-2-carbonyl) amino] piperidin-l-yl} butyl- And 9- {4- [4- (2-benzothiazol-2-yl-benzoylamino) piperidin- 1 -yl] butyl} -9H- fluorene-9- carboxylic acid- (2,2,2- Trifluoroethyl) amide.
[380] Other types of particularly preferred apolipoprotein B secretion / MTP inhibitors are disclosed in International Patent Publication No. WO 98/16526.
[381] Particularly preferred apolipoprotein B secretion / MTP inhibitors disclosed in International Patent Publication No. WO 98/16526 and useful in the methods and pharmaceutical compositions of the present invention include [11a-R] -8 - [(4-cyanophenyl) (Prop-2-enyl) -2,3,11,11a-tetrahydro-6H-pyrazino [l, 2b] isoquinoline- 1,4-dione and [ 11a-R] -cyclopentyl-7- (prop-2-enyl) -8 - [(pyridin- 2- yl) methoxy] -2,3,11,11a- tetrahydro-6H-pyrazino [ , 2b] isoquinoline-1,4-dione.
[382] Other types of particularly preferred apolipoprotein B secretion / MTP inhibitors are disclosed in U.S. Patent No. 5,684,014.
[383] Particularly preferred apolipoprotein B secretion / MTP inhibitors disclosed in U.S. Patent No. 5,684,014 and useful in the methods and pharmaceutical compositions of the present invention include 2-cyclopentyl-2- [4- (2,4-dimethylpyrido [ 3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acetamide.
[384] Another type of particularly preferred apolipoprotein B secretion / MTP inhibitor is disclosed in U.S. Patent No. 5,646,162.
[385] Particularly preferred apolipoprotein B secretion / MTP inhibitors disclosed in U.S. Patent No. 5,646,162 and useful in the methods and pharmaceutical compositions of the present invention include 2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) phenyl] acetamide.
[386] Additional apolipoprotein B secretion / MTP inhibitors that can be used in admixture with the compounds identified by the present invention are disclosed in commonly assigned U. S. Patent Application No. 09/711281, filed November 9,2000. An example of a particularly preferred apolipoprotein B secretion / MTP inhibitor is disclosed in the aforementioned patent application, which is incorporated herein by reference.
[387] Specific cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors are described in detail below. Additional cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in International Patent Publication No. WO 94/00480.
[388] Any HMG-CoA reductase inhibitor may be applied as an additional compound from the mixed treatment aspect of the present invention. The term HMG-CoA reductase inhibitor refers to a compound that is promoted by the enzyme HMG-CoA reductase to inhibit the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acid. Such inhibition can be readily determined by those skilled in the art according to standard assays (see, e. G., Methods of Enzymology , 71 , 455-509, 1981). A variety of such compounds are described and referenced below. U.S. Pat. No. 4,231,938 discloses certain compounds isolated after incubation of microorganisms belonging to the genus Aspergillus , such as lovastatin. In addition, U.S. Patent No. 4,444,784 discloses a synthetic derivative of the above compound, for example simvastatin. In addition, U.S. Patent No. 4,739,073 discloses certain substituted indoles, such as fluvastatin. Also, U.S. Patent No. 4,346,227 discloses ML-236B derivatives such as pravastatin. In addition, European Patent 491,226 teaches certain pyridyldihydroheptenoic acids, such as Rivastatin. Also, U.S. Patent No. 4,647,576 discloses certain 6- [2- (substituted-pyrrol-1-yl) alkyl] pyran-2-ones such as atorvastatin. Other HMG-CoA reductase inhibitors will be known to those skilled in the art. Examples of commercially available products containing an HMG-CoA reductase inhibitor include Baycol (R), Lescol (R), Lipitor (R), Mevacor (R) Pravachol (R) and Zocor (R).
[389] Any HMG-CoA synthase inhibitor may be used as an additional compound in the context of the present combination therapy. The term HMG-CoA synthetase inhibitor is a compound inhibited by biosynthesis of acetyl-coenzyme A and acetoacetyl-coenzyme A from hydroxymethylglutaryl-coenzyme A promoted by the enzyme HMG-CoA synthase. Such inhibition is readily facilitated by those skilled in the art according to standard assays (see for example Methods of Enzymology , 35 , 155-160, 1975 and Methods of Enzymology , 110 , 19-26, 1985) Can be measured. A variety of such compounds are described and referenced below. U.S. Patent 5,120,729 discloses certain beta-lactam derivatives. U.S. Patent No. 5,064,856 discloses certain spiro-lactone derivatives prepared by culturing the microorganism MF5253. U.S. Patent No. 4,847,271 discloses certain oxetane compounds such as 11- (3-hydroxymethyl-4-oxo-2-oxetyl) -3,5,7-trimethyl- Acid derivatives are disclosed. Other HMG-CoA synthetase inhibitors useful in the methods, compositions and kits of the present invention will be known to those skilled in the art.
[390] Any compound that reduces HMG-CoA reductase gene expression may be used as an additional compound in the context of the present combination therapy. Such agents may be HMG-CoA reductase transcription inhibitors that block DNA transcription, or translational inhibitors that inhibit mRA encoding the HMG-CoA reductase and translating it into a protein. Such inhibitors can directly affect transcription or translation, or can be biotransformed into compounds having this property by one or more enzymes in a multistage cholesterol biosynthesis, or accumulate isoprene metabolites that have such activity. Such modulation can be readily determined by those skilled in the art according to standard methods of analysis ( see Methods of Enzymology , 110 , 9-19, 1985). Although some of these compounds are described and referenced below, other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. For example, U.S. Patent No. 5,041,432 discloses certain 15-substituted lanosterol derivatives that are inhibitors of HMG-CoA reductase gene expression. Other oxygenated sterols that inhibit the biosynthesis of HMG-CoA reductase are described in EI Mercer, Prog. Lip. Res ., 32 , 357-416, 1993).
[391] Any compound that has activity as a CETP inhibitor may be used as a second compound in the context of the present combination therapy. The term CETP inhibitor refers to a compound that inhibits the transport of various cholesterol esters and triglycerides from HDL to LDL and VLDL mediated by cholesterol ester transfer protein (CETP). A variety of these compounds are described and referenced below, but other CETP inhibitors will be known to those skilled in the art. For example, U.S. Patent No. 5,512,548 discloses certain polypeptide derivatives that have activity as CETP inhibitors, while certain CETP-inhibiting rosenonolactone derivatives, and phosphate-containing analogs of cholesterol esters, are described in J. Antibiot . , 49 (8), 815-816, 1996] and [ Bioorg. Med. Chem. Lett ., 6 , 1951-1954, 1996, respectively.
[392] Preferred CETP inhibitors that may be used in admixture with the compounds of the present invention include the compounds described in commonly assigned International Patent Publication No. WO 00/17164, incorporated herein by reference.
[393] Any ACAT inhibitor may be used as a further compound in the context of the present combination therapy. The term ACAT inhibitor refers to a compound that inhibits the esterification of dietary cholesterol in a cell by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition can be readily determined by those skilled in the art according to standard assays (e. G., The method described in Heider et al., Journal of Lipid Research , 24 , 1127, 1983). A variety of such compounds are described and referenced below, but other ACAT inhibitors will be known to those skilled in the art. U.S. Patent No. 5,510,379 discloses certain carboxy sulphonates, while WO 96/26948 and WO 96/10559 all disclose urea derivatives with ACAT inhibitory activity.
[394] Any compound that is active as a squalene synthetase inhibitor may be used as a further compound in the context of the present combination therapy. The term squalene synthetase inhibitor refers to a compound that is promoted by an enzyme squalene synthetase to inhibit the formation of squalene by condensation of the two molecules of panesylphosphate. Such inhibition may be readily determined by those skilled in the art according to standard methodology (see reference [Methods of Enzymology, 15, 393-454 , 1969] and [Methods ofEnzymology, 110, 359-373, 1985]). A summary of squalene synthetase inhibitors can be found in Curr. Op. Ther. Patents , 861-4, 1993. European Patent Publication No. EP 0 567 026 A1 discloses certain 4,1-benzoxazepine derivatives as squalene synthetase inhibitors and their use as a treatment and fungicide for hypercholesterolemia. European Patent Laid-Open Publication No. EP 0 645 378 A1 discloses specific 7-and 8-membered heterocycles as squalene synthetase inhibitors and their use as a treatment and prophylaxis of hypercholesterolemia and fungal infections. European Patent Laid-Open Publication No. EP 0 645 377 A1 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful for treating hypercholesterolemia or coronary atherosclerosis. European Patent Laid-Open Publication No. EP 0 611 749 A1 discloses certain substituted acid derivatives useful for the treatment of atherosclerosis. European Patent Laid-Open Publication No. EP 0 705 607 A2 discloses certain condensed 7-membered and 8-membered heterocyclic compounds useful as hypertriglyceridemic agents. International Patent Publication No. WO 96/09827 discloses certain combinations of cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors, including benzoxazepine derivatives and benzothiazepine derivatives. EP 0 701 725 A1 discloses certain combinations of cholesterol absorption inhibitors Discloses a process for preparing certain optically active compounds, including benzoxazepine derivatives having cholesterol and triglyceride lowering activity.
[395] Other compounds that are available for the treatment of atherosclerosis and are commercially available for hyperlipidemia, including hypercholesterolemia, include bile acid sequestrants (e.g., Colestid (R), LoCholest (R) and Questran Questran;) and fibrin acid derivatives (e.g., Atromid (R), Lopid (R), and Tricor (R)). These compounds may also be used in admixture with the compounds of the present invention.
[396] In addition, the compounds of the present invention are administered in combination with a lipase inhibitor and / or a glucosidase inhibitor and can be administered in combination with excessive triglycerides, free fatty acids, cholesterol, cholesterol esters or glucose, including obesity, hyperlipidemia, hyperlipoproteinemia, X syndrome, ≪ RTI ID = 0.0 > and / or < / RTI >
[397] Any lipase inhibitor or glucosidase inhibitor may be applied in admixture with the compounds of the present invention. Preferred lipase inhibitors include gastrointestinal or pancreatic lipase inhibitors. Preferred glucosidase inhibitors include amylase inhibitors.
[398] Lipase inhibitors are compounds that inhibit the metabolism of dietary triglycerides by cleavage by free fatty acids and monoglycerides. Under normal physiological conditions, lipolysis occurs via a two-step process involving acylation of the serine residue of the activated lipase enzyme. Fatty acid-lipase hemiacetal intermediate is formed and then cleaved to release the diglyceride. By further deacetylation, the lipase-fatty acid intermediate is cleaved to produce free lipases, monoglycerides and fatty acids. The resulting free fatty acids and monoglycerides are absorbed at the intrinsic level of the intestine after incorporation into bile acid-phospholipid micelles. Michelle eventually enters the peripheral circulation as Yumi microsphere. Thus, compounds comprising a lipase inhibitor that selectively restricts or inhibits the uptake of an ingested lipid prodrug are useful for treating conditions including obesity, hyperlipidemia, hyperlipidemia, syndrome X, and the like.
[399] Pancreatic lipase mediates metabolic cleavage of fatty acids from triglycerides at carbon positions 1 and 3. The major metabolic sites of the fat consumed are present in the duodenum and in the plant by pancreatic lipases, and pancreatic lipases are generally secreted in the upper part of the small intestine in excess of the amount required for fat breakdown. Since pancreatic lipase is the main enzyme required for the absorption of dietary triglycerides, inhibitors have applications in treating obesity and other related symptoms.
[400] Gastric lipase is an immunologically unique lipase responsible for about 10-40% of the digestion of dietary fat. Gastric lipases are secreted in response to mechanical stimuli, digestion of food, presence of fat meals, or sympathetic agents. Gastric lipolysis of ingested fat is physiologically important in the supply of fatty acids required for intestinally induced pancreatic lipase activity and is also important for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency (see, for example, CK Abrams, et al., Gastroenterology , 92-125, 1987).
[401] A variety of lipase inhibitors are known to those skilled in the art. However, in the practice of the methods, pharmaceutical compositions and kits of the present invention, generally preferred lipase inhibitors are lipstatin, tetrahydrolipstatin, (orlistat), FL-386, WAY-121898, Bay- Is selected from the group consisting of lactones, esterastin, everactone A, eberactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of these compounds and stereoisomers. The compound tetrahydrolipstatin is particularly preferred.
[402] 4-methyl-valeryloxy] -2-hexyl-3-hydroxy-7,7-dihydro- (S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hexyldecanoic acid lactone, tetrahydrolipstatin (orlistat), 2S, 3S, 5S) -Hydroxy-hexadecanoic acid lactone, and variously substituted N-formyl leucine derivatives and stereoisomers thereof are disclosed in U.S. Patent No. 4,598,089.
[403] The pancreatic lipase inhibitor FL-386, 1- [4- (2-methylpropyl) cyclohexyl] -2 - [(phenylsulfonyl) oxy] ethanone and the variously substituted sulfonate derivatives associated therewith are described in U.S. Patent No. 4,452,813 Lt; / RTI >
[404] Pancreatic lipase inhibitor WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-l-yl-carboxylate, and various carbamate esters and pharmaceutically acceptable salts thereof related thereto are described in U.S. Patent 5,512,565, 5,391,571 and 5,602,151.
[405] The lipase inhibitor is Bay-N-3176, N-3-trifluoromethylphenyl-N'-3-chloro-4'-trifluoromethylphenylurea and various related urea derivatives are disclosed in U.S. Patent No. 4,405,644 .
[406] (Kitahara, et al., J. Antibiotics , 40 (11), 1647-1650, 1987) by microbial cultivation of pancreatic lipase inhibitor valyllactone, and Actinomycetes strain MG147- .
[407] A specific method of producing the lipase inhibitor esterase and Streptomyces strain ATCC 31336 by bioassay is disclosed in U.S. Patent Nos. 4,189,438 and 4,242,453.
[408] Methods for their preparation by microbial cultivation of the pancreatic lipase inhibitors everactone A and eberactone B, and actinomycetes strain MG7-G1 are described in Umezawa, et al., J. Antibiotics , 33 , 1594-1596, . The use of everactones A and B in the inhibition of monoglyceride formation is disclosed in Japanese Patent Laid-Open Publication No. 08-143457, published on June 4, 1996.
[409] The lipase inhibitor RHC 80267, cyclo-O, O '- [(1,6-hexanediyl) -bis (iminocarbonyl)] dioxime, and various bis (iminocarbonyl) Petersen et al., Liebig's Annalen , 562 , 205-229, 1949. The use of RHC 80267 to inhibit the activity of myocardial lipoproteins is described in Carroll et al., Lipids , 27 , 305-307, 1992 and Chuang et al., J. Mol. Cell Cardiol. , 22 , 1009-1016, 1990).
[410] Any suitable dose of lipase inhibitor may be used in the context of the present invention including such inhibitors. The dosage of the rapa inhibitor is generally in the range of about 0.01 to about 50 mg, preferably about 0.05 to 10 mg per kilogram body weight of the patient per day, administered in a single dose or in divided doses. For example, when the lipase inhibitor is tetrahydrolipstatin, the dosage of trehalolipstatin is preferably about 0.05 to 2 mg per kilogram body weight of the patient per day. Indeed, the physician will determine the actual dosage of the lipase inhibitor most suitable for the individual patient, and the dosage will vary depending on, for example, age, body weight and response of the particular patient. Although the dosage of the lipase inhibitor is typical, there may, of course, be individual instances where the highest or lowest dosage range of the lipase is valuable, and all such dosages are within the scope of the present invention.
[411] Glucosidase inhibitors inhibit the enzymatic hydrolysis of complex carbohydrates with biodegradable simple sugars, such as glucose, by glycoside hydrolases, such as amylases or maltases. In particular, the rapid metabolism of glucosidase following ingestion of high levels of carbohydrates results in hyperglycemic conditions that lead to increased insulin secretion, increased fat synthesis and decreased fat degradation in hyperlipidemia or diabetic patients. Following hyperglycemia, hypoglycemia frequently occurs due to an increase in existing insulin levels. It is also known that both hypoglycemia and overlying juice are both responsible for the progression of gastritis or duodenal ulceration or promote the production of gastric juice that is favorable to it. Thus, glucosidase inhibitors are known to have utility in promoting the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestines. Thus, the benefits of reducing or preventing harmful symptoms associated with the conversion of carbohydrates into lipids of adipose tissue and incorporation into fatty tissue deposits of dietary fat are also reduced or delayed.
[412] Any glucosidase inhibitor may be used in admixture with the compounds of the present invention, but generally preferred glucosidase inhibitors include amylase inhibitors. Amylase inhibitors are glucosidase inhibitors that inhibit degradation of sugars or glycogen to maltose by enzymes. This inhibition of enzymatic degradation is beneficial in reducing the amount of bioavailable sugars, including glucose and maltose, and thereby reducing the adverse symptoms that accompany it.
[413] A variety of glucosidase and amylase inhibitors are known to those skilled in the art. However, in the practice of the methods, pharmaceutical compositions and kits of the present invention, generally preferred glucosidase inhibitors are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25,637, camiglibose, Amisstate, AI-3688, trestatin, pradimicin-Q and salostatin.
[414] Glucosidase inhibitor acarbose, O-4,6-dideoxy-4 - [[(1S, 4R, 5S, 6S) -4,5,6-trihydroxy-3- (hydroxymethyl) (1 4) -D-glucopyranosyl- (1 > 4) -O- -D-glucopyranosyl- the various amino sugar derivatives related, and the liquid sample Martino lance (Actinoplanes) strains SE 50 (CBS 961.70), SB 18 (CBS 957.70), SE 82 (CBS 615.71), SE 50/13 (CBS 614.71) and SE 50/110 (CBS 674.73) are disclosed in U.S. Patent Nos. 4,062,950 and 4,174,439, respectively.
[415] The glucosidase inhibitor adicosin, composed of adygosine forms 1 and 2, is disclosed in U.S. Patent No. 4,254,256. The preparation and purification of adygosine is also disclosed in Namiki et al., J. Antibiotics , 35 , 1234-1236, 1982.
[416] Glucosidase inhibitor voglibose, 3,4-dideoxy-4 - [[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -2-C- (hydroxymethyl) , And various N-substituted pseudo-amino sugars associated therewith are disclosed in U.S. Patent No. 4,701,559.
[417] Glucosidase inhibitor miglitol, (2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3,4,5-piperidine triol, Various related 3,4,5-trihydroxypiperidines are disclosed in U.S. Patent No. 4,639,436.
[418] Glycosidase inhibitor emiglitate, ethyl p- [2 - [(2R, 3R, 4R, 5S) -3,4,5-trihydroxy-2- (hydroxymethyl) piperidino] ethoxy] Benzoates, various derivatives thereof, and pharmaceutically acceptable acid addition salts thereof are disclosed in U.S. Patent No. 5,192,772.
[419] Glucosidase inhibitor MDL-25,637, 2,6-dideoxy-7-O- -D-glucopyranosyl-2,6-imino-D-glycero-L-gluco-heptitol, various Single disaccharides, and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 4,634,765.
[420] Glucosidase inhibitor camiglibose, methyl 6-deoxy-6- [(2R, 3R, 4R, 5S) -3,4,5-trihydroxy-2- (hydroxymethyl) piperidino] -D-glucopyranoside 3: dihydrate, various deoxy-norgyramycin derivatives related thereto, various pharmaceutically acceptable salts thereof, and their synthetic methods are described in U.S. Patent Nos. 5,157,116 and 5,504,078 Lt; / RTI >
[421] Amylase inhibitors Tendamastat, various related cyclic peptides, and methods for producing them by microbial cultivation of Streptomyces tendae strain 4158 or HAG 1226 are disclosed in U.S. Patent No. 4,451,455.
[422] Methods for their preparation by microbial cultivation of amylase inhibitor AI-3688, various cyclic polypeptides related thereto , and Streptomyces aureofaciens strain FH 1656 are disclosed in U.S. Patent No. 4,623,714.
[423] Amylase inhibitor tristatin, trehalose-containing amino sugars, and Streptomyces dimorphogenes strains NR-320-OM7HB and NR-320-OM7HB, which are related to the amylase inhibitor tristatin, consisting of tristatin A, Methods for their preparation by microbial culture of OM7HBS are disclosed in U.S. Patent No. 4,273,765.
[424] Methods for their preparation by microbial cultivation of glucosidase inhibitor pradimicin- Q and Actinomadura verrucospora strain R103-3 or A10102 are disclosed in U.S. Patent Nos. 5,091,418 and 5,217,877, respectively .
[425] Methods for their preparation by microbial cultivation of the glucosidase inhibitor salvostatin, various mimetic saccharides associated therewith, various pharmaceutically acceptable salts thereof, and Streptomyces albus strain ATCC 21838 are described in U.S. Patent No. 5,091,524 Lt; / RTI >
[426] Preferred glycosidase inhibitors include compounds selected from the group consisting of acarbose, adygosine, voglibose, miglitol, emiglitate, MDL-25,637, camigliibos, pradimicin-Q and salvostatin. Particularly preferred glucosidase inhibitors further include an amylase inhibitor selected from the group consisting of tandem amiates, AI-3688 and trestatin.
[427] In another aspect of the invention, the compounds of formula I may be used in admixture with additional anti-obesity agents. Additional anti-obesity agents are preferably selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, pentamine, neuropeptide Y antagonists, ₃ -adrenoceptor agonists, cholestystinin-A agonists, monoamine reuptake inhibitors, sympathetic stimulants, , Dopamine agonists, melanocyte-stimulating hormone receptor agonists or mimetics, melanocyte-stimulating hormone receptor mimics, cannabinoid receptor antagonists, melanin-enriched hormone antagonists, leptin, leptin mimics, leptin receptor agonists, Consisting of peptide-1 receptor antagonists such as bombesin agonists, thyroid mimics, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon, and ciliary neurotrophic factors Choose from counties The.
[428] Particularly preferred anti-obesity agents are selected from the group consisting of sibutramine, fenfluramine, dexfenfluramine, bromocriptine, pentamine, ephedrine, leptin, phenylpropanolamine, pseudoephedrine, {4- [2- (2- [ ] -2 (R) -hydroxyethylamino) ethoxy] phenyl} acetic acid, {4- [2- (2- [6- Aminopyridin- Ethoxy] phenyl} propionic acid and {4- [2- (2-methylpiperazin-1-yl) 2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenoxy} acetic acid.
[429] Appropriate anorectic agents for the compositions, methods and kits of the present invention may be prepared using methods known to those skilled in the art, for example, pentamine may be prepared as described in U.S. Patent No. 2,408,345; Sibutramine can be prepared as described in U.S. Patent No. 4,929,629; Fenfluramine and dexfenfluramine may be prepared as described in U.S. Patent No. 3,198,834; Bromocriptine can be prepared as described in U.S. Patent No. 3,752,814.
[430] Any suitable dosage of anorectic agent may be used in the context of the present invention including such agents. The dosage of the anorectic agent is generally in the range of about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg per kg body weight of the patient per day, administered in a single dose or in divided doses. For example, if the anorectic agent is pentamer, the dosage of pentamine is about 0.01 to 50 mg, preferably about 0.1 to about 1 mg, per kg body weight of the patient per day. In addition, when the anorectic agent is sibutramine, the dosage is about 0.01 to about 50 mg, preferably about 0.1 to about 1 mg, per kg body weight of the patient per day; When the desensitizing agent is dexfenfluramine and fenfluramine, the dosage ranges from about 0.01 to about 50 mg, preferably from about 0.1 to about 1 mg, per kg body weight of the patient per day; When the depressant is bromocriptine, the dosage range is from about 0.01 to about 10 mg, preferably from about 0.1 to about 1 mg, per kg body weight of the patient per day. Indeed, the physician will determine the actual dosage of the most suitable anorectic agent for the individual patient, and the dosage will vary depending on, for example, age, body weight and response of the particular patient. Although the dosage of the anorectic agent is typical, there may, of course, be individual instances where the highest or lowest dosage range of the anorectic agent is valuable and all such dosages are within the scope of the present invention.
[431] In addition, the compound of the present invention can be used in combination with an antihypertensive agent. Existing commercially available products containing antihypertensive agents include calcium channel blockers such as, for example, Cardizem (R), Adalate (R), Calan (R), Cardene (Registered trademark), Covera (registered trademark), Dilacor (registered trademark), DynaCirc (registered trademark), Procardia XL (registered trademark), Suler (registered trademark) Tiazac 速, Vascor 速, Verelan 速, Isoptin 速, Nimotop 速, Norvasc 速, ; And Plendil (registered trademark); Such as angiotensin converting enzyme (ACE) inhibitors such as Accupril (R), Altace (R), Captopril (R), Lotensin (R) Mavik®, Monopril®, Prinivil®, Univasc®, Vasotec®, and Zestril®) . In addition, diuretics and combinations of these antihypertensive agents have been used and are intended for use in combination with the compounds of the present invention.
[432] In addition, the compound of the present invention can be used in combination with an anti-depressant. Examples of commercially available sedatives that can be used in admixture with the compounds of the present invention include monoamine oxidase inhibitors such as Nardil (R) and Parnate (R); Selective serotonin reuptake inhibitors such as Paxil®, Prozac® and Zoloft®; Tricyclic compounds, such as Asendin (R), Elavil (R), Etrafon (R), Limbitrol (R), Norpramin (R) Such as Pamelor®, Sinequan®, Surmontil®, Tofranil®, Triavil®, and the like) And Vivactil (registered trademark). Additional compounds that can be used to treat depression and which can be used in admixture with the compounds of the invention include, but are not limited to, Desyrel (R), Effexor (R), Remeron (R) (Serzone < (R) > and Wellbutrin (R)).
[433] In addition, the compounds of the present invention can be used in admixture with compounds useful for treating osteoporosis. Examples of commercially available products containing active agents that can be used in combination with the compounds of the present invention include non-phosphonates such as Fosamax (R), and hormone agents such as calcitonin and estrogen. In addition, Evista (registered trademark) can be used in combination with the compound of the present invention.
[434] In addition, the compound of the present invention can be used in combination with a compound useful for regrowing hair. Typically, two drugs approved by the United States Food and Drug Administration for treating male pattern baldness, namely local minoxidil (Rogaine (R), from Pharmacia) Commercially available) and oral finasteride (commercially available from Merck & Co., Inc. as Propecia (R)).
[435] The compounds of the invention are administered to a patient in a therapeutically effective amount. The compounds may be administered alone or as part of a pharmaceutically acceptable composition. In addition, the compound or composition may be administered, for example, as a single injection with a single infusion, or several times as a series of tablets, or may be delivered substantially uniformly over time, for example, using transdermal delivery. It should also be noted that the dose of the compound may vary over time.
[436] In addition, the compounds of the present invention may be administered alone, mixed with other compounds of the present invention, or mixed with other pharmaceutically active compounds. Other pharmaceutically active compounds may be desired to treat the same disease or condition as the compounds of the present invention or to treat other diseases or conditions. If the patient is to be or will be administering a plurality of pharmaceutically active compounds, the compounds may be administered simultaneously or sequentially in any order. For example, in the case of tablets, the compounds can be found in one tablet or in several tablets, which can be administered in one shot or in succession. It should also be appreciated that the composition may be in a different format. For example, one or more compounds may be delivered via a tablet, while the other compound is administered via injection or orally as a syrup. All combinations, delivery methods and order of administration are contemplated.
