MXPA99007938A - Method of using neurotrophic carbamates and ureas - Google Patents
Method of using neurotrophic carbamates and ureasInfo
- Publication number
- MXPA99007938A MXPA99007938A MXPA/A/1999/007938A MX9907938A MXPA99007938A MX PA99007938 A MXPA99007938 A MX PA99007938A MX 9907938 A MX9907938 A MX 9907938A MX PA99007938 A MXPA99007938 A MX PA99007938A
- Authority
- MX
- Mexico
- Prior art keywords
- branched
- straight
- group
- alkyl
- alkenyl
- Prior art date
Links
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 230000000508 neurotrotrophic Effects 0.000 title claims abstract description 23
- 235000013877 carbamide Nutrition 0.000 title abstract description 11
- 150000004657 carbamic acid derivatives Chemical class 0.000 title description 10
- -1 small molecule carbamates Chemical class 0.000 claims abstract description 65
- 108060002921 FKBP2 Proteins 0.000 claims abstract description 10
- 108060002918 FKBP6 Proteins 0.000 claims abstract description 10
- 102100000319 FKBP9 Human genes 0.000 claims abstract description 10
- 108060002920 FPR1 Proteins 0.000 claims abstract description 10
- 108060002058 PPIL1 Proteins 0.000 claims abstract description 10
- 108060002060 PPIL3 Proteins 0.000 claims abstract description 10
- 108060002061 PPIL4 Proteins 0.000 claims abstract description 10
- 108060002923 TIG Proteins 0.000 claims abstract description 10
- 108060007134 rot Proteins 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 53
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
- 125000003342 alkenyl group Chemical group 0.000 claims description 43
- 230000001537 neural Effects 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000000304 alkynyl group Chemical group 0.000 claims description 26
- 208000009025 Nervous System Disease Diseases 0.000 claims description 24
- 206010029305 Neurological disorder Diseases 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000004429 atoms Chemical group 0.000 claims description 12
- 210000002569 neurons Anatomy 0.000 claims description 12
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 10
- 206010061536 Parkinson's disease Diseases 0.000 claims description 10
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 9
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 claims description 9
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 claims description 9
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 208000001293 Peripheral Nervous System Disease Diseases 0.000 claims description 8
- 206010034606 Peripheral neuropathy Diseases 0.000 claims description 8
- 150000003857 carboxamides Chemical class 0.000 claims description 8
- 239000003018 immunosuppressive agent Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- 206010002026 Amyotrophic lateral sclerosis Diseases 0.000 claims description 7
- 210000004556 Brain Anatomy 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 230000008929 regeneration Effects 0.000 claims description 7
- 238000011069 regeneration method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 6
- 208000001183 Brain Injury Diseases 0.000 claims description 6
- 208000005189 Embolism Diseases 0.000 claims description 6
- 206010022114 Injury Diseases 0.000 claims description 6
- 231100000874 brain damage Toxicity 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 6
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000002829 nitrogen Chemical group 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 150000003384 small molecules Chemical class 0.000 claims description 6
- 230000000638 stimulation Effects 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 5
- 229910006069 SO3H Inorganic materials 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 claims description 4
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 102100014139 FKBP1A Human genes 0.000 claims description 4
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 claims description 4
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 4
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005002 aryl methyl group Chemical group 0.000 claims description 4
- 125000003828 azulenyl group Chemical group 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 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 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 230000001861 immunosuppresant Effects 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 4
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 4
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000005412 pyrazyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
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- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 1
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- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 abstract description 12
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- PLRACCBDVIHHLZ-UHFFFAOYSA-N MPTP Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 7
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Abstract
This invention relates to a method of using neurotrophic low molecular weight, small molecule carbamates and ureas 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 NEUROTROPHIC CARBAMATES AND UREAS
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION This invention relates to a method for using small molecule and low molecular weight neurotrophic carbamates and ureas having an affinity to FKBP type immunophilins, as inhibitors of the enzyme activity associated with immunophilin proteins, particularly the activity Enzymatic peptidyl-prolyl, rough or rotamase.
