ZA200205933B - Piperazine and piperidine derivatives. - Google Patents
Piperazine and piperidine derivatives. Download PDFInfo
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- ZA200205933B ZA200205933B ZA200205933A ZA200205933A ZA200205933B ZA 200205933 B ZA200205933 B ZA 200205933B ZA 200205933 A ZA200205933 A ZA 200205933A ZA 200205933 A ZA200205933 A ZA 200205933A ZA 200205933 B ZA200205933 B ZA 200205933B
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- South Africa
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- straight
- branched
- alkynyl
- branched alkyl
- alkenyl
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Description
PIPERAZINE AND PIPERIDINE DERIVATIVES FOR TREATMENT OR PREVENTION OF NEURONAL DAMAGE
TECHNICAL FIELD OF THE INVENI'ION
The present invention relates to piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage associated with neurological diseases. These .. compounds are also useful for stimulating nerve growth.
The invention also provides compositions comprising the compounds of the present invention and methods of oo utilizing: those compositions for treating or preventing neuronal damage or for stimulating nerve growth.
Neurological diseases are associated with the death of or injury to neuronal cells. Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death. A more recent approach involves the promotion of nerve regeneration by promoting neuronal growth.
Neuronal growth, which is critical for the survival of neurons, is stimulated in vitro by nerve: growth factors (NGF). For example, Glial Cell
Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of ) Parkinson’s disease. Insulin and insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PCl2 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al., J.
Neurosci., 6, pp. 1211-1219 (1986)]. Insulin and insulin-like growth factors also stimulate the ’ regeneration of injured motor nerves in vivo and in vitro [Near et al., Proc. Natl. Acad. Sci., pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al.,
Cell Differ., 19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine Cytokine Res., 12, p. 135 (1993)].
There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma and they have poor drug delivery properties.
Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neuronal growth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique
Toran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp. 169-78 (1996); and B. S. McEwen et al., Brain
Res. Dev. Brain. Res., 87, pp. 91-95 (1995)]. The progress of Alzheimer’s disease is slowed in women who take estrogen. Estrogen is hypothesized to complement NGF ) and other neurotrophins and thereby help neurons differentiate and survive.
Other target sites for the treatment of neurodegenerative disease are the immunophilin class of proteins. Immunophilins are a family of soluble proteins that mediate the actions of immunosuppressant drugs such ' as cyclosporin A, FK506 and rapamycin. Of particular interest is the 12 kDa immunophilin, FK-506 binding ’ protein (FKRP12). TFKBP12 binds I'K 506 and rapamycin, leading to an inhibition of T-cell activation and proliferation. Interestingly, the mechanism of action of
FK-506 and rapamycin are different. For a review, see,
S. H. Solomon et al., Nature Med., 1, pp. 32-37 (1995).
It has been reported that compounds with an affinity for
FKBP1l2 that inhibit that protein’s rotomase activity possess nerve growth stimulatory activity. [Lyons et al., Proc. Natl. Acad. Sci. USA, 91, pp. 3191-3195 (1994)]. Many of these such compounds also have immunosuppressive activity.
FK506 (Tacrolimus) has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al. (1994)]). This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerves [B. Gold et al., J. Neurosci., 15, pp. 7509-16 (1995)].
The use of immunosuppressive compounds, however, has drawbacks in that prolonged treatment with these compounds can cause nephrotoxicity [Kopp et al., J.
Am. Soc. Nephrol., 1, p. 162 (1991)], neurological ) deficits [P.C. DeGroen et al., N. Eng. J. Med., 317, p. 861 (1987)] and vascular hypertension [Kahan et al., N.
Eng. J. Med., 321, p. 1725 (1989)].
Sub-classes of FKBP binding compounds which inhibit rotomase activity, but which purportedly lack immunosuppressive function have been disclosed for use in ’ stimulating nerve growth and for neuroprotection [see,
United States patent 5,614,547; WO 96/40633; WO 96/40140;
WO 97/16190; WO 98/13343; WO 98/13355; WO 98/29116; WO 98/29117; WO 98/35675; WO 98/37882; WO 98/3788%; J. P.
Steiner et al., Proc. Natl. Acad. Sci. USA , 94, pp. 2019-23 (1997); and G. S. Hamilton et al., Bioorg. Med.
Chem. Lett., 7, pp. 1785-90 (1997)].
Stimulation of neural axons in nerve cells by piperidine derivatives is described in WO 96/41609.
Clinical use of the piperidine and pyrrolidine derivatives known so far for stimulating axonal growth has not been promising, as the compounds are unstable in plasma and do not pass the blood-brain barrier in adequate amounts.
More recently, classes of compounds which lack the ability to bind FKBP and lack immunosuppressive function have been described for use in stimulating nerve growth and preventing neurodegeneration [see, WO 98/20891; WO 98/20892; WO 98/20893 and WO 99/10340
Though a wide variety of compounds for treating or preventing neurological degenerative diseases have been described, only two of these are currently in clinical trials and none have been approved for commercialization. And while compounds which share ~ certain structural similarities to the compounds disclosed herein have been described in United States patent Nos. 4,115,569 and 4,374,990, neither of those patents specifically teach or suggest the compounds of the present invention, nor is there any teaching that such compounds would have utility in stimulating nerve growth or preventing neurodegeneration.
Thus, there remains a need for the discovery : and design of new compounds and compositions that have the ability to prevent and/or treat neuronal damage associated with ncuropathologic conditions.
