U.S. patent application number 09/814954 was filed with the patent office on 2003-06-19 for method of using neurotrophic sulfonamide compounds.
Invention is credited to Hamilton, Gregory S., Li, Jia-He, Steiner, Joseph P..
Application Number | 20030114492 09/814954 |
Document ID | / |
Family ID | 25175836 |
Filed Date | 2003-06-19 |
United States Patent
Application |
20030114492 |
Kind Code |
A1 |
Hamilton, Gregory S. ; et
al. |
June 19, 2003 |
Method of using neurotrophic sulfonamide compounds
Abstract
This invention relates to a method of using neurotrophic low
molecular weight, small molecule sulfonamide compounds having an
affinity for FKBP-type immunophilins, as inhibitors of the enzyme
activity associated with immunophilin proteins, particularly
peptidyl-prolyl isomerase, or rotamase, enzyme activity.
Inventors: |
Hamilton, Gregory S.;
(Catonsville, MD) ; Li, Jia-He; (Cockeysville,
MD) ; Steiner, Joseph P.; (Hampstead, MD) |
Correspondence
Address: |
GUILFORD PHARMACEUTICALS C/O
FOLEY & LARDNER
3000 K STREET, NW
WASHINGTON
DC
20007-5143
US
|
Family ID: |
25175836 |
Appl. No.: |
09/814954 |
Filed: |
March 23, 2001 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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09814954 |
Mar 23, 2001 |
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09419801 |
Oct 18, 1999 |
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6245783 |
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09419801 |
Oct 18, 1999 |
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09028517 |
Feb 23, 1998 |
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5968957 |
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09028517 |
Feb 23, 1998 |
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08799407 |
Feb 12, 1997 |
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5721256 |
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Current U.S.
Class: |
514/330 ;
514/318; 514/326; 514/340; 514/422; 514/423; 514/424 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 31/18 20130101; A61P 25/00 20180101; A61P 25/16 20180101; A61P
43/00 20180101; A61K 31/40 20130101; A61K 31/445 20130101; A61K
31/4439 20130101; A61P 25/28 20180101 |
Class at
Publication: |
514/330 ;
514/318; 514/326; 514/340; 514/423; 514/424; 514/422 |
International
Class: |
A61K 031/4545; A61K
031/445; A61K 031/4439; A61K 031/401; A61K 031/4025 |
Claims
What is claimed is:
1. A method of effecting a neuronal activity in an animal,
comprising: administering to the animal a neurotrophically
effective amount of a compound of formula I: 26or a
pharmaceutically acceptable salt thereof, wherein: A is CH.sub.2,
oxygen, NH or N-(C1-C4 alkyl); B and D are independently Ar,
hydrogen, (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C1-C6)-straight or branched alkyl or alkenyl
that is substituted with a (C5-C7)-cycloalkyl, (C1-C6)-straight or
branched alkyl or alkenyl that is substituted with a
(C5-C7)-cycloalkenyl, or Ar substituted (C1-C6)-straight or
branched alkyl or alkenyl, wherein, in each case, one or two of the
CH.sub.2 groups of the alkyl or alkenyl chains may contain 1-2
heteroatoms selected from the group consisting of oxygen, sulfur,
SO and SO.sub.2 in chemically reasonable substitution patterns, or
27provided that both B and D are not hydrogen; Q is hydrogen,
(C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched
alkenyl; T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl; Ar is selected from the group
consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic
and bicyclic heterocyclic ring systems with individual ring sizes
being 5 or 6 which may contain in either or both rings a total of
1-4 heteroatoms independently selected from O, N and S; wherein Ar
may contain one to three substituents which are independently
selected from the group consisting of hydrogen, halo, hydroxyl,
nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or
branched alkyl, (C2-C6)-straight or branched alkenyl,
O-(C1-C4)-straight or branched alkyl, O-(C2-C4)-straight or
branched alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino,
carboxyl and phenyl; E is (C1-C6)-straight or branched alkyl,
(C1-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl,
(C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched
alkyl or (C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; J is hydrogen or C1 or C2 alkyl or
benzyl; 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 oxygen,
sulfur, SO or SO.sub.2 substituent therein; n is 0 to 3; and the
stereochemistry at carbon positions 1 and 2 are R or S.
2. The method of claim 1, wherein the neuronal activity is selected
from the group consisting of stimulation of damaged neurons,
promotion of neuronal regeneration, prevention of neurodegeneration
and treatment of neurological disorder.
3. The method of claim 2, wherein the neurological disorder is
selected from the group consisting of peripheral neuropathy caused
by physical injury or disease state, physical damage to the brain,
physical damage to the spinal cord, stroke associated with brain
damage, and neurological disorder relating to
neurodegeneration.
4. The method of claim 3, wherein the neurological disorder
relating to neurodegeneration is selected from the group consisting
of Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
5. The method of claim 1, wherein J and K are taken together and
the compound is represented by formula II: 28wherein n is 1 or 2
and m is 0 or 1.
6. The method of claim 5, wherein the neuronal activity is selected
from the group consisting of stimulation of damaged neurons,
promotion of neuronal regeneration, prevention of neurodegeneration
and treatment of neurological disorder.
7. The method of claim 6, wherein the neurological disorder is
selected from the group consisting of peripheral neuropathy caused
by physical injury or disease state, physical damage to the brain,
physical damage to the spinal cord, stroke associated with brain
damage, and neurological disorder relating to
neurodegeneration.
8. The method of claim 7, wherein the neurological disorder
relating to neurodegeneration is selected from the group consisting
of Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
9. The method of claim 5, wherein: B is selected from the group
consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D
is selected from the group consisting of phenyl, 3-phenylpropyl,
3-phenoxyphenyl and 4-phenoxyphenyl; and E is selected from the
group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl,
2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl,
3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl,
1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl,
2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl,
4-chlorophenyl and E-styrenyl.
10. The method of claim 9, wherein the neuronal activity is
selected from the group consisting of stimulation of damaged
neurons, promotion of neuronal regeneration, prevention of
neurodegeneration and treatment of neurological disorder.
11. The method of claim 10, wherein the neurological disorder is
selected from the group consisting of peripheral neuropathy caused
by physical injury or disease state, physical damage to the brain,
physical damage to the spinal cord, stroke associated with brain
damage, and neurological disorder relating to
neurodegeneration.