2. Description of the Related Art The term "immunofilin" refers to a number of proteins that serve as receptors for the major immunosuppressant drugs, cyclosporin A (CsA), FK506 and rapamycin. The known classes of immunophilins are cyclophilins and proteins that bind to FK506, or FKBP proteins. 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 the cis and trans isomers of peptide and protein substrates for the 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 derive 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 enzyme and inhibit T cell receptor signaling, leading to T cell proliferation. Similarly, the immunophilin complex - FKBP-rapamycin drug interacts with the RAFT1 / FRAP protein and inhibits the signaling of the IL-2 receptor. It has been found that immunophilins are present in 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 molecule and low molecular weight carbamates and ureas with a high affinity to FKBP 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 neurons affected in the disorder. Several neurotrophic factors have been identified that affect specific neuronal 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 therefore been proposed to treat SDAT 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 show excellent bioavailability and specificity. However, when administered chronically, immunosuppressive drugs exhibit a number of potentially serious side effects, including nephrotoxicity, such as impairment of 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-immunosuppressive compound containing small molecule and low molecular weight carbamates and ureas to increase the growth of neurites, and to promote neuronal growth and 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 (spinal cord 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 small molecule and low molecular weight neurotrophic carbamates and ureas having an affinity to 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 enzyme peptidyl-prolyl isomerase or rotamase. 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 (C 1 -C 6) alkyl, straight or branched (C 2 -C 6) alkenyl or alkynyl, straight or branched (C 1 -C 6) alkyl or alkenyl or alkynyl of (C 3) -C6) straight or branched substituted with (C5-C7) cycloalkyl, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl or alkynyl substituted with (C5-C7) cycloalkenyl, alkyl (C 1 -C 6) straight or branched substituted with straight or branched Ar (C 3 -C 6) alkenyl or alkynyl substituted with Ar; any of the CH2 groups of said alkyl chains can be optionally replaced by a heterogeneous atom selected from the group consisting of O, S, SO and SO2 > and NR, wherein R is selected from the group consisting of straight or branched hydrogen, straight or branched (C 1 -C 4) alkyl, straight or branched (C 3 -C 4) alkenyl or alkynyl, and bridging (C 1 -C 4) alkyl wherein a bridge is formed between the nitrogen atom and a carbon atom of said chain which contains the heterogeneous atom to form a ring, and wherein said ring is optionally fused to an Ar group;
J is selected from the group consisting of hydrogen, alkyl
(C1-C6) straight or branched, straight or branched (C3-C6) alkenyl and -CH2Ar;
K is selected from the group consisting of straight or branched (C 1 -C 4) alkyl, -CH 2 Ar, and cyclohexylmethyl; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heterogeneous atom which is selected from the group consisting of O, S, SO and SO2; Z is O or S; Y is O or N, where when Y is O, then Ri is a solitary pair and R2 is selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and alkenyl or (C3-C6) alkynyl straight or branched; and when Y is N, then Ri and R2 are independently selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and straight or branched (C3-C6) alkenyl or alkynyl; or Ri and R2 are taken together to form a 5-6 membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine; Ar is an aromatic carbocyclic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or an aromatic heterocyclic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl , 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1, 2,3, -oxadiazolyl, 1, 2,3, -triazolyl, 1, 3,4, -thiadiazolyl, pyrazinyl, pyrimidinyl, pyrazinyl, 1, 3,5 -triazinyl, 1, 3,5-trityanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1 H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1, 2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1, 2,3,4-tetrahydroisoquininoinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, straight or branched (C1-C6) alkyl, straight (C2-C6) alkenyl or branched, O- [straight or branched (C1-C6) alkyl], O- [straight or branched (C3-C4) alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR3R, carboxyl, N- (straight or branched C 1 -C 5 alkyl or straight or branched C 3 -C 5 alkenyl) carboxamides, N, Nd i- (straight or branched C 1 -C 5 alkyl or straight or branched C 3 -C 5 alkenyl) carboxamides , morpholinyl, piperidinyl, OX, CH2- (CH2) qX, O- (CH2) qX, (CH2) qOX, and CH = CH-X; R3 and R4 are independently selected from the group consisting of straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl, hydrogen and benzyl; or R3 and R can be taken together to form a 5-6 membered heterocyclic ring;
X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl. 3-thienyl and pyrimidyl; q is 0-2; and n is 0 or 1. 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 II or III:
or a pharmaceutically acceptable salt thereof, wherein: Y, Ri and R2 are as defined in claim 1, Ar is as defined in claim 4 and w is 1 or 2. The present invention also relates to a method to effect neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula III or IV: IV
or a pharmaceutically acceptable salt thereof, wherein: Y, Ri and R2 are as defined in claim 1, Ar is as defined in claim 4, J is hydrogen, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl and w is 1 or '2.
