TWI252226B - Small molecule inhibitors of rotamase enzyme activity - Google Patents

Abstract

This invention relates to neurotrophic N-glyoxyl-prolyl ester compounds having an affinity for FKBP-type immunophilins, their preparation and use as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.

Description

1252226 A7 B7 V. Description of invention (1)

I Related Applications The present invention is a continuation of the application in U.S. Patent Application Serial No. 0 8/4 7 9, 4 3 6 which was filed on June 7, 1995. BACKGROUND OF THE INVENTION The present invention relates to a neurotrophic compound having affinity for FKBP-type immunophenometh (immun Gphilin), a method for its preparation, and an enzyme related to an immunophenanthmium (especially a peptide base). a suppressor of the activity of amidoxime isomerase or rotamase. Description of the Know-how 免疫 Immunization of the film means a group of proteins that are the main recipients of immunosuppressive drugs such as Cyclosporin (CsA), FK506, and rapamyc in. The known immunofilm types are ring-film (〇7(:1〇?^1111) and ?}(5 0 6 binding proteins (such as ?0?). Cyclosporin A will bind to phenanthrene, while FK506 and Ray Papamycin binds to FKBP. These immunophene-drug complexes interact with a variety of different intracellular signal transduction lines (which are immunological and neuronal). Immunophila have been known to have 呔-基-脯Amino-mercaptoisomerase (PPIase) or rotamase activity. It has been determined that rotamase activity plays a role in the catalysis of the mutual conversion of cis or trans isomers of immunofilm proteins. Film was first discovered and studied in immune tissues. Those who are familiar with this art first assume that the inhibition of the activity of the anti-feline isomerase results in the inhibition of T-cell proliferation, resulting in such things as cyclosporin A and FK5Q6. The immunosuppressive drug with rapamycin exhibits an immunosuppressive paper scale that applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note first and then fill out this page) Department of Economics Hui Property Bureau employee consumption cooperative printed 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (2) systemic role. Further research has shown that, by the rotational isomerization _ activity inhibition itself Not enough to achieve immunosuppressive activity. Schrei ib ereta 1 ·, Science (1 9 9 0) , 250 : 55 6 - 55 9. It has been shown that human immunopheno-drug complexes interact with ternary protein targets. The mode of action. Schreiber et al., Cel 1 (19 9 1), QA: 8 0 7 -8 1 5. In the case of FKBP-FK5Q6 and FKBP-CsA, these drug-immunized film complexes are bound to The enzyme calcineurin (ca 1 cin eur iη), which inhibits the T-receptor signaling for T-cell proliferation. Similarly, the complex of rapamycin and FKBP interacts with the RAFT 1/FRAP protein. Inhibition of signaling originating from the IL-2 receptor. Immunofluorescence has been found to be present in high concentrations in the central nervous system: the amount of immunofilm is higher in the central nervous system than in the immune system. 10 to 5 Q times. In God Within the tissue, the immunization film appears to affect neuronal protuberance expansion, nitric oxide synthesis, and neurotransmitter release. It has been found that one of the 1 Q 1 2 molar concentrations, such as FK5 Q 6 and rapamycin, is immunized. The stimulating PC 1 2 cells and the _ sensation nerves, that is, the neurites in the dorsal root ganglion cells (DRG s) grow. L y ο nseta 1., Pro.c_,, _.〇i H^t.1 Soi. (1 9 94 ) , 21: 3 1 9 Bu 3 1 9 5 .: In the whole brain animal experiment, FK5 0 6 shows nerve regeneration after facial nerve damage and causes sciatic nerve Functional recovery in damaged animals. Surprisingly, it has been found that a drug having a high affinity for FKBP is a potent rotamase inhibitor which causes a neurotrophic effect. These findings suggest that immunosuppression can be used in the treatment of various peripheral neuropathies and in the regeneration of neurons in the central nervous system (CNS) (please read the notes on the back and fill out this page). Binding---- ----- % This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) • 5-1252226 Α7 Β7 V. Invention description (3) (Please read the notes on the back and fill out this page. ) Preparation. Studies have confirmed that neurodegenerative disorders such as AIDS, Parkinson's disease, and muscle-shrinking lateral sclerosis (ULS) may be due to the loss or reduced availability of a neurotrophic substance. The neurotrophic substance is specific to a particular neuron population affected by the disorder. Several neurotrophic factors have been identified that affect the established neuronal population within the central nervous system. For example, it has been hypothesized that AIDS is caused by a decrease or loss of a nerve growth factor (NGF). Therefore, it has been suggested that exogenous nerve growth factor or other neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin-3 (palpitations) -tr 〇pi η - 3 ), to treat patients with AIDS, to promote the survival of degenerating neuronal populations. Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives print these proteins in various neurological diseases The clinical application is hindered by the difficulty of transporting large proteins to the neural strips and the bioavailability. Relatively, the immunosuppressive drugs with neurotrophic activity are quite small and exhibit excellent bioavailability and specificity. However, when administered chronically, immunosuppressive agents exhibit a variety of potentially serious side effects including nephrotoxicity, such as damage to glomerular filtration, irreversible interstitial fibrosis. Uopp et al (1991), J · Am. Sco Heohrol . . U 162); neurological deficits such as autonomous tremors, or such as no positioning Non-specific angina pectoris (D e G r 〇eneta 1 (1987), N. Eng-1, 1, Med., 317: 861); and the high complications associated with it Blood pressure (Kahan et al (1989), M. Engl This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (4 J. Med·· 321 : 1725 In order to prevent side effects associated with the use of immunosuppressants, the present invention provides a non-immunosuppressive compound containing a small molecule FKBP rotamase inhibitor for promoting various neuropathological conditions. The growth and regeneration of neurons (which can contribute to the repair of neurons), including peripheral nerve damage caused by physical damage or disease states (such as diabetes), and central nervous system (spinal cord and Physical damage to the brain, brain damage associated with stroke, and neurological diseases associated with the treatment of neurodegeneration, including Parkinson's disease, AIDS, and amyotrophic lateral sclerosis. BRIEF DESCRIPTION OF THE DRAWINGS The present invention is a pseudo-related group of novel neurotrophic compounds having a specificity for FKBP-type immunophenone. Once bound to this protein, the neurotrophic compound in this case is an enzyme activity associated with the immunofilm protein and a specific rotation. A powerful inhibitor of the activity of isomerase enzymes, thus stimulating the regeneration and growth of neurons. One of the key features of the compounds of the present invention is that the compounds of the present invention do not exhibit any significant effects other than their neurotrophic activities. Immunosuppressive activity. A preferred embodiment of the invention is a neurotrophic compound having the formula:

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

11 n .^1 ϋ ϋ One: "JI ϋ ϋ ϋ ϋ ^1 I %_ A7 B7 1252226 V. Description of invention (5) where R i is selected from the following groups: optionally C 3 -C a C i -C 3 straight or branched alkyl or alkenyl group substituted with 8 decyl, C 3 or C 5 cycloalkyl, C 5-0 cycloalkenyl, An, wherein the alkane a benzyl, decyl, cycloalkyl or cycloalkenyl group may be optionally substituted with C i -C 4 alkyl, Ci-C* decyl or hydroxy, wherein Αγ is selected from the group consisting of : naphthyl, 2-naphthyl, 2-indenyl, 3-indolyl, 2-furyl, 3-furyl, 2-D-soxazolyl, 2-phenylyl, 3-thienyl, 2- a pyridine group, a pyridyl group, a 4-pyridyl group, and a phenyl group having from 1 to 3 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, trimethyl, C i -C s is an alkyl or alkenyl group, a Ci-Ci alkoxy or a decyloxy group, a phenyl chloride group, a benzyloxy group and an amine group; X is selected from the group consisting of: Oxygen, sulfur, methylene (CH2) or H2; Y傺 selected from the group consisting of chlorine or NR 2 wherein R 2 is hydrogen or C i -C s alkyl; The hydrazine is selected from the group consisting of C 2 -C s straight or branched alkyl or alkenyl groups wherein the alkyl hydrazine is substituted at one or more positions with the following substituents: as defined above Art, C3-Ca cycloalkyl, cycloalkyl group bonded by a cis-Ci-Cs straight or unbranched alkyl or decyl oxime, and Ar2, wherein Ar2 is pseudo-selected from the following group: 243⁄4 Indenyl, 3-indole, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-indolyl, 3-indolyl, 4 - Pyridyl and phenyl, this paper scale applies to China National Standard (CNS) A4 specification mo X 297 mm) ---------- Pack! -Book··------ (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1252226 A7 B7 V. Invention Description (6) Substitutes have 1 to 3値 are selected from the following substituents: hydrogen, halo, hydroxy, nitro, trifluoromethyl, C t - Cs straight or branched alkyl or decenyl, Ci-b alkane Or Ct-C4 bond alkane group, phenoxy group, benzyloxy group and amine group; may be the following fragments:

• CH- I (please read the note on the back and fill out this page) Pack---- Printed by the Intellectual Property Office of the Ministry of Economic Affairs

R3 is selected from the group consisting of: a straight bond or a branched Ci-Ca alkyl group substituted by 3-(8-cycloalkyl) or Ah as defined above and an unsubstituted A ri ; <2 is 0 or NR5, wherein R5 is selected from the following groups: hydrogen, (^ straight or branched alkyl and decenyl; r4 is selected from the following groups: phenyl, benzyl a base, a Ci-Cs linear or branched alkyl group and a nonenyl group, and an L-C5 straight or branched alkyl group and a decyl group substituted by a phenyl group; or a pharmaceutically acceptable salt thereof Or a hydrate. Another preferred embodiment of the invention is a neurotrophic compound having the formula: • Z

