CA2281096A1 - Method of using neurotrophic carbamates and ureas - Google Patents

Method of using neurotrophic carbamates and ureas

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Publication number
CA2281096A1
CA2281096A1 CA 2281096 CA2281096A CA2281096A1 CA 2281096 A1 CA2281096 A1 CA 2281096A1 CA 2281096 CA2281096 CA 2281096 CA 2281096 A CA2281096 A CA 2281096A CA 2281096 A1 CA2281096 A1 CA 2281096A1
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CA
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Patent type
Prior art keywords
straight
group consisting
selected
c6
c1
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA 2281096
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French (fr)
Inventor
Jia-He Li
Joseph P. Steiner
Gregory S. Hamilton
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GPI NIL Holdings Inc
Original Assignee
Guilford Pharmaceuticals Inc.
Jia-He Li
Joseph P. Steiner
Gregory S. Hamilton
Gpi Nil Holdings, Inc.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

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
SACICGRaUND OF THE INVENTIpN
S 1. ~3,eld of Invention This invention relates to a method of using neurotrophic low molecular we=gat, small molecule carbamates and ureas having an affinity for FKHP-tyre immunophilips, as inhibitors o. the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
2. Descriation of Related As~t The term immunophilin refers to a number of proteins that serve as receptors for the principal immunosuppressant drugs, cyclosporin A (CsA), FK506 and rapamycin. Known classes of immunophilins are cyclophilins and FK506 binding proteins, or FKBPs.
Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKHP12. These immunophilin-drsg complexes interf ace with various intracellular signal transduction systems, especially the immune and nervous systems.
Immunophilins are known to have peptidyi-prolyl isorcterase (PPIase) , or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the interconversion of the cis and traps isomers of peptide and protein substrates SUBSTITUTE SHEET (RULE 26) far the immunophilin proteins.
Immunophilins were original 1 y discovered ar_d studi'd in the immune tissue . It was ____tially postulated ~.v those skilled in the art tha= inhibition of 'he ~mmunophilins~ rotamase activit:r leads to inhib_tion c=
T-cell proliferation, th'=eby causi :c W h_ immunosuppressive ac'ivity ex.hib===d by immurosuncressa .t digs, such as cyclosporin A, =K506 and ranamyci:_.
Further study has shown that the inhibition. of rotamase activity, in and of itself, does not result in immunosuppressive activity. Sc hr~iber et al., Science, 1990, vol. 250, pp. 556-559. Irs~ead, immunosuppressicr.
appears to stem from the formulation of a complex of immunosuppressant drug and immurophilin. It has been shown that immunophilin-d_~-ug complexes interact with ternary protein targets as their mode of action.
Schr eiber et al., Cell, 1991, vo_. 66, pp. 807-815. In the case of FF~P-FK506 anc cyclophilin-CsA, the immunophilin-drug complexes bind to the enzyme calcineurin and inhibit the T-cell receptor signallins which leads to T-cell proliferation. Similarly, the immunophilin-drug complex of FsGF-rapamycin interacts with the RAFT1/FRA.p pzotein and inhibits the IL-2 receptor signalling.
Immunophilins have been found to be present at high concentrations in the central nervous system.
SUBSTITUTE SHEET (RULE 26) Immunophilins are enriched IO-~0 times more in the ceatral nervous system than in the immune system. within neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release and neuronal process extension.
Su~risingly, it has been found that certain low molecules= weight, small molecule carbamates and ureas with a higr. affinity for F~iPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects.
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 IS that neurodegenerative disorders such as Alzheimer~s disease, Parkinson's disease, ar_d amyotrophic lateral sclerosis (ALS) may occsr due to the loss, cr decreased availabil ity, of a neurotrophic substance specific for a particular population of neurons affected in the disorder.
Several neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer~s disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat SDAT patients with exogenous nerve growth factor SU6STiTUTE SHEET (RULE 26) or other neurotrophic proteins, such as brain derived growth factor, filial derived growth factor, cilia;-~y neurotrophic factor and neurotropin-3, to increase the survival of degenerating neuror_al populations.
Clinical application ef these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressara drugs with neurotrophic activity are relatively small and ZO display excellent bioavailability and specificity.
However, when administered c:.ror_ically, immunosuppressart drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular .filtration and irreversible interstitial 15 fibrosis (Kopp et al . , J. Am. Soc. Nephrol . , 1991, ?:162); neurological deficits, such as involu.-~tary tremors, or non-specific cerebral angina, such as_ r_or-localized headaches (De Groen et al., N. Erzgl. J. Med., 198'1, 317:861) ; and vascular hypertension with 20 complications resulting therefrom (Kahan et al . , N. Engl.
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 z5 compound containing low molecular weight, small molecul=
carbamates and ureas to enhance neur ite outgrowth, and to SUBSTITUTE SHEET (RULE 26) promote neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: peripheral nerve damage caused bY phys_cal injurlr or disease state such as diabetes;
physical damage to the central nervous system (spinal cord and brain) ; brain damage associated with stroke; and neurological disorders relating to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease?, and amyotrophic lateral sclerosis.