DETAILED DESCRIPTION OF THE INVENTION
Definitions The term "alkyl" means a saturated, branched or unbranched hydrocarbon chain containing 1 to 6 carbon a, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -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 diamyl 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 "phenyl" includes all possible isomeric phenyl radicals, optionally monosubstituted or multisubstituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, halogen and halogenoalkyl.
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 (iii) healing the disease and / or condition, i.e., causing the regression of the disease and / or condition. The inventors have discovered that certain small molecule and low molecular weight carbamates and ureas have an affinity to the FKBP-type immunofilins., particularly FKBP12. It has been found that when carbamates and ureas bind to an FKBP-type immunophilin, they inhibit the activity of prolyl-peptidyl cis-trans isomerase, or rotamase, the activity of the binding protein and unexpectedly stimulate the growth of neurites. This activity 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 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 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 (C 1 -C 6) alkyl, straight or branched (C 2 -C 6) alkenyl or alkynyl, straight or branched (C 1 -C 6) alkyl or alkenyl or alkynyl of (C 3) -C6) straight or branched substituted with (C5-C7) cycloalkyl, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl or alkynyl substituted with (C5-C7) cycloalkenyl, alkyl (C 1 -C 6) straight or branched substituted with straight or branched Ar (C 3 -C 6) alkenyl or alkynyl substituted with Ar; any of the CH2 groups of said alkyl chains can be optionally replaced by a heterogeneous atom selected from the group consisting of O, S, SO and SO2, and NR, wherein R is selected from the group consisting of hydrogen, C1-alkyl -C4) straight or branched, straight or branched (C3-C4) alkenyl or alkynyl and bridging (C1-C4) alkyl wherein a bridge is formed between the nitrogen atom and a carbon atom of said chain containing the heterogeneous atom to form a ring, and wherein said ring is optionally fused to an Ar group; J is selected from the group consisting of hydrogen, straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl and -CH2Ar; K is selected from the group consisting of straight or branched (C 1 -C 4) alkyl, -CH 2 Ar, and cyclohexylmethyl; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heterogeneous atom which is selected from the group consisting of O, S, SO and SO2; Z is O or S; Y is O or N, where when Y is O, then Ri is a solitary pair and R2 is selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and alkenyl or (C3-C6) alkynyl straight or branched; and when Y is N, then Ri and R2 are independently selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and straight or branched (C3-C6) alkenyl or alkynyl; or R-i and R2 are taken together to form a 5-6 membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine; Ar is an aromatic carbocyclic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or an aromatic heterocyclic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl , 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,
1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3-triazinyl, 1,3-trityanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenium, 1 H-indazolyl, benzimidazole, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1, 2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, straight or branched (C1-C6) alkyl, straight (C2-C6) alkenyl or branched, O- [straight or branched (C1-C6) alkyl], O- [straight or branched (C3-C4) alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR3R4, carboxyl, N- (straight or branched C 1 -C 5 alkyl or straight or branched C 3 -C 5 alkenyl) carboxamides, N, N-di- (straight or branched C 1 -C 5 alkyl or straight or branched C 3 -C 5 alkenyl) carboxamides, morpholinyl, piperidinyl, OX, CH2- (CH2) qX, O- (CH2) qX, (CH2) qOX, and CH = CH-X; R3 and R4 are independently selected from the group consisting of straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl, hydrogen and benzyl; or R3 and R can be taken together to form a 5-6 membered heterocyclic ring;
X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl,
2-methylthiazoyl, thiazoyl, 2-thienyl. 3-thienyl and pyrimidyl; q is 0-2; and n is 0 or 1. In a preferred embodiment, J and K are taken together to form a ring of 5-7 members. In another preferred embodiment, at least one of B and D is independently represented by the formula - (CH2) r- (X) - (CH) s-Ar, wherein: r is 1-4; s is 0-1; Ar is as defined in claim 1; and each X is independently selected from the group consisting of CH 2, O, S, SO and SO 2, and NR, wherein R is selected from the group consisting of hydrogen, straight or branched (C 1 -C 4) alkyl, alkenyl or alkynyl of straight or branched (C3-C4) and bridging (C1-C4) alkyl wherein a bridge is formed between the nitrogen atom and the Ar group; In a further preferred embodiment, Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, and 1, 2 , 3,4-tetrahydroquinolinyl, wherein said Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, hydroxyl, nitro, trifluoromethyl, straight or branched (C 1 -C 6) alkyl, O- [ (C1-C6) straight or branched], halogen, -SO3H and -