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). Order ---------

P—9— 1252226 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed A7 B7 V. INSTRUCTIONS (7) Among which are selected from the following groups: straight or branched, optionally replaced by C3-C8 cycloalkyl An alkyl or nonenyl group, a C3 or C5 cycloalkyl group, a C5-C7 cycloalkenyl group, or An, wherein the alkyl, decenyl, cycloalkyl or cyclodecenyl group can be Optionally substituted with C i -C 4 alkyl, Ci -C 4 alkyl or hydroxy, and wherein Ari is selected from the group consisting of naphthyl, 2-naphthyl, 2-co-indole, 3-indole-based , 2-furyl, 3-furyl, oxazolyl, 2-thienyl, 3-nonyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, these substituents having 1 to 3 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C i -C s straight or branched alkyl or alkenyl, Ci-C4 alkane An oxy group or a Ci-C4 nonyloxy group, a benzene group, a benzyl group, and an amine group; Z is selected from the group consisting of C 2 -C s or an alkyl or alkenyl group. Wherein the alkyl chain is substituted at one or more positions to the following substituents : Αγ, C3-Ca cycloalkyl as defined above, a cycloalkyl group bonded to a C^Cs straight or unbranched alkyl or alkenyl chain, or Ar 2 wherein Ar 2 is pseudo-selected In the following groups: 2-mercapto, 3 fluorenyl, 2-furyl, 3-furyl, 2-DSazolyl, 2-thienyl, 3-01 phenyl, 2-pyridyl, 3- Pyridyl, 4-pyridyl and phenyl, these Ar>2 have 1 to 3 brains selected from the following groups: hydrogen, halo, hydroxy, nitro, trimethyl, Ct-Cs Linear or branched alkyl or bondal alkenyl, Ci-C4 alkoxy or Ci-C4 alkoxy, phenoxy-based paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) - ---------I11111!1 ^ --------- (Please read the note on the back and fill out this page) 1252226 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed B7__ five The invention (8) a benzyloxy group and an amine group; or a pharmaceutically acceptable salt or hydrate thereof. A further preferred embodiment of the invention is a neurotrophic compound which has an affinity for the FKBP-type immunofilm and which inhibits the activity of the rotamase of the immunofilm. A further preferred embodiment of the invention is a method for treating a neurological disorder in an animal sputum comprising administering a therapeutically effective amount of one of the therapeutically effective amounts to the FKBP-type immunophenanthrene and inhibiting the immunization A neurotrophic compound of the rotamyl isomerase activity of the film. Another preferred embodiment of the invention is a method for promoting regeneration and growth of neurons in a mammalian sputum comprising administering to a mammal an effective amount of one of the FKBP-type immunofilms A further preferred embodiment of the present invention is a method for inhibiting neuronal degeneration in an animal, which comprises administering a drug to an animal. A neurotrophic compound having an affinity for the FKBP-type immunophenone and inhibiting the activity of the rotational isomerase of the immunophenanthrene in an effective amount. A further preferred embodiment of the present invention is a neurotrophic N-acetaldehyde amidoxime ester compound having the following formula: (Please read the notes on the back and fill out this page)

^1 ϋ 1- tmmm ϋ I amamm I %

This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -11- 1252226 A7 one ____B7____ V. Invention description (9) Among them (please read the note on the back and then fill in this page) R ^ a C t -C 5 linear or branched alkyl or decyl group optionally substituted by a C 3 -C s cycloalkyl group, or i\ri, wherein the Art is selected from the group consisting of Medium: 2-furyl, phenyl or phenyl; X is pseudo-selected from the following groups: gas and sulfur; Y is oxygen; and acetamidine is selected from the group consisting of linear or branched alkyl groups or Alkenyl, wherein alkyl hydrazine is substituted at one or more positions with the following substituents: Ari, C3-Ca ring, /\Γ2 as defined above, wherein the Ar2 is selected from the group consisting of: 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, these substituents have 1 to 3 substituents selected from the group consisting of hydrogen and Ct-C4 alkoxy. A suitable neurotrophic N-acetaldehyde amidoxime ester compound according to the above chemical formula is selected from the group consisting of 3-(2,5-dimethoxyphenyl)-1-propyl (25) 1-(3,3-dimethyl-1,2-dioxopentyl-2-pyrrolidinecarboxylate; 3-(2,5-dimethylphenyl)-1-propan-2-( E) Retaining group (2S)-1-(3,3-dimethyl-1,2-dichloropentyl-2-pyrrolidinecarboxylate; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 2 - (3 , 4,5-trimethoxyphenyl 1-ethyl(2S:)-1-(3,3-dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate; 3- (3-Benzidinyl)-dipropyl(2S)-l-(3,3-dimethyl-1,2-dichloropentyl)-2-pyrrolidinecarboxylate; 3 - (2-pyridyl) 1-propyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl 2-pyrrolidine carboxylate; this paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1252226 A7 B7 V. Description of Invention (10) 3-(4-Pyridyldi 1-propyl(2S)-1-(3,3-II Methyl-1,2-dioxopentyl 2-pyrrolidinecarboxylate; 3-phenyl-1-propyl(2S)-l-(2_but-butyl-1,2-di Oxyethyl)-2-pyrrolidinecarboxylate; 3-phenyl-propylpropyl (2S)-1-(2-cyclohexylethyl-1,2-dioxypyridyl 2-pyrrolidinecarboxylate; 3-(3-Phenidinyl)-propyl (2S)-1 -(2-cyclohexylethyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl) W-propyl(2S)-1-(.2-tert-butyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylate; 3,3-diphenyl-propylpropyl (2S)- 1-(3,3-dimethyl-1,2-dioxopentyl-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1-propyl(2S)-1-(2- Cyclohexyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1-propyl(2S)-N-([2-thienyl]acetaldehyde oxime Pyrrolidinecarboxylate; 3, 3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxybutyl)-2-pyrrolidinecarboxylic acid Ester; 3, 3-diphenyl-propyl (2S)-b-cyclohexylacetaldehyde oxime-2-pyrrolidine carboxylate; and 3,3-diphenyl-propylpropyl (2S.)-1-(2-瞎 ) ) 乙 乙 醯 醯 。 。 。 。 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要 概要Installed in Chinese National Standard (CNS) A4 (210 X 297 mm)---- (Please read the note on the back and fill out this page) 1111111« % Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1252226 Δ7 A7 B7 V. Description of the invention (11) Light micrograph of the nerve knot. Figure 1 shows that Example 17 of the present invention strongly promotes neurite outgrowth in sensory neuron cultures. Explant cultures of chicken dorsal root knots derived from 9-10 day old embryos were treated at various concentrations as shown in Example 17. After 48 hours, the number of neurites with a length greater than one DRG was counted. The number of neurites shown in the untreated DRG 4 was subtracted from the number of neurites of the sample treated in Example 17 to give Example 17 -dependent specific neurite outgrowth. This figure shows the micrograph of Example 17 - Treatment and the quantitative dose-dependent neurite outgrowth stimulated by Example 17. Fig. 2 is a graph showing the quantitative measurement of neurite outgrowth of chicken dorsal root ganglion treated at various concentrations as shown in Example 17. Figure 2 shows that Example 17 of the present invention potently promotes neurite outgrowth in sensory neuron cultures. Explant cultures of chicken dorsal root ganglion derived from 9-10 day old embryos were treated at various concentrations as shown in Example 17. After 48 hours, the number of neurites greater than the length of one DRG explant was counted. The number of neurites shown in the untreated DRG f s was subtracted from the number of neurites of the sample treated in Example 17 to give Example 17-dependent specificity. This figure shows the quantitative dose-dependent neurite outgrowth stimulated by Example 17. Figure 3 is a photo of a light-stained sac of a rat sciatic nerve. Section 3 shows that the embodiment of the present invention promotes regeneration of neurons after sciatic nerve damage. The sciatic nerve of 15 (Tg-heavy male Sprague-Davley rats) was crushed at the same height as the buttocks. Example 1 (30 mg / kgs · c.), inactive (30 mg) was administered once daily. / kgs · c ·) or the internal lipid-loaded paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----------——— — — — — — ^. I -----I (Please read the note on the back and fill out this page) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description (12) 2 days after the agent is smashed. Sacrifice animals, remove The sciatic nerve was cut and the nerve fragments 2 mm away from the crush were cut and stained with Η 1 mes silver staining (Fu to assess the number of axons) and stained with Luxol fast blue method (俾 to evaluate Myelin re-formation. These photographs show sham-operated rats, vehicle-treated damaged animals, and sciatic nerve sections of Example 1 and animals without active treatment. 630 magnifications, per group 4 animals 0 Figure 4 shows the striated membrane protein of each gram [3H]-CFT binding. Figure 4 shows that the neuroimmunized film ligand of the present invention promotes the recovery of dopamine neurons in mice after MPTP treatment. CD 1 mice (25 g) are 30 mg/kg MPTP (ip) per day. The treatment was carried out for 5 days. The animals were also treated with an internal lipid carrier, Example 1 (100 mg/kg s. c.) or Example 17 (as shown in the examples, 40, 20, 10 mg/kg sc). Plus MPTP was applied and continued for 5 days. After 18 days, the mice were sacrificed and the striatum from each group was pooled and processed into a cleaned membrane product. Quantitative analysis [ 3 Η ] -C-FT to the combination of these striated membrane products of each group, to determine the level of dopamine to lotus seed on the surviving nerve end. The combination in the presence of lOuΜ unlabeled CFT provides a non-specific Estimates of sexual association, which were subtracted from the total combined value, were quantified by the combined specificity of [3 Η ] -CFT. The binding was normalized to the protein content of the striatum derived from each experimental group. Staining with anti-tyrosine hydroxylase (TH) Ig derived from MPTP and drug treatment Coronal and sagittal slices of the sputum, quantitative analysis of TH striatum, intermediate forebrain bundle axons and substantia nigra level, which is functional for dopamine (〇1(^3111[1^^丨(:) Neurons (please read the notes on the back and fill out this page). 9 % This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -15—A7 B7 V. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1252226 invention description (13) indicators. Figure 5 is a bar graph of PH]-CFT versus 20 0 ug of membrane protein. Fig. 5 shows the neuroimmunological film ligand of the present invention, which according to the method described in Example 4, promotes the recovery of dopamine neurons in mice after MPTP treatment. Figure 6 is a photomicrograph of coronal and sagittal slices at 6 30 magnification. Figure 6 shows staining of brain slices derived from MPTP and drug treatment with anti-tyrosine hydroxylase (TH) U, which is used to quantify the striate level of TH, which is a functional dobutamine nerve. The indicator of the yuan. Figure 7 is a photomicrograph of coronal and sagittal slices at 50 magnification. Figure 7 shows staining of brain slices derived from MPTP and drug treatment with anti-tyrosine hydroxylase (TH) Ig, and quantitative analysis of the substantia nigra level of TH, a functional dobutamine neuron The indicator of the yuan. Figure 3 is a photomicrograph of the coronal and sagittal slices at 400 magnification. Figure 8 shows staining of brain slices derived from MPTP and drug treatment with anti-tyrosine hydroxylation _ (TH) Ig, and quantitative analysis of TH for the middle forebrain bundle axon level, which is functional An indicator of the neuron of dopamine. DETAILED DESCRIPTION OF THE INVENTION The novel neurotrophic compounds of the present invention are pseudo-small compared to other known compounds that bind to FKBP-type immunofilms, such as rapamycin, FK506 and cyclosporin. molecule. The neurotrophic compounds of the invention have an affinity for FK506 binding proteins such as FKBP-12. When the neurotrophic compound of the present invention is incorporated into FKBP, it was found to unexpectedly inhibit the binding of the egg-based paper to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------ ------Install--------Book--- (Please read the back note and then fill out this page) 1252226 A7 B7 V. Description of invention (14) White matter 脯 基 - peptide 醯Cis-trans isomerase activity or rotamase activity, and stimulate neurite outgrowth, but does not exhibit immunosuppressive effects

More specifically, the present invention relates to a novel group of neurotrophic compounds represented by the following formula: • Z

