Estrogen receptor modulators

专利摘要:
The present invention relates to certain compounds, derivatives thereof, methods for their synthesis, and their use as estrogen receptor modulators. Since the compound of the present invention is a ligand for estrogen receptor, bone loss, fracture, osteoporosis, cartilage degeneration, endometritis, intrauterine fibroids, hot flashes, increased LDL cholesterol levels, cardiovascular disease, cognitive decline, brain degenerative disease, restenosis, It may be useful for the treatment and prevention of various diseases associated with estrogen function, including female breast disease, vascular lax muscle cell proliferation, obesity, incontinence, and cancer (particularly breast cancer, uterine cancer and prostate cancer).
公开号:KR20030042020A
申请号:KR10-2003-7005518
申请日:2001-10-15
公开日:2003-05-27
发明作者:디닌노프랭크피；쳉헬렌와이；김성곤；위제인와이
申请人:머크 앤드 캄파니 인코포레이티드；
IPC主号:

专利说明:

Estrogen receptor modulators
[1] Background of the Invention
[2] Natural and synthetic estrogens include relief of menopausal symptoms, treatment of acne, dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostate cancer, treatment of hot flashes and prevention of cardiovascular disease, It is widely useful therapeutically. Because estrogens are very useful therapeutically, it is of great interest to find compounds that follow estrogen-like behavior in estrogen-responsive tissues.
[3] For example, estrogen-like compounds will be beneficial for the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including postmenopausal or hysterectomized women, patients treated or treated with corticosteroids, and gonadotropia patients. The major bone diseases currently attracting public attention include osteoporosis, hypercalcemia of malignant tumors, osteopenia caused by bone metastasis, periodontal disease, parathyroid hyperplasia, periarticular erosion in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, And glucocorticoid induced osteoporosis. All of these diseases are characterized by bone loss due to an imbalance between bone formation (ie bone destruction) and bone formation that lasts a lifetime at an average of about 14% annually. However, the rate of bone turnover varies from site to site, for example, higher in the holding bones of the spine and in the alveolar bones of the jaw than in the long bones. The potential for bone loss is directly related to bone turnover and can be in excess of 5% per year in the spine immediately after menopause, which leads to an increased risk of fracture.
[4] Currently, about 20 million people in the United States detect fractures of the spine due to osteoporosis. In addition, about 250,000 hip fractures occur each year due to osteoporosis. This clinical situation is associated with 12% mortality in the first two years after fracture, while 30% of patients require care at home after the fracture.
[5] Osteoporosis affects women who have passed about 20 to 25 million menopause in the United States alone. It is theorized that the rapid loss of bone mass in these women is due to the cessation of ovarian estrogen production. Studies have shown that estrogen slows down the loss of bone mass due to osteoporosis, and estrogen replacement therapy is recognized to treat postmenopausal osteoporosis.
[6] In addition to bone mass, estrogens have been shown to affect the biosynthesis of cholesterol and cardiovascular health. Statistically, the incidence of cardiovascular disease in postmenopausal women and men is about the same, but the incidence of cardiovascular disease in premenopausal women is much lower than in men. Since postmenopausal women are deficient in estrogens, estrogens are thought to play a beneficial role in preventing cardiovascular disease. This mechanism is not yet well understood, but evidence is provided that estrogens upregulate low-level lipid (LDL) cholesterol receptors in the liver to remove excess cholesterol.
[7] In postmenopausal women who receive estrogen replacement therapy, lipid concentrations are restored to concentrations comparable to premenopausal levels. Thus, estrogen replacement therapy can effectively treat this disease. However, the side effects of using estrogen for a long time limit the use of such alternative therapies.
[8] Other disease states that affect women after menopause are estrogen dependent breast cancer and uterine cancer. Antiestrogens compounds such as tamoxifen have been commonly used as chemotherapy to treat breast cancer patients. Tamoxifen, a dual antagonist and agonist of estrogen receptors, is advantageous in treating estrogen dependent breast cancer. However, treatment with tamoxifen may not be ideal because tamoxifen agonist behavior enhances its undesirable estrogen side effects. For example, tamoxifen and other compounds that function estrogen receptors tend to increase cancer cell production in the uterus. Better therapies for such cancers would be anti-estrogen compounds with negligible or no agonist properties.
[9] Although estrogens may be beneficial for treating pathological conditions such as bone loss, increased lipid levels, and cancer, long-term estrogen treatment can lead to a variety of diseases, including an increased risk of uterine cancer and endometritis. These and other side effects of estrogen replacement therapy are not tolerated by many women and therefore their use is limited.
[10] Alternative therapies, such as the combination of progestogen and estrogen, have been proposed as an attempt to reduce the risk of cancer. However, patients treated with this therapy suffer from retrograde bleeding, an unacceptable symptom for many older women. In addition, the use of estrogen in combination with progestogen reduces the cholesterol lowering effect, which is an advantage of estrogen therapy. In addition, the long-term effects of progestogen treatment are not known.
[11] As well as postmenopausal women, men with prostate cancer can benefit from antiestrogenic compounds. Prostate cancer is often endocrine sensitive and androgen stimulation promotes tumor growth, while androgen suppression delays tumor growth. Estrogen administration helps to treat and inhibit prostate cancer, because estrogen administration lowers gonadotropin levels, which in turn lower androgen levels.
[12] Estrogen receptors have been found to have two forms, ERα and ERβ. Ligands bind differently to these two forms, and each form has a different tissue that specifically binds to the ligand. Thus, one may have compounds that are specific for ERα and ERβ and confer tissue specificity to specific ligands.
[13] What is needed in the art are compounds that can exhibit the same positive response as estrogen replacement therapy without negative enteric therapy. There is also a need for an estrogen-like compound that exhibits specific effects on different tissues of the body.
[14] Since the compound of the present invention is a ligand for the estrogen receptor, bone loss, fracture, osteoporosis, cartilage degeneration, endometritis, intrauterine fibroids, hot flashes, increased LDL cholesterol, cardiovascular disease, cognitive decline, brain degeneration, restenosis, It may be useful for the treatment and prevention of various diseases associated with estrogen function, including female breast disease, vascular lax muscle cell proliferation, obesity, incontinence, and cancer (particularly breast cancer, uterine cancer and prostate cancer).
[15] Summary of the Invention
[16] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.
[17]
[18] In Formula I above,
[19] R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-8 cycloal Kenyl, phenyl, heteroaryl, heterocyclyl, CF ₃ , -OR ⁶ , halogen, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC ₁ Groups consisting of _-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocycle The aryl group is unsubstituted or C _1-5 alkyl, C _3-8 cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato , Cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl ,
[20] R ⁵ is a group consisting of C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups Wherein these groups are unsubstituted or C _1-5 alkyl, C _3-8 cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thio May be substituted with cyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONZ ₂ , -SO ₂ NZ _2, and -SO ₂ C _1-5 alkyl) Will,
[21] X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone,
[22] R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl, triorganosilyl, C _1-5 alkylcarbonyl, alkoxycarbonyl and CONZ ₂ ,
[23] Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
[24] Z may be a 3 to 8 membered ring together with the nitrogen to which they are bound (the ring may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, may be saturated or unsaturated, and the carbon atoms of the ring are substituted Or C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _{1- 5} alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl).
[25] Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Selected from the group consisting of COC _1-5 alkyl and -SO ₂ C _1-5 alkyl,
[26] n is each independently an integer of 1-5.
[27] The invention also relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
[28] The invention also relates to a method of preparing the pharmaceutical composition of the invention.
[29] The present invention also relates to intermediates useful for the preparation of the compounds of the invention and to the pharmaceutical compositions and methods of making the same.
[30] The present invention also relates to a method of inducing an estrogen receptor modulating effect in a mammal, including administering a compound and a pharmaceutical composition of the present invention to a mammal in need of inducing an estrogen receptor modulating effect.
[31] The invention also relates to a method of inducing an estrogen receptor antagonistic effect in a mammal, including administering a compound of the invention and a pharmaceutical composition to a mammal in need of induction of an estrogen receptor antagonistic effect. Estrogen receptor antagonistic effects may be ERα receptor antagonistic effects, ERβ antagonistic effects, or mixed antagonistic effects of ERα and ERβ.
[32] The invention also relates to a method of inducing an estrogen receptor agonist effect in a mammal, including administering a compound of the invention and a pharmaceutical composition to a mammal in need thereof. Estrogen receptor inhibitory effect may be ERα receptor action effect, ERβ action effect, or mixed antagonistic effect of ERα and ERβ.
[33] The invention also relates to compounds and pharmaceutical compositions according to the invention for diseases related to estrogen function, ie bone loss, fractures, osteoporosis, cartilage degeneration, endometritis, intrauterine fibroids, breast cancer, uterine cancer, prostate cancer, hot flashes, To a woman in need of treatment or prevention of cardiovascular disease, cognitive decline, brain degenerative disease, restenosis, gynecomastia, vascular relaxation muscle cell proliferation, obesity, incontinence. .
[34] The present invention also relates to a method of lowering bone loss, lowering LDL cholesterol levels and inducing vasodilation effects in a mammal, including administering the compounds and pharmaceutical compositions of the invention to a mammal.
[35] The present invention relates to compounds useful as estrogen receptor modulators. Compounds of the invention are described as compounds of formula (I) and pharmaceutically acceptable salts thereof.
[36] Formula I
[37]
[38] In Formula I above,
[39] R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-8 cycloal Kenyl, phenyl, heteroaryl, heterocyclyl, CF ₃ , -OR ⁶ , halogen, C1-5 alkylthio, thiocyanato, cyano, -CO2H, -COOC _1-5 alkyl, -COC _1-5 alkyl , -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocyclyl group Unsubstituted or C _1-5 alkyl, C _3-8 cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano , -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl,
[40] R ⁵ is a group consisting of C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups Wherein these groups are unsubstituted or C _1-5 alkyl, C _3-8 cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thio May be substituted with cyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl) Is selected from
[41] X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone,
[42] R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl, triorganosilyl, C _1-5 alkylcarbonyl, alkoxycarbonyl and CONZ ₂ ,
[43] Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
[44] Z may be a 3 to 8 membered ring together with the nitrogen to which they are bound (the ring may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, may be saturated or unsaturated, and the carbon atoms of the ring are substituted Or C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _{1- 5} alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl).
[45] Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Selected from the group consisting of COC _1-5 alkyl and -SO ₂ C _1-5 alkyl,
[46] n is each independently an integer of 1-5.
[47] In one class of compounds of the invention, X is oxygen and Y is sulfur.
[48] In a class of compounds of the invention, R ¹ , R ² , R ³ and R ⁴ are hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _1-5 alkenyl, C _2-5 alkynyl, -OR ⁶ and halogen.
[49] In a class of compounds of the invention, R ⁵ is selected from the group consisting of C _3-8 cycloalkyl, phenyl, heteroaryl and heterocyclyl groups, which may be unsubstituted or substituted with —OR ⁶ and halogen.
[50] In a class of compounds of the invention, R ⁶ is preferably selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.
[51] The present invention,
[52] (a) reacting a compound of formula II with a compound of formula III under basic conditions to form a compound of formula IV,
[53] (b) ring closing the compound of formula IV of step a under acidic conditions in the presence of a reducing agent to provide a cis compound of formula V,
[54] (c) removing protecting group R ⁶ from formula V to obtain a substituted phenol of formula VI,
[55] (d) alkylating the substituted phenol of formula VI from step c with a reagent of formula HO (CH ₂ ) _n N (Z) ₂ to obtain a compound of formula I,
[56] (e) removing the protecting group from the compound of formula I from step d to obtain a compound of formula VIII or a compound of formula IX; and
[57] (f) removing the remaining protecting group from the compound of formula VIIII or the compound of formula IX from step e to obtain a compound of formula I, preparing a compound of formula I and a pharmaceutically acceptable salt thereof And a stereoisomer of the compound is a cis isomer.
[58] Formula I
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67] In the above formula,
[68] R ¹ is H, F or Cl,
[69] R ² is H or OR ⁶ ,
[70] R ³ is H or OR ⁶ ,
[71] R ⁴ is H or CH ₃ ,
[72] R ⁵ is C _1-5 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups, wherein these groups are unsubstituted or C _1-5 alkyl, C _{3 -8} cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboal Coxyl (-COOC _1-5 alkyl), Carbonyl (-COC _1-5 alkyl), Carboxamido (-CONZ ₂ ), Sulfonamido (-SO ₂ NZ ₂ ) and Sulfonyl (-SO ₂ C _{1 -5} alkyl), and
[73] R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that OR ⁶ may be chemically different, depending on the position present,
[74] X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone,
[75] Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
[76] Z together with the nitrogen to which they are attached form a three to eight membered ring, which ring may contain an atom selected from the group consisting of carbon, oxygen, sulfur and nitrogen, and may be saturated or unsaturated; Unsubstituted or substituted C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — May be substituted with COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl,
[77] Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Independently selected from the group consisting of COC _1-5 alkyl and -SO ₂ C _1-5 alkyl,
[78] n is each independently an integer of 1-5.
[79] The present invention also provides
[80] (a) reacting a compound of formula IID with a compound of formula IIID under basic conditions to form a compound of formula IVD,
[81] (b) ringing formula IVD of step a under acidic conditions in the presence of a reducing agent to provide a racemic, cis compound of formula VD,
[82] (c) performing chiral chromatography using the compound of formula VD from step b to decompose the enantiomeric form to provide a preferential (+) isomer of formula VID,
[83] (d) alkylating the preferred (+) isomer of formula VID from step c with 1-piperidineethanol to obtain a compound of formula VIID,
[84] (e) removing the protecting group from formula VIID from step d to obtain a compound of formula VIIID or a compound of formula IXD, and
[85] (f) removing the remaining protecting group from a compound of formula (VIIID) or a compound of formula (IXD) from step e to obtain a compound of formula (I), the preparation of a compound of formula (ID) and a pharmaceutically acceptable salt thereof The method relates to a stereoisomer of the compound is a cis isomer, and the optical isomer is a preferential (+) isomer having absolute configuration (2S, 3R).
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95] In the above formula,
[96] R ¹ is H, F or Cl,
[97] R ³ is H,
[98] R ⁴ is H or CH ₃ .
[99] The present invention also provides
[100] (a) reacting a compound of formula (IIE) with a compound of formula (IIIE) under basic conditions to form a compound of formula (IVE),
[101] (b) ringing formula IVE in step a under acidic conditions in the presence of a reducing agent to provide a racemic, cis compound of formula VE,
[102] (c) optionally removing a protecting group from formula VE from step b to obtain a substituted phenol of formula VIE,
[103] (d) alkylating the substituted phenol of formula VIE from step c with 1-piperidineethanol to obtain a compound of formula VIIE,
[104] (e) removing the protecting group from formula VIIE to obtain a compound of formula VIIIE or a compound of formula IXE,
[105] (f) removing residual protecting groups from the compound of formula VIIIE or the compound of formula IXE from step e to obtain a compound of formula I; and
[106] (g) degrading the enantiomeric form of formula (I) to provide a preferential (+) isomer of a compound of formula (I) having an (2S, 3R) absolute configuration, or a pharmaceutically acceptable compound of formula (IE) And a stereoisomer of the compound is a cis isomer and the optical isomer is a preferential (+) isomer having absolute configuration (2S, 3R).
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116] In the above formula,
[117] R ¹ is selected from the group consisting of H, F and Cl,
[118] R ³ and R ⁴ are each H,
[119] R ⁷ is selected from the group consisting of H and OH.
[120] The invention also relates to the compounds and compositions described herein, namely novel intermediates useful for preparing compounds of formula (I), (IA), (IB), (IC), (ID) and (IE).
[121] One embodiment of the invention is an intermediate of formula (1).
[122]
[123] In Formula 1 above,
[124] R ¹ is H, F or Cl,
[125] R ² is H or OR ⁶ ,
[126] R ³ is H or OR ⁶ ,
[127] R ⁴ is H or CH ₃ ,
[128] R ⁵ is C _1-5 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups, wherein these groups are unsubstituted or C _1-5 alkyl, C _{3 -8} cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboal Coxyl (-COOC _1-5 alkyl), Carbonyl (-COC _1-5 alkyl), Carboxamido (-CONZ ₂ ), Sulfonamido (-SO ₂ NZ ₂ ) and Sulfonyl (-SO ₂ C _{1 -5} alkyl), and
[129] R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that OR ⁶ may be chemically different, depending on the position present,
[130] Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
[131] Z together with the nitrogen to which they are attached form a three to eight membered ring, which ring may contain an atom selected from the group consisting of carbon, oxygen, sulfur and nitrogen, and may be saturated or unsaturated; Unsubstituted or substituted C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — May be substituted with COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl,
[132] Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Independently selected from the group consisting of COC _1-5 alkyl and —SO ₂ C _1-5 alkyl .
[133] One embodiment of the invention is an intermediate of formula (2).
[134]
[135] In Formula 2 above,
[136] R ¹ is H, F or Cl,
[137] R ² is H or OR ⁶ ,
[138] R ³ is H or OR ⁶ ,
[139] R ⁴ is H or CH ₃ ,
[140] R ⁵ is C _1-5 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups, wherein these groups are unsubstituted or C _1-5 alkyl, C _{3 -8} cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboal Coxyl (-COOC _1-5 alkyl), Carbonyl (-COC _1-5 alkyl), Carboxamido (-CONZ ₂ ), Sulfonamido (-SO ₂ NZ ₂ ) and Sulfonyl (-SO ₂ C _{1 -5} alkyl), and
[141] R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that OR ⁶ may be chemically different, depending on the position present,
[142] Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
[143] Z together form a three to eight membered ring, which ring may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, may be saturated or unsaturated, and the carbon atoms of the ring are unsubstituted or C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, May be substituted with -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl,
[144] Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Independently selected from the group consisting of COC _1-5 alkyl and —SO ₂ C _1-5 alkyl .
[145] Another embodiment of the present invention is an intermediate of formula (3).
[146]
[147] In Formula 3 above,
[148] R ¹ is H, F or Cl,
[149] R ⁶ is hydrogen, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that R ⁶ may be chemically different depending on the position present.
[150] Another embodiment of the present invention is an intermediate of formula (4).
[151]
[152] In Formula 4 above,
[153] R ¹ is H, F or Cl,
[154] R ⁶ is hydrogen, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that R ⁶ may be chemically different depending on the position present.
[155] Another embodiment of the present invention is an intermediate of formula (5).
[156]
[157] In Formula 5 above,
[158] R ¹ is H, F or Cl,
[159] R ² is H or OR ⁶ ,
[160] R ³ is H or OR ⁶ ,
[161] R ⁴ is H or CH ₃ ,
[162] R ⁵ is C _1-5 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups, wherein these groups are unsubstituted or C _1-5 alkyl, C _{3 -8} cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ₆ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, carboxyl (-CO ₂ H), carboal Coxyl (-COOC _1-5 alkyl), Carbonyl (-COC _1-5 alkyl), Carboxamido (-CONZ ₂ ), Sulfonamido (-SO ₂ NZ ₂ ) and Sulfonyl (-SO ₂ C _{1 -5} alkyl), and
[163] R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that OR ⁶ may be chemically different, depending on the position present,
[164] Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ₆ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
[165] Z together with the nitrogen to which they are attached form a three to eight membered ring, which ring may contain an atom selected from the group consisting of carbon, oxygen, sulfur and nitrogen, and may be saturated or unsaturated; Unsubstituted or substituted C _1-5 alkyl, CF ₃ , —OR ₆ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — May be substituted with COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl,
[166] Each V is independently C _1-5 alkyl, CF ₃ , —OR ₆ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Independently from the group consisting of COC _1-5 alkyl and —SO ₂ C _1-5 alkyl.
[167] Another embodiment of the present invention is an intermediate of formula (6).
[168]
[169] In Formula 6 above,
[170] R ¹ is H, F or Cl,
[171] R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that R ⁶ may be chemically different depending on the position present.
[172] Another embodiment of the present invention is an intermediate of formula (7).
[173]
[174] In Formula 7, above,
[175] R ¹ is H, F or Cl,
[176] R ⁶ is H, benzyl, methyl, methoxymethyl or triisopropylsilyl, provided that R ⁶ may be chemically different depending on the position present.
[177] Non-limiting examples of the invention include compounds of the formula:
[178]
[179]
[180]
[181]
[182]
[183]
[184]
[185]
[186]
[187]
[188]
[189] Embodiments of the present invention provide a method for inducing estrogen receptor modulating effects in a mammal, comprising administering a therapeutically effective amount of any of the compounds described above and any pharmaceutical composition to a mammal in need thereof. Way.
[190] One class of this embodiment is a method in which the estrogen receptor regulatory effect is an antagonistic effect.
[191] The subclass of the above embodiment is a method in which the estrogen receptor is an ERα receptor.
[192] The second subclass of this embodiment is the method wherein the estrogen receptor is an ERβ receptor.
[193] The third subclass of this embodiment is the method in which the estrogen receptor regulatory effect is a mixed antagonistic effect of ERα and ERβ receptors.
[194] The second class of this embodiment is the method in which the estrogen receptor regulatory effect is an action effect.
[195] The subclass of the above embodiment is a method in which the estrogen receptor is an ERα receptor.
[196] The second subclass of this embodiment is the method wherein the estrogen receptor is an ERβ receptor.
[197] The third subclass of this embodiment is a method in which the estrogen receptor regulatory effect is a mixed action effect of ERα and ERβ receptors.
[198] Another aspect of the invention is a method of treating or preventing postmenopausal osteoporosis in a woman by administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a woman in need of treatment of postmenopausal osteoporosis.
[199] Another aspect of the present invention is a method of treating or preventing intrauterine fibroids in a mammal by administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a mammal in need thereof.
[200] Another aspect of the invention is a method of treating or preventing stenosis of a mammal by administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a mammal in need of such treatment.
[201] Another aspect of the invention is a method of treating or preventing endometriosis in a mammal by administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a mammal in need of treatment for endometriosis.
[202] Another aspect of the invention is a method of treating or preventing hyperlipidemia in a mammal by administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a mammal in need thereof.
[203] The invention exemplified is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. In addition, the invention illustrated is a pharmaceutical composition prepared by combining any of the compounds described above and a pharmaceutically acceptable carrier. One example of the present invention is a method of preparing a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
[204] The invention further exemplified is the use of any of the compounds described above in the manufacture of a medicament for treating and / or preventing osteoporosis in a mammal. In addition, the present invention, which is further illustrated, includes bone loss, bone resorption, fracture, cartilage degeneration, endometritis, intrauterine fibroids, breast cancer, uterine cancer, prostate cancer, hot flashes, cardiovascular disease, cognitive decline, brain degenerative disease, restenosis , The use of any of the compounds described above in the manufacture of a medicament for treating and / or preventing diseases associated with vasodilator muscle proliferation, incontinence, and / or estrogen function.
[205] The invention also relates to the combination of any of the compounds or any of the pharmaceutical compositions described above with one or more agents useful for the prevention or treatment of osteoporosis. For example, the compounds of the present invention can be administered effectively in combination with other agents in effective amounts, such as organic phosphonates or cathepsin K inhibitors. Non-limiting examples of such organic bisphosphonates include Alendronate, Clauderonate, Ethideronate, Ibandronate, Incadronate, Minodronate, Neridronate, Lizdronate, Pyridronate, Pamideronate, Tiludro Nates, zoleronates, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. Preferred organic bisphosphonates include alendronates, pharmaceutically acceptable salts thereof, and mixtures thereof. Most preferred are alendronate monosodium trihydrate.
[206] The exact dosage of bisphosphonates can be determined by the administration schedule; Oral efficacy of certain bisphosphonates selected; The age, height, sex and condition of the mammal or human; The nature and symptoms of the disease to be treated; And other related medical and physical factors. Therefore, the exact pharmaceutically effective amount cannot be pre-determined and can be easily determined by the caregiver or clinician. Suitable amounts can be determined by routine experiments from animal studies and clinical studies in humans. Generally, an appropriate amount of bisphosphonate is selected to achieve a bone resorption inhibitory effect. That is, the bone resorption amount of bisphosphonate is administered. In humans, an effective oral dosage of bisphosphonates is typically from about 1.5 to about 6,000 μg, preferably from about 10 to about 2000 μg, per kg of body weight.
[207] In the case of human oral compositions comprising an alendronate, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, the unit dosage will typically be based on the active weight of the alendronic acid, ie on the corresponding acid, From about 8.75 mg to about 140 mg of the alendronate compound.
[208] For pharmaceutical use, salts of the compounds of the present invention refer to nontoxic "pharmaceutically acceptable salts". However, other salts may also be useful in the preparation of the compounds or pharmaceutically acceptable salts thereof in accordance with the present invention. When the compound of the present invention contains a basic group, salts included in the term "pharmaceutically acceptable salts" refer to non-toxic salts prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts include, but are not limited to, the following examples: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, chamlate, carbonate, chloride, clavulanate , Citrate, Dihydrochloride, Edetate, Edsylate, Estoleate, Ecylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycolyl asanilate, Hexyl resornate, Hydrabamine, Hydro Bromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate , Kate free, lead sillate, nitrate, N-methylglucamine ammonium salt, Lysates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, subacetates, succinates, tanates, tarts Late, theocate, tosylate, triethoxide and valerate. In addition, when the compound of the present invention contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, and suitable organic Salts formed with ligands, such as quaternary ammonium salts.
[209] The compounds of the present invention have chiral centers and can appear as racemates, racemic mixtures, diastereomeric mixtures, as individual diastereomers, or as enantiomers having all the isomeric forms included in the present invention. Therefore, when the compound is chiral, individual enantiomers that are substantially free of other components are included within the scope of the present invention, and all mixtures of two ethanediomers are included. In addition, polymorphs, hydrates and solvates of the compounds of the invention are included within the scope of the invention.
[210] The present invention includes within its scope prodrugs of the compounds of the present invention. Generally such prodrugs are functional derivatives of the compounds of the invention and are readily converted into the desired compounds in the body. Thus, in the methods of treatment of the present invention, the term "administration" includes the treatment of various described diseases with a compound that is specifically described or a compound that is not specifically described but converted to a compound specified in the body after administration to a patient do. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in Design of Prodrugs, "ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds are described herein. It includes the active species produced when the compound of the invention is introduced into the biological environment.
[211] The term "therapeutically effective amount" means the amount of a medicament or pharmaceutical agent capable of inducing a biological or medical response in a tissue, system, animal or human obtained by a researcher or clinician.
[212] As used herein, the term "bone uptake" refers to the process by which osteoclasts degrade bone.
[213] As used herein, the term "basic condition" refers to the incorporation or use of a base in the reaction medium. According to Lowry-Bronsted's definition, a base is a substance that accepts protons, and according to Lewis' definition, a base is a substance capable of supplying electron pairs to form covalent bonds. Examples of bases used herein include, but are not limited to, tertiary amines such as triethylamine, diisopropylethylamine, and the like.
[214] As used herein, the term "acidic conditions" refers to the incorporation or use of an acid in the reaction medium. According to Laurie-Brooksted's definition, an acid is a substance that provides protons, and by Lewis' definition, an acid is a substance that can take a pair of electrons to form a covalent bond. Examples of acids used herein include strong carboxylic acids (such as trifluoroacetic acid, etc.), strong sulfonic acids (such as trifluoromethanesulfonic acid, etc.), and Lewis acids (such as boron trifluoride etherate, or chlorides). 1 tartaric acid and the like), but is not limited thereto.
[215] As used herein, the term "reducing agent" refers to a reagent that can be reduced. Reduction is the conversion of a functional group or intermediate from one category to a lower category. Examples of reducing agents used herein include, but are not limited to, triethylsilane, triphenylsilane, tri-n-butyl tin hydride, and the like.
