MXPA99007384A - Method of using neutrophic sulfonamide compounds - Google Patents
Method of using neutrophic sulfonamide compoundsInfo
- Publication number
- MXPA99007384A MXPA99007384A MXPA/A/1999/007384A MX9907384A MXPA99007384A MX PA99007384 A MXPA99007384 A MX PA99007384A MX 9907384 A MX9907384 A MX 9907384A MX PA99007384 A MXPA99007384 A MX PA99007384A
- Authority
- MX
- Mexico
- Prior art keywords
- branched
- straight
- alkyl
- alkenyl
- group
- Prior art date
Links
- 150000003456 sulfonamides Chemical class 0.000 title description 5
- -1 small molecule sulfonamide compounds Chemical class 0.000 claims abstract description 69
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 50
- 230000001537 neural Effects 0.000 claims description 43
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 30
- 125000003342 alkenyl group Chemical group 0.000 claims description 29
- 208000009025 Nervous System Disease Diseases 0.000 claims description 25
- 206010029305 Neurological disorder Diseases 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 239000011780 sodium chloride Substances 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 19
- 125000004429 atoms Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000005466 alkylenyl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 15
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- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
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Abstract
This invention relates to a method of using neurotrophic low molecular weight, small molecule sulfonamide compounds having an affinity for FKBP-type immunophilins, as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
Description
METHOD FOR USING COMPOUNDS OF SULFONAM1DA NEUROTROF1COS
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION This invention relates to a method for using small molecule and low molecular weight neutrotrophic sulfonamide compounds having an affinity for FKBP type immunophilins, as inhibitors of the enzyme activity associated with immunophilin proteins, particularly enzyme activity of peptidyl-prolyl isomerase or rotamase.
2. Description of the Related Art The term immunophilin refers to a number of proteins that serve as receptors for the major immunosuppressive drugs, cyclosporin A (CsA), FK506 and rapamycin. The known classes of immunophilins are cyclophilins and binding proteins FK506, or FKBPs. Cyclosporin A binds to cyclophilin A, while FK506 and rapamycin bind to FKBP12. These immunophilin-drug complexes interface with several intracellular signal transduction systems, especially the immune and nervous systems. It is known that immunophilins have enzymatic activity peptidyl-prolyl isomerase (PPIase), or rotamase. It has been determined that rotamase enzyme activity plays a role in the catalysis of the interconversion of cis and trans isomers of peptide and protein substrates for immunophilin proteins. The immunophilins were discovered and originally studied in the immune tissue. It was initially postulated by those skilled in the art that the inhibition of the rotamase activity of the immunophilins leads to the inhibition of T cell proliferation, thereby causing the immunosuppressive activity exhibited by the immunosuppressive drugs, such as cyclosporin A, FK506 and Rapamycin Subsequent studies have shown that the inhibition of rotamase activity, in and of it, does not result in an immunosuppressive activity. Schreiber et al., Science, 1990, vol. 250, pp. 556-559. Instead, immunosuppression appears to be derived from the formulation of an immunosuppressant drug complex and immunophilin. It has been shown that immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al., Cell, 1991, vol. 66, pp. 807-815. In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complexes bind to the calcineurin of the enzyme and inhibit T cell receptor signaling, which leads to the proliferation of T cells. Similarly, the The immunophilin-drug complex of FKBP- rapamycin interacts with the RAFT1 / FRAP protein and inhibits IL-2 receptor signaling. It has been found that immunophilins are 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 the synthesis of nitric oxide, the release of neurotransmitters and the extension of the neuronal process. Surprisingly, it has been found that certain small, low molecular weight peptide sequences with high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Moreover, these rotamase inhibitors lack immunosuppressive activity. These findings suggest the use of rotamase inhibitors to treat several peripheral neuropathies and increase neuronal growth in the central nervous system (CNS). Studies have shown that neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) can occur due to the loss, or decreased availability, of a specific neurotrophic substance for a particular population of affected neurons in the disorder . Several neurotrophic factors have been identified that affect specific neurogenic populations in the central nervous system. For example, the hypothesis has been created that Alzheimer's disease is the result of a decrease or loss of nerve growth factor (NGF). It has then been proposed to treat SADT patients with exogenous nerve growth factor or other neurotrophic proteins such as brain-derived growth factor, glia-derived growth factor, ciliary neurotrophic factor and neurotropin-3, to increase the survival of neuronal populations in degeneration. The clinical application of these proteins in various states of neurological disease is hampered by difficulties in the