(Please read the note on the back and then fill out this page.) Among them, Ri Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 傺 is optionally replaced by C3-C3 cycloalkyl 値 Ci-C3 linear or branch An alkyl or nonenyl group, a C3 or C5 cycloalkyl group, a Cs-C7 cycloalkenyl group, or Ar i wherein the alkyl, bond alkenyl, decyl or decyl alkenyl group is Optionally substituted with a Ci-C4 alkyl group, a Ct_C4 alkyl group or a hydroxyl group, and wherein Αγμ傜 is selected from the group consisting of: naphthyl, 2-naphthyl, 243⁄4 fluorenyl, 3-03⁄4 fluorenyl, 2-furan , 3-furanyl, 2-DS azole, 2-Diphenyl, 3- phenyl, 2-pentidinyl, 3-pyridyl, 4-pyridyl and phenyl, these substituents have 1 Up to 3 择 from the substituents in the following groups: hydrogen, halo, thio, nitro, trifluoromethyl, Ci-Cs or hydrazine alkyl or chain susceptibility, C1-C4 Chlorine or C1-C4 chain chloro, phenoxy, benzyloxy and amine; pseudo-oxygen, sulfur, methylene (C Η 2) or hydrazine 2; oxygen or HR2, where h is false Hydrogen or Ci-Cs alkyl; and % This paper scale applies to Chinese national standards (CNS A4 size (210 X 297 metric tons) 1252226 A7 B7 V. Description of invention (15) (Please read the note on the back and then fill out this page) B is a C2-CS linear or branched alkyl group or a decyl group in which the alkyl chain is substituted at one or more positions with the following substituents: An, C3-C8 cycloalkyl as defined above, a linear or unbranched alkyl group as a MCi-Cs Or a cycloalkyl group attached to the alkenyl group, or Ar 2 , wherein the Αγ2 is selected from the group consisting of 2-mercapto, 3-indolyl, 2-furyl, 3-furanyl, 2 _thiazolyl, 2-thienyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, these substituents having 1 to 3 substituents selected from the group below : hydrogen, halo, hydroxy, nitro, trifluoromethyl, Ci-Cs straight or branched alkyl or bondal alkenyl, Ci-C4 alkoxy or Ci alkoxy, phenoxy, benzyl The oxy group and the amine group; Z can be the following fragment: 0 -T1^ R3 wherein the Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, prints R 3 pseudo-selected from the following group: optionally C 3 -C g cycloalkyl Substituted linear or branched Ci-Ce alkane Or, as defined above, Art and unsubstituted A r 1 ; X 2 is 0 or NR 3 , wherein R s is selected from the following groups: hydrogen, C t - C s straight bond or branched alkane And alkenyl; R 4 is pseudo-selected from the following groups: phenyl, benzyl, C t -C 5 straight or branched alkyl and decenyl and Ci-Cs substituted by phenyl Chain or branch paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 $, invention description (16) alkyl and alkenyl groups of hydrazine; or its pharmaceutically acceptable salts Class or hydrate. Preferred compounds have the formula:

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumer Cooperatives, II Ri傺 is a Ci-C3 straight or branched alkyl or decyl group optionally substituted by c3 -Ca cycloalkyl, : 3 or (: 5 cycloalkyl, C5-Cr cyclodecenyl, or Ar i wherein the alkyl, decenyl, decyl or cyclodecenyl group may be optionally substituted with C ^C4 alkyl, C^C4 alkyl or hydroxy, and wherein Ar is selected from the group consisting of: 1-naphthyl, 2-naphthyl, 2-indolyl, 3-(13⁄4 fluorenyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-phenyl, 3-thantiphenyl, 2-Ptt pyridine, 3-pyridyl, 4-pyridyl and phenyl, such substituents Alkyl or alkenyl group having 1 to 3 fluorene, respectively selected from the group consisting of a hydrogen group, a halogen group, a hydroxyl group, a nitro group, a trimethyl group, a C i -C s linear or branched group, Ci-C4 alkyl chloride or Ci-U decyloxy, phenoxy, benzyloxy and amine; Z 傜 is a β C2-Cs straight or branched alkyl or decenyl, wherein the alkane The base chain is substituted at one or more positions with the following substituents: Ar t, C 3 -Ca 璟 alkyl, as defined above, i - (: 6 straight or unbranched alkyl or alkenyl bond to a cycloalkyl group, or Ar 2, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----------Install--------Book---------^__w (Please read the notes on the back and fill out this page) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (17) Ar2 pseudo-selection from the following group · · 2-palinyl, 3_co-indolyl, 2-furanyl, 3-furyl, 2-thiazole a group, a 2-thiophenyl group, a 3-thiophenyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, and a phenyl group, wherein these Ar have a substituent selected from the group consisting of 1 to 3 fluorene: hydrogen , halo, hydroxy, nitro, tris, methyl, C 1 - C s straight or branched or terpenyl, Ci-CU alkyl or C1-C4 alkoxy, phenoxy a benzyloxy group and an amine group; or a pharmaceutically acceptable salt or hydrate thereof. A preferred neurotrophic N-acetaldehyde amidoxime ester compound has the following formula

H傺 is an alkyl or decenyl group optionally substituted by a 3-(cycloalkyl)-Ci-C5 straight or branched chain, or Art, wherein the ArM is selected from the following groups : 2-furanyl, 2-decenyl or phenyl; X-like images are selected from the group consisting of oxygen and sulfur; Υ is pseudo-oxygen; and B is pseudo-a linear or branched alkyl or alkene a group wherein the alkyl hydrazine is substituted at one or more positions with the following substituents: Αγμ, C3-C8 cycloalkyl, Ar2 as defined above, wherein /\"2 is selected from the group consisting of: 2 - Batch pyridine, 3-0tt pyridine, 4-batch pyridine or phenyl, these paper sizes apply to China National Standard (CNS) A4 specification (210 X 297 mm) -------- ---装--------Book--------- (Please read the phonetic on the back? Please fill out this page) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed five DESCRIPTION OF THE INVENTION (18) The substituent has 1 to 3 substituents selected from the group consisting of hydrogen and C 1 - C 4 -oxyl. The compound of the present invention is present in the form of a stereoisomer. They are enantiomers or diastereomers. The stereochemistry at position 1 is R or S, and preferably S. Those included in the scope of the present invention are enantiomers, racemic forms, and mixtures of diastereomers. The enantiomers or diastereomers can be separated by methods known to those skilled in the art. It is known that immunizations such as FKBP preferentially recognize peptide substrates containing Xaa-pro-Yaa elements. , wherein Xaa and Yaa are lipophilic amino acid residues ° Schreiber eta 1 (1 9 9 0 ) , J , Οτκ , Chem . , 55 : 4984-4986 i Harrison and Stein (1990) Biochemistry, 2_a_: 3 8 1 3 - 3 8 1 6. Thus, a modified amidoxime-like peptide-type compound having a lipophilic substituent should bind to the hydrophobic core of the FKBP active site with high affinity and inhibit its rotamase activity. Preferred compounds of the invention contain R i groups which are not stereochemically large compared to the shape and size of the hydrophobic core of the known F KB P active site. Therefore, very large and/or The highly substituted R i group will bind to the FKBP active site with lower affinity. Preferred compounds of the invention include: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxapentyl)-2-pyrrolidinecarboxylate ; 3-phenyl-1-prop-2-(E)ylidene (2S)-l-(3,3-dimethyl-1,2-dioxopentyl)-2-indolerolanecarboxylic acid The ester paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ^1 ϋ ϋ .^1 11 ϋ a····· ϋ ii n 1252226 A7 B7 V. INSTRUCTIONS (19) 3 -(2,5-Dimethylchlorophenyl)-1-propyl(2S)-1-(3,3-dimethyl-1-1.2-dichloropentyl) -2-pyrrolidine carboxylate; (Please read the note on the back and fill out this page) 3-(3,4,5-Trimethoxyphenyl)-1-propyl (2$)-1-(3 ,3-dimethyl-1.2-dioxopentyl)-2-pyrrolidinecarboxylate; 3-(3,4,5-trimethylchlorophenyl)-1-propan-2-(£)) 23)-1-(3 3. Dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate; 3-(4,5-methylenedichlorophenyl)-propyl (2S) -1_(3,3-dimethyl-1,2-dioxypentylpyrrolidine; 3 - U, 5-methylenedichlorophenyl:)-1-prop-2-(Ε Base group (2S) -1-(3,3-dimethyl-1,2 -dioxypentyl)-2-U bisphenolic acid S; 3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxolanyl -2-pyrrolidinecarboxylate; 3-cyclohexyl-propan-2-(E)phenyl (2S)-l-(3,3-dimethyl-1,2-dioxopentyl)- 2-pyrrolidinecarboxylate; (1R 1,3-1,3-phenyl-1-propyl(2S)-1_(3,3-dimethyl U-dioxopentyl-2-pyrrolidinecarboxylate ; 3-phenyl-dipropyl (2S)-1-(1,2-dioxy-2-[2-furyl])ethyl-2-pyrrolidinecarboxylate; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Printing 3-phenyl-propyl (2S)-1-(1,2-dichloropanpanyl)ethyl-2-pyrrolidinecarboxylate; 3-phenyl-I-propyl (2S)- 1-(1,2 -''Chloro-2-[2-indolyl])ethyl-2-pyrrolidinecarboxylate; 3*·phenyl-I-propyl(2S)-1-( 1,2 - - · Chlorinyl) ethyl-2-pyrrolidine carboxylate; This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Office staff consumption Co-operative printing 5, invention description (2Q) 3- (2, 5-Dimethoxyphenyl)-1-propyl (2S) -1- (3,3-dimethyl-1,2-dichloropentane Base)_2- Pyrrolidine carboxylate; 3-(2,5-dimethylchlorophenyl)-1-propan-2-(E)phenyl (2S.)-1-(3,3-dimethyl-1,2 -dioxypentyl)-2-pyrrolidinecarboxylate; 2-(3,4,5-trimethylchlorophenyl)-1-ethyl (2SW-( 3,3-dimethyl-1,2- Dichloropentyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1-propyl(2S)-1 -(3,3-dimethyl-1,2-dioxypentyl -2 -pyrrolidinecarboxylate; 3-(2-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2- Pyrrolidinecarboxylate; 3-(4-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxaoxypentyl)pyrrolidinecarboxylate; 3-phenyl-propyl (2S)-1-('2-decylidene-1,2-dichloroethyl)-2-pyrrolidinecarboxylate; 3-phenyl-1-propyl (2S) 1-(2-tert-butyl-1,2-dichloroethyl)-2-pyrrolidinecarboxylate; 3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl) Benzyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1, 2 -dioxyethyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-dipropyl(2S)-1-(2-but-butyl-1,2-dioxyethyl)-2 -pyridyl Pyrrolidine carboxylate; 3,3-diphenyl-1-propyl(2$)-1_(3,3-dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate ; Pack---- (Please read the notes on the back and fill out this page) Order --------- %· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)一23-1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5, Invention Description (21) 3 -(3-Pyridyl)-1-propyl (2S) -1- (2-cyclohexyl-1, 2-dioxyethyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-propyl (2S)-N-([2-thienyl]acetaldehyde awake) {!pyrrolidinecarboxylic acid Ester; 3,3-diphenyl-propyl (2S)-1-(3,3-dimethyl-1,2-dichlorobutyl)-2 - stagnation bag vinegar; 3,3-diphenyl -1-propyl(25)-1-cyclohexylethyl light 11-2-indole[:|: carboxylic acid carboxylate; 3, 3-diphenyl-1-propyl (2S) -1- ( 2-Thienyl)acetaldehyde oxime 2-D-pyrrolidine carboxylate. A particularly suitable neurotrophic oxime-acetamide compound is selected from the group consisting of: 3 - (.2, 5-dimethylchlorophenyl)-propyl (2S.) -1- (3, 3-dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate; 3-(2,5-dimethoxyphenyl)-bromo-2-(indol) 2S)-1-(3,3-dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate; 2-(3,4,5-trimethylchlorophenyl)-1-ethyl (2$)-1-(3,3-dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate; 3-(3-pyridyl)-1-propyl (2S -l-(3,3-dimethyl-1,2-dioxapentyl)-2-pyrrolidinecarboxylate; 3 - U-pyridyl)-1-propyl(2S) -1- ( 3,3-Dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate; 3-(4-pyridyl)-propylpropyl(2S)-1-(3,3-dimethyl -1,2-dioxypentyl)-2-pyrrolidine carboxylate; This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----------- --------Book --------- (Please read the note on the back and then fill out this page) -24- 1252226 A7 B7 V. Description of invention (22) 3-Phenyl-propyl (2S)-1-(2-tert-butyl-1,2-diqiethyl -2-pyrrolidine carboxylate; (Please read the note on the back and fill out this page) 3-Phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-di Chloroethyl-2-pyrrolidinecarboxylate; 3 - (3-dtt pyridine)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxyethyl)- 2-pyrrolidinecarboxylate; 3-(3-pyridylbu- 1-propyl(2S)-1-(2-but-butyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylic acid Ester; 3.3-diphenyl-1-propyl (2$)-1_(3,3-dimethyl-1,2-dichloropentyl)-2-pyrrolidinecarboxylate; 3-(3- Iridinyl)-1-propyl(2$)-1-(2-cyclohexyl-1,2-dioxyethyl)-2-fltt-rrolidinecarboxylate; 3-(.3-pyridyl) --propyl (2S)-N-([2-thienyl]acetaldehyde oxime) pyrrolidinecarboxylate; 3.3-diphenyl-propylpropyl (2S)-1-(3,3-dimethyl-1, 2-dioxybutyl 2-pyrrolidinecarboxylate; 3.3-diphenyl-propylpropyl (2S)-1-cyclohexylacetaldehyde oxime-2-pyrrolidine carboxylate; and Ministry of Economic Affairs Intellectual Property Office staff consumption The cooperative printed 3,3-diphenyl-propyl (2S.)-1-(2-thienyl)acetaldehyde hydrazine-24-pyrrolidine carboxylate. The compound of the present invention can be rendered in the form of a salt derived from an inorganic or organic acid or base. The inclusion in such acidic salts is as follows: acetate, adipate, alginate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , citrate, camphorate, 樟 paper scale applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1252226

