WO1998037882A1

WO1998037882A1 - Method of using neurotrophic carbamates and ureas

Info

Publication number: WO1998037882A1
Application number: PCT/US1998/003485
Authority: WO
Inventors: Jia-He Li; Gregory S. Hamilton; Joseph P. Steiner
Original assignee: Guilford Pharmaceuticals Inc.
Priority date: 1997-02-27
Filing date: 1998-02-26
Publication date: 1998-09-03
Also published as: ZA98825B; EP1001762A1; AR011869A1; EP1001762A4; PA8447901A1; JP2001513772A; AU6181698A; CA2281096A1; PE46599A1

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 OF USING NEUROTROPHIC CARBAMATES AND UREAS

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to a method of using neurotrophic low molecular weight, small molecule carbamates and ureas having an affinity for FKBP-tyne immunophilins, as inhibitors of the enzyme activity- associated with immunophilin proteins., particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

2 • Description of Related Art

The term immunophilin refers to a number of proteins that serve as receptors for the principal imiminosuppressant drugs, cyclosporin A (CsA) , FK506 and rapamycin. Known classes of immunophilins are cyclophilins and FK506 binding proteins, or FKBPs . Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12. These immunophili -drug complexes interface with various intracellular signal transduction systems, especially the immune and nervous systems .

Immunophilins are known to have peptidyl-prolyl isomerase (PPIase) , or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the intercσnversiαn of the c±3 and trans isomers of peptide and protein substrates or the immunophilin proteins .

Immunophilins were originally discovered and stu io in the immune tissue. It was initially postulated bv those skilled in the art that inhibition of immunophilins' rotamase activity leads to inhibition of T-cell proliferation, thereby causing che immunosuppressive activity exhibited by immunosuppressant drugs, such as cyclosporin A, FX506 and rapamycin. Further study has shown that the inhibition_, of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al., Science, 1990, vol. 250, pp. 55S-559. Instead, immunosuppressicn appears to stem from the formulation of a complex of immunosuppressant drug and immunophilin. It has been shown that immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al . , Cell , 1991, vol. SS, pp. 807-815. In the case of FKBP-FK50S and cyclαphilin-CsA, the immunophilin-drug complexes bind to the enzyme calcineurin and inhibit the T-ceil receptor signalling which leads to T-cell proliferation. Similarly, the immunophilin-drug complex of FK3P-rapamycin interacts with the RAFTl/FRAP protein and inhibits the IL-2 receptor signalling. Immunophilins have been found to be present at high concentrations in the central nervous system. Immunophilins are enriched 10-50 times more in central nervous system than in the immune system. Withi neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release and neuronal process extension.

Surprisingly, it has been found that certain low molecular weight, small molecule carbamates and ureas with a high affinity for FK3Ps are potent ro_tamase inhibitors and exhibit excellent neurαtrophic eff cts . Furthermore, these rotamase inhibitors are devoid of immunosuppressive activity. These findings suggest the use of rotamase inhibitors in treating various peripheral neuropathies and enhancing neuronal regrowth in the central nervous system (CNS) . Studies have demonstrated that neurαdegenerative disorders such as Alzheimer' s disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) may occur due to the loss, αr decreased availability, of a neurαtrophic substance specific for a particular population of neurons affected in the disorder.

Several neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer' s disease results from a decrease αr loss of nerve growth factor (NGF) . It has thus been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor and neurotro in-3 , to increase the survival of degenerating neuronal populations .

Clinical application of these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailabiiity of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailabiiity and specificity. However, when administered chronically, immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular _.filtration and irreversible interstitial fibrosis (Kopp et al., J. Am. Soc. Nephral., 1991,

1:162) ; neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as non- localized headaches (De Groen et al., N. Ξngl. J. tied., 1987, 317:861) ; and vascular hypertension with complications resulting therefrom (Kahan et al., N. Ξngl.

J^". Med. , 1989, 321:1725) .

To prevent the side effects associated with the use of the immunosuppressant compounds, the present invention provides a method of using a non- immunosuppressive compound containing low molecular weight, small molecule carba ates and ureas to enhance neurite outgrowth, and to promote neuronal growth and regeneration in various neuropatholαgical situations where neuronal repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes_; physical damage to the central nervous system (spinal cord and brain) ; brain damage associated with stroke,- and neurological disorders relating to neurodegeneratiαn, such as Parkinson's disease, SDAT (Alzheimer's disease) , and ayotrophic lateral sclerosis.

SUMMARY OF THE INVENTION

The present invention relates to a method of using a neurαtrophic low molecular weight, small molecule carbamates and ureas having an affinity for FKBP-type immunophilins . Once bound to these proteins , the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity. A key feature of the neurotrophic compounds is that they do not exert any significant immunosuppressive activity.