[216] As used herein, the term “which may be chemically different” means that two or more non-identical R ⁶ substituents may be substituted for one of the R ⁶ substituents that is not identical to the other R ⁶ substituents having ordinary skill in the art. It is meant that it has its own different structure to the extent that it allows the selection of reaction conditions which can be converted to H without affecting.
[217] The term "alkyl" refers to a substitutable monovalent group derived from the conceptual removal of one hydrogen atom from a straight or branched chain acrylic saturated hydrocarbon such as -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -C (CH ₃ ) _3, etc.).
[218] The term "alkenyl" refers to a substitutable monovalent group derived from the conceptual removal of one hydrogen atom from a straight or branched chain acrylic unsaturated hydrocarbon containing one or more double bonds (e.g., -CH = CH ₂ , -CH ₂ CH = CH ₂ , -CH = CHCH ₃ , -CH ₂ CH = C (CH ₃ ) _2, etc.).
[219] The term "alkynyl" refers to a substitutable monovalent group derived from the conceptual removal of one hydrogen atom from a straight or branched chain acrylic unsaturated hydrocarbon containing one or more three bonds (e.g., -CH CHCH, -CH ₂ C ≡ CH, -C≡CCH ₃ , -CH ₂ CH ₂ C -CCH _3, etc.).
[220] The term "cycloalkyl" means a substitutable monovalent group derived from the conceptual removal of one hydrogen atom from a saturated monocyclic hydrocarbon (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl). .
[221] The term “cycloalkenyl” includes substitutable monovalent groups (eg cyclopentenyl or cyclohexenyl) derived from the conceptual removal of one hydrogen atom from a saturated monocyclic hydrocarbon containing a double bond.
[222] The term “heterocyclyl” means a substitutable monovalent group derived by conceptually removing one hydrogen atom from a heterocycloalkane, wherein the heterocycloalkane is one of its carbon atoms from the corresponding saturated monocyclic hydrocarbon or It is derived by replacing two with an atom selected from N, O or S. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Heterocyclyl substituents may be attached to carbon atoms. If the substituent is a nitrogen containing heterocyclyl substituent, it may be attached to a nitrogen atom.
[223] As used herein, the term “heteroaryl” refers to one hydrogen atom from a monocyclic or acyclic aromatic ring system containing one, two, three or four hetero atoms selected from N, O or S. It refers to a substitutable monovalent group derived conceptually. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl and fury Including but not limited to neil. Heteroaryl substituents may be attached to carbon atoms or through heteroatoms.
[224] The term "triorganosilyl" refers to a silyl group trisubstituted by a lower alkyl group, an aryl group or a mixture thereof, and one such substituent may be a lower alkoxy group. Examples of the triorganosilyl group include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, dimethylphenylsilyl, t-butyldiphenylsilyl, phenyl-t-butylmethoxysilyl, and the like. Include.
[225] In the compounds of the present invention, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with groups other than hydrogen. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
[226] In all cases where the term "alkyl" or "aryl" appears at the beginning or end of the term with substituents such as aryl C _0-8 alkyl, it is intended to include the definitions above for "alkyl" and "aryl". Will be. The designated carbon number (eg, C _1-10 ) independently refers to the carbon number at the alkyl or cyclic alkyl moiety or to the alkyl portion of the larger substituent in which the alkyl appears at the beginning and end of the term.
[227] The terms “arylalkyl” and “alkylaryl” include alkyl moieties where alkyl is as described above and aryl moieties where aryl is as described above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl and thienylpropyl. Examples of alkylaryls include, but are not limited to, toluyl, ethylphenyl and propylphenyl.
[228] As used herein, the term “heteroarylalkyl” refers to a system comprising a heteroaryl moiety and an alkyl moiety as defined above. Examples of heteroarylalkyl include, but are not limited to, pyridylmethyl, pyridylethyl and imidazoylmethyl.
[229] The term "halo" includes iodo, bromo, chloro and fluoro.
[230] The term "oxy" means oxygen (O) atom. The term "thio" refers to a sulfur (S) atom. The term "oxo" means = O. The term "oxymino" means a = N-O group.
[231] The term "substituted" should include multiple degrees of substitution by a given substituent. When multiple substituent residues are described or claimed, the substituted compounds may be independently mono- or polysubstituted by one or more described or claimed substituent residues. Independently substituted means that two or more substituents may be the same or different.
[232] Under the standard nomenclature used throughout this specification, the ends of the designated side chains are first described, followed by adjacent functional groups towards the point of attachment. For example, C _1-5 alkylcarbonylamino C _1-6 alkyl substituents are Corresponds to
[233] In the selection of the compounds of the present invention, one of ordinary skill in the art will appreciate that various substituents are available, namely R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , V, X, Y, It will be appreciated that Z, n, m and p are selected in compliance with well known principles for the association of chemical structures.
[234] Representative compounds of the invention typically exhibit less than micromolar affinity for the α and / or β estrogen receptors. Therefore, the compounds of the present invention are useful for treating mammals suffering from diseases related to estrogen function. A pharmaceutically effective amount of a compound of the invention comprising a pharmaceutically effective salt is administered to a mammal to treat diseases associated with estrogen action such as bone resorption, hot flashes and cardiovascular disease.
[235] The compounds of the present invention are useful in racemic form or as individual enantiomers. For convenience, some structures are shown as single enantiomers, but unless otherwise indicated, it is to be understood to include both racemic and enantiomeric forms. Where cis and trans stereochemical structures are indicated for the compounds of the present invention, it should be understood that, unless otherwise stated, such stereochemical structures may be considered relative.
[236] Formula I
[237]
[238] Since most or all of the desired bioactivity is in a single enantiomer, it is generally preferred to administer the compound of formula I as an enantiomerically pure formulation. The racemic mixture can be separated into individual enantiomers by any of a number of conventional methods. Such methods include chiral chromatography, derivatization using chiral adjuvants and then separation by chromatography or crystallization, and fractionation of diastereomeric salts.
[239] The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated diseases. The individual components of such combinations may be administered separately at different time points during the course of treatment, or may be administered simultaneously in divided or single combination forms. Therefore, it is understood that the present invention encompasses all such regimens of concurrent or alternation therapy, and the term “administration” is also correspondingly understood. The range of combinations of the compounds of the invention with other agents useful for treating estrogen-mediated diseases includes, in principle, any combination with any pharmaceutical composition useful for treating diseases associated with estrogen action.
[240] As used herein, the term "composition" includes not only products that contain a particular amount of specific components, but also all products that are produced, directly or indirectly, from a combination of specific amounts of certain components.
[241] The compounds of the present invention may be administered in oral dosage forms such as tablets, capsules (each of which include sustained or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions Can be. Likewise, they may be administered in the form of intravenous administration (temporary injection or infusion), intraperitoneal administration, topical administration (eg artificial lacrimal fluid), subcutaneous administration, intramuscular administration or transdermal administration (eg patch). All these forms are well known to those of ordinary skill in the pharmaceutical arts.
[242] Dosage regimens using the compounds of the invention include the type, species, age, weight, sex and medical condition of the patient; Symptoms of the disease to be treated; Route of administration; Kidney and liver function of the patient; And the specific compound or salt thereof used. A skilled practitioner, veterinarian or clinician can determine and prescribe the effective amount of drug necessary to prevent the symptoms from progressing.
[243] Oral dosages of the invention used to produce the desired effect range from about 0.1 to about 100 mg, preferably 0.01 to 10 mg, most preferably 0.1 to 5.0 mg per kg of body weight per day. Upon oral administration, the composition provides 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 active ingredients to control the dosage according to the condition to the patient to be treated. It is preferably provided in the form of tablets containing mg, 50.0 mg, 100 mg and 500 mg. A medicament typically contains about 0.01 to about 500 mg, preferably about 1 to about 100 mg, of active ingredient. For intravenous administration, the most preferred dosage will range from about 0.1 to about 10 mg / kg / minute during infusion at a constant rate. Advantageously, the compounds of the present invention may be administered in a single daily dose or in divided doses divided into two to four times a day in total. In addition, preferred compounds of the present invention may be administered in intranasal form via topical use of a suitable intranasal vehicle, or via the transdermal route using transdermal skin patch forms well known to those having ordinary skill in the art. . For administration in the form of a transdermal delivery system, the dosage will naturally be administered continuously without interruption throughout the dosage regimen.
[244] In the methods of the invention, the compounds described in detail herein can form the active ingredient and are usually suitably selected and conventional pharmaceuticals in connection with the desired dosage form, i.e. oral tablets, capsules, elixirs, syrups and the like. Administration is in admixture with a suitable diluent, excipient or carrier (collectively referred to herein as a "carrier" substance) to match the particles.
[245] For example, in oral administration in the form of tablets or capsules, the active drug component may be oral, non-toxic, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like. Can be mixed with a pharmaceutically acceptable inert carrier; For oral administration in liquid form, the oral drug component can be mixed with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol and water and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, leading sugars (e.g. glucose or beta-glucose, corn sweeteners, natural and synthetic rubbers (e.g. acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycols, waxes and the like) Lubricants used in this dosage form include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include starch, methyl cellulose, agar, bentonite, xanthan Rubber and the like, but is not limited thereto.
[246] The compounds of the present invention can also be administered in the form of liposome delivery systems such as small monolayer bubbles, large monolayer bubbles, and multilayer bubbles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphadidylcholine.
[247] Compounds of the invention can also be derived by using unicellular antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. . In addition, the compounds of the present invention are useful in controlling biodegradable polymer classes such as polylactic acid, polyglycolic acid, copolymers of polyactinic acid with polyglycolic acid, polyepsilon caprolactone, polyvalent butyric acid, It can be coupled to a block copolymer of polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or bipolar hydrogels.
[248] The novel compounds of the present invention can be prepared according to the schemes and examples below, using suitable materials, and can be further exemplified by the specific examples below. However, only the compounds shown in the examples should not be limited to the classes considered as present invention. The following examples are described in further detail to prepare the compounds of the present invention. Those skilled in the art will readily understand that known compounds of the following preparative conditions and processes can be used to prepare these compounds. All temperatures are in degrees Celsius unless otherwise noted.
[249] Compounds of the present invention are prepared according to the following Scheme I.
[250]
[251] In Scheme I, suitable functionalized bisphenol II (X = O, Y = O), or mercapto-phenol II (X = O, Y = S), prepared as described in the literature, is readily available. Dimethylform in the presence of a bromo-ketone derivative III, which can be easily prepared from the corresponding ketone by bromination with phenyltrimethylammonium tribromide (PTAB), and a tertiary base such as triethylamine, diisopropylethylamine, etc. In a solvent such as amide (DMF), formamide, acetonitrile, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane, etc., continued to react at the temperature of -20 ° C to 80 ° C until the reaction is complete Obtain product IV. When X = Y = O, only R ³ can be -OR ⁶ . Alternatively, when X = Y = O and R ² is -OR ⁶ , the required closed ring intermediates are obtained by exchanging ketone and bromide functional groups with each other. This provision is required to make the compounds of the present invention wherein the presence of certain substituents alters the reactivity of phenolic oxygen atoms.
[252] Intermediate IV is composed of organic acids (e.g. trifluoroacetic acid, triflic acid, etc.) or Lewis acids (e.g. boron trifluoride etherate, first tin chloride, etc.) and reducing agents (e.g. trisubstituted silanes such as triethylsilane, etc.) In the presence of a solvent (e.g., dichloromethane, chloroform, THF, toluene, etc.) in the presence of a ring closure product V by ring closure until the reaction is complete at a temperature of 40 to 100 ℃, wherein the stereochemical structure of the aryl substituent in the newly formed ring And R ⁵ are both cis form. The formation of intermediates with the trans stereochemistry, which is a homologue, is shown in Scheme II below.
[253] In the product V, when R ⁶ is a protecting group, it is subsequently removed in a way that is compatible with its properties. Such methods are described in the literature (Greene, TW andWuts, PGM, Protectivegroups in Organic Synthesis , Third Ed., Wiley, New York (1999)). In addition, it should be understood that any substituent in R ¹ -R ⁴ may be or may contain -OR ⁶ , and R ⁵ may contain -OR ⁶ , wherein R ⁶ is a protecting group. In this example, it should be understood that the protecting groups may be chemically different, that is, they may be selectively removed as needed. For example, in product V, R ⁶ is a methoxymethyl (MOM) group, R ² is -OR ⁶ , where R ⁶ is a benzyl (Bn) group, and R ⁵ is phenyl substituted with R ⁷ Wherein R ⁷ is OR ⁶ , R ⁶ is a triisopropylsilyl (TIPS) group, and all unspecified substituents are hydrogen.
[254] As mentioned above, as part of the synthesis sequence, it is necessary to preferentially remove MOM groups preferentially to obtain TIPS or Bz groups. Using the method found by Green and Wuts, the desired intermediate V is created in which R ⁶ is H, R ² is -OBn, R ⁵ is para-OTIPS-phenyl and all unspecified substituents are hydrogen. You can. In addition, in the product V where R ⁶ should be a protecting group when R ² or R ³ is OR ⁶ , the existing —OR ⁶ groups must be protected with a different protecting group before being removed.
[255] The alcohol intermediate VI is then reacted with a reagent of formula HO (CH ₂ ) _n NZ ₂ according to the Mitsunobu scheme, which is trisubstituted phosphine (eg triphenylphosphine) and diazodicarboxylate (eg diiso). Propylazodicarboxylate) and mixed in a suitable solvent such as THF at 0-80 ° C. until the reaction is complete to give the coupled product I. Variables of the Mitsunobu reaction are well documented in the literature cited herein by reference. Mitsunobu, O. Synthesis , 1981, 1; Castro, BR Org. React. 1983, 29 , 1; Hughes, DL Org. React. 1992, 42 , 335].
[256] Finally, after conducting the Mitsunobu reaction, if any R group in the product I is -OR ⁶ (where R ⁶ is a protecting group) or contains it, using the suitable method found by Green and Wortz Removal to give the final product, wherein R ⁶ is H.
[257]
[258] In Scheme II, which prepares the trans isomer of Formula I, the ketone intermediate IV from Scheme I is reacted with sodium borohydride for several minutes to 0 to ambient temperature in a mixture of methanol and dichloromethane, or THF or the like. The homologue, hydroxyl intermediate VII, is obtained.
[259] The ring closure of intermediate VII is carried out at ambient to reflux in a solvent such as toluene or dichloromethane in the presence of an acid catalyst such as Amberlyst 15, or triflic acid, to give trans compound VIII as the main isomer.
[260] The remainder of Scheme II for preparing trans compound I is the same as that depicted and described in Scheme I.
[261] Compounds of the invention wherein X = O and Y = SO or SO ₂ are prepared as shown in Scheme III.
[262]
[263] In Scheme III, the compound of formula I of the present invention is peroxidized in a solvent such as dichloromethane or the like with an oxidizing agent such as m -chloroperbenzoic acid or pertrifluoroacetic acid at 0 ° C. to reflux temperature to obtain trioxide intermediate X. do. Conversely, intermediate X is selectively deoxygenated at the nitrogen atom by treatment in a biphasic medium (eg ethyl acetate and water) with a reducing agent such as sodium bisulfide or the like to provide a compound of formula (I).
[264] In the compounds of the present invention, X is preferably O and Y is preferably S.
[265] In the compounds of the invention, R ¹ , R ² , R ³ and R ⁴ are preferably hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _1-5 alkenyl, C _1-5 alkynyl, -OR ⁶ and halogen.
[266] In the compounds of the invention, R ⁵ is preferably selected from the group consisting of C _3-8 cycloalkyl, phenyl and substituted phenyl.
[267] The compound of the present invention, R ⁶ is preferably selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.
[268] In the compounds of the present invention, preferred subclasses are those wherein R ¹ and R ⁴ are hydrogen and R ² and R ³ are independently —OH and R ⁵ is independently selected from the group consisting of phenyl and substituted phenyl.
[269] In a compound of the invention, another preferred subclass is that R ¹ is independently selected from fluorine and chlorine, R ⁴ is hydrogen, R ² and R ³ are independently -OH, and R ⁵ is independently phenyl and substituted phenyl Independently selected from the group consisting of.
[270] In the compounds of the invention, the most preferred subclasses are those in which R ¹ and R ⁴ are hydrogen, R ² is —OH and R ⁵ is independently selected from the group consisting of phenyl and para-hydroxy-phenyl.
[271]
[272] In Scheme IV, Intermediate V of Scheme I is reacted in a solvent (e.g. dichloromethane, ether, acetone, etc.) at 1 equivalent or slightly excess oxidizing agent (e.g. m -chloroperbenzoic acid or Careful treatment with dimethyldioxirane, etc.) to mono-oxidize to provide the corresponding sulfoxide intermediate XI. The remaining synthetic portion of Scheme IV is identical to that shown in Scheme I and described for it.
[273] In the compounds of the present invention, X is preferably O and Y is preferably S.
[274] In the compounds of the invention, R ¹ , R ² , R ³ and R ⁴ are preferably hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _1-5 alkenyl, C _1-5 alkynyl, -OR ⁶ and halogen.
[275] In the compounds of the invention, R ⁵ is preferably selected from the group consisting of C _3-8 cycloalkyl, phenyl, and substituted phenyl.
[276] In the compounds of the present invention, R ⁶ is preferably selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and trisopropylsilyl. _.
[277] In the compounds of the present invention, preferred subclasses are those wherein R ¹ and R ⁴ are hydrogen and R ² and R ³ are independently —OH and R ⁵ is independently selected from the group consisting of phenyl and substituted phenyl.
[278] In a compound of the invention, another preferred subclass is that R ¹ is independently selected from fluorine and chlorine, R ⁴ is hydrogen, R ² and R ³ are independently -OH, and R ⁵ is independently phenyl and substituted phenyl Independently selected from the group consisting of.
[279] In the compounds of the invention, the most preferred subclasses are R ¹ and R ⁴ are hydrogen, R ² is -OH and R ⁵ is independently selected from the group consisting of phenyl, meta-hydroxy-phenyl and para-hydroxy-phenyl Will be.
[280] Example 1
[281] General preparation of thiophenol
[282]
[283] Functionalized thiophenols are prepared with minor changes to known methods as described above. Wermer, G .; Biebrich, W. US Pat. Nos. 2,276,553 and 2,332,418].
[284]
[285] The thiophenols shown above are prepared according to literature. See Maxwell, S. J. Am. Chem. Soc . 1947, 69 , 712; Hanzlik, RP et. al. J. Org. Chem. 1990, 55 , 2736.
[286] Example 2
[287] Preparation of 2-thiophene-4-methoxy-benzophenone
[288]
[289] To a mixed solution of anisole (1.49 g, 13.8 mmol) in anhydrous dichloromethane (5 mL) was added AlCl ₃ (1.2320 g, 9.2 mmol), followed by 2-thiophene acetyl chloride (0.57 mL, 4.6 mmol) in N _2. Dropwise at 0 ^o C. The reaction is stirred for 1.5 hours and then poured into a separatory funnel containing ice / brine / EtOAc. The organic layer is further washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The resulting residue is purified by silica gel chromatography using 30% EtOAc / hexane as eluent to afford the desired product as a yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 3.89 (s, 3H), 4.46 (s, 2H), 6.98 (m, 4H), 7.24 (d, 1H), and 8.05 (d, 2H).
[290] Example 3
[291] Preparation of 2-thiophene-4-hydroxy-benzophenone
[292]
[293] The mixture of 2-thiophene-4-methoxy-benzophenone (0.8294 g, 3.5 mmol) and pyridine-HCl (4.0627 g, 35.2 mmol) produced in Example 2 was heated at 190 ^° C. under N ₂ for 6 hours. do. The reaction is monitored by examining the work up aliquot of the reaction by TLC (30% EtOAc / hexanes). The reaction is cooled in an ice bath and ice / H ₂ O is added. The resulting mixture is extracted with EtOAc. The organic extract is washed with 2N HCl and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting brown residue is purified by silica gel chromatography using 30% EtOAc / hexane as eluent to afford the desired product as a yellow / orange solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 4.43 (s, 2H), 5.60 (bs, 1H), 6.90 (d, 2H), 6.92 (m, 1H), 6.97 (m, 1H), 7.22 (d, 1H) and 8.00 (d, 2H).
[294] Example 4
[295] General Preparation of Cycloalkyl-4-hydroxy-benzophenones
[296]
[297] In anhydrous methylene chloride, see Barrio, etal , J. Med. Chem., 1971, 14 , 898, 3.6 equivalents of aluminum chloride and isopropyl mercaptan 3.0 in a stirred solution of 2-cycloalkyl-1- (4-methoxy-phenyl) -ethanone at 0 ° C. Add equivalents. The ice water bath is removed and the reaction mixture is further stirred overnight under an inert atmosphere of nitrogen. The reaction mixture is poured into 2N HCl / ice mixture and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel chromatography yields the corresponding 2-cycloalkyl-1- (4-hydroxy-phenyl) -ethanone.
[298] According to the experimental procedure described above, the following compounds are prepared:
[299] 2-cyclohexyl-1- (4-hydroxy-phenyl) -ethanone: Obtained in 70% yield using methylene chloride-ethyl acetate (50: 1) as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1-2.0 (m, 11H), 2.96 (d, 1H), 5.6 (bs, 1H), 6.92 (d, 2H), and 7.95 (d, 2H) .
[300] 2-cyclopentyl-1- (4-hydroxy-phenyl) -ethanone: Obtained in 74% yield using methylene chloride-ethyl acetate (50: 1) as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.2-1.92 (m, 10H), 2.4 (m, 1H), 2.96 (d, 1H), 5.6 (bs, 1H), 6.91 (d, 2H), And 7.95 (d, 2 H).
[301] Example 5
[302] Preparation of Isopropyl-4-hydroxy-benzophenone
[303]
[304] To a mixture of isovaleric acid (1.4 mL, 13.0 mmol) and phenol (1.0253 g, 10.9 mmol), BF ₃ OEt ₂ (15 mL) is added under nitrogen. The resulting mixture is heated to 80 ° C. for about 3.5 hours. The reaction is poured into ice / 2N HCl and extracted with EtOAc. The organic extract is washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to afford a yellow residue. After silica gel chromatography using 30% EtOAc / hexane as eluent, the final product is isolated as pale yellow oil. Upon standing at ambient temperature, the oil solidifies to give a white solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.01 (d, 6H), 2.27 (m, 1H), 2.81 (d, 2H), 6.99 (d, 2H), 7.93 (d, 2H).
[305] Example 6
[306] Preparation of 4-pyridyl-4-hydroxy-benzophenone
[307]
[308] In a dried flask equipped with a stir bar was loaded a 2.5M solution of nBuLi in hexane (18 mL, 45.0 mmol) and cooled to 0 ° C. under N ₂ . A solution of diisopropylamine (6.4 mL, 45.7 mmol) in distilled THF (20 mL) is added slowly. After stirring for 25 minutes, a solution of 4-picoline (2.0 mL, 21.4 mmol) in distilled THF (8 mL) is added to the reaction. The resulting red solution is stirred for 25 minutes before removing the ice bath. A solution of cyanophenol (2.5670 g, 21.4 mmol) in distilled THF (20 mL) is added over a dropping funnel over 30 minutes. The addition of phenol causes the reaction to become a highly viscous slurry, draining the red / brown tars as oil. Further addition of THF does not alleviate the difficulty of stirring. The reaction is left for 16 hours at ambient temperature and poured into a mixture of ice / saturated NH ₄ Cl / EtOAc. The intermediate enamine precipitated from the mixture as an insoluble yellow solid is collected by vacuum filtration. The solid is redissolved in 2N HCl. EtOAc layer from the filtrate is also collected and extracted with 2N HCl / ice. The acidic aqueous extract is combined with a solution of enamine in 2N HCl and stirred at ambient temperature for 16 hours. The acidic solution is washed with EtOAc and cooled to 0 ° C. and neutralized to pH 7 with saturated NaHCO ₃ . The desired product from the solution is precipitated as a yellow solid, collected, washed with cold water and dried under vacuum. ¹ H 500 MHz NMR (d-acetone) ppm (δ): 4.37 (s, 2H), 6.97 (d, 2H), 7.31 (d, 2H), 8.01 (d, 2H), 8.52 (bs, 2H).
[309] Example 7
[310] Preparation of 3-pyridyl-4-hydroxy-benzophenone
[311]
[312] The procedure as described in Example 6 was followed except that 1 equivalent of HMPA in THF was added to diisopropylamine, followed by addition to the reaction, 3-pyridyl-4-hydroxy-benzophenone 3-picoline From. The post treatment is slightly different in that no hydrolysis with 2N HCl is required. Instead, the reaction is simply partitioned between ice / saturated NH ₄ Cl and EtOAc. The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is triturated with CH ₂ Cl ₂ and EtOAc to afford the desired product as an orange solid. ¹ H 500 MHz NMR (d-acetone) ppm (δ): 4.39 (s, 2H), 6.97 (d, 2H), 7.31 (m, 1H), 7.68 (m, 1H), 8.01 (d, 2H), 8.43 (m, 1 H), 8.52 (m, 1 H).
[313] Example 8
[314] General Preparation of Cycloalkyl-4-triisopropylsilyloxy-benzophenone
[315]
[316] To a stirred solution of 2-cycloalkyl-1- (4-hydroxy-phenyl) -ethanone at 0 ° C., prepared in Example 4 in anhydrous DMF, 1.3 equivalents of diisopropylethylamine and triisopropylchlorosilane 1.2 equivalents of (TIPSCl) is added. The ice water bath is removed and the reaction mixture is further stirred until TLC indicates the reaction is complete under an inert atmosphere of nitrogen (1-3 hours). The reaction mixture is partitioned into ether / 2N HCl / ice, the organic phase is separated, washed twice with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel chromatography yields the corresponding 2-cycloalkyl-1- (4-triisopropyloxy-phenyl) -ethanone.
[317] According to the experimental procedure described above, the following compounds are prepared:
[318] 2-cyclohexyl-1- (4-triisopropylsilyloxy-phenyl) -ethanone: methylene chloride-hexane (1: 1) is used as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.13 (d, 18H), 1-1.99 (m, 14H), 2.78 (d, 1H), 6.91 (d, 2H), and 7.89 (d, 2H) .
[319] 2-cyclopentyl-1- (4-triisopropylsilyloxy-phenyl) -ethanone: methylene chloride-hexane (1: 1) is used as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.2-1.91 (m, 13H), 2.4 (m, 1H), 2.95 (d, 1H), 6.92 (d, 2H), And 7.9 (d, 2 H).
[320] Example 9
[321] General Preparation of Alkyl-4-triisopropylsilyloxy-benzophenones
[322]
[323] To a solution of 2-alkyl-1- (4-hydroxy-phenyl) -ethanone, prepared in Example 3, in distilled THF is added 1.3 equivalents of 60% NaH in inorganics at 0 ° C. under N ₂ . After gas evolution has ceased, 1.1 equivalents are added dropwise and the resulting solution is stirred for 30 minutes. The reaction is partitioned between ice / water and EtOAc. The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by silica gel chromatography yields the corresponding 2-alkyl-1- (4-triisopropylsilyloxy-phenyl) -ethanone.
[324] According to the experimental procedure described above, the following compounds are prepared:
[325] 2- (2-thiophene) -1- (4-triisopropylsilyloxy-phenyl) -ethanone: 15% EtOAc / hexanes is used as chromatographic eluent to separate as an orange / yellow solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.30 (m, 3H), 4.42 (s, 2H), and 6.93-7.98 (m, 7H).
[326] 2- (4-Pyridyl) -1- (4-triisopropylsilyloxy-phenyl) -ethanone: 40% EtOAc / hexanes is used as chromatographic eluent to separate as a yellow solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.30 (m, 3H), 4.28 (s, 2H), 6.97 (d, 2H), 7.35 (m, 1H), 7.69 ( m, 1H), 7.97 (d, 2H), and 8.56 (bs, 2H).
[327] 2- (3-Pyridyl) -1- (4-triisopropylsilyloxy-phenyl) -ethanone: 40% EtOAc / hexanes is used as chromatographic eluent to separate as a yellow solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.20 (m, 3H), 4.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.82 ( d, 2H), and 8.43 (d, 2H).
[328] Example 10
[329] General Bromination Process of Alkyl and Cycloalkyl-4-triisopropylsilyloxy-benzophenones
[330]
[331] To a stirred solution of 2-alkyl- and 2-cycloalkyl-1- (4-triisopropylsilyloxy-phenyl) -ethanone at 0 ° C. in anhydrous THF, prepared in Examples 8 and 9, trimethylammoniumphenyl Add 1.0 equivalent of perbromide. The ice-water bath is removed and the reaction mixture is further stirred for 1 hour under an inert atmosphere of nitrogen. The reaction mixture is partitioned between ethyl acetate / brine / ice / 5% sodium thiosulfate / sodium bicarbonate, the organic phase is separated and washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by silica gel chromatography yields the corresponding 2-cycloalkyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone.
[332] According to the experimental procedure described above, the following compounds are prepared:
[333] 2-cyclohexyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: methylene chloride-hexane (1: 1) is used as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 0.98-2.27 (m, 15H), 4.91 (d, 1H), 6.94 (d, 2H), and 7.94 (d, 2H) .
[334] 2-cyclopentyl-2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: methylene chloride-hexane (1: 1) is used as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.13 (d, 18H), 1.1-2.2 (m, 11H), 2.8 (m, 1H), 4.98 (d, 1H), 6.94 (d, 2H), And 7.96 (d, 2 H).
[335] 2- (2-thiophene) -2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: stirred at 0 ^o C for 40 minutes, separated as dark brown oil, and then purified Used in subsequent reactions without. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.13 (d, 18H), 1.30 (m, 3H), 6.73 (s, 1H), 6.97 (d, 2H), 7.00 (m, 1H), 7.30 ( m, 1H), 7.49 (d, 1H), and 8.00 (d, 2H).
[336] 2- (4-pyridyl) -2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: 2 equivalents of trimethylammoniumphenyl perbromide are added and stirred at 0 ° C. for 1 hour It is isolated as an orange / yellow oil and used in subsequent reactions without purification. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.03 (d, 18H), 1.21 (m, 3H), 6.21 (s, 1H), 6.98 (d, 2H), 7.40 (d, 2H), 7.90 ( d, 2H), and 8.57 (d, 2H).
[337] 2- (3-pyridyl) -2-bromo-1- (4-triisopropylsilyloxy-phenyl) -ethanone: add 2 equivalents of trimethylammoniumphenyl perbromide and stir at 0 ^° C. for 3 hours Separate as orange / yellow oil, used in subsequent reaction without purification. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.13 (d, 18H), 1.30 (m, 3H), 6.30 (s, 1H), 6.98 (d, 2H), and 7.39-8.75 (m, 6H) .
[338] Example 11
[339] Preparation of 2-isopropyl-2-bromo-1- (4-hydroxyphenyl) -ethanone
[340]
[341] By carrying out the procedure as described in Example 10 and using the product obtained in Example 5, 2-isopropyl-2-bromo-1- (4-hydroxyphenyl) -ethanone was isolated as a yellow oil and It is used in the subsequent reaction without purification. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.01 (d, 3H), 1.21 (d, 3H), 2.46 (m, 1H), 4.93 (d, 1H), 6.96 (d, 2H), and 7.96 (d, 2H).
[342] Example 12
[343] General Preparation of Bromoketones
[344]
[345] Where
[346] R is H or MOM.
[347] Step A
[348] To a stirred solution of 3.0 g (13.2 mmoles) of anhydrous deoxybenzoin (freshly boiled with toluene) at 0 ° C. in 25 mL of DMF is added 5.7 mL (5.7 mmoles) of pure diisopropylethylamine. To this stirred solution, 1.25 mL (19.73 mmoles) of chloromethylmethyl ether (MOMCl) was slowly added. The ice-water bath is removed and the mixture is further stirred under nitrogen atmosphere for 18 hours. The mixture is then poured into saturated NaHCO ₃ solution, extracted with EtOAc, and then the extract is washed with water and dried over anhydrous MgSO ₄ . After evaporating the solvent, the residue is purified by silica gel chromatography (EtOAc / hexane = 1: 1) to give the product as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.19 (d, 2H), 7.10 (d, 2H), 6.8 (d, 2H), 5.23 (s, 2H), 4.8 (s, 1 H), 4.2 (s, 2 H), 3.5 (s, 3 H).
