Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-14
2001-12-04
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S357000, C514S360000, C514S365000, C514S374000, C514S385000, C514S192000
Reexamination Certificate
active
06326387
ABSTRACT:
TECHNICAL FIELD OF 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 which binds to the FK-506 binding protein (FKBP) and a neurotrophic factor, such as nerve growth factor NGF. The methods comprise treating nerve cells with the above-described compositions or compositions comprising the FKBP binding compound without a neurotrophic 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
Immunophilins are a family of soluble proteins that mediate the actions of immunosuppressant drugs such as cyclosporin A, FK506 and rapamycin. Of particular interest is the 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 binds FK-506 and rapamycin, leading to an inhibition of T-cell activation and proliferation. Interestingly, the mechanism of action of FK-506 and rapamycin are different. For review, see, S. H. Solomon et al.,
Nature Med
., 1, pp. 32-37 (1995).
FK-506 binds to FKBP12 and the resulting complex binds to and inhibits calcineurin, a cytoplasmic phosphatase. The phosphatase activity of calcineurin is necessary for dephosphorylation and subsequent translocation into the nucleus of the transcription factor NF-AT. NF-AT causes interleukin-2 gene activation which in turn mediates T-cell proliferation.
The rapamycin-FKBP12 complex, on the other hand, associates with a protein of unknown function, termed RAFT1/FRAP. This tripartite complex is known to inhibit various kinases in the cell (i.e., p70S6, p34cdc2, cdk2) which are necessary for cell cycle progression in T-cells. Rapamycin is also known to be a potent antagonist of FK-506, presumably by acting as a competitive inhibitor for the FKBP12 binding.
More recently, it has been discovered that FKBP plays other important roles in the body. It has been found that FKBP12 forms a complex with the intracellular calcium ion channels—the ryanodine receptor (RyR) and the inositol 1,4,5-triphosphate receptor (IP
3
R) [T. Jayaraman et al.,
J. Biol. Chem
., 267, pp. 9474-77 (1992); A. M. Cameron et al.,
Proc. Natl. Acad. Sci. USA
, 92, pp. 1784-44 (1995)], helping to stabilize calcium release. The ryanodine receptor has been found in skeletal muscle, cardiac muscle, brain and other excitable tissues. IP
3
R mediates intracellular calcium release elicited by hormones and neurotransmitters that act at the cell surface to activate phospholipase C and generate inositol 1,4,5-triphophase (IP
3
). Most IP
3
R is found associated with the endoplasmic reticulum, but some may occur on the cell surface and mediate calcium flux into the cell.
For both the RyR and the IP
3
R, it has been demonstrated that FK506 and rapamycin are capable of dissociating FKBP12 from the receptor. In each case, the “stripping” off of FKBP12 leads to increased leakiness of the calcium channel and lower intracellular calcium concentrations.
Another role of FKBP12 is the regulation of neurite outgrowth in nerve cells. W. E. Lyons et al. [
Proc. Natl. Acad. Sci. USA
, 91, pp. 3191-95 (1994)] demonstrated that FK506 acts synergistically with nerve growth factor (NGF) in stimulating neurite outgrowth in a rat pheochromocytoma cell line. Interestingly, rapamycin did not inhibit the effects of FK-506 on neurite outgrowth, but rather was neurotrophic itself, displaying an additive effect with FK-506. In sensory ganglia, FK-506 demonstrated similar neurotrophic effects, but those effects were blocked by rapamycin. These results led the authors to speculate that FK-506 was exerting its neurotrophic effect through its complexing with FKBP12 and calcineurin and inhibition of the latter's phosphatase activity. Alternatively, the authors proposed FK-506 was acting via a “stripping” mechanism, such as that involved in the removal of FKBP12 from RyR and IP
3
R.
In view of the wide variety of disorders that may be treated by stimulating neurite outgrowth and the relatively few FKBP12-binding compounds that are known to possess this property, there remains a great need for additional neurotrophic, FKBP12-binding compounds.
SUMMARY OF THE INVENTION
Applicant has solved the problem referred to above by discovering that two genera of novel FKBP12-binding compounds he had previously co-invented also possess neurotrophic activity. Applicant had previously described a series of acylated amino acid derivatives which bind to FKBP12 in PCT patent publications WO 92/19593 and WO 94/07858. Another series of FKBP12 ligands are described in applicant's U.S. Pat. Nos. 5,192,773 and 5,330,993 and PCT patent publication WO 92/00278. Each series of compounds stimulate neurite outgrowth in the presence of exogenous or endogenous NGF.
The compositions provided comprise a compound from one of the two genera described above and a neuronal growth factor. The methods described herein employ those previously described compounds and compositions comprising them to effectuate neurite outgrowth are useful to treat nerve damage caused by various diseases and physical traumas.
DETAILED DESCRIPTION OF THE INVENTION
According to one embodiment, the present invention provides pharmaceutical compositions which comprise:
a) a compound with affinity for FKBP12 having the formula (I):
and pharmaceutically acceptable derivatives thereof, wherein A in O, NH, or N—(C1-C4 alkyl);
wherein B is hydrogen, CHL—Ar, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl, (C5-C?)-cycloalkenyl or Ar substituted (C1-C6)-alkyl or (C2-C6)-alkenyl, or
wherein L and Q are independently hydrogen, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl;
wherein T is Ar or substituted cyclohexyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O—(C1-C4)-alkyl or O—(C2-C4)-alkenyl and carbonyl;
wherein Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, CF
3
, (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, O—(C1-C4)-straight or branched alkyl or O—((C2-C4)-straight or branched alkenyl), O-benzyl, O-phenyl, amino and phenyl; wherein D is U; E is either oxygen or CH—U, provided that if D is hydrogen, then E is CH—U or if E is oxygen then D is not hydrogen;
wherein each U is independently selected from hydrogen, O—(C1-C4)-straight or branched alkyl or O—((C2-C4)-straight or branched alkenyl), (C1-C6)-straight or branched alkyl or (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl, 2-indolyl, 3-indolyl, [(C1-C4)-alkyl or (C2-C4)-alkenyl]-Ar or Ar;
wherein J is hydrogen or C1 or C2 alkyl; K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl; or wherein J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain an O, S, SO or SO
2
substituent therein;
wherein the stereochemistry at carbon position 1 is R or S;
b) a neurotrophic factor; and
c) a pharmaceutically suitable carrier.
More preferably, in the compound with affinity for FKBP12 in these pharmaceutical compositions: A is oxygen; J is hydrogen or C1 or C2 alkyl; K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylmethyl; or J and K are taken together to form pyrrolidyl or piperidyl; and the stereochemistry at carbon position 1 is S.
In the above preferred compounds wherein J and K are taken together to form pyrrolidyl or piperidyl and E is CH—U, U is preferably dimethylaminophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, nitrophenyl, furyl, indolyl, pyridyl, or methylenedioxyphenyl.
In the above preferred compounds wherein J and K are taken to
Criares Theodore J.
Fish & Neave
Haley Jr. James F.
Horan Nina R.
Vertex Pharmaceuticals Incorporated
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