12. The method of claim 11, wherein the neurological disorder
relating to neurodegeneration is selected from the group consisting
of Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
13. A method of effecting a neuronal activity in an animal,
comprising: administering to the animal a neurotrophically
effective amount of a compound of formula III: 29or a
pharmaceutically acceptable salt thereof, wherein: B and D are
independently Ar, hydrogen, (C1-C6)-straight or branched alkyl,
(C1-C6)-straight or branched alkenyl, (C1-C6)-straight or branched
alkyl or alkenyl that is substituted with a (C5-C7)-cycloalkyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkenyl, or Ar substituted (C1-C6)-straight or
branched alkyl or alkenyl, wherein, in each case, one or two of the
CH.sub.2 groups of the alkyl or alkenyl chains may contain 1-2
heteroatoms selected from the group consisting of oxygen, sulfur,
SO and SO.sub.2 in chemically reasonable substitution patterns, or
30provided that both B and D are not hydrogen; Q is hydrogen,
(C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched
alkenyl; T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl; Ar is selected from the group
consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic
and bicyclic heterocyclic ring systems with individual ring sizes
being 5 or 6 which may contain in either or both rings a total of
1-4 heteroatoms independently selected from O, N and S; wherein Ar
may contain one to three substituents which are independently
selected from the group consisting of hydrogen, halo, hydroxyl,
nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or
branched alkyl, (C2-C6)-straight or branched alkenyl,
O-(C1-C4)-straight or branched alkyl, O-(C2-C4)-straight or
branched alkenyl, O-benzyl, O-phenyl, 1, 2-methylenedioxy, amino,
carboxyl and phenyl; E is (C1-C6)-straight or branched alkyl,
(C1-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl,
(C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched
alkyl or (C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; and m is 0 to 3.
14. The method of claim 13, wherein the neuronal activity is
selected from the group consisting of stimulation of damaged
neurons, promotion of neuronal regeneration, prevention of
neurodegeneration and treatment of neurological disorder.
15. The method of claim 14, wherein the neurological disorder is
selected from the group consisting of peripheral neuropathy caused
by physical injury or disease state, physical damage to the brain,
physical damage to the spinal cord, stroke associated with brain
damage, and neurological disorder relating to
neurodegeneration.
16. The method of claim 15, wherein the neurological disorder
relating to neurodegeneration is selected from the group consisting
of Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
17. A method of effecting a neuronal activity in an animal,
comprising: administering to the animal a neurotrophically
effective amount of a compound of formula IV: 31or a
pharmaceutically acceptable salt thereof, wherein: B and D are
independently Ar, hydrogen, (C1-C6)-straight or branched alkyl,
(C1-C6)-straight or branched alkenyl, (C1-C6)-straight or branched
alkyl or alkenyl that is substituted with a (C5-C7)-cycloalkyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkenyl, or Ar substituted (C1-C6)-straight or
branched alkyl or alkenyl, wherein, in each case, one or two of the
CH.sub.2 groups of the alkyl or alkenyl chains may contain 1-2
heteroatoms selected from the group consisting of oxygen, sulfur,
SO and SO.sub.2 in chemically reasonable substitution patterns, or
32provided that both B and D are not hydrogen; Q is hydrogen,
(C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched
alkenyl; T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl; Ar is selected from the group
consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic
and bicyclic heterocyclic ring systems with individual ring sizes
being 5 or 6 which may contain in either or both rings a total of
1-4 heteroatoms independently selected from O, N and S; wherein Ar
may contain one to three substituents which are independently
selected from the group consisting of hydrogen, halo, hydroxyl,
nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or
branched alkyl, (C2-C6)-straight or branched alkenyl,
O-(C1-C4)-straight or branched alkyl, O-(C2-C4)-straight or
branched alkenyl, O-benzyl, O-phenyl, 1, 2-methylenedioxy, amino,
carboxyl and phenyl; E is (C1-C6)-straight or branched alkyl,
(C1-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl,
(C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched
alkyl or (C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; and m is 0 to 3.
18. The method of claim 17, wherein the neuronal activity is
selected from the group consisting of stimulation of damaged
neurons, promotion of neuronal regeneration, prevention of
neurodegeneration and treatment of neurological disorder.
19. The method of claim 18, wherein the neurological disorder is
selected from the group consisting of peripheral neuropathy caused
by physical injury or disease state, physical damage to the brain,
physical damage to the spinal cord, stroke associated with brain
damage, and neurological disorder relating to
neurodegeneration.
20. The method of claim 19, wherein the neurological disorder
relating to neurodegeneration is selected from the group consisting
of Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] This invention relates to a method of using neurotrophic low
molecular weight, small molecule sulfonamide compounds having an
affinity for FKBP-type immunophilins, as inhibitors of the enzyme
activity associated with immunophilin proteins, particularly
peptidyl-prolyl isomerase, or rotamase, enzyme activity.
[0003] 2. Description of Related Art
[0004] 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 the immune and nervous systems.
[0005] 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.
[0006] 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 formulation of a complex of
immunosuppressant drug and immunophilin. It has been shown that
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 complexes bind to the enzyme calcineurin and
inhibit the T-cell receptor signalling which leads to T-cell
proliferation. Similarly, the immunophilin-drug complex of
FKBP-rapamycin interacts with the RAFT1/FRAP protein and inhibits
the IL-2 receptor signalling.
[0007] Immunophilins have been found to be present at high
concentrations in the central nervous system. Immunophilins are
enriched 10-50 times more 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.
[0008] Surprisingly, it has been found that certain low molecular
weight, small peptidic sequences with a high affinity for FKBPs are
potent rotamase inhibitors and exhibit excellent neurotrophic
effects. Furthermore, these rotamase inhibitors 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.
[0009] 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.
[0010] Clinical application of these proteins in various
neurological disease states is hampered by difficulties in the
delivery and bioavailability of large proteins to nervous system
targets. By contrast, immunosuppressant drugs with neurotrophic
activity are relatively small and display excellent bioavailability
and specificity. 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).
[0011] To prevent the side effects associated with the use of the
immunosuppressant compounds, the present invention provides a
method of using a non-immunosuppressive compound containing low
molecular weight, small molecule peptidic sequences to enhance
neurite outgrowth, and to promote 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.