Y OF THEFT Tnar The present invention relates to a method of using a neurotrophic low molecular weight, small molecule carbamates and ureas having an affinity for FF03P-type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunaphilin proteins, particularly pep tidyl-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 neurotrophically effective amount of a compound of formula I:
SUBSTITUTE SHEET (RULE 26) v I
Ra or a pharmaceutically acceptable salt thereof, where=a:
A is CH=, oxygen, NH or N- ( CI -C4 alkyl ) ;
B and D are independently Ar, hydrogen, (CI-C6)-straight or branched alkyl, (C2-C5)-straight or branched alkenyl or alkynyl, (CS-C'7)-cycloalkyl substituted (CZ-C6)-straight or branched alkyl or (C3-C6)-straight or branched alkenyl or alkynyl, (CS-C7)-cycloalkenyl ZS substituted (C1-C6)-straight or branched alkyl or (C3-C6)-straight or branched alkenyl yr alkynyl, substituted (C1-CS)-straight or branched alkyl, Ar-substituted (C3-Co')-straight or branched alkenyl or alkynyl;
any one of the CHI groups of said alkyl chains may be optionally replaced by a hetercatom selected from the group consisting of O, S, S0, SO~, and NR, wherein R is selected from the group consisting of hydrogen, (CZ-C4)-straight or branched alkyl, (C3-C4) -straight or branched alkenyl or alkynyl, and (CI-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom SUBSTITUTE SHEET (RULE 26) of said heteroatom-containing chain to form a ring, d wherein said ring is optionally fused to an Ar~gz.oup;
J is selected from the group consisting of hydrogen, (Cl-Cfi)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl and -CHZAr; Ft is selected from the group consisting of (Cl-Ca) -straight cr branched alkyl, _~
and cyclohexylmethyl; or J and ~ may be taken together to f°~ a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of 0, S, I 0 SO and SOI ;
Z is O or S ;
Y is O or N, wherein when Y is O, then R~ is a lone pair and Rz is selected from the group consisting of Ar, (Cl-C6)-IS straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; and when Y is N, then R1 and Rz are independently selected from the group consisting of Ar, (C1-C6)-straight or branched alkyl, and (C3-C5)-straight or 20 branched alkenyl or alkynyl; or RL and R= are taken together to form a heterocyclic 5-6 membered r~nc selected from the group consisting of pyrrolid_ne, imidazolidine, pyrazolidine, piperidiae, and piperazine;
Ar is a carbocyclic aromatic group selected from the ZS group consisting of phenyl, i-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a SUBSTITUTE SHEET (RULE 26) heterocyclic aromatic group selected from the groin consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, z_ PYz'idyl , 3 -pyridyl , 4 -pyridyl , PYz'r'olyl , oxazoiyl , thiazolyl, imidazolyl, pyraxolyl, 2-pyrazoliny?, FYrazolidinyl, isoxazolyl, isotriazolyl, Z,Z~3-oxadiazolyl, I,2,3-triazolyl, 1,3,4-thiadiazoiy_, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, indolyl, indolinyl, benzo [bl furanyl, benzo [b] thio-phenyl, i0 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, ~~_ quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl;
1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, i5 phenazinyl, phenothiazinyl, and phenoxazinyl;
Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, vitro, -g0~~r, trifluoromethyl, trifluoromethoxy, (CI-C6)-straight or 20 branched alkyl, (C2-C6)-straight or branched alkenyl, 0-[ (CI-C6) -straight ro branched alkyl) , O- [ (C?-C4) -r_traict or branched alkenyl] , O-beazyl, 0-phenyl., 1, ;.-methylenedioxy, -NR,R" carboxyl, N-(Cl-CS-straight or branched alkyl or C3-C5-straight or branched alkeayl) 25 carboxamides , N, N-di - ( C1-CS -straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, SUHSTiTUTE SHEET (RULE 26) morpholinyl, piperidinyl, 0-X, CF~~z_ (CHI) Q-X, 0- (CFi~) Q_g, ~~_) q-o-X, and CH=C.K_X;
Rl and R, are independently selected from the group consisting of (CI-C6) -straight or branched alkyl, (C3-C6) -straight or branched alkenyl, hydrogen and benzyl;--or ~d R, can be taken together to form a 5-6 membered heterocylic ring;
X is selected from the group cons~.sting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, IO quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2_ methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, ~d pyrimidyl;
q is 0-2; and n is 0 or 1.
15 The present invention also 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 II or III:
i O 'T~ O
x. ~~
~~As O~Y ~ RZ
~i ) . \Y/~O
A=
t l II III
or a pharmaceutically acceptable salt thereof, wherein:
SUBSTITUTE SHEET (RULE 26) Y, Rz and Rz are as defined in claim i, Ar is as defined in claim 4 and w is Z or 2.
The present invention further relates to a method of effecting a neuronal activity ir. ar_ animal, comprisinc:
administering to the animal a neurotrophical~?y effective amount of a compound of formula III or IV:

J\' a~Ar R
Rl v 'o ~a~Ar R~
III IV
or a pharmaceutically acceptable salt thereof, wherein:
ZS Y, R1 and R= are as defined in claim Z, Ar is as defined in claim 4, J is hydroger_, (CI-C5)-straight or branched alkyl or (C3-C6>-straight or branched alkenyl, and w is 1 or 2.