Specifically, the present invention relates to a method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrαphically effective amount of a compound of 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, ₍Cl-CS₎ - straight or branched alkyl, (C2-CS) -straight or branched alkenyl or alkynyl, (C5-C7) -cyclαalkyl substituted ₍C_l- C⁶⁾ -straight or branched alkyl or (C3-C6₎ -straight or branched alkenyl or alkynyl, (C5-C7) -cycloalkenyl substituted ⁽Cl -CS ⁾ -straight or branched alkyl or ₍C3- ^C6) -straight or branched alkenyl or alkynyl, Ar- substituted ⁽Cl-CS) -straight or branched alkyl, Ar- substitut d ^{' (}C3 -Co) -straight or branched alkenyl or alkynyl,-

any one of the CH₂ groups of said alkyl chains may be optionally replaced by a heteroato selected from the group consisting of 0, S, SO, S0₂, and NR, wherein R is selected from the group consisting of hydrogen, ₍C1-C₄₎ - straight or branched alkyl, (C3-C4) -straight or branched alkenyl αr alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon acom 7 of said heteroatαm-containing chain to form a ring, and wherein said ring is optionally fused to an Ar 'group_;

J is selected from the group consisting of hydrogen, ⁽Cl-CS) -straight or branched alkyl, (C3-CS) -straight or branched alkenyl and -CH₂Ar; K is selected from the group consisting of (C1-C4) -straight or branched alkyl, -C.H_j.Ar, and cyclohexylmethyl ; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, s, SO and S0₂;

Z is 0 or S;

Y is 0 or N, wherein when Y is 0, then j, is a lone pair and R₂ is selected from the group consisting of Ar, (Cl-CS) - straight or branched alkyl, and (C3-CS) -straight or branched alkenyl or alkynyl; and when Y is N, then Rj. and R₂ are independently selected from the group consisting of -Ar, (Cl-CS) - straight or branched alkyl, and (C3-C6) -straight or branched alkenyl or alkynyl; or Rj. and R₂ are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, i idazolidine, pyrazolidine, piperidine, and piperazine;

Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naρhthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a 8 heterocyclic aromatic group selected from the grou_t, consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazαlyl, thiazolyl, imidazαlyl, pyraxαlyl, 2-pyrazolinyi, pyrazolidinyl , isoxazolyl, isσtriazolyl, 1,2,3- oxadiazolyl, 1, 2, 3-triazolyl, 1,3 , 4-thiadiazolyi, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3 , 5-triazinyi, 1, 3 , 5-trithianyl, indolizinyl, indolyl, isσindolyl, 3H- indolyl, indolinyl, benzo [b] furanyl, benzo [b] thio-phenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H- quinolizinyl , quinolinyl , 1,2,3,4- tetrahydroquinolinyl , isoquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazσlinyl, 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, -S0_:H, trifluoromethyl, trifluoromethoxy, (Cl-CS) -straight or branched alkyl, (C2-CS) -straight or branched alkenyl, 0-

C (C1-C6) -straight ro branched alkyl] , 0- [ (C3-C4) -.-traic t or branched alkenyl], O-benzyl, 0-phenyl., 1,1- methylenedioxy, -NR₃R,, carboxyl, N- (C1-C5 -straight αr branched alkyl or C3-C5 -straight αr branched alkenyl) carboxamides, N,N-di- (C1-C5- straight or branched alkyl or

C3-C5- straight or branched alkenyl) carboxamides, mcrpholinyl, piperidinyl, 0-X, CH₂- (CH₂),-X, _O-Cca,,^ ⁽CH₂ ⁾ _q-o-X, and CH»CH-X_;

R^j and R. are independently selected from the group consisting of ⁽Cl-CS⁾ -straight or branched alkyl, ₍C3- CS⁾ -straight or branched alkenyl, hydrogen and benzyl ,-or

R^: and R, can be taken together to form a 5-6 membered heterαcylic 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 l.

The present invention also relates to a method of effecting a neuronal activity in an animal, comprising_: administering to the animal a neurotrophically effec^tive amount of a compound of formula II or III_:

II III

αr a pharmaceutically acceptable salt thereof, wherem. Y, j. and R₂ are as defined in claim l, Ar i_{s as} defined in claim 4 and w is 1 or 2.

The present invention further relates to a method of effecting a neuronal activity in an animal, comprisinc_: administering to the animal a neurotrophicaliy effective amount of a compound of formula III or IV_:

III IV

or a pharmaceutically acceptable salt thereof, wherein: Y, Rj. and R₂ are as defined in claim 1, Ar is as defined in claim 4, J is hydrogen, (Cl-CS) -straight or branched alkyl or (C3-CS) -straight or branched alkenyl, and w is 1 or 2.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

"Alkyl" means a branched or unbrancned saturated hydrocarbon chain containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, and the like, unless otherwise indicated. "Halo" means fluoro, chloro, bro o, or iodo, unless otherwise indicated.

"Pharmaceutically acceptable salt" refers to salts of the subject compounds which possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. The salts can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camp orsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate , ethanesulfαnate , fu arate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochioride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, αxalate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salt with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen- containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl , ^_lstyl ^ _g chloride , bromide and iodides , aralkyl halides _U,. benzyl and phenethyl broπύdes and others , water or c< i - soluble or dispersible products are thereby obtained'" ^■P ^βyl. includes all possible isomeric phenvl radicals ^, optionally _monosu^bstituted or multi-substi_tu_te_d »ith subs^tituents selected fro. the group consisttnc of alkyl, alkoxy, hydroxy, halo, and haloalkyl .

