CA2602802A1 - Heterocyclic thioesters and ketones - Google Patents
Heterocyclic thioesters and ketones Download PDFInfo
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- CA2602802A1 CA2602802A1 CA002602802A CA2602802A CA2602802A1 CA 2602802 A1 CA2602802 A1 CA 2602802A1 CA 002602802 A CA002602802 A CA 002602802A CA 2602802 A CA2602802 A CA 2602802A CA 2602802 A1 CA2602802 A1 CA 2602802A1
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- pyrrolidinecarbothioate
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Abstract
This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
Description
TITLE OF THE INVENTION
HETEROCYCLIC THIOESTERS AND KETONES
This application is a divisional of Canadian patent application Serial No.
HETEROCYCLIC THIOESTERS AND KETONES
This application is a divisional of Canadian patent application Serial No.
2,263,927 filed internationally on September 9, 1997 and entered nationally on February 23, 1999.
BACKGROUND OF THE INVENTION
1. Field of Invention This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme 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 the immune and nervous systems.
Immunophilins are known to have peptidyi-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 immuno-suppressant 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 formula-tion of a complex of immunosuppressant drug and immunophilin. 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.
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.
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.
It has been found that picomolar concentrations of an immunosuppres-sant such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory neurons, namely 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.
Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Furthermore, these rotamase inhibitors are devoid of immuno-suppressive 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 neuro-degenerative 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 hypo-thesized 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.
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 neuro-trophic 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).
To prevent the side effects associated with use of the immunosuppressant compounds, the present invention provides non-immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite out-growth, and promoting neuronal growth and regeneration in various neuropath-ological 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
The present invention relates to neurotrophic low molecular weight, small molecule compounds 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 compounds of the present invention is that they do not exert any significant immuno-suppressive activity in addition to their neurotrophic activity.
Specifically, the present invention relates to a compound of formula II:
[Cx2] n CZ-Rl II
OO X
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
XisOorS;
Z is selected from the group consisting of S, CHz, CHR1, and C(R1)2;
Rl is selected from the group consisting of C1-C5, straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, Arl and mixtures thereof, wherein said Rl is unsubstituted or substituted with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C3 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ari or a mixture thereof;
R2 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Arl; and Ari is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl wherein said Ari is unsubstituted or substituted with halo, hydroxy, nitro, Cl-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of the compound of formula II for effecting a neuronal activity; and (ii) a pharmaceutically acceptable carrier.
The present invention further relates to a method of effecting a neuronal activity in an animal, comprising:
administering to the animal an effective amount of the compound of formula II.
This is a first divisional of application No. 2,263,927 and relates to compounds, compositions and uses thereof in which Z is S.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1(A) is a representative photomicrograph of untreated sensory neurons.
BACKGROUND OF THE INVENTION
1. Field of Invention This invention relates to neurotrophic low molecular weight, small molecule heterocyclic thioesters and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme 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 the immune and nervous systems.
Immunophilins are known to have peptidyi-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 immuno-suppressant 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 formula-tion of a complex of immunosuppressant drug and immunophilin. 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.
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.
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.
It has been found that picomolar concentrations of an immunosuppres-sant such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory neurons, namely 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.
Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Furthermore, these rotamase inhibitors are devoid of immuno-suppressive 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 neuro-degenerative 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 hypo-thesized 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.
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 neuro-trophic 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).
To prevent the side effects associated with use of the immunosuppressant compounds, the present invention provides non-immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite out-growth, and promoting neuronal growth and regeneration in various neuropath-ological 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
The present invention relates to neurotrophic low molecular weight, small molecule compounds 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 compounds of the present invention is that they do not exert any significant immuno-suppressive activity in addition to their neurotrophic activity.
Specifically, the present invention relates to a compound of formula II:
[Cx2] n CZ-Rl II
OO X
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
XisOorS;
Z is selected from the group consisting of S, CHz, CHR1, and C(R1)2;
Rl is selected from the group consisting of C1-C5, straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, Arl and mixtures thereof, wherein said Rl is unsubstituted or substituted with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C3 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ari or a mixture thereof;
R2 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Arl; and Ari is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl wherein said Ari is unsubstituted or substituted with halo, hydroxy, nitro, Cl-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of the compound of formula II for effecting a neuronal activity; and (ii) a pharmaceutically acceptable carrier.
The present invention further relates to a method of effecting a neuronal activity in an animal, comprising:
administering to the animal an effective amount of the compound of formula II.
This is a first divisional of application No. 2,263,927 and relates to compounds, compositions and uses thereof in which Z is S.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1(A) is a representative photomicrograph of untreated sensory neurons.
FIG. 1(B) is a representative photomicrograph of compound 1 (10 pM) promoting neurite outgrowth in sensory neurons.
FIG. 1(C) is a representative photomicrograph of compound 1 (1 nM) promoting neurite outgrowth in sensory neurons.
FIG. 1(D) is a representative photomicrograph of compound 1 (1 pM) promoting neurite outgrowth in sensory neurons.
FIG. 2(A) is a representative photomicrograph of untreated sensory neurons.
FIG. 2(B) is a representative photomicrograph of compound 9 (10 pM) promoting neurite outgrowth in sensory neurons.
FIG. 2(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons.
FIG. 2(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.
FIG. 3(A) is a representative photomicrograph of untreated sensory neurons.
FIG. 3(B) is a representative photomicrograph of compound 10 (10 pM) promoting neurite outgrowth in sensory neurons.
FIG. 3(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons.
FIG. 3(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.
FIG. 4 presents quantitation for the recovery of TH-positive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and 10.
- ] -DETAILED DESCRIPTION OF THE INVENTION
Definitions "Alkyl" refers to 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.
"Alkoxy" refers to the group -OR wherein R is alkyl as herein defined.
Preferably, R is a branched or unbranched saturated hydrocarbon chain containing 1 to 3 carbon atoms.
"Halo" refers to fluoro, chloro, bromo or iodo, unless otherwise indicated.
"Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.
"Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture con-taining unequal parts of individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt" refers to a salt of the inventive com-pounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. The salt 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-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. Also, the basic nitrogen-containing groups can be quarternized with agents including: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.
"Phenyl" refers to any possible isomeric phenyl radical, optionally mono-substituted or multisubstituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, halo and haloalkyl.
"Treating" refers to:
(i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it;
(ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
Compounds of the Invention The neurotrophic low molecular weight, small molecule FKBP inhibitor compounds of this invention have an affinity for FKBP-type immunophilins, such as FKBP12. When the neurotrophic compounds of this invention 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 un-expectedly stimulate neurite growth.
FORMULA I
In particular, this invention relates to a compound of formula I:
B
p ~ Z~
y X
W
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectfully attached, form a 5-7 membered saturated or unsaturated hetero-cyclic ring containing any combination of CH2, 0, S, SO, SO2, NH or NR2 in any chemically stable oxidation state;
X is either 0 or S;
Z is either S, CH2, CHRl or C(Rl)Z;
W and Y are independently 0, S, CH2 or H2;
Rl is C1-C6 straight or branched chain alkyl or alkenyl, which is sub-stituted in one or more position(s) with (Arl)n, (Arl)õ connected by a C1-C6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or alkenyl, Ar2 or a combination thereof;
n is 1 or 2;
R2 is either C1-Cg straight or branched chain alkyl or alkenyl, C3-Cg cycloalkyl, C5-C7 cycloalkenyl or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar2 are independently a mono-, bi- or tricyclic, carbo- or hetero-cyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of 0, N, S and a combination thereof.
Suitable mono- and bicyclic, carbo- and heterocyclic rings include, with-out limitation, naphthyl, indolyi, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.
FORMULA II
A preferred embodiment of this invention is a compound of formula II:
[CH2] n CZ_R1 N
II
O~ x O
or a pharmaceutically acceptable salt thereof, wherein:
nis1or2;
XisOorS;
Z is selected from the group consisting of S, CH2, CHR1 and C(Rl)2;
Rl is selected from the group consisting of C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, Ari and mixtures thereof, wherein said R1 is unsubstituted or substituted with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1'C4 a l koxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Arl or a mixture thereof;
R2 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Arl; and Arl is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl wherein said Arl is unsubstituted or substituted with halo, trifluoromethyl, hydroxy, nitro, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C1-C4 alkoxy, CZ-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
Specific examples of these embodiments are presented in TABLE I.