DETAILED DESCRIPTT N OF THE INVENT ON
Detiaitioas "Alkyl" means a branched or uabrancned saturated hY~ocarbon chain containing 1. to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, a-pentyl, n-hexyl, and the like, unless otherwise indicated.
SU9ST1TUTE SHEET (RULE 26) "FTalo~~ means fluoro, chloro, bromo, or iodo, ,~
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 sal is can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochloride hydrobromide, hYdroiodide, 2-hydroxyethanesulfonate, lactate, maleate, IS methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Hase 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 SUBSTITUTE SHEET (RULE 26) WO 98/37882 ~ PCT/US98/03485 chain halides such as decyl, lau=-yl, myristyl ~d Stea z'yl chlorides, bromides and iodides, aralkyl halides 1~~0 Z c_ benzyl and phenethyl bromides and others. Water or o;i soluble or dispersible products are thereby obtained "Phenyl" includes all possible isomeric he p r~yl radicals, optionally monosubsti~uted or mufti-substituted with substituents selected from the group consistir_g of alkyl, alkoxy, hydroxy, halo, and haloalkyl.
"Treatment ~~ covers any treatment of a disease and/or 1~ condition in an animal, particularly a human, ~d includes:
(i~ preventing a disease and/or condition from occurring in a subject which may be predisposed to the disease and/or condition but has not yet been diagnosed IS as having it;
(ii? inhibiting the disease and/or condition, i.e., arresting its development; and ( iii? relieving the disease and/or condition, i . a . , causing regression of the disease and/or condition.
2o The inventors have discovered that certain low molecular weight, small molecule carbamates and areas have an affinity for Fop-type i~~op~lins, particularly FI~pl2, When the carbamates and areas are bound to an Fig-type i~~ophilin, they have been fouad 25 to inhibit the prolyl-peptidyl cis-tracts isomerase activity, or rotamase, activity of the binding protein SUBSTtTUTE SHEET (RULE 26) ~d unexpectedly stimulate neurite growth. This activit Y
is useful, in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of several neurological disorders- lalown 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 ~imal. comprising:
IO administering to the animal a neurotrophically effective amount of a compound of formula I:
J
ZS
I
or a pharmaceutically acceptable salt thereof, wherein:
A is cD:IZ, oxygen, NH or N- (CI-C4 alkyl) ;
H and D are independently Ar, hydrogen, (Ci-C6)-straight or branched alkyl, (C2-C6)-straight yr branched alkenyl or a~lkynyl, (CS-C7)-cycloalkyl substituted (C1-C6 ) -straight or branched alkyl or ( C3 -C6 ) -straight or ZS branched alkenyl or alkynyl, (CS=C7)-cycloalkenyl substituted (C1-C6) -straight or branched alkyl or (C3-SUBSTITUTE SHEET (RULE 2fi) Z'i ~Y RI
Rz C6)-straight or branched alkenyl or aryl, substituted (C1-C6)-straight or branched alkyl, substituted (C3-C6)-straight or branched alkenyl or alkynyl;
any one of the CHz groups of said alkyl chains may be optionally replaced by a heteroatom selected from the group consisting of 0, S, SO, SOZ, and NR, wherein R is selected from the group consisting of hydrogen, (C1-C4)-straight or branched alkyl , ( C3 -Ca ) -straight or branched la alkenyl or alkynyl, and (Cl-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, azd wherein said ring is optionally fused to an Ar group;
J is selected from the group consisting of hydrogen, 15 (Cl-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyi and -CFiZAr; K is selected from the group consisting of (Cl-C4) -straight or branched alkyl, -CF~~Ar, and cyclohexylmethyl ; or J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain 2o a heteroatom selected from the group consisting of 0, S, SO and S0~ ;
Z is 0 or S ;
Y is 0 or N, wherein when Y is 0, then R1 is a lone pair and R= is ZS selected from the group consisting of Ar, (Cl-C6) straight or branched alkyl, and (C3-C6)-straight or SUBSTITUTE SHEET (RULE 26) IS
branched alkenyl or alkynyl; and when Y is N, then R: and AZ are independentl Y
selected from the group consisting of Ar, (C1-C5 )_ straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or al ,-~Yl: o_ R: and Rz are taken together to form a heterocyclic 5-6 membered rinc selected from the group consis~ing of pyrrolidine, imidazolidine, pyrazolidine, piperidine,.and piperazine~
Ar is a carbocyclic aromatic group selected from the group consisting of phenyl, i-naphthyl, 2-naphth 1 Y, 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, pyrrol 1 Y . oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, PYrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3 oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyi, PYridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 13,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H
indolyl, indolinyl, benzo [bt furanyl, benzo [b~ thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, i,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 2$ i,8-aaphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, .phenothiazinyl, and phenoxazinyl;
SUESTtTUTE SHEET (RULE 26) Ar may contain one or more substituents which a=a independently selected from the c~-roup consistinc of hydrogen, halogen, hydroxyl, nitro, -SC.,., trifluoromethyl, trifluoromethoxy, (CI'-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, 0-[ ( CI-C6 ) -straight ro branched alkyl j , O- [ ( C3 -C4 ) - straight or branched alkenylj, 0-benzyl, 0-phenyl, I,2_ methylenedioxy, -NR,R" carboxyl, N-(C1-CS-straight or branched alkyl or C3-C5-straight or branched alkenyl) ZO carboxamides, N,N-di-(CI-C5-straight or branched alkyl or C3-CS-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl,, 0-X, C_-i~- (C~~) 4-X, 0- (~~) q-g~
(CHl) Q-O-X, and CH=CH-X;
R~ and R, are independently selected from the group i5 consisting of (CI-C6)-straight or branched alkyl, (C3 C6 ) -straight or branched alkenyl , hydr ogee and benzyl ; or R, and R, can be taken together to form a 5-6 membered heterocylic ring;
X is selected from the group consisting of 4 20 methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinoiyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2 methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl;
q is 0-2; and 25 n is 0 or I.