"Treatment" covers any treatment of a _disease and/or condition in an animal, particularly a human, and includes :

⁽i⁾ pre^venting a disease and/or con_dition from occurring in a subj ect which may be pre_dis_posed to the ^disease and/or condition but has not ye_t been _diagnose_d as having it ;

⁽ ϋ⁾ inhibiting ^the disease and/or con_dition, i . _e . , arres^ting its developmen_{t ;} an_d

⁽ ϋi⁾ relievin^g the disease and/or con_dition, _i . e . , causing regression of the disease an_d/or con_dition.

^The inventors have discovered tha_t certain lo_w molecular wei^ght , small molecule carbama_tes an_d ureas ^ve an affinity for FKBP-type immunophilins , Particularly ^FKBP12 . When the carbamates an_d ureas are boun^d to an ^FKBP-type immunophilin, they have _been found ^to inhi^bi^t the prolyl -pep t idyl c±s- trans isomerase activity, or rotamase, activity of the bin_ding pro_tein 7882

13 and unexpectedly stimulate neurite growth. This activity is useful in the stimulation of damaged neurons , the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies .

For the foregoing reasons , the present invention relates to a method of effecting a neuronal activity in an animal , comprising: administering to the animal a neurotrophically effective amount of a compound of 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, (Cl-CS) - straight or branched alkyl , (C2 -CS) -straight or branched alkenyl or alkynyl , (C5-C7) -cycloalkyl substituted (Cl- CS) -straight or branched alkyl αr (C3 -CS) -straight or branched alkenyl or alkynyl , (C5-C7) -cycloalkenyl substituted (Cl-CS) -straight or branched alkyl or (C3 - CS⁾ -straight or branched alkenyl or alkynyl, Ar- substituted ⁽Cl-CS⁾ -straight or branched alkyl, Ar- substituted (C3-CS⁾ -straight or branched alkenyl or alkynyl;

any one of the CH₂ groups of said alkyl chains may be optionally replaced by a heteroatom selected from the group consisting of 0, S, SO, S0₂, and NR, wherein R is selected from the group consisting of hydrogen, ₍C1-C4₎ - straight or branched alkyl, (C3-C4) -straight or branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group_;

J is selected from the group consisting of hydrogen, ⁽Cl-CS⁾ -straight or branched alkyl, (C3-CS₎ -straight αr branched alkenyl and -CH₂Ar; K is selected from the group consisting of ⁽C1-C4⁾ -straight or branched alkyl, -CH₂Ar, and cyclohexylmethyl ; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, S, SO and S0₂;

Z is 0 or S;

Y is 0 or N, wherein when Y is 0, then Rj. is a lone pair and R₂ is selected from the group consisting of Ar, ₍Cl-CS₎ - straight or branched alkyl, and (C3-CS₎ -straight or 7882

15 branched alkenyl or alkynyl; and when Y is N, then R^,_ and R₂ are independently selected from the group consisting of Ar, (Cl-CS₎ - straight or branched alkyl, and (C3-CS) -straight or branched alkenyl or alkynyl; or Rj. and R₂ are taken together to form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine,- Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic 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, pyraxαlyl, 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-trithianyl, indolizinyl, indolyl, isoindolyl, 3K- indolyl , indolinyl , benzo [b] furanyl , benzo [b] thio-phenyl , lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H- quinαlizinyl, quinoiinyl, 1, 2, 3, 4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3, -tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl , quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; IS Ar may contain one or more substituents which a- independently selected from the group consisting όl hydrogen, halogen, hydroxyl, ni_Crθ trifluoromethyl, trifluoromethoxy, (Cl-CS) -straight or branched alkyl, ⁽C2-CS) -straight or branched alkenyl, 0-

^{[ (}C1-C6⁾ -straight ro branched alkyl] , 0- [ (C3-C4) -stra^cht or branched alkenyl], O-benzyl, O-phenyl, χ,₂- methylenedioxy, -NR₃R«, carboxyl, N- (C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl₎ carboxamides, ,N-di- ⁽Cl-C5-strai_ght or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl,. 0-X, CH₂- (CH₂)_q-X, 0-₍CH-_)q-χ,

⁽CH₂ ⁾,-0-X, and CH=CH-X_;

R₃ and R, are independently selected from the group consisting of ⁽Cl-CS) -straight or branched alkyl, _(C3- ^CS) -straight or branched alkenyl, hydrogen and benzyl_; or R₃ and R, can be taken together to form a 5-₆ membered heterαcylic ring;

X is selected from the group consisting of ₄- methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3 , 5-dimethylisoxazoyl, isoxazoyl, 2- methylthiazαyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl; q is 0-2; and n is o or l. /37882

17 In a preferred embodiment, J and K are taken together to form a 5-7 membered ring.

In another preferred embodiment, at least one of B and D is independently represented by the formula - ⁽CH₂)_r-(X) -(CH₂),-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 CH₂, 0, S, SO, S0₂, and NR, wherein R is selected from the group consisting of hydrogen, (C1-C4)- straight αr branched alkyl, (C3-C4) -straight αr branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group .