V. INSTRUCTIONS (23) (Please read the note on the back? Please fill out this page again) Cerebral sulfonate, cyclopentane propionate, dihydrochloride, lauryl sulfate, ethanesulfonate Acid salt, fumarate, glucoheptonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate , lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmitate, pectinate, propionate, succinate, tartrate, sulfur Cyanate, tosylate and undecanoate. The basic salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), alkaline earth metal salts (such as calcium salts and magnesium salts), and salts with organic bases (such as dihexylamine salts, N). -Methyl-D_g Inca mine) and salts with amino acids (such as arginine, lysine) and the like. Further, the basic nitrogen-containing group may be quaternized with a reagent such as a lower alkyl halide (e.g., methyl, ethyl, propyl, and butyl chloride, bromide iodide), a dialkyl group. Sulfates (such as dimethyl, diethyl, dibutyl, and dipentyl sulfate), long sulfonium halides (such as sulfhydryl, lauryl, sulfonyl, and stearyl chloride, bromide and Iodide), an aralkyl halide (e.g., benzyl, phenethyl bromide), and the like. Thereby a water- or oil-soluble or floatable product can be obtained. The Ministry of Economic Affairs, the Intellectual Property Office, the Staff Consumer Cooperative, which prints the neurotrophic compound of the present invention, can be administered periodically to a patient who is undergoing treatment for a neurological disorder or other cause, in which it is desired to be able to stimulate, for example, with neurodegeneration. Various peripheral neuropathy and regeneration and growth of neurons within neurological disorders. The compounds of the present invention can also be administered to mammals other than humans for the treatment of various mammalian s. The novel compound of the present invention is pseudo-rotating the activity of the iso-ditch enzyme@本纸标准Applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 V. Invention Description (24) Manufacture and one pole Good level of neurotrophic activity. This activity can be used for stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurological action, and treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathy. Neurological disorders that can be treated include, but are not limited to, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's fistula, myasthenia gravis, muscular dystrophy, muscle-shrinking lateral sclerosis, progressive muscular atrophy, progressive edema Muscle atrophy, prolapsed, ruptured or prolapsed non-spinal disc syndrome, cervical vertebrae dissociation, plexus disorders, thoracic outlet rupture syndrome, such as those by bell, dapsson (daps ο ne ), wallworm, pr Peripheral neuropathy caused by 〇yyria or Gul Uin-Barrg syndrome, AIDS and Parkinson's disease. For these purposes, the compounds of the invention may be administered in the following manner: orally, parenterally, by inhalation spray, topically, rectally, #地地, buccally, vaginally, or via a sputum. An implanted reservoir in the form of a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and carrier dosage formulation. As used herein, the term 'intestinal fistula' includes subcutaneous, intravascular, intramuscular, intraperitoneal, intravertebral, intraventricular, intrasternal, and intracranial injection or infusion techniques. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. In order to be effective in treating the central nervous system, when it is administered peripherally, the immunization film-drug complex must be able to easily pass through the blood-brain barrier. The compound of the present invention which does not cross the blood brain barrier can be effectively administered by an indoor route. The pharmaceutical compositions herein may be in the form of a sterile injectable preparation such as a sterile injectable aqueous or oily dispersion. This floating liquid can be installed according to -27---- (please read the phonetic note on the back side and fill out this page again). This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 V. INSTRUCTIONS (25) (Please read the notes on the back and then fill out this page) Formulated according to techniques known in the art using suitable dispersing or wetting agents and floating agents. The sterile injectable preparation may also be a non-injectable solution or dispersion in a non-toxic parenterally acceptable diluent or solvent, for example, in a 1,3-butanediol. Solution. Among the acceptable vehicles and solvents that can be used are water, Ringer's (Ringer's solution and isotonic sodium solution. In addition, sterile stabilizers are traditionally used as a solvent or dispersion. Floating matrix. For this purpose, any brand of stabilizer oil can be used, including synthetic mono- or di-diglycerides. Fatty acids such as oleic acid and its glyceride derivatives have been found to be useful in the preparation of injectable olive oils. Or II sesame oil, which is in the form of a polyepoxyated form, etc. These oil solutions or dispersions may also contain a long sterol diluent or dispersant. The compound of the invention may, for example, be in the form of a capsule or lozenge or as an aqueous solution. The dosage of the suspension or the solution is administered. For the case of the dosage form for oral administration, the usual carrier includes lactose and corn starch. Lubricants such as magnesium stearate are also typically used. For oral administration in the form of a capsule, useful diluents include lactose and dried corn starch. When aqueous dispersions for oral use are required, the active ingredient is combined with an emulsifier and a suspending agent. To add certain aromatizing agents and/or tinating agents and/or coloring agents. The compounds of the present invention printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs may also be administered in the form of a suppository for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and thus will dissolve in the rectal tract And release, drugs, such as coconut oil, candied fruit, and polyethylene glycol. The compounds of the present invention can also be optically administered, especially to the Chinese National Standard (CNS) A4 specification (this paper size) ( 210 X 297 mm) 1252226 Δ7 Α7 Β7 V. INSTRUCTIONS (26) The condition of treatment relates to areas or organs that can be easily accessed by topical application, including neurological disorders of the eye, pi or lower gastrointestinal tract. It can be easily prepared. (Please read the notes on the back and fill out this page.) Prepare a suitable topical formula for each of these areas. For eye use, the compound of this case can be formulated to match the isotonic tone. a miniaturized suspension in a sterile physiological saline having a P-value, or preferably a solution formulated in an isotonic pH-adjusted sterile physiological saline with or without a benzyl group a 1 k ο nium chloride preservative. Optionally, for ophthalmology, the compound of the present invention can be formulated in an ointment such as petrolatum. For topical use on the skin, the compound of the present invention can be formulated in a containing A suitable ointment of a compound which is a floating or dissolved compound, for example, a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. The compound of the present invention can be formulated in a suitable lotion or cream containing a compound which is either dissolved or dissolved, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate , polysorbate 60, cetyl ester wax, cetyl aryl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. The topical application for the lower gastrointestinal tract can be effected by an enteric preparation (see above) or an appropriate enema formula. The active ingredient compound can be used in the treatment of the above conditions at a dosage level of from about 0.1 to about 10, OOO mg, with a preferred level of from about 0 lias to about 1,000 ms. The amount of active ingredient which can be combined with the carrier materials to form a single dosage form will vary depending upon the host to be treated and the mode of administration. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (27) but can be understood, for any particular patient One of the pending levels will vary with a variety of factors' including the activity of the given compound used, age, weight, general health status, gender, diet, time of administration, rate of excretion, drug combination, and The severity of the pending disease treatment and the form of administration. The compound of the present invention can be administered together with other neurotrophic agents such as neurotrophic growth factor (NGF), glial-derived growth factor, brain-derived growth factor, ciliary neurotrophic growth factor, and neurotrophin-3. . The dosage level of other neurotrophic drugs will depend on the factors previously described and the neurotrophic effectiveness of the combination of drugs. K i test method The inhibition of the activity of the thiol-guanamine oxime isomerase (rotomerase) of the compound of the present invention can be determined by a conventional method described in the literature [MW Harding et al., 3 41: 758 -760 (1 989);