The present invention provides compounds having formula (I):
A compound of the formula: 0 aA —B or p , wherein: each Q is a monocyclic, bicyclic or tricyclic ring system wherein in said ring system: a. each ring is independently partially unsaturated or fully saturated; b. each ring comprises 3 to 7 ring atoms independently selected from C, N, O or S;
Cc. no more than 4 ring atoms in Q are selected from N, O or S; d. any S is optionally replaced with S(O) or
S(0) 2; e. at least one ring comprises a N ring atom that is substituted with R?!; £. one to five hydrogen atoms in Q are ’ optionally and independently replaced with halo, -OH, =0, =N-OR', (C;-C¢)-straight or branched alkyl, Ar- substituted- (C;-Cq) -straight or branched alkyl, (C,-Cg)- straight or branched alkenyl or alkynyl, Ar-substituted- (C,-Cq) -straight or branched alkenyl or alkynyl, 0-(C;-C¢)-
straight or branched alkyl, 0O-[(C,-Cg)-straight or - branched alkyl] -Ar, O-(C,-C¢) straight or branched alkenyl or alkynyl, O-[(C,-C¢)-straight or branched alkenyl or ’ alkynyl] Ar, or O--Ar; and g. Q is not an indole or a pyroglutamic moiety, wherein : each R' is independently selected from (C;-Cio) - straight or branched alkyl, Ar-substituted- (C;-Cio)- straight or branched alkyl, (C,-Ciy)-straight or branched alkenyl or alkynyl, or Ar-substituted- (C,-Cjo) -straight or : branched alkenyl or alkynyl; wherein one to two CH; groups of said alkyl, alkenyl, or alkynyl chains in R! are optionally and independently replaced with O, S, S(O), S(0),, C(O) or N(R?) , wherein when R' is bound to nitrogen, the CH, group of R' bound directly to said nitrogen cannot be replaced with C(O);
Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl, pyraolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4- triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, benoxazolyl, pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, ’ benzo [bl thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, cinnolinyl, phthalazinyl, guinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, or any other chemically feasible monocyclic or bicyclic ring : system, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, 0, or S, wherein each Ar is optionally and independently substituted ) ~~ with one to three substituents selected from halo, hydroxy, nitro, =0, -SO;H, trifluoromethyl, trifluoromethoxy, (C,-C¢)-straight or branched alkyl, (C;-
C¢) -straight or branched alkenyl, O-[(C;-C¢)-straight or branched alkyl], O0- [(C;-C¢) -straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -
N(R*) (R*), carboxyl, N-(C;-C¢-straight or branched alkyl or
C2-C¢-straight or branched alkenyl) carboxamides, N,N-di- (C1-Cs-straight or branched alkyl or C,-Cg-straight or branched alkenyl) carboxamides, N-(C;-C¢-straight or branched alkyl or C;-Ce¢-straight or branched alkenyl) sulfonamides, or N,N-di- (C,-Cs-straight or branched alkyl or C2-Cé-straight or branched alkenyl) sulfonamides; each of R’ and R*! are independently selected from (C:-C¢) -straight or branched alkyl, (C,-C¢)-straight or branched alkenyl or alkynyl, hydrogen, phenyl or benzyl; or wherein R’ and R* are taken together with the nitrogen atom to which they are bound to form a 5-7 membered heterocyclic ring; each R? is independently selected from hydrogen, (C,-
C¢) -straight or branched alkyl, or (C,;-Cs)-straight or branched alkenyl or alkynyl;
X is selected from C(R?*)., N(R?®), N, 0, S, S(O), or
S(0)
Y is selected from a bond, -0-, (C;-C¢)-straight or branched) alkyl, or (C;-C¢)-straight or branched) alkenyl or alkynyl; wherein Y is bonded to the depicted ring via a single bond or a double bond; and wherein one to two of : the CH; groups of said alkyl, alkenyl, or alkynyl is optionally and independently replaced with 0, S, S(O),
S(0),, C(O) or N(R?) ;
Z is -C(0)- or -CH,- p is 0, 1 or 2; each of A and B is independently selected from hydrogen or Ar; or one of A or B is absent; and wherein two carbon ring atoms in the depicted ring structure are optionally linked to one another via a C;-Cs straight alkyl or a C,-C; straight alkenyl to create a bicyclic moiety.
In another embodiment, the invention provides pharmaceutical compositions comprising the compounds of formula (I). These compositions may be utilized in methods for promoting neuronal repair or preventing neuronal damage in a patient or in an ex vivo nerve cell.
More particularly, the methods of this invention are useful in treating various neurological diseases.
Examples of such diseases include peripheral nerve destruction due to physical injury or diseases such as diabetes; physical injuries to the central nervous system (e.g., brain or spinal cord); stroke; neurological disturbances due to nerve degeneration, such as
Parkinson’s disease, Alzheimer’s disease, and amylotrophic lateral sclerosis. . DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds having : formula (I):
oA
Nor
P (I), wherein: each Q is a monocyclic, bicyclic or tricyclic ring system wherein in said ring system: a. each ring is independently partially unsaturated or fully saturated; b. each ring comprises 3 to 7 ring atoms independently selected from C, N, O or S;
Cc. no more than 4 ring atoms in Q are selected from N, O or S; d. any S is optionally replaced with S(O) or
S(O); e. at least one ring comprises a N ring atom that is substituted with R?; £. one to five hydrogen atoms in Q are optionally and independently replaced with halo, -OH, =0, =N-OR!, (C,-C¢)-straight or branched alkyl, Ar- substituted- (C,-Cq) -straight or branched alkyl, (C,-Cg)- straight or branched alkenyl or alkynyl, Ar-substituted- (C2-C¢) -straight or branched alkenyl or alkynyl, 0-(C,;-Cg)- straight or branched alkyl, O-[(C;-C¢)-straight or branched alkyl] -Ar, O-(C,-C¢)-straight or branched alkenyl or alkynyl, 0O-[(C,-C¢)-straight or branched alkenyl or alkynyl} -Ar, or O-Ar; and g. Q is not an indole or a pyroglutamic ] 25 moiety, wherein each R!' is independently selected from (C;-Cio)- straight or branched alkyl, Ar-substituted- (C;-Ciq) - straight or branched alkyl, cycloalkyl-substituted- (C;-
-1 0 -
Cio) -straight or branched alkyl, (C;-Cio)-straight or ’ branched alkenyl or alkynyl, or Ar-substituted- (C;-Cyo)- straight or branched alkenyl or alkynyl; wherein one to two CH, groups of said alkyl, alkenyl, or alkynyl chains in R!' are optionally and independently replaced with 0, S, S(0), S(0);, C(O) or N(R?), wherein when R! is bound to nitrogen, the CH, group of R! directly bound to said nitrogen cannot be replaced with C(O);
Ar is selected from phenyl, 1l-naphthyl, 2-naphthyl, indenyl, azulenyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl , pyraolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadjazolyl, 1,2,4- triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, benoxazolyl, pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzol[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-guinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, or any other chemically feasible monocyclic or bicyclic ring system, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms ’ independently selected from N, O, or S, wherein each Ar is optionally and independently substituted with one to three substituents selected from halo, hydroxy, nitro, =0, -SO3H, trifluoromethyl, trifluoromethoxy, (C;-Cg¢)-straight or branched alkyl, (C;-
Cs) -straight or branched alkenyl, O0-[(C;-Cg¢)-straight or : branched alkyl], O0-[(C;-C¢)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -
N(R?) (RY), carboxyl, N- (C;-Cg straight. or branched alkyl or
C;-Ce¢-straight or branched alkenyl) carboxamides, N,N-di- (C1-Ce¢-straight or branched alkyl or C,-Cg-straight or branched alkenyl) carboxamides, N-(C,-C¢-straight or branched alkyl or C,-Ce¢-straight or branched alkenyl) or sulfonamides, N,N-di- (C;-Cs-straight or branched alkyl or
C,-Cs-straight or branched alkenyl) sulfonamides; each of R?® and R* are independently selected from (C1-Cs) -straight or branched alkyl, (C,-C¢)-straight or branched alkenyl or alkynyl, hydrogen, phenyl or benzyl; or wherein R’ and R* are taken together with the nitrogen atom to which they are bound to form a 5-7 membered heterocyclic ring; each R?’ is independently selected from hydrogen, (C,-
C¢) -straight or branched alkyl, or (C,-C¢)-straight or branched alkenyl or alkynyl;
X is selected from C(R?*),, N(R®), N, 0, S, S(O), or
S(0)2
Y is selected from a bond, -0-, (C;-Cg¢)-straight or branched) alkyl, or (C;-C¢)-straight or branched) alkenyl or alkynyl; wherein Y is bonded to the depicted ring via a single bond or a double bond; and wherein one to two of the CH; groups of said alkyl, alkenyl, or alkynyl is optionally and independently replaced with 0, S$, S(0), ’ S(0)2, C(O) or N(R); p is 0, 1 or 2;
Z is -C(0)- or -CHp-; each of A and B is independently selected from hydrogen or Ar; or one of A and B is absent; and wherein two carbon ring atoms in the depicted ring : structure may be linked to one another via a C;-C, straight alkyl or a C,-C, straight alkenyl to create a bicyclic moiety.