In an additional preferred embodiment, Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isαindαlyl, quinoiinyl, isoquinσlinyl , 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, (Cl-CS) -straight or branched alkyl, 0- C (Cl-CS) -straight or branched alkyl], halogen, S0₃H, and NR₃R₄; and *. «Λ R. are independently selected from the -,» consisting of <C¹-C_S, -straight or branched alkyl; «⁾ -straigh^t or branched alkenyl, hydrogen and benzyl - o- «. «d *. can be taken together

heterocyclic ring .

The ^presen^t invention also relates _to a metho_{d 0}- effecting a neuronal activity in an animal, comprising - a^dministering to the animal a neurotrophically effective amoun^t of a compound of formula _II or m _:

II

I I I

or a pharmaceutically acceptable salt thereof, wherein_: , , and R₂ are as defined in claim ₁, Ar is as defined in claim 4 and w is 1 or 2.

The present invention further relates to a method of effecting a neuronal activity in an animal, comprising_: administering to the animal a neurotrophically effective amount of a compound of formula III or IV_:

III

IV

r a pharmaceutically acceptable salt thereof, ,*.„«,. V. R, and «, are as defined in claim l, _{te is a}. defined in claim , . , _{is hydrogen}, _(C1__M) .

-ched alkyl or ₍C3-c_S) -straight or branched alkenyl, and is i or 2.

The neuronal activity that is effected by the -thods of the present invention m y be selected from the sro p consisting of^: stimulation of damaged neurons Promotion of neuronal regeneration, prevention of neurodegeneration an^d treatment of a neurologica_l dⁱsorder.

H a.ples of a neurological disorder that is "eatable by the methods of the present invention include «"hout limitation: _Crigβninal ^ ^ Slossopnaryngeal neuralgia,- BelLs Palsy,- asthenia *rv_s, ^_BculΛr dystrophy; a yotrophic lateral sclerosxs,- progressive .uscular atrophy,- progressive fculbar inherited .u oular atrophy; hemiated, ruptured or Prolapsed invertebrate disk syndromes_; cervical spondylosis^; plexus disorders; thoracic outlet destruction syndromes; peripheral neuropathies such as those caused by lead, dapsone, ticks, porphyria, or Guillain-Barr syndrome; Alzheimer's disease_; and Parkinson's disease.

The methods of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and a neurological disorder relating to neurodegeneratiαn. Examples of a neurological disorder relating to neurodegeneration include Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis. In the methods of the present invention, the neurotrophic compound may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic phar aceutically-acceptable carriers, ad_juvan_ts and vehicles . The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally, intrathecally, intraventricularly, intrasternal and intracranial injection αr infusion techniques . 98/37882

21 To be effective therapeuticaiiy as central nervous system targets, the neurotrophic compounds should readily penetrate the blood-brain barrier when peripherally administered. Compounds which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route.

The neurotrophic compounds may also be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or .oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-tαxic parenterally-acceptable diluents or solvents, for example, as solutions in 1, 3-butanediol . Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as solvents or suspending mediums. For this purpose, any bland fixed oil such as a synthetic mono- or di-glyceride may be employed. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyσxyethylated versions, are useful in the preparation of injectables. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersant s .

Additionally, the neurotrophic compounds may b_«= e administered orally in the form of capsules, tablets, aqueous suspensions or solutions . Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate. Capsules may contain diluents including lactose and dried com starch. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient . The oral dosage forms may further contain sweetening and/or flavoring and/or coloring agents .

The neurotrophic compounds may further be administered rectally in the form of suppositories .

These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols . Moreover, the neurotrophic compounds may be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin, αr the lower intestinal tract. Suitable topical formulations can be readily prepared for each of these areas . 7882

23

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 adjus_ted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, the compounds may be formulated into ointments, such as petrolatum, for ophthalmic use.

For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, pαlysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical application to the lower intestinal tract can be effected in a rectal suppository formulations (see above) αr in suitable enema formulations. Dosage levels on the order of about 0.1 mg to about

10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about _,000 mg. _The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It is understood, however, that a specific dose level for any particular patient will ^■ depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex, and diet of the patient_; the time _. of administration^; the rate of excretion,- drug combination,- the severity of the particular disease being treated_; an_d the form of administration.

The compounds can be administered with other neurotrophic agents such as neurotrophic growth factor ⁽N^GF⁾ , glial derived growth factor, brain derived grow_th factor, ciliary neurotrophic factor, and neurotropin-₃. The dosage level of other neurotrophic drugs will depend upon the factors previously stated and the neurotrophic effectiveness of the drug combination.

EXAMPLES The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise specified, all percentages are based on 100% by weight of the final compound.

The compounds used in the methods of the present invention may be readily prepared by standard techniσues of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme I, cyclic amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with alcohols ROE to generate esters 2. After removal of .the protecting group, the free amine 3 may be reacted with.a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively. Alternatively, reaction of 1 with amines provides the corresponding amide compounds .

Scheme I

Oapxacrcc

Isocyanates ^{( l}NCO⁾ or isothiocyanates (R^lNCS) 4 may be conveniently prepared from the corresponding readily 2S available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.