SUMMARY OF THE INVENTION
[0012] The present invention relates to a method of using a
neurotrophic low molecular weight, small molecule sulfonamide
compound having an affinity for FKBP-type immunophilins. Once bound
to these proteins, the neurotrophic compounds are potent inhibitors
of the enzyme activity associated with immunophilin proteins,
particularly peptidyl-prolyl isomerase, or rotamase, enzyme
activity. A key feature of the neurotrophic compounds is that they
do not exert any significant immunosuppressive activity.
[0013] Specifically, the present invention relates to a method of
effecting a neuronal activity in an animal, comprising:
[0014] administering to the animal a neurotrophically effective
amount of a compound of formula I: 1
[0015] or a pharmaceutically acceptable salt thereof, wherein:
[0016] A is CH.sub.2, oxygen, NH or N-(C1-C4 alkyl);
[0017] B and D are independently Ar, hydrogen, (C1-C6)-straight or
branched alkyl, (C1-C6)-straight or branched alkenyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkyl, (C1-C6)-straight or branched alkyl or
alkenyl that is substituted with a (C5-C7)-cycloalkenyl, or Ar
substituted (C1-C6) straight or branched alkyl or alkenyl, wherein,
in each case, one or two of the CH.sub.2 groups of the alkyl or
alkenyl chains may contain 1-2 heteroatoms selected from the group
consisting of oxygen, sulfur, SO and SO.sub.2 in chemically
reasonable substitution patterns, or 2
[0018] provided that both B and D are not hydrogen;
[0019] Q is hydrogen, (C1-C6)-straight or branched alkyl or
(C1-C6)-straight or branched alkenyl;
[0020] T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl;
[0021] Ar is selected from the group consisting of phenyl,
1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic
heterocyclic ring systems with individual ring sizes being 5 or 6
which may contain in either or both rings a total of 1-4
heteroatoms independently selected from O, N and S; wherein Ar may
contain one to three substituents which are independently selected
from the group consisting of hydrogen, halo, hydroxyl, nitro,
trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched
alkyl, (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or
branched alkyl, O-(C2-C4)-straight or branched alkenyl, O-benzyl,
O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
[0022] E is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl
substituted with (C1-C4)-straight or branched alkyl or
(C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar;
[0023] J is hydrogen or C1 or C2 alkyl or benzyl; 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 oxygen, sulfur, SO or
SO.sub.2 substituent therein;
[0024] n is 0 to 3; and
[0025] the stereochemistry at carbon positions 1 and 2 are R or
S.
[0026] The present invention also relates to a method of effecting
a neuronal activity in an animal, comprising:
[0027] administering to the animal a neurotrophically effective
amount of a compound of formula III: 3
[0028] or a pharmaceutically acceptable salt thereof, wherein:
[0029] B and D are independently Ar, hydrogen, (C1-C6)-straight or
branched alkyl, (C1-C6)-straight or branched alkenyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkyl, (C1-C6)-straight or branched alkyl or
alkenyl that is substituted with a (C5-C7)-cycloalkenyl, or Ar
substituted (C1-C6)-straight or branched alkyl or alkenyl, wherein,
in each case, one or two of the CH.sub.2 groups of the alkyl or
alkenyl chains may contain 1-2 heteroatoms selected from the group
consisting of oxygen, sulfur, SO and SO.sub.2 in chemically
reasonable substitution patterns, or 4
[0030] provided that both B and D are not hydrogen;
[0031] Q is hydrogen, (C1-C6)-straight or branched alkyl or
(C1-C6)-straight or branched alkenyl;
[0032] T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl;
[0033] Ar is selected from the group consisting of phenyl,
1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic
heterocyclic ring systems with individual ring sizes being 5 or 6
which may contain in either or both rings a total of 1-4
heteroatoms independently selected from O, N and S; wherein Ar may
contain one to three substituents which are independently selected
from the group consisting of hydrogen, halo, hydroxyl, nitro,
trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched
alkyl, (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or
branched alkyl, O-(C2-C4)-straight or branched alkenyl, O-benzyl,
O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
[0034] E is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl
substituted with (C1-C4)-straight or branched alkyl or
(C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; and
[0035] m is 0 to 3.
[0036] The present invention further relates to a method of
effecting a neuronal activity in an animal, comprising:
[0037] administering to the animal a neurotrophically effective
amount of a compound of formula IV: 5
[0038] or a pharmaceutically acceptable salt thereof, wherein:
[0039] B and D are independently Ar, hydrogen, (C1-C6)-straight or
branched alkyl, (C1-C6)-straight or branched alkenyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkyl, (C1-C6)-straight or branched alkyl or
alkenyl that is substituted with a (C5-C7)-cycloalkenyl, or Ar
substituted (C1-C6)-straight or branched alkyl or alkenyl, wherein,
in each case, one or two of the CH.sub.2 groups of the alkyl or
alkenyl chains may contain 1-2 heteroatoms selected from the group
consisting of oxygen, sulfur, SO and SO.sub.2 in chemically
reasonable substitution patterns, or 6
[0040] provided that both B and D are not hydrogen;
[0041] Q is hydrogen, (C1-C6)-straight or branched alkyl or
(C1-C6)-straight or branched alkenyl;
[0042] T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl;
[0043] Ar is selected from the group consisting of phenyl,
1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic
heterocyclic ring systems with individual ring sizes being 5 or 6
which may contain in either or both rings a total of 1-4
heteroatoms independently selected from O, N and S; wherein Ar may
contain one to three substituents which are independently selected
from the group consisting of hydrogen, halo, hydroxyl, nitro,
trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched
alkyl, (C2-C6)-straight or branched alkenyl, O (C1-C4)-straight or
branched alkyl, O-(C2-C4)-straight or branched alkenyl, O-benzyl,
O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
[0044] E is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl
substituted with (C1-C4)-straight or branched alkyl or
(C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; and
[0045] m is 0 to 3.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0046] "Alkyl" means a branched or unbranched saturated hydrocarbon
chain containing 1 to 6 carbon atoms, such as methyl, ethyl,
propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl,
n-hexyl, and the like, unless otherwise indicated.