Holt et al., J. Am. Chenu Soc., 115: 9923-9938 (1989)]. These values were obtained as apparent Ki's and are shown in Table 1. In a chymotrypsin coupling assay, the cis-type of one of the alanine-proline linkages in a model matrix N-expressing base-Ala-Ala_Pro-Phe-p-nitroanilide was monitored spectrometrically. Trans isomerization, in which p-nitroanilide is released from the trans matrix. The inhibition of this reaction caused by the addition of different concentrations of the inhibitor was measured, and the obtained experimental data was analyzed as a function of the inhibitor concentration as a function of the first-order rate constant, to obtain an apparent K i value. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------Package--------Book--- (Please read the back Note: Please fill out this page again) 1252226 A7 B7 V. INSTRUCTIONS (28) Add 950ml of ice-cold analysis buffer (25mΜ HEPES, pH 7·8, ΙΟΟιαΜ NaCl) and lOnil's FKBP (2·5ώΜ) to a plastic colorimetric tube. , with ΙΟπιΜ Tris-Ci, pH 7·5, ΙΟΟπιΜ NaCi, ImM dithiothreitol), 251111 chymotrypsin (5〇111"1111, with 1〇^^1 (:1) And 10 m 1 of the test compound in various concentrations in dimethyl sulphate. The reaction starts by adding 5 ml of the substrate (5 mg/ml of N-amber thiol-AU-Phe-Pro-p-nitrate) Dermatanilide in a three-gas hospital containing 2·35πιΜ LiCl) ° ' Use a spectrometer to monitor the absorbance versus time value at 390 nm for 90 seconds and determine the absorbance versus time value Rate constant. The experimental data of these experiments are shown in Table 1. ° ----------- loaded -------- order --------- (please read first Phonetic on the back? Matters again on this page) Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -31- 1252226 A7 B7

No. Editor, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed, 123456789012345678901234567890 111111111122222222223 Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base, Base Basic group R, armor, methyl, methyl, methyl, methyl, methyl, methyl, methyl, 222, 222, 222, 222, 1-2, 1-2, 1-1-1, 1-1-1 Isothiazyl 1-1-1-1-II ? >>> I-I τ-1 - I rH 1 - I - ϊ 1 - I 1 - * τ ~ ί C \ J ονΙ 'ίΊ ^^1~^ propylpropylpropylpropylmethylethyldiyldiyldiylphenylthiophene-1-hexadihexiumhexyl-1-hexylbutyrryl 1 Ring ring 1, ring 2 - special ring 2

Rf 3-phenylpropyl 3-phenyl-propan-2-(E)phenyl 3-(3,4,5-trimethoxyphenyl.)propyl 3-(3,4,5-trimethoxybenzene -)-propan-2-(E)-supportyl 3-(4,5-methylenedihydro)phenylpropyl 3-(4,5-methylenedioxy)phenylpropan-2- (E) Azide 3-cyclohexylpropyl 3-cyclohexyl-1-propan-2-(E)phenyl (1R)-1,3-diphenyl-1-propyl 3-phenylpropyl 3 -phenylpropyl 3-phenylpropyl 3-phenylpropanyl 3-(2,5-dimethoxyphenyl)phenylpropyl 3-(2,5-dimethoxyphenyl)phenylpropane -2M: E) phenyl 2-(3,4,5-trimethoxyphenyl)ethylpyridinyl)propyl 3-$2-benzachro)propylpropyl)propyl 3-phenylpropyl 3 -Phenylpropyl 3-phenylpropyl 3-(3-β$)-propyl 3-(3-indolyl)propyl 3.3-diphenylpropyl 3-(3-pyridyl) Propyl 3-(3-pyridyl)propyl 3.3-diphenylnonan 3.3-diphenylpropyl 3.3-diphenylpropyl

1250500002 K420676005 1—I C\J 1~~_ ^—I C\J CO 0 9 0 7 5 5 2 ο 19 2 4 1 4 -50500002020000055325503590500 丨:_ i : I ο 2 5

928920 rH (Please read the phonetic on the back? Please fill out this page again) | Installation -------- Order --------- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -32- 1252226 A7 B7 V. INSTRUCTIONS (30) In the mammalian cells, FKBP-1 2 is complexed with the inositol triphosphate receptor (IP 3 R) and the ryanodine receptor (RyR). It is believed that the neurotrophic compounds of the present invention will dissociate FKBP from such complexes, causing calcium channels to become leaky (Cameron et Ii, 1995). Calcium flux is involved in neurite outgrowth and thus may involve IP 3 R receptors and ryanodine receptors in the neurotrophic effects of drugs. Since these drugs bind to the same position of the IP3R receptor pair of FKBP-12, we can assume that the drugs are displaced from FKBP-12. Miscellaneous 栴 栴 栴 逛 逛 逛 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经The entire neural tube cells were cultured on a thin layer of Matri gel-coated 12 well culture plates at 37 ° C in an environment containing 5% CO 2 , and the contents of the plates were supplemented with 2 m Μ The glutamine and 10 V fetal bovine serum of Lieb 〇vitzp 1 us is high in glucosinolate, and the medium also contains cytosine/3-D arabinofuranoside Ura C). After 24 hours, the DRGs were treated with various concentrations of nerve growth factor, immunofilm ligand or NGF plus a combination of drugs. At 48 hours after drug treatment, a pair of Zeiss Ax i overt inverted microscopes were used to visualize the nerve knots under phase difference or Hoff man 讴 wholeness. Light micrographs of the outer plants were obtained and the neurite outgrowth was quantitatively analyzed. The neurites longer than the D G R diameter were counted as a positive reaction' and the total number of neurites in each experimental condition was quantified. Three to four DRGs were cultured each time, and each treatment was repeated twice. Experimental data for these experiments are shown in Table S. A representative photomicrograph of Example 17 is shown in Figure 1; one of the dosages of this example® applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back first) Note on this page)

---111 I Book·!----I % Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1252226 a7 B7 V. Invention description (31) The reaction curve is shown in Figure 2

II_1 Length in chicken dorsal root ganglion (DRG) Example number ED5Q, God ^^ grow out ' nM 2 3 4 5 6 10, 11 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 105 149 190 10 75 , 46 .015 .015 .05 30 6 1100 .013 .025 • 66 .014 .50 500 0 10 100 .50 (Please read the note on the back and fill out this page) One binding --- #私骨神经赫七T?开术(AX 〇t 0 id Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 6-week male Sprague-Dawley rats anesthetized to make the nerves sit at the same height as the hips It was exposed and crushed by a camera. The compound or vehicle was administered subcutaneously to the rats before the damage was injected and administered daily for the next 18 days. The slices of the sciatic nerve were stained with H〇lraes The method was stained, evaluated to estimate the number of axons, and stained with the Lux 0 丨 firm blue method to evaluate the tendon sheath formation. 18 days after the damage, the paper scale applies the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) -34- 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Explicitly, (32) there was a significant reduction in the number of axons in animals treated with vehicle (a reduction of 503⁄4 compared to the untreated control group) and a reduced degree of myelination (compared to In the undamaged control group, there was a 902⁄4 reduction.) Compared to animals treated with vehicle, administration of Example 1 (30 mg/kg sc) daily before and after 18 days of injury resulted in significant The number of axons and the degree of myelination were regenerated (compared to the undamaged control group, the number of axons was reduced by 50⁄4 and the degree of myelination was reduced by 50%). Significantly effective is consistent with its potent activity in inhibiting rotational isomeric IS activity and neurite outgrowth in chicken DRGs. These results are shown in Figure 3. ''Sham " means receiving vehicle But the control animals that were not damaged; 'Λcarrier 〃 means the control animals that were damaged and only received the vehicle (ie, no drug). Example 1 showed a similar similarity to one of the Sham-treated animals. Sex, which confirms that these compounds are in vivo Potent nerve regeneration. Inactive 傺 is a compound that is inactive as a FKBP-12 inhibitor. Animals treated with this compound are similar to animals treated with a carrier, and are treated as in Example 1. The results of the observed nerve regeneration were directly caused by the inhibition of FKBP-12 by Example 1. Quantitative analysis of these experimental data is shown in Table HI.

^_I Number of axons in the treatment group (1 control group) Myelin sham 100 100 Damage: + Carrier (sc·) 50 10 + Example 1 100 50 (3 0 in g / kg sc) + no active 25 25 (30mg/kg sc) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------- Pack! 1!丨定----I--- (Please Read the precautions on the back and fill out this page.) A7 B7 1252226 V. Description of the invention (33) Parkinson's disease in the white mouse PTP fe垣 in the white mouse body (d 〇P am丨nerg丨c) MP TP lesions of neural crest were used as one of the animal models of Parkinson's disease. Male CD1 mice, 4 weeks old, were given a dose of 30 mg/kg MPTP for 5 days per day. Example 1 7 (10 to 40 m g / k g ) or a carrier, together with Μ P T P ' was administered by s. c. for 5 days, and for an additional 5 days after the hydrazine treatment was stopped. Eighteen days after the treatment, the animals were sacrificed and the sciatic nerve was dissected and homogenized. The binding of [3H]-CFT (a radioligand of dopamine to lotus seed) to the striate membrane was performed to quantify the level of dopamine to lotus seed (DAT) after damage and drug treatment. Immunostaining was performed on coronary and sagittal sections using anti-tyrosyl hydroxylase (TH) Ig to quantitatively analyze the survival and recovery rate of neurons of dobutamine. A substantial loss of functional dopamine end was observed in animals treated with MPTP and vehicle as compared to undamaged animals. The injured animals receiving the TH of Example 17 showed a considerable amount of recovery of one of the TH-stained dopamine neurons. Figures 4 and 5 show quantitative analysis of D A T levels' ΓΤΠ Figures 6-8 show the regenerative effect of Example 17 in this model. As analyzed by [3H]-CFT binding, Figure 4. demonstrates the apparent recovery of the functional end of dopamine compared to animals receiving MPTP but not Guilford compounds. Figure 5 shows this experimental data in the form of a histogram. Experiments have shown that animals receiving Example 17 plus MPTP at 40 ms/l showed a recovery rate above 903⁄4 on [3H]-CFT binding. The immunostaining of tyrosine oxidase (one of the neurons of viable dopamine) shown in Figures 6-8 is shown by immunostaining in the striatum, substantia nigra and intermediate forebrain bundle. Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) than accepting damage to this paper. -----------Installation-------- --- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1252226 A7 B7 V. Invention Description (34) But non-drug (MPTP/carrier) animals are accepted for implementation The functional neurons in the animal of Example 17 have a significant and significant recovery. The following examples are intended to be illustrative of preferred embodiments of the invention, but are not to be construed as limiting. All polymer molecular weights are pseudo-average molecular weight. Unless otherwise mentioned, all percentages are based on the weight percent of the final delivery system or formulation being prepared, and all numbers are equal to 100 weight percent. EXAMPLES The compounds of the present invention can be prepared by a variety of different synthetic trains using established chemical transformation methods. The general synthetic route for the compounds of this class is described in Route 1. The preparation of the N-acetaldehyde valine derivative can be carried out by reacting methyl L-proline with methyl oxalate as shown by the route. The formed oxalate can be reacted with various sulfonyl nucleophiles to obtain an intermediate compound. These intermediates are then reacted with various alcohols, guanamine or protected amino acid residues to obtain the propyl esters and acid amines of the present invention. -----------·装--------Book--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office staff Printed by consumer cooperatives