NR3R4; and R3 and R4 are independently selected from the group consisting of straight or branched (C1-C6) alkyl; straight or branched (C3-C6) alkenyl, hydrogen and benzyl; or R3 and R4 can be taken together to form a 5-6 membered heterocyclic ring. 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 II or III:
II or a pharmaceutically acceptable salt thereof, wherein: Y, R1 and R2 are as defined in claim 1, Ar is as defined in claim 4 and w is 1 or 2. 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 III or IV: IV
or a pharmaceutically acceptable salt thereof, wherein: Y, Ri and R2 are as defined in claim 1, Ar is as defined in claim 4, J is hydrogen, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl and w is 1 or '2. The neuronal activity that is effected 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 progressive bulbar 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 spinal cord, 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, intrasternal 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 oily 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, non-volatile oils are commonly used as solvents or suspending media. For this purpose, any soft non-volatile oil tai may be employed as a synthetic mono- or diglyceride. 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 injectable solutions. These oil solutions or suspensions may also contain long chain alcohol 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 and / or flavoring and / or coloring agents. 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 disorders of the eye, the skin or the lower intestinal tract. 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, sorbitan monostearate, polysorbate 60, cetyl ester wax, Cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Topical application to the lower intestinal tract may be carried out in rectal suppository formulations (see above) or in suitable enema 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 the treatment of 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 easily prepared by normal organic chemistry techniques, using the synthetic route indicated below. As described by Scheme I, the cyclic 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, the free amine 3 can reacting with a variety of isocyanates or isothiocyanates to supply the ureas or thioureas, respectively. Alternatively, the reaction of 1 with the amines provides the corresponding amide compounds.
SCHEME I
Check out
The isocyanates (R1NCO) or the isothiocyanates (R1NCS) 4 can be conveniently prepared from the corresponding amines which can be easily obtained by reaction with phosgene or thiophosgene, as shown in Scheme II SCHEME H
EXAMPLE 1 Synthesis of (2S) -1-r (3- (3-pyridyl) -1-propyl (2-methylbuty-3-carbamoippyrrolidin-2-carboxylate)
(2S) -N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate 3- (3-pyridyl) -1-propyl A mixture of N- (tert-butyloxycarbonyl) - was stirred overnight (S) -proline (3.0 g, 13.9 mmoles); 3- (3-pyridyl) -1-propanol (2.90 g, 20.9 mmol); dicyclohexycarbodiimide (4.59 g, 22.24 mmoles), camphor sulfonic acid (1.08 g, 4.63 mmoles) and 4-dimethylaminopyridine (0.60 g, 4.63 mmoles) in dry methylene chloride (100 ml). The reaction mixture was diluted with methylene chloride (50 ml) and water (100 ml), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried with magnesium sulfate and concentrated, and the crude residue was purified on a column with silica gel eluting with ethyl acetate to obtain 4.60 g (95%). of the ester as a thick oil, 1 H NMR (300 MHz, CDCl 3): d 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1 H); 2.71 (t, 2H); 3.50 (m, 2H); 4.15 (m, 2H); 4.18 (m, 1 H); 7.24 (m, 1 H); 7.51 (m, 1 H); 8.48 (m, 2H).
3- (3-Pyridyl) -1-propyl pyrrolidin-2-carboxylate A solution of 3- (3-pyridyl) - (2S) -N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate) was stirred at room temperature. 1-propyl (3.00 g, 9 mmol) in methylene chloride (50 ml) and trifluoroacetic acid (5 ml) for three hours. Saturated potassium carbonate was added until the pH became alkaline and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield
2. 00 g (95%) of the free amine as a thick oil, 1 H NMR (300 MHz,
CDCl 3): d 1.87-2.20 (m, 6H); 2.79 (m, 2H); 3.03 (m, 2H total); 3.07 (m, 2H);
3. 84 (m, 1 H); 4.24 (m, 2H); 7.32 (m, 1 H); 7.60 (m, 1 H); 8.57 (m, 21 H).