The term “ring atom”, as used herein, refers to a backbone atom that makes up the ring. Such ring atoms are selected from C, N, O or S and are bound to 2 or 3 other such ring atoms (3 in the case of certain ring atoms in a bicyclic ring system) . The term “ring atom” does not include hydrogen.
It will be readily apparent to those of skill in the are that the terms “alkyl” and “alkenyl” when used in the definition of Y represent those portions of an aliphatic moiety for which proper valence is completed by the moities bound to Y (i.e., at one end, the ring atom to which Y is bound; and at the other end, A and B).
Thus, as an example, for the purposes of this invention,
Y is considered a C, alkyl in each of the following structures (the moiety representing Y being shown in bold) : i } =CH—CH —oHy-h
B ang B .
The above compounds specifically exclude those compounds in which Q is an indole or a pyroglutamic moiety. Such compounds are known in the art and are not within the scope of the compounds of the present invention. Compounds of formula (I) containing an indole at position Q are described in European Patent
Publication 0 624 575 and in C. Kuehm-Caubere et al., J.
Med. Chem., 40, pp. 1201-10 (1997), and are said to be inhibitors of low density lipoproteins (LDL) and membrane lipid oxidation. Compounds containing a pyroglutamide at : Q are described in United States Patent 5,102,882 and are said to useful as nootropics. ’ Applicants believe that. compounds in which Q is an indole or a pyroglutamide will possess nerve growth
Co stimulatory activity and/or protect against neurodegeneration. Such activity is not disclosed or suggested in the prior art. As such, the methods of the present invention do not exclude the use of compounds wherein Q is an indole or pyroglutamide moiety.
According to a preferred embodiment of the present invention, Q in a compound of formula (I) is selected from a 5 to 6 membered partially unsaturated or fully saturated heterocyclic ring containing a single nitrogen ring atom and four to five carbon ring atoms, wherein said ring is optionally fused to a three-membered ring. Even more preferred is when Q is piperidyl, o pyrrolidyl or =e (3-Azabicyclo[3.1.0)Jhexyl). Most preferred is when Q is piperidyl or pyrrolidyl optionally substituted at one of the ring carbons with phenyl, methyl or hydroxy or Q is 3-Azabicyclo([3.1.0)lhexyl.
According to another preferred embodiment, R! is selected from (C,;-C¢)-straight alkyl, (C1-C¢) -straight alkyl-Ar, (C;-C¢)-straight alkyl-cycloalkyl, (C;-C¢)- : 25 straight or branched alkenyl, or (C;-Cq)-straight or branched alkenyl-Ar. Even more preferred is when R? is selected from methyl, ethyl, -CH,-phenyl, -CHz-methylphenyl, -CH;-methoxyphenyl, -CH,-fluorophenyl, -CH;-difluorophenyl, -CH;-CHz-phenyl, -CH;-cyclopropyl,
-CH;-CH=C(CHs3),, -CH,-CH=CH,, or -CH,-CH=CH-phenyl. : In yet another preferred embodiment, p is 0 or l; and X is C or N.
In another preferred embodiment. of the compound of formula (I), Y is a bond, -~0-, ~CH<, or =CH<. © According to another preferred embodiment, one - of A or B is absent or selected from hydrogen, phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, or difluorophenyl and the other of A or B is selected from phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, or difluorophenyl.
Some of the more preferred embodiments of this invention are the compounds listed in Table 1 and Table 2, below and the compounds set forth in the Examples.
CE
NIT ro ote ~ .
ALTE GHC C
0,00 , (0 C |e” © oh
RE o¥eseN 0 | 0,00 of 0 . $ 2
ST So ;
SO on C
QOCHj4 0 s \
N N
29 N 3 N (oN
N
Even more preferred are compounds 1, 7, 15, 20, 21, 26, 28, 30, 39, 41, 42, 44, 47, 48, 49, 52, 58, 60, 65, 69, 84, 85, 86, 90, 100, 101, 102, 103, 205, 206, 221, 223, 225, 238, 240, 242, 246, 255, 260, 261, 262, 263, 265, 267, 268, 271, 273, 275, 276, 277, 278, or 279.
The compounds of formula (I) may be stereoisomers, geometric isomers or stable tautomers.
The invention envisions all possible isomers, such as E and Z isomers, S and R enantiomers, diastereoisomers, racemates, and mixtures of those.
The compounds of the present invention may be readily prepared using known synthetic methods. For example, compounds of formula (I) may be prepared as shown below in any of Schemes 1 through 7:
SCHEME 1
A v
A O ~ 8
Ce, pe 5 oH + v4 A tBu” Cl NS
N —_— N —/ +ProEtN
PG O DCM PG O
Q=ring where Nis protected with a carbamate 0 protecting grou g group A Y~g : | Method A a 8 or
Deprotect 0% N N —_—
AN
. N R, 0]
H 0) Method A: R;CH»-Br, K,CO3, CH;CN or DMF
Method B: R,CH2-Br, Et3N, BuyNI (cat.), CH,Cl,
SCHEME 2
A
A
Method A ~8
Y. e / pd a) or 2% ont mm TX Method 5 A \__/ N
R; 8) Ry o
Method A: pivaloy! chloride, diisopropylethylamine, CH,Cl
Method B: HOBT, EDC (or other amide coupling reagents), CHCl,
~19-~
SCHEME 3
A .