supply and bioavailability of large proteins for targets in the nervous system. In contrast, immunosuppressive drugs with neurotrophic activity are relatively small and exhibit excellent bioavailability and specificity. However, when administered chronically, immunosuppressive drugs exhibit a number of potentially serious side effects, including nephrotoxicity, such as impaired glomerular filtration and irreversible interstitial fibrosis (Koop 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. Eng. J. Med., 1987, 317: 861); and vascular hypertension with complications resulting therefrom (Kahan et al., N. Engl. J. Med., 1989, 321: 1725). To avoid the side effects associated with the use of the immunosuppressant compounds, the present invention provides a method for using a non-immunosuppressant compound containing small molecule and low molecular weight peptide sequences to increase neurite growth, and to promote growth and neuronal regeneration in several neuropathological situations where neuronal repair can be facilitated, including: damage to peripheral nerves caused by physical injury or disease state such as diabetes, physical damage to the central nervous system (spine and brain); the brain damage associated with embolisms; and neurological disorders that are related to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease), and amyotrophic lateral sclerosis.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a method for using a small molecule, low molecular weight neurotrophic sulfonamide compound having an affinity for FKBP type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzymatic activity associated with immunophilin proteins, particularly the activity of the peptidii-prolyl isomerase or rotamase enzymes. A key feature of neurotrophic compounds is that they do not exert any significant immunosuppressive activity. Specifically, the present invention relates to a method for effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein: A is CH2, oxygen, NH or N- (C1-C4 alkyl); B and D are independently Ar, hydrogen, straight or branched (C1-C6) alkyl, straight or branched (C1-C6) alkenyl, straight or branched (C1-C6) alkyl or alkenyl which is substituted with a cycloalkyl of (C1-C6), straight or branched (C1-C6) alkyl or alkenyl which is substituted with (C5-C7) cycloalkenyl, or straight or branched (C1-C6) alkyl or alkenyl substituted with Ar, wherein, in in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or
as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxy, O-(C 1 -C 4) alkyl, O-alkenyl of (C 1 -C 4) ) and carbonyl; Ar is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, heterocyclic ring systems monocyclic and bicyclic with individual ring sizes of 5 or 6 which may contain in each or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C1-C4) alkyl, straight or branched (C2-C4) O-alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C 1 -C 4) alkenyl, [(C 2 -C 4) alkyl or (C 2 -C 4) alkenyl] - Ar or Ar;
J is hydrogen or C 1 or C 2 alkyl or benzyl; K is straight or branched alkyl, benzyl or cyclohexylmethyl of (C 1 -C 4); or wherein J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain an oxygen, sulfur, SO or SO2 substituent thereon; n is 0 to 3; and the stereochemistry at the carbon 1 and 2 positions are R or S. The present invention also relates to a method for effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula III :
or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 1 -C 6) alkyl or alkenyl ) straight or branched, which is substituted with a straight or branched (C1-C6) cycloalkyl, alkyl or alkenyl which is substituted with (C5-C7) cycloalkenyl, or (C1-C6) alkyl or alkenyl straight or branched substituted with Ar, wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in patterns of substitution chemically reasonable, or
as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, O-alkenyl of (C 1 -C 4) ) and carbonyl; Ar is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furiio, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, heterocyclic ring systems monocyclic and bicyclic with individual ring sizes of 5 or 6 which may contain in each or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C1-C4) alkyl, straight or branched (C2-C4) O-alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C1-C4) alkenyl, [(C2-C4) alkyl or (C2-C4) alkenyl] - Ar or Ar; and m is 0 to 3. The present invention also relates to a method for effecting neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 1 -C 6) alkyl or alkenyl ) straight or branched which is substituted with a straight or branched (C 1 -C 6) cycloalkyl, alkyl or alkenyl which is substituted with (C 5 -C 7) cycloalkenyl, or (C 1 -C 6) alkyl or alkenyl C6) straight or branched substituted with Ar, wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or
as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4, which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4) alkyl, O-alkenyl of (C1 -C4) and carbonyl; Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic heterocyclic ring systems and bicyclics with individual ring sizes of 5 or 6 that can in each or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C 1 -C 4) alkyl, straight or branched (C 2 -C 4) O-alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C 1 -C 4) alkenyl, [(C 2 -C 4) alkyl or (C 2 -C 4) alkenyl] - Ar or Ar; and m is 0 to 3.
DETAILED DESCRIPTION OF THE INVENTION
Definitions The term "alkyl" means a saturated, branched or unbranched 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.