SUBSTITUTE SHEET (RULE 26) In a preferred embodiment, J and K are taken togetrer to form a 5-7 membered ring.
In another preferred emboci.ment, at least one of H
and D is independently represented by the formula (~_) _- (X) - (CF~z),-A.r, wherein:
r is 1-4;
S ZS Q-1;
Ar is as defined in claim 1; and each X is independently selected from the group i0 consisting of CHZ, 0, S, S0, SO=, and NR, wherein R is selected from the group consistir_g of hydrogen, (CI-C4) straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, and (C1-Ca) bridging alkyl wherein a bridge is formed between the nitrogen atom and the Ar 15 group. .
In an additional preferred embodiment, Ar is selected from the group consisting of phenyl, 2-pyridyl, 3-pYz':.dyl, 4-pyridyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 20 1,2,3,4-tetrahydroquinolinyl, wherein said Ar may contain one or mare substituents which are independently s~Iected from the group consisting of hydrcger., hydroxyl, vitro, trifluoromethyl, (CZ-C6)-straight or branched alkyl, 0 f (CI-C6) -straight or branched alkyl] , halogen, SO,Fi, and 2 5 NRI R. ; and SUBSTITUTE SHEET (RULE 26) Rl and R, are independently selected from the group consisting of (CI-C6)-strai ht or branched al '1 ~ ( C3 -C6 ) -straight or branched alkenyl , hydrogen and benzyl ~ or R~ ~d R, can be taken together to form a 5_6 membPr'd heterecyclic ring.
The present invention also relates to a method oL
effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of a compound of formula II or III.
ld Ar ~'~ ,r\,r o ~o y Ri\
y~a At IS
II
III
or a pharmaceutically acceptable salt thereof, wherein:
Y. Rz and Rz are as defined in claim 1, Ar is as 2o defined in claim 4 and w is l 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:
SUESTiTUTE SHEET (RULE 26) ~T
J
Rl\ ~ ~ ~ W0~?~t R~\, 0 ~ I o c~Ar Ri III
IV
or a pharmaceutically acceptable salt thereof, where~:.
_Z.
RI and Rs are as defined in claim Z, Az. is as Zo defined in claim 4, J is hydrogen, (Ci-C6 -straight or branched alkyl or (C3-C6)-straight or branched alke nyl, and w is 1 or 2.
The neuronal activity that is effected by the methods of the present invention may be selected from t he i5 group consisting of: stimulation of damn ged neurons, Promotion of neuronal regeneration, prevention oL
neurodegeneration and treatment of a neurological disorder.
Examples of a neurological disorder that is 20 treatable by the methods of the present invention ' include without limitation: trigeminal neural is g , glossopharyngeal neuralgia; gell~s palsy; myasthenia 3x'avis; muscular dystrophy; amyotrophic lateral sclerosis; pro~essive muscular atrophy; progressive 25 bulbar inherited muscular atrophy; herniated, ~ t ,.
P cared ai Prolapsed invertebrate disk syndromes; cervical SUBSTITUTE SHEET (RULE 26) ZO
spondylosis; plexus disorders; thoracic outlet destruction syndromes; peripheral neuropathies such as those caused by lead, dapsone, t=cks, porphyria, o=
Guillain-Harm syndrome; Alzheimer's 'isease;
Parkinson's disease.
The methods of the prose=t invention a=' Pa=ticslarly useful for treating a neurological disorder selected from the group consist=ng of: peripheral neuropathy caused by physical injury or disease state, 1Q physical damage to the brain, physical damage to the spinal cord, stroke associated wits brain damage, and a neurological disorder relating to neurodegeneration.
Examples of a neurological disorder relating to neuradegeneration include Alzheimer's Disease, ZS Parkinson's Disease, and amyotrop~~ic lateral sclerosis.
In the methods of the p resent invention, the neurotrophic compound may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted 2~ reservoir in dosage fozznulations containing conventional non-toxic pharmaceutically-acceptable cart iers , ad; ;;:rants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally, intrathecally, intraventricularly, 25 intrasternal and intracranial injection or infusion techniques.
