We claim:
1. A method of modifying the calcemic activity of a 1-hydroxylated vitamin D compound to increase in vivo activity, comprising:
altering the conformational equilibrium of the A-ring of a 1a-hydroxylated vitamin D compound to favor a chair conformation for said A-ring that presents the 1-hydroxyl in an axial orientation.
2. The method of claim 1 wherein the step of altering conformational equilibrium comprises locking the chair conformation of the A-ring in a geometry having an axially orientated 1-hydroxyl.
3. The method of claim 2 wherein the step of locking comprises adding an anchoring bond system to the A-ring.
4. The method of claim 3 wherein the anchoring bond system comprises substituents attached to carbon 2 and carbon 3 of the A-ring that have a trans-diequatorial orientation.
5. The method of claim 3 wherein the A-ring and anchoring bond system has the following structure:
22
where R1 and R2 are as described above, and wherein n is an integer having a value of from 1 to 4, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
6. The method of claim 3 wherein the anchoring bond system comprises substituents attached to carbon 3 and carbon 4 of the A-ring that have a trans-diequatorial orientation.
7. The method of claim 3 wherein the A-ring and anchoring bond system has the following structure:
23
where R1 and R2 are as described above, and wherein n is an integer having a value of from 1 to 4, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
8. The method of claim 2 wherein the step of locking comprises adding a flattening bond system to the A-ring.
9. The method of claim 8 wherein the A-ring and flattening bond system has the following structure:
24
where R1 R2 are as described above, and wherein s is an integer having a value of from 1 to 3, and wherein any of the groups CR1R2 may be replaced by an oxygen, sulfur or nitrogen atom.
10. The method of claim 2 wherein the step of locking comprises adding a bridged bond system to the A-ring.
11. The method of claim 10 wherein the bridged bond system comprises substituents attached to carbon 2 and carbon 4 of the A-ring that have a cis-1,3-diaxial orientation.
12. The method of claim 10 wherein the A-ring and bridged bond system has the following structure:
25
where R1 and R2 are as described above, and wherein r is an integer having a value of from 1 to 5, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
13. The method of claim 10 wherein the bridged bond system comprises substituents attached to carbon 2 and carbon 10 of the A-ring that have a cis-1,3-diaxial orientation.
14. The method of claim 10 wherein the A-ring and bridged bond system has the following structure:
26
where R1 and R2 are as described above, and wherein r is an integer having a value of from 1 to 5, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
15. The method of claim 10 wherein the bridged bond system comprises substituents attached to carbon 4 and carbon 10 of the A-ring that have a cis-1,3-diaxial orientation.
16. The method of claim 10 wherein the A-ring and the bridged bond system has the following structure:
27
where R1 and R2 are as described above, and wherein r is an integer having a value of from 1 to 5, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
17. The method of claim 1 wherein the step of altering conformational equilibrium comprises modifying the A-ring by the addition of one or more substituents which interacts with other substituents on the A-ring to provide a driving force to the A-ring to adopt a chair conformation which presents the 1-hydroxyl in said axial orientation.
18. The method of claim 17 wherein the substituent attached to carbon 2 of the A-ring has a conformational free energy value greater than about 1.4 kcalmol and the carbon 2 substituent has an equatorial orientation.
19. The method of claim 17 wherein the A-ring has the following structure:
28
where U is selected from the group consisting of a methyl, a substituted methyl group described by general formula CR1R2R3, an amino group or substituted amino group described by general formula NR1R2, a phosphino group or substituted phosphino group described by general formula PR1R2, an alkyl- or arylsulfinyl group, an alkyl- or arylsulfonyl group, and aryl, and where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents and where R1 and R2, taken together, represent an oxo group, or a group (CH2)m where m is an integer having a value of from 2 to 5.
20. The method of claim 17 wherein the A-ring has the following structure:
29
where U is as described in claim 19 with the proviso that U cannot be an OH group.
21. The method of claim 17 wherein the substituent attached to carbon 10 of the A-ring has a conformational free energy value greater than about 1.4 kcalmol and the carbon 10 substituent has an axial orientation.
22. The method of claim 17 wherein the A-ring has the following structure:
30
where U is as described in claim 19.
23. A method of increasing the biological response of a 1-hydroxylated vitamin D compound comprising
evaluating the conformational equilibrium of the A-ring of a 1-hydroxylated vitamin D compound to determine to what extent said 1-hydroxyl is presented axially or equatorially; and
if presented primarily equatorially, modifying the A-ring by the addition of a substituent thereto which locks said A-ring in a chair conformation that maintains the 1-hydroxyl in said axial orientation; or modifying the A-ring by the addition of a substituent thereto which provides a driving force to the A-ring to adopt a chair conformation which presents the 1-hydroxyl in said axial orientation.