The term "halogen" means fluorine, chlorine, bromine or iodine, unless otherwise indicated. The term "pharmaceutically acceptable salt" refers to salts of the present compounds that possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. The salts can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. The base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salt with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine. and salts with amino acids such as arginine, lysine and others. Likewise, basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and methyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others. Soluble or dispersible products are obtained in water or oil. The term "fenium" includes all possible isomeric phenyl radicals, optionally monosubstituted or multisubstituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxyl, halogen and haloalkyl. The term "treatment" covers any treatment of a disease and / or condition in an animal, particularly a human, and includes: (i) preventing the occurrence of a disease and / or condition in a subject who may be predisposed to the disease and / or condition, but not yet diagnosed as having it; (ii) inhibit the disease and / or condition, that is, slow down its development; and (ii) heal the disease and / or condition, that is, cause the regression of the disease and / or condition. The inventors have discovered that certain small molecule and low molecular weight sulfonamide compounds have an affinity for FKBP type immunophilins, particularly FKBP12. When the sulfonamide compounds bind to an FKBP type immunophilin, they have been found to inhibit the prolyl-peptidyl cis-trans isomerase, or rotamase, activity of the binding protein and unexpectedly stimulate neurite growth. This activated is useful in the stimulation of damaged neurons, in the promotion of neuronal regeneration, in the prevention of neurodegeneration and in the treatment of several neurological disorders that are known to be associated with neuronal degeneration and peripheral neuropathies. For the above reasons, the present invention relates to a method for effecting a neuronal activity in the animal, comprising: administering to the animal a neurotrophically effective amount of a compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein: A is CH2, oxygen, NH or N- (C1-C4 alkyl); B and D are independently Ar, hydrogen, straight or branched (C1-C6) alkyl, straight or branched (C1-C6) alkenyl, straight or branched (C1-C6) alkyl or alkenyl which is substituted with a cycloalkyl of (C 1 -C 6), straight or branched (C 1 -C 6) alkyl or alkenyl substituted with (C 5 -C 7) cycloalkenyl, or straight or branched (C 1 -C 6) alkyl or alkenyl substituted with Ar, wherein, in in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or
as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, O-alkenyl of (C 1 -C 4) ) and carbonyl; Ar is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, heterocyclic ring systems monocyclic and bicyclic with individual ring sizes of 5 or 6 which may contain in each or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C1-C4) alkyl, straight or branched (C2-C4) O-alkenyl, O-benzyl, O-phenylene, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C 1 -C 4) aikenyl, [(C 2 -C 4) alkyl or (C 2 -C 4) alkenyl] - Ar or Ar; J is hydrogen or C 1 or C 2 alkyl or benzyl; K is straight or branched alkyl, benzyl or cyclohexylmethyl of (C 1 -C 4); or wherein J and K can be taken together to form a 5-7 membered heterocyclic ring which may contain an oxygen, sulfur, SO or SO2 substituent therein; n is 0 to 3; and the stereochemistry at the carbon 1 and 2 positions are R or S. In a preferred embodiment, J and K are taken together and the compound is represented by formula II:
I I
wherein n is 1 or 2 and m is 0 or 1. In a most preferred embodiment, B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenium, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3 , 4,5-triemethoxyphenyl, methyl, 1 -naphthyl, 8-quinolyl, 1- (5-N, N-dimethylamino) -naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, -nitrophenyl, 4-chlorophenium and E-styrynyl. The present invention also relates to a method for effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of the formula III:
or a pharmaceutically acceptable salt thereof, wherein:
B and D are independently Ar, hydrogen, straight or branched (C1-C6) alkyl, straight or branched (C1-C6) alkenyl, straight or branched (C1-C6) alkyl or alkenyl which is substituted with a cycloalkyl of (C1-C6), straight or branched (C1-C6) alkyl or alkenyl which is substituted with (C5-C7) cycloalkenyl, or straight or branched (C1-C6) alkyl or alkenyl substituted with Ar, wherein, in in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or
as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, 0- (C 1 -C 4) alkenyl ) and carbonyl; Ar is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, heterocyclic ring systems monocyclic and bicyclic with individual ring sizes of 5 or 6 which may contain in each or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C 1 -C 4) alkyl, straight or branched (C 2 -C 4) O-alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C 1 -C 4) alkenyl, [(C 2 -C 4) alkyl or (C 2 -C 4) alkenyl] - Ar or Ar; and m is 0 to 3. The present invention also relates to a method for effecting neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 1 -C 6) alkyl or alkenyl ) straight or branched, which is substituted with a straight or branched (C1-C6) cycloalkyl, alkyl or alkenyl which is substituted with (C5-C7) cycloalkenyl, or (C1-C6) alkyl or alkenyl straight or branched substituted with Ar, wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in patterns of substitution chemically reasonable, or
as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4, which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4) alkyl, O-alkenyl of (C1 -C4) and carbonyl; Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furiio, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic heterocyclic ring systems and bicyclics with individual ring sizes of 5 or 6 that can in each or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C1-C6) alkyl, straight (C2-C6) alkenyl, or branched, straight or branched (C 1 -C 4) alkyl, straight or branched (C 2 -C 4) O-alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C 1 -C 4) alkenyl, [(C 2 -C 4) alkyl or (C 2 -C 4) alkenyl] - Ar or Ar; and m is 0 to 3.
The neuronal activity that is carried out by the methods of the present invention can be selected from the group consisting of: stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder. Examples of a neurological disorder that is treatable by the methods of the present invention include, without limitation: trigeminal neuralgia; glossopharyngeal neuralgia; Bell's palsy; myasthenia gravis; muscular dystrophy; Amyotrophic Lateral Sclerosis; progressive muscular atrophy; Progressive bulbar inherited muscular atrophy; herniated, ruptured or prolapsed disc syndromes; cervical spondylosis; plexus disorders; syndromes of destruction of the thoracic outlet; peripheral neuropathies such as those caused by lead, dapsone, ticks, porphyria or Guillain-Barré syndrome; Alzheimer's disease and Parkinson's disease. The methods of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spine, embolisms associated with brain damage and a neurological disorder that is related to neurodegeneration. Examples of a neurological disorder that is related to neurodegeneration include: Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.