Scheme II

EXAMPLE 1

-lJ-^vrj .A-T ,._nrnτrrl ^^_,._ _ ^_

A mixture of - ⁽ ter^t-butyioxycarbonyl⁾ - (S) -proline ⁽3-^{0 ;} 13.⁹ mmol^{) ;} 3- ⁽3-Pyridyl) -1-propanol ₍2.₉₀ g_; ⁰.⁹ mmol⁾, dicyclohexylcarbodiimide (₄.5₉ g_{; 22}.2₄ -mol⁾, camphorsulfonic acid (1.08 g_{; 4}. _S3 mmol₎, and ₄- dimethylaminopyridine (o.SO g_{; 4}.63 mmol₎ in dry methylene chloride ⁽100 mL) was stirred overnigh . The reaction mixture was diluted with methylene chlor_ide ₍5₀ m ⁾ and water ^(lO^O mL⁾ , and the layers were separated. The organic phase was washed with water ₍₃ x ιoo ^ , dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting 8/37882

27 with ethyl acetate to obtain 4.60 g (95%) of the ester as a thick oil, ^lK NMR (300 MHz, CDC1₃) : δ 1.45 <_a, 9H₎ ; 1.70-2.05 ( , SH) ; 2.32 (m, IK) ; 2.71 (t, 2H) ; 3.50 ( , 2H) ; 4.15 (m, 2H) ; 4.13 (m, IK) ; 7.24 (m, 1H) ; 7.51 (m, 1H) ; 3. 3 (m, 2H) .

3 - ( 3 -oyridyl ) -1-oropyl oyrrolidine-2 -

A solution of 3- (3-pyridyl) -1-propyl (-2S) -N- ( tert- butyloxycarbonyl)pyrrαlidine-2-carboxylate (3.00 g_; 9 mmol) in methylene chloride (50 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x) . The combined organic extracts were dried and concentrated to yield 2.00 g (95%) of the free amine as a thick oil, ^lH NMR (300 MHz, CDC1₃) : δ 1.37-2.20 (m, 6H) ; 2.79 ( , 2H) ; 3.03 (m, 2H total) ; 3.07 (m, 2H) ; 3.34 (m, 1H) ; 4.24 (m, 2H) ; 7.32 (m, 1H) ; 7.60 (m, 1H) ; 8.57 (m, 2H) .

3- (3 -oyridyl) -l-oropvl (2S) -1- f (2-methvbutvl) - carbamovπpvrrolidine-2-carboxvlate (1) 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 triphαsgene ⁽128 mg; 0.43 mmol) in methylene chloride (5 πvL) . The resulting mixture was refluxed for 1 hour and then cooled to room temperature. 3- (3 -Py idyl) -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 partitioned 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 I) as an oil, ^lH NMR (CDClj, 300 MHz) : δ 0.89-0.93 (m, SH) ; 1.10-1.20 (m, 1H) ; 1.27 (s, 1H) ; 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, 1H) ; 7.53-7.5(5 (dd, 1H) ; 8.46-8.48 (s, 2H) . Anal. Calcd. for C_lsH„NjOj - 0.5 H₂0 : C, 64.02; H, 8.48; N, 11.79. Found: C, 63.72; H, 8.42; N, 11.83.

EXAMPLE 2 Synthesis of 3- (3-pyridyl) -1-propvl (2S) -1- r (1A 1' - dimβ hylpropyl) r>_*τh»movn pyrrolidine-2-carboxylate (2)

Reaction of 3- (3-pyridyl) -1-propyl (2S) -pyrrolidine-

2-carboxylate with the isocyanate generated from tert- amylamine and triphosgene, as described for Example 1, provided the compound of Example 2 (2, Table I) in 62% yield, ^τK NMR (CDC1₃, 300 MHz): δ 0.83 (t, 3H) ; 1.27 (s, SH) ; 1.64-1.71 (m, 2H) ; 1.91-2.02 ( , 7H) ; 2.66-2.71 (t, 2H⁾ ; 3.29-3.42 ( , 2H) ; 4.11-4.15 (t, 3H) ; 4.37-4.41 (_m, 1H) . Anal. Calcd. for C₁₉H₂₉N₃0₃ - 0.5 H₂0: C, 64.04_; H, 3.48; N, 11.79. Found: C, 64.23; H, 8.31; N, 11.30.

EXAMPLE 3 Synthesis of 3- (3-pyridyl) -1-propγl (25) -1- ^{[ (}cvclohβxyl) thiocarbamoyll -Pyrrolidine-2-carboxylate (3) A mixture of cyclohexylisothiocyanate (120 mg,- 0.9 mmol) , 3- (3-pyridyl) -1 -propyl (25) -pyrrolidine-2- carboxylate (200 mg; 0.9 mmol) triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned 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 I) , ^LH NMR (CDC1₃, 300 MHz) : δl.16-1.40 (m, 6H) ; 1.50-1.71 ( , 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, 1H) ; 5.26-5.29 (d, 1H) ; 7.17-7.25

(m, 1H) . Anal. Calcd. f or C_2QH„N₃0₂S : C, 63.57; H, 7.78; N, 11.19. Found: C, 63.25; H, 7.80; N, 11.07.

