Vitamin D analogues and their neuronal effects

Details Vitamin D analogues and their neuronal effects Vitamin D analogues and their neuronal effects

1998-05-21

2001-03-27

Marschel, Ardin H. (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

C514S008100, C514S012200

Reexamination Certificate

active

06207656

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to the use of vitamin D analogues to mediate neuronal effects.
BACKGROUND OF THE INVENTION
Diseases associated with the loss of neurons in different regions of the central nervous system (CNS), including, for example, brain tissue and the spinal cord, are the subject of intense research. Exemplary diseases are Alzheimer's disease, amyotrophic lateral sclerosis (“ALS” or “Lou Gehrig's disease”), Parkinson's disease, Huntington's disease, ischaemia, and stroke. These types of diseases are exemplary of diseases and disorders collectively referred to herein as “neurodegenerative diseases.” The incidence of many neurodegenerative diseases increases rapidly with aging. For example, less than 5% of the population under the age of 65 have Alzheimer's disease. This incidence increases almost exponentially over the age of 65, and as much as 47% of the population over the age of 85 have some form of Alzheimer's disease. See, Katzman et al,
FASEB,
5:278-286 (1991); Evans et al,
JAMA,
262:2551-2556 (1989). A study of individuals over the age of 80 revealed that the brains of substantially all the individuals studied contained at least some age- and/or disease-related loss of neurons. See, Matsuyama et al,
Proceedings of the Fifth International Congress of Neuropathy
, (Exerpta Medica International Congress Series No. 100 eds. Luthy et al) 979-980 (1966). These studies indicate that aging is a major risk factor for the development of neurodegenerative diseases. In fact, there is evidence suggesting that even in the absence of disease, the aging process is associated with neuron loss and memory impairment. Crook et al,
Devel. Neuropsych.,
2(4):261-276 (1986).
The causes of neurodegenerative diseases and the associated loss of neurons, as well as neuron loss associated with aging, remains unclear. It has been proposed that neurodegenerative diseases and the associated loss of neurons may be treated by administering the protein nerve growth factor (NGF). See, Lapchak et al,
Reviews in the Neurosciences,
3:109-119 (1992). NGF is required for the maintenance and survival of sympatic and sensory neurons in the peripheral nervous system, as well as for basal forebrain cholinergic neurons in the central nervous system. See, Lapchak et al,
Reviews in the Neurosciences
, supra.
However, exogenous administration of NGF as a putative therapeutic for neurodegenerative diseases of the CNS is not practical because NGF is unable to cross the blood-brain barrier. Methods for increasing endogenous NGF levels by administering 1,25-dihydroxy vitamin D
3
or an analogue thereof have been proposed as a therapeutic approach. See, Jehan et al,
EJPMOL,
208:189-191 (1991); Wion et al,
J. Neurosciences Res.,
28:110-114 (1991). Similarly, U.S. Pat. No. 4,897,388 describes a method for treating Alzheimer's disease using calcitriol and analogues thereof, while PCT Application PCT/US94/07917 describes methods for protecting against neuron loss using calcitriol and analogues thereof. However, 1,25-dihydroxy vitamin D
3
and many of its analogues increase serum calcium levels at doses that induce NGF. The hypercalcemia elicited by 1,25-dihydroxy vitamin D
3
and many of its analogues leads to wasting, depletion of calcium from bone, and calcification of soft tissues, making these compounds poor therapeutic candidates.
It has also been proposed that neurodegenerative diseases and the associated loss of neurons may be treated by administering or over-expressing other neurotrophic factors, e.g., insulin-like growth factor (IGF), glial cell line-derived neurotrophic factor (GDNF), neurturin, or brain-derived neurotrophic factor (BDNF). See, U.S. Pat. No. 5,093,317; Williams et al,
JPET,
277(2):1140-1151 (1996); Kotzbauer et al,
Nature,