[349] Step B
[350] To a stirred solution of product (423 mg, 1.55 mmol) and imidazole (211 mg, 3.1 mmol) in 0 mL of dry DMF at 0 ° C., triisopropylsilyl chloride (3.1 mmole) is added. The reaction mixture is allowed to warm to room temperature and stirred for a further 2-3 hours. The mixture is quenched by addition of aqueous NaHCO ₃ solution and then extracted with EtOAc. The organic layer is washed with brine and dried over MgSO ₄ . Chromatography (10% EtOAc / hexanes) affords the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H). 6.82 (d, 2H), 5.21 (s, 2H), 4.18 (s, 2H), 3.5 (s, 3H), 1.24 (m, 3H), 1.1 (d, 18H).
[351] Step C
[352] To a mixture of compound (0.5 g, 1.16 mmol) from step B in 100 ml of dry THF, 0.39 g (1.16 mmol) of trimethylphenylammonium perbromide (PTAB) is added at 0 ° C. The ice-water bath is removed and the mixture is stirred for an additional hour. The solution is then filtered, washed with water and brine and then dried over MgSO ₄ . Removal of the solvent yields a mixture of bromo-ketone (MOM group partially removed). The product is used without further purification because it is unstable for chromatography.
[353] Bromoketone with MOM group: ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H) , 6.36 (s, 1 H), 1.24 (m, 3 H), 1.1 (d, 18 H);
[354] Bromoketone without MOM group: ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.94 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H ), 6.36 (s, 1 H), 1.24 (m, 3 H), 1.1 (d, 18 H).
[355] Example 13
[356] Chemical formula Preparation of the compound
[357] The required bromoketone is prepared using the procedure described in Example 12 (step C).
[358] ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.94 (d, 2H), 7.56 (m, 2H), 7.38 (m, 3H), 6.9 (d, 2H), 6.36 (s, 2H), 1.28 (m, 3 H), 1.1 (d, 18 H).
[359] Example 14
[360] Chemical formula Preparation of the compound
[361] The required bromoketone is prepared using the procedure described in Example 12 (step C).
[362] ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.9 (d, 2H), 7.5 (d, 2H), 6.9 (d & d, 4H), 6.4 (s, 1H), 3.8 (s, 3H) , 1.28 (m, 3 H), 1.1 (d, 18 H).
[363] Example 15
[364] Chemical formula Preparation of the compound
[365] Step A
[366] To a stirred solution of 0.1 g (0.37 mmol) and diisopropylethylamine (0.13 mL, 2 equiv) of the monophenol compound from Step A in Example 12 in 5 mL of DMF, pure MOMCl (0.05 mL, 2 equiv) ) Is added slowly and the mixture is heated at 85 ° C. for 3 h under N ₂ . The mixture is then poured into saturated NaHCO ₃ solution, extracted with EtOAc, washed with water and then dried over MgSO ₄ . After evaporation of the solvent, the residue is purified by silica gel chromatography (EtOAc / hexane = 1: 1) to give pure bis-protected MOM product as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.19 (d, 2H), 7.10 (d, 2H), 7.02 (d, 2H), 5.23 (s, 2H), 5.2 (s, 2H), 4.2 (s, 2H), 3.5 (2 s, 6H).
[367] Step B
[368] The product of step A is treated with bromine to give bromoketone. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.0 (d, 2H), 7.45 (d, 2H), 7.10 (2 d, 4H), 6.4 (s, 1H), 5.23 (2 s, 4H), 3.5 (2 s, 6H).
[369] Example 16
[370] Chemical formula Preparation of the compound
[371] 2-thiophenol (0.2 g, 1.6 mmol) and Et ₃ N (0.34 mL, 2 equiv) in 15 mL of DMF To a freshly prepared solution stirred at 0 ° C., bromoketone in 13 mL of DMF (step C of Example 12) Prepared from) slowly add 0.627 g (1.232 mmol) of solution. The reaction mixture is stirred at rt for 3 h, then partitioned between saturated NaHCO ₃ and EtOAc, the layers are separated and the aqueous phase is extracted again with EtOAc. The combined organic layers are dried (Na ₂ SO ₄ ), filtered and then evaporated in vacuo. The resulting oil is purified by flash chromatography (EtOAc / hexane = 1/4) to afford the desired product as an oil.
[372] ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.2-6.6 (m, 8H), 6.8 (d, 2H), 6.2 (s, 1H), 5.24 (s , 2H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 575 (M ⁺ +23).
[373] Example 17
[374] Ring closure of the coupled product
[375]
[376] The procedure as described in Example 16 was carried out to convert 1,2-dihydroxybenzene and the bromide of Example 15 to the product, which was silica gel using EtOAc / hexane (1/4) as eluent. Purification by chromatography. MS m / z 448 (M ⁺ +23).
[377] Example 18
[378] Preparation of the following Compounds A and B
[379]
[380] Silica gel was run using the procedure as described in Example 16 but using 0.83 g (3.6 mmole) of 4-benzyloxy-thiophenol prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, product A and product B are obtained.
[381] A: ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.15 (s, 1H), 7.8 (d, 2H), 7.4 (m, 5H), 6.98 (d, 2H), 6.98 (d , 1H), 6.75 (d & d, 4H), 6.0 (s, 1H), 5.62 (s, 1H), 5.0 (s, 2H), 1.22 (m, 3H), 1.15 (d, 18H).
[382] B: ¹ H NMR (400 MHz, acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.5 (m, 5H), 7.18 (d, 2H), 7.04 (d, 2H), 6.96 (d , 1H), 6.8 (d, 2H), 6.56 (d, 1H), 6.32 (dd, 1H), 6.1 (s, 1H), 5.25 (s, 2H), 5.09 (s, 1H), 3.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
[383] Example 19
[384] Chemical formula Preparation of the compound
[385] Silica gel chromatography using EtOAc / hexane (1/5) as eluent using 1.1 g (2.3 mmoles) of bromoketone prepared from Example 14 followed by a procedure as described in Example 16. Obtain the desired product.
[386] ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 8.46 (br s, 1H), 7.98 (d, 2H), 7.48-7.3 (m, 5H), 7.24 (d, 2H), 7.4 ( d, 1H), 6.92 (d, 2H), 6.82 (d, 2H), 6.56 (d, 1H), 6.38 (dd, 1H), 6.1 (s, 1H), 5.04 (s, 2H), 3.72 (s , 3H), 1.25 (m, 3H), 1.1 (d, 18H).
[387] Example 20
[388] Chemical formula Preparation of the compound
[389] Perform the procedure as described in Example 16, using 0.74 g (1.5 mmol) of bromoketone prepared from Example 12 (Step C), using EtOAc / hexane (1/5) as eluent to silica gel. After chromatography, the desired product is obtained. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 7.92 (d, 2H), 7.46-7.1 (m, 5H), 7.18 (d, 2H), 6.84 (d, 2H), 6.78 (d , 2H), 6.42 (d, 1H), 6.36 (d, 1H), 5.98 (s, 1H), 5.02 (s, 2H), 2.2 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
[390] Example 21
[391] Chemical formula Preparation of the compound
[392] The procedure as described in Example 16 was carried out, using 0.8 g (1.57 mmol) of bromoketone prepared from Example 12 (step C) and the thiophenol derivative prepared from Example 1, EtOAc / hexane (1 / Silica gel chromatography using 5) as eluent yields the desired product. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 7.9 (d, 2H), 7.5-7.3 (m, 5H), 7.12 (d, 2H), 6.9 (d, 1H), 6.84 (d , 2H), 6.79 (d, 2H), 6.4 (d, 1H), 6.0 (s, 1H), 5.1 (s, 2H), 2.1 (s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).
[393] Example 22
[394] Chemical formula Preparation of the compound
[395] The process as described in Example 16 was carried out using 0.56 g (1.1 mmole) of bromoketone prepared from Example 12 (step C) and 0.19 g (0.73 mmole) of thiophenol derivative prepared from Example 1, After silica gel chromatography with EtOAc / hexane (1/5) as eluent, the desired product is obtained. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 7.9 (d, 2H), 7.48-7.3 (m, 5H), 7.16 (d, 2H), 6.84 (d, 2H), 6.78 (d , 2H), 6.42 (d, 1H), 6.38 (d, 1H), 5.96 (s, 1H), 5.1 (s, 2H), 2.6 (q, 2H), 1.22 (m, 3H), 1.1 (d, 18H), 1.1 (t, 3H).
[396] Example 23
[397] Chemical formula Preparation of the compound
[398] The procedure as described in Example 16 was carried out, using 2.04 g (4.33 mmole) of bromoketone prepared from Example 12 (step C) and the thiophenol derivative prepared from Example 1, followed by EtOAc / hexane (1 / Silica gel chromatography using 5) as eluent yields the desired product. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 7.9 (d, 2H), 7.5-7.3 (m, 5H), 7.12 (d, 2H), 6.92 (d, 1H), 6.84 (d , 2H), 6.78 (d, 2H), 6.42 (d, 1H), 6.0 (s, 1H), 5.1 (s, 2H), 2.7 (q, 2H), 1.24 (m, 3H), 1.1 (d & t, 21 H).
[399] Example 24
[400] Chemical formula Preparation of the compound
[401] The procedure as described in Example 16 was carried out, using 2.0 g (4.33 mmole) of bromoketone prepared from Example 12 (step C) and the thiophenol derivative prepared from Example 1, EtOAc / hexane (1 / Silica gel chromatography using 5) as eluent yields the desired product. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 7.8 (d, 2H), 7.62 (d, 2H), 7.48-7.3 (m, 8H), 7.12 (d, 2H), 6.8 (d , 2H), 6.76 (2H, d), 6.28 (d, 1H), 6.18 (d, 1H), 6.0 (s, 1H), 5.24 (s, 2H), 5.05 (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[402] Example 25
[403] Chemical formula Preparation of the compound
[404] The procedure as described in Example 16 was carried out using EtOAc / hexane (1/5) using 1.6 g (3.51 mmole) of bromoketone prepared from Example 13 and a thiophenol derivative prepared from Example 1. Silica gel chromatography after use as a product yields the desired product. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.5-7.2 (m, 10H), 7.0 (d, 1H), 6.92 (d, 2H), 6.54 (d , 1H), 6.35 (dd, 1H), 6.12 (s, 1H), 5.06 (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[405] Example 26
[406] Chemical formula Preparation of the compound
[407] Perform the procedure as described in Example 16, using 2.6 g (5.82 mmoles) of bromoketone prepared from Example 13 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5). Silica gel chromatography after use as a product yields the desired product. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 10H), 6.94 (d, 2H), 6.84-6.74 (m, 3H), 6.24 (s, 1 H), 4.85 (s, 2 H), 1.23 (m, 3 H), 1.1 (d, 18 H).
[408] Example 27
[409] Chemical formula Compound of
[410] The procedure as described in Example 16 was carried out using bromoketone prepared from Example 12 (step C) and the thiophenol derivative prepared from Example 1, with EtOAc / hexane (1/5) as eluent. Silica gel chromatography to give the desired product. ¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 8.0 (d, 2H), 7.4-7.2 (m, 7H), 7.0 (m, 5H), 6.54 (d, 1H), 6.28 (dd , 1H), 6.14 (s, 1H), 5.08 (s, 2H), 1.23 (m, 3H), 1.1 (d, 18H).
[411] Example 28
[412] Chemical formula Preparation of the compound
[413] Silica gel using EtOAc / hexane (1/5) as eluent, following the procedure as described in Example 16, using the bromoketone prepared from Example 13 and the thiophenol derivative prepared from Example 1 After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 8.28 (s, 1H), 7.82 (d, 2H), 7.40 (m, 5H), 7.22 (m, 5H), 6.80 (d, 2H), 6.40 (d, 1H), 6.21 (dd, 1H), 5.80 (s, 1H), 5.00 (s, 2H), 1.24 (m, 3H), 1.10 (d, 18H).
[414] Example 29
[415] Chemical formula Preparation of the compound
[416] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 13 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 8.19 (s, 1H), 7.82 (d, 2H), 7.40 (m, 5H), 7.24 (m, 5H), 6.80 (d, 2H), 6.64 (d, 1H), 6.44 (d, 1H), 5.84 (s, 1H), 5.00 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
[417] Example 30
[418] Chemical formula Preparation of the compound
[419] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 8.20 (s, 1H), 7.81 (d, 2H), 7.40 (m, 5H), 7.02 (d, 2H), 6.75 (d, 4H), 6.36 (d, 1H), 6.20 (dd, 1H), 5.78 (s, 1H), 4.95 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
[420] Example 31
[421] Chemical formula Preparation of the compound
[422] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 8.24 (s, 1H), 7.80 (d, 2H), 7.40 (m, 5H), 7.10 (d, 2H), 6.78 (d, 4H), 6.62 (d, 1H), 6.42 (d, 1H), 5.84 (s, 1H), 4.98 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m / z 650 (M ⁺ +1).
[423] Example 32
[424] Chemical formula Preparation of the compound
[425] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 7.95 (d, 2H), 7.40 (m, 5H), 7.20 (d, 2H), 6.80 (m, 7H), 6.20 (s, 1H ), 4.85 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m / z 616 (M ⁺ +1).
[426] Example 33
[427] Chemical formula Preparation of the compound
[428] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.82 (d, 2H), 7.40 (m, 5H), 7.05 (d, 2H), 6.95 (s, 1H), 6.80 (d, 4H), 6.52 (s, 1 H), 5.64 (s, 1 H), 5.00 (s, 2 H), 1.23 (m, 3 H), 1.10 (m, 18 H); MS m / z 629 (M ⁺ +1).
[429] Example 34
[430] Chemical formula Preparation of the compound
[431] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) d (ppm: 8.24 (s, 1H), 7.80 (d, 2H), 7.40 (m, 5H), 7.10 (d, 2H), 6.78 (d, 2H), 6.76 (d, 2H), 6.64 (d, 2H), 6.45 (d, 2H), 5.86 (s, 1H), 4.98 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m / z 650 (M ⁺ +1).
[432] Example 35
[433] Chemical formula Preparation of the compound
[434] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.82 (d, 2H), 7.40 (m, 5H), 7.24 (m, 3H), 7.20 (d, 2H), 6.82 (d, 2H), 6.80 (d, 2H), 6.58 (d, 2H), 5.65 (s, 1H), 4.80 (d, 2H), 2.22 (s, 3H), 1.23 (m, 3H), 1.10 (m, 18H).
[435] Example 36
[436] Chemical formula Preparation of the compound
[437] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.98 (s, 1H), 7.82 (d, 2H), 7.40 (m, 5H), 7.25 (m, 3H), 7.20 (d, 2H), 7.00 (d, 1H), 6.80 (d, 2H), 6.60 (d, 1H), 5.78 (s, 1H), 4.78 (d, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
[438] Example 37
[439] Preparation of the following Compounds I and II
[440]
[441] Silica gel using EtOAc / hexane (1/5) as eluent, following the procedure as described in Example 16, using the bromoketone prepared from Example 13 and the thiophenol derivative prepared from Example 1 After chromatography, two desired products I and II are obtained. I: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, 2H), 7.40 (m, 5H), 7.25 (m, 3H), 7.16 (d, 2H), 7.04 (s, 1H ), 6.80 (d, 2H), 6.60 (s, 1H), 5.78 (s, 1H), 4.80 (d, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
[442] II: ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, 2H), 7.65 (s, 1H), 7.44 (d, 1H), 7.40 (m, 5H), 7.25 (m, 5H ), 6.96 (d, 1H), 6.80 (m, 3H), 6.00 (s, 1H), 5.15 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
[443] Example 38
[444] Chemical formula Preparation of the compound
[445] A silica gel was prepared using the same procedure as described in Example 16, using bromoketone prepared from Example 12 and the thiophenol derivative prepared from Example 1, using EtOAc / hexane (1/5) as eluent. After chromatography, the desired product is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, 2H), 7.40 (m, 5H), 7.14 (m, 2H), 6.96 (m, 2H), 6.84 (m, 2H), 6.82 (d, 2H), 6.70 (d, 1H), 5.68 (s, 1H), 4.86 d, 2H), 1.23 (m, 3H), 1.10 (m, 18H).
[446] Example 39
[447] Chemical formula General Preparation of Compounds
[448] Using the bromide prepared in Example 10 and a suitable mercaptan prepared in Example 1 and following the procedure as described in Example 16, the following compounds were prepared:
[449] Cyclohexyl Derivatives: Methylene chloride / hexane (3: 1) is used as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.11-2.34 (m, 15H), 4.19 (d, 1H), 5.0 (s, 2H), 6.44 (dd, 1H), 6.54 (d, 1 H), 6.86 (m, 3 H), 7.25-7.72 (m, 7 H).
[450] Cyclopentyl Derivatives: Methylene chloride / hexane (2: 1) is used as chromatography eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.28-2.49 (m, 12H), 4.18 (d, 1H), 5.0 (s, 2H), 6.45-7.77 (m, 12H ).
[451] Example 40
[452] Chemical formula Preparation of the compound
[453] Silica gel chromatography using 30% EtOAc / hexane as eluent was carried out using bromide prepared in Example 11 and a suitable mercaptan prepared in Example 1, followed by a procedure as described in Example 9. The product is obtained as a yellow oil in 77% yield. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.00 (d, 3H), 1.21 (d, 3H), 2.30 (m, 1H), 4.13 (d, 1H), 4.99 (s, 2H), 6.41 -7.72 (m, 12 H), 8.02 (bs, 1 H), 8.80 (bs, 1 H); MS m / z 409 (M ⁺ ).
[454] Example 41
[455] Chemical formula General Preparation of Compounds
[456] Using the bromide prepared in Example 10 and a suitable mercaptan prepared in Example 1 and following the procedure as described in Example 16, the following compounds were prepared:
[457] Cyclohexyl Derivatives: Methylene chloride / hexane (3: 1) is used as the chromatographic eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.11-2.3 (m, 15H), 4.24 (d, 1H), 4.89 (m, 2H), 6.8-7.6 (m, 12H ).
[458] Cyclopentyl Derivatives: Methylene chloride / hexane (2: 1) is used as chromatography eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.26-2.12 (m, 11H), 2.5 (m, 1H), 4.24 (d, 1H), 4.9 (m, 2H), 6.8-7. 69 (m, 12 H).
[459] 4-pyridyl derivative: 30% EtOAc / hexanes are used as chromatographic eluent to separate as yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.28 (m, 3H), 4.84 (q, 2H), 4.88 (s, 1H), 5.63 (s, 1H), and 6.69-8.50 (m, 16 H).
[460] 3-pyridyl derivative: 30% EtOAc / hexanes are used as chromatographic eluent to separate as yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.28- (m, 3H), 4.84 (q, 2H), 4.90 (s, 1H), 5.79 (s, 1H), and 6.70-8.50 (m, 16 H).
[461] Example 42
[462] Chemical formula Preparation of the compound
[463] Silica gel chromatography using 30% EtOAc / hexane as eluent was carried out using bromide prepared in Example 11 and a suitable mercaptan prepared in Example 1 and following the procedure as described in Example 16. The product is obtained as a yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.02 (d, 3H), 1.21 (d, 3H), 2.34 (m, 1H), 4.13 (d, 1H), 4.90 (q, 2H), 6.25 (bs, 1 H), 6.79-7.70 (m, 12 H).
[464] Example 43
[465] Chemical formula Preparation of the compound
[466] Suitable bromide prepared in Example 10 and literature, see Burton, et al , J. Chem. Soc. , 1952, 2193, using a mercaptoquinol prepared according to the method described in the following procedure, and following the procedure as described in Example 16, silica gel chromatography using 30% EtOAc / hexane as eluent gave the desired product. Is obtained as an orange / red oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.10 (d, 18H), 1.27 (m, 3H), 6.00 (s, 1H), and 6.76-7.89 (m, 10H); MS m / z 515 (M ⁺ ).
[467] Example 44
[468] Chemical formula Preparation of the compound
[469] Into a flask loaded with 0.1 g (0.16 mmol) of thio-ketone produced in Example 22 in dichloromethane (about 0.04 M), trifluoroacetic acid (TFA) (2 X 0.062 mL, 10 equiv) was added to N ₂ at room temperature. Apply slowly in the atmosphere. Triethylsilane (2 × 0.05 mL, 4 equiv) was slowly added to the stirred reaction mixture until the starting material was consumed (about 5-6 hours, monitored by TLC). The reaction mixture is poured into saturated NaHCO ₃ / ice water, stirred for 10 minutes and extracted with dichloromethane. The organic extract is washed with brine (2 X 50 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to give a pale yellow oil. Purification by flash chromatography (EtOAc / hexane = 1: 5) affords the desired product as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.44 (m, 5H), 6.98 (d, 1H), 6.90 (d, 2H), 6.75 (d, 2H), 6.68 (d, 2H), 6.65 (d, 1H), 6.63 (d, 2H), 5.51 (d, J = 2.3Hz, 1H), 5.10 (s, 2H), 4.74 (brs, 1H), 4.32 (d, J = 2.3Hz, 1H ), 2.77 (qd, 2H), 1.22 (m, 3H), 1.08 (d, 18H), 1.1 (m, 3H); MS m / z 628.5 (M ⁺ +1).
[470] Example 45
[471] Preparation of a Compound of Formula
[472]
[473] The procedure as described in Example 44 is carried out, followed by purification by silica gel chromatography using 10% EtOAc / hexanes to separate the desired dihydrobenzoxanthines without the MOM protecting group. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.2-6.98 (m, 4H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (2 d, 4H), 5.5 (d , J = 2.2 Hz, 1H), 4.8 (s, 1H), 4.33 (d, J = 2.1 Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 515 (M ⁺ +23).
[474] Other dihydrobenzoxanthines with MOM protecting groups are also isolated. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.2-6.6 (m, 8H), 6.78 (d, 2H), 6.66 (d, 2H), 5.5 (d, J = 2.4 Hz, 1H), 5.14 (s, 2H), 4.35 (d, J = 2.1 Hz, 1H), 3.48 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
[475] Example 46
[476] Chemical formula Preparation of the compound
[477] The procedure as described in Example 71 (step C) is followed to desilylate the dihydrobenzoxanthine produced from Example 45 to afford the product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.2-6.96 (m, 4H), 6.92 (2 d, 4H), 6.82 (d, 2H), 6.6 (d, 2H), 5.52 (d , J = 2.2 Hz, 1H), 5.16 (s, 2H), 4.68 (br s, 1H), 4.38 (d, J = 2.2 Hz, 1H), 3.48 (s, 3H).
[478] Example 47
[479] Preparation of a Compound of Formula
[480]
[481] The ketone produced in Example 17 is converted to the desired product by following the procedure as described in Example 44 except that 5 equivalents of TFA and 2 equivalents of Et ₃ SiH are required to terminate the reaction. The MOM group is removed by mild acid treatment (2N HCl, 75 ^° C.) to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.0 (m, 4H), 6.85 (d, 2H), 6.65 (d, 2H), 5.38 (s, 2H); MS m / z 343 (M ⁺ +23).
[482] Example 48
[483] Chemical formula Preparation of the compound
[484] The ketone produced in Example 18 is converted to the dihydrobenzoxanthine by following the procedure described in Example 44 except that 20 equivalents of TFA and 15 equivalents of Et ₃ SiH are required to terminate the reaction. After purification by silica gel chromatography using 10% EtOAc / hexane as eluent, the desired product is isolated. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1H), 6.84 (d, 2H), 6.76 (d, 2H), 6.7 (dd, 1H ), 6.67 (d, 1H), 6.68 (2 d, 4H), 5.5 (d, J = 2.2 Hz, 1H), 5.04 (br q, 2H), 4.68 (s, 1H), 4.3 (d, J = 2.2 Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 515 (M ⁺ +23).
[485] Example 49
[486] Chemical formula Preparation of the compound
[487] The ketone produced in Example 19 was subjected to the procedure as described in Example 44 except that the reaction was carried out at −10 ° C. for 48 hours in the presence of 20 equivalents of TFA and 2 equivalents of Et ₃ SiH to give the dehydro Convert to benzoxatin. After purification by silica gel chromatography using 10% EtOAc / hexane as eluent, the desired product [20% recovery of starting compound] is separated. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.1-6.6 (m, 11H), 5.54 (d, J = 1.9 Hz, 1H), 5.06 (dd, 2H ), 4.32 (d, 1H), 3.74 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
[488] Example 50
[489] Chemical formula Preparation of the compound
[490] The procedure as described in Example 44 was carried out and the ketone derivative from Example 20 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.46-7.32 (m, 5H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (2 d, 4H), 6.62 (d , 1H), 6.57 (d, 1H), 5.3 (d, J = 2.2Hz, 1H), 4.35 (d, 1H), 2.28 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H) .
[491] Example 51
[492] Chemical formula Preparation of the compound
[493] The procedure as described in Example 44 was carried out and the ketone derivative from Example 21 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 1H), 6.76 (d, 2H), 6.6 (m, 5H ), 5.51 (d, J = 2.2 Hz, 1H), 5.1 (s, 2H), 4.8 (s, 1H), 4.32 (d, 1H), 2.4 (s, 3H), 1.22 (m, 3H), 1.1 (d, 18H).
[494] Example 52
[495] Chemical formula Preparation of the compound
[496] The procedure as described in Example 44 was carried out and the ketone derivative from Example 22 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.85 (d, 2H), 6.78 (d, 2H), 6.66 (m, 5H), 6.56 (d, 1H ), 5.48 (d, J = 2.0 Hz, 1H), 5.04 (br q, 2H), 4.74 (br s, 1H), 4.34 (d, J = 2.0 Hz, 1H), 2.64 (q, 2H), 1.3 (t, 3H), 1.24 (m, 3H), 1.1 (d, 18H).
[497] Example 53
[498] Chemical formula Preparation of the compound
[499] The procedure as described in Example 44 was carried out and the ketone derivative from Example 23 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) d (ppm: 7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 2H), 6.74 (d, 2H), 6.7-6.6 (3 d, 5H), 5.5 (d, J = 2.3Hz, 1H), 5.1 (s, 2H), 4.74 (br s, 1H), 4.32 (d, J = 2.4Hz, 1H), 2.79 (m, 2H) , 1.22 (m, 3H), 1.1 (d & t, 21H); MS m / z 628.5 (M ⁺⁺ 1).
[500] Example 54
[501] Chemical formula Preparation of the compound
[502] The procedure as described in Example 44 was carried out and the ketone derivative from Example 24 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 10H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (2 d, 4H), 6.38 (s , 2H), 5.48 (d, J = 2.1 Hz, 1H), 5.14 (s, 2H), 5.0 (q, 2H), 4.76 (br s, 1H), 4.32 (d, J = 2.1 Hz, 1H), 1.22 (m, 3 H), 1.1 (d, 18 H).
[503] Example 55
[504] Chemical formula Preparation of the compound
[505] The procedure as described in Example 44 was carried out and the ketone derivative from Example 25 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.9-6.82 (m, 4H), 6.76-6.7 (m, 4H) , 5.56 (d, 1H), 5.06 (br q, 2H), 4.36 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).
[506] Example 56
[507] Chemical formula Preparation of the compound
[508] The procedure as described in Example 44 was carried out except that the reaction was carried out at 0 ° C. for 3 hours and 1.7 g (2.83 mmole) of the ketone derivative from Example 26 was dissolved in 5% EtOAc / hexane. Purification by silica gel chromatography using as a product yields the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.34 (m, 5H), 7.2-7.1 (m, 3H), 6.94 (d, 1H), 6.9-6.82 (m, 5H), 6.4 (m, 3H), 5.48 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 4.36 (d, J = 1.9 Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H) .
[509] Example 57
[510] Chemical formula Preparation of the compound
[511] The procedure as described in Example 44 is carried out and the ketone derivative from Example 27 is used to obtain the desired product which is subsequently desilylated using the procedure described in Example 71 (step C). . Purification by silica gel chromatography using 15% EtOAc / hexane as eluent affords the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.32 (m, 5H), 7.09 (d, 1H), 6.9-6.8 (m, 6H), 6.73-6.7 (m, 4H), 5.52 (d, 1H), 5.04 (br q, 2H), 4.34 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).
[512] Example 58
[513] Chemical formula Preparation of the compound
[514] The procedure as described in Example 44 was carried out and the ketone derivative from Example 28 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.75 (d, 2H), 6.55 (d, 2H), 5.55 (d, J = 2.1 Hz, 1H), 5.05 (d, 2H), 4.40 (d, J = 2.1 Hz, 1H), 1.22 (m, 3H), 1.1 (d, 18H) .
[515] Example 59
[516] Chemical formula Preparation of the compound
[517] The procedure as described in Example 44 was carried out and the ketone derivative from Example 29 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.73 (d, 2H), 6.64 (d, 2H), 5.50 (d, J = 2.1 Hz, 1H), 5.05 (d, 2H), 4.43 (d, J = 2.2 Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H) .
[518] Example 60
[519] Chemical formula Preparation of the compound
[520] The procedure as described in Example 44 was carried out and the ketone derivative from Example 30 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.82 (d, 2H), 6.68 (d, 2H), 6.64 (d, 2H), 6.62 (d, 2H ), 6.46 (d, 2H), 5.44 (d, J = 1.9Hz, 1H), 5.02 (d, 2H), 4.30 (d, J = 2.0Hz, 1H), 1.22 (m, 3H), 1.10 (d , 18H); MS m / z 618 (M ⁺ +1).
[521] Example 61
[522] Chemical formula Preparation of the compound
[523] The procedure as described in Example 44 was carried out and the ketone derivative from Example 31 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) d (ppm): 7.5-7.3 (m, 5H), 6.86 (d, 1H), 6.82 (d, 2H), 6.76 (d, 2H), 6.70 (d, 1H ), 6.67 (d, 2H), 6.65 (d, 2H), 5.44 (d, J = 2.0 Hz, 1H), 5.04 (s, 2H), 4.38 (d, J = 1.9 Hz, 1H), 1.23 (m , 3H), 1.10 (d, 18H); MS m / z 634 (M ⁺ +1).
[524] Example 62
[525] Chemical formula Preparation of the compound
[526] The procedure as described in Example 44 was carried out and the ketone derivative from Example 32 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.94 (d, 1H), 6.85 (d, 2H), 6.80 (d, 2H), 6.74 (dd, 2H ), 6.65 (m, 4H), 5.43 (d, J = 2.1 Hz, 1H), 5.05 (d, 2H), 4.30 (d, J = 2.1 Hz, 1H), 1.23 (m, 3H), 1.10 (d , 18H).
[527] Example 63
[528] Chemical formula Preparation of the compound
[529] The procedure as described in Example 44 was carried out and the ketone derivative from Example 33 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.88 (s, 1H), 6.84 (d, 2H), 6.82 (d, 2H), 6.70 (d, 2H ), 6.68 (d, 2H), 6.66 (s, 1H), 5.50 (d, 1H), 5.05 (s, 2H), 4.43 (d, 1H), 2.35 (s, 3H), 1.23 (m, 3H) , 1.10 (d, 18 H).
[530] Example 64
[531] Chemical formula Preparation of the compound
[532] The procedure as described in Example 44 was carried out and the ketone derivative from Example 34 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.24 (s, 1H), 7.20 (s, 1H), 6.82 (d, 2H), 6.68 (d, 2H ), 6.64 (m, 4H), 5.44 (d, J = 2.0 Hz, 1H), 5.05 (d, 2H), 4.28 (d, J = 2.3Hz, 1H), 1.23 (m, 3H), 1.10 (d , 18H).
[533] Example 65
[534] Chemical formula Preparation of the compound
[535] The procedure as described in Example 44 was carried out and the ketone derivative from Example 35 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, 4H), 6.90 (d, 2H), 6.88 (d, 2H), 6.78 (d , 2H), 6.70 (d, 1H), 6.65 (d, 1H), 5.30 (d, J = 1.8Hz, 1H), 5.05 (d, 2H), 4.20 (d, J = 2.3Hz, 1H), 1.23 (m, 3 H), 1.10 (d, 18 H).
[536] Example 66
[537] Chemical formula Preparation of the compound
[538] The procedure as described in Example 44 was carried out and the ketone derivative from Example 36 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, 2H), 7.10 (m, 2H), 6.98 (d, 2H), 6.88 (m , 2H), 6.80 (m, 1H), 6.60 (d, 1H), 5.56 (d, J = 1.8 Hz, 1H), 5.05 (d, 2H), 4.44 (d, J = 2.3 Hz, 1H), 1.23 (m, 3 H), 1.10 (d, 18 H).
[539] Example 67
[540] Chemical formula Preparation of the compound
[541] The procedure as described in Example 44 was carried out and purified by silica gel chromatography using 5% EtOAc / hexane as eluent using the ketone derivative from Example 37 (I) to afford the desired product. . ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.20 (d, 1H), 7.15 (m, 3H), 6.88 (d, 2H), 6.84 (d, 3H), 6.78 (d, 2H), 5.46 (d, J = 2.1 Hz, 1H), 5.15 (s, 2H), 4.39 (d, J = 2.1 Hz, 1H ), 1.23 (m, 3H), 1.10 (d, 18H).
[542] Example 68
[543] Chemical formula Preparation of the compound
[544] The procedure as described in Example 44 was carried out and purified by silica gel chromatography using 5% EtOAc / hexane as eluent using the ketone derivative from Example 37 (II) to afford the desired product. . ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.55 (d, 2H), 7.45 (t, 1H), 7.35 (t, 1H), 7.20 (d, 1H), 7.15 (t, 2H), 6.80-6.90 (m, 4H), 6.78 (d, 2H), 6.76 (d, 2H), 5.42 (d, J = 2.1 Hz, 1H), 5.18 (s, 2H), 4.42 (d, J = 2.1 Hz , 1H), 1.23 (m, 3H), 1.10 (d, 18H).
[545] Example 69
[546] Chemical formula Preparation of the compound
[547] The procedure as described in Example 44 was carried out and the ketone derivative from Example 38 was used to purify by silica gel chromatography using 5% EtOAc / hexane as eluent to afford the desired product. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.36-7.50 (m, 5H), 6.96 (d, 2H), 6.80-6.90 (m, 4H), 6.70-6.78 (m, 5H), 5.42 (d, J = 2.1 Hz, 1H), 5.18 (s, 2H), 4.38 (d, J = 2.1 Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).
[548] Example 70
[549] Chemical formula Chiral separation of
[550] Each enantiomer of racemic dihydrobenzoxanthine obtained from Example 62 was partitioned via chiral chromatography using a Chiralpak AD column using 30% isopropanol in hexane as eluent.
[551] Fast moving isomers: [a] _D = +18.44 ^o (c = 0.725, MeOH).
[552] Slowly moving isomers: [a] _D = -18.85 ^o (c = 0.74, MeOH).
[553] Example 71
[554] Typical manufacture of thin
[555] Chemical formula Preparation of the compound
[556] Step A
[557] Dihydrobenzoxanthine (60 mg, 0.1 mmol) obtained from Example 48 in 4 ml of dry THF (which was dried by azeotropy before use), triphenylphosphine (157 mg, 0.6 mmole), and 1-piperidine To a stirred solution of ethanol (0.08 mL, 0.6 mmol) at 0 ° C., 0.118 mL (0.6 mmol) of diisopropyl azodicarboxylate (DIAD) was added dropwise over 0.2 hours. The resulting pale yellow solution is stirred at room temperature for 2-3 hours. The volatile components are removed in vacuo and the residue is purified by flash chromatography (EtOAc / hexane = 1: 5 followed by 2-3% MeOH / dichloromethane) to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.34 (m, 5H), 7.08 (d, 1H), 6.86 (d, 2H), 6.78-6.64 (m, 8H), 5.5 (d , 1H), 5.01 (br q, 2H), 4.3 (d, 1H), 4.2 (t, 2H), 2.75 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.48 ( m, 2H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 712.4 (M ⁺ +1).
[558] Step B
[559] To a stirred solution of the adduct (71 mg, 0.098 mmol) produced in step A, in 2 mL EtOH / EtOAc / H ₂ O (7: 2: 1), 13 mg (1.2 equiv) of palladium black and ammonium formate (62 mg, 10 equivalents) The resulting mixture is heated at 80 ° C. and monitored by TLC. After 3 hours, the reaction mixture is cooled to room temperature and filtered through a pad of celite to remove the catalyst and the filtrate is partitioned between water and EtOAc. The organic phase is separated, dried over MgSO ₄ and concentrated in vacuo to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.01 (d, 1H), 6.8 (d, 2H), 6.75 (d, 2H), 6.66 (2 d, 4H), 6.54 (dd, 1H ), 6.5 (d, 1H), 5.45 (d, J = 2.3Hz, 1H), 4.28 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.68 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[560] Step C
[561] To a stirred solution of the mixture of the debenzylated product and HOAc (10 equiv) produced in step B in THF is added a solution of tetrabutylammonium fluoride (3 equiv) in THF at room temperature. The resulting solution is stirred for 2 h at rt, then poured into aqueous NaHCO ₃ and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO ₄ , filtered and evaporated. Purification by silica gel chromatography using 5-7% MeOH in methylene chloride as eluent affords the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.95 (d, 2H), 6.92 (d, 1H), 6.78 (d, 2H), 6.71 (d, 2H), 6.48 (d, 2H) , 6.47 (d, 1H), 6.44 (dd, 1H), 5.47 (d, J = 2.1 Hz, 1H), 4.37 (d, J = 2.1 Hz, 1H), 4.1 (t, 2H), 2.85 (t, 2H), 2.65 (br s, 4H), 1.66 (m, 4H), 1.5 (m, 2H).
[562] Example 72
[563] Chemical formula Preparation of the compound
[564] Step A