Y.
H DCM h
OF Ze ph WE
Ry UA! 0 © 0 A
A
"8 ! E eemo 7% Xx + 5B he a
ANT W(t 7 [| d DCM SN N
R, | bo)
Ry
SCHEME 4 0
A DCM Y A
® 7 - ; + Ye _— ) +, op oH / =, B =cs nd aN Tx
N HN. 7X necan—_) N /
I Oo —/ ad l ©
A
RL }
N=C=0 ~B ii HA
DCM N NA
R, ©
SCHEME 5 0
OH + iN WN—80C pivaloyi chloride, i-Pr EIN, N A
R, 0] R; (0)
A
NTSB
: HCVEIOAC (> NH Method A $ ——— EE aE SE a
N Nn] or N N
Method B I
R, 0 R, (0)
Method A (when Y=CO or SO,): Cl-Y(A)B, iPrEIN, CH,Cly,
Method B (when Y=bond or sp3 carbon): Br(orCl)-Y(A)B, K,CO3, CH3CN (or DMF) .
SCHEME 6
A A
\ : \ 7 Rotane-THF i orane-THFE_
An pete AN
A LAH/THF I
R, O al
SCHEME 7
A
A DCM Je A + Yu —_— (7x + —"~8
Ap we (A ue
Boc Boc
A 1) HCVMeOH/EtOAc
EL ec=o a 2) K,CO3/ CHCN / R,CH,-Br ~ — i 7x —_—
DCM a 3) SN DCM 0 =C=0
Boc
A
~B %
YH rR, ©
In the 7 schemes depicted above, the following abbreviations are used: tBu-C(0)-Cl = pivaloyl chloride; iPr;EtN = diisopropylethylamine; DCM = dichloromethane;
HCl = hydrogen chloride gas; EtOAc = ethyl acetate; Et;N = triethylamine; DMF = dimethylformamide; THF = tetrahydrofuran; MeOH - methanol; BuyNI = tetrabutylammonium iodide; HOBT = N-hydroxybenzotriazole;
EDC = 1-(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; LAH = Lithium aluminum hydride. Schemes 3, 4 and 7 are combinatorial chemistry type wherein reactants linked to a polystyrene solid support (“Sp”)
are used. : Each of these schemes are described in more detail in the Example section. ) Onc of skill in the art will be well aware of analogous synthetic methods for preparing compounds of formula (I).
The nerve growth stimulatory activity of the compounds of this invention may be initially assayed using several cell culture assays known in the art. For example, the compounds of this invention may be tested in a neurite outgrowth assay using pheochromocytoma PC12 cells as described by Lyons et al., PNAS, 91, pp. 3191- 3195 (1994). A similar assay may be carried out in SH-
SY5Y human neuroblastoma cells. Alternatively, the chick dorsal root ganglia assay described in United States patent 5,614,547 or in G. SS. Hamilton et al., Bioorg.
Med. Chem. Lett., (1997) and references cited therein, may be utilized.
The compounds of this invention may also be assayed for nerve growth stimulatory activity in vivo using a mouse model of Parkinson's disease [J. P. Steiner et al., Proc. Natl. Acad. Sci. USA, 94, pp. 2019-23 (1997), United States patent 5,721,256] or following surgical sciatic nerve crush in rats.
The neuroprotective activity of the compounds of this invention may be assayed using rat embryo ventral mesencephalic cells in culture which are subsequently ’ exposed to the glutamate receptor agonist NMDA. This assay 1s described in detail in the example section.
According to another embodiment, this invention provides compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
—- 2 2 -
Pharmaceutically acceptable carriers that may : be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum ’ stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxy methylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
In another embodiment, the pharmaceutical composition of the present invention is comprised of a compound of formula (I), a pharmaceutically acceptable carrier, and a neurotrophic factor.
The term "neurotrophic factor," as used herein, refers to compounds which are capable of stimulating growth or proliferation of nervous tissue. Numerous neurotrophic factors have been identified in the art and any of those factors may be utilized in the compositions of this invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active . truncated derivatives such as gIGF-1 and Des (1-3) IGF-I, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and - neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in the compositions of this invention ’ is NCF.
As used herein, the described compounds used in the pharmaceutical compositions and methods of this invention, are defined to include pharmaceutically acceptable derivatives thereof. A "pharmaceutically acceptable derivative" denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote repair or prevent damage of neurons from disease or physical trauma.
If pharmaceutically acceptable salts of the described compounds are used, those salts are preferably derived from inorganic or organic acids and bases.
Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptancate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanocate. Base salts include ammonium salts, alkali
Claims (1)
- CLAIMS We claim:1. A compound of the formula:J. NA Lo P , wherein: each Q is a monocyclic, bicyclic or tricyclic ring system wherein in said ring system:a. each ring is independently partially unsaturated or fully saturated;b. each ring comprises 3 to 7 ring atoms’ independently selected from C, N, O or S;Cc. no more than 4 ring atoms in Q are selected from N, O or S;d. any S is optionally replaced with S(O) or S(0) 5;e. at least one ring comprises a N ring atom that is substituted with R?;£. one to five hydrogen atoms in Q are optionally and independently replaced with halo, -OH, =0, =N-OR', (C;-C¢)-straight or branched alkyl, Ar- substituted- (C;-C¢) -straight or branched alkyl, (C,-Cg)- straight or branched alkenyl or alkynyl, Ar-substituted- (C2-Cg) -straight or branched alkenyl or alkynyl, O- (C1-Cq) - straight or branched alkyl, O-[(C;-C¢)-straight or branched alkyl] -Ar, O-(C,-C¢) -straight or branched alkenyl or alkynyl, O-[(C,-C¢)-straight or branched alkenyl or : alkynyl] -Ar, or O-Ar; and g. Q is not an indole or a pyroglutamic moiety, wherein each R' is independently selected from (C;-Cg)-straight or branched alkyl, Ar-substituted- (C,-C¢)- straight or branched alkyl, cycloalkyl-substituted- (C;- Cg) -straight or branched alkyl, (C,-C¢)-straight or branched alkenyl or alkynyl, or Ar-substituted- (C,-Cg) - straight or branched alkenyl or alkynyl; wherein one to two CH; groups of said alkyl, alkenyl, or alkynyl chains in R' are optionally and independently replaced with 0, S, S(O), S(0)., C(O) or N(R®), wherein when R' is bound to nitrogen, the CH, group of R!' bound directly to said nitrogen cannot be replaced with C(O); Ar is selected from phenyl, l-naphthyl, 2-naphthyl, indenyl, azulenyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl, pyraolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4- triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, benoxazolyl, pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, cinnolinyl, phthalazinyl, guinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, or any other chemically feasible monocyclic or bicyclic ring system, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, O, or S, wherein each Ar is optionally and independently substituted with one to three substituents selected from halo, hydroxy, nitro, -SO3H, =0, trifluoromethyl, trifluoromethoxy, (C:-Cs)-straight or branched alkyl, (C;-~101 Cs) -straight or branched alkenyl, O-[(C;-C¢)-straight or branched alkyl], O-[(C,-C¢)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, - (R*®)(R*), carboxyl, N- (C;-Ce-straight or branched alkyl or C,-Cg- straight or branched alkenyl) carboxamides, N,N-di- (C,-Cs- straight or branched alkyl or C,-C¢-straight or branched alkenyl) carboxamides, N-(C;-Cg¢-straight or branched alkyl or C;-C¢-straight or branched alkenyl) sulfonamides, or N,N-di- (C,-Cs-straight or branched alkyl or C2-Cé-straight or branched alkenyl) sulfonamides;each of R?® and R* are independently selected from (C1-C¢) -straight or branched alkyl, (C;-C¢)-straight or branched alkenyl or alkynyl, hydrogen, phenyl or benzyl; or wherein R® and R* are taken together with the nitrogen atom to which they are bound to form a 5-7 membered heterocyclic ring; X each R? is independently selected from hydrogen, (C;- Ce) ~straight or branched alkyl, or (C,-Cg¢)-straight or branched alkenyl or alkynyl;X is selected from C(R?),, N, N(R? , O, S, S(O), or S(O).Y is selected from a bond, -0-, (C;-Cg)-straight or branched) alkyl, or (C,-C¢)-straight or branched) alkenyl or alkynyl; wherein Y is bonded to the depicted ring via a single bond or a double bond; and wherein one to two of the CH; groups of said alkyl, alkenyl, or alkynyl is optionally and independently replaced with 0, S, S(O), S(0)2, C(O) or N(R);p is 0, 1 or 2;each of A and B is independently selected from hydrogen or Ar; or one of A or B is absent; and wherein two carbon ring atoms in the depicted ring structure may be linked to one another via a C;-C, straight alkyl or a C,-C; straight alkenyl to create a-102- | : bicyclic moiety.2. The compound according to claim 1, wherein Q is selected from a 5 to 6 membered partially unsaturated or fully saturated heterocyclic ring containing a single nitrogen ving atom and four to five carbon ring atoms, wherein said ring is optionally fused to a three-membered ring.3. The compound according to claim 2, wherein Q is selected from piperidyl or pyrrolidyl optionally substituted at one of the ring carbons with phenyl, : methyl or hydroxy; or 3-Azabicyclo[3.1.0]hexyl.4. The compound according to claim 1, wherein R' is selected from (C;-C¢)-straight alkyl, (C;-Cg)- straight alkyl-Ar, (C,-Cg¢)-straight alkyl-cycloalkyl, (C3-C¢) -~straight or branched alkenyl, or (C;-Cg¢)-straight or branched alkenyl-Ar.5. The compound according to claim 4, wherein R' is selected from methyl, ethyl, -CH,-phenyl, -CH;-methylphenyl, -CH;-methoxyphenyl, -CH,-fluorophenyl, -CH;-difluorophenyl, -CH,-CH,-phenyl, -CH,-cyclopropyl, -CH,-CH=C(CH;),, -CH,-CH=CH,, or -CH,-CH=CH-phenyl.6. The compound according to claim 1, : wherein: p is 0 or 1; and X is C or N.7. The compound according to claim 1, wherein : Y is a bond, -0-, ~-CH<«, or =CHc.TO Wo nis PCTAUSO1/04210 r 103A. The compound according to claim 1, wherein one of A or B is.selected from optionally substituted phenyl or optionally substituted pyridyl and the other of A or B is selected from hydrogen, optionally substituted } phenyl, optionally substituted pyridyl, or is absent.9. The compound according to claim 8, wherein ’ one of A or B is absent or is selected from hydrogen, phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, or difluorophenyl and the other of A or B is selected from phenyl, chlorcphenyl, dichlorophenyl, fluorophenyl, or difluorophenyl. : 10. The compound according to claim 1, wherein said compound is selected from any one of compounds 1, 7, 15, 20, 21, 26, 28, 30, 39, 41, 42, 44, 47, 48, 49, 52, 58, 60, 65, 65, 84, 85, 86, $0, 100, 101, 102, 103, 205, 206, 221, 223, 225, 238, 240, 242, 246, 255, 260, 261, 262, 263, 265, 267, 268, 271, 273, 275, 276, 277, 278, or27S.11. A composition comprising a compound according to any one of claims 1 to 10 in an amount sufficient to stimulate nerve growth or prevent neurodegeneration; and a pharmaceutically acceptable carrier.12. The composition according to claim 11, additionally comprising a neurotrophic factor.13. The composition according to claim 12, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives, acidic and basic fibroblast growth factor Amended Sheet - 2003-07-24SUNIL (aFGF and bFGF, respectively), platelet-derived growth . factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary newrotvaghla factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and neurotrophin 4/5 (NT-4/5).14. The