TABLE I
No. n X Z R, R2 1 1 0 CH2 3-Phenylpropyl 1,1-Dimethylpropyl 2 1 0 CH2 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 3 1 0 CH2 3-Phenylpropyl tert-Butyl 4 1 0 CH2 3-(3-Pyridyl)propyl tert-Butyl 5 1 0 CH2 3-(3-Pyridyl)propyl Cyclohexyl 6 1 0 CH2 3-(3-Pyridyl)propyl Cyclopentyl 7 1 0 CH2 3-(3-Pyridyl)propyl Cycloheptyl 8 1 0 CH2 2-(9-Fluorenyl) ethyl 1,1-Dimethylpropyl 9 1 0 S 2-Phenethyl 1,1-Dimethylpropyl 10 2 0 S 2-Phenethyl 1,1-Dimethylpropyl 11 1 0 S Methyl(2-thioindole) 1,1-Dimethylpropyl 12 1 0 S 2-Phenethyl Cyclohexyl 13 2 0 S 2-Phenethyl tert-Butyl 14 2 0 S 2-Phenethyl Phenyl 15 1 0 CH2 3-(4-Methoxyphenyl)propyl 1,1-Dimethylpropyl 16 2 0 CH2 4-(4-Methoxyphenyl)butyl 1, 1-Dimethylpropyl 17 2 0 CH2 4-Phenylbutyl 1,1-Dimethylpropyl 18 2 0 CH2 4-Phenylbutyl Phenyl 19 2 0 CH2 4-Phenylbutyl tert-Butyl 20 1 S CH2 3-Phenylpropyl 1,1-Dimethylpropyl 21 1 S S 2-Phenethyl 1,1-Dimethylpropyl 22 2 S CH2 3-Phenylpropyl 1,1-Dimethylpropyl 23 2 S S 2-Phenethyl 1,1-Dimethylpropyl 24 2 0 CHR, 3-Phenylpropyl 1,1-Dimethylpropyl 25 2 0 CHR, 3-Phenylpropyl Cyclohexyl 26. 2 0 CHR, 3-Phenylpropyl Phenyl 27 2 0 CHR, 3-Phenylpropyl 3,4,5-Trimethoxyphenyl 28 1 0 S 2-Phenethyl Cyclopentyl 29 2 0 S 3-Phenyipropyl tert-Butyl 30 1 0 S 3-Phenyipropyl 1,1-Dimethylpropyl 31 1 0 S 3-(3-Pyridyl)propyl 1, 1 -Dimethylpropyl 32 1 0 S 3-Phenylpropyl Cyclohexyl 33 1 0 S 4-Phenylbutyl Cyclohexyl 34 1 0 S 4-Phenylbutyl 1,1-Dimethylpropyl 35 1 0 S 3-(3-Pyridyl)propyl Cyclohexyl 36 1 0 S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 37 1 0 S 3,3-Diphenylpropyl Cyclohexyl 38 1 0 S 3-(4-Methoxyphenyl) 1,1-Dimethylpropyl propyl 39 2 0 S 4-Phenylbutyl tert-Butyl 40 2 0 S 1,5-Diphenyl-3-pentyl 1, 1 -Dimethylpropyl 41 2 0 S 1,5-Diphenyl-3-pentyl Phenyl 42 2 0 S 3-(4-Methoxyphenyl) 1, 1-Dimethylpropyl propyl 43 2 0 S 3-(4-Methoxyphenyl) Phenyl propyl 44 2 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 45 1 0 S 3,3-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl propyl 46 1 0 S 4,4-Di(4-fluoro)phenyl- 1, 1 -Dimethylpropyl butyl 47 1 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 48 1 0 S 2,2-Diphenylethyl 1,1-Dimethylpropyl 49 2 0 S 2,2-Diphenylethyl 1,1-Dimethylpropyl 50 2 0 S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 51 1 0 S 3-(4-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 52 1 0 S 3-(2-Naphthyl)propyl 1, 1 -Dimethylpropyl 53 2 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 54 1 0 S -?r-(3-~hloro)phenylpropyl 1,1-Dimethylpropyl 55 1 0 S 3-(3-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 56 1 0 S 3-(2-Biphenyl)propyl 1, 1 -Dimethylpropyl 57 1 0 S 3-(2-Fluorophenyl)propyl 1,1-Dimethylpropyl 58 1 0 S 3-(3-Fluorophenyl)propyl 1,1-Dimethylpropyl 59 2 0 S 4-Phenylbutyl 1,1-Dimethylpropyl 60 2 0 S 3-Phenylpropyl 1,1-Dimethylpropyl 61 1 0 S 3-(2-Chloro)phenylpropyl 1,1-Dimethylpropyl 62 2 0 S 3-(3-Chloro)phenylpropyl 1,1-Dimethylpropyl 63 2 0 S 3-(2-Fluoro)phenylpropyl 1,1-Dimethylpropyl 64 2 0 S 3-(3-Fluoro)phenylpropyl 1,1-Dimethylpropyl 65 1 0 S 3-(3,4-Dimethoxyphenyl)- 1,1-Dimethylpropyl propyl 66 1 0 CH2 3-Phenylpropyl Cyclohexyl 67 1 0 CH2 2-Phenylethyl tert-Butyl 68 2 0 CH2 4-Phenylbutyl Cyclohexyl 69 2 0 CHR1 2-Phenylethyl tert-Butyl 70 1 0 CH2 3,3-Di(4-fluorophenyl)- 1,1-Dimethylpropyl propyl 71 2 0 CH2 3-Phenylpropyl 1,1-Dimethylpropyl The most preferred examples of TABLE I are named as follows:
1 (2S)-3,3-dimethyl-l-[2-(5-phenylpentanoyl) pyrrolidinyl]pentane-l,2-dione 2 (2S) -3, 3-dimethyl-l- [2- (5- (3-pyridyl) pentanoyl) pyrrolidinyl]pentane-l,2-dione 3 (2S).-2- (.1_-oXo-.S-phenyl) -pentyl-l- (3, 3-dimethyl-1, 2-dioxobutyl)pyrrolidine 9 2-Phenyl-l-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 10 2-Phenyl-l-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 11 l-{2-benzo[b]thiophen-3-ylmethyl_thio)carbonyl]
pyrrolidinyl}-3,3-dimethylpentane-l,2-dione 12 2-Phenyl-l-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 14 2-Phenyl-l-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 28 2-Phenyl-l-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 29 3-Phenyl-l-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate 30 3-Phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 31 3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 32 3-Phenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 33 4-Phenyl-l-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 34 4-Phenyl-l-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrroliciinecarbothioate 35 3- (3-Pyridyl) -1-propyl (2,S) -1- (2-cyclohexyl-1, 2-dioxoethyl)-2-pyrrolidinecarbothioate 36 3,3-Diphenyl-l-propyl (2S)-1-(3,3=dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 37 3,3-Diphenyl-l-propyl (2S).-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 38 3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 39 4-Phenyl-l-butyl 1-(1,2-dioxo-3,3-dimethylbutyl) -2-piperidinecar,bothioate 40 1,5-Diphenyl-3-.pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 41 1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 42 3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate 43 3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate 44 3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate 45 3,3-Di(para-fluoro)phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 46 4,4-Di(para-fluorophenyl)butyl 1-(3,3-dime-thyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 47 3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 48 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
49 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 50 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 51 3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 52 3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 53 3-(1-Naphthyl)-1-propyl 1-(3,3=dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 54 3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 55 3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 56 3-(2-Biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 57 3-(2-Fluorophenyl)propyl (2S)-1-(3;3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 58 3-(3-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 59 4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 60 3-Phenylpropyl 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 61 3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 62 3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 63 3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 64 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 65 3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 66 (2S)-2-( 1-Oxo-5-phenyl) pentyl-l- (2-Cyclohexyl-1, 2-dioxoethyl)pyrrolidine 67 2-(1-Oxo-4-phenyl)-butyl-l-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine 68 2-(1-Oxo-6-phenyl)-hexyl-l-(2-Cyclohexyl-1,2-dioxoethyl)piperidine 69 2-({1-Oxo-[2-{2'-phenyl}ethyl]-4-phenyl}-butyl-l-(3,3-dimethyl-l,2-dioxobutyl)piperidine 70 (2S) -2- [5, 5-di (4-Fluorophenyl) pentanoyl] -1- (3, 3 dimethyl-1,2-pentanedione)pyrrolidine 71 3,3-Dimethyl-l-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione FORMULA III
Another preferred embodiment is a compound of formula III:
B-C
A
. N 1-f Z Ri or a pharmaceutically acceptable salt thereof, wherein:
A, B, C and D are independently CH2, 0, S, SO, SOZ, NH or NR2;
XisOorS;
Z is S, CH2, CHRI or C(R1)Z;
Rl is C1-C6 straight or branched chain alkyl or alkenyl, which is substi-tuted in one or more position(s) with (Arl)r,, (Arl)õ connected by a C1-C6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or alkenyl, Ar2 or a combination thereof;
n is 1 or 2;
R2 is either C1-C9 straight or branched chain alkyl or alkenyl, C3-C9 cyclo-alkyl, C5-C7 cycloalkenyl or Arl, wherein said alkyl, alkenyl, cycloalkyl or cyclo-alkenyl is e.ither unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar2 are independently a mono-, bi- or tricyclic, carbo- or hetero-cyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of 0, N, S and a combination thereof.
Particularly preferred compounds of formula III are presented in TABLE II.
