Epothilone derivatives
First Claim
Patent Images
1. A compound of the formula:
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wherein;
Q is selected from the group consisting of;
G is selected from the group consisting of alkyl;
substituted alkyl;
substituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
and a 1-methyl-2-(substituted R′
) ethenyl group, wherein R′
is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl;
or a bicyclic heterocyclic group selected from the group consisting of benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, dihydroquinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl;
W is O or NR15 NH;
X is O or H, H;
Y is selected from the group consisting of O;
H, OR16;
OR17, OR17;
NOR18;
H,NHOR19;
H, NR20R21;
H, H; and
CHR22;
wherein OR17, OR17 can be a cyclic ketal;
Z1 and Z2 are independently CH2;
B1 and B2 are independently is selected from the group consisting of OR24, OCOR25, and O—
C(═
O)—
NR26R27, and when B1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal;
B2 is selected from the group consisting of OH, OCOR25, and O—
C(═
O)—
NR26R27;
R1 and R2 are both hydrogen;
R1, R2, R3, R4, R5, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
R6 is methyl;
R9, R10, R16, R17, R24, R25 and R31 are selected from the group consisting of H, alkyl, and substituted alkyl;
R11, R12, R28, R30, R32, and R33 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring; and
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R8 is hydrogen or methyl;
R15, R23 and R29 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R32C═
O;
R33SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
or pharmaceutically acceptable salts thereof, hydrates, or solvates or geometric, optical or stereoisomers thereof;
with the proviso that compounds wherein W and X are both O; and
R1, R2 and R7 are H; and
R3, R4 and R6 are methyl; and
R8 is H or methyl; and
G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and
Q is as defined above are the compound[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione is excluded.
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Accused Products
Abstract
The present invention relates to epothilone derivatives, having the following formula
in which the variables G, W, Q, X, Y, B1, B2, Z1, Z2, and R1-R7 are as defined herein, methods for the preparation of the derivatives and intermediates thereof.
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Citations
73 Claims
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1. A compound of the formula:
-
wherein; Q is selected from the group consisting of;
G is selected from the group consisting of alkyl;
substituted alkyl;
substituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
and a 1-methyl-2-(substituted R′
) ethenyl group, wherein R′
is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl;
ora bicyclic heterocyclic group selected from the group consisting of benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, dihydroquinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl; W is O or NR15 NH;
X is O or H, H;
Y is selected from the group consisting of O;
H, OR16;
OR17, OR17;
NOR18;
H,NHOR19;
H, NR20R21;
H, H; and
CHR22;
wherein OR17, OR17 can be a cyclic ketal;
Z1 and Z2 are independently CH2;
B1 and B2 are independently is selected from the group consisting of OR24, OCOR25, and O—
C(═
O)—
NR26R27, and when B1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal;
B2 is selected from the group consisting of OH, OCOR25, and O—
C(═
O)—
NR26R27;
R1 and R2 are both hydrogen; R1, R2, R3, R4, R5, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
R6 is methyl;
R9, R10, R16, R17, R24, R25 and R31 are selected from the group consisting of H, alkyl, and substituted alkyl;
R11, R12, R28, R30, R32, and R33 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring; and
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R8 is hydrogen or methyl;
R15, R23 and R29 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R32C═
O;
R33SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
or pharmaceutically acceptable salts thereof, hydrates, or solvates or geometric, optical or stereoisomers thereof;
with the proviso that compounds wherein W and X are both O; and
R1, R2 and R7 are H; and
R3, R4 and R6 are methyl; and
R8 is H or methyl; and
G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and
Q is as defined above are the compound [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione is excluded. - View Dependent Claims (2, 4, 5, 6, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 63, 64, 65, 66, 71)
Y is O;
Z1, and Z2, are CH2; and
W is NR15 .
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4. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 1.
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5. The method of claim 4, wherein the cancer is cancer of the breast, ovary, or colon.
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6. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 2.
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11. The method of claim 6, wherein the cancer is cancer of the breast, ovary, or colon.
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13. The compound of claim 1, A compound of the formula:
-
wherein Q is G is 1-methyl-2-(substituted-4-thiazolyl) ethenyl group;
W is NH;
B1 is selected from the group consisting of OR24, OCOR25, and O—
C(═
O)—
NR26R27; and
B2 is selected from the group consisting of OH, OCOR25, and O—
C(═
O)—
NR26R27;
R3, R4, R5, R26, and R27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl;
R6 is methyl;
R8 is hydrogen or methyl;
R24 and R25 selected from the group consisting of H, alkyl, and substituted alkyl;
or pharmaceutically acceptable hydrates or solvates thereof.
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14. The compound of claim 1 13, wherein Q is
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15. The compound of claim 1, wherein W is NR15.