[437] For subsequent administration, the compounds, prodrugs, isomers or pharmaceutically acceptable salts thereof, and other active compounds of the present invention may be administered in any order, as the case may be. In general, the administration is preferably oral. It is even more preferred that the administration is oral and concomitant. However, parenteral or transdermal administration may be appropriate if, for example, the patient to be treated can not swallow or the oral absorption is compromised or undesirable. Where the administration is continuous, the compounds, prodrugs, isomers or pharmaceutically acceptable salts thereof, and other active compounds of the present invention may be administered by the same or different methods, as the case may be.
[438] The present invention also relates to the mixing of individual pharmaceutical compositions in kit form, since one aspect of the present invention is intended to be combined with a pharmaceutically active agent that can be administered separately to treat the disease / condition. Said kit comprising a compound of the invention, a prodrug thereof, or a salt of said compound or prodrug; And two additional pharmaceutical compositions such as additional pharmacologically active compounds. The kit may also comprise a composition containing a compound of the invention, a prodrug thereof, or a salt of such a compound or prodrug; ≪ / RTI > and other compositions containing additional pharmaceutically active compounds. The kit comprises a container, e.g., a slice bottle or a split foil packet, containing the individual compositions. Additional examples of containers include syringes, boxes, bags, and the like. Typically, the kit includes instructions for administration of the individual components. Such a kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e. G., Oral and parenteral), when administered at different dosing intervals, or when measurements of individual components of the combination are made by a prescribing physician This is particularly beneficial when desired.
[439] One example of such a kit is a so-called blister pack. Blister packs are widely known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material, preferably surrounded by a foil of a clear plastic material. During the packaging process, a concave portion is formed in the plastic foil. The concave portion has the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the recesses and the plastic foil is sealed to the face of the foil opposite to the direction in which the concave portion of the sheet of relatively stiff material is formed. As a result, tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet should be such that when the pressure is manually applied to the concave portion, an opening is formed in the sheet at the concave portion so that the tablet or capsule can escape from the blister pack. The tablets or capsules can then be withdrawn through the openings.
[440] For example, it may be desirable to provide a memory supplementary instruction on a kit in the form of a number next to a tablet or capsule, the number corresponding to the date of the prescription for which a particular tablet or capsule should be ingested. Another example of the memory assisted instructions may be stored on the card as printed on the card such as, for example, " first week, Monday, Tuesday, .... .... second week, Monday, It is a calendar. Other variations of the memory supplementary instructions will be readily appreciated. A " daily dose " may be a single tablet or capsule, or multiple tablets or capsules to be taken on a particular day of the week. In addition, a daily dose of a compound of the present invention may consist of one tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules, or vice versa. Memory assisted instructions should reflect this and aid in the administration of the correct active agent.
[441] In another embodiment of the present invention, there is provided a dispenser designed to dispense a daily dose once at a time in accordance with its intended use order. Preferably, the dispenser is equipped with memory-assisted instructions to further promote prescription adaptability. An example of such a memory-assisted indication is a mechanical counter representing the number of dispensed daily doses. Another example of such a memory aid is battery-recharged micro-chip memory coupled with liquid crystal readout, or implicit < RTI ID = 0.0 > indications < / RTI > that remind the date the most recent daily dose was ingested and / Signal.
[442] Any suitable route of administration may be used for the compounds of formula I, isomers, prodrugs and pharmaceutically acceptable salts thereof in the present invention. The compounds of the present invention and the other pharmacologically active agents may be administered orally or rectally or parenterally (for example, intravenously, intramuscularly or subcutaneously), intracisternally, intracutaneously, intraperitoneally, intravesically, locally, locally , Powders, ointments or drops) and oral or nasal sprays.
[443] Compositions suitable for parenteral injection may include a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension, emulsion, and sterile powders for reconstitution into a sterile injectable solution or dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, criselol and the like), suitable mixtures thereof, vegetable oils Oils) and injectable organic esters (e. G., Ethyl oleate). Proper fluidity can be maintained by the use of a coating such as lecithin, by the persistence of the required particle size in the case of dispersions, and by the use of surfactants.
[444] The composition may also include adjuvants such as, for example, preservatives, wetting agents, emulsifying agents and dispersing agents. Microbial contamination of the composition can be prevented with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. The injectable pharmaceutical composition may prolong absorption by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.
[445] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound may be admixed with one or more inert conventional excipients (or carriers), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders (such as starches, lactose, sucrose, mannitol And silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia); (c) wetting agents (e.g., glycerol); (d) disintegrants (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate); (e) solution retarders (e. g., paraffin); (f) an absorption promoting agent (for example, a quaternary ammonium compound); (g) wetting agents (e. g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonyl); And / or (i) a lubricant (e. G., Talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof). In the case of capsules and tablets, the dosage form also includes a buffering agent.
[446] In addition, solid compositions of a similar type can be used as fillers in soft or hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.
[447] Solid dosage forms such as tablets, dragees, capsules and granules may be made into coatings and shells, such as enteric coatings and coatings well known in the art. They may also contain opacifying agents and may also be compositions that release compounds or compounds in a delayed manner. Examples of encapsulating compositions that can be used are polymeric materials and waxes. The compound may also be in the form of a micro-capsule, optionally with one or more of the above excipients.
[448] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the above compounds, the liquid dosage forms may also contain water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, Fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and sorbitan, or a mixture of these substances, and the like, and the like, for example, As well as inert diluents commonly used in the art
[449] In addition to the inert diluent, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
[450] Suspensions other than compounds may be prepared, for example, from the reaction of ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonyl, agar-agar, A mixture of water and the like.
[451] The composition for rectal or vaginal administration is preferably a suppository, which comprises a compound of the present invention and cocoa butter, polyethylene glycol or suppository wax which dissolves in the rectum or vaginal cavity to release the compound because it is a solid at room temperature but liquid at body temperature Lt; RTI ID = 0.0 > non-irritating < / RTI > excipient or carrier.
[452] Dosage forms for topical administration of the compounds of the present invention may include ointments, powders, sprays and inhalants. The compounds or compounds are mixed under sterile conditions with a physiologically acceptable carrier and optional preservatives, butter, or propellants that may be required. In addition, ophthalmic preparations, ointments, powders and solutions are intended to be within the scope of the present invention.
[453] For example, the mixture of the present invention is preferably administered as a topical composition for treating hair loss. The carrier of the topical composition preferably aids in penetrating the compound of the present invention into the skin to reach around the hair follicle. The topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, hair conditioners, milk, cleansers, moisturizers,
[454] Topical compositions containing the active compound may be formulated in the art such as, for example, water, alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2, myristyl propionate, Can be mixed with various well-known carrier materials. Other materials suitable for use as topical carriers include, for example, emollients, solvents, wetting agents, thickeners and powders. Examples of materials of this type that can be used alone or as a mixture of one or more are described, for example, in WO 00/72810, 2000, published December 7, 2000, which is incorporated herein by reference. International Patent Publication No. WO 00/72811, published December 7, 2000, International Patent Publication No. WO 00/72812, published December 7, 2000, international patent published on December 7, 2000 WO 00/72813, WO 00/72920, published December 7, 2000, and WO 00/73292, published December 7, 2000, both of which are incorporated herein by reference. Are described in several patent publications relating to the treatment of hair. All such patent publications are incorporated herein by reference.
[455] In addition, the topical compositions of the present invention may optionally comprise an active enhancer. Active enhancers may be selected from a variety of molecules that may act in different ways to enhance the hair growth effect of the compounds of the present invention. Certain types of active hardeners include other hair growth stimulants and penetration enhancers. Examples of administration methods for hair loss treatment, such as liposome delivery system and iontophoresis, as well as hair growth stimulants and penetration enhancers are described in the above-mentioned patent publications. It is also possible to use a Telogen Conversion Assay to determine the ability of the test compound to convert a mouse in the resting phase of the hair growth cycle ("telogen") into a growth phase in the hair growth cycle ("Anagen" ) Are described in the above-mentioned patent publication.
[456] The compounds of the present invention may be administered at doses ranging from about 0.7 to about 7,000 mg per day. For normal adults having a body weight of about 70 kg, doses ranging from about 0.001 to about 100 g per kg of body weight are usually sufficient. Even more preferably, the dosage may be from 0.001 to 10 mg per kg of body weight. The specific dosage and dosage range that may be used depends on a number of factors including the needs of the patient, the severity of the condition or disease to be treated and the drug activity of the compound to be administered. Determination of the dosage range and optimal dosage for a particular patient is well known to those skilled in the art in view of this disclosure. It is also to be noted that the compounds of the present invention can be used in sustained-release preparations, controlled-release preparations and delayed-release preparations. Such formulations and their manufacture are known to those skilled in the art in view of this disclosure.
[457] In addition, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention are administered to mammals other than humans. The dosage regimen and dosage to be administered to such a mammal will depend, for example, on the animal species and the disease or disorder to be treated. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention may be prepared by any suitable method, for example by mixing the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the invention with a lubricant, paste, together with a suitable diluent, such as carbowax or canoe bar wax, for example, by mixing the compound of the invention, the prodrug, the isomer and the pharmaceutically acceptable salt with a suitable diluent such as peanut oil, sesame oil or corn oil May be administered to animals in any suitable form, such as, for example, oral, parenteral or transdermal, for example, capsules, buccal, tablets, pellets, etc., prepared by dispersing in a pharmaceutically acceptable oil. In addition, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention may be administered to an animal as an implant. Such agents can be prepared by conventional methods according to standard veterinary practice.
[458] Alternatively, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention may be administered with water, for example, in the form of a liquid or aqueous concentrate. In addition, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention may be administered as animal feeds, for example, a concentrated feed additive or a pre-mixture, usually mixed with a suitable animal feed, can do. The carrier promotes uniform distribution of the compounds, prodrugs, isomers and pharmaceutically acceptable salts of the present invention, for example, in the final feed in which the premix has been mixed. Suitable carriers include liquids such as water, oils (e.g., soy, corn and cottonseed) or volatile organic solvents, and solids such as alfafas, soybean, cottonseed, flaxseed, corn, corn, , Small amounts of food, including components and bone and mineral mixtures, and various suitable meals.
[459] The compounds of formula (I), the isomers thereof, the prodrugs of such compounds, or the pharmaceutically acceptable salts of such compounds, isomers or prodrugs, demonstrate activity by one or more of the assays described below:
[460] Method 1
[461] Oxygen consumption
[462] As will be appreciated by those skilled in the art, animals typically consume more oxygen while increasing energy expenditure. In addition, metabolic fuels, such as glucose and fatty acids, are oxidized to CO ₂ and H ₂ O accompanied by heat release, which is commonly referred to in the art as heat generation. Therefore, measurement of oxygen consumption in animals, including humans and pet animals, is an indirect measure of heat production. Indirect calorimetry is generally used by an expert in the art for measuring the energy consumption, such as humans, in animals.
[463] Those skilled in the art understand that increased energy consumption and the accompanying burning of metabolic fuels that generate heat are effective in treating obesity, for example. As is well known to those skilled in the art, thyroid hormones affect cardiac function, for example by increasing heart rate and increasing oxygen consumption accompanied by heat production.
[464] The ability of the compounds of the invention to cause a heat producing reaction can be demonstrated according to the following protocol.
[465] A. Experiments
[466] This in vivo assay was designed to evaluate the efficacy and cardiac effects of compounds that are tissue-selective thyroid hormone agonists. The measured efficacy endpoint is systemic oxygen consumption and liver mitochondrial alpha-glycerophosphate dehydrogenase (" mGPDH ") activity. The measured endpoint of the heart is cardiac weight and cardiac mGPDH activity. This protocol comprises the steps of (a) administering to a Zucker rats for about 6 days, (b) measuring oxygen consumption, (c) harvesting tissue to produce mitochondria, and then assaying enzyme activity .
[467] B. Manufacture of rats
[468] Male hyperlipidemic Jurkat rats, ranging in weight from about 400 to about 500 grams, were housed in each cage for about 3 to 7 days under standard laboratory conditions before study initiation.
[469] A prodrug of a compound of formula I or a pharmaceutically acceptable salt thereof, a prodrug of a compound of formula I or a salt thereof, a vehicle or a T ₃ sodium salt is administered for about 6 days at about 3 to about 6 hours, Dose by oral feeding. A prodrug of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug of a compound of formula (I) or a salt thereof, or a T ₃ sodium salt is suitably dissolved in a small amount of about 1 N NaOH, followed by addition of about 0.25% methylcellulose Appropriate volumes were made with approximately 0.01 N NaOH (10: 1, 0.01 N NaOH / MC: 1 N NaOH). The dose was about 1 ml.
[470] C. Oxygen consumption
[471] Approximately one day after administration of the final dose of compound, oxygen consumption was measured using an open circuit, indirect calorimeter (Oxymax; Columbus Instrument, 43204 Columbus Ohio, USA). Prior to each experiment, the Oxymax gas sensors were calibrated to N ₂ gas and gas mixtures (approximately 0.5% CO ₂ , approximately 20.5% O ₂ and approximately 79% N ₂ ).
[472] The subject rats were removed from the cage and the body weight was recorded. The rats were placed in a chamber (43 x 43 x 10 cm) of sealed Oxymax and the chamber was placed in an active monitor and the flow rate of air through the chamber was set at about 1.6 to about 1.7 L / min.
[473] The OxyMax software then calculated the oxygen consumption (ml / kg / hr) of the rat based on the difference between the flow rate of the air passing through the chamber and the oxygen content at the inlet and outlet. The active monitor has 15 infrared beams disposed about one inch apart on each axis, recording the mobility activity when two consecutive beams are blocked, and recording the result as a count.
[474] Oxygen consumption and mobility activity are measured every about 10 minutes for about 5 to about 6.5 hours. The hibernation oxygen consumption was calculated by averaging values subtracted from the first five times for each rat and the values obtained over a time period when the mobility activity exceeded about 100 times.
[475] Method 2
[476] Binding to Thyroid Hormone Receptors
[477] The activity of binding of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt of such compound or isomer ("test thyroid mimetic compound") to a thyroid hormone receptor can be demonstrated in the following protocol.
[478] A. Preparation of insect cell nucleus extract
[479] (High Five) cell pellet (BTI-TN, obtained after about 48 hours of infection with Baculovirus (GibcoBRL (R), Geddesburg, MD) expressing human TR Or TR (10 mM Tris, pH 8.0; 1 mM MgCl ₂ ; 1 mM DTT; 0.05% Tween) in an ice cold sample buffer (Invitrogen, Carlsbad, CA) (Tween) 20; 1 mM 4- (2-aminoethyl) -benzenesulfonyl fluoride; 25 [mu] g / ml leupeptin). After incubation on ice for about 10 minutes, the suspension was centrifuged at 20 strokes using a Dounce homogenizer (VWR (R) Scientific Products, West Chester, Pennsylvania, USA) Homogenized and centrifuged at 800 x g for 15 min at 4 < 0 > C. The pellet was suspended in a buffer solution (0.4 M KCl; 10 mM Tris, pH 8.0; 1 mM MgCl ₂ ; 1 mM DTT; 0.05% Tween 20) and incubated on ice for about 30 minutes. The suspension was centrifuged at 100,000 x g for 30 minutes at 4 < 0 > C. The supernatant (nuclear extract) was stored at approximately -80 占 폚 in 0.5 ml aliquots.
[480] B. Binding analysis
[481] A competitive binding assay to measure the interaction of test thyroid mimic compounds with the thyroid hormone receptors alpha 1 and beta 1 (TRa and TRb) was performed according to the following protocol.
[482] A solution of the test thyroid mimetic compound (final compound concentration 20 mM) was prepared using 100% DMSO as the solvent. Each compound was dissolved in assay buffer (5 mM Tris-HCl, pH 8.0; 50 mM NaCl; 2 mM EDTA; 10% (vol / vol) glycerol; 1 mM DTT) containing 0.4 nM ¹²⁵ IT ₃ (specific activity about 2200 Ci / Lt; / RTI > to give various solutions with compound concentrations ranging from about 10 [mu] M to about 0.1 nM.
[483] High-five insect cell nucleus extracts containing TR Or TR Were diluted to a total protein concentration of 0.0075 mg / ml using the assay buffer as a diluent.
[484] Each thyroid mimic compound dilution (containing 0.4 nM ¹²⁵ IT ₃ ) in a constant volume (100 μl) was combined with diluted nuclear extract containing TRα or TRβ at the same dose (100 μl) and incubated at room temperature for about 90 minutes. 150 [mu] l of the binding reaction sample was removed and placed into a 96-well filter plate (Millipore (R), Bedford, Mass.) Previously washed with ice-cold assay buffer. The plate was vacuum filtered using a filter manifold (Millipore). Each well was washed five times with the addition of 200 [mu] l of ice-cold assay buffer, followed by vacuum filtration. The plate was removed from the vacuum filtration manifold and the bottom of the plate was briefly dried on a paper towel followed by the addition of 25 μl of Wallac (EG & G Wallac) OptiFace Supermix (EG & G Wallac, (Optiphase Supermix) scintillation cocktail was added to each well and the top of the plate was covered with a plastic sealing tape (Microplate Press-on Adhesive Sealing Film, Packard, Downers Grove, Ill. Instrument Co., Inc.) and radioactivity was quantitated using a Wallac Microbeta 96-well plate scintillation counter.
[485] The binding activity was then calculated by dividing the amount of ¹²⁵ I-T3 by the amount of the test compound in the presence of increasing amounts of the test compound relative to the amount of ¹²⁵ I-T3 in the absence of the test compound (expressed as the control amount), followed by linear regression analysis to determine the IC ₅₀ .
[486] Preferred compounds of the present invention include
[487] N- {4- [3- (Cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[488] N- {4- [3- (Cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid;
[489] N- {3-Chloro-4- [3- (cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[490] N- {3-Chloro-4- [3- (cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid;
[491] N- {3-Chloro-4- [4-hydroxy-3- (l-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -5-methyl-phenyl} -malonic acid;
[492] N- {3,5-Dichloro-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid;
[493] N- {3,5-Dimethyl-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid;
[494] N- {3-Chloro-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[495] N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
[496] N- [3,5-Dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid;
[497] N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[498] N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[499] N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[500] N- [3-Chloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[501] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[502] N- [3-Chloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[503] N- [3-Chloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -2-methyl-malonamic acid;
[504] N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
[505] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[506] N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
[507] N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[508] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -2-methyl-malonamic acid;
[509] N- [3-Chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[510] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -2-methyl-malonamic acid;
[511] N- [3-Chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[512] N- [4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[513] N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[514] N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[515] N- {4- [3- (4-Fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[516] N- [4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[517] N- [4- (3-Cyclobutylacetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[518] N- (4- {3 - [(4-Fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -3,5-dimethyl-phenyl) -malonic acid;
[519] N- {4- [3- (2-Cyclopentyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[520] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid methyl ester;
[521] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester;
[522] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid ethyl ester;
[523] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester;
[524] N- [3-Chloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[525] N- [3-Chloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -2-methyl-malonamic acid;
[526] N- [4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[527] N- [4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -2-methyl-malonamic acid;
[528] N- {4- [3- (2-Cyclobutyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[529] N- {4- [3- (4-Fluoro-benzyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[530] N- [4- (7-hydroxy-indan-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid;
[531] N- [3-Chloro-4- (3-cyclobutylacetyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[532] N- [3-Chloro-4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[533] N- {3-Chloro-4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[534] N- (3-Chloro-4- {3 - [(4-fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -5-methyl-phenyl) -malonic acid;
[535] N- {3-Chloro-4- [3- (2-cyclobutyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[536] N- {3-Chloro-4- [3- (2-cyclopentyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[537] N- [3-Chloro-4- (7-hydroxy-indan-4-yloxy) -5-methyl-phenyl] -malonic acid;
[538] 5-methyl-phenyl] -malonamic acid < / RTI > < RTI ID = 0.0 &;
[539] N- [4- (7-Hydroxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid;
[540] N- [4- (7-Hydroxy-2-R-methyl-1-oxo-indan-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid;
[541] N- [4- (7-Hydroxy-2-S-methyl-1-oxo-indan-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid;
[542] N- [4- (7-Hydroxy-2,2-dimethyl-1-oxo-indan-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid;
[543] N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid;
[544] N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid; And
[545] N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -2-methyl-malonamic acid.
[546] More preferred compounds of the present invention include
[547] N- {4- [3- (Cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[548] N- {3-Chloro-4- [4-hydroxy-3- (l-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -5-methyl-phenyl} -malonic acid;
[549] N- {3,5-Dichloro-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid;
[550] N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
[551] N- [3,5-Dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid;
[552] N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[553] N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[554] N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[555] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[556] N- [3-Chloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[557] N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
[558] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[559] N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
[560] N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[561] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -2-methyl-malonamic acid;
[562] N- [3-Chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[563] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -2-methyl-malonamic acid;
[564] N- [3-Chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[565] N- [4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[566] N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[567] N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
[568] N- {4- [3- (4-Fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[569] N- [4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[570] N- (4- {3 - [(4-Fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -3,5-dimethyl-phenyl) -malonic acid;
[571] N- {4- [3- (2-Cyclopentyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
[572] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid methyl ester;
[573] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester;
[574] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid ethyl ester;
[575] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester;
[576] N- [3-Chloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
[577] N- [4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
[578] N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid;
[579] N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid; And
[580] N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -2-methyl-malonamic acid.
[581] The following examples are provided for illustrative purposes only, and do not limit the scope of the specification, including the claims, in any way.
[582] In the present application, the following abbreviations or acronyms are used with the following specified meanings:
[583] AcOH: acetic acid;
[584] APCI ⁺ : atmospheric pressure chemical ionization, cation mode;
[585] APCI ^- : atmospheric pressure chemical ionization, anion mode;
[586] Calc: calculated;
[587] DEE: diethoxyethane;
[588] DME: dimethoxyethane;
[589] DMF: N, N-dimethylformamide;
[590] DMSO: dimethylsulfoxide;
[591] ES ⁺ : electrospray ionization, cationic mode;
[592] Et: ethyl;
[593] EtOAc: ethyl acetate;
[594] EtOH: ethanol;
[595] Equiv: equivalent (s);
[596] Hex: hexane;
[597] KHMDS: potassium bis (trimethylsilyl) amide;
[598] Me: methyl;
[599] MeOH: methanol;
[600] MS: mass spectrometry;
[601] MSA: Methanesulfonic acid;
[602] NMP: 1-methylpyrrolidone;
[603] NMR: nuclear magnetic resonance;
[604] RT: room temperature;
[605] TEA: triethylamine;
[606] TES: treethylsilane;
[607] TFA: trifluoroacetic acid;
[608] THF: tetrahydrofuran;