[565] Using the procedure as described in Example 71 (Step A), the dihydrobenzoxanthine obtained from Example 53 is coupled with 1-piperidineethanol. After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent, the desired adduct is obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.98 (d, 1H), 6.92 (d, 2H), 6.74 (2 d, 4H), 6.65 (d, 1H), 6.62 (d, 2H ), 5.5 (d, 1H), 5.1 (s, 2H), 4.31 (d, 1H), 4.09 (m, 2H), 2.75 (t, 2H), 2.55 (m, 2H), 2.5 (m, 4H) , 1.6 (m, 4H), 1.45 (m, 2H), 1.22 (m, 3H), 1.1 (m, 21H).
[566] Step B
[567] The adduct produced in step A is debenzylated using the procedure as described in Example 71 (step B) to afford the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.92 (d, 1H), 6.89 (d, 2H), 6.72 (d & d, 4H), 6.62 (d, 2H), 6.5 (d, 1H ), 5.5 (d, J = 2.2 Hz, 1H), 4.3 (d, J = 2.2Hz, 1H), 4.1 (m, 2H), 2.8 (t, 2H), 2.68 (m, 2H), 2.58 (br s, 4H), 1.64 (m, 4H), 1.48 (m, 2H), 1.2 (m, 3H), 1.09 (d & m, 21H).
[568] Step C
[569] The debenzylation product produced in step B is desilylated using the procedure as described in Example 71 (step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.0 (d, 2H), 6.79 (d, 2H), 6.76 (d, 1H), 6.71 (d, 2H), 6.47 (d, 3H) , 5.46 (d, J = 2.2Hz, 1H), 4.38 (d, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (m, 2H), 2.6 (m, 4H), 1.62 ( m, 4H), 1.5 (m, 2H), 1.1 (t, 3H); MS m / z 493.2 (M ⁺ +1).
[570] Example 73
[571] Chemical formula Preparation of the compound
[572] Step A
[573] Dihydrobenzoxanthine obtained from Example 45 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent, the desired adduct is obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14-6.92 (m, 4H), 6.8 (d, 2H), 6.76 (d, 2H), 6.72 (d, 2H), 6.64 (d, 2H ), 5.48 (d, J = 2.2 Hz, 1H), 4.34 (d, J = 2.1 Hz, 1H), 4.1 (m, 2H), 2.85 (m, 2H), 2.6 (m, 4H), 1.65 (m , 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[574] Step B
[575] The adduct produced in step A is desilylated using the procedure as described in Example 71 (step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14-6.92 (m, 4H), 6.06 (d, 2H), 6.78 (d, 2H), 6.72 (d, 2H), 6.48 (d, 2H), 5.48 (d, J = 2.1 Hz, 1H), 4.44 (d, 1H), 4.1 (t, 2H), 2.78 (t, 2H), 2.58 (br s, 4H), 1.64 (m, 4H) , 1.5 (m, 2 H); MS m / z 450.2 (M ⁺ +1).
[576] Example 74
[577] Chemical formula Preparation of the compound
[578] Step A
[579] Dihydrobenzoxanthine obtained from Example 46 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent, the desired adduct is obtained as an oil. ¹ H NMR (400 MHz, CDCl) δ (ppm): 7.14-6.94 (m, 4H), 6.96 (d, 2H), 6.84 (2 d, 4H), 6.66 (d, 2H), 5.5 (d, J = 2.1Hz, 1H), 5.12 (s, 2H), 4.5 (d, J = 2.1Hz, 1H), 4.04 (t, 2H), 3.42 (s, 3H), 2.75 (t, 2H), 2.55 ( br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 495.2 (M ⁺ +1).
[580] Step B
[581] The adduct (10 mg, 0.02 mmole) produced in step A is deprotected at room temperature with TFA (10 equiv) and MeOH (6 equiv) in CH ₂ Cl ₂ to afford the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14-6.92 (m, 4H), 6.84 (2 d, 4H), 6.66 (d, 2H), 6.6 (d, 2H), 5.45 ( d, J = 2.2Hz, 1H), 4.45 (d, J = 2.2Hz, 1H), 4.05 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H) , 1.5 (m, 2H); MS m / z 450.2 (M ⁺ +1).
[582] Example 75
[583] Chemical formula Preparation of the compound
[584] The dioxane derivative obtained from Example 47 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A) to afford the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.04 (d, 2H), 6.98-6.84 (m, 4H), 6.82 (d, 2H), 6.74 (d, 1H), 6.63 (d, 2H), 6.56 (d, 2H), 5.36 (d, 1H), 5.33 (d, J = 3.0 Hz, 1H), 4.02 (m, 2H), 2.8 (m, 2H), 2.6 (br s, 4H) , 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 432 (M ⁺ ).
[585] Example 76
[586] Chemical formula Preparation of the compound
[587] Step A
[588] Dihydrobenzoxanthine obtained from Example 49 is desilylated using the procedure as described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2 (d, 1H), 6.9 (d, 2H), 6.88 (d, 2H), 6.68 (m, 6H ), 5.53 (d, J = 2.2 Hz, 1H), 4.33 (d, J = 2.3 Hz, 1H), 3.75 (s, 3H).
[589] Step B
[590] The desilylation product obtained from step A is coupled with 1-piperidineethanol using the procedure as described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.08 (d, 1H), 6.9 (d, 2H), 6.84 (d, 2H), 6.76 (d, 2H ), 6.66 (m, 4H), 5.52 (d, 1H), 5.03 (s, 2H), 4.32 (d, 1H), 4.06 (t, 2H), 3.75 (s, 3H), 2.75 (t, 2H) , 2.5 (br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H).
[591] Step C
[592] The adduct produced in step B is debenzylated using the procedure as described in Example 71 (step B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.96 (d, 2H), 6.92 (d, 1H), 6.82 (d, 2H), 6.78 (d, 2H), 6.63 (d, 2H) , 6.48 (dd, 1H), 6.44 (d, 1H), 5.5 (d, J = 2.2 Hz, 1H), 4.42 (d, J = 2.2 Hz, 1H), 4.08 (t, 2H), 3.68 (s, 3H), 2.78 (t, 2H), 2.59 (br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H); MS m / z 479.4 (M ⁺ +1).
[593] Example 77
[594] Chemical formula Preparation of the compound
[595] Step A
[596] Dihydrobenzoxanthine obtained from Example 50 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.83 (d, 2H), 6.75 (d, 2H), 6.69 (d, 2H), 6.62 (d, 2H), 6.5 (d, 1H), 6.48 (d, 1H), 5.42 (br s, 1H), 4.3 (br s, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H ), 1.44 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[597] Step B
[598] The adduct generated in step A is debenzylated using the procedure as described in Example 71 (step B).
[599] Step C
[600] The debenzylation product obtained from step B is desilylated using the procedure as described in Example 71 (step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.76 (d, 2H), 6.7 (d, 2H), 6.49 (d, 2H), 6.4 (d, 1H) , 6.32 (d, 1H), 5.43 (d, J = 2.3Hz, 1H), 4.4 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.6 (br s , 4H), 2.18 (s, 3H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 479.2 (M ⁺ +1).
[601] Example 78
[602] Chemical formula Preparation of the compound
[603] Step A
[604] The dihydrobenzoxanthine obtained from Example 51 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[605] Step B
[606] The adduct generated in step A is debenzylated using the procedure as described in Example 71 (step B). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.9 (d, 2H), 6.89 (d, 1H), 6.73 (m, 4H), 6.62 (d, 2H), 6.52 (d, 1H), 5.5 (d, 1H), 4.3 (d, 1H), 4.1 (br s, 2H), 2.8 (br t, 2H), 2.6 (br s, 4H), 2.2 (s, 3H), 1.6 (m, 4H ), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[607] Step C
[608] The debenzylation product obtained from step B is desilylated using the procedure as described in Example 71 (step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.02 (d, 2H), 6.76 (d, 2H), 6.7 (d, 2H), 6.47 (2 d, 3H), 5.48 (d, J = 2.3Hz, 1H), 4.38 (d, J = 2.3Hz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 2.1 (s, 3H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 479.2 (M ⁺ +1).
[609] Example 79
[610] Chemical formula Preparation of the compound
[611] Step A
[612] Dihydrobenzoxanthine obtained from Example 53 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[613] Step B
[614] The adduct generated in step A is desilylated using the procedure as described in Example 71 (step B).
[615] Step C
[616] The debenzylation product obtained from step B is desilylated using the procedure as described in Example 71 (step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ , the desired product is obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.76 (d, 2H), 6.7 (2H, d), 6.48 (d, 2H), 6.41 (d, 1H) , 6.3 (d, 1H), 5.44 (d, J = 2.2Hz, 1H), 4.4 (d, J = 2.2Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s , 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 3H); MS m / z 493.2 (M ⁺ +1).
[617] Example 80
[618] Chemical formula Preparation of the compound
[619] Step A
[620] Dihydrobenzoxanthine obtained from Example 54 is coupled with 1-piperidineethanol using the procedure as described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 10H), 6.86 (d, 2h), 6.78 (d, 2H), 6.74 (d, 2H), 6.64 (d, 2H ), 6.38 (s, 2H), 5.48 (d, 1H), 5.14 (s, 2H), 5.02 (q, 2H), 4.32 (d, 1H), 4.08 (t, 2H), 2.8 (t, 2H) , 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[621] Step B
[622] The adduct produced in step A is debenzylated using the procedure as described in Example 71 (step B). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained as an oil.
[623] Step C
[624] The debenzylation product produced in step B is desilylated using the procedure as described in Example 71 (step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.94 (d, 2H), 6.78 (d, 2H), 6.72 (d, 2H), 6.5 (d, 2H), 6.06 (d, 1H) , 6.02 (d, 1H), 5.42 (d, J = 2.2Hz, 1H), 4.33 (d, J = 2.2Hz, 1H), 4.09 (t, 2H), 2.8 (t, 2H), 2.6 (br s , 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m / z 482.2 (M ⁺ +1).
[625] Example 81
[626] Chemical formula Preparation of the compound
[627] Step A
[628] The dihydrobenzoxanthine produced from Example 55 is desilylated using the procedure as described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) d (ppm): 7.48-7.32 (m, 5H), 7.2-7.1 (m, 4H), 6.94-6.84 (2 d, 4H), 6.7 (m, 4H) , 5.56 (d, J = 2.1 Hz, 1H), 5.04 (br q, 2H), 4.74 (s, 1H), 4.37 (d, J = 2.1 Hz, 1H).
[629] Step B
[630] The desilylation product produced in step A is coupled with 1-piperidineethanol using the procedure as described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.32 (m, 5H), 7.2-7.04 (m, 4H), 6.94-6.86 (m, 4H), 6.76-6.66 (m, 4H) , 5.54 (br s, 1H), 5.04 (br s, 2H), 4.38 (br s, 1H), 4.06 (t, 2H), 2.76 (t, 2H), 2.5 (br s, 4H), 1.6 (m , 4H), 1.42 (m, 2H).
[631] Step C
[632] The adduct produced in step B is debenzylated using the procedure as described in Example 71 (step B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.2-7.14 (m, 3H), 6.94 (m, 3H), 6.9 (d, 2H), 6.74 (d, 2H), 6.48 (dd, 1H), 6.45 (d, 1H), 5.53 (d, J = 2.3 Hz, 1H), 4.46 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.58 (br s, 4H) , 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ⁺ +1).
[633] Example 82
[634] Chemical formula Preparation of the compound
[635] Step A
[636] The dihydrobenzoxanthine produced from Example 56 is desilylated using the procedure as described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.96 (m, 2H), 6.92 (d, 1H), 6.88 (d , 2H), 6.84 (d, 1H), 6.74 (dd, 1H), 6.66 (d, 2H), 5.48 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.37 (d, J = 2.1 Hz, 1H); MS m / z 428.2 (M ⁺ +1).
[637] Step B
[638] The desilylation product produced in step A is coupled with 1-piperidineethanol using the procedure as described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[639] Step C
[640] The adduct produced in step B is debenzylated using the procedure as described in Example 71 (step B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14-7.02 (m, 3H), 6.92 (m, 4H), 6.8 (d, 1H), 6.74 (d, 2H), 6.58 (d, 1H), 6.51 (dd, 1H), 5.42 (br s, 1H), 4.45 (br s, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 ( m, 4H), 1.5 (m, 2H); MS m / z 449.2 (M ⁺ +1).
[641] Example 83
[642] Chemical formula Preparation of the compound
[643] Step A
[644] To a well stirred solution of dihydrobenzoxanthine (30 mg, 0.061 mmol) prepared from Example 74 (step A), meta-chlorobenzoic acid (m-CPBA) in methylene chloride is added at 0 ^° C. The ice bath is removed and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is quenched with NaHSO ₃ and stirred for an additional 30 minutes. The aqueous layer is extracted with EtOAc, the organic layer is washed with brine, dried over MgSO ₄ and then evaporated to give a residue, which is used in the next step without further purification. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.82 (dd, 1H), 7.67 (dt, 1H), 7.28 (m, 2H), 7.2 (d, 2H), 7.03 (d, 2H) , 6.92 (d, 2H), 6.82 (d, 2H), 6.32 (d, 1H), 5.12 (s, 2H), 4.84 (d, 1H), 4.2 (br t, 2H), 3.40 (s, 3H) , 3.2 (m, 2H), 3.0 (m, 4H), 1.75 (m, 4H), 1.6 (m, 2H).
[645] Step B
[646] The MOM protection group is removed by performing the procedure as described in Example 74 (Step B). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.82 (dd, 1H), 7.64 (dt, 1H), 7.26 (m, 2H), 7.04 (d, 2H), 6.06 (d, 2H) , 6.76 (d, 2H), 6.65 (d, 2H), 6.24 (d, J = 1.9 Hz, 1H), 4.71 (d, 1H), 4.1 (t, 2H), 2.72 (t, 2H), 2.5 ( br s, 4H), 1.6 (m, 4H), 1.45 (m, 2H); MS m / z 481.1 (M ⁺ +1).
[647] Example 84
[648] Chemical formula Preparation of the compound
[649] Step A
[650] To a well stirred solution of dihydrobenzoxanthine (60 mg) prepared from Example 73 (step A), 5 equivalents of m-CPBA in CH ₂ Cl ₂ are added at 0 ^° C. The ice bath is removed and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is quenched with saturated solution of NaHSO ₃ and saturated NaHCO ₃ and stirred for a further 30 minutes. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine and dried over MgSO ₄ . The solvent is removed by evaporation to give an oily residue which is purified by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent to afford the pure product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.85 (dd, 1H), 7.66 (m, 1H), 7.28 (m, 2H), 7.12 (d, 2H), 6.86 (d, 2H) , 6.8 (d, 2H), 6.7 (d, 2H), 6.22 (d, J = 2.1 Hz, 1H), 4.72 (d, J = 2.3Hz, 1H), 4.08 (m, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H); MS m / z 637 (M ⁺ +23).
[651] Step B
[652] The silyl protecting group is removed by carrying out the procedure as described in Example 71 (step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ , the desired product is separated. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.81 (dd, 1H), 7.64 (m, 1H), 7.35 (m, 2H), 7.2 (d, 2H), 6.82 (2 d, 4H), 6.6 (d, 2H), 6.28 (d, J = 2.2Hz, 1H), 4.69 (d, J = 2.2Hz, 1H), 4.2 (t, 2H), 3.08 (t, 2H), 2.85 ( br s, 4H), 1.7 (m, 4H), 1.55 (m, 2H).
[653] Example 85
[654] Chemical formula Preparation of the compound
[655] Step A
[656] Using the procedure described in Example 83 (Step A), the dihydrobenzoxanthine (20 mg, 0.028 mmol) obtained from Example (Step A) was oxidized by m-CPBA at room temperature. The crude material is used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.84 (d, 1H), 7.7-7.4 (m, 5H), 7.02 (d, 2H), 6.88 (dd, 1H), 6.82 (d, 2H ), 6.76 (2 d, 4H), 6.72 (d, 1H), 6.22 (d, J = 2.2 Hz, 1H), 5.18 (q, 2H), 4.28 (d, J = 2.1 Hz, 1H), 4.09 (t, 2H), 2.8 (t, 2H), 2.55 (br s, 4H), 1.63 (m, 4H), 1.48 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[657] Step B
[658] The product from Step A was deblocked using the standard procedure described in Example 71 (Step B) to give a debenzylated product, which was used without further purification.
[659] Step C
[660] The silyl protecting group is removed by carrying out the procedure as described in Example 71 (step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the final product is isolated. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.62 (d, 1H), 7.14 (d, 2H), 6.84 (2 d, 4H), 6.68 (dd, 1H), 6.6 (d, 2H), 6.55 (d, 1H), 6.22 (d, 1H), 4.55 (d, J = 2.1 Hz, 1H), 4.1 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H) , 1.64 (M, 4H), 1.5 (M, 2H); MS m / z 496.1 (M ⁺ +1).
[661] Example 86
[662] Chemical formula Preparation of the compound
[663] Step A
[664] To a solution of dihydrobenzoxanthine (100 mg, 0.167 mmol) produced in Example 48 in CH ₂ Cl ₂ , triethylamine (0.07 mL), catalytic amount of N, N-dimethylaminopyridine (DMAP) and acetic anhydride ( 0.034 mL, 2 equivalents) is added at room temperature. The resulting mixture is stirred for 30 minutes and then poured into saturated NaHCO ₃ . The aqueous layer is extracted with CH ₂ Cl ₂ and then dried over anhydrous Na ₂ SO ₄ . The solvent is evaporated to give an oil which is subjected to silica gel chromatography using 10% EtOAc / hexane as eluent to afford the product. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48-7.34 (m, 5H), 7.08 (d, 1H), 6.99 (d, 2H), 6.94 (d, 2H), 6.76 (d, 2H ), 6.72-6.67 (m, 4H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.34 (d, 1H), 2.3 (d, 3H), 1.22 (m, 3H), 1.1 (d , 18 H).
[665] Step B
[666] The silyl protecting group is removed by carrying out the procedure as described in Example 71 (step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is separated. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48-7.34 (m, 5H), 7.09 (d, 1H), 7.04 (d, 2H), 6.98 (d, 2H), 6.78 (d, 2H ), 6.7 (m, 2H), 6.59 (d, 2H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.74 (s, 1H), 4.36 (d, 1H), 2.2 (s, 3H ).
[667] Step C
[668] The desilylation product (80 mg, 0.165 mmol) obtained from step B is subjected to the procedure as described in Example 71 (step A) to couple with 1-piperidineethanol. After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent, the desired product is separated. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48-7.34 (m, 5H), 7.08 (d, 1H), 7.04 (d, 2H), 6.98 (d, 2H), 6.82 (d, 2H ), 6.7 (dd, 1H), 6.68 (d, 1H), 6.68 (d, 2H), 5.58 (d, J = 2.2 Hz, 1H), 5.05 (br q, 2H), 4.36 (d, J = 2.2 Hz, 1H), 4.05 (t, 2H), 2.68 (t, 2H), 2.5 (br s, 4H), 2.25 (s, 3H), 1.6 (m, 4H), 1.45 (m, 2H); MS m / z 597.3 (M ⁺ +1).
[669] Step D
[670] To a solution of 10 mg (0.017 mmol) of the adduct produced from Step C in dry THF is added 4 equivalents of a 1.0 M super hydride solution in THF. The resulting mixture is stirred for 2 h at 0 ° C. and then warmed to rt (30 min). The reaction mixture is hydrolyzed with H ₂ O / NaHCO ₃ . The aqueous layer is extracted with EtOAc, the organic layer is separated, dried and evaporated to give an oil which is used in the next step without further purification.
[671] Step E
[672] The crude product from step D was deblocked using the standard procedure described in Example 71 (step B), purified by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, and then final Obtain the product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.92 (d, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 6.65 (d, 2H), 6.58 (d, 2H) , 6.46 (dd, 1H), 6.42 (d, 1H), 5.44 (d, J = 2.1 Hz, 1H), 4.38 (d, 1H, J = 2.3Hz, 1H), 4.04 (t, 2H), 2.78 ( t, 2H), 2.6 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 465 (M ⁺ +1).
[673] Example 87
[674] Chemical formula Preparation of the compound
[675] Step A
[676] The desilylation product obtained from Example 57 is subjected to the procedure as described in Example 71 (Step A) to couple with 1-pyriridineethanol. After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent, the desired product is separated.
[677] Step B
[678] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B) to afford the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.98-6.76 (m, 9H), 6.5 (dd, 1H), 6.46 (d, 1H), 5.52 (d, J = 2.3 Hz, 1H) , 4.5 (d, 1H), 4.05 (t, 2H), 2.80 (t, 2H), 2.62 (br s, 4H), 1.62 (m, 4H), 1.5 (m, 2H); MS m / z 466.2 (M ⁺ ).
[679] Example 88
[680] Chemical formula Chiral separation of
[681] The racemic dihydrobenzoxanthine obtained in Example 81 (step C) is partitioned via chiral chromatography on a Chiralpak AD column using 20% EtOH in hexane as eluent.
[682] Fast moving isomers: [a] _D = +33.43 ^o (c = 1.205, MeOH).
[683] Slow moving isomers: [a] _D = -34.2 ^o (c = 1.09, MeOH).
[684] Example 89
[685] Chemical formula Chiral separation of
[686] The racemic dihydrobenzoxanthine obtained in Example 82 (step C) is partitioned via chiral chromatography on a Chiralpak AD column using 20% EtOH in hexane as eluent.
[687] Fast moving isomers: [a] _D = +32.4 ^o (c = 1.36, MeOH).
[688] Slowly moving isomers: [a] _D = -31.3 ^o (c = 1.37, MeOH).
[689] Example 90
[690] Chemical formula Preparation of the compound
[691] Dihydrobenzoxanthine from Example 58 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.85 (2d, 4H), 6.68 (d, 2H), 6.55 (d , 2H), 5.55 (d, 1H), 5.04 (s, 2H), 4.40 (d, 1H).
[692] Step B
[693] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[694] Step C
[695] The adduct (80 mg, 0.144 mmol), 20 mg of palladium black and 5 drops of AcOH in 4 mL of ethanol are stirred under a hydrogen gas balloon and monitored by TLC. After 18 hours, the reaction mixture is filtered through a pad of celite to remove the catalyst, the filtrate is neutralized by the addition of saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer is separated, dried over MgSO ₄ and concentrated in vacuo to afford the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.20-7.02 (m, 3H), 6.92 (m, 4H), 6.78 (d, 2H), 6.30 (d, 2H), 5.55 (d, J = 2.1 Hz, 1H), 4.50 (d, J = 2.3Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 467 (M ⁺ +1).
[696] Example 91
[697] Chemical formula Preparation of the compound
[698] Step A
[699] The dihydrobenzoxanthine produced from Example 59 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.90 (d, 1H), 6.85 (d , 2H), 6.70 (d, 2H), 6.65 (d, 1H), 5.50 (d, 1H), 5.04 (s, 2H), 4.42 (d, 1H).
[700] Step B
[701] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[702] Step C
[703] The adduct produced in step B is debenzylated using the procedure described in Example 71 (step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.14-7.02 (m, 3H), 6.92 (d, 2H), 6.85 (d, 2H), 6.74 (d, 2H), 6.58 (d, 1H), 6.41 (d, 1H), 5.52 (d, J = 2.3Hz, 1H), 4.55 (d, J = 2.3Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 ( br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).
[704] Example 92
[705] Chemical formula Preparation of the compound
[706] Step A
[707] The dihydrobenzoxanthine obtained from Example 60 is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.80 (d, 2H), 6.70 (2d, 4H), 6.60 (d, 2H), 6.40 (2d, 2H ), 5.40 (s, 1H), 4.90 (d, 2H), 4.20 (s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H ), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[708] Step B
[709] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B).
[710] Step C
[711] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.93 (d, 3H), 6.78 (d, 2H), 6.69 (d, 2H), 6.50 (d, 2H), 6.28 (m, 1H) , 5.46 (d, J = 1.8Hz, 1H), 4.39 (d, J = 2.2Hz, 1H), 4.05 (t, 2H), 2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (m , 4H), 1.5 (m, 2H); MS m / z 482.2 (M ⁺ +1).
[712] Example 93
[713] Chemical formula Preparation of the compound
[714] Step A
[715] The dihydrobenzoxanthine obtained from Example 61 is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.85 (m, 3H), 6.70 (d, 4H), 6.63 (d, 2H), 6.60 (d, 1H ), 5.42 (s, 1H), 5.02 (d, 2H), 4.40 (s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H ), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[716] Step B
[717] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B) to afford the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.82 (d, 2H), 6.78 (d, H), 6.70 (2d, 4H), 6.62 (d, 2H), 6.58 (d, 1H) , 5.40 (d, 1H), 4.30 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H) ; MS m / z 655 (M ⁺ +1).
[718] Step C
[719] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.92 (d, 2H), 6.75 (d, 2H), 6.68 (d, 2H), 6.60 (d, 1H), 6.50 (d, 2H), 6.42 (d, 1H), 5.42 (d, J = 2.2Hz, 1H), 4.42 (d, J = 2.3Hz, 1H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (brs, 4H ), 1.62 (m, 4H), 1.48 (m, 2H); MS m / z 499 (M ⁺ +1).
[720] Example 94
[721] Chemical formula Preparation of the compound
[722] Step A
[723] Dihydrobenzoxanthine obtained from Example 62 is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[724] Step B
[725] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B).
[726] Step C
[727] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained as a white solid. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 7.04 (d, 2H), 6.90 (dd, 3H), 6.72 (d, 2H), 6.64 (d, 1H), 6.59 (d, 2H ), 6.57 (dd, 1H), 5.44 (d, J = 2.3 Hz, 1H), 4.52 (d, J = 2.1 Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ +1).
[728] Example 95
[729] Chemical formula Preparation of the compound
[730] Step A
[731] The dihydrobenzoxanthine obtained from Example 63 is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[732] Step B
[733] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B).
[734] Step C:
[735] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained as a white solid. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 7.00 (d, 2H), 6.85 (s, 1H), 6.80 (d, 2H), 6.78 (d, 2H), 6.59 (d, 2H ), 6.52 (s, 1H), 5.49 (d, J = 2.3 Hz, 1H), 4.65 (d, J = 2.2 Hz, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 479 (M ⁺ +1).
[736] Example 96
[737] Chemical formula Preparation of the compound
[738] Step A
[739] The dihydrobenzoxanthine obtained from Example 64 is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.20 (s, 1H), 6.85 (d, 2H), 6.70 (2d, 4H), 6.63 (d, 2H ), 6.60 (s, 1H), 5.42 (s, 1H), 5.02 (q, 2H), 4.30 (s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H ), 1.62 (m, 4H), 1.5 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
[740] Step B
[741] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B) to afford the desired product. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 7.10 (s, 1H), 6.98 (d, 2H), 6.82 (d, 2H), 6.78 (d, 2H), 6.70 (d, 2H ), 6.68 (s, 1H), 5.50 (d, 1H), 4.50 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H ), 1.5 (m, 2H).
[742] Step C
[743] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 7.12 (s, 1H), 7.02 (d, 2H), 6.80 (dd, 4H), 6.69 (s, 1H), 6.60 (d, 2H ), 6.42 (d, 1H), 5.55 (d, J = 2.3 Hz, 1H), 4.54 (d, J = 2.1 Hz, 1H), 4.07 (t, 2H), 2.78 (t, 2H), 2.55 (brs , 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m / z 499 (M ⁺ +1).
[744] Example 97
[745] Chemical formula Preparation of the compound
[746] Step A
[747] The dihydrobenzoxanthine produced from Example 65 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 5H), 6.95 (m, 3H), 6.64-6.70 (m, 2H), 5.46 (d, J = 1.8 Hz, 1H), 5.04 (s, 2H), 4.42 (d, J = 2.0 Hz, 1H).
[748] Step B
[749] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[750] Step C
[751] The adduct produced in step B is debenzylated using the procedure described in Example 71 (step B) to afford the desired product. ¹ H NMR (500 MHz, CD ₃ OD) d (ppm: 7.00-7.12 (m, 6H), 6.90 (d, 2H), 6.75 (d, 2H), 6.42 (s, 1H), 5.42 (d, J = 2.1 Hz, 1H), 4.48 (d, J = 2.3Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 ( m, 2H); MS m / z 463 (M ⁺ +1).
[752] Example 98
[753] Chemical formula Preparation of the compound
[754] Step A
[755] The dihydrobenzoxanthine produced from Example 66 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.95 (d, 2H), 6.92 (d, 2H), 6.90 (d , 1H), 6.78 (d, 1H), 6.70 (d, 2H), 5.52 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.46 (d, J = 2.2 Hz, 1H).
[756] Step B
[757] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[758] Step C
[759] The adduct produced in step B is debenzylated using the procedure described in Example 71 (step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05-7.15 (m, 5H), 6.90 (d, 2H), 6.79 (d, 2H), 6.65 (d, 1H), 6.55 (d, 1H), 5.50 (d, J = 2.1 Hz, 1H), 4.62 (d, J = 2.3Hz, 1H), 4.10 (t, 2H), 2.80 (t, 2H), 2.60 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).
[760] Example 99
[761] Chemical formula Preparation of the compound
[762] Step A
[763] The dihydrobenzoxanthine produced from Example 67 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 7.08 (s, 1H), 6.95 (d, 2H), 6.86 (m , 3H), 6.70 (d, 2H), 5.42 (d, J = 2.1 Hz, 1H), 5.14 (s, 2H), 4.40 (d, J = 2.0 Hz, 1H).
[764] Step B
[765] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[766] Step C
[767] The adduct produced in step B is debenzylated using the procedure described in Example 71 (step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05-7.15 (m, 3H), 6.95 (m, 3H), 6.90 (d, 2H), 6.75 (d, 2H), 6.72 (s, 1H), 5.45 (d, J = 2.0Hz, 1H), 4.52 (d, J = 2.3Hz, 1H), 4.10 (t, 2H), 2.80 (t, 2H), 2.60 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).
[768] Example 100
[769] Chemical formula Preparation of the compound
[770] Step A
[771] The dihydrobenzoxanthine produced from Example 68 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H), 6.92-6.80 (m, 5H), 6.78 (d, 2H), 6.70 (d, 2H), 5.40 (d, J = 2.1 Hz, 1H), 5.20 (s, 2H), 4.46 (d, J = 2.0 Hz, 1H).
[772] Step B
[773] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[774] Step C
[775] The adduct produced in step B is debenzylated using the procedure described in Example 71 (step B) to afford the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 7.05-7.15 (m, 3H), 6.95 (d, 2H), 6.90 (d, 2H), 6.80 (d, 1H), 6.75 (d, 2H), 6.70 (d, 1H), 5.38 (d, J = 1.8 Hz, 1H), 4.56 (d, J = 2.1 Hz, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.60 ( br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS m / z 483 (M ⁺ +1).
[776] Example 101
[777] Chemical formula Chiral separation of
[778] The racemic dihydrobenzoxanthine obtained in Example 100 (step C) is partitioned via chiral chromatography on a Chiralpak AD column using 20% EtOH in hexane as eluent.
[779] Fast moving isomers: [a] _D = +26.09 ^o (c = 1.025, MeOH).
[780] Slow moving isomers: [a] _D = -25.44 ^o (c = 0.95, MeOH).
[781] Example 102
[782] Chemical formula Preparation of the compound
[783] Step A
[784] The dihydrobenzoxanthine produced from Example 69 is desilylated using the procedure described in Example 71 (Step C). The desired product is obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 7.5-7.3 (m, 5H), 6.95 (d, 2H), 6.90 (m, 3H), 6.85 (m, 3H), 6.74 (dd, 1H ), 6.70 (d, 2H), 5.45 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 4.35 (d, J = 2.1 Hz, 1H).
[785] Step B
[786] The desilylation product obtained from step A is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained, which is used without further purification.
[787] Step C
[788] The adduct produced in step B is debenzylated using the procedure described in Example 71 (step B) to give the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ (ppm): 6.98 (d, 2H), 6.94 (m, 2H), 6.80 (m, 5H), 6.60 (d, 1H), 6.75 (dd, 1H) , 5.40 (d, J = 1.8Hz, 1H), 4.50 (d, J = 2.1Hz, 1H), 4.08 (t, 2H), 2.78 (t, 2H), 2.60 (br s, 4H), 1.6 (m , 4H), 1.5 (m, 2H); MS m / z 466 (M ⁺ +1).
[789] Example 103
[790] Chemical formula Chiral Preparation of the (+) Isomers of
[791] Step A
[792] The fast moving (+)-dihydrobenzoxatin obtained in Example 70 is coupled to 1-piperidineethanol using the procedure described in Example 71 (step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[793] Step B
[794] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B).
[795] Step C
[796] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained as a white solid. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1H ), 6.50 (d, 1H), 6.48 (d, 2H), 5.38 (d, J = 2.0 Hz, 1H), 4.38 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t , 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ +1); [a] _D = +27.68 ^o (c = 0.49, MeOH).
[797] Example 104
[798] Chemical formula Chiral Preparation of (-) Isomers of
[799] Step A
[800] The slow moving (-)-dihydrobenzoxanthine obtained from Example 70 is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ , the desired adduct is obtained.
[801] Step B
[802] The adduct produced in step A is debenzylated using the procedure described in Example 71 (step B).
[803] Step C
[804] The debenzylation product from Step B is desilylated using the procedure described in Example 71 (Step C). After purification by silica gel chromatography using 5% MeOH / CH ₂ Cl ₂ as eluent, the desired product is obtained as a white solid. ¹ H NMR (500 MHz, Acetone-d ₆ ) δ (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70 (d, 2H), 6.60 (d, 1H ), 6.50 (d, 1H), 6.48 (d, 2H), 5.38 (d, J = 2.0 Hz, 1H), 4.38 (d, J = 2.3Hz, 1H), 4.08 (t, 2H), 2.8 (t , 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 2H); MS m / z 465 (M ⁺ +1); [a] _D = -26.33 ^o (c = 0.515, MeOH).
[805] Example 105
[806] Chemical formula General Preparation of Compounds
[807] Phase A: Reductive Closure
[808] 68 μL (0.087 mmol) pure trifluoroacetic acid (TFA) in a solution stirred at −23 ° C. under N ₂ atmosphere of cyclopentyl-thio-ketone 102.2 mg (0.17 mmole) produced in Example 41 in 1 ml of dichloromethane. Add. To the reaction mixture stirred at −23 ° C., 41.4 μL (0.259 mmol) of pure triethylsilane are slowly added and the resulting mixture is stirred for an additional 3 hours. The reaction mixture is partitioned between ethyl acetate / saturated NaHCO ₃ / ice / brine, the organic phase is separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography using methylene chloride / hexane (1: 1) as eluent to afford cis-cyclopentyl-dihydrobenzoxatin derivatives. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.12 (d, 18H), 1.26-2.12 (m, 12H), 2.5 (m, 1H), 4.24 (d, 1H), 4.9 (m, 2H), 6.8-7. 69 (m, 12 H).
[809] Starting from the cyclohexyl derivative prepared in Example 41 and using the above procedure, the corresponding cis-cyclohexyl-benzoxatin was prepared after purification by silica gel chromatography using methylene chloride-hexane (1: 1). do. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.11-1.9 (m, 14H), 3.2 (t, 1H), 5.03 (s, 2H), 5.44 (d, J = 2.5 Hz, 1H), 6.66-7.47 (m, 12H).
[810] Step B: Desilylation
[811] To a stirred solution of 89.6 mg (0.156 mmole) of the cis-cyclopentyl derivative prepared in Step A in THF at 0 ° C., sequentially, 13.3 μL of acetic acid (0.234 mmol) and 171 μL of tetrabutylammonium fluoride (0.171 mmol) in THF 1M solution) is stirred. The mixture is stirred at 0 ° C. for 0.5 h and then partitioned between ethyl acetate / 2N HCl / ice / brine, the organic phase is separated, washed with brine and then with anhydrous sodium sulfate. Dry, filter and evaporate. The residue is purified by silica gel chromatography using methylene chloride / ethyl acetate (50: 1) as eluent to afford phenol derivatives. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.32-1.94 (m, 9H), 3.51 (dd, J = 5.5, 2.5 Hz, 1H), 5.03 (s, 2H), 5.42 (d, J = 2.3 Hz, 1H), 6.67-7.47 (m, 12H).
[812] Starting from the cyclohexyl derivatives prepared in the above examples and using the above procedure, the corresponding cis-cyclohexyl-benzoxatin phenols are prepared. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.11-1.93 (m, 11H), 3.23 (t, J = 3 Hz, 1H), 5.03 (s, 2H), 5.44 (d, J = 2.3 Hz, 1H ), 6.66-7.47 (m, 12H).
[813] Step C: Mitsunobu Reaction
[814] 0 of a mixture of 56.3 mg (0.135 mmol) of cis-cyclopentyl derivative, 53.6 μL (0.404 mmol) of 1-piperidineethanol and 123.5 mg (0.47 mmol) of triphenylphosphine in 1 mL of dry THF. ^o To the stirred solution at C, add 87.4 μL (0.444 mmol) of pure diisopropylazodicarboxylate (DIAD). The ice-water bath is removed and the mixture is stirred for an additional 6 hours. The mixture is partitioned between ethyl acetate / 2N HCl / ice / brine, the organic phase is separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using ethyl acetate-methanol (9: 1) as eluent to afford the adduct. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.33-2.0 (m, 15H), 2.56 (m, 4H), 2.82 (t, J = 6Hz, 2H), 3.51 (dd, J = 5.4, 2.4Hz , 1H), 4.16 (t, J = 6 Hz, 2H), 5.02 (s, 2H), 5.42 (d, J = 2.3 Hz, 1H), 6.66-7.46 (m, 12H).