In the methods of the present invention, the neurotrophic compound can be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or by means of a reservoir implanted in dosage formulations containing adjuvants, vehicles and auxiliaries not toxic and pharmaceutically acceptable. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intraestemal, and intracranial injection or infusion techniques. To be effective therapeutically as targets of the central nervous system, neurotrophic compounds must easily penetrate the blood-brain barrier when administered peripherally. Compounds that can not penetrate the blood-brain barrier can be effectively administered by an intraventricular route. The neurotrophic compounds can also be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic and parenterally-acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile and fixed oils are commonly employed as solvents or suspending media. For this purpose, any soft fixed oil such as a synthetic mono- or diglyceride can be employed. Fatty acids are useful in the preparation of injectable solutions, such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated versions, which are useful in the preparation of injectables. These oil solutions or suspensions may also contain long chain alkoxy diluents or dispersants. In addition, the neurotrophic compounds can be administered orally in the form of capsules, tablets, suspensions or aqueous solutions. The tablets may contain carriers such as lactose and corn starch, and / or lubricating agents such as magnesium stearate. The capsules may contain diluents, including lactose and dried corn starch. The aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient. Oral dosage forms may also contain sweetening agents and / or flavorings and / or colorants. The neurotrophic compounds can also be administered rectally in the form of a suppository. 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 liberalize the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. Moreover, the neurotrophic compounds can be administered topically, especially when the conditions desired for the treatment involve areas or organs easily accessible by topical application, including neurological, eye, skin or lower intestinal tract disorders. Suitable topical formulations can be easily 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 can be formulated into ointments, such as petrolatum, for ophthalmic use. For topical application to the skin, the compounds may be formulated in suitable ointments containing the suspended or dissolved compounds in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, mixed product of polyoxyethylene and polyoxypropylene, emulsification wax and water. Alternatively, the compounds may be formulated in suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbital monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Topical application to the lower intestinal tract can be carried out in rectal suppository formulations (see above) or in suitable edema formulations. Dosage levels in the order of about 0.1 mg to about 10,000 mg of the compound of the active ingredient are useful in treating the above conditions, with levels of about 0.1 mg to about 1,000 mg being preferred. The amount of active ingredient that can be combined with the carrier materials to produce an individual dosage form will vary depending on the host treated and the particular mode of administration. However, it is understood that a specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed; Age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; the combination of the drug; the severity of the particular disease that is being treated and the form of administration. The compounds can be administered with other neurotrophic agents such as neurotrophic growth factor (NGF), glia-derived growth factor, brain-derived growth factor, ciliary neurotrophic factor and neurotropin-3. The dosage level of other neurotrophic drugs will depend on the factors mentioned above and the neurotrophic effectiveness of the drug combination.
EXAMPLES
The following examples are illustrative of the present invention and are not intended to be limitations thereto. Unless otherwise specified, all percentages are based on 100% by weight of the final compound. The compounds used in the methods of the present invention can be readily prepared by normal organic chemistry techniques, using the synthetic route indicated below. As described by Scheme I, amino acids 1 protected by appropriate P blocking groups in the amino acid nitrogen can be reacted with alcohols ROH for general esters 2. After removal of the protecting group, free amine 3 can be made reacting with various sulfonium chlorides 4 to supply the final products 5 with good to excellent yields.
SCHEME I
Vulnerability
In the compounds indicated in Scheme I above, E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, substituted (C 5 -C 7) cycloalkenyl) with straight or branched (C1-C4) alkyl or straight or branched (C1-C4) alkenyl, [((C2-C4) alkyl or (C2-C4) alkenyl] - Ar or Ar; and R is ( CH2) nCHBD, wherein B and D are independently Ar, hydrogen, straight or branched (C1-C6) alkyl, linear or branched (C1-C6) alkenyl, straight or branched (C1-C6) alkyl or alkenyl which are substituted with a linear or branched (C5-C7) cycloalkyl, alkyl or alkenyl of (C1-C6) which is substituted with a (C5-C7) cycloalkenyl, or Ar substituted with (C1-C6) alkyl or alkenyl linear or branched, wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chamay contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in substitution patterns. chemically reasonable, or
as long as B and D are not hydrogen.
EXAMPLE 1 Synthesis of (2S) -N- (α-toluenesulfonyl) pyrrolidin-2-carboxylate of 3- (3-pyridiD-1-propyl (1)
N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylic acid 3- (3-pyridiD-1-propyl) A mixture of N- (tert-butyloxycarbonyl) - (S) -proline was stirred overnight. 6.0 g, 28 mmol), 3- (3-pyridyl) -1-propanol (5.80 g, 41.8 mmol), dicyclohexylcarbodiimide (9.20 g, 44.48 mmol), camphorsulfonic acid (21.60 g, 9.26 mmol) and 4-dimethylaminopyridine (1.12 g). g, 9.26 mmoles) in dry methylene chloride (200 mL) The reaction mixture was filtered through celite, concentrated and purified on a column with silica gel eluting with 40% ethyl acetate in hexane to obtain 5.0 g of the product as a clear oil (53%) 1 H NMR (300 MHz, CDCl 3): d 1.42 (s,
9H); 1 .43-1.95 (m, 6H); 2.68 (m, 2H); 3.46-3.52 (m, 2H); 4.11-4.22 (m, 2H);
4. 33 (m, 1 H); 7.17-7.24 (m, 1 H); 7.47 (m, 1 H); 8.43 (s, 2H).