[0047] "Halo" means fluoro, chloro, bromo, or iodo, unless
otherwise indicated.
[0048] "Pharmaceutically acceptable salt" refers to salts of the
subject compounds which possess the desired pharmacological
activity and which are neither biologically nor otherwise
undesirable. The salts can be formed with inorganic acids such as
acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
thiocyanate, tosylate and undecanoate. Base salts include ammonium
salts, alkali metal salts such as sodium and potassium salts,
alkaline earth metal salts such as calcium and magnesium salts,
salt with organic bases such as dicyclohexylamine salts,
N-methyl-D-glucamine, and salts with amino acids such as arginine,
lysine, and so forth. Also, the basic nitrogen-containing groups
can be quarternized with such agents as lower alkyl halides, such
as methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0049] "Phenyl" includes all possible isomeric phenyl radicals,
optionally monosubstituted or multi-substituted with substituents
selected from the group consisting of alkyl, alkoxy, hydroxy, halo,
and haloalkyl.
[0050] "Treatment" covers any treatment of a disease and/or
condition in an animal, particularly a human, and includes:
[0051] (i) preventing a disease and/or condition from occurring in
a subject which may be predisposed to the disease and/or condition
but has not yet been diagnosed as having it;
[0052] (ii) inhibiting the disease and/or condition, i.e.,
arresting its development; and
[0053] (iii) relieving the disease and/or condition, i.e., causing
regression of the disease and/or condition.
[0054] The inventors have discovered that certain low molecular
weight, small molecule sulfonamide compounds have an affinity for
FKBP-type immunophilins, particularly FKBP12. When the sulfonamide
compounds are bound to an FKBP-type immunophilin, they have been
found to inhibit the prolyl-peptidyl cis-trans isomerase activity,
or rotamase, activity of the binding protein and unexpectedly
stimulate neurite growth. This activity is useful in the
stimulation of damaged neurons, the promotion of neuronal
regeneration, the prevention of neurodegeneration, and the
treatment of several neurological disorders known to be associated
with neuronal degeneration and peripheral neuropathies.
[0055] For the foregoing reasons, the present invention relates to
a method of effecting a neuronal activity in an animal,
comprising:
[0056] administering to the animal a neurotrophically effective
amount of a compound of formula I: 7
[0057] or a pharmaceutically acceptable salt thereof, wherein:
[0058] A is CH.sub.2, oxygen, NH or N-(C1-C4 alkyl);
[0059] B and D are independently Ar, hydrogen, (C1-C6)-straight or
branched alkyl, (C1-C6)-straight or branched alkenyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkyl, (C1-C6)-straight or branched alkyl or
alkenyl that is substituted with a (C5-C7)-cycloalkenyl, or Ar
substituted (C1-C6)-straight or branched alkyl or alkenyl, wherein,
in each case, one or two of the CH.sub.2 groups of the alkyl or
alkenyl chains may contain 1-2 heteroatoms selected from the group
consisting of oxygen, sulfur, SO and SO.sub.2 in chemically
reasonable substitution patterns, or 8
[0060] provided that both B and D are not hydrogen;
[0061] Q is hydrogen, (C1-C6)-straight or branched alkyl or
(C1-C6)-straight or branched alkenyl;
[0062] T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl;
[0063] Ar is selected from the group consisting of phenyl,
1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic
heterocyclic ring systems with individual ring sizes being 5 or 6
which may contain in either or both rings a total of 1-4
heteroatoms independently selected from O, N and S; wherein Ar may
contain one to three substituents which are independently selected
from the group consisting of hydrogen, halo, hydroxyl, nitro,
trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched
alkyl, (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or
branched alkyl, O-(C2-C4)-straight or branched alkenyl, O-benzyl,
O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
[0064] E is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl
substituted with (C1-C4)-straight or branched alkyl or
(C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar;
[0065] J is hydrogen or C1 or C2 alkyl or benzyl; 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 oxygen, sulfur, SO or
SO.sub.2 substituent therein;
[0066] n is 0 to 3; and
[0067] the stereochemistry at carbon positions 1 and 2 are R or
S.
[0068] In a preferred embodiment, J and K are taken together and
the compound is represented by formula II: 9
[0069] wherein n is 1 or 2 and m is 0 or 1.
[0070] In a more preferred embodiment, B is selected from the group
consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D
is selected from the group consisting of phenyl, 3-phenylpropyl,
3-phenoxyphenyl and 4-phenoxyphenyl; and E is selected from the
group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl,
2-thienyl, 2,4, 6-triisopropylphenyl, 4-fluorophenyl,
3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl,
1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl,
2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl,
4-chlorophenyl and E-styrenyl.
[0071] The present invention also relates to a method of effecting
a neuronal activity in an animal, comprising:
[0072] administering to the animal a neurotrophically effective
amount of a compound of formula III: 10
[0073] or a pharmaceutically acceptable salt thereof, wherein:
[0074] B and D are independently Ar, hydrogen, (C1-C6)-straight or
branched alkyl, (C1-C6)-straight or branched alkenyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkyl, (C1-C6)-straight or branched alkyl or
alkenyl that is substituted with a (C5-C7)-cycloalkenyl, or Ar
substituted (C1-C6)-straight or branched alkyl or alkenyl, wherein,
in each case, one or two of the CH.sub.2 groups of the alkyl or
alkenyl chains may contain 1-2 heteroatoms selected from the group
consisting of oxygen, sulfur, SO and SO.sub.2 in chemically
reasonable substitution patterns, or 11
[0075] provided that both B and D are not hydrogen;
[0076] Q is hydrogen, (C1-C6)-straight or branched alkyl or
(C1-C6)-straight or branched alkenyl;
[0077] T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl;
[0078] Ar is selected from the group consisting of phenyl,
1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic
heterocyclic ring systems with individual ring sizes being 5 or 6
which may contain in either or both rings a total of 1-4
heteroatoms independently selected from O, N and S; wherein Ar may
contain one to three substituents which are independently selected
from the group consisting of hydrogen, halo, hydroxyl, nitro,
trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched
alkyl, (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or
branched alkyl, O-(C2-C4)-straight or branched alkenyl, O-benzyl,
O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
[0079] E is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl
substituted with (C1-C4)-straight or branched alkyl or
(C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; and
[0080] m is 0 to 3.