SUBSTITUTE SHEET (RULE 26) To be effective therapeutically as central nervous system targets, the neurotrophic compounds should readily penetrate the blood-brain bar=ier when peripherally administered. Coctroounds which ca.-inot penetrate the Mood-brain barrier can be effect_vely administers dbyan ntraventricular route.
The neurotrophic compounds may also be administered in the forth of sterile injectable preparations, for example, as sterile injectable aaueous or .oleaginous suspensions. These suspensions may be formulated according to technicues 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-toxic parenterally-acceptable diluents or solvents, for example, as solutions in 1,3-bucanediol. 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. Far this purpose, any bland fixed oiI such as a synthetic mono- or di-glyceride may be employed. Fatcy acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables. These oil solutions yr suspensions may SUBSTITUTE SHEET (RULE 26) also contain long-chain alcohol diluents or dispe=g~ts.
Additionally, the neurotrophic compounds ma,y be administered orally in the fo=-,z of capsules, tablet aqueous suspensions or solutions. Tablets may contair_ cart-iers such as lactose and corn starch, and/or lubricating agents such as macr._esium stearate . Capsules may contain diluents including lactose and dried coz-n starch. Aqueous suspensions may contain emulsifying arsd 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 fo_" of suppositories.
These compositions can be prepared by mixing the drug 1S with a suitable non-irritating excipient which is solid at room temperature, but liquid at rectal temperature and, therefore, will melt in the =ectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
Moreover, the neurotrophic compounds may be administered topically, especially whey. the cor_ditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin, or the Lower 25 intestinal tract. Suitable topical formulations can be readily prepared for each of these areas.
SUt3STtTUTE SHEET (RULE 26) 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 ir_ isotonic, pH adjusted sterile saline, either with o~ 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 ZO 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 Z5 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, polysorbate 6C1, cetyl ester wax, 20 cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Topical application to the lower intestinal tract can be effected in a rectal suppository foz~ulations (see above? or in suitable enema formulations.
25 Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in SUBSTITUTE SHEET (RULE 26) the treatment of the above coed=tions, with preferred levels of about 0.1 mg to about 1,000 mg. The amount of active ingredient that may be combined with the carri'r materials to produce a single dosage form will vary depending upon the host treatec and the particular mede of administration.
It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the rate of excretion; drug combination;
the severity of the particular disease being treated; and the form of administration.
The compounds can be adm_nistered with other neurotrophic agents such as neurotrophic growth factor tNGF), filial derived growth factor, brain derived growth factor, ciliary neurotrophic factor, and neurotrepin-3.
The dosage level of other neurotrophic drugs will deaend upon the factors previously stated and the neurotrophic effectiveness of the drug combination.
ALES
The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise specified, all percentages are SUBSTITUTE SHEET (RULE 26) based on i00i by weight of the final compound.
The compounds used in the methods of the present invention may be readily prepared by standard techni~es of organic chectristry, 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 ROF~
to generate esters 2. After removal of .the protecting group, the free amine 3 may be reacted with.a variety of Zo isocyanates or isothiocyanates to provide the. final ureas or thioureas, respectively. Alternatively, reaction of i with amines provides the corresponding amide compounds .
~: ) m ~:gym ox R-ox -.---~ o--a w0liaq t~uetioa --..

~t~ m G'i=) m ' Ri-N-C.Z
0-R --.:.~. ,0-R
CHiCh Z
H 4 N~ O
Ri Isocyanates (R1NC0) or isothiocyanates (RINGS) 4 may be conveniently prepared from the corresponding readily SUSST1TUTE SHEET (RULE 26) S
available amines by reaction with phosgene o r thiophosgene, as depicted in Scheme rI, Scheme II
Z
N~12 +
C1 ~~1 R1 NCZ

-, ,_ ~- i cz--~ -carboy i ate ( Z ) 3-( -o~~-;d~i ) _Z_prowt a V ~ r-ssrt L. , y r.
~. S c3~r1 ) DYZ' O ~ ;
d~ ne 2 car~,r"~,i ~..
A mixture of N- ( tert-butyloxycarbonyl ) - ( S ) -pro 1 ine (3.0 g; 13.9 mmol) ; 3-(3-P rid i Y Y-)-Z-propanol (2.90 g;
20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.2a mmol), camphorsulfonic acid (I.08 g; 4.63 mmol), and a_ dimethylaminopyridine (a_6o ~. " ~., _ _.
- l methylene chloride (100 mL) was stirred overnigh . The reaction mixture was diluted with methylene chloride (50 and water (i00 mL), and the layers were separated.
The organic phase was washed With water (3 x 100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting SUBSTITUTE SHEET (RULE 26) with ethyl acetate to obtain 4.60 g (g5i) of the est er as a thick oil, 1H Nl~t (300 MHz, CDCl~) : b 1.45 (s; gH
):
1.70-2.05 (m, SH) ; 2.32 (m, ZH) ; 2.7i (t, 2H) ; 3.50 (m, 2H), 4.~~ (m, ZH); 4.I8 (m, Wi; 7.24 (m 1H); 7.51 (m IH) ; 8 .48 (m, 2H) .