TABLE II
No. A B C X Z Rl R2 72 CH2 S CH2 0 S 2-phenethyl 3,3-dimethyl-pentyl 73 CH, S CH2 0 C'H2 3-phenylpropyl 3, 3-dimethyl-pentyl 74 C:-:, CH, N'ri 0 S 2-phenethyl 3,3-dimethyl-pentyl 75 0:1 , S CH2 S S 2-phenethyl 3, 3-dimethyl-pentyl FORMULA IV
A further preferred embodiment of this invention is a compound of formula IV:
I
IV
o X
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C and D are independently CH2, 0, S, SO, SOZ, NH or NR2;
XisOorS;
Z is S, CH2, CHR1 or C(R1)2;
R1 is C1-C5 straight or branched chain alkyl or alkenyl, which is substi-tuted in one or more position(s) with (Arl), (Arl)n connected by a C1-C6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or alkenyl, Ar2 or a combination thereof;
n is l or 2;
R2 is either C1-C9i straight or branched chain alkyl or alkenyl, C3-C9 cyclo-alkyl, C5-C7 cycloalkenyl or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cyclo-alkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4, straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar2 are independently a mono-, bi- or tricyclic, carbo- or hetero-cyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of 0, N, S and a combination thereof.
Particularly preferred compounds of formula IV are presented in TABLE III.
TABLE III
No. A B C D X Z R, R2 76 CH, CH0 0 CH2 0 CH, 3-phenylpropyl 3,3-dimethylpentyl 77 CH2 CH0 0 CH0 0 S 2-phenethyl 3,3-dimethylpentyl 78 CH, CH, S CH0 0 CH33-phenylpropyl 3,3-dimethylpentyl - - - -79 CH, CH, S CH1 0 S 2-phenethyl 3,3-dimethylpentyl The compounds of this invention possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual stereoisomers.
The individual stereoisomers may be obtained by using an optically active start-ing material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compound of formula (I). It is understood that the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the scope of the present invention. The compounds of this invention possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. The individual enantiomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis. It is understood that the individual R-and S-stereoisomers as well as mixtures of stereoisomers and encompassed by this invention. The S-stereoisomer is most preferred due to its greater activity.
FORMULAE IA, IIA, IIIA and IVA
According to an aspect, the invention relates to compounds of formulae IA, IIA, IIIA and IVA outlined below. The invention also relates to pharma-ceutical compositions comprising these compounds. Moreover, the invention relates to administering to an animal a neurotrophically effective amount of a compound of formulae IA, IIA, IIIA or IVA.
B
A N
N
O O
O
IA
(CH2)n N
N
O O
O
/ B'-C
N
O
IIIA
B/ C D
I I
AN N
O O
O
Method of Using the Compounds of the Invention The compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12, which is present in the brain. When the inventive compounds bind to FKBP in the brain, they exhibit excellent neuro-trophic activity. 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.
For the foregoing reasons, the present invention further relates to a method of effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of a compound of formulae I, II, III or IV.
In a preferred embodiment, 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.
The neurological disorders that may be treated include but are not limited to: 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-Barre syndrome; Alzheimer's disease; and Parkinson's disease.
The compounds 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, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.
Examples of neurological disorders relating to neurodegeneration are Alzheimer's Disease, Parkinson's Disease and amyotrophic lateral sclerosis.
For these purposes, the compounds 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, intra-venous, intramuscular, intraperitoneally, intrathecally, intraventricularly, intrasternal and intracranial injection or infusion techniques.
To be effective therapeutically as central nervous system targets, the 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.
The compounds may be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oieaginous sus-pensions. These suspensions may be formulated according to techniques known 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 conven-tionally 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.
Additionally, the 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 sus-pending agents combined with the active ingredient. The oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents.
The compounds may also be administered rectally the form of supposi-tories. 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.
Furthermore, the 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.
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.
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 polyoxypro-pylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active com-pound 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.
Topical application to the lower intestinal tract can be effected in rectal suppository formulations (see above) or in suitable enema formulations.
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 condi-tions, 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.
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.
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 pre-viously stated and the neurotrophic effectiveness of the drug combination.
Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical composition comprising:
(i) a neurotrophically effective amount of the compound of formula I, II, III or IV, and (ii) a pharmaceutically acceptable carrier. The above discussion relating to the utility and administration of the compounds of the present invention also applies to the pharmaceutical compositions of the present invention.
Examples 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.
Synthesis of (2S)-2-(1-oxo-5-phenyl)-pentyl-l-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine (1) (2S)-2-(1-oxo-5-phenyl)pentyl-N-benzYlpyrroliciine.
1-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 mL of THF was added to 0.24 g (10 mmol) of magnesium turnings in 50 mL of refluxing THF. After the addition was complete, the mixture was refluxed for an additional 5 hours, and then added slowly to a refluxing solution of N-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 mL of THF. After 2 hours of further reflux, the mixture was cooled and treated with 5 mL of 2 N HCl. The reaction mixture was diluted with ether (100 mL) and washed with saturated NaHCO3, water and brine. The organic phase was dried, concentrated and chromatographed, eluting with 5:1 CH2C12:EtOAc to obtain 2.05 g(64%) of the ketone as an oil, 1H NMR (CDC13; 300 MHz): 1.49-2.18 (m, 8H); 2.32-2.46 (m, 1H); 2.56-2.65 (m, 2H); 2.97-3.06 (m, 1H); 3.17-3.34 (m, 1H); 3.44-3.62 (m, 1H); 4.02-4.23 (m, 2H); 7.01-7.44 (m, 10H).
(2S)-2-(1-oxo-5-phenyl)pentylpyrrolidine.. The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mg) was hydrogenated at 40 psi in a Paar shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The free amine was obtained as a yellow oil (230 mg; 100 0), 1H NMR (CDC13;
300 MHz): 1.75-2.34 (m, 10H) ; 2.55 (m, 2H); 2.95 (dm, 1H) ; 3. 45-3. 95 (m, 1H) ; 4. 05 (m, 1H) ; 7. 37 (m, 5H) (2S)-2-(l-oxo-5-phenyl)pentyl-l-(1,2-dioxo-2-methoxyethyl)pyrrolidine. To a solution of (2S)-2-(1-oxo-5-phenyl)pentylpyrrolidine (230 mg; 1.0 mmol) in CH2C12(20 mL) at 0 C was added dropwise methyloxalyl chloride (135 mg; 1.1 mmol). After stirring at 0 C for 3 hours, the reaction was quenched with saturated NH9C1 and the organic phase was washed with water and brine and dried and concentrated. The crude residue was purified on a silica gel column, eluting with 20:1 CH2C12:EtOAc to obtain 300 mg of the oxamate as a clear oil (98%), 'H NMR
(CDC13; 300 MHz): 1.68 (m, 4H); 1.91-2.38 (m, 4H); 2.64 (t, 2H); 3.66-3.80 (m, 2H); 3.77, 3.85 (s, 3H total);
4.16 (m, 2H); 4.90 (m, 1H); 7.16 (m, 3H); 7.27 (m, 2H).
(2S)-2-({1-oxo-5-pheny-1}-pentyl-.1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine (1). To a solution oi t}'ie oxamate above (250 mg; 0.79 mmol) in anhydrous ether (15 mL), cooled to - 78 C, was added 1,1-dimethylpropyl-magnesium chloride (0.8 mL of a 1.0 M solution in ether;
0.8 mmol). After stirring the resulting mixture at -78 C
for 2 hours, the reaction was quenched by the addition of 2 mL of saturated NH4C1, followed by 100 mL of EtOAc.
The organic phase was washed with brine, dried, concentrated, and purified on a silica gel column, eluting with 50:1 CH2C12:EtOAc. Compound 1 was obtained as a clear oil, 120 mg, 'H NMR (CDC13, 300 MHz) b 0.87 (t, 3H, J=7.5); 1.22 (s, 3H); 1.25 (s, 3H); 1.67 (m, 4H);
1.70-2.33 (m, 6H) ; 2.61 (t, 2H, J=7.1); 3.52 (m, 2H); 4.17 (t, 2H, J=6.2) ; 4.52 (m, 1H) ; 7. 16--7.49 (m, 5H) . Anal.
Calcd. for C22H31NO3 - H20: C, 70.37; H, 8.86; N, 3.73.
Found: 70.48; H, 8.35; N, 3.69.
Synthesis of 2-phenyl-l-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate (9) Methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-Pvrrolidinecarboxylate. A solution of L-proline methyl ester hydrochloride (3.0'8 g; 18.60 mmol) in dry methylene chloride was cooled to 0 C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formed slurry under a nitrogen atmosphere for 15 min, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0 C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over MgSO9 and concentrated. The crude residue was purified on a silica gel column; eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for,trans rotamer given. 1H NMR (CDC13) 5 1.93 (dm, 2H); 2.17(m, 2H); 3.62(m, 2H); 3.71 (s, 3H);
3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, 1=8.4, 3.3).
Methyl (2S)-1-(1,2-dioxo-3 3-dimethylpentyl)-2-pyrrolidinecarboxylate.
