Methods and compositions for stimulating neurite growth

Details Methods and compositions for stimulating neurite growth Methods and compositions for stimulating neurite growth

1998-11-23

2001-01-09

Cintins, Marianne M. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S012200, C514S341000

Reexamination Certificate

active

06172086

ABSTRACT:

TECHNICAL FIELD THE INVENTION
The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating nerve cells with the above compositions or compositions comprising the compound without a neurotropic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
BACKGROUND OF THE INVENTION
Neurological diseases are associated with the death or injury of neuronal cells. The loss of dopaminergic neurons in the substantia nigra is the etiological cause for Parkinson's disease. Although the molecular mechanism of neurodegeneration in Alzheimer's disease is yet to be established, it is clear that brain inflammation, and deposition of beta-amyloid protein and other such agents may inhibit the survival of neurons and mitigate the growth of neurites used for communication between neurons. In patients suffering from brain ischemia or spinal cord injuries, extensive neuronal cell death is observed. Currently, there are no satisfactory treatments for these diseases.
Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death. A more recent approach involves the promotion of nerve regeneration by promoting neurite outgrowth.
Neurite outgrowth, which is critical for the survival of neurons, is stimulated in vitro by nerve growth factors (NGF). For example, Glial Cell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of Parkinson's disease. Insulin and Insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PC12 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al.,
J. Neurosci
., 6, pp. 1211-1219 (1986)]. Insulin and Insulin-like growth factors also stimulate the regeneration of injured motor nerves in vivo and in vitro [Near et al., PNAS, pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al.,
Cell Differ
., 19, p. 1 (1986)] and growth [M. A. Walter et al.,
Lymphokine Cytokine Res
., 12, p. 135 (1993)].
There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma. And they have poor drug delivery properties.
Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neurite outgrowth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique Toran-Allerand et al.,
J. Steroid Biochem. Mol. Biol
., 56, pp. 169-78 (1996); and B. S. McEwen et al.,
Brain Res. Dev. Brain. Res
., 87, pp. 91-95 (1995)]. The progress of Alzheimer's disease is slowed in women who take estrogen. Estrogen is hypothesized to complement NGF and other neurotrophins and thereby help neurons differentiate and survive.
Tacrolimus, an immunosuppressive drug, has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al., PNAS, 91, pp. 3191-3195 (1994)]. This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher,
Nature
, 371, pp.336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [Gold et al.,
J. Neurosci
., 15, pp. 7509-16 (1995)].
Though a wide variety of neurological degenerative disorders may be treated by stimulating neurite outgrowth, there are relatively few agents known to possess these properties. Thus, there remains a great need for new pharmaceutically acceptable compounds and compositions that have the ability to stimulate neurite outgrowth in patients.
SUMMARY OF THE INVENTION
Applicants have solved the above problem by discovering that compounds invented by one of the co-applicants for use in reversing multi-drug resistance previously also surprisingly and unexpectedly possess neurotropic activity. These amino acid derivatives are disclosed in U.S. Pat. No. 5,543,423.
These compounds stimulate neurite outgrowth in the presence of exogenous or endogenous NGF. The compositions disclosed herein comprise a compound from the genera described above and a neuronal growth factor. The methods to stimulate neurite outgrowth disclosed herein employ the above amino acid derivatives either alone or in combination with a neuronal growth factor. The methods are useful in treating nerve damage caused by various neurological diseases and physical traumas and also in ex vivo nerve regeneration.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions which comprise three components. The first component is a compound having the formula (I):
and pharmaceutically acceptable derivatives thereof, wherein R
1
, B and D are independently selected from hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl-substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl-substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl-substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl-substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, or Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl; provided that R
1
is not hydrogen.
Any one of the CH
2
groups in the alkyl chains is of R
1
, B and D is optionally replaced by a heteroatom selected from O, S, SO, SO
2
and NR; wherein R is hydrogen, (C1-C6) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl. The (C1-C4) bridging alkyl, together with the nitrogen and a carbon atom of said heteroatom-containing chain, form a ring. That ring may also be optionally fused to an Ar group.
Preferably, B and D are independently selected from H, 3-Pyr-(CH
2
)
3
—, 4-Pyr-(CH
2
)
2
—, 3-Im-(CH
2
)
2
—, and Ph-(CH
2
)
2
—. R
1
is preferably selected from CH
3
—, PhCH
2
—, 4-Cl—PhCH
2
—, 4-F—PhCH
2
—, 4-PyCH
2
—, and 1H-Im-CH
2
—.
Each Ar is independently selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl.
Preferred Ar groups of this invention are phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydroquinolinyl.
Any Ar may be optionally substituted with one to three substituents independently selected from halogen, hydroxyl, nitro, —SO
3
H, trifluoromethyl, trifluoromethoxy, (C1-C6) straight or branched alkyl, O-((C1-C6) straig

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