3- (3-pyridyl) -1-propyl pyrrolidine-2-carboxylate A solution of 3- (3-pyridyl) -1-propyl N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate) was stirred at room temperature at room temperature. 3.0 g, 8.9 mmole) in methylene chloride (40 mL) and trifluoroacetic acid (8 mL) for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 1.60 g (77%) of the free amine as a thick oil, 1 H NMR (300 MHz, CDCl 3): d 1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m, 1 H); 2.94 (m, 1 H); 3.71 (m, 1 H); 4.1 1 (m, 2H); 7.18 (m, 1 H); 7.45 (m, 1 H); 8.41 (m, 2H).
(2S) -N- (3- (3-pyridyl) -1- propyl (3-pyrrolidine-2-carboxylate) 3- (3-pyridyl) -1- pyrrolidine-2-carboxylate 3-pyrrolidine-2-carboxylate propyl (200 mg, 0.9 mmol) and a-toluenesulfonyl chloride (160 mg, 0.9 mmol) in methylene chloride (20 mL) with triethylamine (90 mg, 0.9 mmol) and stirred for two hours at room temperature. The reaction medium was filtered to remove the solids and applied directly to a column with silica gel, eluting with 50% ethyl acetate in hexane, to obtain 150 mg
(43% d) of compound 1 (Table I) as a clear oil, 1 H NMR (300 MHz,
CDCl 3): d 1.81-1.85 (m, 2H); 1.95-2.02 (m, 3H); 2.10-2.25 (m, 1 H); 2.69-2.74
(t, 2H); 2.85-2.97 (m, 1 H); 3.24-3.27 (m, 1 H); 4.16-4.20 (m, 2H); 4.29 (d, 1 H);
4. 34 (m, 1 H); 4.45 (d, 1 H); 7.20-7.25 (m, 1 H); 7.35 (m "3H); 7.49-7.52 (m, 3H);
8. 46 (s, 2H). Analysis Calculated for C2oH24N2? 3S: C, 91.83; H, 6.23; N, 7.21.
Found: C, 61.59; H, 6.24; N, 7.17.
EXAMPLE 2 Synthesis of 1- (a-tolylsuifonyl) -2-pipecoynate of 4-phenyl-1-butyl (2)
1- (Methyl a-tolysulfonyl-2-pipecolinate To a solution of methyl pipecolinate hydrochloride (1.79 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dry methylene chloride (20 mL) was added. a-toluenesulfonyl chloride (1.9 g, 10 mmol) The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo.The crude residue was purified on a column with silica gel, eluted with ethyl acetate, ethyl, to provide 2.20 g (74%) of the product as an oil which solidified upon standing, 1 H NMR (300 MHz, CDCl 3): d 1.26-1.71 (m, 5H), 2.15 (d, 1 H), J = 14.4); 3.17 (dt, 1 H); 3.45 (d, 1 H J = 12.6); 3.78 (s, 3H); 4.28 (s, 2H); 4.58 (m, 1 H); 7.26-7.48 (m, 5H).
N- (α-tolylsulfonyl) -2-pipecolic acid Methyl 1- (α-tolylsulfonyl) -2-pipecolinate (2.0 g, 6.72 mmol) in ethanol (25 mL) was dissolved and treated with 20 mL of lithium hydroxide. 1 N. The mixture was stirred for 2 hours at room temperature, and then diluted with ethyl acetate (200 mL) and acidified (pH 2) with 1 N HCl. The organic layer was washed with brine, dried with sulfate of magnesium and concentrated to obtain 1.90 g (100%) of the acid as a white solid.
1- (α-Tolylsulfonyl) -2-pipecolinate 4-phenyl-1-butyl (2) A solution of N- (α-tolylsulfonyl) -2-pipecolic acid (400 mg; 1.41 mmol), dicyclohexylcarbodiimide (312 mg, 1.5 mmol), dimethylaminopyridine (7 mg) and
4-phenyl-1-butanol (240 mg, 1.60 mmol) in 100 mL of methylene chloride. The mixture was filtered through celite, concentrated and purified on a column with silica gel, eluting with 25% ethyl acetate in hexane, to obtain 380 mg (48%) of compound 2 (Table I) as a clear oil, 1H
NMR (300 MHz, CDCl 3): d 1.10-1.69 (m, 5H); 1.70 (tt, 4H, J = 6.1, 6.6); 2.15
(m, 1 H); 2.66 (t, 2H, J = 6.6); 3.16 (m, 1 H); 3.45 (m, 1 H); 4.19 (t, 2H, J = 6.1);
4. 28 (s, 2H); 4.58 (m, 1 H); 7.18-7.47 (m, 10H). Analysis Calculated for C23H23NO S: C, 66.48; H, 7.03; N, 3.37. Found: C, 66.34; H, 7.06; N,
3. 41
EXAMPLE 3 Synthesis of 1,5-diphenyl-3-pentyl (N- (α-toluenesulfonyl) pipecolate) (3)
3-Phenyl-1-propanal Oxalyl chloride (2.90 g, 2.29 mmol) in methylene chloride (50 mL), cooled to -78 ° C, with dimethyl sulfoxide (3.4 mL) in 10 mL of methylene chloride was treated. . After stirring for 5 minutes, 3-phenyl-1-propanol (2.72 g, 20 mmol) in 20 mL of methylene chloride was added, and the resulting mixture was stirred at -78 ° C for 15 minutes, treated with ethyl acetate. mL of triethylamine was stirred an additional 15 minutes and poured into 100 mL of water. The layers were separated, the organic phase was dried and concentrated, and the crude residue was purified on a column with silica gel, eluting with 10% ethyl acetate in hexane, to obtain 1.27 g (47%) of the aldehyde as a clear oil, 1 H NMR (300 MHz, CDCl 3): d 2.80 (m, 2H); 2.98 (m, 2H); 7.27 (m, 5H); 9.81 (s, 1 H).