[0081] The present invention further relates to a method of
effecting a neuronal activity in an animal, comprising:
[0082] administering to the animal a neurotrophically effective
amount of a compound of formula IV: 12
[0083] or a pharmaceutically acceptable salt thereof, wherein:
[0084] B and D are independently Ar, hydrogen, (C1-C6)-straight or
branched alkyl, (C1-C6)-straight or branched alkenyl,
(C1-C6)-straight or branched alkyl or alkenyl that is substituted
with a (C5-C7)-cycloalkyl, (C1-C6)-straight or branched alkyl or
alkenyl that is substituted with a (C5-C7)-cycloalkenyl, or Ar
substituted (C1-C6)-straight or branched alkyl or alkenyl, wherein,
in each case, one or two of the CH.sub.2 groups of the alkyl or
alkenyl chains may contain 1-2 heteroatoms selected from the group
consisting of oxygen, sulfur, SO and SO.sub.2 in chemically
reasonable substitution patterns, or 13
[0085] provided that both B and D are not hydrogen;
[0086] Q is hydrogen, (C1-C6)-straight or branched alkyl or
(C1-C6)-straight or branched alkenyl;
[0087] T is Ar or substituted 5-7 membered cycloalkyl with
substituents at positions 3 and 4 which are independently selected
from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl,
O-(C1-C4)-alkenyl and carbonyl;
[0088] Ar is selected from the group consisting of phenyl,
1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic
heterocyclic ring systems with individual ring sizes being 5 or 6
which may contain in either or both rings a total of 1-4
heteroatoms independently selected from O, N and S; wherein Ar may
contain one to three substituents which are independently selected
from the group consisting of hydrogen, halo, hydroxyl, nitro,
trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched
alkyl, (C2-C6)-straight or branched alkenyl, O-(C1-C4)-straight or
branched alkyl, O-(C2-C4)-straight or branched alkenyl, O-benzyl,
O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
[0089] E is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl
substituted with (C1-C4)-straight or branched alkyl or
(C1-C4)-straight or branched alkenyl, [(C2-C4)-alkyl or
(C2-C4)-alkenyl)]-Ar or Ar; and
[0090] m is 0 to 3.
[0091] The neuronal activity that is effected by the methods of the
present invention may be selected from the group consisting of:
stimulation of damaged neurons, promotion of neuronal regeneration,
prevention of neurodegeneration and treatment of a neurological
disorder.
[0092] Examples of a neurological disorder that is treatable by the
methods of the present invention include without limitation:
trigeminal neuralgia; glossopharyngeal neuralgia; Bell's Palsy;
myasthenia gravis; muscular dystrophy; amyotrophic lateral
sclerosis; progressive muscular atrophy; progressive bulbar
inherited muscular atrophy; herniated, ruptured or prolapsed
invertebrate disk syndromes; cervical spondylosis; plexus
disorders; thoracic outlet destruction syndromes; peripheral
neuropathies such as those caused by lead, dapsone, ticks,
porphyria, or Guillain-Barr syndrome; Alzheimer's disease; and
Parkinson's disease.
[0093] The methods of the present invention are particularly useful
for treating a neurological disorder selected from the group
consisting of: peripheral neuropathy caused by physical injury or
disease state, physical damage to the brain, physical damage to the
spinal cord, stroke associated with brain damage, and a
neurological disorder relating to neurodegeneration. Examples of a
neurological disorder relating to neurodegeneration include
Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral
sclerosis.
[0094] In the methods of the present invention, the neurotrophic
compound may be administered orally, parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir in dosage formulations containing conventional
non-toxic pharmaceutically-acceptable carriers, adjuvants and
vehicles. The term parenteral as used herein includes subcutaneous,
intravenous, intramuscular, intraperitoneally, intrathecally,
intraventricularly, intrasternal and intracranial injection or
infusion techniques.
[0095] To be effective therapeutically as central nervous system
targets, the neurotrophic compounds should readily penetrate the
blood-brain barrier when peripherally administered. Compounds which
cannot penetrate the blood-brain barrier can be effectively
administered by an intraventricular route.
[0096] The neurotrophic compounds may also be administered in the
form of sterile injectable preparations, for example, as sterile
injectable aqueous or oleaginous suspensions. These suspensions may
be formulated according to techniques known in the art using
suitable dispersing or wetting agents and suspending agents. The
sterile injectable preparations may also be sterile injectable
solutions or suspensions in non-toxic parenterally-acceptable
diluents or solvents, for example, as solutions in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as
solvents or suspending mediums. For this purpose, any bland fixed
oil such as a synthetic mono- or di-glyceride may be employed.
Fatty acids such as oleic acid and its glyceride derivatives,
including olive oil and castor oil, especially in their
polyoxyethylated versions, are useful in the preparation of
injectables. These oil solutions or suspensions may also contain
long-chain alcohol diluents or dispersants.
[0097] Additionally, the neurotrophic compounds may be administered
orally in the form of capsules, tablets, aqueous suspensions or
solutions. Tablets may contain carriers such as lactose and corn
starch, and/or lubricating agents such as magnesium stearate.
Capsules may contain diluents including lactose and dried corn
starch. Aqueous suspensions may contain emulsifying and suspending
agents combined with the active ingredient. The oral dosage forms
may further contain sweetening and/or flavoring and/or coloring
agents.
[0098] The neurotrophic compounds may further be administered
rectally in the form of suppositories. These compositions can be
prepared by mixing the drug with a suitable non-irritating
excipient which is solid at room temperature, but liquid at rectal
temperature and, therefore, will melt in the rectum to release the
drug. Such materials include cocoa butter, beeswax and polyethylene
glycols.
[0099] Moreover, the neurotrophic compounds may be administered
topically, especially when the conditions addressed for treatment
involve areas or organs readily accessible by topical application,
including neurological disorders of the eye, the skin, or the lower
intestinal tract. Suitable topical formulations can be readily
prepared for each of these areas.
[0100] For topical application to the eye, or ophthalmic use, the
compounds can be formulated as micronized suspensions in isotonic,
pH adjusted sterile saline, or, preferably, as a solution in
isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, the
compounds may be formulated into ointments, such as petrolatum, for
ophthalmic use.