(2S) -1-r (2-methylbutyl) -carbamoyl] pyrrolidin-2-carboxylate of 3- (3-pyridyl) -1-propyl
A solution of 2-methylbutylamine (113 mg, 1.3 mmol) and triethylamine (132 mg, 1.3 mmol) in methylene chloride (5 ml) was added to a solution of triphosgene (128 mg, 0.43 mmol) in methylene chloride (5 mM). my). The resulting mixture was refluxed for 1 hour and then cooled to room temperature. (3- (3-pyridyl) -1-propyl (2S) -pyrrolidine-2-carboxylate (300 mg, 1.3 mmol) in 5 ml of methylene chloride was added and the resulting mixture was stirred for 1 hour and then separated between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 250 mg (55%) of the compound of Example 1 (1, Table 1) as an oil, 1 H NMR ( CDCl 3, 300 MHz): d 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1 H);
1. 27 (s, 1 H); 1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m,
2H); 2.92-3.54 (m, 4H); 4.16-4.20 (dt, 2H); 4.45-4.47 (m, 2H); 7.21-7.29 (m
1 HOUR); 7.53-7.56 (dd, 1 H); 8.46-8.48 (s, 2H). Analysis calculated for C19H29N3? 3
- 0.5 H2O: C, 64.02; H, 8.48; N, 1 1.79. Found: C, 63.72; H, 8.42; N,
1 1.83.
EXAMPLE 2 Synthesis of (2S) -1-f (1 M '-dimethylpropiQcarbamoippyrrolidin-2-carboxylate of 3- (3-pyridyl) -1-propyl (2)
The reaction of (2S) -pyrrolidine-2-carboxylic acid 3- (3-pyridyl) -1-propyl with the isocyanate generated from ter-amylamine and triphosgene, as described for example 1, gave the compound of Example 2 (2, Table 1) in 62% yield, 1 H NMR (CDCl 3, 300 MHz): d 0.83 (t, 3H); 1.27 (s, 6H); 1.64-1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H); 3.29-3.42 (m, 2H); 4.1 1-4.15 (t, 3H); 4.37-4.41 (m, 1 H). Analysis calculated for C19H29N3? 3 - 0.5 H2O: C, 64.04; H, 8.48; N, 1 1.79. Found: C 64.23; H, 8.31; N, 11.30.
EXAMPLE 3 Synthesis of (2SH -r (cyclohexylHiocarbamoip-pyrrolidin-2-3- (3-pyridiB) -1-propylcarboxylate (3)
A mixture of cyclohexylisothiocyanate (120 mg, 0.9 mmol), 3- (3-pyridyl) -1-propyl (2S) -pyrrolidine-2-carboxylate (200 mg, 0.9 mmol) and triethylamine (90 mg, 0.9 mmol) was stirred. ) in 20 ml of methylene chloride for 1 hour and then separated between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 160 mg (47%) of the compound of Example 3 (3, Table 1), 1 H NMR (CDCl 3, 300 MHz): d 1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.40-3.60 (m, 2H); 4.17-4.26 (m, 2H); 4.95-4.98 (d, 1 H); 5.26-5.29 (d, 1 H); 7.17-7.25 (m, 1 H). Analysis calculated for C2oH29N3O2S: C, 63.97; H, 7.78; N, 1 1.19. Found: C, 63.25; H, 7.80; N, 1.07.
EXAMPLE 4 Synthesis of (2S) -1-r (cyclohexyl) carmaboip-pyrrolidin-2-carboxylate 3- (3-pyridyl) -1-propyl (4)
A mixture of cyclohexylisocyanate (100 mg, 0.9 mmol), 3- (3-pyridyl) -1-propyl (2S) -pyrrolidine-2-carboxylate (200 mg, 0.9 mmol) and triethylamine (90 mg, 0.9 mmol) was stirred. ) in 20 ml of methylene chloride for 1 hour and then separated between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 120 mg (36%) of the compound of Example 4 (4, Table 1) 1 H NMR (CDCl 3, 300
MHz): d 1.10-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m, 4H); 2.67-2.73 (t,
2H); 3.31-3.44 (m, 3H); 4.12-4.16 (m, 2H); 4.39-4.42 (m, 1 H); 7.25-7.34 (m,
1 HOUR); 7.25-7.55 (dd, 1 H); 8.45 (s, 2H). Analysis calculated for C2oH29N3? 3 - 0.6
H2O: C, 64.88; H, 8.22; N, 11.35. Found: C, 64.60; H, 8.18; N, 11.21.