EXAMPLE 4 Synthesis of 3 - (3 -pyridyl) -1-proPyl (2S) -1-

[ (cvelohexyl) e? hamnγn -pyrrolidine-2-carboxylate (4) A mixture of cyclohexylisocyanate (100 mg_{; 0}.9 mmol), 3- (3-pyridyl) -1-propyl (2S) -pyrrolid^'ine-2- carboxylate (200 mg; 0.9 mmol) and triethyla ine (90 mg_;

0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned 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 (35%) of the compound of Example 4 (4, Table I) , ^LH NMR (CDClj, 300 MHz): δ 1.10-1.27 (m, SH) ; 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, 1H) ; 7.25-7.34 (m, 1H) ; 7.25-7.55 (dd, 1H) ; 8.45 (s, 2H) . Anal . Calcd. for ^C _2oH₂₉N₃0₃ - 0.6 H₂0: 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-PΓOPVI (25)-l-ffl-

A mixture of 1-adamantylisocyanate (250 g; 0.9 mmol), 3-3-pyridyl) -l-propyl ( 2S) -pyrrolidine-2- carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned 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 tsσ mg ⁽38%) of the compound of Example 4 (4, Table I₎ , i_jj NMR ⁽CDClj, 300 MHz): δ 1.39-1.44 (d, 2H) ; 1.65 (s, 4K₎ 1.95-2.07 (m, 8H) ; 2.07-2.20 ( , 5K) ; 2.71-2.76 (m, 2K) 3.37-3.45 (m, 1H) ; 3.50-3.60 ( , 1H) ; 4.09-4.18 (m, 2H! 4.99-5.21 (d, 1H) ; 7.21-7.25 ( , 1H) . Anal. Calcd. for Cι«H₃₃N₃0₂S - 0.4 H₂0: 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 FK5Q6 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis- trans isomerase activity of FKBP may be measured as an indicator of this affinity.

Ki Test Procedure Inhibition of the peptidyl-prolyl isomerase

(rotamase) activity of the inventive compounds can be evaluated by known methods described in the literature

(Harding, et al., Nature, 1989, 341:758-760; Holt et al .

J". Am. Chem. Soc , 115:9923-9938). These values are obtained as apparent i's and are presented in Table II.

The c±s - trans isomerization of an alanine-proline bond in a model substrate, Ν-succinyl-Ala-Ala-Pro-Phe-p- nitroanilide, is monitored spectrophotometrically in a 7882

32 chymotrypsin-coupled assay, which releases para- nitroanilide from the trans form of the substrate-. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order ra_te constant as a function of inhibitor concentration to yield the apparent Ki values .

In a plastic cuvette are added 950.mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl) , 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml in 1 mM

HC1) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe- para-nitroanilide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol) .

The absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.

The data for these experiments for representative compounds are presented in Table II under the column "Ki".

The neurotrophic effects of the carbamates and ureas used in the methods of the present invention can be demonstrated in cellular biological experiments in vitro, as described below .

Chick Dorsal Root Ganglion Culture* *TL<Λ ffeurite _Outgrowth

Dorsal root ganglia were dissected from chick embryos of ten day gestation . Whale ganglion explants were cultured on thin layer Matrigel -coated ₁₂ well plates with Liebαvitz L15 plus high . glucose media supplemented with 2 mM glutamine and ₁0% fetal calf serum, and also containing 10 μ_M cytosine _β-D arabinofuranoside (Ara C) at 37°C in an environmen_t containing 5% C0₂. Twenty- four hours later, the _DR_Gs were treated with various immunophilin ligands . For_ty- eight hours after drug treatment , the ganglia _were visualize^d under phase contrast or Hoffman _Mo_dulation contrast with a Zeiss Axiovert inver_ted microscope . ^Photomicrographs of the explants were made , and neurite outgrowth was quant itated. Neurites lon_ger than _the D_RG ^diameter were counted as positive , with to_tal number of neurites quantitated per each experimental condition. ^Three to four DRGs are cultured per well , an_d each treatment was performed in duplicate .

The data for these experiments for representa_tive compounds are presented in the "ED50 " column of Ta_ble II . TAS&E I

Examples

1 1 0 2 3 -pyridyl H 2 -methylbutyl H

2 1 0 2 3 -pyridyl E 1 , 1-dimethylpropyl H 1 s 2 3-pyridyl K cyclohexyl H

4 1 0 2 3 -pyridyl H cyclohexyl H

5 1 s : 2 3 -pyridyl K 1 -adamantyl H

TABLE

In Viζro Activitv of Example Compounds

Example Po. Ki.nM. EDSO.πM

1 70 0.065

2 742 1

3 131 0.292

4 1482 n.d.

