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AssigneeNone recorded
InventorsDavid Lauffer, Ronald Tomlinson, Eckhard Ottow, Martyn Botfield
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The present invention relates to acyclic piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage associated with neurological diseases. These compounds are also useful for stimulating nerve growth. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage or for stimulating nerve growth.
A compound having the formula (I):
A method for promoting neuronal repair or preventing neuronal damage in a patient or in an ex vivo nerve cell comprising the step of administering to said patient or said cell an amount of a compound sufficient to promoting neuronal repair or preventing neuronal damage, wherein said compound has the formula:
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Radicals derived from carboxylic acids: from aliphatic carboxylic acids
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
Drugs for skeletal disorders
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The present invention relates to acyclic piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage associated with neurological diseases. These compounds are also useful for stimulating nerve growth. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage or for stimulating nerve growth.
Neurological diseases are associated with the death of or injury to neuronal cells. 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 neuronal growth.
Neuronal growth, 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., Proc. Natl. Acad. Sci., 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)].
To N-ethylpipecolinic acid (0.157 g , 1.0 mmol) in 14 mL of dry CH2Cl2 was added pivaloyl chloride (0.121 g, 1.01 mmol) neat. After 1 hr, 1 mL of the resulting reaction solution was added to 14 wells of a reaction block containing morpholinomethyl polystyrene HL resin (100 mg, 0.4 mmol) and the appropriate amine derivative (0.2 mmol) in 2 mL of dry CH2Cl2. After shaking for 12 hrs, polystyrene methyl isocyanate (80 mg, 0.1 mmol) was added and the reaction solution was shaken an additional 12 hrs. Filtration and evaporation afforded the crude amide derivatives. Purification was accomplished with solid phase extraction (SPE-C) with methanol and methanol/ammonia to give the desired product. Compounds 1 and 2 were synthesized in this manner.
To N-cycloheanecarbodiimide-N′-propyloxymethyl polystyrene resin (150 mg, 0.15 mmol) in the wells of a reaction block was added the appropriate amino acid derivative (0.075 mmol) neat. To each well was added 3 ml of the appropriate amine (0.1 mmol) in dry CH2Cl2. After shaking for 12 hrs, polystyrene methyl isocyanate (80 mg, 0.05 mmol) was added and the reaction solution was shaken an additional 12 hrs. Filtration and evaporation afforded the crude amide derivatives. Purification was accomplished with reverse phase HPLC with H2O/acetonitrile (0.1% TFA) to give the desired product as a trifluoroacetate salt. Compounds 1, 5, 9, 10, 12, 13 and 19 of Table 2 were prepared by this method.
To bromoacetic acid (935 mg, 6.78 mmol) in 30 mL of CH2Cl2 was added diisopropylcarbodiimide (856 mg, 6.78 mmol). After 0.5 h, the resulting white percipitate was removed by filtration and the filtrate was treated with 1-N-phenylpiperazine (1.10 g, 6.78 mmol) and the solution was stirred for 10 h. Concentration and purification by flash chromatography (CH2Cl2/EtOAc) afforded the title compound 1.63 g, (84% yield). MS (MH+) m/z 284.91