Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-21
2002-10-08
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S533000, C548S537000
Reexamination Certificate
active
06462072
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to neurotrophic low molecular weight, small molecule cyclic ester or amide derivatives having an affinity for FKBP-type immunophilins, pharmaceutical compositions comprising the same, and methods of using the same to effect a neuronal activity.
2. Description of Related Art
The term immunophilin refers to a number of proteins that serve as receptors for the principal immunosuppressant drugs, cyclosporin A (CsA), FK506, and rapamycin. Known classes of immunophilins are cyclophilins and FK506 binding proteins, or FKBPs. Cyclosporin A binds to cyclophilin A, while FK506 and rapamycin bind to FKBP12. These immunophilin-drug complexes interface with various intracellular signal transduction systems, especially in the immune and nervous systems.
Immunophilins are known to have peptidyl-prolyl isomerase (PPIase), or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the interconversion of the cis and trans isomers of peptide and protein substrates for the immunophilin proteins.
Immunophilins were originally discovered and studied in the immune tissue. It was initially postulated by those skilled in the art that inhibition of the immunophilins' rotamase activity leads to inhibition of T-cell proliferation, thereby causing the immunosuppressive activity exhibited by immunosuppressant drugs, such as cyclosporin A, FK506, and rapamycin. Further study has shown that the inhibition of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al.,
Science
, 1990, vol. 250, pp. 556-559. Instead, immunosuppression appears to stem from the formation of a complex of immunosuppressant drugs with immunophilins. It has been shown that the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al.,
Cell
, 1991, vol. 66, pp. 807-815. In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complex binds to the enzyme calcineurin and inhibits the T-cell receptor signaling necessary to T-cell proliferation. Similarly, the immunophilin-drug complex of FKBP-rapamycin interacts with the RAFT1/FRAP protein and inhibits the IL-2 receptor signaling also necessary to T-cell proliferation. In either case, T-cell proliferation is inhibited.
In addition to immune tissues, immunophilins have also been found in the central nervous system. Immunophilin concentrations are 10-50 times greater in the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release, and neuronal process extension.
It has been found that picomolar concentrations of immunosuppressants such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory neurons such as dorsal root ganglion cells (DRGs) Lyons et al.,
Proc. of Natl. Acad. Sci
., 1994, vol. 91, pp. 3191-3195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury.
However, when administered chronically, immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al.,
J. Am. Soc. Nephrol
., 1991, 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as non-localized headaches (De Groen et al.,
N. Engl. J. Med
., 1987, 317:861); and vascular hypertension with complications resulting therefrom (Kahan et al.,
N. Engl. J. Med
., 1989, 321:1725).
Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects, but are devoid of immunosuppressive activity. These findings suggest the use of rotamase inhibitors in treating various peripheral neuropathies and enhancing neuronal regrowth in the central nervous system (CNS).
Studies have demonstrated that neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), may occur due to the loss, or decreased availability, of a neurotrophic substance specific for a particular population of neurons affected in the disorder.
Several neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer's disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor and neurotropin-3, to increase the survival of degenerating neuronal populations.
The present invention provides compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite outgrowth, and promoting neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes; physical damage to the central nervous system (spinal cord and brain); brain damage associated with stroke; and neurological disorders relating to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease) and amyotrophic lateral sclerosis. The inventive compounds are also useful for treating alopecia, promoting hair growth, treating vision disorder, improving vision, treating memory impairment and enhancing memory performance in an animal.
SUMMARY OF THE INVENTION
The present invention relates to neurotrophic low molecular weight, small molecule cyclic ester and amide derivatives having an affinity for FKBP-type immunophilins. Once bound to these proteins, the compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity. The compounds may or may not exert immunosuppressive activity.
Specifically, the present invention relates to a compound of formula I
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated carbocyclic or heterocyclic ring, said heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO
2
, N, NH, and NR;
R, R
1
, and R
2
are independently C
1
-C
9
straight or branched chain alkyl, C
2
-C
9
straight or branched chain alkenyl, C
3
-C
9
cycloalkyl, C
3
-C
9
cycloalkenyl, or Ar, wherein said R, R
1
, and R
2
are independently unsubstituted or substituted with one or substituent(s);
Ar is an aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO
2
, N, NH and NR;
W and X are independently O, S, CH
2
or H
2
;
Y is O or S; and
Z is O, NH or NR.
A preferred embodiment of this invention is a compound of formula II
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO
2
, N, NH and NR;
R and R
1
are independently C
1
-C
9
straight or branched chain alkyl, C
2
-C
9
straight or branched chain alkenyl, C
3
-C
9
cycloalkyl, C
3
-C
9
cycloalkenyl, or Ar, wherein said R and R
1
are independently unsubstituted or substituted with one or more substituent(s);
R
2
is C
3
-C
9
cycloalkyl, C
3
-C
9
cycloalkenyl or Ar, wherein said cycloalkyl or cycloalkenyl is unsubstituted or substituted with one or m
Hamilton Gregory S.
Limburg David C.
GPI NIL Holdings Inc.
Liu Hong
Raymond Richard L.
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