1, 5-Diphenyl-3-pentanol A solution of 2- (bromoethyl) -benzene (1.73 g, 9.33 mmol) in diethyl ether (10 mL) was added to a stirred suspension of magnesium turnings (250 mg, 10.18 mmol) in 5 mL of ether. The reaction was started with a heat gun, and after the addition was complete the mixture was heated in an oil bath for 30 minutes. 3-Phenyl-1-propanal (1.25 g, 9.33 mmol) in 10 mL of ether was added and reflux continued for one hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted with 2x ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on column with silica gel
(10% ethyl acetate in hexane) provided 1.42g (63%) of the diphenylic alcohol, 1 H NMR (300 MHz, CDCl 3): d 1.84 (m, 4H); 2.61-2.76 (m, 4H); 3.65
(m, 1 H); 7.19-7.29 (m, 10H).
N- (α-Toluenesulfonyl) -pipecolate from 1,5-diphenyl-3-pentyl (3). A mixture of N- (α-tolylsulfonyl) -2-pipecolic acid (380 mg, 1.34 mmol), 1,5-diphenyl-3-pentane (485 mg, 2.01 mmol), dicyclohexylcarbodiimide (445 mg, 2.15 mmol), acid Camphor-suphonic (105 mg, 0.45 mmol) and dimethylaminopyridine (55 mg, 0.45 mmol) in 20 mL of methylene chloride was stirred overnight at room temperature. The mixture was filtered with celite, concentrated and purified on a column with silica gel, eluting with 15% ethyl acetate in hexane, to obtain 270 mg (40%) of compound 3 (table 1) as a clear oil. , 1 H NMR (CDCl 3, 300 MHz): d 0.80 (m, 4H); 1.23-1.97 (m, 5H); 2.15 (d, 1 H); 2.61-2.69 (m, 4H); 3.23 (m, 1 H); 3.44 (dm, 1 H); 4.27 (s, 2H); 4.53 (d, 1 H J = 4.5); 5.06 (m, 1 H); 7.16-7.34 (m, 15H). Anal, caled, for C3oH35NO4S: C, 71.26; H, 6.98; N, 2.77. Found: C, 72.82; H, 7.17; N 2.53. As discussed above, the sulfonamide compounds used in the methods of the present invention have an affinity for the protein that binds to FK506, particularly FKBP12. Inhibition of the cis-trans prolyl-peptidyl isomerase activity of FKBP can be measured as an indicator of this affinity.
Procedure of Ki test Inhibition of peptidyl-prolyl isomerase activity
(rotamase) of the compounds of the invention 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 the apparent Ki values and are presented in Table 1. The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-AIa-Ala-Pro-Phe-p-nitroanuide, is monitors with spectrophotometer in an assay coupled with chymotrypsin, which releases p-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of the inhibitor is determined, and the data is analyzed as a change in the first order rate constant as a function of the concentration of the inhibitor to supply the apparent Ki values. 950 mL of ice-cold regulatory buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-CI pH 7.5, 100 mM NaCl, dithiothreitol 1 were added in a plastic container. mM), 25 mL of chymotrypsin (50 mg / mL in 1 mM HCl) and 10 mL of the test compound in different concentrations in dimethyl sulfoxide.
The reaction is initiated by the addition of 5 ml of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg / ml in LiCl in 2.35 mM trifluoroethanol). The absorbance at 390 nm against time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance data files versus time. The data for these experiments for representative compounds are presented in table 1 under the "Ki" column. The neurotrophic effects of the compounds of the present invention can be demonstrated in in vitro cell biological experiments, as described below.
Culture of chicken dorsal root ganglia and neurite prolongation Dorsal root ganglia of chicken embryos of 10 days of gestation were dissected. Complete lymph node explants were cultured in 12-well plates coated with Matrigel in thin layer with Liebovitz L15 plus medium high in glucose supplemented with 2 mM glutamine and 10% fetal bovine serum, and also containing 10 μM of β-D arabinofuranoside of cytosine (Ara C) at 37 ° C in an environment containing 5% CO2. Twenty-four hours later, the dorsal root ganglia (DRG) were treated with various immunophilin ligands. Forty-eight hours after treatment with the drug, the ganglia were visualized, under phase contrast or Hoffman modulation contrast with an inverted Zeiss Axiovert microscope. Photomicrographs of the explants were made, and the neurite prolongation was quantified. The neurites with diameter greater than the diameter of GRD were counted as positive, quantifying the total number of neurites for each experimental condition. Three to four GRD were grown in each cavity, and each treatment was performed in duplicate. The data for these experiments for the representative compounds are presented in column "ED50" of table 1.