[815] Starting from the cyclohexyl derivatives prepared in the above examples and using the above procedure, the corresponding cis-cyclohexyl-benzoxatin adducts are prepared. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.11-1.93 (m, 17H), 2.6 (m, 4H), 2.87 (m, 2H), 3.2 (d, J = 2.5Hz, 1H), 4.2 ( m, 2H), 5.02 (s, 2H), 5.44 (d, J = 2.1 Hz, 1H), 6.65-7.46 (m, 12H).
[816] Step D: Debenzylation:
[817] 36.6 mg (0.0069 mmol) of cis-cyclopentyl derivative prepared in Step C, 14.7 mg (0.014 mmol) of palladium black and 87.1 mg (0.138) of ammonium formate in 2 mL of ethanol-ethyl acetate-water (7: 2: 1) The stirred mixture of mmole) is heated at 80 ° C. for 2 hours. The mixture was filtered through celite and washed well with ethyl acetate, the filtrate was partitioned between ethyl acetate / saturated sodium bicarbonate / brine, the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate and filtered Then evaporate. The residue is purified by silica gel chromatography using ethyl acetate-methanol (9: 1) as eluent to afford the final product. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.33-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.48 (t, J = 2.3 Hz, 1H), 4.18 ( m, 2H), 5.38 (d, J = 2.3 Hz, 1H), 6.5 (m, 1H), 6.63 (d, 2.9 Hz, 1H) 6.74 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), and 7.34 (d, J = 8.7 Hz, 2H).
[818] Starting from the cyclohexyl derivatives prepared in the above examples and using the above procedure, the corresponding cis-cyclohexyl-benzoxatin adducts are prepared. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.00-1.90 (m, 18H), 2.6 (m, 4H), 2.81 (t, 2H), 3.19 (t, J = 3.0 Hz, 1H), 4.18 ( m, 2H), 5.38 (d, J = 2.3 Hz, 1H), 6.43 (m, 1H), 6.62 (d, J = 3.0 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.87 ( d, J = 8.7 Hz, 2H), and 7.34 (d, J = 8.7 Hz, 2H); MS m / z 454 (M ⁺ ).
[819] Example 106
[820] Chemical formula Preparation of the compound
[821] Phase A: Reductive Closure
[822] Starting from the isopropyl adduct (0.0208 g, 0.049 mmol) prepared in Example 42 and using the procedure described in Example 105 (step A), the crude product was isolated after stirring at −23 ° C. for 6 hours 20 minutes. do. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent affords the desired product as a yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.95 (d, 3H), 0.98 (d, 3H), 1.95 (m, 1H), 3.30 (t, J = 3 Hz, 1H), 5.03 (s, 2H), 5.42 (d, J = 2.6 Hz, 1H), 6.66-7.47 (m, 12H).
[823] Step B: Mitsunobu Reaction
[824] The dihydrobenzoxanthine prepared in step A was coupled with 1-piperidineethanol using the procedure described in Example 105 (step C) except that the reaction was slowly warmed from 0 ° C. to ambient temperature over 3.5 hours. Ring. Purification by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent affords the desired product as a pale yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.30 (t, J = 3 Hz, 1H), 4.20 (t, 2H), 5.03 (s, 2H), 5.42 (d, J = 2.6 Hz, 1H), 6.66-7.49 (m , 12H).
[825] Step C: Debenzylation
[826] Starting from the compound prepared in step B and using the procedure described in Example 105 (step D), silica gel chromatography was performed using 10% MeOH / CH ₂ Cl ₂ as eluent and the corresponding cis-isopropyl. Prepare benzoxatin adducts. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95 (m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.26 (t, J = 3.0 Hz, 1H), 4.20 (t, 2H), 5.37 (d, J = 2.5 Hz, 1H), 6.47 (dd, 1H), 6.65 (d, J = 3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), and 7.35 (d, J = 8.7 Hz, 2H); MS m / z 414 (M ⁺ ).
[827] Example 107
[828] Chemical formula Preparation of the compound
[829] Phase A: Reductive Closure
[830] Starting from the 2-thiophene adduct prepared in Example 43 (0.0208 g, 0.049 mmol) and slightly modifying the procedure described in Example 105 (step A), the mixture was stirred at 0 ° C. for 1 hour and 40 minutes. The crude product is then separated. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent affords the desired product as a red oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.11 (d, 18H), 1.24 (m, 3H), 4.67 (d, J = 2.0 Hz, 1H), 5.50 (d, J = 1.8 Hz, 1H) , 6.60-7.12 (m, 10 H).
[831] Step B: Protection by MOM
[832] To a solution of dihydrobenzoxanthine (0.0629 g, 0.13 mmol) prepared in Step A above in distilled THF (1 mL) add 60% NaH in mineral oil (0.0090 g, 0.19 mmol) at 0 ° C. under N ₂ . After gas evolution has ceased, MOMCl (0.013 mL, 0.16 mmol) is added dropwise to the reaction. After 30 minutes, an additional 1.3 equivalents of MOMCl is added to the reaction. According to TLC, the reaction ends within 5 minutes. The resulting dark red solution is partitioned between EtOAc and ice / H ₂ O. The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The desired product is used in the subsequent reaction without purification. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.11 (d, 18H), 1.24 (m, 3H), 3.52 (s, 3H), 4.67 (d, J = 2.1 Hz, 1H), 5.14 (m, 2H), 5.50 (d, J = 1.8 Hz, 1H), 6.60-7.12 (m, 10H).
[833] Step C: Desilylation
[834] The dihydrobenzoxanthine prepared in step B above was desilylated using the procedure described in Example 105 (step B), silica gel chromatography using 30% EtOAc / hexane as eluent and the desired product were carried out. Obtained as a colorless oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 3.52 (s, 3H), 4.69 (d, J = 1.8 Hz, 1H), 5.15 (m, 2H), 5.51 (d, J = 1.8 Hz, 1H) , 6.60-7.15 (m, 10 H).
[835] Step D: Mitsunobu Reaction
[836] The procedure described in Example 105 (step C) was carried out except that the reaction was warmed over 4 hours at 0 ° C. to ambient temperature to convert the material prepared in the previous step to the desired product, and silica gel chromatography (Elution once with 30% EtOAc / hexanes, then second with 10% MeOH / CH ₂ Cl ₂ ). ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.40-2.60 (m, 10H), 2.79 (t, 2H), 3.52 (s, 3H), 4.10 (t, 2H), 4.69 (d, J = 1.8 Hz, 1H), 5.15 (m, 2H), 5.51 (d, J = 1.8 Hz, 1H), 6.60-7.15 (m, 10H).
[837] Step E: Deprotection of MOM
[838] A mixture of the material prepared in step D (0.0401 g, 0.080 mmol) and 2 N HCl (0.20 mL, 0.40 mmol) in MeOH (1.0 mL) is heated at 60 ° C. for 2.5 h under N ₂ . The reaction is partitioned between EtOAc and ice / saturated NaHCO ₃ . The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is triturated with Et ₂ O and the desired product is obtained as a white solid. ¹ H 500 MHz NMR (d ₆ -acetone + CD ₃ OD) ppm (δ): 1.50-3.19 (m, 10H), 3.23 (t, 2H), 4.30 (t, 2H), 5.00 (d, J = 1.8 Hz , 1H), 5.51 (d, J = 1.8 Hz, 1H), 6.57-7.25 (m, 10H); MS m / z 454 (M ⁺ )
[839] Example 108
[840] Chemical formula Preparation of the compound
[841] Phase A: Reductive Closure
[842] The procedure as described in Example 44 was carried out and 0.0792 g of 3-pyridyl derivative prepared in 44, Example 41 was stirred at ambient temperature for 5 hours before conversion to the corresponding benzoxatin. Chromatography on silica gel using 30% EtOAc / hexane as eluent then separates the desired product from the reaction mixture. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.11 (d, 18H), 1.24 (m, 3H), 4.36 (d, J = 2.1 Hz, 1H), 5.05 (s, 2H), 5.50 (d, J = 1.6 Hz, 1H), 6.77-8.43 (m, 16H).
[843] Step B: Desilylation
[844] The procedure as described in Example 105 (Step B) was followed to desilylate the dihydrobenzoxanthine prepared in Step A, eluted once with silica gel chromatography (50% EtOAc / hexanes, then 30%). Elution with EtOAc / hexanes) to afford the desired product. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 4.42 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 5.50 (d, J = 1.6 Hz, 1H), 6.77-8.43 (m, 16H).
[845] Step C: Mitsunobu Reaction
[846] The procedure prepared in Example 105 (step C) was carried out except that the reaction was warmed from 0 ° C. to ambient temperature over 4 hours to give 10% MeOH / CH ₂ Cl ₂ as the eluent. Use as a chromatograph on silica gel and then convert to the desired product. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.38 (d, J = 1.8 Hz, 1H), 5.07 ( s, 2H), 5.50 (d, J = 1.8 Hz, 1H), 6.77-8.43 (m, 16H).
[847] Step D: Debenzylation
[848] Starting from the material prepared in step C above and using the procedure described in Example 105 (step D), silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent followed by the corresponding cis-3- Prepare pyridyl-dihydrobenzoxatin adducts. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.36 (d, J = 2.1 Hz, 1H), 5.45 ( d, J = 1.9 Hz, 1H), 6.59-8.43 (m, 11H); MS m / z 449 (M ⁺ ).
[849] Example 109
[850] Chemical formula Preparation of the compound
[851] Phase A: Reductive Closure
[852] The procedure as described in Example 44 is carried out to 0.1871 g of the 4-pyridyl derivative prepared in Example 41 is stirred at ambient temperature for 30 minutes and then converted to its corresponding dihydrobenzoxatin. Silica gel chromatography using 30% EtOAc / hexane as eluent then separates the desired product from the reaction mixture. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.11 (d, 18H), 1.24 (m, 3H), 4.32 (d, 1H), 5.08 (s, 2H), 5.50 (d, 1H), 6.60- 8.39 (m, 16 H).
[853] Step B: Desilylation
[854] The procedure as described in Example 105 (step B) was carried out to desilylate the dihydrobenzoxanthine produced in step A, eluted once with silica gel chromatography (50% EtOAc / hexanes, then 30%). Eluting with EtOAc / hexanes) to afford the desired product. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 4.33 (d, 1H), 5.07 (s, 2H), 5.46 (d, 1H), 6.63-8.37 (m, 16H).
[855] Step C: Mitsunobu Reaction
[856] The procedure prepared in Example 105 (step C) was carried out except that the reaction was warmed from 0 ° C. to ambient temperature over 5 hours, and the material prepared in the previous step was chromatographed on silica gel (10% MeOH / CH). Eluting once with ₂ Cl ₂ , then eluting with 20% EtOAc / CH ₂ Cl ₂ ) and converting to the desired product. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.40-2.60 (m, 10H), 2.80 (t, 2H), 4.14 (t, 2H), 4.32 (d, J = 3.0 Hz, 1H), 5.06 ( s, 2H), 5.49 (d, J = 2.1 Hz, 1H), 6.79-8.38 (m, 16H).
[857] Step D: Debenzylation
[858] Starting from the material prepared in step C and using the procedure described in Example 105 (step D), chromatography on silica gel (eluted once with 30% EtOAc / hexanes and then 10% MeOH / CH ₂ Cl ₂ Eluting with a second time) to afford the desired product as a 4: 1 cis / trans mixture.
[859] Cis isomer: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.10 (t, 2H), 4.30 (d, J = 2.0 Hz, 1H) , 5.44 (d, J = 1.8 Hz, 1 H), 6.59-8.40 (m, 11 H).
[860] Trans isomer: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.40-2.70 (m, 10H), 2.80 (t, 2H), 4.15 (t, 2H), 4.38 (d, J = 8.7 Hz, 1H) , 4.92 (d, J = 8.7 Hz, 1 H), 6.59-8.46 (m, 11 H); MS m / z 449 (M ⁺ ).
[861] Example 110
[862] Chemical formula Preparation of the compound
[863] Step A: Reduction
[864] Sufficient amount of sodium borohydride was added to a stirred solution of 265.1 mg (0.449 mmol) of cyclopentyl-thio-ketone produced in Example 41 in 3 mL of methanol-dichloromethane (1: 1) by adding Terminate the reduction reaction. The reaction mixture was partitioned between ethyl acetate / 2N HCl / ice / brine, the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford crude cyclopentyl-thio-carbinol, It is used without further purification in the subsequent reaction.
[865] Step B: Closing
[866] A mixture of 266 mg (0.449 mmol) of crude product prepared in Step A and 89 mg of Amberlyst 15 in 3 mL of toluene is stirred at ambient temperature for 2 hours. The resin is removed by filtration and washed well with ethyl acetate. The filtrate is evaporated and the residue obtained is purified by silica gel chromatography using dichloromethane-hexane (1: 1) as eluent to give a trans-dihydro-benzoxatin derivative. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.13 (d, 18H), 1.26-1.94 (m, 12H), 3.64 (dd, J = 7.8 Hz, 5.5 Hz, 1H), 4.78 (d, J = 7.8 Hz, 1H), 5.02 (s, 2H), 6.6-7.45 (m, 12H).
[867] Step C: Desilylation
[868] The procedure described in step B of Example 105 is carried out to desilylate 228.5 mg (0.397 mmol) of the material prepared in the previous step to obtain the corresponding phenol.
[869] Step D: Mitsunobu Reaction
[870] The procedure set forth in Example C of Example 105 is followed to convert the material prepared in the previous step to the corresponding trans-cyclopentyl-dihydrobenzoxatin adduct. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.39-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.66 (dd, J = 7.8Hz, 5.5Hz, 1H) , 4.21 (m, 2H), 4.81 (t, J = 7.8 Hz, 2H), 5.01 (s, 2H), 6.64-7.49 (m, 12H).
[871] Step E: Debenzylation
[872] Using the procedure described in step D of Example 105, the material prepared in the previous step is converted to the corresponding trans-cyclopentyl-dihydrobenzoxatin product. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.29-2.0 (m, 15H), 2.6 (m, 4H), 2.88 (m, 2H), 3.67 (dd, J = 8Hz, 5Hz, 1H), 4.18 (m, 2H), 4.77 (t, J = 8 Hz, 2H), 6.5 (dd. J = 2.7 Hz, 8.7 Hz, 1H), 6.65 (d, 2.7 Hz, 1H) 6.77 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 7.5 Hz, 2H), and 7.27 (d, J = 7.5 Hz, 2H).
[873] Example 111
[874] Chemical formula General Preparation of Compounds
[875] Steps A and B: Reduction and Closure
[876] Using the thio-ketone prepared in Example 39 and using the procedures described in steps A and B above, the following compounds were prepared:
[877] Trans-cyclohexyl derivative: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 0.98-1.8 (m, 14H), 3.37 (dd, J = 2.5 Hz, 8.1 Hz, 1H), 5.01 (s, 2H), 5.05 (d, J = 8.1 Hz, 1H), 6.6-7.44 (m, 12H).
[878] Trans-cyclopentyl derivatives: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.14 (d, 18H), 1.28-1.9 (m, 12H), 4.53 (m, 1H), 4.93 (d, 1H), 5.01 (s, 2H), 6.6-7.43 (m, 12H).
[879] Step C: Desilylation
[880] Using the trans-dihydrobenzoxatin prepared in the above step and using the procedure described in step B of Example 105, the following compounds are prepared:
[881] Trans - cyclohexyl phenol: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.0-1.8 (m, 11H), 3.3 (m, 1H), 5.05 (s, 2H), 5.1 (d, 1H), 6.6 -7.44 (m, 12 H).
[882] Trans-cyclopentyl phenol: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.29-2.0 (m, 9H), 3.55 (dd, J = 5.7 Hz, 7.6 Hz, 1H), 4.95 (d, J = 7.6 Hz, 1H), 5.02 (s, 2H), 6.6-7.45 (m, 12H).
[883] Step D: Mitsunobu Reaction:
[884] Using the trans-dihydrobenzoxatin phenol prepared in the previous step and using the procedure described in step C of Example 105 above, the following compounds were prepared:
[885] Trans - cyclohexyl adduct: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.84 (m, 2H), 3.37 (m, 1H), 4.17 (t, J = 6 Hz, 2H), 5.0 (s, 2H), 5.08 (d, J = 7.8 Hz, 1H), 6.6-7.43 (m, 12H).
[886] Trans-cyclopentyl adduct: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.29-2.0 (m, 15H), 2.58 (m, 4H), 2.84 (m, 2H), 3.55 (m, 1H), 4.17 (m, 2H), 4.94 (d, J = 7.3 Hz, 1H), 5.0 (s, 2H), 6.6-7.72 (m, 12H).
[887] Step E: Debenzylation
[888] Using the trans-dihydrobenzoxatin adduct prepared in the previous step and using the procedure described in step D of Example 105 above, the following compounds were prepared:
[889] Trans - cyclohexyl adduct: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.0-1.8 (m, 17H), 2.58 (m, 4H), 2.86 (m, 2H), 3.33 (m, 1H), 4.16 (m, 2H), 5.08 (d, J = 7.8 Hz, 1H), 6.4-7.23 (m, 7H).
[890] Trans-cyclopentyl adduct: ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 1.29-2.0 (m, 15H), 2.68 (m, 4H), 2.94 (m, 2H), 3.51 (m, 1H), 4.2 (m, 2H), 4.95 (d, J = 7.4 Hz, 1H), 6.45-7.31 (m, 7H).
[891] Example 112
[892] Chemical formula Preparation of the compound
[893] Step A: Silylation
[894] To a stirred solution of isopropyl-thio-ketone (0.0395 g, 0.097 mmol) in Example 42 in distilled THF (1 mL) at 0 ° C. was added 60% NaH in mineral oil (0.0183 g, 0.20 mmol). Then TIPSCl (0.048 mL, 0.22 mmol) is added. After 35 minutes, an additional 1 equivalent of TIPSCl is added to terminate the reaction. The reaction is partitioned between EtOAc and ice / H ₂ O and the organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford the desired product. The crude material is used in the next step without further purification.
[895] Step B: Reduction
[896] To a solution of the crude product (0.097 mmol) prepared in step A above in distilled THF (1 mL) is added a 1 M solution of super-hydride in THF (0.15 mL, 0.15 mmol) at 0 ° C. under N ₂ . The reaction mixture is stirred for 20 minutes and partitioned between EtOAc and ice / H ₂ O. The organic layer is further washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the desired product. The crude material is used in the next step without further purification. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.90-1.40 (m, 49H), 1.69 (m, 1H), 3.10 (dd, 1H), 4.60 (d, 1H), 5.05 (s, 2H) , 6.70-7.50 (m, 12H).
[897] Step C: Desilylation
[898] To a solution of the material (0.097 mmol) prepared in the previous step in distilled THF (1 mL), AcOH (0.018 mL, 0.32 mmol) was added under N ₂ at 0 ^° C. and TBAF in THF (0.29 mL, 0.29 mmol). Add 1M solution. After 15 minutes, the reaction is partitioned between EtOAc and ice / saturated NaHCO ₃ . The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by silica gel chromatography using 40% EtOAc / hexane as eluent affords the desired product as a yellow foam. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.92 (d, 3H), 0.98 (d, 3H), 1.59 (m, 1H), 2.86 (dd, 1H), 4.62 (d, 1H), 5.02 ( q, 2H), 6.77-7.45 (m, 12H).
[899] Step D: Closing
[900] The procedure as described in Example 110 (step B) is carried out to convert the material (0.0366 g, 0.089 mmol) produced in the previous step for 5 hours and 15 minutes at ambient temperature before conversion to trans-dihydrobenzoxatin. . Purification by silica gel chromatography using 30% EtOAc / hexane as eluent affords the desired product as a white solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98 (d, 3H), 1.03 (d, 3H), 1.78 (m, 1H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1H) , 4.82 (d, J = 8.4 Hz, 1H), 5.02 (s, 2H), 6.63-7.46 (m, 12H).
[901] Step E: Mitsunobu Reaction
[902] According to the procedure described in Example 105 (step C), the material (0.0266 g, 0.068 mmol) prepared in the previous step was warmed at 0 ° C. over ambient temperature over 4 hours 20 minutes with the corresponding trans-isopropyl-dihydro Convert to benzoxatin adduct. Silica gel chromatography (eluted once with 10% MeOH / CH ₂ Cl ₂ and _second with 30% EtOAc / hexanes) affords the desired product as a white solid. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.78 (m, 1H), 2.58 (m, 4H), 2.85 (t, 2H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1H), 4.18 (t, 2H), 4.83 (d, J = 8.4 Hz, 1H), 5.02 (s, 2H) , 6.63-7.46 (m, 12H).
[903] Step F: Debenzylation
[904] Following the procedure described in Example 105 (step D), the material (0.0395 g, 0.068 mmol) produced in the previous step is converted to the corresponding trans-isopropyl-dihydrobenzoxatin product. Purify by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.78 (m, 1H), 2.58 (m, 4H), 2.85 (t, 2H), 3.57 (dd, J = 3.7 Hz, J = 8.5 Hz, 1H), 4.18 (t, 2H), 4.83 (d, J = 8.4 Hz, 1H), 6.48-7.29 (m, 7H ); MS m / z 414 (M ⁺ ).
[905] Example 113
[906] Chemical formula Preparation of the compound
[907] Step A: Silylation
[908] The procedure as described in Example 112 (step A) is carried out to silylate the isopropyl-thio-ketone (0.6314 g, 1.5 mmol) produced in Example 40. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent affords the desired product as a yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98-1.30 (m, 49H), 2.35 (m, 1H), 4.38 (d, 1H), 4.99 (q, 2H), 6.33-7.79 (m, 12H ).
[909] Step B: Reduction
[910] The procedure as described in Example 112 (step B) must be carried out to reduce the material (0.8009 g, 1.1 mmol) produced in step A to the corresponding alcohol and use in the next step without further purification. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98-1.30 (m, 49H), 1.90 (m, 1H), 2.92 (dd, 1H), 4.59 (d, 1H), 5.05 (q, 2H) , 6.47-7.43 (m, 12H).
[911] Step C: Desilylation
[912] The procedure as described in Example 112 (step C) is carried out to deprotect the material (0.022 mmol) separated in step B to give the desired product which is used in the next step without further purification.
[913] Step D: Closing
[914] The procedure as described in Example 110 (step B) is carried out, and the material produced in the previous step is stirred at ambient temperature for 22 hours and then converted to the corresponding trans-dihydrobenzoxatin. Purification by silica gel chromatography using 30% EtOAc / hexane as eluent affords the desired product as a colorless oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98 (d, 3H), 1.03 (d, 3H), 1.79 (m, 1H), 3.45 (dd, 1H), 4.98 (d, 1H), 5.02 ( s, 2H), 6.59-7.46 (m, 12H); MS m / z 393 (M ⁺ ).
[915] Step E: Mitsunobu Reaction
[916] Following the procedure described in Example 105 (step C), the material (0.008 g, 0.020 mmol) produced in the previous step was warmed at 0 ° C. over ambient temperature over 6 hours and then the corresponding trans-isopropyl-dihydro Convert to benzoxatin adduct. Purification by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent affords the desired product as a pale yellow oil. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, 6H), 1.79 (m, 1H), 2.58 (m, 4H), 2.81 (t, 2H), 3.50 (dd, J = 3.8 Hz, J = 8.3 Hz, 1H), 4.18 (t, 2H), 4.97 (d, J = 8.2 Hz, 1H), 5.01 (s, 2H) , 6.59-7.46 (m, 12H).
[917] Step F: Debenzylation
[918] Following the procedure described in Example 105 (step D), the material (0.0085 g, 0.017 mmol) prepared in the previous step is converted to the corresponding trans-isopropyl-dihydrobenzoxatin product. Purification by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ as eluent. ¹ H 500 MHz NMR (CDCl ₃ ) ppm (δ): 0.98 (d, 3H), 1.02 (d, 3H), 1.49-1.70 (m, 6H), 1.75 (m, 1H), 2.61 (m, 4H), 2.85 (t, 2H), 3.41 (dd, J = 3.8 Hz, J = 8.3 Hz, 1H), 4.18 (t, 2H), 4.96 (d, J = 8.2 Hz, 1H), 6.43-7.26 (m, 7H MS m / z 414 (M ⁺ ).
[919] Example 114
[920] Chemical formula Preparation of the compound
[921] Performing the procedure as described in Example 16 and using 0.36 g (2.5 mmol) of 1,2-benzenedithiol commercially available from Aldrich, using EtOAc / hexane (1/5) as eluent After silica gel chromatography, 221 mg (about 20% of impurities) of the desired product are obtained.
[922] Example 115
[923] Preparation of the following compounds A, B and C
[924]
[925] Using the procedure from Example 44 and purifying by chromatography using 10% EtOAc / hexanes, 121 mg (80%) of the three mixtures (A: B: C = 1: 0.1: 0.25) are separated.
[926] Example 116
[927] Preparation of the following Compounds A and B
[928]
[929] Step A
[930] The tin obtained from Example XX is coupled to 1-piperidineethanol using the procedure described in Example 71 (Step A). After purification by silica gel chromatography using 3% MeOH / CH ₂ Cl ₂ as eluent, the desired adduct is obtained as a mixture.
[931] Step B
[932] The adduct from Step A is desilified using the procedure described in Example 71 (Step C). The desired product A is isolated as a white solid by HPLC (Meta Chem Polaris C 184.6 x 50, 5 μm; gradient 5-75% acetonitrile on reverse phase column). A: ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.2 (m, 2H), 7.1 (m, 2H), 6.9 (m, 2H), 6.8 (m, 4H), 6.55 (d, 2H), 4.75 (m, 2H), 4.3 (m, 2H), 3.6 (br d, 2H), 3.5 (m, 2H), 3.0 (br t, 2H), 1.95 (m, 2H), 1.8 (m , 4H); (MS m / z 464 (M ⁺ ). B: ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.4 (m, 2H), 7.3 (m, 2H), 7.1 (d, 2H), 6.95 (d, 2H), 6.8 (d, 2H), 6.6 (d, 2H), 4.3 (br t, 2H), 3.6 (br d, 2H), 3.5 (br t, 2H), 3.05 (br t, 2H), 2.0 (br d, 2H), 1.8 (m, 4H); MS m / z 462 (M ⁺ ).
[933] Test method
[934] The usefulness of the compounds of the present invention can be readily determined by methods well known to those skilled in the art. These methods include, but are not limited to, the methods described below.
[935] Estrogen Receptor Binding Assay
[936] Estrogen receptor ligand binding assays are designed as a scintillation proximity assay by using tritized estradiol and recombinantly expressed estrogen receptors. Full length recombinant human ER-α or ER-β protein is produced in a baculovirus expression system. ER-α or ER-β extracts are diluted 1: 400 in phosphate buffered saline containing 6 mM α-monothiolglycerol. A 200 μL aliquot of diluted receptor formulation is added to each well of a 96 well flashplate. The plate is covered with Saran Wrap and incubated overnight at 4 ° C.
[937] The next morning, 20 μL aliquots of phosphate buffered saline containing 10% bovine serum albumin are added to each well of a 96 well plate and incubated at 4 ° C. for 2 hours. The plates are then washed with 200 μL of buffer containing 20 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 50 mM KCl and 6 mM α-monothiolglycerol. To perform the assay on plates coated with these receptors, 178 μL of the same buffer is added to each well of a 96 well plate. Then 20 μL of H- ³ estradiol 10 nM solution is added to each well of the plate.
[938] Test compounds are evaluated in concentration ranges of 0.01 nM to 1000 nM. Test compound mother liquor should be prepared in 100% DMSO at 100 times the final concentration desired for assay testing. The amount of DMSO in test wells of 96 well plates should not exceed 1%. The final addition to the assay plate is a 2 μL aliquot of test compound, which should constitute 100% DMSO. Seal the plates and allow them to equilibrate for 3 hours at room temperature. Count the plates in a scintillation counter mounted to count 96 well plates.
[939] Ovarian restrained rat black
[940] In ovarian excision (OVX) rat assays, estrogen deficiency induces cancer cell osteoprogenitors (eg, low bone minerals [BMD; mg / cm ² ]) and links bone uptake and bone formation promotion. Both BMD and bone resorption / osteolytic results are used to model bone changes seen as postmenopausal women. The OVX rat assay is the primary bioassay used by all major academic and industrial laboratory studies to study the efficacy of new chemicals under the pretext of preventing estrogen-deficient bone loss.
[941] Ovaries of Sprague-Dawley female rats between 6 and 8 months of age are excised and begin treatment for 42 days with a vehicle or combined dose of test compound within 24 hours. Groups treated with untreated Siamese-OVX and alendronate (0.003 mg / kg, s.c., q.d.) or 17-β-estradiol treated (0.004 mg / kg, s.c., q.d.) groups are included as positive controls. Test compounds are administered orally or subcutaneously, or by infusion through an implanted minipump subcutaneously. Prior to necropsy, in vivo double labeling, bone trace fluorochromes are terminated with calcein (8 mg / kg, subcutaneous administration). At necropsy, blood, femur, spinal body segment and uterus are obtained.
[942] A general final step in ovarian excised rat assays includes assessment of bone mass, bone uptake and bone formation. For bone mass, the endpoint is the region containing the BMD of the distal femoral bone simple, about 20% cancerous bone. Areas with about 25% cancerous bone in the spinal segment can also be used for BMD measurements. BMD measurements are made by dual energy x-ray absorbance (DXA, Hologic 4500A; Waltham, Mass.). For bone resorption, the endpoint is intrauterine deoxypyridinolin crosslinking, bone collagen breakdown product (μDPD; expressed in nM DPD / nM creatinine). This measurement is performed with commercially available kits (Pyrilinks; Metra Biosystems, Mountain View, CA). For bone formation, endpoints are histomorphologic measurements of mineralization surface and mineral juxtaposition, osteoclast number and activity. This measurement is performed on the demineralized near tibia metaphyseal tip 5 μm using a semiautomatic system (Bioquant: R & B Biometrics: Nashville, TN). Similar endpoints and measurement techniques for each endpoint are commonly used in postmenopausal women.
[943] Rat Cholesterol Lowering Assay
[944] Approximately 250 g weight of Sprague-Dawley rats (5 per group) are administered subcutaneously for 4 days with a compound of the invention dissolved in propylene glycol. One group of five rats received only vehicle. On day 5, rats are euthanized with carbon dioxide and their blood samples are obtained. Plasma concentrations of cholesterol are assayed from these samples using a commercial cholesterol measurement kit (Sigma).
[945] MCF-7 Estrogen Dependent Proliferation Assay
[946] MCF-7 cells (ATCC # HTB-22) are human mammary adenocarcinoma cells that require estrogen for growth. Growth medium (GM) for MCF-7 cells is the minimum essential medium (no phenol red) supplemented up to 10% with fetal bovine serum (FBS). FBS acts as the sole source of estrogen, so that GM supports the total growth of cells and is used for regular growth of cell culture. MCF-7 cells are placed in medium in which 10% charcoal-dextran treated fetal bovine serum (CD-FBS) is replaced with FBS, and the cells cease to divide and remain viable. CD-FBS does not contain detectable concentrations of estrogen and the medium containing such serum is called estrogen depletion medium (EDM). Addition of estradiol to EDM stimulates the growth of MCF-7 cells in a dose dependent manner with an EC ₅₀ of 2 pM.
[947] Growing MCF-7 cells are washed several times with EDM and then the cultures are kept in EDM for at least 6 days to deplete cells of endogenous estrogen. On day 0 (at start of assay), these estrogen depleted cells are plated into 96 well cell culture plates at a density of 1000 cells / well in EDM at a volume of 180 μL / well. On day 1, test compounds are diluted in a 10-fold dilution series in EDM and 20 μL of this dilution is added to 180 μL of medium in a suitable well of the cell plate, resulting in a 1:10 dilution of additional test compound. On days 4 and 7 of the assay, culture supernatants are aspirated, replaced with fresh EDM, and test compounds diluted as described above. The assay ends at 8-10 days, at which point a suitable control reaches 80-90%, confluence. At this point the culture supernatant is aspirated and the cells are washed twice with PBS, the wash is aspirated and the protein content of each well is measured. Each drug dilution is evaluated for at least 5 wells and the dilution range of the test compound in the assay is from 0.001 nM to 1000 nM. An assay of this type is used to determine the estradiol agonist potential of a test compound.
[948] To assess antagonist activity of test compounds, MCF-7 cells are maintained in EDM for at least 6 days. On day 0 (at the start of the assay) these estrogen depleted cells are plated into 96 well cell culture plates at a density of 1000 cells / well in EDM at a volume of 180 μL / well. On day 1, the test compound is applied to the cells in fresh medium containing 3pM estradiol. On days 4 and 7 of the assay, culture supernatants are aspirated and replaced with fresh EDM containing 3pM estradiol and test compound. The assay is terminated on days 8-10, at which point a suitable control reaches 80-90% confluency and the protein content of each well is measured as described above.
[949] Rat Endometriosis Model
[950] animal:
[951] Species: Rattus norvegicus
[952] Genus: Sprague-Dowley CD
[953] Supplier: Charles River Laboratories, Relais, NC
[954] Gender: Female
[955] Weight: 200 to 240 g
[956] Rats are pooled in polycarbonate cages to provide Teklad Global Diet 2016 (Madison, WI) and bottled reverse osmosis purified H ₂ O ad libitium. They are maintained at a light / dark cycle of 12 hours / 12 hours.
[957] Rats are euthanized with Telazol ^™ (20 mg / kg, ip) and oxymorphone (0; 2 mg / kg, sc) and placed on a sterile drape so that the abdomen contacts the surface. Body temperature is maintained using a base speed blanket. The surgical site is shaved with a clipper and cleaned using three cycles of betadine / isopropyl alcohol or Duraprepa ^R (3M). The incised area is covered with a sterile drape.
[958] Using sterile treatment techniques, an abnormal incision 5 cm below the midline is made to the skin. Lateral ovarian incision is performed. Ligand the left uterine blood vessel and incise the 7 mm segment of the left fallopian tube. Suture the uterus with 4-0 joist sutures. The myometrium is aseptically separated from the uterus and cut to 5 x 5 mm. The cut uterine part is implanted into the epithelial lined ventral abdominal wall of the segment facing the dorsal wall. The explanted uterine tissue is sutured at four corners to the body wall using sterile 6-0 silk. The abdominal muscle layer is closed using sterile 4-0 chromed joists. The skin incision is closed using sterile stainless surgical clips. Release estrogen pellets (Innovative Research of America, 0.72 ng / pellet; circulating estrogen equivalent 200-250 pg / mL) maintained in sterile 90 days are implanted subcutaneously into the dorsal scapula. A sterile implantable programmed temperature transponder (IPTT) (BMDS, Seaford, DE) is injected subcutaneously into the dorsal scapula. Observe until the rat can fully walk and rest for 3 weeks to recover from surgery.
[959] Three weeks after implantation of the uterine tissue, rats are subjected to repeated laparotomy using sterile surgical site preparation and techniques. Graft tolerance for explants is assessed and the area measured with a caliper and recorded. Rats with the same rejected graft were excluded from the study. Rats that generate similar mean extracorporeal graft volume per group are sorted.
[960] Drug or vehicle (control) treatment commences one day after second initiation and lasts for 14 days. Body temperature is recorded at 10 am every other day using a BMDS scanner.
[961] At the end of the 14 day treatment period, rats are euthanized with a CO ₂ overdose. Blood is collected by cardiac puncture for circulating estrogen concentration measurements. The abdomen is examined, the ex vivo implant is examined, measured and dissected and the wet weight recorded. The right fallopian tube is incised and the wet and dry weights are recorded.
[962] Pharmaceutical composition
[963] In a particular embodiment of the invention, 25 mg of the compound from Example 71 is formulated with sufficiently finely divided lactose to yield a total amount of 580-590 mg and filled into a size 0 hard gelatin capsule.