A solution of methyl (2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecar-boxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78 C and treated with 14.2 mL of a 1.0 M solution of 1,1-dimethylpropyl-magnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil, 'H NMR (CDC13): b 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J=8.4, 3.4).
(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid. A
mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0 C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCI, diluted with water, and extracted into 100 mL of inethylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g(870) of snow-white solid which did not require further purification, 1H NMR (CDC13): b 0.87 (t, 3H); 1.22, 1.25 (s, 3H each);
1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m,.1H);
3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
2-phenyl-l-ethyl 1-(3,3-dimethyl-12-dioxopentyl)-2-pyrrolidinecarbothioate (9) . To a solution of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (241 mg; 1.0 mmol) in CHZC12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 C and treated with a solution of phenethyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2ClZ. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo;
the crude residue was purified by flash chromatography (10:1 hexane:EtOAc) to obtain 302 mg (84%) of 9 as an oil, 'H NMR (CDC13, 300 MHz) : b 0.85 (t, 3H, J=7.5); 1.29 (s, 3H); 1.31 (s, 3H); 1.70-2.32 (m, 6H); 2.92 (t, 2H, J=7.4); 3.22(t, 2H, J=7.4); 3.58 (m, 2H); 4.72 (m, 1H);
7.23-7.34 (m, 5H). Anal. Calcd. for C20HZ7N03S - 0.4H20:
C, 65.15; H, 7.60; N, 3.80. Found: C, 65.41; H; 7.49;
N, 3.72.
Synthesis of 2-phenyl-l-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate (10) Methyl 1-(1,2-dioxo-2-methoxyethyl)-2-piperidine-carboxylate. A solution of methyl pipecolate hydrochloride (8.50 g; 47.31 mmol) in dry methylene chloride (100 mL) was cooled to 0 C and treated with triethylamine (10.5 g; 103 mmol; 2.1 eq) After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (8.50 g;
69.4 mmol) in methylene chloride (75 mL) was added dropwise. The resulting mixture was stirred at 0 C for 1.5 hours. After filtering to remove solids, the organic phase was washed with water, dried over MgSO4 and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 9.34 g(860) of the product as a reddish oil.
Mixture of cis-trans amide rotamers; data for trans rotamer given. 1H NMR (CDC13) b 1.22-1.45 (m, 2H) 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m, 1H); 3.55 (m, 1H) ; 3.76 (s, 3H) ; 3.85, 3.87 (s, 3H total) ; 4.52 (dd, 1H).
Methyl 1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-piperidine -carboxylate. A solution of methyl 1-(1,2-dioxo-2-methoxyethyl)-2-piperidinecarboxylate (3.80 g; 16.57 mmol) in 75 mL of tetrahydrofuran (THF) was cooled to -78 C and treated with 20.7 mL of a 1.0 M solution of 1,1-dimethyl-propyl-magnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 3.32 g (74%) of the oxamate as a colorless oil, 'R NMR (CDC13): 6 0.88 (t, 3H); 1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H); 3.41 (m, 1H); 3.76 (s, 3H); 5.32 (d, 1H).
1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid. A
mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0 C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCI, diluted with water, and extracted into 100 mL
of methylene chloride. The organic extract was washed with brine and con-centrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification, 1H NMR (CDC13): 6 0.89 (t, 3H); 1.21, 1.24 (s, 3H each);
1.42- 1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42 (m, 1H); 5.31 (d, 1H).
2-phenyl-l-ethyl (2S)-1-(3,3-dimethyl-1 2-dioxopentyl)-2-piperidinecarbothioate (10). To a solution of 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid (255 mg; 1.0 mmol) in CHZC12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 C and treated with a solution of phenethyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2C12. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo;
the crude residue was purified by flash chromatography (10 : 1 hexane : EtOAc) to obtain 300 mg (80%) of 10 as an oil, iH NMR (CDC13, 300 MHz) : d 0. 94 (t, 3H, J=7.5) ; 1.27 (s, 3H) ; 1.30 (s, 3H) ; 1. 34-1. 88 (m, 7H) ; 2.45 (m, 1H) ;
2.90 (t, 2H, J=7.7); 3.26 (t, 241, J=7.7); 3.27 (m, 1H);
3.38 (m, 1H); 5.34 (m, 1H); 7.24-7.36 (m, 5-H). Anal.
Calcd. for C21H29N03S: C, 67.17; H, 7.78; N, 3.73. Found:
C, 67.02; H, 7.83; N, 3.78.
As discussed above, the compounds 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 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 K1's and are presented for representative compounds in Table IV. The cis-trans iso-merization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymo-trypsin-coupled assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of differ-ent 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 K1 values.
In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM
HEPES, pH 7.8, 100 mM NaCI), 10 mL of FKBP (2.5 mM 10 mM Tris-CI pH 7.5, 100 mM NaCI, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/mI in 1 mM HCI) and 10 L 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 2.35 mM LiCI trifluoro-ethanol).
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.
The data for these experiments for representative compounds are presented in Table IV under the column "Ki".
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 The neurotrophic effects of the FKBP inhibitor compounds were demon-strated by evaluating the ability of the compounds to promote neurite out-growth in cultured chick sensory neurons from dorsal root ganglia. 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 gluta-mine and 10% fetal calf serum, and also containing 10 pM cytosine P-D
arabinofuranoside (Ara C) at 37 C in an environment containing 5% COZ.
Twenty-four hours later, the DRGs were treated with various concentrations of nerve growth factor, immunophilin ligands or combinations of NFG plus drugs.
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 out-growth 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 duplicate.
Dose-response curves were generated from which ED50 values were obtained. The results of these experiments are presented in Table IV under the column "ED50". Representative photomicrographs of untreated (control) sensory neurons and of compounds 1 (10 pM, 1 nM, 1 pM) , 9 (10 pM, 1 nM, 100 nM) and 10 (10 pM, 1 nM, 100 nM) promoting neurite outgrowth in sensory neurons are shown m FIG.'s 1(A-D), 2(A-D) and 3(A-D), respectively.
MPTP Model of Parkinson's Disease 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 homogenized. Immunostaining was per-formed 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.
The results of these experiments are presented in TABLE IV under the column "% TH recovery". Quantitation for the recovery of TH-positive dopa-minergic neurons in the striatum of animals receiving compounds 1, 9 and 10, and for representative control and lesioned animals not receiving the test drugs, are presented in FIG. 4.
TABLE IV
In Vitro Test Results Example # Ki. nM ED50, nM % TH recoverv 1 31 0.4 23 9 104 0.5 61 12 0.8 54 11 299 0.36 53 12 442 0.025 --14 313 0.9 48 28 108 0.9 41 29 59 0.003 50 30 11 0.00025 65 31 8.7 -- 31 34 34 0.9 48 38 8.9 0.011 37.32 -46 757 -- -=
-- --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.
FIG. 1(C) is a representative photomicrograph of compound 1 (1 nM) promoting neurite outgrowth in sensory neurons.
FIG. 1(D) is a representative photomicrograph of compound 1 (1 pM) promoting neurite outgrowth in sensory neurons.
FIG. 2(A) is a representative photomicrograph of untreated sensory neurons.
FIG. 2(B) is a representative photomicrograph of compound 9 (10 pM) promoting neurite outgrowth in sensory neurons.
FIG. 2(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons.
FIG. 2(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.
FIG. 3(A) is a representative photomicrograph of untreated sensory neurons.
FIG. 3(B) is a representative photomicrograph of compound 10 (10 pM) promoting neurite outgrowth in sensory neurons.
FIG. 3(C) is a representative photomicrograph of compound 9 (1 nM) promoting neurite outgrowth in sensory neurons.
FIG. 3(D) is a representative photomicrograph of compound 9 (100 nM) promoting neurite outgrowth in sensory neurons.
FIG. 4 presents quantitation for the recovery of TH-positive dopaminergic neurons in the striatum of animals receiving compounds 1, 9 and 10.
- ] -DETAILED DESCRIPTION OF THE INVENTION
Definitions "Alkyl" refers to 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.
"Alkoxy" refers to the group -OR wherein R is alkyl as herein defined.
Preferably, R is a branched or unbranched saturated hydrocarbon chain containing 1 to 3 carbon atoms.
"Halo" refers to fluoro, chloro, bromo or iodo, unless otherwise indicated.
"Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.
"Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture con-taining unequal parts of individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt" refers to a salt of the inventive com-pounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. The salt 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-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. Also, the basic nitrogen-containing groups can be quarternized with agents including: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.
"Phenyl" refers to any possible isomeric phenyl radical, optionally mono-substituted or multisubstituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, halo and haloalkyl.
"Treating" refers to:
(i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it;
(ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
Compounds of the Invention The neurotrophic low molecular weight, small molecule FKBP inhibitor compounds of this invention have an affinity for FKBP-type immunophilins, such as FKBP12. When the neurotrophic compounds of this invention 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 un-expectedly stimulate neurite growth.