[0101] For topical application to the skin, the compounds can be
formulated into suitable ointments containing the compounds
suspended or dissolved in, for example, mixtures with one or more
of the following: mineral oil, liquid petrolatum, white petrolatum,
propylene glycol, polyoxyethylene polyoxypropylene compound,
emulsifying wax and water. Alternatively, the compounds can be
formulated into suitable lotions or creams containing the active
compound suspended or dissolved in, for example, a mixture of one
or more of the following: mineral oil, sorbitan monostearate,
polysorbate 60, cetyl ester wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0102] Topical application to the lower intestinal tract can be
effected in a rectal suppository formulations (see above) or in
suitable enema formulations.
[0103] Dosage levels on the order of about 0.1 mg to about 10,000
mg of the active ingredient compound are useful in the treatment of
the above conditions, with preferred levels of about 0.1 mg to
about 1,000 mg. The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration.
[0104] It is understood, however, that a specific dose level for
any particular patient will depend upon a variety of factors,
including the activity of the specific compound employed; the age,
body weight, general health, sex, and diet of the patient; the time
of administration; the rate of excretion; drug combination; the
severity of the particular disease being treated; and the form of
administration.
[0105] The compounds can be administered with other neurotrophic
agents such as neurotrophic growth factor (NGF), glial derived
growth factor, brain derived growth factor, ciliary neurotrophic
factor, and neurotropin-3. The dosage level of other neurotrophic
drugs will depend upon the factors previously stated and the
neurotrophic effectiveness of the drug combination.
EXAMPLES
[0106] The following examples are illustrative of the present
invention and are not intended to be limitations thereon. Unless
otherwise specified, all percentages are based on 100% by weight of
the final compound.
[0107] The compounds used in the methods of the present invention
may be readily prepared by standard techniques of organic
chemistry, utilizing the general synthetic pathway depicted below.
As described by Scheme I, amino acids 1 protected by suitable
blocking groups P on the amino acid nitrogen may be reacted with
alcohols ROH to generate esters 2. After removal of the protecting
group, the free amine 3 may be reacted with various sulfonyl
chlorides 4 to provide final products 5 in good to excellent yield.
14
[0108] In the compounds depicted above in Scheme I, E is
(C1-C6)-straight or branched alkyl, (C1-C6)-straight or branched
alkenyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl substituted with
(C1-C4)-straight or branched alkyl or (C1-C4)-straight or branched
alkenyl, [(C2-C4)-alkyl or (C2-C4)-alkenyl)]-Ar or Ar; and R is
(CH.sub.2).sub.nCHBD, wherein B and D are independently Ar,
hydrogen, (C1-C6)-straight or branched alkyl, (C1-C6)-straight or
branched alkenyl, (C1-C6)-straight or branched alkyl or alkenyl
that is substituted with a (C5-C7)-cycloalkyl, (C1-C6)-straight or
branched alkyl or alkenyl that is substituted with a
(C5-C7)-cycloalkenyl, or Ar substituted (C1-C6)-straight or
branched alkyl or alkenyl, wherein, in each case, one or two of the
CH.sub.2 groups of the alkyl or alkenyl chains may contain 1-2
heteroatoms selected from the group consisting of oxygen, sulfur,
SO and SO.sub.2 in chemically reasonable substitution patterns, or
15
[0109] provided that both B and D are not hydrogen.
Example 1
Synthesis of
3-(3-Pyridyl)-1-propyl(2S)-N-(.alpha.-toluenesulfonyl)pyrroli-
dine-2-carboxylate (1)
3-(3-Pyridyl)-1-propyl
N-(tert-butyloxy-carbonyl)pvrrolidine-2-carboxylate
[0110] A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (6.0 g;
28 mmol); 3-(3-pyridyl)-1-propanol (5.80 g; 41.8 mmol),
dicyclohexylcarbodiimide (9.20 g; 44.48 mmol), camphorsulfonic acid
(21.60 g; 9.26 mmol) and 4-dimethylaminopyridine (1.12 g; 9.26
mmol) in dry methylene chloride (200 mL) was stirred overnight. The
reaction mixture was filtered through Celite, concentrated, and
purified on a silica gel column eluting with 40% ethyl acetate in
hexane to obtain 5.0 g of the product as a clear oil (53%), .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.1.42 (s, 9H); 1.43-1.95 (m, 6H);
2.68 (m, 2H); 3.46-3.52 (m, 2H); 4.11-4.22 (m, 2H); 4.33 (m, 1H);
7.17-7.24 (m, 1H); 7.47 (m, 1H); 8.43 (s, 2H).
3-(3-Pyridyl)-1-propyl pyrrolidine-2-carboxylate
[0111] A solution of 3-(3-pyridyl)-1-propyl
N-(tert-butyloxycarbonyl)pyrro- lidine-2-carboxylate (3.0 g; 8.9
mmol) in methylene chloride (40 mL) and trifluoroacetic acid (8 mL)
was stirred at room temperature for three hours. Saturated
potassium carbonate was added until the pH was basic, and the
reaction mixture was extracted with methylene chloride (3.times.).
The combined organic extracts were dried and concentrated to yield
1.60 g (77%) of the free amine as a thick oil, .sup.1H NMR (300
MHz, CDCl.sub.3): .delta.1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m,
1H); 2.94 (m, 1H); 3.71 (m, 1H); 4.11 (m, 2H); 7.18 (m, 1H); 7.45
(m, 1H); 8.41 (m, 2H).
3-(3-Pyridyl)-1-propyl
(2S)-N-(.alpha.-toluene-sulfonyl)pyrrolidine-2-carb- oxylate
(1)
[0112] A solution of 3-(3-Pyridyl)-1-propyl
pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and
.alpha.-toluenesulfonyl chloride (160 mg; 0.9 mmol) in methylene
chloride (20 mL) was treated with triethylamine (90 mg; 0.9 mmol)
and stirred for 2 hours at room temperature. The reaction mixture
was filtered to remove solids and applied directly to a silica gel
column, eluting with 50% ethyl acetate in hexane, to obtain 150 mg
(43%) of compound 1 (Table I) as a clear oil, .sup.1H NMR (300 MHz,
CDCl.sub.3) : .delta.1.81-1.85 (m, 2H); 1.95-2.02 (m, 3H);
2.10-2.25 (m, 1H); 2.69-2.74 (t, 2H); 2.85-2.97 (m, 1H); 3.24-3.27
(m, 1H); 4.16-4.20 (m, 2H); 4.29 (d, 1H); 4.34 (m, 1H); 4.45 (d,
1H); 7.20-7.25 (m, 1H); 7.35 (m, 3H); 7.49-7.52 (m, 3H); 8.46 (s,
2H). Anal. Calcd. for C.sub.20H.sub.24N.sub.2O.sub.3S: C, 61.83; H,
6.23; N, 7.21. Found: C, 61.59; H, 6.24; N, 7.17.