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16. The compound of claim 1, wherein X and Y are each O.
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17. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 13.
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18. The method of claim 17, wherein the cancer is cancer of the breast, ovary, or colon.
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19. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 14.
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20. The method of claim 19, wherein the cancer is cancer of the breast, ovary, or colon.
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21. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 15.
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22. The method of claim 21, wherein the cancer is cancer of the breast, ovary, or colon.
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23. A method of treating breast cancer, ovarian cancer, colon cancer, head and neck cancer, lung cancer, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, prostate cancer, bladder cancer, or pancreatic cancer in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 16.
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24. The method of claim 23, wherein the cancer is cancer of the breast, ovary, or colon.
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25. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1.
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26. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 2.
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29. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 13.
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30. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 14.
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31. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 15.
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32. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 16.
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33. The method of claim 4, further comprising administering one or more of an additional anti-cancer agent.
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34. The method of claim 33, wherein the additional anti-cancer agent acts in a phase of the cell cycle other than the G2-M phase.
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35. The method of claim 34, wherein the additional anti-cancer is a thymidilate synthase inhibitor, a DNA cross linking agent, a topoisomerase I or II inhibitor, a DNA alkylating agent, a ribonuclase reductase inhibitor, a cytotoxic factor, or a growth factor inhibitor.
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36. The method of claim 4, further comprising administering radiation therapy.
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37. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle or diluent.
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38. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable vehicle or diluent.
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41. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable vehicle or diluent.
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42. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable vehicle or diluent.
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43. A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable vehicle or diluent.
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44. A pharmaceutical composition comprising the compound of claim 16 and a pharmaceutically acceptable vehicle or diluent.
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45. A method of treating melanoma, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or Karposi'"'"'s sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 1.
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46. A method of treating melanoma, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or Karposi'"'"'s sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 2.
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49. A method of treating melanoma, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or Karposi'"'"'s sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 13.
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50. A method of treating melanoma, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or Karposi'"'"'s sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 14.
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51. A method of treating melanoma, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or Karposi'"'"'s sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 15.
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52. A method of treating melanoma, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or Karposi'"'"'s sarcoma in a patient in need of said treatment which comprises administering to said patient a therapeutically effective amount of a compound of claim 16.
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63. The compound of claim 1, wherein G is a 1-methyl-2-(substituted-4-thiazolyl) ethenyl group.
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64. The compound of claim 63, wherein G is a 1-methyl-2-(methyl-4-thiazolyl) ethenyl group.
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65. The compound of claim 1, wherein G is a 1-methyl-2-(alkyl oxazolyl) ethenyl group.
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66. The compound of claim 65, wherein G is a 1-methyl-2-(methyl oxazolyl) ethenyl group.
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71. The compound of claim 1, wherein the substituents for the substituted 4-R′
- group of G are selected from alkyl, hydroxyalkyl, and oxo.
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3. A compound selected from the group consisting of:
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[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclonexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-1,5,5,7,9-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-Phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;
[1S-[1R*,3R*,7R*,10S*,11R*,12R* ,16S*]]-N-Phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;
[4S-[4R*,7S*,8R*,9R*,15R*]]-N-Phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;
[4S-[4R*,7S*,8R*,9R*,15R*]]-N-Phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione;
and the pharmaceutically acceptable salts, solvates and hydrates thereof. - View Dependent Claims (7, 12, 27, 39, 47)