24. The method of claim 23 wherein the step of modifying the A-ring comprises adding an anchoring bond system to the A-ring.
25. The method of claim 24 wherein the anchoring bond system is added between substituents attached to carbons 2 and 3 of the A-ring.
26. The method of claim 24 wherein the anchoring bond system is added between substituents attached to carbons 3 and 4 of the A-ring.
27. The method of claim 23 wherein the step of modifying the A-ring comprises adding a flattening bond system to the A-ring.
28. The method of claim 27 wherein the flattening bond system is added between substituents attached to carbons 2 and 3 of the A-ring.
29. The method of claim 23 wherein the step of modifying the A-ring comprises adding a bridged bond system to the A-ring.
30. The method of claim 29 wherein the bridged bond system is added between substituents attached to carbons 2 and 4 of the A-ring.
31. The method of claim 29 wherein the bridged bond system is added between substituents attached to carbons 2 and 10 of the A-ring.
32. The method of claim 29 wherein the bridged bond system is added between substituents attached to carbons 4 and 10 of the A-ring.
33. The method of claim 23 wherein the step of modifying the A-ring comprises adding a substituent to carbon 2 of the A-ring having a conformational free energy value greater than about 1.4 kcalmol.
34. The method of claim 23 wherein the step of modifying the A-ring comprises adding a substituent to carbon 10 of the A-ring having a conformational free energy value greater than about 1.4 kcalmol.
35. A compound having the formula:
31
where Y1 and Y2, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group; where Y3, Y4, Y5, Y6, Y7 and Y8, which may be the same or different, are each selected from the group consisting of hydrogen, a methyl group or substituted methyl group of the formula CR1R2R3, an amino group or substituted amino group of the formula NR1R2, a phosphino group or substituted phosphino group of the formula PR1R2, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, and aryl, where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an alkyl substituted amino group, and an aryl substituted amino group, and where R1 and R2 taken together represent an oxo group or a group (CH2)m where m is an integer having a value of from 2 to 5; or Y3 and Y4 when taken together represent a methylene group; or Y7 and Y8 when taken together represent a methylene group; where Y2 and Y6, or Y2 and Y7, when taken together may represent the group (CR1R2)n where n is an integer having a value of from 1 to 4 and wherein any of the groups CR1R2 may be replaced by an oxygen, sulfur or nitrogen atom; where Y5 and Y8, or Y5 and Y3, or Y3 and Y8, when taken together may represent the group (CR1R2)r where r is an integer having a value of from 1 to 5 and wherein any of the groups CR1R2 may be replaced by an oxygen, sulfur or nitrogen atom; and where Y5 and Y6 when taken together represent the group CR4R5 where R4 and R5, which may be the same or different, are each selected from the group consisting of hydrogen and Y3 with the proviso that R4 and R5 cannot be a hydroxyl; and where R4 and Y2 when taken together may represent the group (CR1R2)s where s is an integer having a value of from 1 to 3; and R is represented by the structure below
32
where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, OY, CH2OY, CCY and CHCHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, COR10 and a radical of the structure:
33
where x and y, independently, represent the integers from 0 to 5, where R6 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R7, R8, and R9, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R6 and R7, taken together, represent an oxo group, or an alkylidene group, CR7R8, or the group (CH2)p, where p is an integer from 2 to 5, and where R8 and R9, taken together, represent an oxo group, or the group (CH2)q, where q is an integer from 2 to 5, and where R10 represents hydrogen, hydroxy, protected hydroxy, or C1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups CH(CH3), CH(R3), or CH(R2) at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
36. The compound of claim 35 having the formula:
34
where U is selected from the group consisting of a methyl, a substituted methyl group described by general formula CR1R2R3, an amino group or substituted amino group described by general formula NR1R2, a phosphino group or substituted phosphino group described by general formula PR1R2, an alkyl- or arylsulfinyl group, an alkyl- or arylsulfonyl group, and aryl, and where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents and where R1 and R2, taken together, represent an oxo group, or a group (CH2)m where m is an integer having a value of from 2 to 5.
37. The compound of claim 35 having the formula:
35
where R1 and R2 are as described in claim 36, and wherein n is an integer, having a value of from 1 to 4, and wherein any of the groups CR1R2-may be replaced by an oxygen, sulfur or nitrogen atom.
38. The compound of claim 35 having the formula:
36
where U is as described in claim 36 with the proviso that U cannot be an OH group.
39. The compound of claim 35 having the formula:
37
where R1 and R2 are as described in claim 36, and wherein s is an integer having a value of from 1 to 3, and wherein any of the groups CR1R2-may be replaced by an oxygen, sulfur or nitrogen atom.