FORMULA I
In particular, this invention relates to a compound of formula I:
B
p ~ Z~
y X
W
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectfully attached, form a 5-7 membered saturated or unsaturated hetero-cyclic ring containing any combination of CH2, 0, S, SO, SO2, NH or NR2 in any chemically stable oxidation state;
X is either 0 or S;
Z is either S, CH2, CHRl or C(Rl)Z;
W and Y are independently 0, S, CH2 or H2;
Rl is C1-C6 straight or branched chain alkyl or alkenyl, which is sub-stituted in one or more position(s) with (Arl)n, (Arl)õ connected by a C1-C6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or alkenyl, Ar2 or a combination thereof;
n is 1 or 2;
R2 is either C1-Cg straight or branched chain alkyl or alkenyl, C3-Cg cycloalkyl, C5-C7 cycloalkenyl or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar2 are independently a mono-, bi- or tricyclic, carbo- or hetero-cyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of 0, N, S and a combination thereof.
Suitable mono- and bicyclic, carbo- and heterocyclic rings include, with-out limitation, naphthyl, indolyi, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.
FORMULA II
A preferred embodiment of this invention is a compound of formula II:
[CH2] n CZ_R1 N
II
O~ x O
or a pharmaceutically acceptable salt thereof, wherein:
nis1or2;
XisOorS;
Z is selected from the group consisting of S, CH2, CHR1 and C(Rl)2;
Rl is selected from the group consisting of C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, Ari and mixtures thereof, wherein said R1 is unsubstituted or substituted with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1'C4 a l koxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Arl or a mixture thereof;
R2 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl and Arl; and Arl is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl wherein said Arl is unsubstituted or substituted with halo, trifluoromethyl, hydroxy, nitro, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, C1-C4 alkoxy, CZ-C4 alkenyloxy, phenoxy, benzyloxy, amino or a mixture thereof.
Specific examples of these embodiments are presented in TABLE I.
TABLE I
No. n X Z R, R2 1 1 0 CH2 3-Phenylpropyl 1,1-Dimethylpropyl 2 1 0 CH2 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 3 1 0 CH2 3-Phenylpropyl tert-Butyl 4 1 0 CH2 3-(3-Pyridyl)propyl tert-Butyl 5 1 0 CH2 3-(3-Pyridyl)propyl Cyclohexyl 6 1 0 CH2 3-(3-Pyridyl)propyl Cyclopentyl 7 1 0 CH2 3-(3-Pyridyl)propyl Cycloheptyl 8 1 0 CH2 2-(9-Fluorenyl) ethyl 1,1-Dimethylpropyl 9 1 0 S 2-Phenethyl 1,1-Dimethylpropyl 10 2 0 S 2-Phenethyl 1,1-Dimethylpropyl 11 1 0 S Methyl(2-thioindole) 1,1-Dimethylpropyl 12 1 0 S 2-Phenethyl Cyclohexyl 13 2 0 S 2-Phenethyl tert-Butyl 14 2 0 S 2-Phenethyl Phenyl 15 1 0 CH2 3-(4-Methoxyphenyl)propyl 1,1-Dimethylpropyl 16 2 0 CH2 4-(4-Methoxyphenyl)butyl 1, 1-Dimethylpropyl 17 2 0 CH2 4-Phenylbutyl 1,1-Dimethylpropyl 18 2 0 CH2 4-Phenylbutyl Phenyl 19 2 0 CH2 4-Phenylbutyl tert-Butyl 20 1 S CH2 3-Phenylpropyl 1,1-Dimethylpropyl 21 1 S S 2-Phenethyl 1,1-Dimethylpropyl 22 2 S CH2 3-Phenylpropyl 1,1-Dimethylpropyl 23 2 S S 2-Phenethyl 1,1-Dimethylpropyl 24 2 0 CHR, 3-Phenylpropyl 1,1-Dimethylpropyl 25 2 0 CHR, 3-Phenylpropyl Cyclohexyl 26. 2 0 CHR, 3-Phenylpropyl Phenyl 27 2 0 CHR, 3-Phenylpropyl 3,4,5-Trimethoxyphenyl 28 1 0 S 2-Phenethyl Cyclopentyl 29 2 0 S 3-Phenyipropyl tert-Butyl 30 1 0 S 3-Phenyipropyl 1,1-Dimethylpropyl 31 1 0 S 3-(3-Pyridyl)propyl 1, 1 -Dimethylpropyl 32 1 0 S 3-Phenylpropyl Cyclohexyl 33 1 0 S 4-Phenylbutyl Cyclohexyl 34 1 0 S 4-Phenylbutyl 1,1-Dimethylpropyl 35 1 0 S 3-(3-Pyridyl)propyl Cyclohexyl 36 1 0 S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 37 1 0 S 3,3-Diphenylpropyl Cyclohexyl 38 1 0 S 3-(4-Methoxyphenyl) 1,1-Dimethylpropyl propyl 39 2 0 S 4-Phenylbutyl tert-Butyl 40 2 0 S 1,5-Diphenyl-3-pentyl 1, 1 -Dimethylpropyl 41 2 0 S 1,5-Diphenyl-3-pentyl Phenyl 42 2 0 S 3-(4-Methoxyphenyl) 1, 1-Dimethylpropyl propyl 43 2 0 S 3-(4-Methoxyphenyl) Phenyl propyl 44 2 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 45 1 0 S 3,3-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl propyl 46 1 0 S 4,4-Di(4-fluoro)phenyl- 1, 1 -Dimethylpropyl butyl 47 1 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 48 1 0 S 2,2-Diphenylethyl 1,1-Dimethylpropyl 49 2 0 S 2,2-Diphenylethyl 1,1-Dimethylpropyl 50 2 0 S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 51 1 0 S 3-(4-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 52 1 0 S 3-(2-Naphthyl)propyl 1, 1 -Dimethylpropyl 53 2 0 S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 54 1 0 S -?r-(3-~hloro)phenylpropyl 1,1-Dimethylpropyl 55 1 0 S 3-(3-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 56 1 0 S 3-(2-Biphenyl)propyl 1, 1 -Dimethylpropyl 57 1 0 S 3-(2-Fluorophenyl)propyl 1,1-Dimethylpropyl 58 1 0 S 3-(3-Fluorophenyl)propyl 1,1-Dimethylpropyl 59 2 0 S 4-Phenylbutyl 1,1-Dimethylpropyl 60 2 0 S 3-Phenylpropyl 1,1-Dimethylpropyl 61 1 0 S 3-(2-Chloro)phenylpropyl 1,1-Dimethylpropyl 62 2 0 S 3-(3-Chloro)phenylpropyl 1,1-Dimethylpropyl 63 2 0 S 3-(2-Fluoro)phenylpropyl 1,1-Dimethylpropyl 64 2 0 S 3-(3-Fluoro)phenylpropyl 1,1-Dimethylpropyl 65 1 0 S 3-(3,4-Dimethoxyphenyl)- 1,1-Dimethylpropyl propyl 66 1 0 CH2 3-Phenylpropyl Cyclohexyl 67 1 0 CH2 2-Phenylethyl tert-Butyl 68 2 0 CH2 4-Phenylbutyl Cyclohexyl 69 2 0 CHR1 2-Phenylethyl tert-Butyl 70 1 0 CH2 3,3-Di(4-fluorophenyl)- 1,1-Dimethylpropyl propyl 71 2 0 CH2 3-Phenylpropyl 1,1-Dimethylpropyl The most preferred examples of TABLE I are named as follows:
1 (2S)-3,3-dimethyl-l-[2-(5-phenylpentanoyl) pyrrolidinyl]pentane-l,2-dione 2 (2S) -3, 3-dimethyl-l- [2- (5- (3-pyridyl) pentanoyl) pyrrolidinyl]pentane-l,2-dione 3 (2S).-2- (.1_-oXo-.S-phenyl) -pentyl-l- (3, 3-dimethyl-1, 2-dioxobutyl)pyrrolidine 9 2-Phenyl-l-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 10 2-Phenyl-l-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 11 l-{2-benzo[b]thiophen-3-ylmethyl_thio)carbonyl]
pyrrolidinyl}-3,3-dimethylpentane-l,2-dione 12 2-Phenyl-l-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 14 2-Phenyl-l-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 28 2-Phenyl-l-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 29 3-Phenyl-l-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate 30 3-Phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 31 3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 32 3-Phenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 33 4-Phenyl-l-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 34 4-Phenyl-l-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrroliciinecarbothioate 35 3- (3-Pyridyl) -1-propyl (2,S) -1- (2-cyclohexyl-1, 2-dioxoethyl)-2-pyrrolidinecarbothioate 36 3,3-Diphenyl-l-propyl (2S)-1-(3,3=dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 37 3,3-Diphenyl-l-propyl (2S).-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 38 3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 39 4-Phenyl-l-butyl 1-(1,2-dioxo-3,3-dimethylbutyl) -2-piperidinecar,bothioate 40 1,5-Diphenyl-3-.pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 41 1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 42 3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate 43 3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate 44 3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate 45 3,3-Di(para-fluoro)phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 46 4,4-Di(para-fluorophenyl)butyl 1-(3,3-dime-thyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 47 3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 48 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
49 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 50 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 51 3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 52 3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 53 3-(1-Naphthyl)-1-propyl 1-(3,3=dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 54 3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 55 3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 56 3-(2-Biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 57 3-(2-Fluorophenyl)propyl (2S)-1-(3;3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 58 3-(3-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 59 4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 60 3-Phenylpropyl 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarbothioate 61 3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 62 3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 63 3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 64 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 65 3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 66 (2S)-2-( 1-Oxo-5-phenyl) pentyl-l- (2-Cyclohexyl-1, 2-dioxoethyl)pyrrolidine 67 2-(1-Oxo-4-phenyl)-butyl-l-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine 68 2-(1-Oxo-6-phenyl)-hexyl-l-(2-Cyclohexyl-1,2-dioxoethyl)piperidine 69 2-({1-Oxo-[2-{2'-phenyl}ethyl]-4-phenyl}-butyl-l-(3,3-dimethyl-l,2-dioxobutyl)piperidine 70 (2S) -2- [5, 5-di (4-Fluorophenyl) pentanoyl] -1- (3, 3 dimethyl-1,2-pentanedione)pyrrolidine 71 3,3-Dimethyl-l-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione FORMULA III
Another preferred embodiment is a compound of formula III:
B-C
A
. N 1-f Z Ri or a pharmaceutically acceptable salt thereof, wherein:
A, B, C and D are independently CH2, 0, S, SO, SOZ, NH or NR2;
XisOorS;
Z is S, CH2, CHRI or C(R1)Z;
Rl is C1-C6 straight or branched chain alkyl or alkenyl, which is substi-tuted in one or more position(s) with (Arl)r,, (Arl)õ connected by a C1-C6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or alkenyl, Ar2 or a combination thereof;
n is 1 or 2;
R2 is either C1-C9 straight or branched chain alkyl or alkenyl, C3-C9 cyclo-alkyl, C5-C7 cycloalkenyl or Arl, wherein said alkyl, alkenyl, cycloalkyl or cyclo-alkenyl is e.ither unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar2 are independently a mono-, bi- or tricyclic, carbo- or hetero-cyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of 0, N, S and a combination thereof.