[609] TLC: Thin layer chromatography.
[610] Example 1
[611] N- [4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid
[612] Step A: 4- (3-Isopropyl-4-methoxy-phenoxy) -3,5-dimethyl-
[613] The title compound of step A (778 mg) was prepared according to J. Med. Chem. , 38, bis according to the method described in the 695-707 (1995) (3-isopropyl-4-methoxyphenyl) iodonium borate to the iodonium tetrafluoroborate (2.50g, 4.88 mmol) and 2,6-dimethyl-4 Was prepared from Nitrophenol (540 mg, 3.25 mmol).
[614] Step B: 4- (2,6-Dimethyl-4-nitro-phenoxy) -2-isopropyl-phenol
[615] CH ₂ Cl ₂ (12㎖) of 4- (3-isopropyl-4-methoxy-phenoxy) -3,5-dimethyl-nitrobenzene (500mg, 1.59 mmol) (CH 2 Cl To a solution of boron tribromide a 1M, 3.2㎖, 3.2 mmol of ₂₎ was added. The resulting mixture was stirred at room temperature for 1 hour and then quenched with water (15 mL) and 1M HCl (10 mL). After stirring at room temperature for 30 minutes, the solution was extracted three times with CH ₂ Cl ₂ (20 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound of step B. [ The title product of Step B was used in the next step without further purification. MS (APCI < ">) Calcd: 301, found 300.2 (M-1).
[616] Step C: 4- (4-Amino-2,6-dimethyl-phenoxy) -2-isopropyl-phenol
[617] To a solution of 4- (2,6-dimethyl-4-nitro-phenoxy) -2-isopropyl-phenol (478 mg, 1.59 mmol) in a mixture of ethanol (10 mL) and EtOAc (30 mL) Pd / C, 100 mg). The mixture was hydrogenated at 50 psi at room temperature for 2 hours. The mixture was filtered through Celite (R) and concentrated to give 458 mg of the title compound of Step C as a brown solid. The title product of Step C was used in the next step without further purification. MS (APCI < ">) Calcd: 271.2, found 270.2 (M-1).
[618] Step D: Preparation of N- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[619] To a solution of 4- (4-amino-2,6-dimethyl-phenoxy) -2-isopropyl-phenol (39 mg, 0.14 mmol) in THF (2 ml) was added triethylamine (22 [ Malonyl chloride (16 [mu] L, 0.15 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. The solution was concentrated and the residue was purified by preparative TLC (2.5% MeOH in CH ₂ Cl ₂ ) to give the title compound of Step D (31 mg). MS (APCI < ">) Calcd: 371.3, found 370.3 (M-1).
[620] Step E: Preparation of N- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid
[621] MeOH (1㎖) and H ₂ O (1㎖) of mixture of N- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] words acid methyl ester ( 29 mg, 0.08 mmol) in THF (5 mL) was added 3N KOH (0.9 mmol, 0.3 mL). After stirring at room temperature for 4 h, H ₂ O (10 mL) was added. The solution was washed twice with EtOAc (10 mL) and acidified with 1N HCl. The aqueous solution was extracted three times with EtOAc (10 mL). The combined organic extracts were washed with brine, dried and concentrated to give Step E as a white solid and the title compound of Example 1 (20mg). MS (APCI < ^- >) Calcd: 357.1, found 356.1 (M-1).
[622] The title compounds of the following Examples 1-1 to 1-5 were obtained using the appropriate starting materials in a similar manner to the reaction sequence described in Example 1.
[623] Example 1-1
[624] N- [3,5-Dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -malonamic acid methyl ester
[625] MS (APCI < ^- >) Calcd: 411.1, found 409.9 (M-1).
[626] Examples 1-2
[627] N- [4- (3-tert-butyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[628] MS (APCI < ">) Calcd: 385.3, found 384.3 (M-1).
[629] Example 1-3
[630] N- [4- (3-2-tert-butyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid
[631] MS (APCI < ">) Calcd: 371.3, found 370.3 (M-1).
[632] Examples 1-4
[633] N- [3,5-Dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -malonic acid
[634] MS (APCI < ">) Calcd: 397.0, found 396.3 (M-1).
[635] Examples 1-5
[636] N- [4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid ethyl ester
[637] MS (APCI < ">) Calcd: 385.3, found 384.3 (M-1).
[638] Example 2
[639] N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[640] Step A: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl chloride
[641] 4- (4-methoxy-phenoxy) -3,5-dichloro-nitrobenzene (700 mg, 2.2 mmol) was added in portions to a solution of chlorosulfonic acid (2.0 mL) cooled at 0 占 폚. The resulting mixture was stirred at 0 < 0 > C for 5 minutes and then at room temperature for 2.5 hours. The solution was added dropwise to ice water (40 mL) and the product was extracted three times with EtOAc (50 mL). The combined organic extracts were dried and concentrated to give the title compound of Step A (920 mg) as crude product, which was used in the next step without purification. MS (APCI ^-) Calcd: 410.9, found: 392.1 (M-1-Cl + OH, sulfonic acid).
[642] Step B: N-Cyclopropyl-5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonamide
[643] To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl chloride (920 mg, 2.2 mmol) in CH ₂ Cl ₂ (25 mL) Ethylamine (470 [mu] L, 3.4 mmol) and cyclopropylamine (170 [mu] L, 2.5 mol) were added. The resulting mixture was stirred at 0 < 0 > C for 5 minutes and then at room temperature for 6 hours. Water (30 mL) and 1N HCl (1 mL) were added and the solution was extracted three times with EtOAc (50 mL). The combined EtOAc extracts were dried and concentrated. The product was purified by chromatography to give the title compound of Step B (652 mg). MS (APCI) calcd: 432.0, found: 430.9 (M-I).
[644] Step C: N-Cyclopropyl-5- (2,6-dichloro-4-amino-phenoxy) -2-methoxy-benzenesulfonamide
[645] The title product of step C (96 mg) was prepared in analogy to the procedure described in step B of Example 1 from N-cyclopropyl-5- (2,6-dichloro-4-amino-phenoxy) Prepared according to the method from N-cyclopropyl-5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonamide (100 mg). The mixture was hydrogenated for 2 hours, filtered through celite and concentrated. The title product of Step C was used in the next step without further purification. MS (APCI < ">) Calcd: 402.0, found 401.3 (M-1).
[646] Step D: N-Cyclopropyl-5- (2,6-dichloro-4-amino-phenoxy) -2-hydroxy-benzenesulfonamide
[647] The title product of Step D (52mg) was prepared in analogy to the procedure described in Step C of Example 1 from N-cyclopropyl-5- (2,6-dichloro-4-amino-phenoxy) (2,6-dichloro-4-amino-phenoxy) -2-methoxy-benzenesulfonamide (96 mg, 0.24 mmol) according to the method used in step 2c. Boron tribromide (1M in CH ₂ Cl ₂ , 712 μl, 0.71 mmol) was used. After addition of water, the mixture was extracted three times with EtOAc (15 mL). The combined organic extracts were dried and concentrated. The title product of Step D was purified by preparative TLC (40% EtOAc in hexanes). MS (APCI < ">) Calcd: 388.2, found 387.2 (M-1).
[648] Step E: Preparation of N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid methyl ester
[649] The title product N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid methyl ester (53 mg) (2,6-dichloro-4-amino-phenoxy) -2-hydroxy-benzenesulfonamide (52 mg) by an analogous method to that described in Example 1b). MS (APCI < ">) Calcd: 488.2, found 487.2 (M-1).
[650] Step F: N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[651] Step F and the title product of Example 2 N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid (42 mg) (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid methyl ester (53 mg) was prepared from N- [3,5- Respectively. MS (APCI < ⁺ & gt ^; ) Calcd: 474.0, found 475.6 (M + l).
[652] Using the appropriate starting materials, the title compounds of the following Examples 2-1 to 2-15 were obtained in a similar manner to the reaction sequence described in Example 2.
[653] Example 2-1
[654] N- [3,5-Dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid ethyl ester
[655] MS (APCI < ^- >) Calcd: 516.0, found 515.4 (M-1).
[656] Example 2-2
[657] N- [3,5-Dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[658] MS (APCI < ^- >) Calcd: 488.0, found 487.1 (M-1).
[659] Example 2-3
[660] 4-Hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester
[661] MS (APCI < ^- >) Calcd: 496.1, found 495.4 (M-1).
[662] Examples 2-4
[663] N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid
[664] MS (APCI < ⁺ & gt ^; ) Calcd: 468.1, found 469.1 (M + l).
[665] Example 2-5
[666] N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-5-isopropyl- phenoxy) -phenyl] -malonic acid
[667] MS (APCI ^-) Calcd: 516.1, found: 471.4 (M-1-CO 2).
[668] Examples 2-6
[669] N- [3,5-Dichloro-4- (4-hydroxy-3-isopropylsulfamoyl-phenoxy) -phenyl] -malonic acid
[670] MS (APCI ^-) calculated: 476.02, found: 475.0 (M-1).
[671] Examples 2-7
[672] Hydroxy-phenoxy) -3,5-dichloro-phenyl] -malonamic acid methyl ester
[673] MS (APCI < ^- >) Calcd: 490.0, found 489.0 (M-1).
[674] Examples 2-8
[675] N- [3,5-Dichloro-4- (3-heptylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[676] MS (APCI ^-) calculated: 532.08, found: 531.0 (M-1).
[677] Examples 2-9
[678] N- {3,5-Dichloro-4- [3- (4-fluoro-phenylsulfamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[679] MS (APCI < ^- >) Calcd: 528.0, found: 526.7 (M-1).
[680] Examples 2-10
[681] N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl- phenyl] -malonic acid
[682] MS (APCI < ^- >) Calcd: 448.1, found 447.0 (M + l).
[683] Examples 2-11
[684] N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid
[685] MS (APCI < ^- >) Calcd: 434.1, found 433.1 (M + l).
[686] Examples 2-12
[687] N- [4- (3-Cyclopentylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid
[688] MS (APCI < ^- >) Calcd: 462.1, found 461.1 (M + l).
[689] Examples 2-13
[690] N- [4- (3-Cyclohexylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid
[691] MS (APCI < ^- >) Calcd: 476.2, found 475.1 (M + l).
[692] Examples 2-14
[693] N- [3,5-Dichloro-4- (3-cyclopentylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[694] MS (ES) calcd: 502.0, found: 500.9 (M-I).
[695] Examples 2-15
[696] N- [3,5-Dichloro-4- (3-cyclohexylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid
[697] MS (ES) calcd: 516.0, found: 514.9 (M-I).
[698] The title compound of the following Examples 2-16 was obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 2.
[699] Examples 2-16
[700] 4- [3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid
[701] Example 3
[702] N- [3,5-Dichloro-4- (4-hydroxy-3-nonylcarbamoyl-phenoxy) -phenyl] -malonic acid
[703] Step A: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy-benzaldehyde
[704] To a solution of 3,5-dichloro-4- (4-methoxy-phenoxy) -nitrobenzene (3.14 g, 10.0 mmol) in TFA (30 ml) was added hexamethylenetetramine (2.10 g, 15.0 mmol) . The resulting mixture was stirred at 75 < 0 > C for 2 hours and then concentrated to a viscous oil. The residue was dissolved in H ₂ O (30 mL) and stirred at room temperature. To this suspension was added enough saturated aqueous NaHCO ₃ to neutralize the remaining TFA and then the mixture was extracted three times with EtOAc (30 mL). The combined EtOAc extracts were washed twice with saturated aqueous NaHCO ₃ (30 mL) and dried over Na ₂ SO ₄ . The dried extract was filtered and concentrated to give the title compound of Step A (3.67 g) as a yellow solid. The title product of Step A was used in the next step without further purification. MS (APCI ^-) Calcd: 341.0, found: 340.1 (M-1).
[705] Step B: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy-
[706] To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) - (tert-butyldimethylsilyloxy) -pyrrolidine in a mixture of THF (50 mL), tert- To a solution of 2-methoxy-benzaldehyde was added dropwise a solution of sodium chlorite (7.1 g, 79 mmol) in potassium phosphate buffer (100 mL of a 0.6M solution, 60 mmol). The resulting mixture was vigorously stirred at room temperature for 16 hours and then acidified with 1M HCl (200 mL). The resulting mixture was extracted three times with EtOAc (150 mL). The combined EtOAc extracts were washed with 1M HCl (250㎖) 2 times, water (250㎖), 10% NaHSO ₃ and brine (250㎖). The extract was dried with Na ₂ SO ₄ , filtered and concentrated to give 3.1 g of the title compound of Step B as a yellow solid. The title product of Step B was used in the next step without further purification. MS (ES < ^- >) Calcd: 357.0, found 356.0 (M-1).
[707] Step C: Preparation of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-N-nonyl-benzamide
[708] To a suspension of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzoic acid (150 mg, 0.42 mmol) in CH ₂ Cl ₂ (2 ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and 1-hydroxybenzotriazole hydrate (77 mg, 0.50 mmol) were added with stirring at room temperature. To the resulting yellow solution was added nonylamine (154 [mu] L, 1.84 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then the solvent was removed under a dry nitrogen flow. The residue was purified by preparative TLC (5% Et ₂ O, 45% hexane, 50% CH ₂ Cl ₂ ) to give the title compound of Step C (173 mg). MS (APCI < ⁺ & gt ^; ) Calcd: 482.1, found 483.2 (M + l).
[709] Step D: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-hydroxy-N-nonyl-benzamide
[710] CH ₂ Cl ₂ (3㎖) of 5-solution of BBr benzamide To a solution of _{(173mg, 0.36 mmol) 3 -} (2,6- dichloro-4-nitro-phenoxy) -2-methoxy -N- nonyl (1 M solution in CH ₂ Cl ₂ , 0.72 mL) was added. The resulting mixture was stirred at room temperature for 1.5 hours, then quenched by the addition of MeOH (1 mL) and water (10 mL). The resulting mixture was stirred at room temperature for 30 min, then further diluted with 1 M HCl (10 mL) and extracted three times with CH ₂ Cl ₂ (5 mL). The combined CH ₂ Cl ₂ extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 168 mg of the title compound of Step D as a viscous oil. The title product of Step D was used in the next step without further purification. MS (APCI < ^- >) Calcd: 468.1, found 467.2 (M-1).
[711] Step E: 5- (4-Amino-2,6-dichloro-phenoxy) -2-hydroxy-N-nonyl-benzamide
[712] A solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-hydroxy-N-nonyl-benzamide (168 mg, 0.36 mmol) in a mixture of EtOH (3 mL) (10% Pd / C, 100 mg). The resulting mixture was hydrogenated at 55 psi for 1.5 h at room temperature. The mixture was filtered through celite and concentrated to give the title compound of Step E (115 mg) as a tan solid. The title product of Step E was used in the next step without further purification. MS (APCI < ⁺ & gt ^; ) Calcd: 438.1, found: 439.3 (M + l).
[713] Step F: N- [3,5-Dichloro-4- (4-hydroxy-3-nonylcarbamoyl-phenoxy) -phenyl] -malonamic acid methyl ester
[714] To a solution of 5- (4-amino-2,6-dichloro-phenoxy) -2-hydroxy-N-nonyl-benzamide (75 mg, 0.17 mmol) in anhydrous THF (2 ml) was added methyl malonyl chloride Mu] l, 0.18 mmol) at 0 [deg.] C with stirring. The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by preparative TLC (2% MeOH in CH ₂ Cl ₂ ) to give the title compound of Step F (78 mg) as a solid. MS (APCI < ⁺ & gt ^; ) Calcd: 538.2, found: 539.1 (M-1).
[715] Step G: Preparation of N- [3,5-Dichloro-4- (4-hydroxy-3-nonylcarbamoyl-phenoxy) -phenyl]
[716] (78 mg, 0.14 mmol) was dissolved in MeOH (2 mL), water (1.5 < RTI ID = 0.0 & ML) and 1 M NaOH (0.5 mL, 0.5 mmol). The resulting solution was stirred at room temperature for 2 hours and then 0.1 M KOH (15 mL) was added. Solution of Et ₂ O and 1 EtOAc: extracted twice The organic washings were washed three times and the combined mixture to 1 (10㎖) in 0.1M KOH (10㎖). The combined basic solutions were acidified with concentrated HCl and extracted three times with EtOAc (15 mL) and the combined organic extracts were washed with brine. The dried extract was filtered and concentrated to give Step G and the title compound of Example 3 (64mg). MS (APCI < ⁺ & gt ^; ) Calcd: 524.1, found: 525.1 (M +).
[717] The title compounds of the following Examples 3-1 to 3-26 were obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 3. [
[718] Example 3-1
[719] Phenoxy] -5-methyl-phenyl} -malonamic acid < RTI ID = 0.0 >
[720] MS (APCI ^-) Calcd: 478.2, found: 433.5 (M-1-CO 2).
[721] Example 3-2
[722] N- {4- [3- (Cyclopentyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonic acid
[723] MS (APCI ^-) Calcd: 440.2, found: 395.2 (M-1-CO 2).
[724] Example 3-3
[725] N- {4- [4-Hydroxy-3- (isopropyl-methyl-carbamoyl) -phenoxy] -3,5-dimethyl-phenyl} -malonic acid
[726] MS (APCI < ">) Calcd: 414.2, found 413.0 (M-1).
[727] Example 3-4
[728] N- [3,5-Dichloro-4- (4-hydroxy-3-methylcarbamoyl-phenoxy) -phenyl] -malonamic acid
[729] MS (APCI < ⁺ & gt ^; ) Calcd: 412.02, Found: 413.0 (M-I).
[730] Example 3-5
[731] N- [4- (3-butylcarbamoyl-4-hydroxy-phenoxy) -3,5-dichloro-phenyl] -malonamic acid
[732] MS (APCI < ⁺ & gt ^; ) Calcd: 454.07, found 455.1 (M + l).
[733] Examples 3-6
[734] N- [3,5-Dichloro-4- (4-hydroxy-3-isopropylcarbamoyl-phenoxy) -phenyl] -malonic acid
[735] MS (APCI < ⁺ & gt ^; ) Calcd: 440.05, found 441.0 (M + l).
[736] Examples 3-7
[737] N- [3,5-Dichloro-4- (3-heptylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[738] MS (APCI < ⁺ & gt ^; ) Calcd: 496.12, found 497.1 (M + l).
[739] Examples 3-8
[740] N- {4- [3- (Cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid
[741] MS (APCI < ^- >) Calcd: 426.3, found 425.3 (M-1).
[742] Examples 3-9
[743] N- {3,5-Dichloro-4- [3- (4-fluoro-phenylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[744] MS (APCI < ⁺ & gt ^; ) Calcd: 492.03, Found: 493.0 (M + 1).
[745] Examples 3-10
[746] N- [3,5-Dichloro-4- (3-cyclopentylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid
[747] MS (APCI < ⁺ & gt ^; ) Calcd: 466.1, found 467.2 (M + l).
[748] Examples 3-11
[749] N- [3,5-Dichloro-4- (3-cycloheptylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[750] MS (ES ^< ⁺ & gt ^; ) Calcd: 494.1, Found: 495.0 (M + l).
[751] Examples 3-12
[752] N- {3,5-Dichloro-4- [4-hydroxy-3- (l-isopropyl-2- methyl- propylcarbamoyl) -phenoxy] -phenyl} -malonic acid
[753] MS (APCI ⁺⁾ Calcd: 496.1, found: 453.3 (M + 1-CO 2).
[754] Examples 3-13
[755] N- {3,5-Dichloro-4- [3- (cyclohexylmethyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[756] MS (APCI ⁺⁾ Calcd: 494.1, found: 451.2 (M + 1-CO 2).
[757] Examples 3-14
[758] N- {3,5-Dichloro-4- [3- (cyclohexylmethyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid
[759] MS (ES ^< ⁺ & gt ^; ) Calcd: 508.1, found: 508.9 (M + l).
[760] Examples 3-15
[761] N- {3,5-Dichloro-4- [3 - ((1R) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[762] MS (APCI < ⁺ & gt ^; ) Calcd: 508.1, Found: 509.2 (M + l).
[763] Examples 3-16
[764] N- {3,5-Dichloro-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid
[765] MS (APCI < ⁺ & gt ^; ) Calcd: 508.1, found: 509.3 (M + l).
[766] Examples 3-17
[767] N- {4- [3- (Cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid methyl ester
[768] MS (APCI < ⁺ & gt ^; ) Calcd: 440.3, found 441.3 (M + l).
[769] Examples 3-18
[770] N- [3,5-Dichloro-4- (3-cyclohexylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[771] MS (APCI ⁺⁾ Calcd: 480.1, found: 437.2 (M + 1-CO 2).
[772] Examples 3-19
[773] N- {3,5-Dichloro-4- [3- (cyclohexyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[774] MS (ES ^< ⁺ & gt ^; ) Calcd: 494.1, found 494.8 (M + l).
[775] Examples 3-20
[776] N- [3,5-Dichloro-4- (3-cyclooctylcarbamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[777] MS (APCI < ⁺ & gt ^; ) Calcd: 508.1, Found: 509.2 (M + l).
[778] Examples 3-21
[779] N- {3,5-Dichloro-4- [3- (cyclooctyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid
[780] MS (ES ^< ⁺ & gt ^; ) Calcd: 522.1, found 522.8 (M + l).
[781] Examples 3-22
[782] N- {3,5-Dichloro-4- [3- (cyclopentyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[783] MS (ES ^< ⁺ & gt ^; ) Calcd: 480.1, Found: 480.8 (M + l).
[784] Examples 3-23
[785] N- {3,5-Dichloro-4- [3- (cycloheptyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonnamic acid
[786] MS (ES ^< ⁺ & gt ^; ) Calcd: 508.1, found: 508.8 (M + l).
[787] Examples 3-24
[788] Methyl-carbamoyl] -phenoxy} -phenyl) -malonamic acid < RTI ID = 0.0 >
[789] MS (ES ^< ⁺ & gt ^; ) Calcd: 510.1, found 510.9 (M + l).
[790] Examples 3-25
[791] Methyl-carbamoyl] -4-hydroxy-phenoxy} -phenyl) -malonamic acid < RTI ID = 0.0 >
[792] MS (ES ^< ⁺ & gt ^; ) Calcd: 522.1, found: 522.9 (M + l).
[793] Example 3-26
[794] Methyl-carbamoyl] -4-hydroxy-phenoxy} -phenyl) -malonamic acid < RTI ID = 0.0 >
[795] MS (ES ^< ⁺ & gt ^; ) Calcd: 522.1, found 522.8 (M + l).
[796] The title compounds of the following Examples 3-27 through 3-29 were obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 3. < Desc /
[797] Examples 3-27
[798] N- {3-Chloro-4- [3- (cyclobutyl-methyl-carbamoyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid
[799] Example 3-28
[800] N- {3,5-Dimethyl-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[801] Example 3-29
[802] Phenoxy] -5-methyl-phenyl} -malonamic acid < RTI ID = 0.0 >
[803] Example 4
[804] N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid
[805] Step A: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy- (4- fluoro-benzenesulfonyl)
[806] (1 g, 3.4 mmol), p-fluorophenylsulfonyl chloride (1.33 g, 6.8 mmol) and Eaton ' s reagent were added to a solution of 4- (4-methoxy-phenoxy) -3,5- The mixture was stirred at 110 < 0 > C for 4.5 hours and the solution discolored to brown. The brown solution was poured into ice water and extracted three times with EtOAc (30 mL). The combined extracts were washed with 3 portions of saturated sodium bicarbonate (50 mL) and brine (50 mL), dried and concentrated. The residue was the title compound (468mg) of step A and purified by (20% EtOAc in hexanes) to give the purified by chromatography .MS (APCI ^-) Calcd: 471.0, found: 470.0 (M-1).
[807] Step B: 4- (2,6-Dichloro-4-nitro-phenoxy) -2- (4-fluoro-benzenesulfonyl)
[808] To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy- (4- fluoro-benzenesulfonyl) -benzene (468 mg, 0.99 mmol) in CH ₂ Cl ₂ To the solution was added boron tribromide (IM in CH ₂ Cl ₂ , 2.0 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 2 hours and quenched with water (50 mL). After stirring at room temperature for 1 hour, the solution was extracted three times with CH ₂ Cl ₂ (20 mL). The combined organic extracts were dried and concentrated to give the title compound of step B (454 mg). The title product of Step B was used in the next step without further purification. MS (APCI < ^- >) Calcd: 457.0, found 456.0 (M-1).
[809] Step C: 4- (4-Amino-2,6-dichloro-phenoxy) -2- (4-fluoro-benzenesulfonyl)
[810] To a solution of 4- (2,6-dichloro-4-nitro-phenoxy) -2- (4-fluoro-benzenesulfonyl) -phenol (454 mg, 0.99 mmol) in a mixture of ethanol (10 mL) and EtOAc ) Was added catalyst (10% Pd / C, 100 mg). The mixture was hydrogenated at 45 psi for two hours at room temperature. The mixture was filtered through celite and concentrated to give the title compound of Step C (405 mg) as a solid. The title product of Step C was used in the next step without further purification. MS (APCI < ^- >) Calcd: 427.0, found 426.1 (M-1).
[811] Step D: Preparation of N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid methyl ester
[812] The title product of step D, N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid methyl ester (170 mg) Prepared from 4- (4-amino-2,6-dichloro-phenoxy) -2- (4-fluoro-benzenesulfonyl) -phenol (137 mg) according to a method similar to the method described in step D of Example 1 Respectively. MS (APCI ^-) Calcd: 527.0, found: 526.0 (M-1).
[813] Step E: Preparation of N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl}
[814] The title product of step E (105 mg) was obtained in analogy to Example < RTI ID = 0.0 > 4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonoic acid according to a similar manner to that described in step E of Naphthoic acid methyl ester (108 mg). MS (APCI ^-) Calcd: 513.0, found: 512.1 (M-1).
[815] The title compound of the following Example 4-1 was obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 4. < Desc /
[816] Example 4-1
[817] N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid ethyl ester
[818] MS (APCI < ^- >) Calcd: 541.0, found: 540.0 (M-1).
[819] Example 4-2
[820] N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonic acid
[821] Step A: 4-Fluoro-benzenesulfinic acid
[822] A mixture of 4-fluorobenzenesulfonyl chloride (50.0 g, 257 mmol), sodium sulfite (48.6 g, 386 mmol) and sodium bicarbonate (108 g, 1.28 mol) was heated to 100 ° C in water. The resulting solution was stirred at 100 < 0 > C for 1.5 hours, then cooled at room temperature and carefully acidified with concentrated hydrochloric acid. The resulting precipitate was extracted three times with EtOAc (250 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Drying in vacuo afforded the title compound of Step A (35.8 g) as a solid. MS (APCI ^-) Calcd: 160.0, found: 195.1 (M + 35, Cl - adduct).
[823] Step B: 2- (4-Fluoro-benzenesulfonyl) -benzene-l, 4-diol
[824] A solution of benzoquinone (23.5 g, 217 mmol) in EtOH (500 mL) was added to a solution of 4-fluoro-benzenesulfinic acid in EtOH (300 mL) and water (500 mL) at room temperature over 30 min. The resulting solution was stirred at room temperature for 2 hours and then diluted with hot water (4 L). The solution was cooled to 4 [deg.] C for 62 hours to form crystals. The crystalline solid was collected by suction filtration, washed three times with water (500 mL) and twice with hexane (500 mL) and dried to give the title compound of Step B (40.8 g). MS (APCI ^-) Calcd: 268.0, found: 267.1 (M-1).
[825] Step C: 4- (2,6-Dimethyl-4-nitro-phenoxy) -2- (4-fluoro-benzenesulfonyl)
[826] To a solution of 2- (4-fluoro-benzenesulfonyl) -benzene-l, 4-diol (10.0 g, 37.3 ml) in anhydrous 1-methyl-2-pyrrolidinone ) Was sprayed with dry nitrogen for 15 minutes at room temperature. The solution was cooled to 0 C and potassium bis (trimethylsilyl) amide (18.59 g, 93.2 mmol) was added in one portion to give a thick red suspension. The suspension was warmed to room temperature while continued spraying. 18-crown-6 (10.8 g, 41.0 mmol) was added in one portion and the solution was cooled to 0 < 0 > C. 2-Chloro-l, 3-dimethyl-5-nitro-benzene (8.30 g, 44.7 mmol) was added to the cooling suspension to obtain a brown solution and the application was stopped. The solution was allowed to warm to room temperature and stirred under dry nitrogen for 3 hours. The crude reaction product was poured into 1 M HCl (1 L) at 0 < 0 > C and extracted three times with EtOAc (300 mL). The combined extracts were washed with 1 M HCl (1 L) 4 times and brine (1 L), dried over sodium sulfate, treated with activated carbon and filtered. The filtrate was concentrated to a tan solid which was 1: 9: 10 methanol: hexanes: using CH ₂ Cl ₂ (1.5㎖) and filtered through silica gel (150g). The filtrate was concentrated to give the title compound of Step C (11.4 g) as a tan solid. The title product of Step C was used in the next step without further purification. MS (APCI < ^- >) Calcd: 417.1, found 416.0 (M-1).
[827] Step D: 4- (4-Amino-2,6-dimethyl-phenoxy) -2- (4-fluoro-benzenesulfonyl) -phenol
[828] To a solution of 4- (2,6-dimethyl-4-nitro-phenoxy) -2- (4-fluoro-benzenesulfonyl) -phenol (11.4 g, 27.4 mmol) in a mixture of ethanol (200 mL) and EtOAc mmol) was added catalyst (10% Pd / C, 2.29 g). The mixture was hydrogenated at room temperature under 45 psi for 4 h. The mixture was filtered through celite and concentrated to give the title compound of Step D (10.5 g) as a tan solid. The title product of Step D was used in the next step without further purification. MS (APCI < ^- >) Calcd: 387.1, found 386.2 (M-1).
[829] Step E: Preparation of N- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid methyl ester
[830] To a solution of 4- (4-amino-2,6-dimethyl-phenoxy) -2- (4-fluoro-benzenesulfonyl) -phenol (5.53 g, 14.3 mmol) in dry THF (30 ml) (1.68 mL, 15.7 mmol) was added. The solution was stirred at room temperature for 2 hours and then concentrated to a pink solid. The solids were dissolved in a minimal amount of CH ₂ Cl ₂ and solubilized in silica gel using 2% methanol in CH ₂ Cl ₂ . The solution was concentrated to a pink solid and the solid dissolved in EtOAc (30 mL) and cyclohexane (200 mL) was added gradually to give an oily solid which was more crystalline after stirring at room temperature. The suspension was stirred at room temperature for 24 hours and then filtered. The white solid was washed with cyclohexane (20 ml) 3 times and petroleum ether (20 ml) and dried to give the title compound of Step E (4.88 g). MS (APCI < ⁺ & gt ^; ) Calcd: 487.1, found 488.3 (M + l).
[831] Step F: N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-
[832] To a solution of N- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonamic acid methyl ester (7.14 g, 14.6 mmol) in dichloromethane was added 5M potassium hydroxide solution (8.8 ml, 44 mmol) to give a reddish brown solution. The solution was stirred at room temperature for 45 minutes and then diluted with water (200 mL). The solution was washed three times with EtOAc (50 mL) and the combined washings were extracted with 0.1 M KOH (50 mL). The combined basic aqueous solution was acidified with concentrated HCl and extracted three times with EtOAc (50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to a dark amber oil. The oil was dissolved in EtOAc (20 mL) and cyclohexane (100 mL) was added to give an oil which solidified slowly upon stirring at room temperature. The suspension was stirred at room temperature for 64 hours and then filtered. The solid was washed three times with cyclohexane (50 mL) and dried to give Step F as a solid and 6.26 g of the title compound of Example 4-2. MS (APCI < ⁺ & gt ^; ) Calcd: 473.1, found 474.3 (M + l).
[833] The title compound of the following Example 4-3-A was obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 4-2.
[834] Example 4-3-A
[835] Phenoxy] -5-methyl-phenyl} -malonamic acid methyl ester (prepared according to the procedure described for the synthesis of N- {3-chloro-4- [
[836] The title compound of the following Example 4-3 was obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 4-2.
[837] Example 4-3
[838] Phenoxy] -5-methyl-phenyl} -malonamic acid < RTI ID = 0.0 >
[839] MS (APCI < ">) Calcd: 493.0, found 492.0 (M-1).
[840] Example 4-4
[841] Phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid < RTI ID = 0.0 &