composition according to claim 13, wherein said truncated derivatives of IGF-1 are gIGF-1 and Des (1-3) IGF-I.15. The composition according to claim 11, wherein said composition is formulated for oral or parenteral administration to a patient.16. The composition according to claim 12, wherein said composition is formulated for oral or parenteral administration to a patient.17. A method for promoting neuronal repair or preventing neuronal damage in an ex vivo nerve cell comprising the step of administering to said cell an amount of a compound sufficient to promoting neuronal repair or preventing neuronal damage, wherein said compound has the formula: po JP a” NTS ) Lr P , wherein: each Q 1s a meonocyclic, bicyclic or tricyclic ring system wherein in said ring system:a. each ring is independently partially unsaturated or fully saturated; Amended Sheet — 2003-07-24-104a b. each ring comprises 3 to 7 ring atoms independently selected from C, N, O or S;Cc. no more than 4 ring atoms in Q are . selected from N, O or §S;d. any S is optionally replaced with S(O) or Amended Sheet -- 2003-07-24S(0) 5;e. at least one ring comprises a N ring atom that is substituted with R'; and :f. one to five hydrogen atoms in Q are . optionally and independently replaced with halo, -OH, =O, =N-OR', (C;-Cq)-straight or branched alkyl, Ar- substituted- (C;-C¢) -straight or branched alkyl, (C,-Ce)- straight or branched alkenyl or alkynyl, Ar-substituted- (C2-C¢) -straight or branched alkenyl or alkynyl, 0-(C;-C¢)- straight or branched alkyl, O-[(C;-C¢) -straight or branched alkyl] -Ar, 0-(C,-C¢) -straight or branched alkenyl or alkynyl, O-[(C,-C¢)-straight or branched alkenyl or alkynyl] -Ar, or O-Ar; wherein each R' is independently selected from (C;-Cg) - straight or branched alkyl, Ar-substituted- (C,-Cg) - straight or branched alkyl, cycloalkyl-substituted- (C,- Ce) -straight or branched alkyl, (C,-C¢)-straight or branched alkenyl or alkynyl, or Ar-substituted- (C,-Cg)- straight or branched alkenyl or alkynyl; wherein one to two CH; groups of said alkyl, alkenyl, or alkynyl chains in R' are optionally and independently replaced with 0, S, S(0), S(0),, C(O) or N(R?), wherein when R! is bound to nitrogen, the CH, group of R' bound directly to said nitrogen cannot be replaced with C(O); Ar is selected from phenyl, 1l-naphthyl, 2-naphthyl, indenyl, azulenyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl , pyraclidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4- triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, benoxazolyl, pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, S5-pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,WO (1/58891 PCT/USO1/04210 isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, or any other chemically feasible monocyclic or bicyclic ring system, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, O, or S, wherein each Ar is optionally and independently substituted with one to three substituents selected from halo, hydroxy, nitro, -SO3H, =0, trifluoromethyl, trifluoromethoxy, (C;-C¢)-straight or branched alkyl, (C,- : Ce) -straight or branched alkenyl, O0-[(C,-C¢)-straight or branched alkyl], O0-[(C,-Cg)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, -N(R’) (R*), carboxyl, N- (C,-Cg-straight or branched alkyl or C,-Cg-straight or branched alkenyl) carboxamides, N,N-di- (C1-Ce-straight or branched alkyl or C,-Cg¢-straight or branched alkenyl) carboxamides, N-(C;-C¢-straight or branched alkyl or C,-Ce¢-straight or branched alkenyl) sulfonamides, or N,N-di- (C;-C¢-straight or branched alkyl or C,-Cg¢-straight or branched alkenyl) sulfonamides;each of R’ and R* are independently selected from (C1-C¢) ~straight or branched alkyl, (C;-C¢)-straight or branched alkenyl or alkynyl, hydrogen, phenyl or benzyl; or wherein R’ and R! are taken together with the nitrogen atom to'which they are bound to form a 5-7 membered heterocyclic ring;R® is selected from hydrogen, (C;-C¢)-straight or branched alkyl, or (C,-C¢)-straight or branched alkenyl or alkynyl;X is selected from C, N(R?®), N, O, S, S(O), or S(0),oo : WO (11/38891 PCT/VSO1/04210 Y is selected frow a bond, 0, (Cpe) straight or branched) alkyl, or (C2-C¢) ~straight or branched) alkenyl or alkynyl; wherein Y is bonded to the depicted ring via a single bond or a double bond; and wherein one to two of } the CH; groups of said alkyl, alkenyl, or alkynyl is optionally and independently replaced with 0, Ss, s(0), S(0),, C(O) or N(R); p is 0, 1 or 2; each of A and B is independently selected from hydrogen or Ar; and wherein two carbon ring atoms in the depicted ring structure may be linked to one another via a C;-C, straight alkyl or a C;-C, straight alkenyl to create a bicyclic moiety.18. A method for promoting neuronal repair or preventing neuronal damage in an ex vivo nerve cell, glial cell, chromafin cell or stem cell comprising the step of administering to said cell a compound according : to any one of claims 1 to 10 in an amount sufficient to promote neuronal repair or prevent neuronal damage.19. A compound of the formula: TE PP a” NT ) Lo P , wherein: ) each Q is a monocyclic, bicyclic or tricyclic ring system wherein in said ring system:a. each ring is independently partially unsaturated or fully saturated;b. each ring comprises 3 to 7 ring atoms independently selected from C, N, O or S; Amended Sheet — 2003-07-24~107a~-Cc. no more than 4 ring atoms in Q are selected from N, O or S;d. any S 1s optionally replaced with S(0) or Amended Sheet - - 2003-07-24: zo WO 01/38891 PCT/USO1/0210 Loy 5(0) 5;e. at: least one ring comprises a N ring atom that is substituted with R'; and£. one to five hydrogen atoms in Q are optionally and independently replaced with halo, ~-OH, =O, =N-OR?, (C1-Cs) ~straight or branched alkyl, Ar- substitured- (C1-Cg) -straight ar hranched alkyl, (Cy-Cq) - straight or branched alkenyl or alkynyl, Ar-substituted- (C;-Cq) ~straight or branched alkenyl or alkynyl, 0-(C;-Cs) - straight or branched alkyl, O- [(C,-C¢) ~straight or branched alkyl] -Ar, 0-(C;-Cq) -straight or branched alkenyl or alkynyl, O-((C;-C¢)-straight or branched alkenyl or alkynyl] -Ar, or O-Ar; wherein each R' is independently selected from (C,-Ce) - straight or branched alkyl, Ar-substituted- (Cy;-Cq) - straight or branched alkyl, cycloalkyl-substituted- (C,- Ce) -straight or branched alkyl, (C2-Cg) -straight or branched alkenyl or alkynyl, or Ar-substituted- (Cy-Cg)- straight or branched alkenyl or alkynyl; wherein one to two CH; groups of said alkyl, alkenyl, or alkynyl chains in R! are optionally and independently replaced with 0, S, S(0), S(0),, C(O) or N(R?) , wherein when R' is bound to nitrogen, the CH, group of R® bound directly to said nitrogen cannot be replaced with C(O); Ar is selected from phenyl, l-naphthyl, 2-naphthyl, indenyl, azulenyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl , } pyraolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-criazolyl, 1,3,4-thiadiazolyl, 