-
-
8. A compound having the formula:
-
or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, optical isomer or stereoisomer thereof. - View Dependent Claims (9, 10, 28, 40, 48)
-
-
53. A compound of the formula:
-
wherein; Q is selected from the group consisting of;
G is selected from the group consisting of alkyl;
substituted alkyl;
substituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
and a 1-methyl-2-(substituted R′
) ethenyl group, wherein R′
is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl;
or a bicyclic heterocyclic group selected from the group consisting of benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, dihydroquinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl;X is O or H, H;
Y is selected from the group consisting of O;
H, OR16;
OR17, OR17;
NOR18;
H, NHOR19;
H, NR20R21;
H, H; and
CHR22;
wherein OR17, OR17 can be a cyclic ketal;
Z1 and Z2 are independently CH2;
B1 and B2 are independently is selected from the group consisting of OR24, OCOR25, and O—
C(═
O)-NR26R27, and when B1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal;
B2 is selected from the group consisting of OH, OCOR25, and O—
C(═
O)—
NR26R27;
R1 and R2 are both hydrogen; R1, R2, R3, R4, R5, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
R6 is methyl;
R9, R10, R16, R17, R24, R25 and R31 are selected from the group consisting of H, alkyl, and substituted alkyl;
R11, R12, R28, R30, R32, and R33 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring; and
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R8 is hydrogen or methyl;
R15 is hydrogen; R15, R23 and R29 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R32C═
O;
R33SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
or pharmaceutically acceptable salts, hydrates, or solvates or geometric, optical or steroisomers thereof, with the proviso that the compound [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione is excluded. - View Dependent Claims (54, 55, 56, 57, 58, 59, 60, 61, 67, 68, 69, 70, 72)
-
-
62. A compound of the formula:
-
wherein; Q is selected from the group consisting of;
G is selected from the group consisting of alkyl;
substituted alkyl;
substituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
a 1-methyl-2-(substituted R′
) ethenyl group, wherein R′
is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl;
or a bicyclic heterocyclic group selected from the group consisting of benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, dihydroquinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl;
W is O or NR15 NH;
X is O or H, H;
Y is selected from the group consisting of O;
H, OR16;
OR17, OR17;
NOR18;
H, NHOR19;
H, NR20R21;
H, H; and
CHR22;
wherein OR17, OR17 can be a cyclic ketal;
Z1 and Z2 are independently CH2;
B1 and B2 are independently is selected from the group consisting of OR24, OCOR25, and O—
C(═
O)—
NR26R27 , and when B1 is OH and Y is OH, H, they can form a six-membered ring ketal or acetal ;
B2 is selected from the group consisting of OH, OCOR25, and O—
C(═
O)—
NR26R27;
R1 and R2 are both hydrogen; R1, R2, R3, R4, R5, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
R6 is methyl;
R9, R10, R16, R17, R24, R25 and R31 are selected from the group consisting of H, alkyl, and substituted alkyl;
R11, R12, R28, R30, R32, and R33 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring; and
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R8 is hydrogen or methyl;
R15, R23 and R29 are selected from the group consisting of H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
R32C═
O;
R33SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
or pharmaceutically acceptable salts, hydrates, or solvates or geometric, optical or steroisomers thereof;
wherein substituted alkyl is an alkyl group substituted with from one to four substituents selected from the group consisting of halo;
trifluoromethyl;
trifluoromethoxy;
hydroxy;
alkoxy;
cycloalkoxy;
heterocyclooxy;
oxo;
alkanoyl;
aryloxy;
alkanoyloxy;
amino;
alkylamino;
arylamine;
aralkylamino;
cycloalkylamino;
heterocycloamino;
disubstituted amines wherein the substituents are selected from alkyl, aryl, and aralkyl;
alkanoylamino;
optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl;
arylamino optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl;
aralkanoylamino optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl;
thio;
alkylthio;
aralkylthio;
cycloalkylthio;
heterocyclothio;
alkylthiono;
arylthiono;
aralkylthiono;
alkylsulfonyl;
arylsulfonyl;
aralkylsulfonyl;
sulfonamido optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl;
nitro;
cyano;
carboxy;
carbamyl optionally substituted with halogen, alkyl, alkoxy, aryl, or araralkyl;
alkoxycarbonyl;
aryl;
substituted aryl;
guanidino; and
heterocyclo; and
substituted aryl is an aryl group substituted with from one to four substituents selected from the group consisting of alkyl;
substituted alkyl;
halo;
trifluoromethyl;
trifluoromethoxy;
hydroxy;
alkoxy;
cycloalkoxy;
heterocyclooxy;
alkanoyl;
alkanoyloxy;
amino;
alkylamino;
aralkylamino;
cycloalkylamino;
heterocycloamino;
dialkylamino;
alkanoylamino;
thio;
alkylthio;
cycloalkylthio;
heterocyclothio;
ureido;
nitro;
cyano;
carboxy;
carboxyalkyl;
carbamyl;
alkoxycarbonyl;
alkylthiono;
arylthiono;
alkylsulfonyl;
sulfonamido; and
aryloxy each of which may be optionally substituted with halo, hydroxy, alkyl, alkoxy, substituted aryl, substituted alkyl, or substituted aralkyl;
with the proviso that compounds wherein W and X are both O; and
R1, R2 and R7 are H; and
R3, R4 and R6 are methyl; and
R8 is H or methyl; and
G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and
Q is as defined above are the compound [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione is excluded. - View Dependent Claims (73)
-
Specification
-
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Current AssigneeR-pharm us operating llc
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Original AssigneeBristol-Myers Squibb Company
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InventorsJohnson, James A., Borzilleri, Robert M., Kim, Soong-Hoon, Vite, Gregory D.
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Primary Examiner(s)Kifle; Bruck
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Application NumberUS12/539,498Time in Patent Office441 DaysField of Search540/452, 540/462, 540/463, 540/468, 514/183, 514/365, 514/366US Class Current514/183CPC Class CodesC07D 417/06 linked by a carbon chain co...C07D 491/04 Ortho-condensed systemsC07D 491/044 with only one oxygen atom a...C07D 493/04 Ortho-condensed systems