[842] Step A: N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl- malonanoic acid methyl ester
[843] To a solution of 4- (4-amino-2,6-dimethyl-phenoxy) -2- ((2-pyridinyl) 4-fluoro-benzenesulfonyl) -phenol (200 mg, 0.4 mmol). The mixture was stirred at 150 < 0 > C under nitrogen for 18 hours. Excess dimethyl -Methyl malonate was removed by distillation under vacuum. The residue was purified by preparative TLC (5% MeOH in CH ₂ Cl ₂ ) to give 155 mg of the title compound of Step A as a foam.
[844]
[845] Step B: Preparation of N- {4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-
[846] 4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methoxyphenyl) -propionamide in H ₂ O / MeOH (1/1, -2-methyl-malonamic acid methyl ester (155 mg, 0.31 mmol) in dichloromethane (5 mL) was added IN NaOH (0.6 mL, 0.6 mmol). After stirring at room temperature for 1 hour, the solution was diluted with EtOAc (15 mL) and extracted three times with 0.1 N NaOH (10 mL). The combined basic extracts were acidified with 1 M HCl and extracted three times with EtOAc (15 mL). The organic extracts were combined, washed with brine, dried and concentrated to give Step B as a solid and 131 mg of the title compound of Example 4-4.
[847]
[848] The title compounds of the following Examples 4-5 to 4-8 were obtained using the appropriate starting materials in a similar manner to the reaction sequence described in Example 4-4.
[849] Example 4-5
[850] Phenoxy] -5-methyl-phenyl} -2-methyl-malonanoic acid methyl ester < RTI ID = 0.0 >
[851]
[852] Examples 4-6
[853] Phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid < RTI ID = 0.0 >
[854]
[855] Examples 4-7
[856] Phenoxy] -phenyl} -2-methyl-malonamic acid methyl ester < RTI ID = 0.0 > (3-fluoro-benzenesulfonyl)
[857]
[858] Examples 4-8
[859] Phenoxy] -phenyl} -2-methyl-malonamic acid < RTI ID = 0.0 > (3-fluoro-benzenesulfonyl)
[860]
[861] Example 5
[862] N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[863] Step A: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl chloride
[864] The title product of step A: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl chloride (8.8 g) was prepared from 4- ( Methoxy-phenoxy) -3,5-dichloro-nitrobenzene (7.0 g). MS (APCI ^-) Calcd: 410.9, found: 392.1 (M-1-Cl + OH, sulfonic acid).
[865] Step B: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfinic acid
[866] To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfonyl chloride (4.26 g, 10.3 mmol) in water (40 ml) was added sodium sulfite (3.89 g, 30.9 mmol ) And sodium bicarbonate (5.19 g, 61.8 mol). The resulting mixture was heated under reflux for 2 hours and then cooled to room temperature. The solution was acidified with concentrated HCl (5 mL) and water (40 mL) was added. The aqueous solution was extracted five times with EtOAc (80 mL). The combined organic extracts were washed twice with brine (50 mL), dried and concentrated to give the title compound of step B (2.56 g) as a solid. The title product of Step B was used in the next step without further purification. MS (APCI < ^- >) Calcd: 376.9, found: 375.8 (M-1).
[867] Step C: 5- (2,6-Dichloro-4-nitro-phenoxy) -2-methoxy- (cyclopropylmethanesulfonyl)
[868] To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy-benzenesulfinic acid (1.0 g, 2.64 mmol) in ethanol was added NaOH (116 mg, 2.89 mmol) and cyclopropylmethyl bromide 1.40 ml, 14.5 mmol). The resulting mixture was stirred at 70 < 0 > C for 6 hours, then at 50 < 0 > C for 20 hours and concentrated to dryness. The residue was dissolved in 1N HCl (40 mL) and extracted four times with EtOAc (40 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (CH ₂ Cl ₂ : hexane 4: 1) to give the title compound of Step C (160 mg) as a solid. MS (APCI ^-) Calcd: 431.0, found: 430.2 (M-1).
[869] Step D: 2-Cyclopropylmethanesulfonyl-4- (2,6-dichloro-4-nitro-phenoxy) -phenol
[870] To a solution of 5- (2,6-dichloro-4-nitro-phenoxy) -2-methoxy- (cyclopropylmethanesulfonyl) -benzene (160 mg, 0.37 mmol) in CH ₂ Cl ₂ Boron Bromide (IM in CH ₂ Cl ₂ , 0.74 mL, 0.74 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours and water (15 mL) was added. After stirring at room temperature for 1 hour, the solution was extracted three times with EtOAc (20 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (100% CH ₂ Cl ₂ ) to give the title compound of step D (76 mg). MS (APCI < ">) Calcd: 417.0, found 416.2 (M-1).
[871] Step E: 4- (4-Amino-2,6-dichloro-phenoxy) -2-cyclopropylmethanesulfonyl-phenol
[872] To a solution of 2-cyclopropylmethanesulfonyl-4- (2,6-dichloro-4-nitro-phenoxy) -phenol (76 mg, 0.18 mmol) in ethanol (2 ml) ). The mixture was hydrogenated at 45 psi at room temperature for 12 hours. The mixture was filtered through celite and concentrated to give the title compound of Step E (43 mg) as a solid. The title product of Step E was used in the next step without further purification. MS (APCI ^-) Calcd: 387.0, found: 386.2 (M-1).
[873] Step F: N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid ethyl ester
[874] To a solution of 4- (4-amino-2,6-dichloro-phenoxy) -2-cyclopropylmethanesulfonyl-phenol (43 mg, 0.11 mmol) in THF (2 ml) was added triethylamine ) And ethyl malonyl chloride (14 [mu] l, 0.11 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solution was concentrated and the residue was purified by preparative TLC (2% MeOH in CH ₂ Cl ₂ ) to give the title compound of Step F (42 mg). MS (APCI < ">) Calcd: 501.0, found 500.3 (M-1).
[875] Step G: N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[876] Step G and the title product of Example 5 N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonanoic acid (4 mg) (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid ethyl ester (5 mg) according to the method described in step E of . MS (APCI ^-) Calcd: 473.0, found: 428.3 (M-1-CO 2).
[877] The title compounds of the following Examples 5-1 to 5-29 were obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 5.
[878] Example 5-1
[879] 4-Hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid methyl ester
[880] MS (APCI < ^- >) Calcd: 481.1, found 480.1 (M-1).
[881] Example 5-2
[882] 4-Hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid methyl ester
[883] MS (APCI < ^- >) Calcd: 467.1, found 466.2 (M-1).
[884] Example 5-3
[885] N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid
[886] MS (APCI < ^- >) Calcd: 467.1, found 466.2 (M-1).
[887] Examples 5-4
[888] 4-Hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester
[889] MS (APCI < ^- >) Calcd: 481.1, found 480.1 (M-1).
[890] Example 5-5
[891] 4-Hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester
[892] MS (APCI < ^- >) Calcd: 495.1, Found: 494.1 (M-1).
[893] Examples 5-6
[894] N- [3-Chloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl- phenyl] -malonic acid
[895] MS (APCI < ^- >) Calcd: 453.1, found 452.1 (M-1).
[896] Examples 5-7
[897] N- [3,5-Dichloro-4- (3-ethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid methyl ester
[898] MS (APCI < ^- >) Calcd: 461.0, found 460.1 (M-1).
[899] Examples 5-8
[900] N- [3,5-Dichloro-4- (4-hydroxy-3-methanesulfonyl-phenoxy) -phenyl] -malonamic acid methyl ester
[901] MS (APCI < ">) Calcd: 447.0, found 446.1 (M-1).
[902] Examples 5-9
[903] N- [3,5-Dichloro-4- (3-ethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid methyl ester
[904] MS (APCI < ">) Calcd: 447.0, found 446.1 (M-1).
[905] Examples 5-10
[906] N- [3,5-Dichloro-4- (4-hydroxy-3-methanesulfonyl-phenoxy) -phenyl] -malonamic acid
[907] MS (APCI < ">) Calcd: 433.0, found 432.0 (M-1).
[908] Examples 5-11
[909] 4-Hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid ethyl ester
[910] MS (APCI < ^- >) Calcd: 475.2, found 474.3 (M-1).
[911] Examples 5-12
[912] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[913] MS (APCI ^-) Calcd: 461.2, found: 460.2 (M-1).
[914] Examples 5-13
[915] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid
[916] MS (APCI < ⁺ & gt ^; ) Calcd: 447.1, found 448.2 (M + l).
[917] Examples 5-14
[918] N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid ethyl ester
[919] MS (APCI < ^- >) Calcd: 515.1, found 514.2 (M-1).
[920] Examples 5-15
[921] N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[922] MS (APCI < ⁺ & gt ^; ) Calcd: 487.0, found 488.0 (M + l).
[923] Examples 5-16
[924] N- [4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid
[925] MS (APCI < ^- >) Calcd: 447.1, found 446.3 (M-1).
[926] Examples 5-17
[927] N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl- phenyl] -malonic acid
[928] MS (APCI < ^- >) Calcd: 461.2, found 460.3 (M-1).
[929] Example 5-18-A
[930] Methyl-phenyl) -2-methyl-malonamic acid methyl ester < RTI ID = 0.0 >
[931]
[932] Examples 5-18
[933] Methyl-phenyl) -2-methyl-malonamic acid < RTI ID = 0.0 >
[934]
[935] Examples 5-19
[936] N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -N-isopropyl-malonamic acid
[937] MS (APCI < ">) Calcd: 503.2, found 502.3 (M-1).
[938] Examples 5-20
[939] N- [3-chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid
[940] MS (APCI < ^- >) Calcd: 495.1, Found: 494.0 (M-1).
[941] Example 5-21-A
[942] Methyl-phenyl] -2-methyl-malonamic acid methyl ester (Example < RTI ID = 0.0 &
[943]
[944] Examples 5-21
[945] Methyl-phenyl] -2-methyl-malonamic acid < RTI ID = 0.0 >
[946]
[947] Examples 5-22
[948] N- [3,5-Dichloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[949] MS (APCI < ^- >) Calcd: 501.0, found 499.5 (M-1).
[950] Examples 5-23
[951] N- [3,5-Dichloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[952] MS (APCI < ^- >) Calcd: 515.1, found 513.9 (M-1).
[953] Examples 5-24
[954] N- [3-Chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid
[955] MS (APCI < ^- >) Calcd: 481.1, found 480.0 (M-1).
[956] Examples 5-25
[957] N- [4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl- phenyl] -malonic acid
[958] MS (APCI ^-) Calcd: 475.2, found: 474.0 (M-1).
[959] Examples 5-26
[960] N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3-methyl- phenyl] -malonic acid
[961] MS (ES) calcd: 461.2, found: 460.0 (M-I).
[962] Examples 5-27
[963] N- [4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid
[964] MS (ES) calcd: 461.2, found: 460.0 (M-I).
[965] Examples 5-28
[966] N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3-methyl- phenyl] -malonic acid
[967] MS (ES) calcd: 433.1, found: 434.0 (M-I).
[968] Examples 5-29
[969] N- [3-Chloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid
[970] MS (APCI < ^- >) Calcd: 467.1, found 466.3 (M-1).
[971] Example 6
[972] N- {4- [3- (4-Fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonic acid
[973] Step A: Preparation of [5- (2,6-dimethyl-4-nitro-phenoxy) -2-methoxy-phenyl] - (4-fluoro-phenyl)
[974] To a solution of 4- (4-methoxy-phenoxy) -3,5-dichloro-nitrobenzene (2.7 g, 10 mmol) and p-fluorobenzoyl chloride (4.0 g, 3.0 ml, 25 mmol) in methylene chloride ) Was added titanium tetrachloride (1M in methylene chloride, 50 mL, 50 mmol). The reaction mixture was stirred at room temperature for 3 days, poured into ice (100 g) and stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted three times with methylene chloride (50 mL). The combined organic extracts were washed with 5% sodium carbonate (200 mL) and brine (150 mL), dried and concentrated. The residue was triturated with ether-petroleum ether. The solid was filtered and collected to give the title compound of Step A (2.1 g) as a tan solid. MS (APCI < ">) Calcd: 395.2, found 394.2 (M-1).
[975] Step B: Preparation of [5- (2,6-dimethyl-4-nitro-phenoxy) -2-hydroxy-phenyl] - (4-fluoro-phenyl)
[976] Phenyl) -methanone (1.4 g) was prepared in analogy to Example < RTI ID = 0.0 > 4-nitro-phenoxy) -phenyl] - (4-fluoro-phenyl) -methanone (1.5 g) was obtained as a white solid following the procedure described in step 4 of Example 4, Lt; / RTI > MS (APCI < ^- >) Calcd: 381.2, found: 380.2 (M-1).
[977] Step C: Preparation of [5- (4-amino-2,6-dimethyl-phenoxy) -2-hydroxy-phenyl] - (4-fluoro-phenyl)
[978] The title product of step C, [5- (4-amino-2,6-dimethyl-phenoxy) -2-hydroxy-phenyl] - (4-fluoro-phenyl) 4-nitro-phenoxy) -2-hydroxy-phenyl] - (4-fluoro-phenyl) -methanone (1.4 g) Lt; / RTI > MS (APCI < ">) Calcd: 351.2, found 350.2 (M-1).
[979] Step D: Preparation of N- {4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonic acid methyl ester
[980] The title product N- {4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonanoic acid methyl ester (274 mg) 2-hydroxy-phenyl] - (4-fluoro-phenyl) -methanone (prepared as described in example 1 step D) 250 mg). MS (APCI < ^- >) Calcd: 451.2, found 450.2 (M-1).
[981] Step E: Preparation of N- {4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl}
[982] Step E and the title product of Example 6 N- {4- [3- (4-Fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5- dimethyl- phenyl} -malonanic acid (crude title product 50.3 mg) was prepared from N- {4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl- Phenyl} -malonamic acid methyl ester (50 mg). MS (APCI < ^- >) Calcd: 437.1, found 436.1 (M-1).
[983] The title compounds of the following Examples 6-1 to 6-5 were obtained using the appropriate starting materials in a similar manner to the reaction sequence described in Example 6.
[984] Example 6-1
[985] N- [4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid
[986] MS (APCI < ^- >) Calcd: 425.2, found 424.2 (M-1).
[987] Example 6-2
[988] Methoxy-phenoxy) -3,5-dichloro-phenyl] -malonamic acid methyl ester
[989] MS (ES) calcd 467.1, found 466.0 (M-1).
[990] Example 6-3
[991] N- [4- (2-acetyl-5-isopropyl-4-methoxy-phenoxy) -3,5-dichloro-phenyl] -malonic acid
[992] MS (APCI ^-) Calcd: 453.1, found: 409.2 (M-1-CO 2).
[993] Example 6-4
[994] N- [4- (2-Benzoyl-5-isopropyl-4-methoxy-phenoxy) -3,5-dichloro-phenyl] -malonamic acid methyl ester
[995] MS (ES) calcd: 529.1, found: 530.0 (M + l).
[996] Examples 6-5
[997] N- [4- (2-Benzoyl-5-isopropyl-4-methoxy-phenoxy) -3,5-dichloro-phenyl] -malonamic acid methyl ester
[998] MS (APCI ^-) Calcd: 515.1, found: 472.2 (M + 1-CO 2).
[999] The title compounds of the following Examples 6-6 to 6-9 were obtained using the appropriate starting materials in a similar manner to the reaction sequence described in Example 6.
[1000] Examples 6-6
[1001] N- [4- (3-Cyclobutylacetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid
[1002] Examples 6-7
[1003] N- [3-Chloro-4- (3-cyclobutylacetyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid
[1004] Examples 6-8
[1005] N- [3-Chloro-4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -5-methyl- phenyl] -malonic acid
[1006] Examples 6-9
[1007] Chloro-4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy) -5-methyl- phenyl] -malonamic acid
[1008] Example 7
[1009] Methyl-4-hydroxy-phenoxy} -3,5-dimethyl-phenyl) -malonamic acid < EMI ID =
[1010] Step A: N- (4- {3 - [(4-Fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -3,5-dimethyl-
[1011] To a solution of N- {4- [3- (4-fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonoic acid in a mixture of EtOH / EtOAc (4: (222 mg, 0.49 mmol) in dichloromethane (5 mL) was added a nickel catalyst (2 mL, washed with water and methanol). The mixture was hydrogenated at 50 psi for 1 hour at room temperature. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound of Step A (159 mg) as a white solid. MS (APCI < ^- >) Calcd: 453.2, found 452.2 (M-1).
[1012] Step B: N- (4- {3 - [(4-Fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -3,5-
[1013] Phenoxy) -3,5-dimethyl-phenyl) -methanone hydrochloride The title compound of step B and Example 7 was reacted with N- (4- {3 - [(4-fluoro- -Malonic acid (156 mg) was prepared from N- (4- {3- [(4-fluoro-phenyl) -hydroxy- methyl] -4- hydroxy- phenoxy} -3,5-dimethyl-phenyl) -malonamic acid methyl ester (157 mg).
[1014] The title compound of the following Example 7-1 was obtained using a suitable starting material in a similar manner to the reaction sequence described in Example 7.
[1015] Example 7-1
[1016] Hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonamic acid N- [4- [3- (2-cyclopentyl-
[1017] MS (ES < ^- >) Calcd: 427.2, found 426.4 (M-1).
[1018] The title compounds of the following Examples 7-2 to 7-5 were obtained using the appropriate starting materials in a manner analogous to the reaction sequence described in Example 7.
[1019] Example 7-2
[1020] Hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonamic acid N- [4- [3- (2-cyclobutyl-
[1021] Example 7-3
[1022] Methyl-4-hydroxy-phenoxy} -5-methyl-phenyl} -malonamic acid < EMI ID =
[1023] Example 7-4
[1024] Hydroxy-phenoxy] -5-methyl-phenyl} -malonamic acid < RTI ID = 0.0 >
[1025] Examples 7-5
[1026] Hydroxy-phenoxy] -5-methyl-phenyl} -malonamic acid < RTI ID = 0.0 >
[1027] Example 8
[1028] N- {4- [3- (2-Cyclopentyl-ethyl) -4-hydroxy-phenoxy] -3,5- dimethyl-phenyl} -malonic acid
[1029] Step A: Synthesis of 2-cyclopentyl-1- [5- (2,6-dimethyl-4-nitro-phenoxy) -2- methoxy-phenyl]
[1030] The title product of Step A 2-Cyclopentyl-1- [5- (2,6-dimethyl-4-nitro-phenoxy) -2-methoxy-phenyl] -ethanone was prepared according to the procedure described in Step A of Example 6 Was prepared from 4- (4-methoxy-phenoxy) -3,5-dimethyl-nitrobenzene (1.00 g) and cyclopentyl-acetyl chloride (1.34 g). MS (APCI < ">) Calcd: 439.1, found 438.3 (M-1).
[1031] Step B: 2-Cyclopentyl-1- [5- (2,6-dimethyl-4-nitro-phenoxy) -2-methoxy-phenyl]
[1032] Phenol] -ethanone (200 mg, 0.52 mmol) in CH ₂ Cl ₂ (0.5 ml) was added dropwise to a solution of 2-cyclopentyl-1- [5- (2,6- And trifluroacetic acid (0.34 ml) in dichloromethane (5 ml) was added triethylsilane (212 mg, 1.83 mmol). After stirring at room temperature for 18 hours, the reaction mixture was poured into water (15 mL) and extracted with EtOAc (20 mL). The EtOAc extract was washed with 2 portions of saturated sodium bicarbonate (15 mL) and brine (15 mL), dried and concentrated. The residue was purified by preparative TLC (CH ₂ Cl ₂ : hexane 2: 3) to give the title compound of Step B (186 mg) as an oil. MS (APCI < ^- >) Calcd: 369.2, found 468.3 (M-1).
[1033] Step C: 2-Cyclopentyl-l- [5- (2,6-dimethyl-4-nitro- phenoxy) -2-hydroxy-phenyl]
[1034] 2-Cyclopentyl-1- [5- (2,6-dimethyl-4-nitro-phenoxy) -2-hydroxy-phenyl] -ethane in step C was converted to the title compound by the method described in step B of Example 4 Prepared from 2-cyclopentyl-1- [5- (2,6-dimethyl-4-nitro-phenoxy) -2-methoxy-phenyl] -ethane (186 mg). MS (APCI < ">) Calcd: 355.2, found 354.2 (M-1).
[1035] Step D: 2-Cyclopentyl-l- [5- (4-amino-2,6-dimethyl- phenoxy) -2-hydroxy-phenyl]
[1036] 2-cyclopentyl-1- [5- (4-amino-2,6-dimethyl-phenoxy) -2-hydroxy-phenyl] -ethane (172 mg, crude title product) Phenoxy] -2-hydroxy-phenyl] -ethane in accordance with the method described in step C of Example 1c)], was prepared from 2-cyclopentyl-1- [5- (2,6- dimethyl-4-nitro- phenoxy) -2-hydroxy-phenyl] -ethane. MS (APCI ^-) Calcd: 325.2, found: 324.2 (M-1).
[1037] Step E: Preparation of N- {4- [3- (2-cyclopentyl-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonanoic acid methyl ester
[1038] The title product N- {4- [3- (2-cyclopentyl-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonic acid methyl ester (122 mg) 2-hydroxy-phenyl] -ethane (crude starting material 172 mg) was prepared from 2-cyclopentyl-1- [5- . MS (APCI < ^- >) Calcd: 425.2, found 424.2 (M-1).
[1039] Step F: N- {4- [3- (2-Cyclopentyl-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid
[1040] Step F and the title product N- {4- [3- (2-cyclopentyl-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonamic acid (88 mg) Phenoxy] -3,5-dimethyl-phenyl} -malonanoic acid methyl ester was prepared from methyl N- {4- [3- (2-cyclopentyl-ethyl) -4-hydroxy-phenoxy] Ester (122 mg). MS (APCI ^-) Calcd: 411.2, found: 410.2 (M-1).
[1041] Example 9
[1042] Cyclobutyl-2-hydroxy-5- [4- (2-hydroxy-acetylamino) -2,6-dimethyl- phenoxy] -N-
[1043] Step A: 5- [4- (2-Benzyloxy-acetylamino) -2,6-dimethyl-phenoxy] -N- cyclobutyl-2-hydroxy-N-methyl-
[1044] (4-amino-2,6-dimethyl-phenoxy) -N-cyclobutyl-2-hydroxy-N-methyl-benzamide (as described for Step F of Example 3) (164 [mu] L, 1.2 mmol) and benzyloxyacetyl chloride (95%, 195 [mu] L, 1.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours and then 1M HCl (25 mL) and EtOAc (25 mL) were added. The organic layer was separated and washed with 1 M HCl (25 mL) twice and brine (25 mL), dried and concentrated. The residue was purified by preparative TLC (EtOAc: hexane 1: 1) to give the title compound of Step A (531 mg) as a solid. MS (APCI < ">) Calcd: 488.2, found 487.3 (M-1).
[1045] Step B: N-Cyclobutyl-2-hydroxy-5- [4- (2-hydroxy- acetylamino) -2,6- dimethyl- phenoxy] -N-methyl-
[1046] (50 mg) was added to a solution of 5- [4- (2-benzyloxy-acetylamino) -2,6-dimethyl-phenoxy] -N-cyclobutyl- Was added catalyst (10% Pd / C, 10 mg). The reaction mixture was hydrogenated at 50 psi at room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to give Step B and the title compound of Example 9 (40 mg) as a white solid. MS (APCI < ^- >) Calcd: 398.2, found: 372.2 (M-1).
[1047] The title compounds of the following Examples 9-1 to 9-4 were obtained using an appropriate starting material in a similar manner to the reaction sequence described in Example 9.
[1048] Example 9-1
[1049] 2-Benzyloxy-N- [3-chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl- phenyl] -acetamide
[1050] MS (APCI < ^- >) Calcd: 529.1, found: 528.3 (M-1).
[1051] Example 9-2
[1052] 4-Hydroxy-phenoxy) -5-methyl-phenyl] -2-hydroxy-acetamide <
[1053] MS (APCI < ^- >) Calcd: 439.1, found: 538.2 (M-1).
[1054] Example 9-3
[1055] 2-Benzyloxy-N- [4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl- phenyl] -acetamide
[1056] MS (APCI ^-) Calcd: 509.2, found: 508.2 (M-1).
[1057] Examples 9-4
[1058] 4-Hydroxy-phenoxy) -3,5-dimethyl-phenyl] -2-hydroxy-acetamide
[1059] MS (APCI < ^- >) Calcd: 419.1, found 418.3 (M-1).
[1060] Example 10
[1061] Hydroxy-4'-hydroxy-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1062] Step A: 4- (3-Bromo-4-methoxy-phenoxy) -3,5-dimethylnitrobenzene
[1063] To a solution of 3,5-dimethyl-4- (4'-methoxyphenoxy) nitrobenzene (prepared according to J. Med. Chem. , 38 , 703, 1995, 4.0 g) in chloroform (150 ml) To the solution was added N-bromosuccinimide (2.6 g) and trifluoroacetic acid (1.1 ml) and the resulting mixture was heated at reflux for 90 minutes. Additional N-bromosuccinimide (2.6 g) and trifluoroacetic acid (1.1 ml) were added and then further heated for 18 hours. The reaction was washed with aqueous sodium bicarbonate to give the title compound (5.0g) of Step A as an orange solid and dried with Na ₂ SO ₄ and concentrated. MS (APCI < ⁺ & gt ^; ) Calcd: 351, found 352 (M + l).
[1064] Step B: 4- (3-Bromo-4-methoxy-phenoxy) -3,5-dimethyl-phenylamine
[1065] A mixture of the title product of Step A (5.0 g) and 10% palladium on carbon (0.6 g) in ethyl acetate (100 ml) was hydrogenated at 50 psi for 3 h. The reaction was filtered through celite and concentrated to give the title compound of Step B (4.3 g) as a yellow solid. MS (APCI < ⁺ & gt ^; ) Calcd: 321, found 322 (M + l).
[1066] Step C: Preparation of N- [4- (6-hydroxy-4'-hydroxy-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1067] To a suspension of indole resin N-4 of Reaction N (prepared according to J. Org. Chem. , 63 , 5300-5301, 1998, 45 g, 0.33 meq / g) in anhydrous dichloroethane (500 ml) - (3-bromo-4-methoxy-phenoxy) -3,5-dimethyl-phenylamine (9.7 g) and activated 3 A molecular sieve (21 g) with sealed porous bag was added. The reaction was purged with nitrogen and shaken overnight at room temperature. Tetramethylammonium triacetoxyborohydride (20 g) was added and shaking continued for 48 hours. Sodium borohydride (24 g) was then added and shaking continued for 6 hours. The resulting resin was collected and washed successively with 300 ml each of dichloromethane, methanol, dimethylformamide, tetrahydrofuran, methanol, dichloromethane, methanol and dichloromethane. The resin was dried in a vacuum oven at room temperature overnight under nitrogen to give resin-bound amine N-5 of the formula N (resin B) (IR: 1690, 1211 cm ^-1 ).
[1068] To a suspension of resin B (1.2 g, 0.37 meq / g) in anhydrous dimethylformamide (18 ml) was added N, N-diisopropylethylamine (0.39 ml), mono- tert- butylmalonate (360 mg) Methyl fluoroformamidinium hexafluorophosphate (600 mg) was added. The reaction was purged with nitrogen and shaken at room temperature for 18 hours and the resulting resin was collected and washed successively with 20 mL each of dichloromethane, methanol, dimethylformamide, tetrahydrofuran, methanol, dichloromethane, methanol and dichloromethane . After drying in a vacuum oven at room temperature for 12 hours, the resin was reprocessed with all reagents and incubated and washed as described above. The resin was dried in a vacuum oven under nitrogen at room temperature for 18 hours to give the resin-bound amide O-1 (Resin C) of Scheme O (IR: 1730, 1662 cm ^-1 ).
[1069] To a suspension of resin C (44 mg) and tetrakis (triphenylphosphine) palladium (0) (3.4 mg) in degassed DMF (0.15 ml) was added a solution of 4-methoxyphenylboronic acid (0.40 M solution in degassed DMF 0.15 Ml) was added and an aqueous solution of sodium carbonate (37 ml of a 2.0 M solution) was added. The reaction was purged with nitrogen and shaken at 80 [deg.] C for 16 hours. The resulting resin was collected and washed successively with 0.25 mL each of dichloromethane, methanol, 50% aqueous methanol, methanol, dichloromethane, methanol and dichloromethane. The resin-bound amide P-1 (Resin D) in Scheme P was dried in a vacuum oven under nitrogen at room temperature for 18 hours and then suspended in a solution of boron tribromide (0.43 M solution in dichloromethane, 0.35 ml). After stirring at room temperature for 16 h, dichloromethane (0.25 ml) and aqueous methanol (14% solution of water in methanol, 0.18 ml) were added and the reaction continued for 4 h. The reaction contents were transferred to a silica gel (about 100 mg) and a basic alumina (200 mg) column and the product was eluted with acetonitrile. Removal of the solvent in vacuo gave the title compound of Step C and Example 10. MS (APCI < ⁺ & gt ^; ) Calcd: 421, found 422 (M + l).
[1070] The title compounds of the following Examples 10-1 to 10-8 were obtained using a suitable starting material, including Resin C and the appropriate boronic acid, in a manner analogous to the reaction sequence described in Step C of Example 10.
[1071] Example 10-1
[1072] Methyl-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1073] MS (APCI < ⁺ & gt ^; ) Calcd: 419, found 420 (M + l).
[1074] Example 10-2
[1075] Hydroxy-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1076] MS (APCI < ⁺ & gt ^; ) Calcd: 423, found 424 (M + l).
[1077] Example 10-3
[1078] Hydroxy-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1079] MS (APCI < ⁺ & gt ^; ) Calcd: 473, found 474 (M + l).
[1080] Example 10-4
[1081] 3-yl-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1082] MS (APCI < ⁺ & gt ^; ) Calcd: 411, found: 412 (M + l).
[1083] Examples 10-5
[1084] Methyl-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1085] MS (APCI < ⁺ & gt ^; ) Calcd: 419, found 420 (M + l).
[1086] Examples 10-6
[1087] Methyl-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1088] MS (APCI < ⁺ & gt ^; ) Calcd: 419, found 420 (M + l).
[1089] Examples 10-7
[1090] N - [4- (6-hydroxy-3'-nitro-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1091] MS (APCI < ⁺ & gt ^; ) Calcd: 450, found 451 (M + l).
[1092] Examples 10-8
[1093] Amino-6-hydroxy-biphenyl-3-yloxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester
[1094] MS (APCI < ⁺ & gt ^; ) Calcd: 420, found 421 (M + l).
[1095] Example 11
[1096] N- [4- (3-Bromo-4-methoxy-phenoxy) -3,5- dimethyl-phenyl] -malonic acid
[1097] To a suspension of resin C (44 mg) prepared as described in example 10 step C, 50% trifluoroacetic acid (0.4 ml) in dichloromethane was added and the mixture was shaken at room temperature for 4 hours. The resin used was filtered off and washed twice with dichloromethane. The solvent was removed in vacuo to afford the title compound of Example 11. MS (APCI < ⁺ & gt ^; ) Calcd: 407, found 408 (M + l).
[1098] Example 12
[1099] N- [4- (3-Bromo-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid
[1100] A suspension of resin C (44 mg), prepared as described in Example 10, Step C, was added to a solution of boron tribromide (0.43 M solution in dichloromethane, 0.35 ml) and shaken at room temperature for 16 hours. Dichloromethane (0.25 mL) and aqueous methanol (14% solution of water in methanol, 0.18 mL) were added and shaken continuously for 4 h. The reaction contents were transferred to a silica gel (about 100 mg) and a basic alumina (200 mg) column and the product was eluted with acetonitrile. The solvent was removed in vacuo to give the title compound of Example 12. MS (APCI < ⁺ & gt ^; ) Calcd: 407, found 408 (M + l).
[1101] The title compounds of the following Examples 13 to 13-4 were obtained using the appropriate starting materials in a similar manner to the reaction sequence described in Scheme Q. [
[1102] Example 13
[1103] N- [4- (7-Hydroxy-indan-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid
[1104] Example 13-1
[1105] N- [3-chloro-4- (7-hydroxy-indan-4-yloxy) -5-methyl-phenyl] -malonamic acid
[1106] Example 13-2
[1107] N- [4- (7-Hydroxy-2-R-methyl-1 -oxo-indan-4-yloxy) -3,5-dimethyl-
[1108] Example 13-3
[1109] N- [4- (7-Hydroxy-2-S-methyl-1 -oxo-indan-4-yloxy) -3,5-dimethyl-
[1110] Example 13-4
[1111] N- [4- (7-Hydroxy-2,2-dimethyl-1 -oxo-indan-4-yloxy) -3,5-dimethyl-phenyl] -malonic acid
[1112] The title compounds of the following Examples 14 to 14-1 were obtained using the appropriate starting materials in a similar manner to the reaction sequence described in Scheme R. < Desc /
[1113] Example 14
[1114] 5-methyl-phenyl] -malonamic acid < / RTI > < RTI ID = 0.0 &
[1115] Example 14-1
[1116] 3-dihydro-1H-isoindole-4-yloxy) -3,5-dimethyl-phenyl] -malonamic acid
[1117] The title compound of the following Example 15 was obtained using an appropriate starting material in a similar manner to the reaction sequence described in Scheme H.
[1118] Example 15
[1119] N- {4- [3- (4-Fluoro-benzyl) -4-hydroxy-phenoxy] -3,5-dimethyl- phenyl} -malonic acid