TABLE 1
IN VITRO ACTIVITY OF THE EXAMPLE COMPOUNDS
Compound Ki.nM DE50.nM
4-phenyl-1-butyl-N- (o-toIuensulfoniI) pipecolato (2)
1, 5-diphenyl-3-pentyl-N- (o-toluenesulfonyl) -pipecolate (3)
1, 7-diphenyl-4-heptyl-N- (para-toluenesulfonyl) -pipeleate TABLE 1 (CONTINUED)
IN VITRO ACTIVITY OF THE EXAMPLE COMPOUNDS
Compound Ki.nM DE50, nM
3- (3-pyridyl) -1-propyl- (2S) -N- (o-toluenesulfonyl) -pyrrolidine-2-carboxylate (1)
4- enyl-1-butyl-N- (para-toluenesulfonyl) -pipecolate
4-phenyl-1-butyl-N- (benzenesulfonyl) pipecolate MPTP MODEL OF PARKINSON DISEASE The remarkable neurotrophic and neurodegenerative effects of the compounds of the present invention were further demonstrated in an animal model of neurodegenerative disease. The MPTP lesion of dopaminergic neurons in mice was used as an animal model of Parkinson's disease. White mice were dosed
CD1 four-week-old males intraperitoneally with 30 mg / kg of MPTP for 5 days. The test compounds (4 mg / kg), or the vehicle, were administered subcutaneously together with the MPTP for 5 days, as well as for an additional 5 days after the conclusion of the MPTP treatment. After 18 days of treatment with MPTP, the animals were sacrificed and the striatum bodies were dissected and fixed for perfusion. Immuno-staining was performed on the sagittal and coronal sections of the brain using 1 g of anti-tyrosine hydroxylase to quantify the survival and recovery of dopaminergic neurons. In animals treated with MPTP and vehicle, a substantial loss of functional dopaminergic terminals was observed in comparison with non-injured animals. The injured animals that received the test compounds showed a significant recovery of dopaminergic neurons stained with TH. Table 2 presents the quantification of the recovery of TH-positive dopaminergic neurons in the striatum of animals that received compounds 1, 2, 5 and 6 in this model.
TABLE II
IN VIVO ACTIVITY OF THE EXAMPLE COMPOUNDS
SELECTED
Compound% Rescue, immunostaining TH at 4 mg / kq, s.c.
3- (3-pyridyl) -1-propyl- (2S) -N- (o-toluenesulfonyl) -pyrrolidine-2-carboxylate (1)
4-phenyl-1-butyl-N- (o-toluenesulfonyl) pipecolate (2)
4-phenyl-1-butyl-N- (para-toluenesulfonyl) - pipecolato
4-phenyl-1-butyl-N- (benzenesulfonyl) pipecolate
All publications and patents identified above are incorporated in the present invention for reference. Having thus described the invention, it will be obvious that it may vary in many ways. Such variations should not be considered as a deviation from the scope and scope of the invention and all modifications are designed to be included within the scope of the following claims.
Claims (2)
- NOVELTY OF THE INVENTION CLAIMS 1. - The use of a compound according to formula I: or a pharmaceutically acceptable salt thereof, wherein: A is CH2, oxygen, NH or N- (C1-C4 alkyl); B and D are independently Ar, hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, straight or branched (C 1 -C 6) alkyl or alkenyl which is substituted with a cycloalkyl of (C5-C7), straight or branched (C1-C6) alkyl or alkenyl which is substituted by (C5-C7) cycloalkenyl, or straight or branched (C1-C6) alkyl or alkenyl substituted by Ar, wherein each In this case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, O-alkenyl of (C 1 -C 4) ) and carbonyl: Ar is selected from the group consisting of phenyl, 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes of 5 or 6 and which may contain in either or both ring a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain 1 to 3 substitutes which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C1-C6) alkyl, straight (C2-C6) alkenyl or branched, straight or branched (C1-C4) O-alkyl, straight or branched (C2-C4) O-alkenyl O-benzyl, O-phenyl, 1, 2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 5 -C 7) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C1-C4) alkenyl, [(C2-C4) alkyl or aikenyl] (C2-C4)] - Ar or Ar; J is hydrogen or C 1 or C 2 alkyl or benzyl; K is straight or branched alkyl, benzyl or cyclohexylmethyl of (C 1 -C 4); or wherein J and K may be taken together to form a 5- to 7-membered heterocyclic ring which may contain an oxygen substituent, sulfur SO or SO2 therein; n is o a 3; and the stereochemistry in carbon positions 1 and 2 are R or S, for the manufacture of a medicament for affecting neuronal activity in an animal.