5 116 0.141 MPTP Mod«7 „* t--_Tfcin_{aon w} -,-.^

The remarkable neurotrophic and neuroregenerative effects of the present inventive compounds were f_urthe. ^'demonstrated in an animal model of neurodegenerative disease^, MPT lesioning of dopaminergic neurons in mice w s used as an animal model of Parkinson's Disease. Four week old male CD1 white mice were dosed i.p. _{with 3Q} g/kg of MPTP for 5 days. Test compounds ₍₄ mg/kg₎ , or vehicle, were administered s.c. along with'-the MPTP for S days, as well as for an additional 5 days following cessation of MPTP treatment. At 18 days following MPTP treatment, the animals were sacrificed and the striata were dissected and perfusion-fixed. Immunostaining was performed on saggital and coronal brain sections using anti-tyrosine hydroxylase 1 g to quantitate survival and recovery of dopaminergic neurons. m animals treated with MPTP and vehicle, a substantial loss of functional dopaminergic terminals was observed as compared to non- lesioned animals. Lesioned animals receiving test compounds showed a significant recovery of TH-stained dopaminergic neurons. Table III presents ςuantitation for the recovery of TH-positive dopaminergic neurons in the striatum of animals receiving compounds _l, ₂, 5 and ^s in this model. 35 TABLE III

In Vivo Activity of Example Compounds Exam^ple No . % Recovery of γy

∑mmnostaininσ, 4 m<τ/ _^ s.c

1 27. 47 2 n.d. 3 56. .13 4 59, .79 5 52, .32

All publications and patents identified above are hereby incorporated by reference. The invention being thus described, it will be obvious that the same may be varied in many ways . Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

WHAT IS CLAIMED IS :

1. A method of effecting a neuronal activity in an animal, comprising : administering to the animal a neurotrophicall_y effective amount of a compound of 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, (Cl-CS) - straight or branched alkyl, (C2-C5) -straight or branched alkenyl or alkynyl, (C5-C7) -cycloalkyl substituted (Cl- CS) -straight or branched alkyl or (C3-CS) -straight or branched alkenyl or alkynyl, (C5-C7) -cycloalkenyl substituted (C1-C5) -straight or branched alkyl - '.C2- C6) -straight or branched alkenyl or alkynyl, Ar- substituted (Cl-CS) -straight or branched alkyl, Ar- substituted (C3-CS) -straight or branched alkenyl or alkynyl; any one of the CH₂ groups of said alkyl chains be optionally replaced by a heteroatom selected f_rom ^ group consisting of 0, s, SO, S0₂, and NR, wherein R selected from the group consisting of hydrogen, ₍ci-_C4) - straight or branched alkyl, ⁽C3-C4) -straight or branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatαm-cαntaining chain to form a ring, and wherein said ring is optionally fused to ah _.Ar group_;

J is selected from the group consisting of hydrogen, ⁽Cl-CS⁾ -straight or branched alkyl, (C3-C6) -straight or branched alkenyl and -CH₂Ar; K is selected from the group consisting of ^(C1-C4⁾ -straight or branched alkyl, -CH₂Ar, and cyclohexylmethyl; or J and may be taken together to form a 5-⁷ membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, _S, SO and S0₂;

Z is 0 or S;

Y is 0 or N, wherein when Y is 0, then , is a lone pair and R₂ is selec^ted from the group consisting of Ar, _(Cl-_CS) - straight or branched alkyl, and (C3-C6) -straight or branched alkenyl or alkynyl; and when Y is N, then R, and R₂ are independently selected from the group consisting of Ar, (C_l-_CS) - straight or branched alkyl, and (C3-C6) -straight or branched alkenyl or alkynyl; or R, and R_{2 arβ} ^ together to form a heterocyclic 5-6 membered ri selected from the group consisting of _PyrroIidiM ^" ⁱmⁱdazolidine, pyrazolidine, piperidine, and piperazine,- Ar is a carbocyclic aromatic group selected from th- group consisting of phenyl, l-naphthyl, 2-naphthyi «denyl. azulenyl, fluorenyl, and anthracenyl_; or a heterocyclic aromatic group selected from the grou_p consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, ₂- PVridyl, 3-pyridyl, 4-pyridyl, pyrro^, _0χazolyi, thiazαlyl, imidazolyl , pyraxolyl , ₂-pyrazolinyl , pyrazαlidinyl, isoxazαlyl, isotriazαlyl, _1#2#3. oxadiazolyl, ¹, 2, 3-triazolyl, 1, 3 , ₄-thiadiazάlyl, pyridazinyl, pyrimidinyl, pyrazinyl, ₁, 3, 5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isαindolyl, 3H- iadolyl, indolinyl, benzo [b] furanyl, benzo _[b_] thio-phenyl, IH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, ₄H- quinolizinyl, quinoiinyl, 1,2, 3 , 4-tetrahydroquinolinyl, isoquinolinyl , i , ₂ , ₃ , 4 -tetrahydroisαquinolinyl , cinnolinyl, phthalazinyl , αuinazolinyl, quinoxalinyl, ¹,8-naphthyridinyl, pteridinyl, carbazolyi, acridinyl _, Phenazinyl, phenothiazinyl, and phenαxazinyl _;

Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, -so₃K, trifluoromethyl, trifluoromethoxy, (C1-C6) -straight or branched alkyl, ⁽C2-C6⁾ -straight or branched alkenyl, ₀- [ ⁽Cl-CS⁾ -straight ro branched alkyl], 0-[(c -C ),_gti. • or branched alkenylI , O-benzyi, O-phenyl, _{l t} z_ methylenedioxy, -NR₃R„ carboxyl, N- (Cl-CS-straight Or branched alkyl or C3-C5-straight or branched alkenyl₎ carboxamides, N,^N-di- ⁽Cl-CS-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholin l, piperidinyl, O-X, CH₂- (CH₂)_q *-χ, ₀- ₍CH,2₎* cj-x*" /

R₃ and R₄ are independently selected from the group consisting of ⁽Cl-CS⁾ -straight αr branched alkyl, ₍C₃- CS⁾ -straight or branched alkenyl, hydrogen and benzyl_; or R₃ and R, can be taken together to form a 5-₆ membered heterocylic 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.