权利要求:
Claims (20)
[1" claim-type="Currently amended] Compounds of formula (I) and pharmaceutically acceptable salts thereof.
Formula I

In Formula I above,
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-8 cycloal Kenyl, phenyl, heteroaryl, heterocyclyl, CF ₃ , -OR ⁶ , halogen, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _{1 A} group consisting of _-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, heterocycle The aryl group is unsubstituted or C _1-5 alkyl _, C _3-8 cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato , Cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl ,
R ⁵ is a group consisting of C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-8 cycloalkenyl, phenyl, heteroaryl and heterocyclyl groups Wherein these groups are unsubstituted or C _1-5 alkyl, C _3-8 cycloalkyl, CF ₃ , phenyl, heteroaryl, heterocyclyl, -OR ⁶ , halogen, amino, C _1-5 alkylthio, thio May be substituted with cyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONZ ₂ , -SO ₂ NZ ₂ and -SO ₂ C _1-5 alkyl) Is selected from
X and Y are each independently selected from the group consisting of oxygen, sulfur, sulfoxide and sulfone,
R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl, triorganosilyl, C _1-5 alkylcarbonyl, alkoxycarbonyl and CONZ ₂ ,
Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
Z together with the nitrogen to which they are attached is a 3 to 8 membered ring (the ring may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, may be saturated or unsaturated, and the carbon atoms of the ring are substituted Or C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _{1- 5} alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl).
Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Selected from the group consisting of COC _1-5 alkyl and -SO ₂ C _1-5 alkyl,
n is each independently an integer of 1-5.
[2" claim-type="Currently amended] The compound and pharmaceutically acceptable salt thereof of claim 1, wherein Y is sulfur and X is oxygen.
[3" claim-type="Currently amended] The method of claim 2,
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, —OR ⁶ and halogen Selected from the group consisting of one of R ² and R ³ is —OH,
R ⁵ is selected from the group consisting of C _3-8 cycloalkyl, phenyl, heteroaryl and heterocyclyl groups, which may be unsubstituted or substituted with —OR ⁶ and halogen,
And a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl.
[4" claim-type="Currently amended] The chemical formula of claim 3, wherein
A compound selected from the group consisting of compounds of and pharmaceutically acceptable salts thereof.
[5" claim-type="Currently amended] The compound of formula Ia and a pharmaceutically acceptable salt thereof.