- 2. The use according to claim 1, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuronal degeneration and treatment of neurological disorder 3.- The use according to claim 2, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spine, embolism associated with brain damage and neurological disorder related to neuronal degeneration. 4. The use according to claim 3, wherein the neurological disorder related to neuronal degeneration is selected from the group consisting of Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis. 5. The use according to claim 1, wherein J and K are taken together and the compound is represented by formula II: wherein n is lO 2 and m is 0 or 1. 6.- The use of compliance with claim 5, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuronal degeneration and treatment of neurological disorder 7. The use according to claim 6, wherein the neuroiogenic disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or condition of disease, physical damage to the brain, physical damage to the spine, embolism associated with brain damage and neurological disorder related to neuronal degeneration. 8. The use according to claim 7, wherein the neurological disorder related to neuronal degeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. 9. - The use according to claim 5, wherein B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl and 3-phenylpropyl; D is selected from the group consisting of fenium, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and E is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3 , 4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1- (5-N, N-dimethylamino) naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2- nitrophenyl, 4-chlorophenyl and E-styrynyl. 10. The use according to claim 9, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuronal degeneration and treatment of neurological disorder 1 1.- The use according to claim 10, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spine, embolism associated with brain damage and disorder Neurological related to neuronal degeneration. 12. The use according to claim 1, wherein the neurological disorder related to neuronal degeneration is selected from the group consisting of Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis. 13. The use of a compound according to formula III or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, straight or branched (C1-C6) alkyl, (C1-) alkenyl C6) straight or branched, straight or branched (C1-C6) alkyl or alkenyl which is substituted with a straight or branched (C5-C7) cycloalkyl, alkyl or alkenyl which is substituted with an alkenyl ring of (C5-C7), or straight or branched (C1-C6) alkyl or alkenyl substituted with Ar, wherein each, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 carbon atoms. heterogeneous selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable replacement patterns, or as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4, which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4) alkyl, O-alkenyl of (C1) -C4) and carbonyl; Ar is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, heterocyclic ring systems monocyclic and bicyclic with individual ring sizes of 5 or 6 which may contain in either or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C 1 -C 4) alkyl, straight or branched (C 2 -C 4) O-alkenyl, O-benzyl, O-phenyl, 1,2, methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 5 -C 7) cycloalkyl, (C 5 -C 7) cycloalkenyl substituted with straight (C 1 -C 4) alkyl or branched or straight or branched (C 1 -C 4) alkenyl, [(C 2 -C 4) alkyl or alkenyl) of (C 2 -C 4)] - Ar or Ar; and m is 0 to 3, for the manufacture of a medicament for affecting neuronal activity in an animal. 14. The use according to claim 13, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuronal degeneration and treatment of neurological disorder 15. - The use according to claim 14, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to! brain, physical damage to the spine, embolism associated with brain damage and neurological disorder related to neuronal degeneration. 16. The use according to claim 15, wherein the neurological disorder related to neuronal degeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. 17. The use of a compound according to formula IV: or a pharmaceutically acceptable salt thereof, wherein: B and D are independently Ar, hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkenyl, (C 1 -C 6) alkyl or alkenyl ), which is substituted with a straight or branched (C5-C7) cycloalkyl, alkyl or alauenyl group which is substituted with a (C5-C7) cycloalkenyl, or (C1-C6) alkyl or alkenyl straight or branched substituted with Ar wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may contain 1-2 heterogeneous atoms selected from the group consisting of oxygen, sulfur, SO and SO2 in substitution patterns chemically reasonable or as long as both B and D are not hydrogen; Q is hydrogen, straight or branched (C 1 -C 6) alkyl or straight or branched (C 1 -C 6) alkenyl; T is Ar or 5-7 membered cycloalkyl substituted with substituents at positions 3-4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, O-alkenyl (C 1 -C 4) ) and carbonyl; Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl. 2-pyridyl, 3-pyridyl, 4-pyridyl-q, monocyclic and bicyclic ring systems, heterocyclic with individual ring sizes of 5 or 6 which may contain in 1 or both rings a total of 1-4 heterogeneous atoms independently selected from O, N and S; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, straight or branched (C 1 -C 6) alkyl, straight (C 2 -C 6) alkenyl or branched, straight or branched (C1-C4) alkyl, straight or branched (C2-C4) O-alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; E is straight or branched (C1-C6) alkyl, straight or branched (C1-C6) alkenyl, (C5-C7) cycloalkyl, (C5-C7) cycloalkenyl substituted with straight (C1-C4) alkyl or branched or straight or branched (CI-C4) alkenyl, [(C2-C4) alkyl or (C2-C4) alkenyl] - Ar or Ar; and m is 0 to 3, for the manufacture of a medicament for affecting neuronal activity in an animal. 18. The use according to claim 17, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuronal degeneration and treatment of neurological disorder 19.- The use according to claim 18, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spine, embolism associated with brain damage and neurological disorder related to neuronal degeneration. 20. - The use according to claim 19, wherein the neurological disorder related to neuronal degeneration is selected from the group consisting of Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08799407 | 1997-02-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99007384A true MXPA99007384A (en) | 2000-07-01 |
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