EXAMPLE 5 Synthesis of 3- (3-pyridyl) -1-propyl (2S) -1-r (1-adamantyl) thiocarbamoy-Pyrrolidin-2-carboxylate (5)
A mixture of 1-adamantyl isocyanate (250 mg, 0.9 mmol), (2S) -pyrididine-2-carboxylic acid 3- (3-pyridyl) -1-propyl ester (200 mg, 0.9 mmol) and triethylamine (90 mg; 0.9 mmoles) in 20 ml of methylene chloride for 1 hour and then separated between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 150 mg (38%) of the compound of Example 4 (4, Table 1), 1 H NMR (CDCl 3, 300 MHz): d 1.39-1.44 (d, 2H); 1.65 (s, 4H); 1.95-2.07 (m, 8H); 2.07-2.20 (m, 5H); 2.71-2.76 (m, 2H); 3.37-3.45 (m, 1 H); 3.50-3.60 (m, 1 H); 4.09-4.18 (m, 2H);
4. 99-5.21 (d, 1 H); 7.21-7.25 (m, 1 H). Analysis calculated for C 24 H 33 N 3 2 2 S - 0.4 H 2 O: C, 66.30; H, 7.84; N, 9.66. Found: C, 66.41; H, 7.79; N, 9.50. As discussed above, the carbamates and ureas used in the methods of the present invention have an affinity for the protein that binds to FK506, particularly FKBP12. Inhibition of the prolyl-peptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity.
PROCEDURE OF THE PROOF Kl
The inhibition of the peptidyl prolyl isomerase (rotamase) activity 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. Am. Chem. Soc, 115: 9923-9938). These values are obtained as the apparent Ki values and are presented in table II. The cis-trans somerization of an alanine-proline binding in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored with spectrophotometer in a test coupled with chymotrypsin, which releases p-nitroanilide coming 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 were added in a plastic container.
1 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 versus 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 II under the "Ki" column. The neurotrophic effects of the carbamates and ureas used in the methods of the present invention can be demonstrated in in vitro cell biological experiments, as described below.
CULTIVATION OF DORSAL ROOT GANGLIA AND PROLONGATION OF NEURITES
Dorsal root ganglia of chicken embryos were dissected
days of gestation 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 containing also 10 μM of β-D arabinofuranoside of cytosine (Ara C) at 37 ° C in an environment containing 5% C02. Twenty-four hours later, the dorsal root ganglia (DRG) were treated with various immunophilin ligands. Forty-eight hours after treatment with the drug, the nodes 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 "DE50" of table II.
TABLE 1
EXAMPLES No. m B 10 1 I O 2 3-pyridyl H 2 -methylbutyl H
2 1 O 2 3-pyridyl H 1, 1-dimethypropyl H
3 1 S 2 3-pyridyl H cyclohexyl H
4 1 O 2 3-pyridyl H cyclohexyl H
1 S 2 3-pyridyl H 1-adamantyl H
TABLE II In vitro activity of the compounds of Example
Example No. Ki, nM DE50, nM 1 70 0.065 2 742 1 3 131 0.292 4 1482 n.d. 5 116 0.141
MPTP MODEL OF PARKINSON'S DISEASE
The remarkable neurotrophic and neuroregenerative 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. Four week old male CD1 white mice were dosed 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 III 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 III In vivo activity of the selected example compounds
Example No.% Rescue, immunostaining TH at 4 mq / kq, s.c. 1 27.47 2 n. d. 3 56.13 4 59.79 5 52.32 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 (25)
1. - The use 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 (C 1 -C 6) alkyl, straight or branched (C 2 -C 6) alkenyl or alkynyl, straight or branched (C 1 -C 6) alkyl or alkenyl or alkynyl of (C 3) -C6) straight or branched substituted with (C5-C7) cycloalkyl, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl or alkynyl substituted with (C5-C7) cycloalkenyl, alkyl (C 1 -C 6) straight or branched substituted with straight or branched Ar (C 3 -C 6) alkenyl or alkynyl substituted with Ar; any of the CH2 groups of said alkyl chains may be optionally replaced by a heterogeneous atom selected from the group consisting of O, S, SO, and S02) and NR, wherein R is selected from the group consisting of hydrogen, (C1) alkyl -C4) straight or branched, straight or branched (C3-C4) alkenyl or alkynyl and bridging (C1-C4) alkyl wherein a bridge is formed between the nitrogen atom and a carbon atom of said chain containing the heterogeneous atom to form a ring, and wherein said ring is optionally fused to an Ar group; J is selected from the group consisting of hydrogen, straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl and -CH2Ar; K is selected from the group