In Formula Ia above,
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, —OR ⁶ and halogen Selected from the group consisting of one of R ² and R ³ is —OH,
R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl,
R ⁷ is selected from the group consisting of hydrogen, C _1-5 alkyl, halogen, trifluoromethyl and —OR ⁶ ,
Each Z is independently a group consisting of hydrogen, C _1-5 alkyl and trifluoromethyl, wherein the alkyl group is unsubstituted or C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 Substituted by alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl May be selected), or
Z may be a 3 to 8 membered ring together with the nitrogen to which they are bound (the ring may contain atoms selected from the group consisting of carbon, oxygen, sulfur and nitrogen, may be saturated or unsaturated, and the carbon atoms of the ring are substituted Or C _1-5 alkyl, CF ₃ , -OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, -CO ₂ H, -COOC _1-5 alkyl, -COC _{1- 5} alkyl, -CONV ₂ , -SO ₂ NV ₂ , and -SO ₂ C _1-5 alkyl) can be substituted).
Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Independently selected from the group consisting of COC _1-5 alkyl and -SO ₂ C _1-5 alkyl,
n are each independently an integer of 1 to 5,
m is each independently an integer of 1-4.
[6" claim-type="Currently amended] The chemical formula of claim 5, wherein
A compound selected from the group consisting of pharmaceutically acceptable salts thereof.
[7" claim-type="Currently amended] The compound of formula Ib and a pharmaceutically acceptable salt thereof.