权利要求:
Claims (27)
[1" claim-type="Currently amended] Claims 1. A compound of formula (I), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such compound, isomer or prodrug:
Formula I

In this formula,
W is (a) -O-, (b) -S-, (c) -SO-, (d) -SO 2 -, (e) -CH 2 -, (f) -CF 2 -, (g) -CHF-, (h) -C (O ) -, (i) -CH (OH) -, (j) -NR a or (k) ego;
R < ⁰ > is (a) hydrogen; (b) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, (ii) halogen, ₃ and (iv) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 substituent selected from the group consisting of phenyl substituted with 0 or 1 substituent selected from the group consisting of -OCF ₃ ; (c) -C (O) R ^h ; (d) -S (O) ₂ R ^h ; Or (e) halogen;
R ^1, R ^2, R ³ and R ⁶ are each independently (a) hydrogen, (b) _{halogen, (c) - (C 1} -C 8) _{alkyl, (d) -CF 3, (} e) -OCF ₃ , (f) -O (C ₁ -C ₈ ) alkyl or (g) -CN;
R ⁴ is selected from the group consisting of: (a) - (C ₁ -C ₁₂ ) alkyl, (b) - (C ₂ -C ₁₂ ) alkenyl substituted with 0 to 3 substituents independently selected from the following group V, C ₂ -C ₁₂₎ alkynyl, (d) halogen, (e) -CN, (f ) -OR b, (g) aryl, (h) _{heteroaryl, (i) - (C 3} -C 10) cycloalkyl Alkyl, (j) heterocycloalkyl, (k) -C (O) OR ^c , (1) -NR ^a C (O) R ^d , (m) -NR ^a C (O) NR ^c R ^d , ) -NR ^a S (O) ₂ R ^d , (o) -NR ^a R ^d or (p) -C (O) R ^c ; Or R ³ and R ⁴ has the formula together with the carbon atom to which they are attached - (CH _{2) i} - tan forming the summons ring, or the formula of (wherein, i is 3, 4, 5 or 6 a) - (CH _{2) k} -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ;
R ⁵ is (a) -OH, (b) -O (C 1 -C 6) alkyl, (c) -OC (O) R f, (d) F , or (e) -C (O) OR c , or Or R ⁴ and R ⁵ together with the carbon atoms to which they are attached form -CR ^c = CR ^a -NH-, -N = CR ^a -NH, -CR ^c = CR ^a -O-, -CR ^c = CR ^a - S-, -CR ^c = N-NH- and -CR ^a = CR ^a -CR ^a = N-;
R ⁷ is (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl;
R ⁸ and R ⁹ are each independently (a) hydrogen, (b) - (C ₁ -C ₆ ) alkyl, (c) aryl or (d) halogen;
R ¹⁰ is _{(a) - (C 0 -C} 1) alkyl, -C (O) OH, (b ) - (C 0 -C 1) alkyl, ^{-C (O) OR f, (} c) - (C 0 - C ₁ ) alkyl-C (O) NR ^c R ^d or (d) - (C ₀ -C ₁ ) alkyl-OH;
In each case R ^a is independently - (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 - (C ₃ -C ₆ ) cycloalkyl or methoxy;
A R ^b is independently in each occurrence (a) hydrogen, (b) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₂₎ alkyl, (c) aryl, (d) (E) - (C ₃ -C ₁₀ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) NR ^c R ^d or (h) -C (O) R ^f ;
R ^c and R ^d in each occurrence are each independently selected from the group consisting of (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0 to 3 substituents independently selected from the following group VI, (c) (C ₂ -C _{12) alkenyl, (d) - (C 2} -C 12) alkynyl, (e) aryl, (f) _{heteroaryl, (g) - (C 3} -C 10) cycloalkyl or ( h) heterocycloalkyl; Or R ^c and R ^d are the atom they are attached (s) and with -O-, -NR ^e -, and 3-to 10-which may or may not include a heteroaryl of claim 2, selected from the group consisting of -S- (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , (c) oxo, (d) -CN, (e) phenyl and (f ) -NR &^lt; ^a &^gt; R &^lt; ^g &^gt;;
R ^e is (a) hydrogen, (b) -CN, (c ) to the optionally substituted with 0 to 3 substituents independently selected from Group V in each occurrence - (C ₁ -C ₁₀₎ alkyl, (d) - (C ₂ -C _{10) alkenyl, (e) - (C 2} -C 10) _{alkoxy, (f) - (C 3} -C 10) cycloalkyl, (g) aryl, (h) heteroaryl, (i ) -C (O) R ^f , (j) -C (O) OR ^f , (k) -C (O) NR ^a R ^f or (l) -S (O) ₂ R ^f ;
In each case R ^f is independently - (a) - (C ₁ -C ₁₀ ) alkyl, (b) - (C ₂ -C ₁₀ ) alkenyl substituted by 0 to 3 substituents independently selected from the following group VI , (c) - (C ₂ -C ₁₀ ) alkynyl, (d) - (C ₃ -C ₁₀ ) cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl;
To R ^g are independently in each occurrence (a) _{hydrogen, (b) - (C 1} -C 6) _{alkyl, (c) - (C 2} -C 6) alkenyl, (d) aryl, (e) - ^{C (O) R f, (} f) -C (O) oR f, (g) -C (O) NR a R f, (h) -S (O) 2 R f , or (i) - (C ₃ -C ₈₎ cycloalkyl;
R ^h is selected from the group ^consisting of (a) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, ) -CF _3, and (iv) substituted from the group consisting of -OCF ₃ to 0 or 1 substituent selected from the group consisting of phenyl substituted by 0 or 1 substituent selected - (C ₁ -C ₆₎ alkyl; (b) (1) - ( C 1 -C 4) alkyl, (2) halogen, ₍₃₎ -CF 3, and (4) phenyl substituted from the group consisting of -OCF ₃ to selected from 0 to 2 substituents independently ; _{(c) - (C 3 -C} 6) cycloalkyl; Or (d) heterocycloalkyl;
Group V is (a) _{halogen, (b) -CF 3, (} c) -OCF 3, (d) -OH, (e) _{oxo, (f) - (C 1} -C 6) alkoxy, (g) - CN, (h) aryl, (i) _{heteroaryl, (j) - (C 3} -C 10) cycloalkyl, (k) ^{heterocycloalkyl, (l) -SR f, (} m) -S (O) R ^{f, (n) -S (o} ) 2 R f, (o) -S (o) 2 NR a R f, (p) -NR a R g , or (q)
-C (O) NR < ^a > R <^f;
Group VI is (a) halogen, (b) hydroxy, (c) _{oxo, (d) - (C 1} -C 6) alkoxy, (e) aryl, (f) heteroaryl, (g) - (C ₃ -C ₈₎ cycloalkyl, (h) heterocycloalkyl, (i) -CN, or (j) -OCF _3, and;
However, the substituent R ⁴ is substituted with 0 to 3 substituents independently selected from the Group V - and (C ₁ -C ₁₂₎ alkyl, wherein if V is a substituent group of oxo, oxo groups - (C ₁ -C ₁₂ ) Alkyl at a carbon atom other than the C ₁ carbon atom;
In each case, the aryl is independently (a) _{halogen, (b) - (C 1} -C 6) alkyl, (c) -CN, (d ) -SR f, (e) -S (O) R f, _{(f) -S (O) 2} R f, (g) - (C 3 -C 6) cycloalkyl, (h) -S (O) 2 NR a R f, (i) -NR a R g, ( ^{j) -C (O) NR a} R f, (k) -OR b, (l) - perfluoro - (C ₁ -C ₄₎ alkyl, and (m) independently selected from the group consisting of -COOR ^f 0 Phenyl or naphthyl substituted with up to four substituents;
However, the substituent (s) on the aryl ^{-SR f, -S (O) R} f, -S (O) 2 R f, -S (O) 2 NR a R f, -NR a R g, -C ( O) NR ^a R ^f , -OR ^b or -COOR ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
(A) halogen, (b) - (C ₁ -C ₄ ) alkyl, (c) - (C ₁ -C ₄ ) alkyl, ^{_{CF 3, (d) -OR b}} , (e) -NR a R g , and (f) -CO ₂ R 5 a circle having the ^f 0 to 3 substituents independently selected from the group consisting of, 6-, 7 membered, 8-membered, 9-membered or 10-membered ring or heterocyclic ring wherein the monocyclic heteroaryl ring is condensed to a benzene ring or another heteroaryl ring;
Provided that when the substituent (s) on the heteroaryl is -OR ^b , -NR ^a R ^g or -CO ₂ R ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
Heterocycloalkyl in each occurrence is independently O, NR ^e and having from 1 to 3 heteroatoms selected from the group consisting of S, (a) - (C 1 -C 4) alkyl, ^(b) -OR b, (c) oxo, (d) -CN, (e) phenyl and (f) -NR ^a R ^g , 8-membered, 9-membered or 10-membered ring or a dicyclic alkyl ring.
[2" claim-type="Currently amended] The method according to claim 1,
W is O; R < ⁰ > is hydrogen; R ¹ is located at position 5; R ² is located at position 3; R ¹ and R ² are each independently hydrogen, - (C ₁ -C ₆ ) alkyl, halogen or CN.
[3" claim-type="Currently amended] 3. The method of claim 2,
R ³ is hydrogen, - (C ₁ -C ₄ ) alkyl or halogen; R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ substituted by cycloalkyl, and heterocycloalkyl 0 to 3 substituents independently selected from the group consisting of - (C ₁ -C _{10) alkyl, (b) - (c 3} -C 8) cycloalkyl, (c) heterocycloalkyl, (d) -C (O) R c, (e) -OR b, (f) - NR ^a C (O) R ^d , (g) -NR ^a C (O) NR ^c R ^d or (h) -NR ^a S (O) ₂ R ^d ; Or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, 4, 5 or 6, or - (CH ₂ ) _k -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ; However, the substituent R ⁴ is 0 to 3 substituted with a substituent - if the (C ₁ -C ₁₀₎ alkyl, oxo groups - a (C ₁ -C ₁₀₎ substituted at carbon atoms other than the C ₁ carbon atom in the alkyl compound.
[4" claim-type="Currently amended] The method of claim 3,
R ⁵ is -OH, -OC (O) R ^f or -F; R ^f is - (C ₁ -C ₁₀ ) alkyl substituted with 0 to 3 substituents independently selected from the group VI; R ⁶ is hydrogen, halogen, or - (C ₁ -C ₄₎ alkyl; R < ⁷ > is hydrogen or methyl; R ⁸ and R ⁹ are each independently hydrogen, - (C ₁ -C ₆ ) alkyl or halogen.
[5" claim-type="Currently amended] 5. The method of claim 4,
R ⁴ is - (C ₀ -C ₂ ) alkyl- (C ₃ -C ₆ ) cycloalkyl, - (C ₁ -C ₁₀ ) alkyl or - (C ₀ -C ₂ ) alkyl-aryl; R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[6" claim-type="Currently amended] 5. The method of claim 4,
R ⁴ is -CH (OH) - aryl, -CH (OH) - heteroaryl, -CH (OH) - (C 0 -C 2) alkyl, - (C ₃ -C ₈₎ cycloalkyl or -CH (OH) - (C ₀ -C ₂ ) alkyl-heterocycloalkyl; R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[7" claim-type="Currently amended] The method according to claim 6,
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) -phenyl-4-F, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Each is hydrogen and R < ¹⁰ > is -C (O) OH;
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) -phenyl-4-F, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a hydrogen and R ¹⁰ is -C (O) OCH _3;
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) CH ₂ -cyclopentyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Hydrogen and R < ¹⁰ > is -C (O) OH;
Wherein R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) CH ₂ -cyclobutyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Hydrogen and R < ¹⁰ > is -C (O) OH;
When R ¹ is Cl, R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) -phenyl-4-F, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Hydrogen and R < ¹⁰ > is -C (O) OH;
Wherein R ¹ is Cl, R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) -cyclopentyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; And
Wherein R ¹ is Cl, R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -CH (OH) -cyclobutyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH.
[8" claim-type="Currently amended] 5. The method of claim 4,
R ⁴ is -C (O) - aryl, -C (O) - heteroaryl, -C (O) - (C ₀ -C ₂₎ alkyl, - (C ₃ -C ₈₎ cycloalkyl, or -C (O) - (C ₀ -C ₂ ) alkyl-heterocycloalkyl; R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[9" claim-type="Currently amended] 9. The method of claim 8,
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -phenyl-4-F, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Each is hydrogen and R < ¹⁰ > is -C (O) OH;
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -phenyl-4-F, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a hydrogen and R ¹⁰ is -C (O) OCH _3;
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -CH ₂ -cyclopentyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Each is hydrogen and R < ¹⁰ > is -C (O) OH;
R ¹ is CH ₃ , R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -CH ₂ -cyclobutyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Each is hydrogen and R < ¹⁰ > is -C (O) OH;
Wherein R ¹ is Cl, R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -cyclobutyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
R ¹ is Cl, R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -cyclopentyl, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; And
R ¹ is Cl, R ² is CH ₃ , R ³ is hydrogen, R ⁴ is -C (O) -phenyl-4-F, R ⁵ is -OH and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Gt; is hydrogen and R < ¹⁰ > is -C (O) OH.
[10" claim-type="Currently amended] A compound of formula (A), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such a compound, isomer or prodrug:
A