384-467-470 (1996). GDNF has been found to stimulate and prevent the loss of mesencephalic dopaminergic neurons, somatic motor neurons and basal forebrain cholinergic neurons. See, Williams et al,
JPET
, supra. Neurturin was recently discovered and has been found to stimulate and prevent the loss of sympathetic and sensory neurons in the peripheral nervous system (PNS). These are the neurons in the PNS that NGF act upon. The activity profile of neurturin in the CNS has not yet been publicly described. Along with NGF, BDNF and neurotrophin 3 (NT-3) are members of a family of trophic factors known as “neurotrophins.” BDNF has been found to prevent the loss of basal forebrain cholinergic cells, as well as several other neuronal cell types. See, Williams et al,
JPET
, supra. NT-3 has been found to prevent the loss of multiple neuronal cell types, including sympatic and sensory neurons in the PNS.
As discussed above, exogenous administration of GDNF, neurturin, NT-3, and/or BDNF as a putative therapeutic for neurodegenerative diseases is not practical because these neurotrophic factors are generally unable to cross the blood-brain barrier. Thus, increasing endogenous levels of these neurotrophic factors by peripherally administering small molecules which can cross the blood-brain barrier is an important therapeutic approach.
Another type of disease affecting neurons is multiple sclerosis. Multiple sclerosis is thought to result from central nervous system demyelination brought about by chronic inflammatory autoimmune reaction. It has been proposed to treat multiple sclerosis by the administration of vitamin D. For example U.S. Pat. No. 5,716,946 to DeLuca discloses the use of 1,25-dihydroxy vitamin D
3
or analogs thereof to treat multiple sclerosis. However, as discussed previously 1,25-dihydroxy vitamin D
3
and many of its analogues undesirably increase serum calcium levels at doses useful for treating multiple sclerosis.
Therefore, it is an object of the present invention to provide a method of treating neurodegenerative diseases or multiple sclerosis using low calcemic vitamin D analogues. It is another object of the present invention to provide a method for facilitating the production of neurotrophic factors or inhibiting the degradation or loss of neural cells.
SUMMARY OF THE INVENTION
The present invention is directed, inter alia, to methods of using low calcemic vitamin D analogues for treating neurodegenerative diseases, for facilitating the endogenous production of neurotrophic factors, such as GDNF, CTNF, NGF, NRT, NT-3 and BDNF, for inhibiting the degradation, dysfunction, or loss of neural cells, or enhancing the phenotype of neural cells or neuronal processes.
The vitamin D analogues that are useful in the present invention include compounds of Formula I:
wherein Z is selected from the group consisting of
and wherein
X is a hydrogen atom or a hydroxy group;
R
1
and R
2
each independently represent a hydrogen atom or a C
1
-C
6
alkyl group that is optionally substituted with one or more deuterium or fluorine atoms, or R
1
and R
2
, taken together with the carbon atom bearing the X group, form a C
3
-C
8
cyclic ring that is optionally substituted with one or more deuterium or fluorine atoms;
R
3
is a hydrogen atom, a C
1
-C
10
alkyl group that is optionally substituted with one or more deuterium or fluorine atoms or YR
4
, wherein Y is —CO—, —COO—, —COS—, —CS—, —CSO—, —CSS—, —SO— or —SO
2
— and R
4
is a hydrogen atom or a C
1
-C
10
alkyl group that is optionally substituted with one or more deuterium or fluorine atoms; and
Q is a single bond or a C
1
-C
8
alkylene group that is optionally substituted with one or more deuterium or fluorine atoms.
Preferred compounds of Formula (I) include Compound (A), when Z is Y
1
, Compound (B), when Z is Y
2
; Compound (C), when Z is Y
3
; Compound (D), when Z is Y
4
, or Compound (E), when Z is Y
5
:
In another embodiment of the present invention, the compounds of Formula (I) may be administered to treat peripheral neuropathy or to treat multiple sclerosis.
Additionally, the low calcemic vitamin D analogues, including, for example, the compounds of Formula (I), may be used in the manufacture of a medicament for the prevention

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