consisting of straight or branched (C 1 -C 4) alkyl, -CH 2 Ar, and cyclohexylmethyl; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heterogeneous atom which is selected from the group consisting of O, S, SO and SO2; Z is O or S; Y is O or N, where when Y is O, then Ri is a solitary pair and R2 is selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and alkenyl or (C3-C6) alkynyl straight or branched; and when Y is N, then Ri and R2 are independently selected from the group consisting of straight or branched hydrogen, cyclohexyl, adamantyl, straight or branched (C1-C6) alkyl and straight or branched (C3-C6) alkenyl or alkynyl; or Ri and R2 are taken together to form a 5-6 membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine; Ar is an aromatic carbocyclic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or an aromatic heterocyclic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl , 2- pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1, 2,3, -oxadiazolyl, 1, 2,3, -triazolyl, 1, 3,4, -thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 3,5- triazinyl, 1, 3,5-trityanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1 H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1, 2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, straight or branched (C1-C6) alkyl, straight (C2-C6) alkenyl or branched, 0- [straight or branched (C1-C6) alkyl], 0- [straight or branched (C3-C4) alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, - NR3R4, carboxyl, N- (straight or branched C1-C5 alkyl or straight or branched C3-C5 alkenyl) carboxamides, N, N-di- (straight or branched C1-C5 alkyl or straight C3-C5 alkenyl or branched) carboxamides, morpholinyl, piperidinyl, OX, CH2- (CH2) qX, 0- (CH2) qX, (CH2) qOX, and CH = CH-X; R3 and R4 are independently selected from the group consisting of straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl, hydrogen and benzyl; or R3 and R4 can be taken together to form a 5-6 membered heterocyclic ring; X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl. 3-thienyl and pyrimidyl; q is 0-2; and n is 0 or 1, in the preparation of a medicament for effecting neuronal activity in an animal.
2. The use according to claim 1, wherein J and K are taken together to form a ring of 5-7 members.
3. The use according to claim 1, wherein at least one of B and D is independently represented by the formula - (CH2) r (X) - (CH) s-Ar, wherein: r is 1- 4; s is 0-1; Ar is as defined in claim 1; and each X is independently selected from the group consisting of CH 2, O, S, SO and SO 2, and NR, wherein R is selected from the group consisting of hydrogen, straight or branched (C 1 -C 4) alkyl, alkenyl or alkynyl of straight or branched (C3-C4) and bridging (C1-C4) alkyl wherein a bridge is formed between the nitrogen atom and the Ar group;
4. The use according to claim 1, wherein: Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1, 2,3 , 4-tetrahydroisoquinolinyl and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar may contain one or more substituents that are independently selected from the group consisting of hydrogen, hydroxyl, nitro, trifluoromethyl, straight (C1-C6) alkyl or branched, 0- [straight or branched (C 1 -C 6) alkyl], halogen, -SO 3 H and -NR 3 R 4; and R3 and R are independently selected from the group consisting of straight or branched (C1-C6) alkyl; straight or branched (C3-C6) alkenyl, hydrogen and benzyl; or R3 and R4 can be taken together to form a 5-6 membered heterocyclic ring.
5. - The use according to any of the claims 1-4, where the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neuron degeneration! and treatment of neurological disorder
6. The use in accordance with re-identification 5, 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 cord spinal, embolism associated with brain damage and neurological disorder related to neuronal degeneration.
7. The use according to claim 6, 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.
8. The use of a compound of formula II or formula III: III or a pharmaceutically acceptable salt thereof, wherein Y, R1 R2 are as defined in claim 1, Ar is as defined in claim 1 and w is 1 or 2, in the preparation of a medicament for carrying out an activity neuronal in an animal.
9. The use according to claim 8, 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.
10. The use according to claim 9, 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. 1.
The use according to claim 10, 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.