J-'j-DVririvl -~_prODVT
DVr Oliriino -, .a c - L -CarbOXVl a f-ra ---A solution of 3 - (3 -pyridyl ) -1-propyl (~2S) -N- ( tert-I0 butylo~,carbonyl)pyrrolidine-2-carboxylate (3.00 g; 9 Col) 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 ZS methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 2.00 g (95%) of the free amine as a thi ck oil , LH NCR ( 3 0 0 l~z , CDC1, ) : b 1.87-2.20 (m, 6H); 2.79 (m, 2H); 3.03 (m, 2H total); 3.07 (m, 2H) ; 3.84 (m., IH) ; 4.24 (m, 2H ) ; 7.32 (m, 1H) ; ''.60 20 (m, 1H) ; 8 .57 (m, ZH) .
~- t ~ -D i d T ) ~ DrODYl t ~) _ 1 ~ f 7 ~e~ t- Lu carbamoVZ 1 ny~olidTne-~_carbo~ r~ a~ (Z) A solution of 2-methylbutylamine (I13 mg; 1..3 mmol) 25 and triethylamine (132 mg; 1.3 mmol) in methylene chloride (5 mL) was added to a solution of triphosgene SUBSTITUTE SHEET (EiULE 26) (128 mg; 0.43 mmol) in methylene chloride (S mL). The resulting mixture was refluxed for 1 hour and then cooled to room temperature . 3 - ( 3 -Pyr idyl ) -- 1.-propyl ( 2S) -pyrrolidine-2-carboxylate (300 mg; 1.3 mmol) in 5 ~ o_ S 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~c ethyl acetate/hexane) to obtain 250 mg (55~c) of the compound of Example 1 (1, Table I) as an oil, 1H Nl~t (CDCi" 300 I~iz) : b 0.89-0.93 (m, 6H) ; 1.10-1.20 (m, IH) ; 1.27 (s, 1H) ; 1.36-1.60 (cn, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H);
2. 9Z-3 .54 (m, 4H) ; 4.16-4.20 (dt, 2H) ; 4.45-4.47 (m, 2H) ;
I5 7.2I-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 8.46-8.48 (s, 2H).
Anal. Calcd. for C19H~9N,0~ - 0.5 HzO: C, 64.02; H, 8.48;
N~ 11.79. Found: C, 63.72; H, 8.42; N, 11.83.
E~A1~LE 2 ~atheais of 3- (3-vvridvl) -1-vrovvl (2S) 1 C (1' 1' dimethvTnrowl)carbamovllvvrrolidiae 2 carboxv~ate 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, LH NIA (CDC1" 300 l~iz) : b 0.83 (t, 3H) ; 1.27 (s, SUSST1TUTE SHEET (RULE 26) 6H); 1.64-1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t 2H); 3.29-3.42 (m, 2H); 4.27.-4.15 (t, 3H); 4.37-4.
41 (m, 1H) . Anal. Calcd. for ClyHx9Ny - 0 .5 HBO: C, 64.04 F~ , 8.48; N, 11.79. Found: C, 64.23; H, 8.31; N, 11.30.
S
ExAMPLE 3 thesis of 3- (3-pvridvl) 1 eranvT r~e~ , -y-1 (cvclohexvl) thiocarbamovll ovrrolidiae 2 carbo ~, late (3 ) A mixture of cyclohexylisothiocyanate (120 mg; 0,9 mmol), 3-(3-pyridyl)-1-propyl (2 S)-pyrrolidine-2 carboxylate (200 mg; 0.9 mmol) triethylamine (90 mg; 0,g 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 nrcrnr,; r. .,t,-__ _ __ dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) 160mg (47%) of to obtain the compound of Example 3 (3, Table T) 1H NMR (CDCl~, , 300 l~iz) : b1.16-1.40 (m, 6H) ; 1.50-..71(m,4H) ; 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.40-3.60 (m,ZH); 4.17-4.26 (m, 2H) ; 4.95-4.9.8 (d, 1F~) ; 5.26-5.29(d,1H) ; 7.17-7.25 (m, 1H) . Anal . Calcd. for C~pH=9N7~2SC, 63 . S7; fi, : . 78 ;

N. 11.19. Found: C, 63.25; H, 7.80;N, 11.07.

Synthesis of 3-(3-wridvl) 1 oronvl (2S) I
(( (evclohexvl) carbaiaovl7 avrrolidiae 2 carbo~~ late (4) SUBSTITUTE SHEET (RULE 26) A mixture of cyclohexylisocyanate (i0o mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrralidine-2-carboxylate (200 mg; 0.9 mmol) a-nd triethylamine (90 mg;
0.9 moral) in 20 mL of methylene chloride was stirred for 5 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 (36%) of the compound of Example 4 (4, Table I) , 1H
10 NMR (CDC1" 300 MHz): b i.10-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m, 4H); 2.67-2.73 (t, 2H); 3.31-3.44 (m, 3H); 4.12-4.16 (m, 2H); 4.39-4.42 (m, IH); 7.25-7.34 (m,.