RLimRUgX GH ν-ζ coupling method

The human paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -37- 1252226 A7 r-^ B7 i, invention description (35) (please read the notes on the back and fill out this page) Example 1_ 3-Phenyl-1-propyl(2S)-l-(3,3-dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate (Example 1) Preparation of methyl (2S) -1- (1,2-dichloro-2-methylethyl)-2-pyrrolidine carboxylate by a solution of L-guanamine in anhydrous dichloromethane A solution of the acid methyl ester hydrogen chloride (3.08 g, 13.60 mmol) was cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmol, 2.1 eq). After 15 minutes of stirring in a nitrogen atmosphere, 'dropped one by one' (a pair of methyl chlorophyll chloride (3.2 〇s, 2 δ · 12) in methylene chloride (45 πι丨) Mm ο 1 ) The resulting solution. The resulting mixture was subjected to a simmering reaction for 1.5 hours. After the solids were removed by filtration, the water was first removed from the organic phase on M g S 0 4 . The product was dried and concentrated to give a crude oil (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Cis-trans-indoleamine rotamer; data on trans-rotation isomers are as follows: H NMR (CDC13): d.1.93 (dm, 2H); 2.17 (m, 2H); 3.S2 (m , 2H); 3·71 (s, 3H); 3.79, 3.84 (s, 3H total)· 4.85 (dd, 1H, J = a.4, 3.3). k Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Synthesis of (2S)-1-(1,2-dichloro-3,3-dimethylpentyl:)-2-pyrrolidinecarboxylate A mixture of 30 ml of tetrahydrofuran (THF) (2S)-Bu (1,2-dioxy-2-methoxyethyl)-2-pyridyl The solution of the alkanoic acid ester (2.35g, 10.90 ιππιο 1 ) is cooled to -78 °C, and one of the 14 · 2m丨 is applied to the paper scale. The Chinese National Standard (CNS) A4 specification (210 X) is applied. 297 mm) A7 1252226 B7____ V. INSTRUCTIONS (36) (Please read the notes on the back and fill out this page) 1 in TH F . Ο Μ 1,1 -Dimethylpropylmagnesium chloride solution for treatment Q After 3 hours at a temperature of -78 ° C, the mixture was poured into saturated ammonium chloride (1 0 0 m 1 ) and taken up with ethyl acetate. The organic phase was washed with water, dried and concentrated, and the crude material obtained after solvent removal was purified on a hexane column and eluted with 253⁄4 ethyl acetate in hexane to obtain one. 2. Colorless oil 2. l〇s oxalate (75%) &quot;•H NMR (CDC13) : d Ο .83 (t, 3Η) ; 1.22, 1.25 (s, 3H each)/ 1.75 (dm , 2H) / 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.75 (s, 3H); 4.52 (dm, IK, J = 8.4, 3.4). (2S) -1-( 1,2-dioxo-3,3-dimethylpentyl)-2-pyrrole Synthesis of a carboxylic acid to a methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10g, 8.2 3inm〇l) A mixture of IN LiOH (15 ml) and Methanol (50 nii) printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs was stirred at 0 ° C for 30 minutes and stirred at room temperature overnight. The mixture was acidified to a Ρ Η value of 1 using 1 N HCl and diluted with water and extracted into 1 〇〇 m 1 of chloromethane. The organic phase was washed with brine and concentrated to give a white solid (l. LH NMR (CDCl3) i: M 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H) ; 3.5 3 (dd, 2H, J = 10.4/ 7.3); 4.55 (dd, 1H, J 3.6, 4.1). This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (37) 3-Phenyl-I-propyl(2S)-l-(3,3-dimethyl-1,2-dioxolanyl -2~ Synthesis of pyrrolidine carboxylate (Example 1) for one (2 S ) - 1 - (1 , 2 -dioxo-3,3) in dichloromethane (20 m 1 ) -Dimethylpentyl)-2-3 is slightly shorter than the acid (60〇1118, 2.49[11[11〇1), 3-phenyl-propanol (50 8 nig, 3.73mmo 1 :), a mixture of dicyclohexylsulfonated diimine (822 mg, 3.98ramol), camphoric acid (190 meg, g. 8mraol) and 4-dimethylaminopyridine, stirred overnight under a nitrogen atmosphere . The reaction mixture was filtered through a celite to remove solids and concentrated under vacuum, and the crude residue was taken on a flash column (with 253⁄4 ethyl acetate in hexane). Purification was carried out to obtain 720 mg of Example 1 (80 V) as a colorless oil. , NMR (CDC13): d 0.84 (t, 3H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.93 (m, 5H); 2.22 (m, 1H); 2.64 (m, 2K); 3.47 (m, 2H); 4.14 (m, 2H); 4.51 (d, 1H); 7. IS (m, 3H); 7.26 (m, 2H). Using the method of Example 1. The following exemplified examples were obtained: Example 2 3-Phenyl-propylpropan-2-(E)phenyl (2S)-1-(3,3-dimethyl-1,2-dichloropentyl 2 - pyrrolidine carboxylate 80%, lH NMR (3SO Mhz, CDCl3) : d 0.8〇(tf 3H); · 1.21 (s, 3H); 1.25 (s, 3H) / 1.54-2.10 (m, 5H ); 2.10-2.37 (m, 1H); 3.52-3.55 (m, 2H); 4.5&amp; (dd, 1H, J=3.3, 8.9); 4.73-4.33 (m, 2H); S.27 (m, 1H); 6.S7 (dd, 1H, J= 15.9) ; 7.13-7:50 (m, 5H) .· (Please read the phonetic 3 on the back and fill in this page) *Install

— ·ϋ ϋ ϋ 一梦口, a···· am I % This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints five , invention description (38) storage example 3 3 - (3, 4,5-trimethoxyphenyl)-propyl (2S)-1-(3,3-dimethyl-i, 2-dioxopentyl 2-Btt-Pyranecarboxylate J Si%, lR NMR (CDC13): d 0.34 (tr 3H) ; 1.15 (s, 3H); 1.24 (s, 3H); 1.71 (dm, 2K); 1.98 (m, 5K); 2.24 (m, 1H) ; 2. S3 (m, 2H) ; 3.51 (t, 2H) ; 3.79 (s, 3H); 3.83 (s, 3H); 4.14 (m, 2H); 4.52 (m , 1H); 6.36 (s, 2H). Example 4 3-(3,4,5-trimethoxyphenylbuprop-2-(1)phenyl (2$)-1 -(3,3 - dimethyldioxypentyl)-2-pyrrolidine carboxylate 56%, lH NT4R (CDCI3): d 0.35 (t, 3Η); 1.22 (s, 3Η) / 1.25 (s, 3H); 1.50- 2.11 (m, 5H); 2.11-2.40 (m, 1H) ; 3.55 (m, 2H) ; 3.85 (s, 3H) ; 3.88 (s, 6H) ; 4.5S (dd, 1H); 4.81 (m, 2H S.22 (m, 1H); S.53 (d, 1H, · J = IS); 6.S3 (s, 2H). Rich Example 5 3-(.4,5-Methylene) Oxyphenyl phenylbupropyl (2$b 1-(3,3-dimethyl-1, 2-Dioxypentyl)-2-pyrrolidinecarboxylate 32%, NMR (350 MHz, CDC13): d 0.8S (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H); -2.10 (m, 5H); 3,3S, 3.79 (m, 2H); 4.53 (dd, lH, J = 3.8, aS); 4.Sl- 4.89 (m, 2H); 5.95 (s, 2H); 6.10 (cn, 1H) ; 5.57 (dd, IK J = S.2, 15.8); S.75 (d, 1H, J = 8.Q); s.83 (dd, 1H, J = 1.3, 3.0) ; S.93 (s, 1H). Excited R 3-(4,5-Methylenedioxyphenylbupro-2-(E)phenyl (25)-b (3 3 -dimethyl Base-1,2-dioxopentyl-2-pyrrolidinecarboxylate (please read the notes on the back and fill out this page) _Binding--------- % This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) -41- A7 1252226 B7__ V. Description of invention (39) / 3 2%, l7d NMR (3 SO MKz, CDC13) : d 0.3S (t/ 3H); 1.22 (s, 3H); 1.25 (S/ 3K); 1.50^2.10 (m, 5H); 2.10-2.39 (m, 1H); 3.36-3.79 (m, 2K); 4.53 (dd, 1H, J = : 3.8, QG); 4.S1-4.89 (m, 2K) ; 5.96 (S/ 2K); S.10 (m, 1H) ; 6.57 (dd, 1K/ J=: G.2, 15.3); S .75 (d, 1H, J = 8.0), · S.83 (dd, 1H, J = :L.3/ 8·. S.93 (s, 1H). Excited Example 8 3-Cyclohexyl-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine Carboxylate 92%, XH NMR (360 MHz, CDCl3): d 0.3S (t, 3H); 1.13-1.40 (m + 2 singlets, 9H total); 1.50-1.87 (m, 3H); 1.87- 2.44 5H 3.34-3.82 (m, 2H); 4.40-4.76 (m, 3H); 5.35-5.60 (m, 1H); 5.60-5.82 (dd, 1H, J = 6.5, IS). )-1,3-Diphenyl-propyl (2S)-1-(3,3-dimethyl-1,2-dioxypentyl)-2-pyrrolidine 90%, lH NKR (3S0) MKz, CDCl3) : d 0.85 (t, 3H) ; 1.20 (s, 3H); 1.23 (s7 3K); 1.49-2.39 (m, 7H); 2.4G-2.86 (m, 2H) ; 3.25-3.30 (m , 2H) ; 4.42-4.82 (m, 1H) ; 5.82 (td, 1H, J = lS, 6.7); 7.05-7.21 (m, 3K); 7.21-7.46 (m, 7H). Example 1 0 3 -Phenyl-1-propyl(2S)-1-(1,2-dioxy-2-[2-furyl])ethyl-2-pyrrolidinecarboxylate

99%, LH NMR (300 MHz, CDC13): d 1.5S-2.41 (m, 6H); 2.72 (t, 2H, J =: 7.5); 3.75 (m, 2H); 4.21 (m, 2H); .SI (m, 1H); S.53 (m, 1H); 7.1S-7.29 (m, 5H); 7.73 (m, 2H). This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297). _)------------ Order--------- (Please read the notes on the back and fill out this page) Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing -42- A7 1252226 B7_ V. Invention description (40 ) SJMLUL 3-phenyl-1-propyl (2S)-1-(1,2-dichloro-phenyl)ethyl _2-pyrrolidine carboxylate