1,2,4-. triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, benoxazolyl, pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, S-pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, Amended Sheet -- 2003-07-24. WL OLDNEY | PCT/US01/04210 isoindolyl, 3H-indolyl, indolinyl, benzo [b) turanyl, benzo (b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydrogquinelinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, or any other chemically feasible monocyclic or bicyclic ring system, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, O, or S, wherein each Ar is optionally and independently substituted with one to three substituents selected from halo, hydroxy, nitro, -SO;H, =0, trifluoromethyl, trifluoromethoxy, :(C;-Cs) -straight or branched alkyl, (C;- - Ce) -straight or branched alkenyl, 0-[(C,-Cg)-straight or branched alkyl], 0-((C,-C¢)-straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, - N(R?) (R*), carboxyl, N-(C,-Ce¢-straight or branched alkyl or C2-Cs-straight or branched alkenyl) carboxamides, N,N-di- (C1-Cs-straight or branched alkyl or C;-Cg¢-straight or branched alkenyl) carboxamides, - N-(C;-Cg-straight or branched alkyl or C,-Ce¢-straight or branched alkenyl) . sulfonamides, or N,N-di- (C,-Cg-straight or branched alkyl or C;-C¢-straight or branched alkenyl) sulfonamides; each of R' and R! are independently selected from (C1-Cq) -straight or branched alkyl, (C2-Cg) -straight or branched alkenyl or alkynyl, hydrogen, phenyl or benzyl; or wherein R’ and R' are taken together with the nitrogen atom to’ which they are bound to form a 5-7 membered heterocyclic ring;R? is selected from hydrogen, (C,-Cg¢)-straight or branched alkyl, or (C;-C¢)-straight or branched alkenyl or alkynyl;X is selected from C, N(R?’), N, O, §, S(O), or S(O), Amended Sheet —~ 2003-07-24-109%a--Y is selected from a bond, -0-, (C;-Cg)-straight or branched) alkyl, or (C,-C¢) -straight or branched) alkenyl or alkynyl; wherein Y is bonded to the depicted ring via a single bhond or a double bond; and wherein one to two of the CH, groups of said alkyl, alkenyl, or alkynyl is optionally and independently replaced with 0, §, S(O), S(0),, C(O) or N(R);p is 0, 1 or 2;each of A and B is independently selected from hydrogen or Ar; and wherein two carbon ring atoms in the depicted ring structure may be linked to one another via a C;-C, straight alkyl or a C;-C4 straight alkenyl to create aAmended Sheet — 2003-07-24 bicyclic moiety, for use in a method for promoting neuronal repair or preventing neuronal damage in a patient comprising the step of administering to said patient an amount of said compound sufficient to promoting neuronal repair or preventing neuronal damage.20. A compound according to any one of claims 1 to 10 for use in a method for promoting neuronal repair or preventing neuronal damage in a patient comprising the step of administering to said patient said compound in an amount sufficient to promote neuronal repair or prevent neuronal damage.21. The compound according to claim 19, said method comprising the additional step of administering to said patient a neurotrophic factor either as part of a multiple dosage form together with said compound or as a separate dosage form.22. The compound according to claim 20, said method comprising the additional step of administering to sald patient a neurotrophic factor either as part of a multiple dosage form together with said compound or as a separate dosage form.23. The compound according to claim 21 or 22, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors Amended Sheet — 2003-07-24~111- (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT- 4/5).24. The compound according to claim 23, wherein said truncated derivatives of IGF-1 are gIGF-1 and Des (1-3) IGF-I.25. The compound according to claim 17, wherein said method is used to treat a patient suffering from a disease selected from trigeminal neuralgia, glosspharyngeal neuralgia, Bell’s Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome’s, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neurophathies, other peripheral myelin disorders, Alzheimer’s disease, Gullain-Barre syndrome, Parkinson’s disease and other Parkinsonian disorders, ALS, Tourette's syndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic injury, neuropathy associated with diabetes, spinal cord injuries, facial nerve injury and other trauma, chemotherapy- and other medication-induced neuropathies, Huntington’s disease, and protein fibrillization diseases.26. The compound according to claim 25, wherein said peripheral neurophathies are caused by lead, dapsone, ticks, or porphyria. Amended Sheet — 2003-07-24+11227. The gompound according to claim 25, wherein said method is used to treat a patient suffering from a disease selected from Diffuse Lewy Body disease, Alzheimer’s disease-Lewy Body variant, Famillal British Dementia, and Frontotemporal Dementia.28. The compound according to claim 20, wherein said method is used to treat a patient suffering from a disease selected from trigeminal neuralgia, glosspharyngeal neuralgia, Bell’s Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome’s, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, other peripheral myelin disorders, Alzheimer’s disease, Gullain-Barre syndrome, Parkinson’s disease and other Parkinsonian disorders, ALS, Tourette’s syndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic injury, neuropathy associated with diabetes, spinal cord injuries, facial nerve injury and other trauma, chemotherapy- and other medication-induced neuropathies, Huntington’s disease, and protein fibrillization diseases.29. The compound according to claim 28, wherein said peripheral neuropathies are caused by lead, dapsone, ticks, or porphyria. Amended Sheet - - 2003-07-2430. The compound according to claim 25, wherein said method is used to treat a patient suffering from a disease selected from Diffuse Lewy Body disease, Alzheimer’s disease-Lewy Body variant, Famillal British Dementia, and Frontotemporal Dementia.31. The compound according to claim 19 or 20, wherein said method is used to treat a patient suffering from a disease selected from trigeminal neuralgia, glosspharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome’s, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, other peripheral myelin disorders, Alzheimer’s disease, Gullain-Barre syndrome, Parkinson's disease and other Parkinsonian disorders, ALS, Tourette's syndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic injury, neuropathy associated with diabetes, spinal cord injuries, facial nerve injury and other trauma, chemotherapy- and other medication-induced neuropathies, Huntington's disease, and protein fibrillization diseases.32. The compound according to claim 31, wherein said peripheral neurophathies are caused by lead, dapsone, ticks, or porphyria. Amended Sheet — 2003-07-24WO OL/HHHOL pe /us01/0421.033. The sompoand according to claim 31, wherein said method is used to