1H); 7.25-7.55 (dd, 1H); 8.45 (s, 2H). Anal. Calcd. for CxoHisN~O~ - 0 . 6 H=O : C, 64 . 86 ; H, 8 . 22 ; N, 11. 35.. Found I5 C, 64.60; H, 8.18; N, 11.21.
EXAb~LE 5 ~vnthesis of 3- (3-cvridyl) 1 vrowl (ZS) 1 (1 tvl)thiocarbamovll pvrrolidine Z Garb ~ late (5) 20 A mixture of 1-adamantyiisocyanate (250 mg; 0.9 mmol) , 3~3-pyridyl) -I-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 25 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column SUBSTITUTE SHEET (RULE 26) chromatography (50~ ethyl acetate/hexane) to obtain I50 mJ (38~c) of the compound of Example 4 (4, Table I) , :H
(CDCl" 300 hBiz) : b 1.39-1.44 (d, 2H) ; 1.65 (s, 4H) ;
1.95-2.07 (m, 8H); 2.07-2.20 (m, SH); 2.71-2.76 (m, 2H);
3.37-3.45 (m, 1H); 3.50-3.60 (m, 1H); 4.09-4.18 (m, ZH);
4.99-5.21 (d, 1H) ; 7.21-7.25 (m, 1H) . Anal.. Calcd. for WHmNIyS - 0.4 HBO: C, 66.30; E., 7.84; N, 9.66. Found:
C, 66.41; H, ?.79; N, 9.50.
A.s discussed above, the carbamates and ureas used in the methods of the present invention have an affinity for the FK506 binding protein, particularly FKHPI2. The inhibition of the prolyl peptidyl cis-tracts isomerase activity of FKHP may be measured as an indicator of this affinity.
~~. Test procedur.
Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the inventive compounds can be evaluated by known methods described in the literature (Handing, et al., Nature, 1989, 341:758-760; Holt et 21.
Chew. Soc., 115:9923-9938). These values are obtained as apparent Ki's and are presented in Table II.
The cis-tracts isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a SUBSTITUTE SHEET (RULE 26) chymot=-yosin-coupled assn Y. which releases P a nitroanilide from the traps fo=:a of the substrate. The inhibition of this reaction caused by the addition °=
dzfferert concentrations of in:~=b'_tor is determined, and the data is analyzed as a chaag2 in first-order rac~
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 KEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in ZO mM Tris-C1 pK 7.5, 100 mM NaCl, 1 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-A1a-phe-Pro-Phe-para-nitroanilide, S 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 represPnt~.tive compounds are presented in Table II under the column nK~n.
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, SUBSTITUTE SHEET (RULE 26) as described below.

thick Dorsal Rcat c~~w.., s vu Cu tares and Neu; ~ ha ~~
Dorsal root ganglia were dissected from ch~
_c.c e~ryos of ten day gestation. Whole ganglion expl~ts were cultured on thin layer Matrigel-coated 12 well plates with Liebovitz L15 plus high .glucose media supplemented with 2 mM glutamine and 10,~ fetal calf serum, and also containing 10 ~M cytosine B-D
ara.binofuranoside tAra C) at 37~C in an environment containing 5's COl. Twenty-four hours later, the DRGs were treated with various immunophilin Iigands. Forty-eight hours after drug treatment, the ganglia were visualized under phase contrast or Hoffman Modulation contrast with a Zeiss Axiovert inverted microscope.
Photomicrographs of the explants were made, and neurite outgrowth was quantitated. Neurites longer than the DRG
diameter were counted as positive, with total number of neurites quantitated per each experimental condition.
Three to four DRGs are cultured per well, and each treatment was performed in duplicate.
The data for these experiments for representative compounds are presented in the '~ED50 ~~ column of Table II.
SUBSTITUTE SHEET (RULE 26) TABLE I
Examples ( CH2 ) m D
n 'B
~N R1 T~, n ~ ~ Q H_ $i 1 1 ~ 2 3-pyridyl a 2-methylbutyl g 2 i 2 3-pyridyl r 1,1-dimeth 1 ro a ~
Y P PY-_ 1 S 2 3-PYridYl ~ cyclohexyl 4 1 ~ 2 3-PYridyl F. cyclohexyl g I5 5 1 S 2 3-pyridyl F. 1-adamantyl g TAH~LE
Ii Vit ro i vi ry ExamnTA rim".".
X~m ~la No Ac of ED50 , r~M
Ki-aM

1 ~0 0.065 I3I 0.292 1482 a.d.