Particularly preferred compounds of formula III are presented in TABLE II.
TABLE II
No. A B C X Z Rl R2 72 CH2 S CH2 0 S 2-phenethyl 3,3-dimethyl-pentyl 73 CH, S CH2 0 C'H2 3-phenylpropyl 3, 3-dimethyl-pentyl 74 C:-:, CH, N'ri 0 S 2-phenethyl 3,3-dimethyl-pentyl 75 0:1 , S CH2 S S 2-phenethyl 3, 3-dimethyl-pentyl FORMULA IV
A further preferred embodiment of this invention is a compound of formula IV:
I
IV
o X
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C and D are independently CH2, 0, S, SO, SOZ, NH or NR2;
XisOorS;
Z is S, CH2, CHR1 or C(R1)2;
R1 is C1-C5 straight or branched chain alkyl or alkenyl, which is substi-tuted in one or more position(s) with (Arl), (Arl)n connected by a C1-C6 straight or branched chain alkyl or alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or alkenyl, Ar2 or a combination thereof;
n is l or 2;
R2 is either C1-C9i straight or branched chain alkyl or alkenyl, C3-C9 cyclo-alkyl, C5-C7 cycloalkenyl or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cyclo-alkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4, straight or branched chain alkyl or alkenyl, hydroxyl or a combination thereof; and Arl and Ar2 are independently a mono-, bi- or tricyclic, carbo- or hetero-cyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of 0, N, S and a combination thereof.
Particularly preferred compounds of formula IV are presented in TABLE III.
TABLE III
No. A B C D X Z R, R2 76 CH, CH0 0 CH2 0 CH, 3-phenylpropyl 3,3-dimethylpentyl 77 CH2 CH0 0 CH0 0 S 2-phenethyl 3,3-dimethylpentyl 78 CH, CH, S CH0 0 CH33-phenylpropyl 3,3-dimethylpentyl - - - -79 CH, CH, S CH1 0 S 2-phenethyl 3,3-dimethylpentyl The compounds of this invention possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual stereoisomers.
The individual stereoisomers may be obtained by using an optically active start-ing material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compound of formula (I). It is understood that the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the scope of the present invention. The compounds of this invention possess at least one asymmetric center and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. The individual enantiomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis. It is understood that the individual R-and S-stereoisomers as well as mixtures of stereoisomers and encompassed by this invention. The S-stereoisomer is most preferred due to its greater activity.
FORMULAE IA, IIA, IIIA and IVA
According to an aspect, the invention relates to compounds of formulae IA, IIA, IIIA and IVA outlined below. The invention also relates to pharma-ceutical compositions comprising these compounds. Moreover, the invention relates to administering to an animal a neurotrophically effective amount of a compound of formulae IA, IIA, IIIA or IVA.
B
A N
N
O O
O
IA
(CH2)n N
N
O O
O
/ B'-C
N
O
IIIA
B/ C D
I I
AN N
O O
O
Method of Using the Compounds of the Invention The compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12, which is present in the brain. When the inventive compounds bind to FKBP in the brain, they exhibit excellent neuro-trophic activity. 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.
For the foregoing reasons, the present invention further relates to a method of effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of a compound of formulae I, II, III or IV.
In a preferred embodiment, 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.
The neurological disorders that may be treated include but are not limited to: 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-Barre syndrome; Alzheimer's disease; and Parkinson's disease.
The compounds 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, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.
Examples of neurological disorders relating to neurodegeneration are Alzheimer's Disease, Parkinson's Disease and amyotrophic lateral sclerosis.
For these purposes, the compounds 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, intra-venous, intramuscular, intraperitoneally, intrathecally, intraventricularly, intrasternal and intracranial injection or infusion techniques.
To be effective therapeutically as central nervous system targets, the 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.
The compounds may be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oieaginous sus-pensions. These suspensions may be formulated according to techniques known 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 conven-tionally 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.
Additionally, the 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 sus-pending agents combined with the active ingredient. The oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents.
The compounds may also be administered rectally the form of supposi-tories. 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.
Furthermore, the 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.
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.
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 polyoxypro-pylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active com-pound 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.
Topical application to the lower intestinal tract can be effected in rectal suppository formulations (see above) or in suitable enema formulations.
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 condi-tions, 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.
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.
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 pre-viously stated and the neurotrophic effectiveness of the drug combination.
Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical composition comprising:
(i) a neurotrophically effective amount of the compound of formula I, II, III or IV, and (ii) a pharmaceutically acceptable carrier. The above discussion relating to the utility and administration of the compounds of the present invention also applies to the pharmaceutical compositions of the present invention.
Examples 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.
Synthesis of (2S)-2-(1-oxo-5-phenyl)-pentyl-l-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine (1) (2S)-2-(1-oxo-5-phenyl)pentyl-N-benzYlpyrroliciine.
1-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 mL of THF was added to 0.24 g (10 mmol) of magnesium turnings in 50 mL of refluxing THF. After the addition was complete, the mixture was refluxed for an additional 5 hours, and then added slowly to a refluxing solution of N-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 mL of THF. After 2 hours of further reflux, the mixture was cooled and treated with 5 mL of 2 N HCl. The reaction mixture was diluted with ether (100 mL) and washed with saturated NaHCO3, water and brine. The organic phase was dried, concentrated and chromatographed, eluting with 5:1 CH2C12:EtOAc to obtain 2.05 g(64%) of the ketone as an oil, 1H NMR (CDC13; 300 MHz): 1.49-2.18 (m, 8H); 2.32-2.46 (m, 1H); 2.56-2.65 (m, 2H); 2.97-3.06 (m, 1H); 3.17-3.34 (m, 1H); 3.44-3.62 (m, 1H); 4.02-4.23 (m, 2H); 7.01-7.44 (m, 10H).
(2S)-2-(1-oxo-5-phenyl)pentylpyrrolidine.. The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mg) was hydrogenated at 40 psi in a Paar shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The free amine was obtained as a yellow oil (230 mg; 100 0), 1H NMR (CDC13;
300 MHz): 1.75-2.34 (m, 10H) ; 2.55 (m, 2H); 2.95 (dm, 1H) ; 3. 45-3. 95 (m, 1H) ; 4. 05 (m, 1H) ; 7. 37 (m, 5H) (2S)-2-(l-oxo-5-phenyl)pentyl-l-(1,2-dioxo-2-methoxyethyl)pyrrolidine. To a solution of (2S)-2-(1-oxo-5-phenyl)pentylpyrrolidine (230 mg; 1.0 mmol) in CH2C12(20 mL) at 0 C was added dropwise methyloxalyl chloride (135 mg; 1.1 mmol). After stirring at 0 C for 3 hours, the reaction was quenched with saturated NH9C1 and the organic phase was washed with water and brine and dried and concentrated. The crude residue was purified on a silica gel column, eluting with 20:1 CH2C12:EtOAc to obtain 300 mg of the oxamate as a clear oil (98%), 'H NMR
(CDC13; 300 MHz): 1.68 (m, 4H); 1.91-2.38 (m, 4H); 2.64 (t, 2H); 3.66-3.80 (m, 2H); 3.77, 3.85 (s, 3H total);
4.16 (m, 2H); 4.90 (m, 1H); 7.16 (m, 3H); 7.27 (m, 2H).