40. The compound of claim 35 having the formula:
38
where R1 and R2 are as described in claim 36, and wherein n is an integer having a value of from 1 to 4, and wherein any of the groups CR1R2-may be replaced by an oxygen, sulfur or nitrogen atom.
41. The compound of claim 35 having the formula:
39
where U is as described in claim 36.
42. The compound of claim 35 having the formula:
40
where R1 and R2 are as described in claim 36, and wherein r is an integer having a value of from 1 to 5, and wherein any of the groups CR1R2-may be replaced by an oxygen, sulfur or nitrogen atom.
43. The compound of claim 35 having the formula:
41
where R1 and R2 are as described in claim 36, and wherein r is an integer having a value of from 1 to 5, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
44. The compound of claim 35 having the formula:
42
where R1 and R2 are as described in claim 36, and wherein r is an integer having a value of from 1 to 5, and wherein any of the groups CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom.
45. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 35 together with a pharmaceutically acceptable excipient.
46. The pharmaceutical composition of claim 45 in dosage unit form.
47. The pharmaceutical composition of claim 46 containing about 0.01 g to about 100 g of said at least one compound.
48. The pharmaceutical composition of claim 45 in topical form.
49. The pharmaceutical composition of claim 45 in oral form.
50. A method of treating metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 35.
51. The method of claim 50 where the disease is senile osteoporosis.
52. The method of claim 50 where the disease is postmenopausal osteoporosis.
53. The method of claim 50 where the disease is steroid-induced osteoporosis.
54. The method of claim 50 where the disease is low bone turnover osteoporosis.
55. The method of claim 50 where the disease is osteomalacia.
56. The method of claim 50 where the disease is renal osteodystrophy.
57. The method of claim 50 where the disease is rickets.
58. The method of claim 50 where the disease is vitamin D resistant rickets.
59. The method of claim 50 wherein the compound is administered orally.
60. The method of claim 50 wherein the compound is administered parenterally.
61. The method of claim 50 wherein the compound is administered transdermally.
62. The method of claim 50 wherein the compound is administered in a dosage of from 0.1 g to 50 g per day.
63. A method of treating a disease characterized by abnormal cell proliferation or cell differentiation comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 35.
64. The method of claim 63 where the disease is psoriasis.
65. The method of claim 63 where the disease is a cancer selected from the group consisting of leukemia, colon cancer, breast cancer and prostate cancer.
66. The method of claim 63 where the disease is a skin disorder selected from the group consisting of dermatitis, eczema and keratosis.
67. A method of treating a disease characterized by an imbalance in the immune system comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 35.
68. The method of claim 67 where the disease is multiple sclerosis.
69. The method of claim 67 where the disease is diabetes mellitus.
70. The method of claim 67 where the disease is transplant rejection.
71. A method of treating rheumatoid arthritis comprising administering to a patient with rheumatoid arthritis an effective amount of a compound as claimed in claim 35.
72. A method of treating asthma comprising administering to a patient with asthma an effective amount of a compound as claimed in claim 35.
73. A method of treating hypertension comprising administering to a patient with hypertension an effective amount of a compound as claimed in claim 35.
74. A method of treating hypocalcemia comprising administering to a patient with hypocalcemia an effective amount of a compound as claimed in claim 35.
75. A method of treating hypoparathroidism comprising administering to a patient with hypoparathyroidism an effective amount of a compound as claimed in claim 35.
76. A method of treating female infertility which comprises administering to a female mammal an effective amount of a compound as claimed in claim 35.
77. A method of treating acne comprising administering to a patient with acne an effective amount of a compound as claimed in claim 35.
78. A method of treating alopecia comprising administering to a patient with alopecia an effective amount of a compound as claimed in claim 35.
79. A method of treating skin conditions selected from the group consisting of lack of skin firmness, wrinkles, lack of dermal hydration and insufficient sebum secretion which comprises administering to a patient by topical, oral or parenteral means an effective amount of a compound as claimed in claim 35.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An apparatus, comprising:
a voltage regulator for generating a regulated output voltage responsive to an input voltage and drive control signals;
an error amplifier for generating an error voltage signal responsive to the regulated output voltage and a reference voltage;
a PWM modulator for generating a PWM control signal responsive to the error voltage signal, a ramp voltage and an inverse of the reference voltage,
control circuitry within the PWM modulator for maintaining the error voltage signal applied to the PWM modulator at substantially a same DC voltage level over the reference voltage operating range and maintaining the error voltage signal above a minimum value of the ramp voltage; and
driver circuitry for generating the drive control signals responsive to the PWM control signal.
2. The apparatus of claim 1 further including a variable gain high pass filter for amplifying the error voltage signal by a gain equal to an inverse of the reference voltage.