Example 2
Synthesis of 4-Phenyl-1-butyl
1-(.alpha.-tolylsulfonyl)-2-pipecolinate (2)
Methyl 1-(.alpha.-tolylsulfonyl)-2-pipecolinate
[0113] To a solution of methyl pipecolinate hydrochloride (1.79 g;
10 mmol) and triethylamine (1.01 g; 10 mmol) in dry methylene
chloride (20 mL) was added .alpha.-toluenesulfonyl chloride (1.9 g;
10 mmol). The resulting mixture was stirred at room temperature
overnight and then concentrated in vacuo. The crude residue was
purified on a silica gel column, eluting with ethyl acetate, to
provide 2.20 g (74%) of the product was an oil which solidified
upon standing, .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.1.26-1.71
(m, 5H) ; 2.15 (d, 1H, =14.4) ; 3.17 (dt, 1H); 3.45 (d, 1H, =12.6);
3.78 (s, 3H); 4.28 (s, 2H); 4.58 (m, 1H); 7.26-7.48 (m, 5H).
N-(.alpha.-tolylsulfonyl)-2-pipecolic acid
[0114] Methyl 1-(.alpha.-tolylsulfonyl)-2-pipecolinate (2.0 g; 6.72
mmol) was dissolved in ethanol (25 mL) and treated with 20 mL of 1N
lithium hydroxide. The mixture was stirred for 2 hours at room
temperature, and then diluted with ethyl acetate (200 mL) and made
acidic (pH 2) with 1N HCL. The organic layer was washed with brine,
dried over magnesium sulfate, and concentrated to obtain 1.90 g
(100%) of the acid as a white solid.
4-Phenyl-1-butyl 1-(.alpha.-tolylsulfonyl)-2-pipecolinate (2)
[0115] A solution of N-(.alpha.-tolylsulfonyl)-2-pipecolic acid
(400 mg; 1.41 mmol), dicyclohexylcarbodiimide (312 mg; 1.5 mmol),
dimethylaminopyridine (7 mg) and 4-phenyl-1-butanol (240 mg; 1.60
mmol) in 100 mL of methylene chloride was stirred overnight at room
temperature. The mixture was filtered through Celite, concentrated,
and purified on a silica gel column, eluting with 25% ethyl acetate
in hexane, to obtain 380 mg (48%) of compound 2 (Table I) as a
clear oil, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.10-1.69 (m,
5H); 1.70 (tt, 4H, =6.1 , 6.6); 2.15 (m, 1H); 2.66 (t, 2H, =6.6);
3.16 (m, 1H); 3.45 (m, 1H); 4.19 (t, 2H, =6.1); 4.28 (s, 2H); 4.58
(m, 1H); 7.18-7.47 (m, 10H). Anal. Calcd. for
C.sub.23H.sub.29NO.sub.4S: C, 66.48; H, 7.03; N, 3.37. Found: C,
66.34; H, 7.06; N, 3.41.
Example 3
Synthesis of 1,5-Diphenyl-3-pentyl
(N-(.alpha.-toluenesulfonyl)pipecolate (3)
3-Phenyl-1-propanal
[0116] Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride
(50 mL), cooled to -78.degree. C., was treated with
dimethylsulfoxide (3.4 mL) in 10 mL of methylene chloride. After
stirring for 5 minutes, 3-phenyl-1-propanol (2.72 g; 20 mmol) in 20
mL of methylene chloride was added, and the resulting mixture was
stirred at -78.degree. C. for 15 minutes, treated with 14 mL of
triethylamine, stirred an additional 15 minutes, and poured into
100 mL of water. The layers were separated, the organic phase was
dried and concentrated, and the crude residue was purified on a
silica gel column, eluting with 10% ethyl acetate in hexane, to
obtain 1.27 g (47%) of the aldehyde as a clear oil, .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta.2.80 (m, 2H); 2.98 (m, 2H); 7.27 (m,
5H); 9.81 (s, 1H).
1,5-Diphenyl-3-pentanol
[0117] A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) in
diethylether (10 mL) was added to a stirred slurry of magnesium
turnings (250 mg; 10.18 mmol) in 5 mL of ether. The reaction was
initiated with a heat gun, and after the addition was complete the
mixture was heated on an oil bath for 30 minutes.
3-Phenyl-1-propanal (1.25 g; 9.33 mmol) was added in 10 mL of
ether, and reflux was continued for 1 hour. The reaction was cooled
and quenched with saturated ammonium chloride, extracted into
2.times. ethyl acetate, and the combined organic portions were
dried and concentrated. Chromatographic purification on a silica
gel column (10% ethyl acetate in hexane) delivered 1.42 g (63%) of
the diphenyl alcohol, .sup.1H NMR (300 MHz, CDCl.sub.3) :
.delta.1.84 (m, 4H); 2.61-2.76 (m,4H); 3.65 (m, 1H); 7.19-7.29 (m,
10H).
1,5-Diphenyl-3-pentyl N-(.alpha.-toluenesulfonyl)-pipecolate
(3)
[0118] A mixture of N-(.alpha.-tolylsulfonyl)-2-pipecolic acid (380
mg; 1.34 mmol), 1,5-diphenyl-3-pentanol (485 mg; 2.01 mmol),
dicyclohexylcarbodiimide (445 mg; 2.15 mmol), camphorsulfonic acid
(105 mg; 0.45 mmol) and dimethylaminopyridine (55 mg; 0.45 mmol) in
20 mL of methylene chloride was stirred overnight at room
temperature. The mixture was filtered through Celite, concentrated,
and purified on a silica gel column, eluting with 15% ethyl acetate
in hexane, to obtain 270 mg (40%) of compound 3 (Table I) as a
clear oil, .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.0.80 (m, 4H);
1.23-1.97 (m, 5H); 2.15 (d, 1H); 2.61-2.69 (m, 4H); 3.23 (m, 1H);
3.44 (dm, 1H) ; 4.27 (s, 2H) ; 4.53 (d, 1H, =4.5) ; 5.06 (m, 1H);
7.16-7.34 (m, 15H). Anal. calcd. for C.sub.30H.sub.35NO.sub.4S: C,
71.26; H, 6.98; N, 2.77. Found: C, 72.82; H, 7.17; N, 2.53.