(2S)-2-({1-oxo-5-pheny-1}-pentyl-.1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine (1). To a solution oi t}'ie oxamate above (250 mg; 0.79 mmol) in anhydrous ether (15 mL), cooled to - 78 C, was added 1,1-dimethylpropyl-magnesium chloride (0.8 mL of a 1.0 M solution in ether;
0.8 mmol). After stirring the resulting mixture at -78 C
for 2 hours, the reaction was quenched by the addition of 2 mL of saturated NH4C1, followed by 100 mL of EtOAc.
The organic phase was washed with brine, dried, concentrated, and purified on a silica gel column, eluting with 50:1 CH2C12:EtOAc. Compound 1 was obtained as a clear oil, 120 mg, 'H NMR (CDC13, 300 MHz) b 0.87 (t, 3H, J=7.5); 1.22 (s, 3H); 1.25 (s, 3H); 1.67 (m, 4H);
1.70-2.33 (m, 6H) ; 2.61 (t, 2H, J=7.1); 3.52 (m, 2H); 4.17 (t, 2H, J=6.2) ; 4.52 (m, 1H) ; 7. 16--7.49 (m, 5H) . Anal.
Calcd. for C22H31NO3 - H20: C, 70.37; H, 8.86; N, 3.73.
Found: 70.48; H, 8.35; N, 3.69.
Synthesis of 2-phenyl-l-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate (9) Methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-Pvrrolidinecarboxylate. A solution of L-proline methyl ester hydrochloride (3.0'8 g; 18.60 mmol) in dry methylene chloride was cooled to 0 C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formed slurry under a nitrogen atmosphere for 15 min, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0 C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over MgSO9 and concentrated. The crude residue was purified on a silica gel column; eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for,trans rotamer given. 1H NMR (CDC13) 5 1.93 (dm, 2H); 2.17(m, 2H); 3.62(m, 2H); 3.71 (s, 3H);
3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, 1=8.4, 3.3).
Methyl (2S)-1-(1,2-dioxo-3 3-dimethylpentyl)-2-pyrrolidinecarboxylate.
A solution of methyl (2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecar-boxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78 C and treated with 14.2 mL of a 1.0 M solution of 1,1-dimethylpropyl-magnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil, 'H NMR (CDC13): b 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J=8.4, 3.4).
(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid. A
mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0 C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCI, diluted with water, and extracted into 100 mL of inethylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g(870) of snow-white solid which did not require further purification, 1H NMR (CDC13): b 0.87 (t, 3H); 1.22, 1.25 (s, 3H each);
1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m,.1H);
3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
2-phenyl-l-ethyl 1-(3,3-dimethyl-12-dioxopentyl)-2-pyrrolidinecarbothioate (9) . To a solution of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (241 mg; 1.0 mmol) in CHZC12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 C and treated with a solution of phenethyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2ClZ. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo;
the crude residue was purified by flash chromatography (10:1 hexane:EtOAc) to obtain 302 mg (84%) of 9 as an oil, 'H NMR (CDC13, 300 MHz) : b 0.85 (t, 3H, J=7.5); 1.29 (s, 3H); 1.31 (s, 3H); 1.70-2.32 (m, 6H); 2.92 (t, 2H, J=7.4); 3.22(t, 2H, J=7.4); 3.58 (m, 2H); 4.72 (m, 1H);
7.23-7.34 (m, 5H). Anal. Calcd. for C20HZ7N03S - 0.4H20:
C, 65.15; H, 7.60; N, 3.80. Found: C, 65.41; H; 7.49;
N, 3.72.
Synthesis of 2-phenyl-l-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate (10) Methyl 1-(1,2-dioxo-2-methoxyethyl)-2-piperidine-carboxylate. A solution of methyl pipecolate hydrochloride (8.50 g; 47.31 mmol) in dry methylene chloride (100 mL) was cooled to 0 C and treated with triethylamine (10.5 g; 103 mmol; 2.1 eq) After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (8.50 g;
69.4 mmol) in methylene chloride (75 mL) was added dropwise. The resulting mixture was stirred at 0 C for 1.5 hours. After filtering to remove solids, the organic phase was washed with water, dried over MgSO4 and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 9.34 g(860) of the product as a reddish oil.
Mixture of cis-trans amide rotamers; data for trans rotamer given. 1H NMR (CDC13) b 1.22-1.45 (m, 2H) 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m, 1H); 3.55 (m, 1H) ; 3.76 (s, 3H) ; 3.85, 3.87 (s, 3H total) ; 4.52 (dd, 1H).
Methyl 1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-piperidine -carboxylate. A solution of methyl 1-(1,2-dioxo-2-methoxyethyl)-2-piperidinecarboxylate (3.80 g; 16.57 mmol) in 75 mL of tetrahydrofuran (THF) was cooled to -78 C and treated with 20.7 mL of a 1.0 M solution of 1,1-dimethyl-propyl-magnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 3.32 g (74%) of the oxamate as a colorless oil, 'R NMR (CDC13): 6 0.88 (t, 3H); 1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H); 3.41 (m, 1H); 3.76 (s, 3H); 5.32 (d, 1H).
1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid. A
mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0 C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCI, diluted with water, and extracted into 100 mL
of methylene chloride. The organic extract was washed with brine and con-centrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification, 1H NMR (CDC13): 6 0.89 (t, 3H); 1.21, 1.24 (s, 3H each);
1.42- 1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42 (m, 1H); 5.31 (d, 1H).
2-phenyl-l-ethyl (2S)-1-(3,3-dimethyl-1 2-dioxopentyl)-2-piperidinecarbothioate (10). To a solution of 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid (255 mg; 1.0 mmol) in CHZC12 (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, the solution was cooled to 0 C and treated with a solution of phenethyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH2C12. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo;
the crude residue was purified by flash chromatography (10 : 1 hexane : EtOAc) to obtain 300 mg (80%) of 10 as an oil, iH NMR (CDC13, 300 MHz) : d 0. 94 (t, 3H, J=7.5) ; 1.27 (s, 3H) ; 1.30 (s, 3H) ; 1. 34-1. 88 (m, 7H) ; 2.45 (m, 1H) ;
2.90 (t, 2H, J=7.7); 3.26 (t, 241, J=7.7); 3.27 (m, 1H);
3.38 (m, 1H); 5.34 (m, 1H); 7.24-7.36 (m, 5-H). Anal.
Calcd. for C21H29N03S: C, 67.17; H, 7.78; N, 3.73. Found:
C, 67.02; H, 7.83; N, 3.78.
As discussed above, the compounds 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 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 K1's and are presented for representative compounds in Table IV. The cis-trans iso-merization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymo-trypsin-coupled assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of differ-ent 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 K1 values.
In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM
HEPES, pH 7.8, 100 mM NaCI), 10 mL of FKBP (2.5 mM 10 mM Tris-CI pH 7.5, 100 mM NaCI, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/mI in 1 mM HCI) and 10 L 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 2.35 mM LiCI trifluoro-ethanol).
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.
The data for these experiments for representative compounds are presented in Table IV under the column "Ki".
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 The neurotrophic effects of the FKBP inhibitor compounds were demon-strated by evaluating the ability of the compounds to promote neurite out-growth in cultured chick sensory neurons from dorsal root ganglia. 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 gluta-mine and 10% fetal calf serum, and also containing 10 pM cytosine P-D
arabinofuranoside (Ara C) at 37 C in an environment containing 5% COZ.
Twenty-four hours later, the DRGs were treated with various concentrations of nerve growth factor, immunophilin ligands or combinations of NFG plus drugs.
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 out-growth 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 duplicate.
Dose-response curves were generated from which ED50 values were obtained. The results of these experiments are presented in Table IV under the column "ED50". Representative photomicrographs of untreated (control) sensory neurons and of compounds 1 (10 pM, 1 nM, 1 pM) , 9 (10 pM, 1 nM, 100 nM) and 10 (10 pM, 1 nM, 100 nM) promoting neurite outgrowth in sensory neurons are shown m FIG.'s 1(A-D), 2(A-D) and 3(A-D), respectively.
MPTP Model of Parkinson's Disease 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 homogenized. Immunostaining was per-formed 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.