81%, lH NMR (300 MHz, CDC13): d 1.83-2.41 (m, 6R); 2.72 (dm, 2H); 3.72 (m7 2H); 4.05 (m, 1H); 4.22 (m, IK); 4.54 (m, IK); 7.13-7.29 7.75 (dm, 1H); 8.05 (m, 1H). Reagent 1 3 3-phenyl-1-propyl (2S) -1- (1,2-dioxo Benzyl-2-phenyl)ethyl-2-pyrrolidinecarboxylate 99%, lH NMR (300 MHz, CDCI3): d 1.97-2.32 (m, 6K); 2.74 (t, 2H, J = 7.5); 3.57 (m, 2H); 4.24 (m, 2H); 4.S7 (m, 1H); 5.95- 7.28 (m, 5H)·; 7.51-7.S4 (m, 3H); 8.03-3.0 9 (m , 2H). 实例例14 3- (2, 5-Dimethoxyphenyl)-propyl (2S) -1- (3.,3-dimethyl-1,2-dioxopentyl 2 - pyrrolidine carboxylate 99%, lH NMR (300 MHz, CDC13): d 0.87 (t, 3H); 1.22 (s, 3H); 1.26 (s, 3H); 1.59 (m, 2H); 1.96 (m , 5H); 2.24 (m, 1H); 2.S3 (m, 2H); 3.55 (m, 2H); 3.75 (s, 3H); 3.77 (s, 3H); 4.17 (m, 2H); 4.53 ( d, 1H); 5.72 (m, 3H). Excited Example 1 5 3 - (2, 5-Dimethylchlorophenyl:)-1-propan-2-(E)phenyl (2S) - ΙΟ, 3 - dimethyl-1,2-dioxypentyl)-2-pyrrolidinecarboxylate 99%, lK NMR (300 MHz, CDCl3): d 0.87. (t, 3H); (s, 3H); 1.25 (s, 3H); 1.S7 (m, 2H); 1.78 (m, 1H); 2.07 (m, 2H); 2.2S (m, 1H); 3.52 (m, 2H) 3.78 (s, 3K); 3.80 (s, 3H); 4.54 (m; IK); 4.81 (m, 2H); 6.29 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ( Please read the notes on the back and fill out this page. 0 emamm ϋ· &gt;^i tmmmm emmf a .^1 ϋ i^i Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -43-1252226 A7 B7 V. Description of Invention (41) Example 1 6 2-(3,4,5-trimethylbenzenephenyl 1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl) 2-pyrrolidinecarboxylate 97%, lK NMR (300 MH2/CDC13): d 0.84 (t, 3H); 1.15 (s, 3H); 1.24 (s, 3H); 1.71 (dm, 2H); m, 5H); 2.24 (m, 1H); 2.53 (m, 2H); 3.51 (t, 2H); 3.79 (s, 3H); 3.83 (s, 3H); 4.14 (m, 2H); 4.52 (m , 1H); 6.36 (s, 2H). Example 1 7 3-(3-Pyridinyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dichloro Amyl)-2-pyrrolidinecarboxylate 80%, LK NMR (CDC13/300 MHz): d 0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.39 (m, 2H); 1.90-2.30 (m, 4H) / 2.30-2.50 (m, 1 H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53 (m, 1H); 7.22 (mf 1H) / 7.53 (dd, 1H); 8.45. 1 8 3 -(2-Pyridinyl)-propyl (2S)-1-(3,3-dimethyl-1,2-dioxypentyl)-2 - batch of tower vinegar 88%, LH NMR (CDC13/300 MHz): d 0.84 (t, 3H); 1.22, 1-27 (s, 3H each); 1.S8-2.32 (m, 8H); 2.88 (t, 2H, J 7.5); 3.52 ( m, 2H); 4.20 (m, 2H); 4.51 (m, 1H); 7.09- 7.19 (m, 2H); 7.59 (m, 1H); 8.53 (d, 1H, J=4.9). Q 3-(4-Pyridinyl)-dipropyl(2S)-1-(3,3-dimethyl- 1,2-dichloropentyl-2-pyrrolidinecarboxylate This paper scale applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) (Please read the note on the back and fill out this page) Order---- SI. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1252226 A7 B7 V. Invention Description ( 42) 91%, LH NMR (CDC13/300 MHz): d 6.92-S.80 (m, 4H); 6.28 (m, 1H); 5.25 (d, 1H, J = 5.7); 4.12 (m, IK) 4.08 (s, (please read the notes on the back and fill out this page) 3K); 3.79 (s, 3H); 3.30 (m, 2H); 2.33 (m, 1H); </ RTI> </ RTI> </ RTI> <RTIgt; 1-(2-cyclohexyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylate

91%, XH NMR (CDC13, 300 MHz): d 1.09-1.33 (m, 5H); 1.62-2.33 (cn, 12H); 2.S9)t:, 2H, J=7.5); 3.15 (dm, 1H) ; 3.58 (m, 2H); 4.16 (m, 2H); 4.53, 4.34 (d, 1H total); 7.19 (m, 3H); 7.29 (m, 2H).

EXAMPLE 2 1 3-Phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dichloroethyl)-2-pyrrolidinecarboxylate % NMR (CDC13, (3 MHz); 1.29 (s, 9H); IS (m, 2H) ; 4.53 (m, ΊΗ) ; 7.19 (m, 3H) ; 7.30 (m, 2H). Trial Example 22 3 -Phenyl-propyl (2S) -1- (2-cyclohexyl Base-1,2-dioxyethyl)-2-pyrrolidine carboxylate Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed NMR (CDCI3, 300 MHz): d 0 .38 (m, 2H) ; 1.1S ( m, 4H); 1.43-1.51 (m, 2H); 1.67 (m, 5K); 1.94-2.01 (m, 6H); 2.6S-2.87 (m, 4H); 3.S2-3.77 (m, 2H) 4.15 (m, 2H); 4.36 (m, 1H); 7.17-7.32 (m, 5H). Trial Example 23 3 - (3-pyridyl)-propyl (2S) -1- (2-cyclohexyl Base-1,2-dioxyethyl)-2-pyrrolidine-45- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 $ Ministry of Economic Affairs Intellectual Property Bureau Printed by the Employees' Cooperatives. V. Inventions (43) 7〇%, LH NMR (CDC1), 300 MHz) ··d 0·87 (ra, 2H); 1.15 (m, 4H); 1.49 ( Πτ, 2H); 1.S8 (m, 4H); 1.95-2.32 (m, 7H); 2.71 (m, 2H); 2.85 (m, 2H); 3.S3-3.78 (m, 2H); 4.19 ( m, 2K); 5.30 (m, 1H); 7.23 (m, IK); 7.53 (m, 1H) ; 8.4^ (rn, 2H). -(3-Util pyridine propylidene (2S) -1 - ( 2-but-butyl-1, 2

-Dioxyethyl)-2-pyrrolidinecarboxylate 83%, lH NMR (CDC13, 300 MHz): d 1.29 (s, 9H); 1.95-2.04 (m, 5H); 2.31 (m, 1H); 2.72 (t, 2H, J = 7.5); 3.52 (m, 2H); 4.13 (m, 2H); 4.52 (m, 1H); 7.19-7.25 (m, 1H); 7.53 (m, 1H); 8.4S (m, 2H). Example 2 5 3,3-Diphenyl-1-propyl(2$)-1-(3,3-dimethyl-1,2-dioxopentyl)-2 -pyrrolidinecarboxylate 4 _ (CDC13, 300 MHz) : d 0 . 85 (t, 3H) ; 1.21, 1.26 (s, 3H each); 1.S3-2.04 (m, 5H) ; 2.31 (m, 1H) ; 2.40 (m, 2K); 3.51 (m, 2H); 4.08 (m, 3H); 4.52 (m, 1H); 7.18-7.31 (m, 10H). · Example 26 _ pyridine) Bupropyl (2S)-l-(2-decyl-1,2-dioxyethyl)-2-pyrrolidinecarboxylate % NMR (CDC13/3Q0 MHz): d 1.24-1.28 (m, 5H); 1.88 -2.35 (m, 11H); 2.72 (t, 2H, J = 7.5); 3.00-3.33 (dm, 1H); 3.59 (m, 2H); 4.19 (ττι, 2H) ; 4.55 (m, 1H) ; 7.20 -7.24 (m, 1H); 7.53 (m, 1H); 8.47 (m, 2H). ' 窖旆 2 2 7 3 - (3 -pyridylbubupropyl (2S:)-N- ([2-thienyl) ]Acetaldehyde oxime)pyrrolidine carboxylate This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) PCT) ------------------- Order --------- (Please read the notes on the back and fill out this page) 1252226 A7 B7 V. Invention (44) (-H NMR (CDC13/ 3 00 MHz): d 1.81-2.39 (m, 6H); 2.72 (dm, 2H); 3.73 (m, 2H); 4.21 4.95 (m, 1H); 7.19 ( m, 2H); 7.51 (ra, 1H); (Read the note on the back first? Please fill out this page again) 7.80 (d, 1H); 8.04 (d, 1H); 8.4g 2K). Money: 128 3, 3-diphenyl-1-propyl (2S) -1- (3, 3-dimethyl-1,2-dichlorobutyl)-2-pyrrolidine carboxylate

99%, lR NMR (CDC13, 300 MHz): d 1.27 (s, 9H); 1.9S (m, 2H) / 2.44 (m, 4H), 3.49 (rri/ IH) ; 3.64 (m, IK) ; 4.03 (m, 4H) 4.53 (dd, 1H); 7.24 (m, 1QH). Implementation., Example 2 9 3 ,3-diphenyl-propyl (2S)-dihexyl acetaldehyde oxime - 2-B ratio Alkyl carboxylate. 91%, H NMR (CDC丄3, 3 00 MHz): d 1.32 (m, SH) ; 1.54-2.41' (m, 10H) ; 3.20 (dm, 1H) ; 3.S9 (m, 2H) ; 4.12 (cn, 4H); 4.52 (d, 1H); 7*23 (m, 10H). 实盖例30 3 , 3 -Diphenyl-propyl (2S) -1- ( 2- phenyl) Aldehyde-2-pyrrolidinecarboxylate 7ττ, 75%, -Η NMR (CDC13/ 300 MHz for the Consumer Property Agency of the Ministry of Economic Affairs): d 2.04 (m, 3H); 2.25 (m, 2H); 2.48 (cn, IE); 3.70 (m, 2H); 3.82-4.18 (m, 3H total); 4.54 (m, 1H); 7.25 (m, 11H); 7.76 (dd, 1H); 8.03 (m, 1H) The preparation of the desired substituted alcohol can be carried out by a variety of methods known to those skilled in the art of organic synthesis. If the synthetic route is not acceptable, the base or Ο paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 6222 52 A7g V. Description of the invention (45) Aryl aldehyde can be used with methyl (triphenylphosphoranylidene) acetate is reacted to be benzylated to phenylpropanol to provide a variety of different trans-cinnamate; such latter can be exemplified by an excess of lithium hydride Reduction of the double bond by catalytic hydrogenation and reduction of the salt and ester by reduction of the appropriate reducing agent to form a saturated alcohol. Optionally, the trans-cinnamate can be used by hydrogenation. Isobutyl aluminum is reduced to (E)-allyl alcohol. Will become a coating diameter 1 [ phqp-cHcaacH-rchq ---^

THF

R ^^.ccacH^ Lithium aluminum hydride (Please read the note on the back and fill out this page) Gasification Diisobutyl Aluminum Π

Pd/C Lithium hydride or diisobutylaluminum hydride - CGGCH, printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. • Longer alcohols can be prepared by the same materialization of benzyl and higher aldehydes. Optionally, such aldehydes can be prepared by the conversion of the corresponding phenylacetic acid with a carboxylic acid and a phenylethyl group with a higher alcohol. A general method for the synthesis of acrylates, exemplified by methyl (3,3,5-trimethylol)trans-cinnamate. · A ratio of 3 in tetrahydrofuran (250 m丨) A solution of 4,5-trimethylchlorobenzazole (5.0 g, 25.48 mmol) and methyl (triphenylphosphoranylidene) acetate (10 · 〇s, 29.9 liiiino 1.) was refluxed overnight. After cooling, the reaction mixture was diluted with 200 m 1 of ethyl acetate.