In this formula,
R ¹ and R ² are each independently -CH ₃ or -Cl;
R ⁴ is -SO ₂ -NH-cyclopropyl, -SO ₂ -NH-cyclobutyl, -SO ₂ -NH-cyclopentyl, -SO ₂ -NH-cyclohexyl, -SO ₂ -NH- (C ₁ -C ₈₎ unsubstituted or substituted by alkyl, or -SO ₂ -NH--fluoro phenyl;
R ⁸ and R ⁹ are each independently hydrogen or methyl;
R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[11" claim-type="Currently amended] 11. The method of claim 10,
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclopropyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclopropyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclopropyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-CH (CH ₃ ) ₂ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -SO ₂ -NH- (CH ₂ ) ₃ -CH ₃ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -SO ₂ -NH- (CH ₂ ) ₆ -CH ₃ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH- (4-fluoro-phenyl), R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -NH-cyclohexyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH; And
A compound wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -NH-cyclohexyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH.
[12" claim-type="Currently amended] A compound of formula (A), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such a compound, isomer or prodrug:
A

In this formula,
R ¹ and R ² are each independently -CH ₃ or -Cl;
R ⁴ is _{-C (O) N (CH 3} ) - (C 3 -C 8) cycloalkyl, -C (O) NH-CH (CH (CH 3) 2) 2, -C (O) N (CH _{3) -CH (CH (CH 3} ) 2) 2, -C (O) N (CH 3) -CH (CH 3) 2, -C (O) NH-CH (CH 3) - cyclohexyl, -C (O) NH-CH ₂ - cyclohexyl, -C (O) N (CH 3) -CH 2 - cyclohexyl, -C (O) N (CH 3) -CH (CH 3) - cyclohexyl, or fluoro -C (O) NH-phenyl unsubstituted or substituted with halo;
R ⁸ and R ⁹ are each independently hydrogen or methyl;
R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[13" claim-type="Currently amended] 13. The method of claim 12,
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Wherein R ¹ is CH ₃ , R ² is CH ₃ and R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OCH ₃ ;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -cyclobutyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Wherein R ¹ is Cl, R ² is CH ₃ and R ⁴ is -C (O) NH-CH (CH (CH ₃ ) ₂ ) ₂ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C Phosphorus compounds;
Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) NH-CH (CH (CH ₃ ) ₂ ) ₂ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C compound;
A compound wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) NH-CH (CH ₃ ) -cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ and R ⁴ is -C (O) N (CH ₃ ) -cyclopentyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -C (O) N (CH ₃ ) -CH (CH ₃ ) ₂ , R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C OH;
Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) NH- (4-fluoro-phenyl) and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -C (O) NH-CH ₂ -cyclohexyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -CH ₂ -cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH. ;
A compound wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -cyclohexyl and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -C (O) N (CH ₃ ) -cyclopentyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -cycloheptyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C (O) OH;
Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -CH (CH (CH ₃ ) ₂ ) ₂ and R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C O) OH; And
Wherein R ¹ is Cl, R ² is Cl and R ⁴ is -C (O) N (CH ₃ ) -CH (CH ₃ ) -cyclohexyl, R ⁸ and R ⁹ are each hydrogen and R ¹⁰ is -C OH. ≪ / RTI >
[14" claim-type="Currently amended] A compound of formula (A), an isomer thereof, a prodrug of such compound or isomer, or a pharmaceutically acceptable salt of such a compound, isomer or prodrug:
A