12. The use of a compound of the formula III or IV: III or a pharmaceutically acceptable salt thereof, wherein: Y, R-i and R2 are as defined in claim 1, Ar is. as defined in claim 1, J is hydrogen, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl and w is 1 or 2, in the preparation of a medicament for effecting neuronal activity in an animal
13. The use according to claim 12, 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.
14. The use according to claim 13, 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.
15. The use according to claim 14, 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.
16. A pharmaceutical composition, comprising 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 (C 1 -C 6) alkyl, straight or branched (C 2 -C 6) alkenyl or alkynyl, straight or branched (C 1 -C 6) alkyl or alkenyl or alkynyl of (C 3) -C6) straight or branched substituted with (C5-C7) cycloalkyl, straight or branched (C1-C6) alkyl or straight or branched (C3-C6) alkenyl or alkynyl substituted with (C5-C7) cycloalkenyl, alkyl of straight or branched (C1-C6) substituted with straight or branched (C3-C6) ar, alkenyl or alkynyl substituted with Ar; any of the CH2 groups of said alkyl chains may be optionally replaced by a heterogeneous atom selected from the group consisting of O, S, SO and SO2, and NR, wherein R is selected from the group consisting of hydrogen, alkyl ( C1-C4) straight or branched, straight or branched (C3-C4) alkenyl or alkynyl and bridging (C1-C4) alkyl where a bridge is formed between the nitrogen atom and a carbon atom of said chain that contains the heterogeneous atom to form a ring, and wherein said ring is optionally fused to an Ar group; J is selected from the group consisting of hydrogen, straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl and -CH2Ar; K is selected from the group consisting of straight or branched (C 1 -C 4) alkyl, -CH 2 Ar, and cyclohexylmethyl; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heterogeneous atom which is selected from the group consisting of O, S, SO and SO2; Z is O or S; Y is O or N, where when Y is O, then Ri is a solitary pair and R2 is selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and alkenyl or. straight or branched (C3-C6) alkynyl; and when Y is N, then Ri and R2 are independently selected from the group consisting of Ar, straight or branched (C1-C6) alkyl and straight or branched (C3-C6) alkenyl or alkynyl; or Ri and R2 are taken together to form a 5-6 membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine; Ar is an aromatic carbocyclic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or an aromatic heterocyclic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl , 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, sotriazolyl, 1, 2,3, -oxadiazolyl, 1, 2,3, -triazolyl, 1, 3,4, -thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 3,5 -triazinyl, 1, 3,5-trityanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1 H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1, 2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, straight or branched (C1-C6) alkyl, straight (C2-C6) alkenyl or branched, O- [straight or branched (C1-C6) alkyl], O- [straight or branched (C3-C4) alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR3R, carboxyl, N- (straight or branched C 1 -C 5 alkyl or straight or branched C 3 -C 5 alkenyl) carboxamides, N, N-di- (straight or branched C 1 -C 5 alkyl or straight or branched C 3 -C 5 alkenyl) carboxamides, morpholinyl, piperidinyl, OX, CH2- (CH2) qX, O- (CH2) qX, (CH2) q-0-X, and CH = CH-X; R3 and R4 are independently selected from the group consisting of straight or branched (C1-C6) alkyl, straight or branched (C3-C6) alkenyl, hydrogen and benzyl; or R3 and R4 can be taken together to form a 5-6 membered heterocyclic ring; X is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinoxy, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiozoyl, thiazoyl, 2-thienyl. 3-thienyl and pyrimidyl; q is 0-2; and n is 0 or 1, for the preparation of a medicament for effecting neuronal activity in an animal.
17. The pharmaceutical composition according to claim 16, 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.
18. The pharmaceutical composition according to claim 17, 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, associated embolism with brain damage and neurological disorder related to neuronal degeneration.
19. The pharmaceutical composition according to claim 18, 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.
20. The use of any of claims 1, 8 or 12, wherein the compound is non-immunosuppressant:
21. The pharmaceutical composition of claim 16, wherein the compound is non-immunosuppressant.
22. The use of a neurotrophic compound containing carbamate or urea of small molecule and low molecular weight in the preparation of a medicament for the treatment of a neurological disorder, wherein the compound has an affinity to an immunophilin type FKBP.
23. The use according to claim 22, wherein the FKBP type immunophilin is FKBP-12.
24. The use according to claim 23, wherein the compound inhibits the rotamase activity of the FKBP type immunophilin.
25. A use substantially as described above in the present invention. 26.- A pharmaceutical composition substantially as described above in the present invention.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/805,646 | 1997-02-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99007938A true MXPA99007938A (en) | 2000-09-04 |
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