treat a patient suffering from a disease selected from Diffuse Lewy Body disease, Alzheimer’s disease-Lewy Body variant, Famillal British Dementia, and Frontotemporal Dementia.34. The compound according to claim 23, wherein said method is used to treat a patient suffering from a disease selected from trigeminal neuralgia, glosspharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome’'s, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, other peripheral myelin disorders, Alzheimer’s disease, Gullain-Barre syndrome, Parkinson’s disease and other Parkinsonian disorders, ALS, Tourette's syndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic injury, neuropathy associated with diabetes, spinal cord injuries, facial nerve injury and other trauma, chemotherapy- and other medication-induced neuropathies, Huntington’s disease, and protein fibrillization diseases.35. The compound according to claim 34, wherein said peripheral neurophathies are caused by lead, dapsone, ticks, or porphyria. Amended Sheet - 2003-07-2436. The compound according to claim 34, wherein said method is used to treat a patient suffering from a disease selected from Diffuse Lewy Body disease, Alzheimer’s disease-Lewy Body variant, Famillal British Dementia, and Frontotemporal Dementia.37. Use of a compound of the formula: Pq Y—B J IN a” ON a Ng p . wherein: each Q is a monocyclic, bicyclic or tricyclic ring system wherein in said ring system:a. each ring is independently partially unsaturated or fully saturated;b. each ring comprises 3 to 7 ring atoms independently selected from C, N, O or S;c. no more than 4 ring atoms in Q are selected from N, 0 or S;d. any S 1s optionally replaced with S(O) or ~~ - ee Amended Sheet - 2003-07-24 a. . WO 01/3889 PCTAIS01/04210 Ilo S(O) y;e. at- least one ring comprises a N ring atom that is substituted with RY; and :£. one to five hydrogen atoms in Q are optionally and independently replaced with halo, -OH, =O, =N-OR', (C;-Ce)-straight or branched alkyl, Ar- substituted- (C-0g) -straight or branched alkyl, (C,-Cg)- straight or branched alkenyl or alkynyl, Ar-substituted- : (C2-C¢) straight or branched alkenyl or alkynyl, O-(C,-Cé) - straight or branched alkyl, O- [(C1-C¢) ~straight or branched alkyl] -Ar, O- (C;-Cg) -straight or branched alkenyl or alkynyl, O-((C;-Cg¢)-straight or branched alkenyl or alkynyl] -Ar, or O-Ar; wherein each R! is independently selected from (C,-Cg)- straight or branched alkyl, Ar-substituted- (C;-Cq) - straight or branched alkyl, cycloalkyl-substituted- (C;- Cg) -straight or branched alkyl, (C;-Cq)-straight or branched alkenyl or alkynyl, or Ar-substituted- (C,-Cg)- straight or branched alkenyl or alkynyl; wherein one to two CH, groups of said alkyl, alkenyl, or alkynyl chains in R' are optionally and independently replaced with 0, S, S(O), S(0),, C(O) or N(R?) , wherein when R' is bound to nitrogen, the CH, group of R' bound directly to said nitrogen cannot be replaced with C(O); Ar is selected from phenyl, 1l-naphthyl, 2-naphthyl, indenyl, azulenyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl , ] pyraolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-. triazolyl, 1,2, ,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, benoxazolyl, pyridaziny}, 2- pyrimidinyl, 4-pyrimidinyl, S-pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, Amended Sheet - 2003-07-24 x WO D1/.8891 PCTS 1/04210 isoindolyl, 3H indolyl, indolinyl, benzo (b] furanyl, benzo [b] thiophenyl, l1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, guinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, cinnolinyl, phthalazinyl,: quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, or any other chemically feasible monocyclic or bicyclic ring system, wherein each ring consists of 5 to 7 ring atoms and wherein each ring comprises 0 to 3 heteroatoms independently selected from N, O, or S, wherein each Ar is optionally and independently substituted with one to three substituents selected from halo, hydroxy, nitro, -SO0;H, =O, trifluoromethyl, trifluoromethoxy, (C,-Cs) -straight or branched alkyl, (C;- - Cg) -straight or branched alkenyl, O0-{(C,-Cs)-straight or branched alkyl], O0-[(Cy-Cs) -straight or branched alkenyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, - N(R’) (R*), carboxyl, N- (C,-Ce-straight or branched alkyl or C:~Cg straight or branched alkenyl) carboxamides, N,N-di- (C1-Cg-straight or branched alkyl or C;-Cgs-straight or branched alkenyl) carboxamides, N- (C;-Cs-straight or branched alkyl or C,-C¢-straight or branched alkenyl) sulfonamides, or N,N-di-(C,-C¢-straight or branched alkyl or C;-C¢-straight or branched alkenyl) sulfonamides: each of R' and R* are independently selected from (C1-Cg) -straight or branched alkyl, (C;-C¢)-straight or branched alkenyl or alkynyl, hydrogen, phenyl or benzyl; or wherein R’ and R' are taken together with the nitrogen atom to'which they are bound to form a 5-7 membered heterocyclic ring;} R?’ is selected from hydrogen, (C;-Cq)-straight or branched alkyl, or (C2-Cs) -straight or branched alkenyl or alkynyl;X is selected from C, N(R}), N, 0, S, S(O), or S(0), Amended Sheet. - 2003-07-24-118~ Y is selected from a bond, -0-, (C,-Cg)-straight or branched) alkyl, or (C;-Cg)-straight or branched) alkenyl or alkynyl; wherein Y is bonded to the depicted ring via a single bond or a double bond; and wherein one to two of the CH, groups of said alkyl, alkenyl, or alkynyl is optionally and independently replaced with 0, Ss, S(O), S$(0);, C(O) or N(R); p is 0, 1 or 2; each of A and B is independently selected from hydrogen or Ar; and wherein two carbon ring atoms in the depicted ring structure may be linked to cone another via a C;-C, straight alkyl or a C;-C, straight alkenyl to create a bicyclic moiety in the manufacture of a medicament for use in a method for promoting neuronal repair or preventing neuronal damage in a patient comprising the step of administering to said patient an amount of said compound sufficient to promoting neuronal repair or preventing neuronal damage.38. Use of a compound according to claims 1 to in the manufacture of a medicament for use in a method for promoting neuronal repair or preventing neuronal damage in a patient comprising the step of administering to said patient said compound in an amount sufficient to promote neuronal repair or prevent neuronal damage.39. A compound according to claim 1, as specifically described herein. Amended Sheet — 2003-07-24
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18194400P | 2000-02-11 | 2000-02-11 |
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| Publication Number | Publication Date |
|---|---|
| ZA200205933B true ZA200205933B (en) | 2003-07-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200205933A ZA200205933B (en) | 2000-02-11 | 2002-07-24 | Piperazine and piperidine derivatives. |
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| ZA (1) | ZA200205933B (en) |
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