In this formula,
R ¹ and R ² are each independently -CH ₃ or -Cl;
R ⁴ is selected from the group consisting of -SO ₂ -CH ₂ -cyclopropyl, -SO ₂ -CH ₂ -cyclobutyl, -SO ₂ -CH ₂ -cyclopentyl, -SO ₂ -CH ₂ -cyclohexyl, -SO ₂ -cyclopentyl or -SO ₂ -cyclohexyl;
R ⁸ and R ⁹ are each independently hydrogen or methyl;
R ¹⁰ is -C (O) OH, -C (O) OCH _3, or -C (O) OCH ₂ CH ₃ .
[15" claim-type="Currently amended] 15. The method of claim 14,
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₃ ;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is methyl and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is H, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₂ CH ₃ ;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopropyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclopropyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₂ CH ₃ ;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OCH ₃ ;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is methyl and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is Cl, R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is methyl, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclohexyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclobutyl, R ⁸ is methyl, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -CH ₂ -cyclohexyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH;
Compounds wherein R ¹ is CH ₃ , R ² is CH ₃ , R ⁴ is -SO ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH; And
A compound wherein R ¹ is Cl, R ² is CH ₃ , R ⁴ is -SO ₂ -cyclopentyl, R ⁸ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is -C (O) OH.
[16" claim-type="Currently amended] N- {4- [3- (Cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- {3-Chloro-4- [4-hydroxy-3- (l-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -5-methyl-phenyl} -malonic acid;
N- {3,5-Dichloro-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid;
N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
N- [3,5-Dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid;
N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [3-Chloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -2-methyl-malonamic acid;
N- [3-Chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -2-methyl-malonamic acid;
N- [3-Chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
N- {4- [3- (4-Fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- [4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- (4- {3 - [(4-Fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -3,5-dimethyl-phenyl) -malonic acid;
N- {4- [3- (2-Cyclopentyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid methyl ester;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid ethyl ester;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester;
N- [3-Chloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid methyl ester;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid methyl ester;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid ethyl ester;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid methyl ester;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid methyl ester;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -2-methyl-malonanoic acid methyl ester;
Phenoxy} -phenyl} -2-methyl-malonamic acid, isomers and isomers of these compounds Or a prodrug of an isomer, and a pharmaceutically acceptable salt of said compound, isomer or prodrug.
[17" claim-type="Currently amended] Thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, hyperlipidemia, , A prodrug thereof, a prodrug thereof, an isomeric prodrug thereof, or a pharmaceutical composition of such a compound, isomer or prodrug for the manufacture of a medicament for the treatment of a symptom selected from the group consisting of osteoporosis and alopecia Uses of acceptable salts.
[18" claim-type="Currently amended] 18. The method of claim 17,
Uses where the symptoms are obesity.
[19" claim-type="Currently amended] 19. The method of claim 18,
Wherein the medicament further comprises an anorectic agent.
[20" claim-type="Currently amended] 20. The method of claim 19,
Wherein the anorectic agent is selected from the group consisting of pentamine, sibutramine, penfluramine, dexfenfluramine and bromocriptine.
[21" claim-type="Currently amended] 16. A pharmaceutical composition comprising a compound according to claim 16, an isomer thereof, a prodrug thereof, or a prodrug thereof, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.
[22" claim-type="Currently amended] Use of a compound of formula (I), an isomer thereof, a prodrug of such a compound or isomer, or a pharmaceutically acceptable salt of such a compound, isomer or prodrug for the manufacture of a medicament for the treatment of alopecia in a mammal:
Formula I