2. The method of claim l, wherein the neuronal activity is selected from the group consisting of stⁱmulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and 8/37882

41 treatment of neurological disorder.

3. The method of claim 2 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

4. The method of claim 3, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

5. The method of claim 1, wherein, in formula I, J and K are taken together to form a 5-7 membered ring.

S. The method of claim 5, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

7. The method of claim 6, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical _i^,

^{* ■L,a}iury Q_j- disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated _th v, _• -c orain

^•damage, and neurological disorder relatinc t neurodegeneration.

⁸. The method of claim 7, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Dⁱsease, and amyotrophic lateral sclerosis.

9. The method of claim S, wherein, in formula I, a_t least one of B and D is independently represented by the forτmxla - ⁽CH₂ ⁾ _c- (X) - (CH₂) _f-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 CH₂, 0, s, SO, S0₂, and NR, wherein R is selected from the group consisting of hydrogen, (C₁-C4₎ - straight or branched alkyl, (C3-C4) -straight or branched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar group.

1⁰. The method of claim 9, wherein the neuronal 98/37882

43 activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

11. The method of claim 10, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused. by physical injury or disease state, physical damage to -the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

12. The method of claim 11, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's

Disease, Parkinson's Disease, and amyotrophic lateral sclerosis .

13. A method of claim 1, wherein, in formula I:

Ar is selected from the group consisting of phenyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl, iso indolyl, quinoiinyl , isoquinolinyl , 1 , 2 , 3 , 4 - t e t r ahydr α i s o quino 1 iny 1 , and 1, 2 , 3 , 4- tetrahydroquinolinyl, wherein said Ar may contain one or more substituents which are independently selected from the g o p consisting of hydrogen, hydroxyl, nit α trifluoromethyl, ⁽Cl-CS⁾ -straight or branched alkyl, O- t ⁽Cl-CS⁾ -straight or branched alkyl], halogen, S0₃H,^'and N^R,; and

*³ and R, are independently selected from the group consisting of ⁽Cl-CS⁾ -straight or branched alkyl, _(C3- «⁾ -straight or branched alkenyl, hydrogen and benzyl_; or *: and R, can be taken together to form a 5-6 membered heterocyclic ring.

1^{4 •} The method of claim 13 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

15. The method of claim 14, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, Physical damage to the spinal cord, stroke associa_ted with brain damage, and neurological disorder relating _to neurodegeneration.

16. The method of claim 15, wherein the neurological disorder relating to neurodegeneration is /3

45 selected from the group consisting of Alzheime_r' s Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

17. A method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula II or III_:

II III

or a pharmaceutically acceptable salt thereof, wherein: Y, Rj_, and R₂ are as defined in claim 1, Ar is as defined in claim 4 and w is 1 or 2.

18. The method of claim 17, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

19 The method of claim 18 , wherein the neurological disorder is selected from _the „. ^uae group consⁱsting of peripheral neuropathy caused by p_hysica injury or disease state, physical damage to the brain^" Physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

20. The method of claim 19, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

21. A method of effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of a compound of formula in or IV_:

III IV

or a harmaceutically acceptable salt thereof , wherein _: Y, R, and R, are as defined in. claim i, ^ _{ig ag} defined in claim 4, ^j _is hydrogen, (Cl-CS) -straight H branched alkyl or ⁽C3-CS⁾ -straight or branched alkenyl, and w is l or 2.

22. The method of claim 21, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

23. The method of claim 22, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, Physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

2⁴. The method of claim 23, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis . AMENDED CLAIMS

[received by the International Bureau on 10 July 1998 ( 10.07.98) ; original claim 1 amended ; remaining claims unchanged (2 pages)] any one of the CH₂ groups of said alkyl chains may be optionally replaced by a heteroatom selected from the group consisting of 0, S , SO , S0₂ , and NR, wherein R is selected from the group consisting of hydrogen, (C1-C4 ) -straight or branched alkyl , (C3 -C4 ) -straight or branched alkenyl or alkynyl , and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom- containing chain to form a ring, and wherein said ring is optionally fused to an Ar group ;

J is selected from the group consisting of hydrogen, (C1-C6) -straight or branched alkyl, (C3-C6)- straight or branched alkenyl and -CH₂Ar; K is selected from the group consisting of (C1-C4) -straight or branched alkyl, -CH₂Ar, and cyclohexylmethyl ; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, S, SO and S0₂ ; Z is 0 or S; Y is 0 or N, wherein when Y is 0, then j_. is a lone pair and R₂ is selected from the group consisting of Ar, (C1-C6)- straight or branched alkyl, and (C3-C6) -straight or branched alkenyl or alkynyl ; and when Y is N, then R_x and R₂ are independently selected from the group consisting of Ar, hydrogen, cyclohexyl, adamantyl, (C1-C6) -straight or branched alkyl, and (C3-C6) -straight or