This paper scale is applicable to China National Standard (CNS) A4 specification (21〇X 297 mm) —48-1252226 A7 B7 5. Inventive Note (46), and washed with 2x200 ml of water, dried and vacuumed Concentrated under. The crude residue was chromatographed on a pad of EtOAc EtOAc (EtOAc) . lH NMR (3 00

Mhz; CDC13) : d.3.78 (s, 3K) ; 3.85 (s, SH) ; S.32 (d, 1H, J = l〇) ; S.72 (s, 2H) ; 7.59 (d, 1H, J = IS). A general method for the synthesis of saturated alcohols from acrylates, exemplified by (3,4,5-trimethoxy)phenylpropanol: Under argon atmosphere, a 値1 A solution of methyl (3,3,5-trimethoxy)trans-cinnamate (1.31 g, 7·17_〇1) in tetrahydrofuran (30 ml) was added dropwise to A solution of lithium aluminum hydride in THF (35 ml) was stirred and stirred. After the addition was completed, the mixture was heated to 75 ° C for 4 hours. After cooling, it was quenched by carefully adding 15 ml of 2N NaOH and then adding 50 ml of water. The resulting mixture was filtered through Celite to remove the solids and the filter cake was washed with ethyl acetate. The combined organic fractions were washed with water, dried and concentrated in vacuo, and purified on a EtOAc EtOAc EtOAc. Alcohol (533⁄4) 〇LH; NkR (3QQ Mhz; CDCl3): d 1 · 23 (br, 1H); 1.87 (m, 2H); 2.61 (t, 2H, J = 7.1); 3.S6 (t, 2H 3.80 (s, 3H); 3.83 (s, SH), · S.40 (s, 2H). A general method for synthesizing trans-allyl alcohol from acrylates. China National Standard (CNS) A4 specification (210 X 297 mm) λ-. (Please read the notes on the back and fill out this page) ---------Book --------- · Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed -49-1252226 A7 B7 V. Description of Invention (47) / (3,4,5-Trimethoxy)phenylpropane-(E-butanol for illustration · Cool a solution of methyl (3,3,5-trimethoxy)trans-cinnamate (1. 35s, 5.35mmo I) in toluene (25ml) to _ a solution consisting of diisobutylaluminum hydride (10. 25 ml) at 10 ° C and a gg of gg in toluene 1.0M solution, 11.25iumo 1) was treated. At 〇°C, the reaction mixture was stirred for 3 hours, then it was quenched with 3 nrl of methanol, and the pH was adjusted with IN HC. The reaction mixture was extracted into ethyl acetate, and the organic phase was washed with water, dried and concentrated, and purified on a hexane column to give 25% ethyl acetate in hexane. The extraction was carried out to obtain a concentrated oil of 0.96 s (803⁄4). lK NMR (3 60 Mhz; CDCl3): d 3.35 (s, 3H); 3.37 (s, SH); 4.32 (d, 2H, J = 5.6) 5.29 (dt, IK, J = 15.3, 5.7), 6.54 (d, 1H, J =: 15.3); 6.51 (s, 2H). The invention has thus been described in detail, and it is apparent that the invention can be varied The changes in the manner of the Q will not be considered to be in the spirit and scope of the present invention, and all such variations are considered to fall within the scope of the appended claims. — — — — — — — — — — — · 1111111 t 111!! ^^^- (Please read the note on the back first? Then fill out this page) Printed by the Intellectual Property Intelligence Bureau Staff Consumer Cooperative Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1252226 A7 B7 V. Inventive Description (48) Brief Description of the Drawings Fig. 1 is a treatment of various concentrations shown in Example 7 of the present invention. Light micrograph of the dorsal root knot of chicken. Fig. 2 is a graph showing the quantitative measurement of neurite outgrowth of chicken dorsal root ganglion treated at various concentrations as shown in Example 17. Figure 3 is a light micrograph of one of the sciatic nerve sections of rats. - Figure 4 shows the [3H]-CF1^# combination of each microgram of striated membrane protein. Figure 5 is a bar graph of [3h]-CFT for a membrane protein of 200 // g. Figure 6 is a photomicrograph of the coronal and sagittal slices at 630 magnification. Figure 7 is a photomicrograph of a coronal and sagittal brain slice at 50 magnification. Figure 8 is a photomicrograph of a coronal and sagittal brain slice at 400 magnification. (Please read the notes on the back and fill out this page) ϋ ϋ ϋ I ϋ ϋ 一-0, a 1 I- I ϋ · quasi-if- home country with moderate ruler sheet _I__J Ministry of Economic Affairs Intellectual Property Office staff Consumer cooperatives print 10 grid rules 4 S)

Claims (1)

1252226 No. 881 183 Patent Application No. 12 Application 1$Profit Correction 94 Years -so- BS Month VI. Application for Guidance I 1 1 · A Compound with the following formula: Announcement γ-Z Among them, the Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, i ^ 2. R1 is a Ci-Cg linear or branched alkyl or chain thinner optionally substituted by a C3-C8 cycloalkyl group. a radical, a C3 or C5 cycloalkyl, a C5-C7 cycloalkyl, wherein the alkyl, chain, cycloalkyl or cycloalkyl hydrazine can be optionally substituted C--C4 alkyl, Ci-C4 alkenyl or hydroxy, -- or Ari, wherein An is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indenyl, 3-吲π-radyl, 2-furanyl, 3-furyl, 2-mercapto, 2-thienyl, 3-thienyl, 2-pyridyl, 3-indenyl, 4-pyridyl and phenyl These substituents have 1 to 3 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, difluoromethyl, Ci-C6 straight or branched alkyl or alkene a group, a Ci-G alkoxy group or a Ci-C4 chain methoxy group, a phenoxy group, a oxy group, and an amine group; X is oxygen; γ is oxygen; and lanthanide is chlorine. For example, the compound of the scope of patent application, in which Rj is selected from the following -52- ί----------- installed - (please read the back sheet of this note first) Ψ 1252226 D8, the patented range group. Ci-C9 linear or branched alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-monopyranyl, 2-thienyl, 2-thiazolyl and 4-hydroxylated base. 3. The compound of claim 3, wherein R1 is a 匕-匕 linear or branched alkyl or alkenyl group optionally substituted by a C3-C6 cycloalkyl group, or It is selected from the group consisting of 2-indolyl, 2-thiophenyl or phenyl. Group: 4. The compound of claim 1 is selected from the group consisting of the following group (2S)-1 (3,3-dimercapto-1,2-didecanoic acid; oxypentyl)- 2-. Pyrrolic acid; (S) 1 (ι,2-_oxo-2-cyclohexyl)ethyl-2- π ratio slightly burned Wei (2S) — 1~(1,2-dioxo-4-cyclohexyl Butyl-2-pyrrolidinecarboxylic acid; (2S) 1 (i,2-oxo-2-(n-fumantyl)ethyl)_2-0-pyrrolidine carboxylic acid; f cooperate to print 3⁄4 (Μ) 1 (1,2-oxo-2-dissyl)ethyl)-2-. Bihaxamic acid; (2S)-^d,2-dioxy-2-[thiazolyl]ethyl)-2-pyrrolidinecarboxylic acid; C2 magic-1弋1,2-dioxo-2-stupid (2)-(3S)-1~(3,3-dimercapto-2-dioxy-4-hydroxybutyl)-2-pyrrolidinecarboxylic acid; -53- § 舀家标立堤打 BS 1252226 VI. Application for the range of guidance (2S)-1 -(3,3-dimethyl-I 2 dioxopentyl)-2-pyrrolecarboxylamine; 1-[ 1-(3,3-dimethyl-1,2-oxopentyl)-l-proline]-L-phenylalanine; 1-[1-(3,3-dimethyl-oxopentane) Base)- l-proline]-L-benzene leucine; Bu [1-(3,3-dimethyl-I,2-dioxypentyl)-L-proline]-L-benzene Glycine; 1 -[1-(3,3-dimethyl 1'2-oxopentyl)-L-prosin]-L-isoleucine. 5. The compound of claim 3, which is selected from the following group: (2S)-l-(3,3-dimethyl- 1,2-dioxypentyl)_2-π ratio p (2S)-l-(2-tert-butyl-1,2-ethoxyethyl)_2-σpyrrolidine carboxylic acid; (2S)-1-(2-cyclohexylethyl- 1,2-dioxyethyl)-2-pyrrolidin; (2S)-1-(2-cyclohexyl-i,2-dioxyethyl)-2_pyrrolidinecarboxylic acid; The property bureau employee consumption cooperative printed 3⁄4 (2S)-N-([2-thienyl]acetaldehyde oxime)pyrrolidinecarboxylic acid; (2S)-1 -cyclohexylacetaldehyde oxime-2-pyrrolidinecarboxylic acid. 6. A compound of claim 1 which is a monooxy 3,3-methylpentyl)-2-pyrrolidinecarboxylic acid. A method of preparing a compound according to any one of claims 1 to 3, which comprises (a) bringing the corresponding mercapto valerate to phase -54---- 1252226 Methyl grass as claimed in the patent application reacts with the chlorine; (b) reacts the product of step (a) with a nucleophilic reagent; and (C) hydrolyzes step (b) in the presence of a base The product was obtained to obtain the compound. 8. The method of claim 7, wherein the compound is a derivative of N-acetaldehyde proline which is as defined in Item 3. The method of claim 7 of the patent scope comprises the step of hydrolyzing the product of step (b) in the presence of lithium hydroxide.如. The method of claim 7, wherein the compound is as defined in claim 6 of the scope of the patent application. A method of cultivating a chemical compound as claimed in claim 6 which comprises a mixed sulfhydryl group (28)·Η1 dioxo-3,3-dimethylpentyldipyrrolidine-carboxylate, hydr Lithium and methanol. Ministry of Economic Affairs, Intellectual Property Bureau, staff consumption cooperation.