The results of these experiments are presented in TABLE IV under the column "% TH recovery". Quantitation for the recovery of TH-positive dopa-minergic neurons in the striatum of animals receiving compounds 1, 9 and 10, and for representative control and lesioned animals not receiving the test drugs, are presented in FIG. 4.
TABLE IV
In Vitro Test Results Example # Ki. nM ED50, nM % TH recoverv 1 31 0.4 23 9 104 0.5 61 12 0.8 54 11 299 0.36 53 12 442 0.025 --14 313 0.9 48 28 108 0.9 41 29 59 0.003 50 30 11 0.00025 65 31 8.7 -- 31 34 34 0.9 48 38 8.9 0.011 37.32 -46 757 -- -=
-- --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.
Claims (45)
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
2. The compound of claim 1, wherein said Ar1 and Ar2 are independently selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
3. A compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
4. The compound of claim 3, wherein:
n is 1; and X is O.
n is 1; and X is O.
5. The compound of claim 4, which is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
1-(2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]
pyrrolidinyl}-3-,3-dimethylpentane-l,2-dione;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-l-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-i-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2--pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; and 3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
1-(2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]
pyrrolidinyl}-3-,3-dimethylpentane-l,2-dione;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-l-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-i-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-l-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2--pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; and 3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
6. The compound of claim 3, wherein:
n is 2; and X is O.
n is 2; and X is O.
7. The compound of claim 6, which is selected from the group consisting of:
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(-2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(-2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
8. A compound which is 3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate.
9. A compound which is 3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate
10. A compound which is 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
11. A compound which is 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
12. A compound which is 3-[4-(Trifluoromethyl)phenyl) propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
13. A compound which is 3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate.
14. A compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position (s) with (Ar1) n, -C2-C6 straight or branched chain alkenyl,substituted in one or more position(s) with (Ar1) n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position (s) with (Ar1) n, -C2-C6 straight or branched chain alkenyl,substituted in one or more position(s) with (Ar1) n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
15. The compound of claim 14, selected from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
16. A compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
17. The compound of claim 16, consisting of:
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
18. A pharmaceutical composition comprising:
(i) a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.
(i) a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising:
(i) a compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; and (ii) a pharmaceutically acceptable carrier.
(i) a compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; and (ii) a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19, wherein said compound is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl) phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl) phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
21. A pharmaceutical composition comprising:
(i) a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.
(i) a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.
22. The pharmaceutical composition of claim 21, wherein said compound is selected from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
23. A pharmaceutical composition comprising:
(i) a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C3-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C6 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1l, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.
(i) a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C3-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C6 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1l, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof; and (ii) a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23, wherein said compound is:
morpholine;
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
morpholine;
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
25. The pharmaceutical composition according to any one of claims 18-24, further comprising one or more additional neurotrophic agent(s).
26. The pharmaceutical composition of claim 25, wherein said one or more additional neurotrophic agent(s) is/are independently selected from the group consisting of neurotrophic growth factor (NGF), glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor and neurotropin-3.
27. The pharmaceutical composition of claim 26, wherein said one or more additional neurotrophic agent(s) is neurotrophic growth factor (NGF).
28. Use of a compound for treating a neurological disease in an animal, wherein the compound is of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
29. Use of a compound for treating a neurological disease in an animal, wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C9 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6,straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C9 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6,straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
30. The use of claim 29, wherein said compound is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
1-{2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]
pyrrolidinyl}-3-,3-dimethylpentane-1,2-dione;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3- dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2-({1-Oxo-6-phenyl}-hexyl-1-(3,3-dimethyl-1,2-dioxobutyl) piperidine;
3,3-Dimethyl-1-[2-(4-phenylbutanoyl)piperidino]-1,2-pentanedione;
3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbuty-1)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-di.methyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 2-((1-Oxo-[2-(2'-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
1-{2-[(benzo[b]thiophen-3-ylmethylthio)carbonyl]
pyrrolidinyl}-3-,3-dimethylpentane-1,2-dione;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3- dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2-({1-Oxo-6-phenyl}-hexyl-1-(3,3-dimethyl-1,2-dioxobutyl) piperidine;
3,3-Dimethyl-1-[2-(4-phenylbutanoyl)piperidino]-1,2-pentanedione;
3,3-Dimethyl-1-[2-(5-phenylpentanoyl)piperidino]-1,2-pentanedione;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbuty-1)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-di.methyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 2-((1-Oxo-[2-(2'-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.
31. Use of a compound for treating a neurological disease in an animal, wherein the compound is of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
32. The use of claim 31, wherein said compound is selected from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
33. Use of a compound for treating a neurological disease in an animal, wherein the compound is of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
34. The use of claim 33, wherein said compound is:
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
35. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH, or NR2 in any chemically stable oxidation state;
X is either O or S;
Z is S;
W and Y are independently O, S, CH2, or H2;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
36. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C5 straight or branched chain alkyl, -C2-C5 straight or branched chain alkenyl, and -Ar1, wherein said R1 is unsubstituted or substituted in one or more positions with halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, Ar1, or a combination thereof;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, Ar1 is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl, or naphthyl, wherein said Ar1 is unsubstituted or substituted in one or more positions with halo, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof.
37. The use of claim 36, wherein said compound is selected from the group consisting of:
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethy1-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Fluorophenvl)propvl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl (2S)-1-(2-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethy1-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Diphenyl-l-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
3,3-Di(para-Fluoro)phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;
4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(1-Naphthyl)-1-propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[4-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-[3-(Trifluoromethyl)phenyl]propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Fluorophenvl)propvl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;
2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;
4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;
1,5-Diphenyl-3-pentyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate;
3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate;
2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(3-Chlorophenyl)-1-propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;
3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate.
38. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
39. The use of claim 38, wherein said compound is selected from the group consisting of:
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carbothioate; and 2-Phenylethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-(pyr-3-azolidine)carbothioate.
40. Use of a compound for effecting a neuronal activity in an animal, wherein the compound is of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
or a pharmaceutically acceptable salt thereof, wherein:
A, B, C, and D are independently CH2, O, S, SO, SO2, NH, or NR2;
X is O or S;
Z is S;
R1 is selected from the group consisting of:
-C1-C6 straight or branched chain alkyl substituted in one or more position(s) with (Ar1)n, -C2-C6 straight or branched chain alkenyl substituted in one or more position(s) with (Ar1)n, -C3-C8 cycloalkyl, -C3-C8 cycloalkyl connected by a C1-C6 straight or branched chain alkyl or a C2-C6 straight or branched chain alkenyl, and -Ar2;
n is 1 or 2;
R2 is selected from the group consisting of:
-C1-C9 straight or branched chain alkyl, -C2-C9 straight or branched chain alkenyl, -C3-C8 cycloalkyl, -C5-C7 cycloalkenyl, and -Ar1, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted in one or more position(s) with C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, hydroxyl, or a combination thereof; and Ar1 and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof.
41. The use of claim 40, wherein said compound is:
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
2-Phenylethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-morpholinecarbothioate.
42. The use according to any one of claim 35-41, 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.
43. The use of claim 42, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic injury to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.
44. The use of claim 43, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.
45. A process of preparing a compound of the formula:
comprising reacting a compound of formula or activated derivatives thereof with a compound of formula HS-R1, wherein n is 1 or 2;
R1 is a C1-C6 straight or branched chain alkyl substituted with phenyl, and R2 is a C1-C9 straight or branched chain alkyl.
comprising reacting a compound of formula or activated derivatives thereof with a compound of formula HS-R1, wherein n is 1 or 2;
R1 is a C1-C6 straight or branched chain alkyl substituted with phenyl, and R2 is a C1-C9 straight or branched chain alkyl.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/721,765 | 1996-09-25 | ||
| US08/721,765 US5786378A (en) | 1996-09-25 | 1996-09-25 | Heterocyclic thioesters |
| US08/904,461 US5990131A (en) | 1996-09-25 | 1997-08-01 | Heterocyclic thioesters and ketones |
| US08/904,461 | 1997-08-01 | ||
| CA002263927A CA2263927C (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002263927A Division CA2263927C (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2602802A1 true CA2602802A1 (en) | 1998-04-02 |
Family
ID=38830291
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002602791A Abandoned CA2602791A1 (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
| CA002602802A Abandoned CA2602802A1 (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
| CA002602798A Abandoned CA2602798A1 (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002602791A Abandoned CA2602791A1 (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002602798A Abandoned CA2602798A1 (en) | 1996-09-25 | 1997-09-09 | Heterocyclic thioesters and ketones |
Country Status (1)
| Country | Link |
|---|---|
| CA (3) | CA2602791A1 (en) |
-
1997
- 1997-09-09 CA CA002602791A patent/CA2602791A1/en not_active Abandoned
- 1997-09-09 CA CA002602802A patent/CA2602802A1/en not_active Abandoned
- 1997-09-09 CA CA002602798A patent/CA2602798A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CA2602798A1 (en) | 1998-04-02 |
| CA2602791A1 (en) | 1998-04-02 |
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