3. The apparatus of claim 2, wherein the variable gain high pass filter is responsive to a variable gain control signal.
4. The apparatus of claim 2, wherein the variable gain high pass filter maintains the error voltage signal at a same DC voltage level.
5. The apparatus of claim 1, wherein the PWM modulator further comprises:
a latch circuit for generating the PWM control signal responsive to a pulse output and a first control signal;
a first comparator for a first output responsive to the ramp voltage and the error voltage signal;
a pulse generator circuit for generating the pulse output responsive to the first output; and
a second comparator for generating the first control signal responsive to a comparison of combination of the error voltage and a current sense signal with a second ramp signal.
6. The apparatus of claim 5, wherein the control circuitry further includes:
a multiplier for multiplying an inverse of the reference voltage by a nominal up ramp slew rate signal; and
a current source for generating the second RAMP signal at a node associated with the current source responsive to a balance current and an output of the multiplier.
7. The apparatus of claim 1 further including a current sensor for generating a current sense signal that is applied to the regulated output voltage.
8. A method for generating a PWM control signal, comprising:
comparing a ramp voltage with an error voltage signal and generating a pulse signal responsive thereto;
modifying the error voltage signal responsive to a current sense signal;
generating a first voltage responsive to an inverse of the reference voltage and a nominal upramp slew rate signal;
comparing the modified error voltage signal with the first voltage to generate a first control signal; and
generating the PWM control signal responsive to the pulse signal and the first control signal.
9. The method of claim 8, wherein the step of generating the first voltage further includes:
multiplying the nominally upramp slew rate signal with the inverse of the reference voltage to generate a second control signal; and
controlling a current source responsive to the second control signal and a current control signal to generate the first voltage.
10. The method of claim 8 further including:
applying the PWM control signal to a voltage regulator;
generating drive control signals responsive to the PWM control signal;
generating a regulated output voltage responsive to an input voltage and the drive control signals; and
generating an error voltage signal responsive to the regulated output voltage and the reference voltage.
11. The method of claim 10 further including amplifying the error voltage signal by a gain equal to an inverse of the reference voltage.
12. The method of claim 11, wherein the amplifying further comprises amplifying the amplifying the error voltage signal responsive to a variable gain control signal.
13. The method of claim 10 further including:
generating a current sense signal responsive to a current through and inductor of the voltage regulator; and
applying the current sense signal to the regulated output voltage.
14. The method of claim 8, further including maintaining the error voltage signal at a same DC voltage level over an operating range of the reference voltage.
15. The method of claim 8 further including:
generating a current sense signal responsive to a current through and inductor of the voltage regulator; and
applying the current sense signal to the regulated output voltage.
16. A PWM controller for generating a PWM control signal for a voltage regulator, comprising:
a first input for receiving an error voltage signal;
a second input for receiving a ramp voltage signal;
a third input for receiving an inverse reference voltage;
an output for providing the PWM control signal;
modulator circuitry for generating the PWM control signal responsive to the error voltage signal, the ramp voltage signal and the inverse of the reference voltage; and
control circuitry for maintaining the error voltage signal applied to the modulator circuitry at substantially a same DC voltage level over the reference voltage operating range and maintaining the error voltage signal above a minimum value of the ramp voltage.
17. The PWM controller of claim 16, wherein the modulator circuitry further comprises:
a latch circuit for generating the PWM control signal responsive to a pulse output and a first control signal;
a first comparator for a first output responsive to the ramp voltage and the error voltage signal;
a pulse generator circuit for generating the pulse output responsive to the first output; and
a second comparator for generating the first control signal responsive to a comparison of combination of the error voltage and a current sense signal with second ramp signal.
18. The PWM controller of claim 17 wherein the control circuitry further comprises:
a multiplier for multiplying an inverse of the reference voltage by a nominal up ramp slew rate signal; and
a current source for generating the second RAMP signal at a node associated with the current source responsive to a balance current and an output of the multiplier.
19. The PWM controller of claim 16 wherein the modulator circuitry reduces the gain of the PWM modulator by a factor of the inverse of the reference voltage.
20. A system, comprising:
a voltage regulator for generating a regulated output voltage at an output responsive to an input voltage and drive control signals;
an error amplifier for generating an error voltage signal responsive to the regulated output voltage and a reference voltage;
a PWM modulator for generating a PWM control signal responsive to the error voltage signal, a ramp voltage and an inverse of the reference voltage,
control circuitry within the PWM modulator for maintaining the error voltage signal applied to the PWM modulator at substantially a same DC voltage level over the reference voltage operating range and maintain the error voltage signal above a minimum value of the ramp voltage;
driver circuitry for generating the drive control signals responsive to the PWM control signal; and
a load coupled to the output of the voltage regulator.
21. The system of claim 20, wherein the load is selected from a group consisting of a processor, a memory, an input device, an output device and a storage device.