116 0.141 SU6STtTUTE SHEET {RULE 26) MPTP Model of Pa~-k~ aeon ~ . rs a The remarkable neurotrophic and neuroregenerative effects of the present inventive compounds were fort .-he_ demonstrated in an animal model of neurodegenerat' zve disease. MPTP Iesioning of dopaminergic neurons in mice was used as an animal model of Par.'tinson' s Disease . Four week old male CDi white mice we_~ dosed i:p. with 3~
mg~kg of MPTP for 5 days. Test compounds.(4 mg~kg~~ or vehicle, were administered s.c. along with'~the MPTP for Z~ 5 days, as well as for an additional 5 days followin g cessatZOn of MPTP treatment. At i8 days following MPTP
treatment, the animals were sacrificed and the striates were dissected and perfusion-fixed. Immunostaining was performed on saggital and coronal brain sections using 15 anti-tyrosine hydroxylase 1 g to auantitate survival and recovery of dopaminergic neurons. In animals treated with MFTP and vehicle, a substantial loss of functional dopaminergic terminals was observed as compared to non lesioned animals. Lesioned ar_imals receiving test 2~ compounds showed a si gnificant recovezy of TH_stained dopaminergic neurons. Table I:I presert~ cuantitatior.
for the recovery of TH_positive dopaminergic neurons is the striatum of animals receiving compounds 1, 2, 5 and 6 in this model.
SUBSTITUTE SHEET (RULE 26) TABLE IT_I
Ir~Vi.vo Activity of ExartroT a Comno ,nr~~
Exam~Ia Vo ~overv TmmL_~_ostai nines. a ~,~. ~,__ V / (~( I
27.47 r. . d .
56.13 59.79 1D 5 52.32 All publications and patents identified above are hereby incozporated by reference.
ZS 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 modif icatioas are intended to be included within the 2a scope of the following claims.
SUBSTITUTE SHEET {RULE 26)

Claims (24)

1. 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);
H and D are independently Ar, hydrogen, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl or (C3-C6)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkenyl substituted (C1-C6) -straight or branched alkyl or (C3-C6)-straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6)-straight or branched alkyl, Ar-substituted (C3-C6)-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 O, S, SO, SO2, 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-C5)-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 O, S, SO and SO2;
Z is O or S;
Y is O or N, wherein when Y is O, then R1 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 R1 and R2 are independently selected from the group consisting of Ar, hydrogen, 38a cyclohexyl, adamantyl, (C1-C6)-straight or branched alkyl, and (C3-C6)-straight or branched alkenyl or alkynyl; or R1 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, pyraxolyl, 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, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b) thio-phenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl;
Ar may contain one or more substituents which are independently selected from the group consisting of hudrogen, halogen, hydroxyl, nitro, -SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O-[(C1-C6)-straight ro branched alkyl] , O-[(C3-C4)-straight or branched alkenyl], O-benzyl, O-phenyl, 1-2-methylenedioxy, -NR1R4, carboxyl, N-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, N,N-di-(C1-C5-straight or branched alkyl or C3-C5-straight or branched alkenyl) carboxamides, morpholinyl, piperidinyl , O-X, CH2-(CH2)q-X, O-(CH2)q-X, (CH2)q-O-X, and CH=CH-X;
R3 and R4 are independently selected from the group consisting of (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl, hydrogen and benzyl; or R1 and R4 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 1, 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.
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.
6. 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 injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurelogical disorder relating to neurodegeration.
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 5, wherein, in formula I, at least one of B and D is independently represented by the formula -(CH) r- (X) - (CH2) s-Ar, wherein:
r is 1-4;
s is 0-1;
Ar is as deffined in claim 1; and each X is independently selected from the group consisting of CH2, O, S, SO, SO2, 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 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, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein said Ar may contain one or more substituents which are independently selected from the group consisting of hydrogen, hydroxyl, nitro, trifluoromethyl, (C1-C6) -straight or branched alkyl, O-[(C1-C6) -straight or branched alkyl) , halogen, SO3H, and NR3R4; and R3 and R4 are independently selected from the group consisting of (C1-C6)-straight or branched alkyl, (C3-C6) -straight or branched alkenyl, hydrogen and benzyl; or R3 and R4 can be taken together to form a 5-6 membered heterocyclic ring.
14. 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 associated with brain damage, and neurological disorder relating to neurodegeneration.
16. The method of claim 15, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer'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:
or a pharmaceutically acceptable salt thereof, wherein:
Y, R1 and R2 are as defined in claim 1, Ar is as defined in claim 4 and w is 1 or 2.
18. The method of claim 17, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion or neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.
19. The method of claim 18, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the 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 III or IV:
or a pharmaceutically acceptable salt thereof, wherein:

Y, R1 and R2 are as defined in claim 1, Ar is as defined in claim 4, J is hydrogen, (C1-C6) -straight or branched alkyl or (C3-C6) -straight or branched alkenyl, and w is 1 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.
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US6395758B1 (en) * 1998-08-14 2002-05-28 Gpi Nil Holdings, Inc. Small molecule carbamates or ureas for vision and memory disorders
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CA2383086A1 (en) * 1999-09-08 2001-03-15 Joseph P. Steiner Non-peptidic cyclophilin binding compounds and their use
CA2389368A1 (en) 1999-12-01 2001-06-07 Agouron Pharmaceuticals, Inc. Compounds, compositions, and methods for stimulating neuronal growth and elongation
CA2430409A1 (en) * 2000-11-28 2002-06-06 Guilford Pharmaceuticals Inc. Bisubstituted carbocyclic cyclophilin binding compounds and their use
CA2435829A1 (en) * 2001-01-25 2002-08-01 Guilford Pharmaceuticals Inc. Trisubstituted carbocyclic cyclophilin binding compounds and their use
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