In this formula,
W is (a) -O-, (b) -S-, (c) -SO-, (d) -SO 2 -, (e) -CH 2 -, (f) -CF 2 -, (g) -CHF -, (h) -C ( O) -, (i) -CH (OH) -, (j) -NR a or (k) ego;
R < ⁰ > is (a) hydrogen; (b) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, (ii) halogen, ₃ and (iv) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 substituent selected from the group consisting of phenyl substituted with 0 or 1 substituent selected from the group consisting of -OCF ₃ ; (c) -C (O) R ^h ; (d) -S (O) ₂ R ^h ; Or (e) halogen;
R ^1, R ^2, R ³ and R ⁶ are each independently (a) hydrogen, (b) _{halogen, (c) - (C 1} -C 8) _{alkyl, (d) -CF 3, (} e) -OCF ₃ , (f) -O (C ₁ -C ₈ ) alkyl or (g) -CN;
R ⁴ is selected from the group consisting of: (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0-3 substituents independently selected from the following group V, (c) - (C ₂ -C ₁₂ ) _{(d) - (c 2 -C} 12) alkynyl, (e) halogen, (f) -CN, (g ) -OR b, (h) -SR c, (i) -S (O) R c, (O) ₂ R ^c , (k) aryl, (l) heteroaryl, (m) - (C ₃ -C ₁₀ ) cycloalkyl, (n) heterocycloalkyl, ^{_{O) 2 NR c R d,}} (p) -C (O) NR c R d, (q) -C (O) OR c, (r) -NR a c (O) R d, (s) -NR ^{a c (O) NR c R} d, (t) -NR a S (O) , and ^{_{2 R d, (u) -NR}} a R d , or (v) -C (O) R c; Or R ³ and R ⁴ has the formula together with the carbon atom to which they are attached - (CH _{2) i} - tan forming the summons ring, or the formula of (wherein, i is 3, 4, 5 or 6 a) - (CH _{2) k} -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ;
R ⁵ is (a) -OH, (b) -O (C 1 -C 6) alkyl, (c) -OC (O) R f, (d) F , or (e) -C (O) OR c , or ; Or R ⁴ and R ⁵ together with the carbon atoms to which they are attached form -CR ^c = CR ^a -NH-, -N = CR ^a -NH, -CR ^c = CR ^a -O-, -CR ^c = CR ^a -S -, -CR ^c = N-NH- and -CR ^a = CR ^a -CR ^a = N-;
R ⁷ is (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl;
R ⁸ and R ⁹ are each independently (a) hydrogen, (b) - (C ₁ -C ₆ ) alkyl, (c) aryl or (d) halogen;
R ¹⁰ is _{(a) - (C 0 -C} 1) alkyl, -C (O) OH, (b ) - (C 0 -C 1) alkyl, ^{-C (O) OR f, (} c) - (C 0 - C ₁ ) alkyl-C (O) NR ^c R ^d or (d) - (C ₀ -C ₁ ) alkyl-OH;
In each case R ^a is independently - (a) hydrogen or (b) - (C ₁ -C ₆ ) alkyl substituted with 0 or 1 - (C ₃ -C ₆ ) cycloalkyl or methoxy;
A R ^b is independently in each occurrence (a) hydrogen, (b) to the optionally substituted with 0 to 3 substituents independently selected from Group V - (C ₁ -C ₁₂₎ alkyl, (c) aryl, (d) (E) - (C ₃ -C ₁₀ ) cycloalkyl, (f) heterocycloalkyl, (g) -C (O) NR ^c R ^d or (h) -C (O) R ^f ;
R ^c and R ^d in each occurrence are each independently selected from the group consisting of (a) hydrogen, (b) - (C ₁ -C ₁₂ ) alkyl substituted with 0 to 3 substituents independently selected from the following group VI, (c) (C ₂ -C _{12) alkenyl, (d) - (C 2} -C 12) alkynyl, (e) aryl, (f) _{heteroaryl, (g) - (C 3} -C 10) cycloalkyl or ( h) heterocycloalkyl, provided that when R ⁴ is a residue -SR ^c , -S (O) R ^c or -S (O) ₂ R ^c , then R ^c is not hydrogen; Or R ^c and R ^d are the atom they are attached (s) and with -O-, -NR ^e -, and 3-to 10-which may or may not include a heteroaryl of claim 2, selected from the group consisting of -S- (A) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , (c) oxo, (d) -CN, (e) phenyl and (f ) -NR &^lt; ^a &^gt; R &^lt; ^g &^gt;;
R ^e is (a) hydrogen, (b) -CN, (c ) to the optionally substituted with 0 to 3 substituents independently selected from Group V in each occurrence - (C ₁ -C ₁₀₎ alkyl, (d) - (C ₂ -C _{10) alkenyl, (e) - (C 2} -C 10) _{alkoxy, (f) - (C 3} -C 10) cycloalkyl, (g) aryl, (h) heteroaryl, (i ) -C (O) R ^f , (j) -C (O) OR ^f , (k) -C (O) NR ^a R ^f or (l) -S (O) ₂ R ^f ;
In each case R ^f is independently - (a) - (C ₁ -C ₁₀ ) alkyl, (b) - (C ₂ -C ₁₀ ) alkenyl substituted by 0 to 3 substituents independently selected from the following group VI , (c) - (C ₂ -C ₁₀ ) alkynyl, (d) - (C ₃ -C ₁₀ ) cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl;
To R ^g are independently in each occurrence (a) _{hydrogen, (b) - (C 1} -C 6) _{alkyl, (c) - (C 2} -C 6) alkenyl, (d) aryl, (e) - ^{C (O) R f, (} f) -C (O) oR f, (g) -C (O) NR a R f, (h) -S (O) 2 R f , or (i) - (C ₃ -C ₈₎ cycloalkyl;
R ^h is selected from the group ^consisting of (a) (1) - (C ₃ -C ₆ ) cycloalkyl, (2) heterocycloalkyl and (3) (i) - (C ₁ -C ₄ ) alkyl, ) -CF _3, and (iv) substituted from the group consisting of -OCF ₃ to 0 or 1 substituent selected from the group consisting of phenyl substituted by 0 or 1 substituent selected - (C ₁ -C ₆₎ alkyl; (b) (1) - ( C 1 -C 4) alkyl, (2) halogen, ₍₃₎ -CF 3, and (4) phenyl substituted from the group consisting of -OCF ₃ to selected from 0 to 2 substituents independently ; _{(c) - (C 3 -C} 6) cycloalkyl; Or (d) heterocycloalkyl;
Group V is (a) _{halogen, (b) -CF 3, (} c) -OCF 3, (d) -OH, (e) _{oxo, (f) - (C 1} -C 6) alkoxy, (g) - CN, (h) aryl, (i) _{heteroaryl, (j) - (C 3} -C 10) cycloalkyl, (k) ^{heterocycloalkyl, (l) -SR f, (} m) -S (O) R ^{f, (n) -S (o} ) 2 R f, (o) -S (o) 2 NR a R f, (p) -NR a R g , or (q)
-C (O) NR < ^a > R <^f;
Group VI is (a) halogen, (b) hydroxy, (c) _{oxo, (d) - (C 1} -C 6) alkoxy, (e) aryl, (f) heteroaryl, (g) - (C ₃ -C ₈₎ cycloalkyl, (h) heterocycloalkyl, (i) -CN, or (j) -OCF _3, and;
However, the substituent R ⁴ is substituted with 0 to 3 substituents independently selected from the Group V - and (C ₁ -C ₁₂₎ alkyl, wherein if V is a substituent group of oxo, oxo groups - (C ₁ -C ₁₂ ) Alkyl at a carbon atom other than the C ₁ carbon atom;
In each case, the aryl is independently (a) _{halogen, (b) - (C 1} -C 6) alkyl, (c) -CN, (d ) -SR f, (e) -S (O) R f, _{(f) -S (O) 2} R f, (g) - (C 3 -C 6) cycloalkyl, (h) -S (O) 2 NR a R f, (i) -NR a R g, ( ^{j) -C (O) NR a} R f, (k) -OR b, (l) - perfluoro - (C ₁ -C ₄₎ alkyl, and (m) independently selected from the group consisting of -COOR ^f 0 Phenyl or naphthyl substituted with up to four substituents;
However, the substituent (s) on the aryl ^{-SR f, -S (O) R} f, -S (O) 2 R f, -S (O) 2 NR a R f, -NR a R g, -C ( O) NR ^a R ^f , -OR ^b or -COOR ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
(A) halogen, (b) - (C ₁ -C ₄ ) alkyl, (c) - (C ₁ -C ₄ ) alkyl, ^{_{CF 3, (d) -OR b}} , (e) -NR a R g , and (f) -CO ₂ R 5 a circle having the ^f 0 to 3 substituents independently selected from the group consisting of, 6-, 7 membered, 8-membered, 9-membered or 10-membered ring or heterocyclic ring wherein the monocyclic heteroaryl ring is condensed to a benzene ring or another heteroaryl ring;
Provided that when the substituent (s) on the heteroaryl is -OR ^b , -NR ^a R ^g or -CO ₂ R ^f , substituents R ^b , R ^f and R ^g are not aryl or heteroaryl;
Heterocycloalkyl in each occurrence is independently O, NR ^e and having from 1 to 3 heteroatoms selected from the group consisting of S, (a) - (C 1 -C 4) alkyl, ^(b) -OR b, (c) oxo, (d) -CN, (e) phenyl and (f) -NR ^a R ^g , 8-membered, 9-membered or 10-membered ring or a dicyclic alkyl ring.
[23" claim-type="Currently amended] 23. The method of claim 22,
W is O; R < ⁰ > is hydrogen; R ¹ is located at position 5; R ² is located at position 3; R ¹ and R ² are each independently hydrogen, - (C ₁ -C ₆ ) alkyl, halogen or CN.
[24" claim-type="Currently amended] 24. The method of claim 23,
R ³ is hydrogen, - (C ₁ -C ₄ ) alkyl or halogen; R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ substituted by cycloalkyl, and heterocycloalkyl 0 to 3 substituents independently selected from the group consisting of - (C ₁ -C ₁₀₎ alkyl, (b) -S (O) 2 NR c R d, (c) -C (O) NR c R d, (d) -S (O) 2 R c, (e) - (c ₃ -C ₈₎ cycloalkyl, (f) heterocycloalkyl, (g) -C (O) R c, (h) -OR b, (i) -SR c, (j) -S (O) ^{R c, (k) -NR a} c (O) R d, (l) -NR a c (O) NR c R d , or ^{(m) -NR a S (O} ) 2 R d , or; Or R ³ and R ⁴ together with the carbon atom to which they are attached form a carbocyclic ring of the formula - (CH ₂ ) _i -, wherein i is 3, 4, 5 or 6, or - (CH ₂ ) _k -Q- (CH _{2) l} - (wherein, Q is -O-, -S- or -NR ^e -, and; k is 0, 1, 2, 3, 4 or 5; l is 0, 1, 2 (B) -OR ^b , (c) - (C ₁ -C ₄ ) alkyl, (b) -OR ^b , Substituted with 0-4 substituents independently selected from the group consisting of (d) -CN, (e) phenyl and (f) -NR ^a R ^g ; However, the substituent R ⁴ is 0 to 3 substituted with a substituent - if the (C ₁ -C ₁₀₎ alkyl, oxo groups - a (C ₁ -C ₁₀₎ substituted at carbon atoms other than the C ₁ carbon atom in the alkyl Use of compounds.
[25" claim-type="Currently amended] 25. The method of claim 24,
R ⁵ is -OH, -OC (O) R ^f or -F; R ^f is - (C ₁ -C ₁₀ ) alkyl substituted with 0 to 3 substituents independently selected from the group VI; R ⁶ is hydrogen, halogen, or - (C ₁ -C ₄₎ alkyl; R < ⁷ > is hydrogen or methyl; R ⁸ and R ⁹ are each independently hydrogen, - (C ₁ -C ₆ ) alkyl or halogen.
[26" claim-type="Currently amended] 26. The method of claim 25,
R ⁴ is (a) F, hydroxy, oxo, aryl, heteroaryl, - (C ₃ -C ₈₎ substituted by cycloalkyl, and heterocycloalkyl 0 to 3 substituents independently selected from the group consisting of - (C ₁ -C ₁₀₎ alkyl, (b) -S (O) 2 NR c R d, (c) -C (O) NR c R d, (d) -S (O) 2 R c, (e) - (C ₃ -C ₈ ) cycloalkyl, (f) heterocycloalkyl or (g) -C (O) R ^c ; Wherein R ¹⁰ is -C (O) OH, -C (O) OCH ₃ or -C (O) OCH ₂ CH ₃ , or a pharmaceutically acceptable salt or prodrug thereof.
[27" claim-type="Currently amended] 27. The method of claim 26,
N- {4- [3- (Cyclobutyl-methylcarbamoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- {3-Chloro-4- [4-hydroxy-3- (l-isopropyl-2-methyl-propylcarbamoyl) -phenoxy] -5-methyl-phenyl} -malonic acid;
N- {3,5-Dichloro-4- [3 - ((1S) -cyclohexyl-ethylcarbamoyl) -4-hydroxy-phenoxy] -phenyl} -malonic acid;
N- [3,5-Dichloro-4- (3-cyclopropylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
N- [3,5-Dichloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -phenyl] -malonamic acid;
N- [3-Chloro-4- (3-cyclobutylsulfamoyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [4- (3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [4- (3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [3-Chloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [3,5-Dichloro-4- (3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [3,5-Dichloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -phenyl] -malonic acid;
N- [4- (3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -2-methyl-malonamic acid;
N- [3-Chloro-4- (3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -2-methyl-malonamic acid;
N- [3-Chloro-4- (3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [4- (3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
N- {4- [3- (4-Fluoro-benzoyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- [4- (3-cyclopentyl acetyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- (4- {3 - [(4-Fluoro-phenyl) -hydroxy-methyl] -4-hydroxy-phenoxy} -3,5-dimethyl-phenyl) -malonic acid;
N- {4- [3- (2-Cyclopentyl-1-hydroxy-ethyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid methyl ester;
N- [3-Chloro-4- (3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonamic acid ethyl ester;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid ethyl ester;
N- [4- (3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonamic acid methyl ester;
N- [3-Chloro-4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -5-methyl-phenyl] -malonic acid;
N- [4- (3-cyclopentanesulfonyl-4-hydroxy-phenoxy) -3,5-dimethyl-phenyl] -malonic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -malonic acid methyl ester;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid methyl ester;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -malonamic acid ethyl ester;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid methyl ester;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -2-methyl-malonamic acid;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid methyl ester;
N- {3-Chloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -5-methyl-phenyl} -2-methyl-malonamic acid;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -2-methyl-malonanoic acid methyl ester;
N- {3,5-Dichloro-4- [3- (4-fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -phenyl} -2-methyl-malonamic acid;
N- {4- [3- (4-Fluoro-benzenesulfonyl) -4-hydroxy-phenoxy] -3,5-dimethyl-phenyl} -malonic acid;
Phenoxy] -3,5-dimethyl-phenyl} -malonic acid methyl ester, isomers, isomers or isomers thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. And prodrugs thereof, and pharmaceutically acceptable salts of these compounds, isomers or prodrugs.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-03-31|Priority to US19361800P

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2000-03-31|Priority to US60/193,618

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2001-03-07|Application filed by 화이자 프로덕츠 인코포레이티드

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2001-03-07|Priority to PCT/IB2001/000317

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2002-11-29|Publication of KR20020089420A

优先权:

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申请号 | 申请日 | 专利标题

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US19361800P| true| 2000-03-31|2000-03-31|

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US60/193,618|2000-03-31|

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PCT/IB2001/000317|WO2001072692A1|2000-03-31|2001-03-07|Malonamic acids and derivatives thereof as thyroid receptor ligands|