In Formula Ib above,
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, C _1-5 alkyl, C _3-8 cycloalkyl, C _2-5 alkenyl, C _2-5 alkynyl, —OR ⁶ and halogen Selected from the group consisting of one of R ² and R ³ is —OH,
R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl,
R ⁷ is selected from the group consisting of hydrogen, C _1-5 alkyl, halogen, trifluoromethyl and —OR ⁶ ,
R ⁸ is independently hydrogen, C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl , -COC _1-5 alkyl, -CONV ₂ , -SO ₂ NV ₂ and -SO ₂ C _1-5 alkyl,
Each V is independently C _1-5 alkyl, CF ₃ , —OR ⁶ , halogen, amino, C _1-5 alkylthio, thiocyanato, cyano, —CO ₂ H, —COOC _1-5 alkyl, — Is selected from the group consisting of COC _1-5 alkyl and -SO ₂ C _1-5 alkyl,
m is each independently an integer of 1 to 4,
p is an integer of 1-4 each independently.
[8" claim-type="Currently amended] 8. A compound according to claim 7, wherein











Compounds selected from the group consisting of: and pharmaceutically acceptable salts thereof.
[9" claim-type="Currently amended] The compound of formula Ic and a pharmaceutically acceptable salt thereof.

In Formula Ic above,
R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, C _1-5 alkyl, —OR ⁶ and halogen, provided that one of R ² and R ³ is —OH,
R ⁶ is selected from the group consisting of hydrogen, C _1-5 alkyl, benzyl, methoxymethyl and triisopropylsilyl,
R ⁷ is selected from the group consisting of hydrogen, C _1-5 alkyl, halogen, trifluoromethyl and —OR ⁶ ,
m is independently an integer of 1 or 2.
[10" claim-type="Currently amended] The compound of claim 9 wherein




A compound selected from the group consisting of compounds of and pharmaceutically acceptable salts thereof.
[11" claim-type="Currently amended] The compound and pharmaceutically acceptable salt thereof of claim 1, wherein X is sulfur and Y is sulfur.
[12" claim-type="Currently amended] The compound of claim 11, wherein
A compound selected from the group consisting of compounds of and pharmaceutically acceptable salts thereof.
[13" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
[14" claim-type="Currently amended] A pharmaceutical composition prepared by combining the compound according to claim 1 with a pharmaceutically acceptable carrier.
[15" claim-type="Currently amended] A process for the preparation of a pharmaceutical composition comprising combining the compound of claim 1 with a pharmaceutically acceptable carrier.
[16" claim-type="Currently amended] A method of inducing an estrogen receptor modulating effect in a mammal, comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of inducing an estrogen receptor modulating effect.
[17" claim-type="Currently amended] The method of claim 16, wherein the estrogen receptor modulating effect is an estrogen receptor agonizing effect.
[18" claim-type="Currently amended] 18. The method of claim 17, wherein the estrogen receptor action is an ERα receptor action.
[19" claim-type="Currently amended] A method of treating or preventing postmenopausal osteoporosis in a woman by administering a therapeutically effective amount of a compound according to claim 1 to a woman in need of treating postmenopausal osteoporosis.
[20" claim-type="Currently amended] A method of treating or preventing a disease selected from the group consisting of estrogen dependent breast cancer, intrauterine fibroids, restenosis, endometriosis and hyperlipidemia, comprising administering to a woman in need thereof a therapeutically effective amount of a compound according to claim 1 .

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NO20031737L|2003-06-19|

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IS6761A|2003-03-27|

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ECSP034558A|2003-06-25|

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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:
2000-10-19|Priority to US24158200P

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2000-10-19|Priority to US60/241,582

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2001-10-15|Application filed by 머크 앤드 캄파니 인코포레이티드

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2001-10-15|Priority to PCT/US2001/042735

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2003-05-27|Publication of KR20030042020A

优先权:

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申请号 | 申请日 | 专利标题

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US24158200P| true| 2000-10-19|2000-10-19|

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US60/241,582|2000-10-19|

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PCT/US2001/042735|WO2002032377A2|2000-10-19|2001-10-15|Estrogen receptor modulators|