[0119] As discussed above, the sulfonamide compounds used in the
methods of the present invention have an affinity for the FK506
binding protein, particularly FKBP12. The inhibition of the prolyl
peptidyl cis-trans isomerase activity of FKBP may be measured as an
indicator of this affinity.
Ki Test Procedure
[0120] Inhibition of the peptidyl-prolyl isomerase (rotamase)
activity of the inventive compounds can be evaluated by known
methods described in the literature (Harding, et al., Nature, 1989,
341:758-760; Holt et al. J. Am. Chem. Soc., 115:9923-9938). These
values are obtained as apparent Ki's and are presented in Table I.
The cis-trans isomerization of an alanine-proline bond in a model
substrate, N-succinyl-Ala-Ala-Pro-Phe-p-n- itroanilide, is
monitored spectrophotometrically in a chymotrypsin-coupled assay,
which releases para-nitroanilide from the trans form of the
substrate. The inhibition of this reaction caused by the addition
of different concentrations of inhibitor is determined, and the
data is analyzed as a change in first-order rate constant as a
function of inhibitor concentration to yield the apparent Ki
values.
[0121] In a plastic cuvette are added 950 mL of ice cold assay
buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in
10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of
chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at
various concentrations in dimethyl sulfoxide. The reaction is
initiated by the addition of 5 mL of substrate
(succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM
LiCl in trifluoroethanol).
[0122] The absorbance at 390 nm versus time is monitored for 90
seconds using a spectrophotometer and the rate constants are
determined from the absorbance versus time data files.
[0123] The data for these experiments for representative compounds
are presented in Table I under the column "Ki".
[0124] The neurotrophic effects of the compounds of the present
invention can be demonstrated in cellular biological experiments in
vitro, as described below.
Chick Dorsal Root Ganglion Cultures and Neurite Outgrowth
[0125] Dorsal root ganglia were dissected from chick embryos of ten
day gestation. Whole ganglion explants were cultured on thin layer
Matrigel-coated 12 well plates with Liebovitz L15 plus high glucose
media supplemented with 2 mM glutamine and 10% fetal calf serum,
and also containing 10 .mu.M cytosine .beta.-D arabinofuranoside
(Ara C) at 37.degree. C. in an environment containing 5% CO.sub.2.
Twenty-four hours later, the DRGs were treated with various
immunophilin ligands. Forty-eight hours after drug treatment, the
ganglia were visualized under phase contrast or Hoffman Modulation
contrast with a Zeiss Axiovert inverted microscope.
Photomicrographs of the explants were made, and neurite outgrowth
was quantitated. Neurites longer than the DRG diameter were counted
as positive, with total number of neurites quantitated per each
experimental condition. Three to four DRGs are cultured per well,
and each treatment was performed in duplicate.
[0126] The data for these experiments for representative compounds
are presented in the "ED50" column of Table I.
1TABLE I In Vitro Activity of Example Compounds Compound Ki, nM
ED50, nM 16 34 0.031 4-phenyl-1-butyl-N-(.alpha.-toluenesulfonyl)
pipecolate (2) 17 107 0.133 1,5-diphenyl-3-pentyl-N-(.al-
pha.-toluenesulfonyl)- pipecolate (3) 18 332 1.0
1,7-diphenyl-4-heptyl-N-(para-toluenesulfonyl)- pipecolate 19 72
0.002 3-(3-pyridyl)-1-propyl-(2S)-N-(.alpha.-toluenesulfonyl)-
pyrrolidine-2-carboxylate (1) 20 504 --
4-phenyl-1-butyl-N-(para-toluenesulfonyl)- pipecolate 21 470 --
4-phenyl-1-butyl-N-(benzenesulfonyl) pipecolate
MPTP Model of Parkinson's Disease
[0127] The remarkable neurotrophic and neuroregenerative effects of
the present inventive compounds were further demonstrated in an
animal model of neurodegenerative disease. MPTP lesioning of
dopaminergic neurons in mice was used as an animal model of
Parkinson's Disease. Four week old male CD1 white mice were dosed
i.p. with 30 mg/kg of MPTP for 5 days. Test compounds (4 mg/kg), or
vehicle, were administered s.c. along with the MPTP for 5 days, as
well as for an additional 5 days following cessation of MPTP
treatment. At 18 days following MPTP treatment, the animals were
sacrificed and the striata were dissected and perfusion-fixed.
Immunostaining was performed on saggital and coronal brain sections
using anti-tyrosine hydroxylase 1 g to quantitate survival and
recovery of dopaminergic neurons. In animals treated with MPTP and
vehicle, a substantial loss of functional dopaminergic terminals
was observed as compared to non-lesioned animals. Lesioned animals
receiving test compounds showed a significant recovery of
TH-stained dopaminergic neurons. Table II presents quantitation for
the recovery of TH-positive dopaminergic neurons in the striatum of
animals receiving compounds 1, 2, 5 and 6 in this model.
2TABLE II In Vivo Activity of Selected Example Compounds % Rescue,
TH Immunostaining Compound at 4 mg/kg, s.c. 22 44.31
3-(3-pyridyl)-1-propyl-(2S)-N-(.alpha.-toluenesulfonyl)-
pyrrolidine-2-carboxylate (1) 23 38.00
4-phenyl-1-butyl-N-(.alpha.-toluenesulfonyl) pipecolate (2) 24
4-phenyl-1-butyl-N-(para-toluenesulfonyl)- pipecolate 25 29.22
4-phenyl-1-butyl-N-(benzenesulfonyl) pipecolate
[0128] All publications and patents identified above are hereby
incorporated by reference.
[0129] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *