AU2005202769A1 - Acyclic and Cyclic Amine Derivatives - Google Patents

Acyclic and Cyclic Amine Derivatives Download PDF

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Publication number
AU2005202769A1
AU2005202769A1 AU2005202769A AU2005202769A AU2005202769A1 AU 2005202769 A1 AU2005202769 A1 AU 2005202769A1 AU 2005202769 A AU2005202769 A AU 2005202769A AU 2005202769 A AU2005202769 A AU 2005202769A AU 2005202769 A1 AU2005202769 A1 AU 2005202769A1
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Prior art keywords
same
straight
ring
alkyl
optionally
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AU2005202769A
Inventor
David J. Lauffer
Michael D. Mullican
Roger Tung
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Priority claimed from AU64972/00A external-priority patent/AU6497200A/en
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Description

-1-
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Invention Title: Vertex Pharmaceuticals Incorporated CULLEN CO.
Level 26 239 George Street Brisbane Qld 4000 Acyclic and Cyclic Amine Derivatives The following statement is a full description of this invention, including the best method of performing it, known to us: -la- ;i 1 TECHNICAL FIELD OF THE INVENTION 0 The present invention relates to acyclic and 0D 5 cyclic amine derivatives for treating or preventing C neuronal damage associated with neurological diseases.
C' -Th6 invention also provides compositions comprising the o compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.
BACKGROUND OF THE INVENTION 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 PC12 cells and in cultured sympathetic, and sensory neurons [Recio-Pinto et J.
Neurosci., 6, pp. 1211-1219 (1986)]. Insulin and insulin-like growth factors also stimulate the -2in o regeneration of injured motor nerves in vivo and in vitro 0 Ci [Near et al., Proc. Natl. Acad. Sci., pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 t i (1994)). Similarly, fibroblast growth factor (FGF) C- 5 stimulates neural proliferation Gospodarowicz et al., Cell Differ., 19, p. 1 (1986)] and growth A. Walter et al., Lymphokine Cytokine Res., 12, p. 135 (1993)].
r There are, however, several disadvantages c-i Sassociated with the use of nerve growth factors for Cql 10 treating neurological diseases. They do not readily o cross the blood-brain barrier. They are unstable in c 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 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 -3o that mediate the. actions of immunosuppressant drugs such CA as cyclosporin A, FK506 and rapamycin. Of particular interest is the 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 binds FK-506 and rapamycin, C 5 leading to an inhibition of T-cell activation and proliferation. Interestingly, the mechanism of action of 0 FK-506 and rapamycin are different. For a review, see, S. H. Solomon et al., Nature Med., 1, pp. 32-37 (1995).
SIt has been reported that compounds with an affinity for in FKBP12 that inhibit that protein's rotomase activity o 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 Sharkey and S. P. Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve 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 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)].
-4o More recently, sub-classes of FKBP binding ci compounds which inhibit rotomase activity, but which purportedly lack immunosuppressive function have been disclosed for use in stimulating nerve growth [see, c- 5 United States patent 5,614,547; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner et al., Proc. Natl. Acad. Sci.
0" USA., 94, pp. 2019-23 (1997); and G. S. Hamilton et al., Bioorg. Med. Chem. Lett., 7, pp. 1785-90 (1997)3.
Stimulation of neural axons in nerve cells by ci I 10 piperidine derivatives is described in WO 96/41609.
oClinical 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.
Though a wide variety of neurological degenerative diseases may be treated by promoting repair of neuronal damage, there are relatively few agents known to possess these properties. Thus, there remains a need for new compounds and compositions that have-the ability to either prevent or treat neuronal damage associated with neuropathologic disorders.
SUMMARY OF THE INVENTION The invention provides compounds of formula
(I)
D>)x 0 and pharmaceutically acceptable derivatives thereof, Swherein: X is selected from -CH 2
CH
2 -CH=CH-, -C(OH)CH 2
-CH
2
=C(F)CH
2
-C(F)=CH
2
-P(O)(OH)CH
2 -CH2S(0) 2
-C(S)NR
I
-C(O)CH
2 CH(OH)-, -C(OH)CF 2 -C(0)CF2-, -CH(F)CH 2
-C(F)
2
CH
2
-CH
2
-CH
2
C(F)
2
VO
N N
N
A, B and R 1 are independently E, (C 1
-C
1 o)-straight or branched alkyl, (C 2 -Clo)-straight or branched alkenyl or alkynyl, or (Cs-C 7 )-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (Cs-C7)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the -CH 2 groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by
-S(O)
2 or -N(R 3 or, B and R 1 are independently hydrogen;
R
3 is hydrogen, (C'-C 4 )-straight or branched alkyl,
(C
3
-C
4 )-straight or branched alkenyl or alkynyl, or (CI-C 4 bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R 3 is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused; E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms -6o independently selected from C, N, N(R 3 O, S, or C< S(0)2; and wherein no more than 4 ring atoms are selected Sfrom N, N(R 3 S, or S(0)2; wherein I to 4 hydrogen atoms in E are optionally.
Cl 5 and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO0H, trifluoromethyl, 0trifluoromethoxy, (CI-C6)-straight or branched alkyi, (C2-Cs)-straight or branched alkenyl, O-[(CI-C 6 )-straight o or branched alkyl), (C3-C)-straight or branched .alkenyl], (CH 2
(R
s
(CH
2 )n-NH(R) -(CH 2 )n-Z,
S(CH
2
(CH
2
(CH
2
(CH
2 )n-Z O-(CH 2 )n-Z,
(CH
2
S-(CH
2 CH=CH-Z, 1,2-methylenedioxy, C(0)OH, C(0)O-[(Ci-Cs)-straight or branched alkyl], C(O)0-(CH 2 )n-Z or C(0)-N(R 4
(R
5 each of R 4 and R 5 are independently hydrogen, (Ci-Cs)-straight or branched alkyl, (C 3 -Cs)-straight or branched alkenyl, or wherein R 4 and R 5 when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, N(R 3 O, S, or S(0)2; wherein said alkyl, alkenyl or alkynyl groups in R 4 and R 5 are optionally substituted with Z.
each n is independently 0 to 4; each Z is independently selected from a saturated, :partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 0, S, or S(0)2; and wherein no more than 4 ring atoms are selected from N, N(R 3 O, S, or S(0)2; wherein 1 to 4 hydrogen atoms in Z are optionally o and independently replaced with halo, hydroxy, nitro, C( cyano, C(0)OH, (C1-C 3 )-straight or branched alkyl, S0-(Ci-C 3 )-straight or branched alkyl, C(O)O-[I C-C 3 )-straight or branched alkyl], amino, CA 5 NH[(CL-C 3 )-straight or branched alkyl], or N-[(C1-C 3 )-straight or branched alkyl] 2 IND J is H, methyl, ethyl or benzyl; Si. K and K 1 are independently selected from o (Ci-C 6 )-straight or branched alkyl, (C 2
-C
6 )-straight or V) 10 branched alkenyl or alkynyl, or cyclohexylmethyl, wherein o 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E; wherein K and K 1 are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O-(Ci-C 6 )-alkyl, O-(CH 2
NO
2 C(0)OH, C(O)-0-(C 1 -alkyl, C(O)NRR 5
NR
4
R
5 and (CH 2 or, J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R 3 O, S, S(0), or S(0) 2 wherein 1. to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (Ci-CG)-straight or branched alkyl,
(C
2
-C
6 )-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any -CH 2 group in said alkyl, alkenyl or alkynyl substituent is optionally and independently replaced by or -N(R 3 and wherein said heterocyclic ring is optionally fused with E; G, when present, is -S(0) 2 or In o Y is oxygen, or C wherein R6 is hydrogen, E, (Cl-C 6 )-straight or branched alkyl, (C 3
-C
6 )-straight or branched alkenyl or alkynyl; or wherein R 6 and D are taken together with the C- 5 atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring' optionally contains 1 to 3 CN additional heteroatoms independently selected from 0, S, 1^ N, N(R SO, or S02; and wherein said ring is optionally o benzofused; D is hydrogen, (CI-C 7 )-straight or branched o alkyl, (C2-C 7 )-straight or branched alkenyl or alkynyl, (Cs-C7)-cycloalkyl or cycloalkenyl optionally substituted with (Ci-C 6 )-straight or branched alkyl or (C 2 -straight or branched alkenyl or alkynyl, (C1-C 7 -alkyl] -E,
(C
2 -C)-alkenyl or alkynyl]-E, or- E; wherein 1 to 2 of the CH 2 groups.of*said alkyl, alkenyl or alkynyl chains in D is optionally replaced by -S(0 2 or -N(R 3 provided that when J is hydrogen or G is selected from S0 2 or C(O)C(O)-Y, wherein Y is 0; then D is not hydrogen; and x is 0 or 1.
In another embodiment, the invention provides pharmaceutical compositions comprising the compounds of formula These compositions may be utilized in methods treating various neurological diseases which are influenced by neuronal regeneration and axon growth or for stimulating neuronal regeneration in an ex vivo nerve cell. Examples of such diseases include peripheral nerve destruction due to physical injury or diseases such as diabetes; physical injuries to the central nervous system -9brain 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 invention provides compounds of formula oA
(I)
and pharmaceutically acceptable derivatives thereof, wherein: X is selected from -CH 2
CH
2 -CH=CH-, -C(OH)CH 2
-CH
2
=C(F)CH
2
-C(F)=CH
2 -P (OH) CH 2
-CH
2 S(O) -C(S)NR 1
-C(O)CH
2 CH(OH)-, -C(OH)CF 2
-C(O)CF
2
-CH(F)CH
2 -C(F)2CH 2
-CH
2
-CH
2 C(F)2-,
N
S/N or
N
A, B and R 1 are independently E, (Ci-Cio)-straight or branched alkyl, (C2-C1o)-straight or branched alkenyl or alkynyl, or (C5-C7)-cycloalkyl or cycloalkenyl;. wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (Cs-C 7 )-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the -CH 2 groups in said alkyl, alkenyl, or alkynyl groups o is optionallyand independently replaced C -S(0) 2 or or, B and R 1 are independently hydrogen;
R
3 is hydrogen, (C1-C4)-straight or branched alkyl, Ci 5 (C 3
-C
4 )-straight or branched alkenyl or alkynyl, or (Ci-C 4 bridging alkyl, wherein a bridge is formed between the O nitrogen atom to which said R 3 -is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, o and wherein said ring is optionally benzofused;
V
n 10 E is a saturated, partially saturated or o unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 0, S, or S(0)2; and wherein no more than 4 ring atoms are selected from N, N(R 3 0, S, or S(0)2; wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO 3 H, trifluoromethyl, trifluoromethoxy, (Ci-Cs)-straight or branched alkyl, (C2-Cs)-straight or branched alkenyl, (C-C 6 )-straight or branched alkyl], -0-[(C3-C 6 )-straight or branched alkenyl] (CH2) n-N(R 4
(R
5 (CH2) n-NH (R4) (CH2) n-Z, (CH2) n-N(R4- (CH2) Z) (R 5 -(CH2) n-Z) (CH2) n-Z, O-(CH2)n-Z,
(CH
2
S-(CH
2 CH=CH-Z, 1,2-methylenedioxy, C(0)OH, C(0)O-[(Ci-C6)-straight or branched alkyl], C(0)0-(CH 2 )n-Z or C(0)-N(R 4
(R
5 each of R 4 and R 5 are independently hydrogen, (Ci-Cs)-straight or branched alkyl, (C 3 -Cs)-straight or branched alkenyl, or wherein R 4 and Rs, when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring -11in 0 optionally contains 1 to 3 additional heteroatoms Ci independently selected from N, N(R O, S, or S(0)2; wherein said alkyl, alkenyl or alkynyl groups in R 4 and R 5 are optionally substituted with Z.
Ci 5 each n is independently 0 to 4; each Z is independently selected from a saturated, 0 partially saturated or unsaturated, monocyclic or
VO
bicyclic ring system, wherein each ring comprises:5 to 7 Sring atoms independently selected from C, N, N(R 3 0, S, VI 10 or S(0)2; and wherein no more than 4 ring atoms are o selected from N, N(R 3 0, S, or S(0)2; wherein, to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(0)OH, (Ci-C 3 )-straight or branched alkyl, O- (C-C 3 )-straight or branched alkyl, (Ci-C 3 )-straight or branched alkyl], amino, NH[ (C1-C 3 )-straight or branched alkyl], or
(C-C
3 )-straight or branched alkyl] 2 J is H, methyl, ethyl or benzyl; K and K I are independently selected from (Ci-C 6 -straight or branched alkyl, (C 2
-C
6 )-straight or branched alkenyl or alkynyl, or. cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E; wherein K and K 1 are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O-(C 1
-C
6 )-alkyl, O-(CH 2
NO
2 C(0)OH, C(O)-0-(C-C)-alkyl, C(O)NR 4
R
5
NR
4
R
5 and (CH 2 or, J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 -12- S.additional heteroatoms selected from N, N(R 3 O, S, S(0), Ci or S(0)2, wherein 1 to 4 hydrogen atoms in said Sheterocyclic ring are optionally and independently replaced with (C 1 -straight or branched alkyl, C( 5 (C2-C6)-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any -CH2- group in said alkyl, 0" alkenyl or alkynyl substituent is optionally and
VO
0" independently replaced by o or -N(R 3 and wherein said heterocyclic ring is Vl 10 optionally fused with E; o G, when present, is or Y is oxygen, or N(R 6 wherein R 6 is hydrogen, E, (C 1
-C
6 )-straight or branched alkyl, (C3-Cs)-straight or branched alkenyl or alkynyl; or wherein R 6 and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, N(R3), SO, or SO2; and wherein said ring is optionally benzofused; D is hydrogen, (C 1 -C7)-straight or branched alkyl, (C 2
-C
7 )-straight or branched alkenyl or alkynyl, (Cs-C 7 )-cycloalkyl or cycloalkenyl optionally substituted with (C 1
-C
6 )-straight or branched alkyl or (C 2
-C
7 )-straight or branched alkenyl or alkynyl, [(CI-C 7 )-alkyl]-E,
[(C
2 -C7)-alkenyl or alkynyl]-E, or E; wherein 1 to 2 of the CH 2 groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by or -N(R3); -13o provided that when J is hydrogen or G is selected C from -S(0) 2 S0 2 or C(O)C(O)-Y, Swherein Y is 0; then D is not hydrogen; and x is 0 or 1.
C 5 According to a preferred embodiment, each of A and B in formula is (CI-Cio) straight or branched S'alkyl, wherein 1-2 hydrogen atoms in said alkyl are
VO
optionally substituted with E.
SIn another preferred embodiment, B is hydrogen.
c( l 10 According to another preferred embodiment, each Sof A and B in formula is -CH 2
-CH
2 -E or -CH 2
-CH
2
-CH
2
-E.
According to another preferred embodiment, D in formula is (Ci-C7) straight or branched alkyl, E or [(Ci-C 6 )-straight or branched alkyl]-E.
According to a more preferred embodiment, D is .an aromatic .monocyclic or bicyclic ring system, wherein each ring comprises 5-7 ring atoms independently selected from C, N, 0 or S, and wherein no more than 4 ring atoms are selected from N, 0 or S.
According to an even more preferred embodiment, D is phenyl or CI-C straight or branched alkyl group.
According to another preferred embodiment, E in formula is a monocyclic or bicyclic aromatic ring system, wherein said ring comprises 5-7 ring atoms independently selected from C, N, N(R 3 O, S, or S(0)2, and wherein 1 to 4 ring atoms are independently selected from N, N(R 3 0, S, or S(0)2.
Preferred embodiments of E include phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, -14o isothiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, C pyrimidinyl, 1,3,5-trazinyl, 1,3,5-trithianyl, Sbenzo[b]furanyl, benzo(b]thiophenyl, purinyl, cinnolinyl, phthalazinyl, isoxazolyl, triazolyl,.oxadiazolyl, C 5 pyrimidinyl, pyrazinyl, indolinyl, indolizinyl, isoindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, h .isoquinolinyl, quinazolinyl, quinoxalinyl,
NO
1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, o phnazinyl, phenothiazinyl, phenoxazinyl and in benzothiazolyl, wherein E is optionally substituted as Sdescribed above.
More preferred embodiments of E include phenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolyl,. isoindolyl, benzimidazolyl, benzothiophenyl,. uinolinyl, isoquinolinyl, and benzothiazolyl, wherein E is optionally substituted as described above.
According to another preferred embodiment, J is H, methyl, ethyl or benzyl; and K is selected from (C 1
-C
6 )-straight or branched alkyl, (C 2 -Cs)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E.
According to another preferred embodiment, J and K, taken together with the nitrogen atom, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R 3 O, S, S(O), or wherein 1 to 4 hydrogen atoms in said heterocyclic ring.are optionally and independently o replaced with (C1-C)-straight or branched alkyl, (C (C 2
-C
6 )-straight or branched alkenyl or alkynyl, oxo, Shydroxyl or Z; and wherein any -CH2- group said heterocyclic ring is optionally and independently C( 5 replaced by or and wherein said heterocyclic ring is optionally fused with E.
According to yet another preferred embodiment, o X is selected from -CH 2
CH
2 -CH=CH-, -C(OH)CH 2
-CH
2
-C(F)=CH
2
-CH
2
-C(S)NR
1 o -C(0)CH 2 CH(OH)-, -C(OH)CF 2
-C(O)CF
2
-CH(F)CH
2
N."
-C(F)
2
CH
2
-CH
2
-CH
2
C(F)
2 or N The compounds of formula 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. It is preferred that the substituent in the. 2 position have the S configuration.
The compounds of the present invention may be readily prepared using known synthetic methods. For synthetic methods for the preparation of X, which are amide bond bioisosteres see: "Peptidomimetics Protocols" in Methods on Molecular Medicine,. Vol 30, 1999, Humana Press, Totowa New Jersey, Kazmierski, Ed.
Examples of synthetic schemes that may be used to produce the compounds of this invention are set forth in Schemes 1 through 6 below.
C Scheme 1 JF/ P b e Noc occ SK 1 K 1 K K d PPh c J,'oc A K K SN A JNN A 2 1 a p-toluenesulfonyl chloride; diisopropylethylamine and
CH
2 C12; b Nal and acetone; followed by PPh3 and
O
H A toluene; c NaH, and THF; followed by .d Pd/C, H 2 gas, and MeOH; e HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH 2 )x-Br, K 2
CO
3 and DMF if (G)x (CH 2 or diisopropylethylamine, and
CH
2 C1 2 if wherein X is 0 or 1.
-17- Scheme 2 K K JNocO>Y a
K
CT b
K
K j1< C
N
K K, D-cx S 3 1.
a =HOBT, EDC, and CH 2 C12; Lawesson's reagent and toluene; c HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH 2 )x-Br, K 2 C0 3 and DMF if or D-C(O)-Cl, diisopropylethylaine, and 0H 2 C1 2 if wherein X is 0 or 1.
(CH
2 )x-Br, K 2 C9 3 and DMF if (G)x (CH 2 or D-C(O)-C1, diisopropylethylanine, and CH 2 Cl 2 if wherein X is 0 or 1.
Scheme 3 KH K N a JB iT AB IQCYN Oc 1 3
NH
2 A
AN
K K K K, N C
N
NA: N7~ b a H 2
NNH
2
.H
2 0, and ethanol; b NaN 2 acetic acid, and
H
2 0; c HC1(g)/ethyl acetate or TFA/dichloromethane; followed by (CH 2
K
2 C0 3 and DMF if (CH 2 or D- -1so C(O)-Cl, diisopropylethylaxine, and CH 2 Cl 2 if o wherein X is 0 or 1.
Scheme 4 '4K
K
1 0 K\/Kl0 b ~N>$KH a- l v S0 CH 3 C lI Kl K. 0( Thi KKK K .K 1 K 0 K K 1
FF
z I Aocx BOC 6 a =N,O-dimethylhydroxylanine hydrochloride, EDC, diisopropylethylamine, and C11 2 C1 2 b =3- (trirethylsilyl)propargyl magnesium bromide and THF; c= Bu 4 NF/THF; d aryl halide (]Br or (Ph 3
P)
4 Pd(0), Et 3
N,'
and THF; e 5% Pd/C, H'2 (1 atm) and MeGH; f Et 2
N-SF
3 and C11 2 C1 2 g NaBH 4 'and NeON,, when X' =CH (OH) or DAST, and CH 2 Cl 2 when X CEF; hi HCl /ethyl acetate or TFA/dichloromethane; followed by (CH 2
K
2 00 3 and DNF if (CH 2 or D-C(O)-C1, diisopropylethylanine, and
CH
2 C1 2 if wherein x is 0 or 1; z 0 or 1; and X' -CH(OH)- or -CHF-.
-19- Scheme Pps a
N
SBZ
K1 NA
CBZ
K
N
&BZ B ,Ab
C
K F
A
6B 67B K K, JIIN A D I) F- NaH and TEF;"followed by aldehyde derivative; b= NBS, Bu 4 NF/HF, and CE 2 C1 2 followed by KQLBu, and Et 2 O; C= 'P145, and CH 3 CN; followed by (CH 2
K
2 C0 3 and DMF if
(CH
2 or diisopropylethylamine, and
CH
2 Cl 2 if wherein x is Q-or 1.
Scheme 6
OC
K K 1 0 b Boc K KI 0 J -N zL A c
B
d, e K K 1 z K K FF JN N A
BOC
d K K FF JN A D N z a N,O-dimethylhydroxylamine hydrochloride, EDC, MgBr'
"A
diisopropylethylamine, and CH 2 C12; b B and THF; c Et 2
N-SF
3 and CH 2 C1 2 d NaBH 4 and MeOH, when X' CH(OH), or DAST and CH 2 C1 2 when X CHF; e HCl(g)/ethyl acetate or TFA/dichloromethane; followed by (CH 2 )x-Br,
K
2 C0 3 and DMF if (G)x (CH 2 or D-C(O)-C1, diisopropylethylamine, and CH 2 C1 2 if wherein x is 0 or 1; z 0 or 1; and X' -CH(OH)- or
-CHF-.
One of skill in the art will also be well aware of analogous synthetic methods for preparing compounds of formula According to another embodiment, this invention provides compositions comprising a compound of formula and a pharmaceutically acceptable carrier.
-21- 0 Pharmaceutically acceptable carriers that may C be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum rC 5 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 V 10 chloride, zinc salts, colloidal silica, magnesium o 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 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 -22- 0 neurotrophic factors (CNTF), glial cell line-derived C( neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and Sneurotrophin 4/5 The most preferred neurotrophic factor in the compositions of this invention C( 5 is NGF.
As used herein, the described compounds used in 0" the pharmaceutical compositions and methods of this invention, are defined to include pharmaceutically o acceptable derivatives thereof. A "pharmaceutically acceptable derivative" denotes any pharmaceutically o 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, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, -23o succinate, tartrate, thiocyanate, tosylate and C- undecanoate. Base salts include ammonium salts, alkali metal .salts, such as sodium and-potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, (C 5 salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts .with amino acids 0 such-as arginine, lysine, and so forth. Also,-the basic nitrogen-containing groups can be quaternized with such o agents as lower alkyl halides, such as methyl, ethyl, tV 10' propyl, and butyl chloride, bromides and iodides; dialkyl o sulfates, such as dimethyl, diethyl, dibutyl and dianyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
The described compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given .biological system blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, -24o intramuscular, intra-articular, intra-synovial, C intrasternal, intrathecal, intrahepatic, intralesional Sand intracranial injection or infusion techniques.
Preferably, the compositions are administered orally, C- 5 intraperitoneally or intravenously.
Sterile injectable forms of the compositions of O .this invention may be aqueous or oleaginous suspension.
VO
These suspensions may be formulated according to o techniques known in the art using suitable dispersing or c-I I) 10 wetting agents -nd suspending agents. The sterile o injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution.in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In o the case of tablets for oral use, carriers which are 0 commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule ci 5 form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient' is -combined with emulsifying
IND
and suspending agents. If desired, certain sweetening, o flavoring or coloring agents may also be added.
I) 10 Alternatively; the. pharmaceutical compositions 0of this invention may be administered in the form. of cisuppositories for rectal administration. These can be prepared by mixing the agent with a 'suitable non-irritating excipient which-is solid at room temperature but liquid at rectal temperature and therefore' will melt in the rectum to release the drug.
Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment -26- In o containing the active component suspended or dissolved in ci one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid ci 5 petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical Va compositions can be'formulated in a suitable lotion or ci o cream containing the active components suspended or ci IV) 10 dissolved in one or more pharmaceutically acceptable ocarriers. Suitable carriers include, but are not limited ci to, mineral oil, sorbitan monostearate, polysorbate cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also-be administered by nasal aerosol or inhalation.. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
-27- O The amount of both a described compound and the optional neurotrophic factor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the Ci 5 particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 100 mg/kg body weight/day of the described
NO
compound'can be administered. If a neurotrophic factor ci ois present in the composition, then a dosage of between I 10 0.01 pg 100 mg/kg body weight/day of the neurotrophic ofactor can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen 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, diet,.. time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredients will also depend upon the particular described compound and neurotrophic factor in the composition.
According to another embodiment, this invention provides methods for promoting repair or preventing neuronal damage or neurodegeneration in vivo or in an ex vivo nerve cell. Such methods comprise the step of treating nerve cells with any of the compounds described above. Preferably, this method promotes repair or prevents neuronal damage or neurodegeneration in a patient, and the compound is formulated into a -28o composition additionally comprising a pharmaceutically Ci acceptable carrier. The amount of the compound utilized Sin these methods is between about 0.01 and 100 mg/kg body weight/day.
Ci 5 According to an alternate embodiment, the method of promoting repair or preventing neuronal damage 0 or neurodegeneration comprises the additional step of
VO
treating nerve cells with a neurotrophic factor, such as Sthose contained in the pharmaceutical compositions of i) this invention. This embodiment includes administering Sthe compound and the neurotrophic agent in a. single dosage form or in separate, multiple dosage forms. If separate dosage forms are utilized, they may be administered concurrently, consecutively or within less than about 5 hours of one another.
Preferably, the methods of this invention are used to stimulate axonal growth in nerve cells. The compounds are, therefore, suitable for treating or preventing neuronal damage caused by a wide variety of diseases or physical traumas. These include, but are not limited to, Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, Tourette's syndrome, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, spinal cord injuries and facial nerve crush.
In a particularly preferred embodiment of the invention, the method is used to treat a patient suffering from trigeminal neuralgia, glosspharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, -29o progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome's, Scervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, such as those caused by lead, dapsone, ticks, or porphyria, other peripheral myelin-disorders, Alzheimer's disease, D Gullain-Barre syndrome, Parkinson's disease and other i Parkinsonian disorders, ALS, Tourette's syndrome, 0 multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural Sparopathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, neuropathy associated with diabetes, spinal cord injuries, facial nerve crush and other trauma, chemotherapy- and other medication-induced neuropathies, and Huntington's disease.
More preferably, the compositions of the present invention are used for treating Parkinson's disease, amylotrophic lateral sclerosis, Alzheimer's disease, stroke, neuralgias, muscular atrophies, and Guillain-Barr4 syndrome.
For use of the compounds according to the invention as medications, they are administered in the form of a pharmaceutical preparation containing not only the active ingredient but also carriers, auxiliary substances, and/or additives suitable for enteric or parenteral administration. Administration can be oral or sublingual as a solid in the form of capsules or tablets, as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions, or rectal in the form of suppositories, or in the form of solutions for injection can be given subcutaneously, intramuscularly, or 0q intravenously, or which can be given topically or intrathecally. Auxiliary substances for the desired medicinal formulation include the inert organic and inorganic carriers known to those skilled in the art, such as water, gelatin, gum arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene
IN
*-glycols, etc. The medicinal formulations may also ci o contain preservatives, stabilizers, wetting agents, ci emulsifiers, or salts to change the osmotic pressure or oas buffers.
Solutions or suspensions for injection are suitable for parenteral administration, and especially aqueous solutions of the active compounds in polyhydroxy-ethoxylated castor oil.
Surface-active auxiliary substances such as salts of gallic acid, animal or vegetable phospholipids, or mixtures of them, and liposomes or their components, can be used as carrier systems.
The neurotrophic effect of the compounds of formula of the present invention and their physiologically acceptable salts can be determined by the methods of W. E. Lyons et al., Proc. Natl. Acad. Sci.
USA, Vol. 91, pp. 3191-3195 (1994) and W. E. Lyons et al., Proc. Natl. Acad. Sci. USA, Vol. 91, pages 3191-3195 (1994), the disclosures of which are herein incorporated by reference.
In order-that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are -31not to be construed as limiting the scope of the invention in any way.
EXAMPLE 1 Compounds 100-295 Compounds 101-296 are synthesized via the method set forth in Scheme 1, above. In all of the examples, "Ph" is phenyl.
Compounds 100-148 have the formula:
A
1)
B
D with the individual variables defined in the table below.
Cmpd A G)x-D 100 -CH3 101 Same as above -CH2CH 3 102 Same as above -C(=O)-CH 3 103 .Same as above -CH2-Ph 104 Same as above -C(=O)-Ph 105 Same as above -C(=O)-O-CH 2 -Ph 106 Same as above 107 -CH3 108 Same as above -CH 2
CH
3 -32- Cmpd A -(G)x-D 109 Same as above -C(=O)-CH3 110 Same as above -CH2-Ph 111 Same as above -Ph 112 Same as above C -O-CH 2 -Ph 113 Same as above 114 -CH3 115 Same as above -CH2CH3 116 Same as above -C(=0)-CH3 117 Same as above -CH2-Ph 118 Same as above -C(=O)-Ph 119 Same as above -O-CH2-Ph 120 Same as above 121 -CH3 122 Same as above -CH 2
CH
3 123 Same as above -CH3 124 Same as above -CH 2 -Ph 125 Same as above -C(=0)-Ph 126 Same as above -C(=0)-O-CH 2 -Ph 127 Same as above 128 -CH3 129 Same as above -CH 2
CH
3 130 Same as above -C(=O)-CH3.
131 Same as above -CH2_Ph 132 Same as above -C(=O)-Ph 133 Same as above -C -O-CH2-Ph 134 Same as above 135 -CH3 136 Same as above -CH 2
CH
3 137 Same as above -C(=O)-CH 3 138 Same as above -CH2-Ph 139 Same as above -C(=0)-Ph 140 Same as above -C(=0)-O-CH 2 -Ph -33- Cmpd A -(G)x-D 141 Same as above 142
-C
H3 143 Same as above -CH 2
CH
3 144 Same as above -CH3 145 Same as above -CH 2 Ph 146 Same as above -C(=0)-Ph 147 Same as above -C(=O)-O-CH2-Ph 148 Same as above Compounds 149-197 have the formula:
A
N B D x with the individual variables defined in the table below.
Cmpd A -(G)x-D 149 -CH3 1 1 150 Same as above -CH 2
CH
3 151. Same as above -C(=O)-CH3 152 Same as above -CH2-Ph 153. Same as above -C(=O)-Ph 154 Same as above -C(=0)-O-CH 2 -Ph 155 Same as above -34- Cmpd A -(G)x-D 156 -CH3 157 Same as above -CH 2 CH3 158 Same as above -C(=O)-CH3 159 Same as above -CH2-Ph 160 Same as above -C(=O)-Ph 161 Same as above -C -O-CH 2 -Ph 162 Same as above 163 -CH3 164 Same as above -CH 2
CH
3 165 Same as above -CH 3 166 Same as above -CH2_Ph 167 Same as above -C(=0)-Ph 168 Same as above -C(=0)-0-CH 2 -Ph 169 Same as above 170 -CH3 171 Same as above -CH 2
CH
3 172 Same as above -C(=O)-CH3 173 Same as above -CH2-Ph 174 Same as above -C(=0)-Ph 175 Same as above -C(=0)-O-CH 2 -Ph 176 Same as above -C 177 -CH3 178 Same as above -CH 2
CH
3 179 Same as above -C(=O)-CH 3 180 Same as above -CH2-Ph 181 Same as above -C(=O)-Ph 182 Same as above -C -O-CH 2 -Ph 183 Same as above Cmpd A -(G)x-D
B
184
-CH
3 185 Same as above -CH 2
CH
3 186 Same as above -C(=0)-CH 3 187 Same as above -CH2-Ph 188 Same as above -C(=O)-Ph 189 Same as above -C (=0)-O-CH 2 -Ph 190 Same as above 191 C H 3 192 Same as above -CH 2
CH
3 193 Same as above
-CH
3 194 Same as above -CH 2 .Ph 195 Same as above -C(=O)-Ph 196 Same as above -C(=O)-O-CH 2 -Ph 197 Same as above Compounds 198-246 have the formula:
A
B
D with the individual variables defined in the table below.
Cmpd A -(G)x-D
-B
198
-C
H 3 199 Same as above -CH 2
CH
3 200 Same as above -C(=O)-CH 3 -36- Cmpd A (G)x-D 201 Same as above -CH 2 -Ph 202 Same as above -C(=O)-Ph 203 Same as above -O-CH 2 -Ph 204 Same as above 205 -CH3 206 Same as above -CH2CH 3 207 Same as above -C(=O)-CH 3 208 Same as above -CH 2 .Ph 209 Same as above -C(=0)-Ph 210 Same as above -C -O-CH2-Ph 211 Same as above -C -Ph 212 -CH 3 213 Same as above -CH2CH3 214 Same as above -C(=O)-CH3 215 Same as above -CH2-Ph 216 Same as above -C(=O)-Ph 217 Same as above -O-CH 2 -Ph 218 Same as above 219 -CH3 220 Same as above -CH 2
CH
3 221 Same as above -C(=0)-CH 3 222 Same as above -CH2-Ph 223 Same as 'above -Ph 224 Same as above -C -O-CH 2 -Ph 225 Same as above -C(=0)-Ph 226
-CH
3 227 Same as above -CH 2
CH
3 228 Same as above -CH 3 -37- Cmpd A -(G)x-D 229 Same as above -CH-2Ph 230 Same as above -C(=0)-Ph 231 Same as above -C(=0)-0-CH 2 -Ph 232 Same as above 233 -CH3 234 Same as above -CH 2 CH3 235 Same as above -C(=O)-CH 3 236 Same as above -CH2-Ph 237 Same as above -C(=O)-Ph 238 Same as above -C(=O)-O-CH2-Ph 239 Same as above 240 -C H3 241 Same as above -CH2CH 3 242 Same as above -C(=0)-CH3 243 Same as above -CH 2 -Ph 244 Same as above -C(=0)-Ph 245 Same as above -C(=0)-0-CH 2 -Ph 246 Same as above Compounds 247-295 have the formula:
A
B
D x with the individual variables defined in the table below.
-38- Cmpd A -(G)x-D 247 -CH 3 248 Same as above -CH 2
CH
3 249 Same as above -C(=0)-CH 3 250 Same as above -CH2-Ph 251 Same as above -C(=0)-Ph 252 Same as above -C(=O)-O-CH 2 -Ph 253 Same as above 254 -CH 3 255 Same as above -CH 2 CH3 256 Same as above -C(=O)-CH3 257 Same as above -CH2-Ph 258 Same as above -C(=0)-Ph 259 Same as above -C -O-CH 2 -Ph 260 Same as above 261 -CH3 262 Same as above -CH 2
CH
3 263 Same as above -C(=0)-CH 3 264 Same as above -CH 2 -Ph 265 Same as above -C(=0)-Ph 266 Same as above -C(=0)-0-CH 2 -Ph 267 Same as above 268 -CH3 -39- Cmpd A 269 Same as above -CH 2 CH3 270 Same as above -CH3 271 Same as above -CH 2 -Ph 272 Same as above -C(=0)-Ph 273 Same as above -C(=0)-0-CH 2 -Ph 274 Same as above 275
-CH
3 276 Same as above -CH 2
CH
3 277 Same as above -C(=0)-CH3 278 Same as above -CH2_Ph 279 Same as above -C(=0)-Ph 280 Same as above -C (=0)-O-CH 2 -Ph 281 Same as above 282 -CH3 283 Same as above -CH 2
CH
3 284 Same as above -CH3 285 Same as above -CH 2 -Ph 286 Same as above -C(=0)-Ph 287 Same as above -O-CH 2 -Ph 288 Same as above 289 -CH 3 290 Same as above -CH 2
CH
3 291 Same as above -C(=0)-CH 3 292 Same as above -CH 2 -Ph 293 Same as above C(=0)-Ph 294 Same as above -O-CH 2 -Ph 295 Same as above EXAMPLE 2 Compounds 296-519 Compounds 296-519 are synthesized via the method set forth in Scheme 2, above.
Compounds 296-407 have the formula:
R'
A
N
DAx with the individual variables defined in the table below.
Cmpd A CH Cmpd A Ri -(G)x-D
B
296 H -CH3 297 Same as above H -CH 2
CH
3 298 Same as above H -C(=O)-CH3 299 -Same as above H -CH 2 -Ph 300 .Same as above H -C(=0)-Ph 301 Same as above H -C(=0)-O-CH 2 -Ph 302 Same as above H 303 Same as above CH 3 -CH3 304 Same as above CH3 -CH 2
CH
3 305 Same as above CH 3 -C(=O)-CH3 306 Same as above CH3 -CH 2 -Ph 307 Same as above CH 3 -C(=O)-Ph 308 Same as above CH 3
-C(=O)-O-CH
2 -Ph 309 Same as above CH 3 310 Same. as above CH 2
CH
3
-CH
3 311 Same as above CH 2
CH
3
-CH
2
CH
3 312 Same as above CH 2
CH
3 -CH3 313 Same as above CH 2
CH
3 -CH2-Ph 314 Same as above CE 2
CH
3 -C(=O)-Ph 315 Same as above CH 2
CH
3 2 -Ph 316 Same as above CH 2
CH
3 -C 317 Same as above CH2Ph -CH 3 318 Same as above CH 2 Ph -CH 2 CH3 319 Same as above CH 2 Ph -C(=O)-CH3 320 Same as above Ck 2 Ph -CH 2 _Ph 321 Same as above CH 2 Ph -C(=O)-Ph -41- Cmpd# A x-D i'L B 322 Same as above CH 2 Ph -C -O-CH2-Ph 323 Same as above CH 2 Ph 324 H -CH3 325 Same as above H -CH 2
CH
3 326 Same as above H -C(=0)-CH 3 327 Same as above H -CH 2 -Ph 328 Same as above H -C(=0)-Ph 329 Same as above H -C(=0)-0-CH 2 -Ph 330 Same as above H 331 Same as above CH3 -CH3 332 Same as above CH 3
-CH
2
CH
3 333 Same as above CH 3 -C(=0)-CH 3 334 Same as above CH 3
-CH
2 -Ph 335- Same as above CH 3 -C(=0)-Ph 336 Same as above CH 3 -C(=0)-0-CH 2 -Ph 337 Same as above CH3 338 Same as above CH 2
CH
3 -CH3 339 Same as above CH 2
CH
3
-CH
2
CH
3 340 Same as above CH 2
CH
3 -C(=O)-CH3 341 Same as above CH 2
CH
3 -CH2-Ph 342 Same as above CH 2
CH
3 343 Same as above CH 2
CH
3 -C -O-CH 2 -Ph 344 Same as above CH 2
CH
3 345 Same as above CH 2 Ph -CH3 346 Same as above CH 2 Ph -CH 2 CH3 347 Same as above CH 2 Ph -C(=0)-CH3 348 Same as above CH 2 Ph -CH 2 -Ph 349 Samne as above CH 2 Ph -C(=0)-Ph 350 Same as above CH 2 Ph -C(=0)-0-CH 2 -Ph 351 Same as above CH 2 Ph 352 N H -CH3 353 Same as above H -CH 2
CH
3 -42- Cmpd AR (G)-D 354 Same as above H -C(=O)-CH3 355 Sane as above H -CH 2 -Ph 356 Same as above H -CV=O)-Ph 357 Same as above H -C(=O)-O-CH 2 -Ph* 358 Same as above H 359 Sane as--above CH3 -CH3 360 Same as bove CM 3
-CH
2 CH3 361 Same as above CM 3
-CM
3 362 Same as above CH 3
-CH
2 -Ph 363 Same as above CH 3 -C(=O)-Ph 364 Same as above CH 3
-C(=O)-Q-CH
2 -Ph 365 Same as above CM 3 -C -C -Ph 366 Same as above CH 2
CH
3 -CH3 367 Same as above CM 2
CM
3
-CH
2 C 3 368 Same as above CH 2
CH
3 -C(=O)-CH3 Same .as, above CH 2
CH
3
-CH
2 -Ph 370 Same as above CH 2
CH
3 -C(=O)-Pb 371 Same as above CH 2 CHJ -C(=O)-O-CH 2 -Ph 372 Same as above CM 2
CH
3 373 Same as above CH 2 Ph -CH3 374 Sane as above CH 2 Ph -CH 2
CH
3 375 Same as above CH 2 Ph -C(=O)-CH3 376 Same as above CH 2 Ph -CH2-Ph 377 Same as above CH 2 Ph -C(=O)-Ph 378 Same as above CH 2 Ph -C(=O)-O-CH 2 -Ph 379 Same as above CH 2 Ph 380 H -CH 3 381 Same as above H -CH 2
CH
3 382 Same as above H -C(=O)-CH 3 383 Same as above H -CH 2 -Ph 384 Same as above H -C(=O)-Ph 385 Same as above H -C(=O)-O-CH 2 -Ph 386 Same as above H 387 Same as above CH 3 -CH3 388 Same as above CH 3
-CH
2
CH
3 389 Same as above CH 3
-C(=O)-CH
3 390 Same as above CH 3
-CM
2 -Ph 391 Same as above CH 3 -C(=O)-Ph 392 Same as above CM 3 -C(=O)-0-CH 2 -Ph 393 Same as above CH 3 -43- Cmpd A R x-D 39 SaBas above CH2CH3 -CH3 394 Same as above CH 2
CH
3 -CH2CH 3 395 Same as above CH 2
CH
3 -0 C 2
CH
3 396 Same as .above CH 2
CH
3 -C(=0)-CH 3 397 Same as above CH 2
CH
3
-CH
2 -Ph 398 Same as above CH 2
CH
3 -C (=0)-Ph 399 Same as above CH 2
CH
3 -C -0-CH 2 -Ph 400 bame as above CH 2
CH
3 -C -Ph 401 Same as above CH 2 Ph -CH 3 402 Same as above CH 2 Ph -CH2CH 3 403 Same as.above CH 2 Ph -C -CH3 404 Same as above CH 2 Ph -CH 2 -Ph 405 Same as above CH 2 Ph -C(=0)-Ph 406 Same as above CH 2 Ph -C -O-CH2-Ph 407 Same as above CH 2 Ph Compounds 408-519 have the formula: R1 N N A x ,with the individual variables defined in the table below.
cmpd A R -(G)x-D
B
408 H -CH3 409 Same as above H -CH 2
CH
3 410 Same as above H -CH3 411 Same as above H -CH 2 -Ph 412 Same as above H -C(=O)-Ph 413 Same as above H -C(=O)-0-CH 2 -Ph -44- Cmpd A Ri (G)-D 414 Same as above H 415 Same as above CH 3 -CH3 416 Same as above CH3 -CH 2 CH3 417 Same as above CH 3 -C(=O)-CH3 418 Same as above CH 3
-CH
2 -Ph 419 Same as above CH3 -C(=0)-Ph 420 Same as above CH 3 -C -O-CH 2 -Ph 421 Same as above CH 3 422 Same as above CH 2
CH
3 -CH3 423 Same as above CH 2
CH
3
-CH
2 CH3 424 Same as above CH 2 CH3 -C(=0)-CH3 425 Same as above CH 2
CH
3
-CH
2 -Ph 426 Same as above CH 2
CH
3 -C(=0)-Ph 427 Same as above CH 2
CH
3 -C -O-CH2-Ph 428 Same as above CH 2
CH
3 429 Same as above CH 2 Ph -CH3 430 Same as above' CH 2 Ph -CH 2 CH3 431 Same as above CH 2 Ph -C(=0)-CH 3 432 Same as above CH 2 Ph -CH2-Ph 433 Same as above CH2Ph -C(=0)-Ph 434 Same as above CH 2 Ph -C(=0)-O-CH2-Ph 435 Same as above CH 2 Ph 436 H -CH3 437 Same as above H -CH 2
CH
3 438 Same as above H -C(=O)-CH3 439 Same as above H -CH 2 -Ph 440 Same as above H -C(=0)-Ph 441 Same as above H -C(=0)-O-CH2-Ph 442. Same as above H 443 Same as above CH 3
-CH
3 444 Same as above CH 3
-CH
2
CH
3 445 Same as above CH 3 -C(=O)-CH3 446 Same as above CH 3
-CH
2 -Ph 447 Same as above CH 3 -C(=0)-Ph 448 Same as above CH 3 -C(=0)-0-CH 2 -Ph 449 Same as above CH 3 450 Same as above CH 2
CH
3
-CH
3 451 Same as above CH 2
CH
3
-CH
2 CH3 452 Same as above CH 2
CH
3 -C(=0)-CH 3 453 Same as above CH 2
CH
3 -CH2-Ph Cmpd A Ri 454 Same as above CH 2
CH
3 -C -Ph 455 Same as above CH 2
CH
3 -C (=0)-0-CH 2 -Ph 456 Same as above CH 2
CH
3 457 Same as above CH 2 Ph -CH3 458 Same as above CH 2 Ph -CH 2
CH
3 459 Same as above CH 2 Ph -C(=0)-CH 3 460 Same as 'above CH2Ph -CH2-Ph 461 Same as above CH 2 Ph -C(=0)-Ph 462 Same as above CH 2 Ph -O-CH 2 -Ph 463 Same as above CH 2 Ph 464 N H -CH3
NJ
4-- 465 Same as above H -CH 2
CH
3 466 Same as above H -C(=O)-CH3 467 Same as above H -CH 2 -Ph 468 Same as above H -C(=0)-Ph 469 Same as above H -C(=0)-D-CH 2 -Ph 470 Same as above H 471 Same as above CH 3 -CH3 472 Same as above CH 3
-CH
2
CH
3 473 Same as above CH3 -C(=0)-CH 3 474 Same as above CH 3
-CH
2 -Ph 475 Same as above CH 3 -C(=0)-Ph 476 Same as above CH 3 -C(=0)-0-CH 2 -Ph 477 Same as above CE 3 -C 478 Same as above CH 2
CH
3 -CH3 479 Same as above CH 2
CH
3
-CH
2
CH
3 480 Same as above CH 2
CH
3
-C(=O)-CH
3 481 Same as above CH 2
CH
3
-CH
2 -Ph 482 Same as above CH 2
CH
3 -C(=0)-Ph 483 Same as above CH2CH 3 -C(=0)-0-CH2-Ph 484 Same as above CH 2
CH
3 485 Same as above CH2Ph -CH3 486 Same as above CH 2 Ph -CH 2
CH
3 487 Same as above CH 2 Ph -C(=O)-CH 3 -46- Cmpd A R x-D
B
488 Same as above CH 2 Ph -CH 2 -Ph 489 Same as above CH 2 Ph -C(=0)-Ph 490 Same as above CH 2 Ph -C(=0)-O-CH 2 -Ph 491 Same as above CH2Ph 492 H -CH3 493 Same as above H -CH 2
CH
3 494 Same as above H -C(=0)-CH 3 495 Same as above H -CH 2 .Ph 496 Same as above H -C(=0)-Ph 497 Same as above H -C(=0)-O-CH 2 -Ph 498 Same as above H 499 Same as above CH 3
-CH
3 500 Same as above CH 3
-CH
2 CH3 501 Same as above .CH 3 -C(=0)-CH 3 502 Same as above CH 3
-CH
2 -Ph 503 Same as above CH 3 -C(=0)-Ph 504 Same as above CH 3 -C(=0)-0-CH2-Ph 505 Same as above CH 3 506 Same as above CH 2
CH
3 -CH3 507 Same as above CH 2
CH
3
-CH
2
CH
3 508 Same as above CH 2
CH
3 -C(=O)-CH3 509 Same as above CH 2
CH
3
-CH
2 -Ph 510 Same as above CH 2
CH
3 -Ph 511 Same as above CH 2 CH3 -C -0-CH 2 -Ph 512 Same as above CH 2
CH
3 -Ph 513 Same as above CH 2 Ph -CH3 514 Same as above CH2Ph -CH 2 CH3 515 Same as above CH 2 Ph -C(=0)-CH3 516 Same as above CH 2 Ph -CH 2 ,Ph 517 Same as above CH 2 Ph -C(=0)-Ph 518 Same as above CH 2 Ph -C -O-CH 2 -Ph 519 Same as above CH 2 Ph -47- EXAMPLE 3 Compounds 520-561 Compounds 520-561 are synthesized via the method set forth in Scheme 3, above.
.Compounds 520-540 have the formula: A B NN D x with the individual variables defined in the table below.
Cmpd A -(G)x-D 520 -CH3 521 Same as above -CH 2
CH
3 522 Same as above -C(=0)-CH 3 523 Same as above -CH2-Ph 524 Same as above -C(=O)-Ph 525 Same as above -C -O-CH 2 -Ph 526 Same as above 527 -CH3 528 Same as above -CH 2
CH
3 529 Same as above -C(=0)-CH 3 530 Same as above -CH2-Ph 531 Same as above -C(=0)-Ph 532 Same as above -C -0-CH 2 -Ph 533 Same as above 534 N -CH3 -48- Cmpd -(G)x-D
B
535 Same as above -CH 2 CHj 536 Same as above -C(=O)-CH 3 537 Same as above -CH2-Ph 538 Same as above -C(=O)-Ph 539 Same as above -C -O-CH 2 -Ph 540 Same as above Compounds 541-561 have the formula: A B
N
N
D 'x with the individual variables defined in the table below.
Cmpd A -(G)x-D 541 -CH 3 542 Same as above -CH 2
CH
3 543 Same as above -C(=0)-CH3 544 Same as above -CH 2 .Ph 545 Same as above -C(=O)-Ph 546 Same as above -C(=O)-O-CH 2 -Ph 547 Same as above 548 -CH3 549 Same as above -CH 2
CH
3 550 Same as above -C(=O)-CH3 551 Same as above -CH2-Ph 552 Same as above -C(=0)-Ph 553 Same as above -C(=O)-O-CH 2 -Ph -49- Cmpd A -D 554. Same as above 555 -CH3 556 Same as above -CH2CH 3 557 Same as above -C(=O)-CH 3 558 Same as above -CH2-Ph 559 Same as above -C(=0)-Ph 560 Same as above -C(=O)-0-CH 2 -Ph 561 Same as above EXAMPLE 4 Compounds 562-771 Compounds 562-771 are synthesized via the method set forth in Scheme 4 or Scheme 6, above.
Compounds 562-596 have the formula:
H
0 with the individual variables defined in the table below.
Cmpd A -(G)x-D 562 -CH 3 563 Same as above -CH 2
CH
3 564 Same. as above -C(=0)-CH 3 565 Same as above -CH2-Ph 566 Same as above -C(=0)-Ph 567 Same as above -C -O-CH 2 -Ph 568 Same as above Cmpd A -(G)x-D 569 -CH 3 570 Same as above -CH 2
CH
3 571 Same as above -C(=0)-CH 3 572. Same as above -CH2-Ph 573 Same as above -C(=0)-Ph 574 Same as above -C(=0)-O-CH 2 -Ph 575 Same as above -C 576 -CH3 577 Same as above -CH 2
CH
3 578 Same as above -C(=O)-CH3 579 Same as above -CHzPh 580 Same as above -C(=O)-Ph 581 Same as above -C(=0)-O-CH 2 -Ph 582 Same as above -C -C -Ph 583' -CH3 584 Same as above -CH 2
CH
3 585 Same as above -C(=0)-CH 3 586 Same as above -CH 2 -Ph 587 Same as above -C(=O)-Ph 588 Same as above -C(=O)-O-CH 2 -Ph 589 Same as above 590 -CH3 591 Same as above -CH 2
CH
3 592 Same as above -C(=0)-CH 3 593 Same as above -CH 2 -Ph 594 Same as above -C(=O)-Ph 595 Same as above -C(=O)-0-CH 2 -Ph 596 Same as above Compounds 597-631 have the formula: -51- HO A D with the individual variables defined in the table below.
Cmpd A -(G)x-D 597 -CH 3 598 Same as above -CH 2
CH
3 599 Same as above -C(=O)-CH3 600 Same as above -CH 2 .Ph 601 Same as above -C(=0)-Ph 602 Same as above -C(=O)-O-CH 2 -Ph .603. :Same.as above (=O)-Ph 604
-CH
3 605 Same as above -CH 2
CH
3 606 Same as above -C (=0)-CH 607 Same as above -CH2-Ph 608 Same as above -C(=O)-Ph 609 Same as above -C(=O)-O-CH 2 -Ph 610 Same as above 611 -CH3 612 Same as above -CH 2
CH
3 613 Same as above -C(=O)-CH 3 614 Same as above -CH2-Ph 615 Same as above -C(=O)-Ph 616 Same as above -C(=0)-O-CH 2 -Ph 617 Same as above 618 -CH3 619 Same as above -CH 2
CH
3 620 Same as above -C(=0)-CH 3 621 Same as above -CH2-Ph 622 Same as above -C(=O)-Ph -52- Cmpd A x-D 623 Same as above -C(=0)-O-CH 2 -Ph 624 Same as above 625 -CH3 626 Same as above -CH 2 CH3 627 Same as above -C(=0)-CH 3 628 Same as above -CH 2 -Ph 629 Same as above -C(=O)-Ph 630 Same as above -C(=0)-O-CH 2 -Ph 631 Same as above Compounds 632-666 have the formula: 0 .A with the individual variables defined in the table below.
Cmpd A -(G)x-D 632 CH3 633 Same as above -CH 2
CH
3 634 Same as above -C(=O)-CH 3 635 Same as above -CH2_Ph 636 Same as above -C(=O)-Ph 637 Same as above 2 -Ph 638 Same as above 639
-CH
3 640 Same as above -CH 2
CH
3 641 Same as above -C(=0)-CH3 642 Same as above -CH2-Ph 643 Same as above -C(=0)-Ph 644 Same as above -O-CH2-Ph 645 Same as above 646 -CH3 -53- Cmpd A (G)x-D 647 Same as above -CH 2
CH
3 648 Same as above -C(=O)-CH3 649 Same as above -CH2-Ph 650 Same as above -C(=O)-Ph 651 Same as above -C(=O)-O-CH 2 -Ph 652 Same as above -Ph 653 CH3 654 Same as above -CH 2
CH
3 655 Same as above -C(=O)-CH 3 656 Same as above -CH 2 -Ph 657 Same as above -C(=O)-Ph 658 Same as above -C(=O)-O-CH 2 -Ph 659 Same as above 660 -CH 3 661 Same as above -CH 2
CH
3 662 Same as above -C(=O)-CH 3 663 Same as above -CH2-Ph 664 Same as above -C(=O)-Ph 665 Same as above -C(=O)-O-CH 2 -Ph 666 Same as above -C(=0)-Ph Compounds 667-701 have the formula:
NA
D with the individual variables defined in the table below.
Cmpd A -(G)x-D 667 -CH3 668 Same as above -CH 2
CH
3 669 Same as above -C(=O)-CH 3 670 Same as above -CH 2 aPh -54- Cmpd
(G)-D
671 Same as above -C(=0)-Ph 672 Same as above -C(=0)-O-CH 2 -Ph 673 Same as above 674
-CH
3 675 Same as above -CH 2
CH
3 676 Same as above -C(=0)-CH 3 677 Same as above -CH2-Ph 678 Same as above -C(=O)-Ph 679 Same as above -C(=0)-O-CH 2 -Ph 680 Same as above 681
-CH
3 682 Same as above -CH 2
CH
3 683 Same as above -C(=0)-CH 3 684 'Same as above -CH_2Ph 685 Same as above -C(=0)-Pb 686 Same as above -C(=0)-O-CH 2 -Ph 687 Same as above 688
-CH
3 689 Same as above -CH2CH 3 690 Same as above -C(=O)-CH 3 691 Same as above -CH2_Ph 692 Same as above -C(=0)-Ph 693 Same as above -C(=0)-O-CH 2 -Ph 694 Same as above 695 -CH 3 696 Same as above -CH 2
CH
3 697 Same as above -C(=O)-CH 3 698 Same as above -CH2-Ph 699 Same as above -C(=0)-Ph 700 Same as above -C(=0)-0-CH 2 -Ph 701 Same as above Compounds 702-736 have the formula: K K-F F J A D with the individual variables defined in the table below.
Cmpd A (G)x-D 702
-CH
3 703 Same as above -CH 2
CH
3 704 Same as above -C(=0)-CH 3 705 Same as above -CH 2 -Ph -706 Same as above 707 Same as above -C -O-CH2-Ph 708 -Same as above -C(=O)-Ph 709 -CH3 710 Same as above -CH 2 CH3 711 Same as above -C(=0)-CH 3 712 Same as above -CH 2 -Ph 713 Same as above -C(=0)-Ph 714 Same as above -C(=0)-O-CH 2 -Ph 715 -Same as above 716 /-CH 3 717 Same as above -CH2CH 3 718 Same as above -C(=0)-CH 3 719 Same as above -CH 2 -Ph 720 Same as above -C(=0)-Ph 721 Same as above -C -O-CH 2 -Ph 722 Same as above 723 N -CH3 724 Same as above -CH2CH3_ -56- Cmpd A (G)x-D 725 Same as above -C(=O)-CH 3 726 Same as above -CH2-Ph 727 Same as above -C(=0)-Ph 728 Same as above -C -O-CH 2 -Ph 729 Same as above -Ph 730 -CH3 731 Same as above -CH 2
CH
3 732 Same as above -C(=0)-CH 3 733 Same as above -CH2-Ph 734 Same as above -C(=0)-Ph 735 Same as above -C(=0)-O-CH 2 -Ph 736 Same as above Compounds 737-771 have the formula:
F
NA
A with the individual variables defined in the table below.
Cmpd A x-D 737 CH3 738 Same as above -CH 2
CH
3 739 Same as above -C(=0)-CH3 740 Same as above -CH2-Ph 741 Same as above -C(=O)-Ph 742 Same as above -C (=O)-O-CH2-Ph 743 Same as above -Ph 744 -CH3 745 Same as above -CH 2
CH
3 746 Same as above -C(=0)-CH 3 747 Same as above -CH 2 -Ph 748 Same as above -C(=O)-Ph 749 Same as above -O-CH 2 -Ph 750 Same as above -C -57- Cmpd A -(G)x-D 751 -CH 3 752 Same as above
-CH
2
CH
3 753 Same as above -C(=0)-CH3 754 Same as above -CH 2 .Ph 755 Same as above -C(=0)-Ph 756 Same as above -0-CH2-Ph 757 Same as above 758 N -CH3 759 Same as above -CH 2
CH
3 760 Same as above -C(=O)-CH 3 761 Same as above -CH 2 .Ph 762 Same as above -C(=O)-Ph 763 Same as above -C -O-CH 2 -Ph 764 Same as above 765
-CH
3 766 Same as above -CH 2
CH
3 767 Same as above -C(=0)-CH3 768 Same as above -CH 2 -Ph 769 Same. as above -C(=0)-Ph 770 Same as above -O-CH 2 -Ph 771 Same as above -Ph EXAMPLE Compounds 772-967 Compounds 772- are synthesized via the method set forth in Scheme 5, above.
Compounds 772-820 have the formula: -58-
A
D' 'x with the individual variables defined in the table below -59- Cmpd A -(G)x-D 772 -CH3 773 Same as above -CH2CH 3 774 Same as above -CH3 775 Same as above -CH2_Ph 776 Same as above -C(=O)-Ph 777 Same as above -C(=O)-0-CH 2 -Ph 778 Same as above 779 -CH3 780 Same as above -CH 2
CH
3 781 Same as above -C(=O)-CH 3 782 Same as above -CH2-Ph 783 Same as above -C(=O)-Ph 784 Same as above -O-CH2-Ph 785 Same as above 786 CH3 787 Same as above -CH 2
CH
3 788 Same as above -C(=O)-CH 3 789 Same as above -CH2_Ph 790 Same as above -C(=0)-Ph 791 Same as above -C(=0)-O-CH 2 -Ph 792 Same as above -Ph 793
-CH
3 Cmpd A 794 Same as above -CH 2
CH
3 795- Same as above -C(=O)-CH 3 796 Same as above -CH2-Ph 797 Same as above -C(=O)-Ph 798 Same as above -C(=O)-O-CH 2 -Ph 799 Same as above 800 -CH3 801 Same as above -CH 2
CH
3 802 Same as above -C(=0)-CH3 803 Same as above -CH 2 -Ph 804 Same as above -C(=0)-Ph 805 Same as above -C(=O)-O-CH 2 -Ph 806 Same as above 807 -CH3 808 Same as above -CH 2
CH
3 809 Same as above -C(=O)-CH 3 810 Same as above -CH 2 -Ph 811 Same as above -C(=0)-Ph 812 Same as above -C(=O)-O-CH 2 -Ph 813 Same as above 814 -CH3 815 Same as above -CH 2
CH
3 816 Same as above -C(=O)-CH 3 817 Same as above -CH2-Ph 818 Same as above -C(=0)-Ph 819 Same as above -C(=O)-O-CH 2 -Ph 820 Same as above Compounds 821-869 have the formula: -61-
F
A
B
x with the individual variables defined in the table below Cmpd A
-D
821
-CH
3 822 Same as above -CH 2 CH3 823 Same as above -C(=0)-CH3 824 Same as above -CH2-Ph 825 Same as above -C(=0)-Ph 826 Same as above -C(=0)-0-CH2-Ph 827 Same as above 828 -CH3 829 Same as above -CH 2
CH
3 830 Same as above -C(=0)-CH3 831 Same as above -CH2_Ph 832 Same as above -C(=0)-Ph 833 Same as above -C(=0)-0-CH2-Ph 834 Same as above 835 -CH3 836 Same as above -CH2CH 3 837 Same as above -C(=0)-CH 3 -62- Cmpd A -(G)x-D
B
838 Same as above -CH 2 .Ph 839 Same as above -C(=0)-Ph 840. .Same as above -C(=O)-0-CH 2 -Ph 841 Same as above 842 -CH 843 Same as above -CH 2
CH
3 844 Same as above -C(=O)-CH 3 845 Same as above -CH 2 -Ph 846 Same as above -C(=O)-Ph 847 Same as above -C(=0)-0-CH2-Ph 848 Same as above -Ph 849 -CH3 850 Same as above -CH 2
CH
3 851 Same as above -C(=O)-CH3 852 Same as above -CH2-Ph 853 Same as above -C(=0)-Ph 854 Same as above -C(=0)-O-CH 2 -Ph 855 Same as above 856 C -CH3 857 Same as above -CH2CH 3 858 Same as above -C(=0)-CH3 859 Same as above -CH 2 .Ph 860 Same as above -C(=O)-Ph 861 Same as above -C(=0)-O-CH2-Ph 862 Same as above 863 -CH3 864 Same as above -!CH 2 CH3 865 Same as above -C(=O)-CH 3 866 Same as above -CH2-Ph 867 Same as above -C(=O)-Ph 868 Same as above -C(=0)-O-CH 2 -Ph 869 Same as above -63- Compounds 870-918 have the formula:
A
NO B
F
D x with the individual variables defined in the table below Cmpd A -(G)x-D 870 -CH 3 871 Same as above -CH 2
CH
3 872 Same as above -C(=O)-CH 3 873 Same as above -CH 2 -Ph 874 Same as above -C(=0)-Ph 875 Same as above -C(=0)-O-CH2-Ph 876 Same as above 877 -CH3 878 Same as above -CH 2
CH
3 879 Same as above -C(=O)-CH 3 880 Same as above -CH2-Ph 881 Same as above -C{=0)-Ph 882 Same as above -C(=O)-O-CH 2 -Ph 883 Same as above -Ph -64- Cmpd A -D
B
884
-CH
3 885 Same as above -CH2CH 3 886 Same as above -C(=O)-CH 3 887- Same as above -CH2-Ph 888 Same as above -C(=0)-Ph 889 Same as above -C(=0)-0-CH 2 -Ph 890 Same as above 891 -CH3 892 Same as above -CH 2
CH
3 893 Same as above -C(=0)-CH 3 894 Same as above -CH2_Ph 895 Same as above -C(=0)-Ph 896 Same as above -C(=O)-O-CH 2 -Ph 897 Same as above 898 -CH3 899 Same as above -CH 2
CH
3 .900 Same as above -C(=0)-CH 3 901 Same as above -CH2-Ph 902 Same as above -C(=O)-Ph 903 Same as above -C(=O)-O-CH 2 -Ph 904 Same as above 905 -C H3 906 Same as above -CH 2 CH3 907 Same as above -C(=0)-CH3 908 Same as above -CH2-Ph 909 Same as above -C(=0)-Ph 910 Same as above -C(=0)-O-CH 2 -Ph 911 Same as above 912 S
-CH
3 913 Same as above -CH 2
CH
3 Cmpd A (x- 914 Same as above -C(=O)-CH 3 915 Seine as above -CH 2 -Pb .916 Same as above -Ph 917 'Same as above -C -O-CH 2 -Ph 918 Samne as above -C -C -Ph Compounds 919-967 have the formula:
F
A
B
the table below with the individual variables defined in Cmnpd A
B
919
-CH
3 920 Same as above -CH 2
CH
2 921 Same as above -C -CHr 922 Same as above -CH 2 -Ph 923 Samne as above -c -Ph 924 sane as above -C -O-C1 2 -Ph 925 samne as above -C -Ph -66- Cmpd A 926 -CH3 927 Same as above -CH 2 CH3 928 Same as above -C(=O)-CH 3 929 Same as above -CH2,Ph 930 Same-as above -C -Ph 931 Same as above -C(=O)-O-CH 2 -Ph 932 Same as above 933 -CH3 934 Same as above -CH2CH 3 935 Same as above -C(=O)-CH 3 936 Same as above -CH 2 -Ph 937 Same as above -C(=O)-Ph 938 Same as above -C(=O)-O-CH 2 -Ph 939 Same as above 940 -CH3 941 Same as above -CH 2
CH
3 942 Same as above -C(=O)-CH3 943 Same as above -CH2-Ph 944 Same as above -C(=O)-Ph 945 Same as above -C(=O)-0-CH 2 -Ph 946 Same as above 947 -CH3 948 Same as above -CH 2
CH
3 949 Same as above -C(=O)-CH 3 950 Same as above -CH2-Ph 951 Same as above -C(=O)-Ph 952 Same as above -C(=O)-O-CH 2 -Ph 953 Same as above -67- Cmpd A
B
954 -CH3 955 Same as above -CH 2
CH
3 956 Same as above -C(=O)-CH3 957 Same as above -CH 2 -Ph 958 Same as above -C?=0)-Ph 959 Same as above -C(=O)-O-CH 2 -Ph 960 Same as above 961 -CH 3 962 Same as above -CH 2
CH
3 963 Same as above -C(=O)-CH 3 964 Same as above -CH2-Ph 965 Same as above -Ph 966 Same as above -C(=0)-O-CH 2 -Ph 967 Same as above While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the products, processes and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific embodiments which have been presented by way of example.

Claims (17)

1. A compound having formula 1 A SNS B A)x D (I) and pharmaceutically acceptable derivatives thereof, wherein: X is.selected from -CH 2 CH 2 -CH=CH-, -C(OH)CH2-, -CH 2 =C(F)CH 2 -C(F)=CH 2 (OH)CH 2 -CH 2 SO 2 -C(S)NR 1 -C(O)CH 2 CH(OH)-, -C(OH)CF 2 -C(0)CF 2 -CH(F)CH2-, -C(F) 2 CH 2 N or N A, B and R 1 are independently E, (Ci-C 10 )-straight or branched alkyl, (C 2 -Clo)-straight or branched alkenyl or alkynyl, or (C 5 -C 7 )-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (Cs-C 7 )-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the -CH 2 groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by or -N(R 3 -69- o or, B and R 1 are independently hydrogen; 0 R 3 is hydrogen, (Ci-Ci)-straight or branched alkyl, S(C 3 -C 4 )-straight or branched alkenyl or alkynyl, or (Ci-C 4 bridging alkyl, wherein a bridge is formed between the C-i nitrogen atom to which said R 3 is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, 0 and wherein said ring is optionally benzofused; VO E is a saturated, partially saturated or o unsaturated, or aromatic monocyclic or bicyclic ring l system, wherein each ring comprises 5 to 7 ring atoms o independently selected from C, N, N(R 3 O, S, or r S(0)2; and wherein no more than 4 ring atoms are selected from N, N(R 3 O, S, or S(0)2; 'wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, S03H, trifluoromethyl, trifluoromethoxy, (Ci-Cs)-straight or branched alkyl, (C 2 -C 6 -straight or branched alkenyl, 0- [(Ci-C 6 )-straight or branched alkyl], O-[(C 3 -C 6 )-straight or branched alkenyl], (CH2)n-N(R) (R 5 (CH2)n-NH(R 4 (CH2)n- Z (CH2) (R4- (CH2) n-Z) (Rs- (CH2) n-Z) (CH2)n-Z, O-(CH2)n-Z, (CH 2 S-(CH 2 CH=CH-Z, 1,2-methylenedioxy, C(0)OH, 1 -C6)-straight or branched alkyl], C(0)0-(CH 2 )n-Z or C(O)-N(R 4 (R 5 each of R' and R 5 are independently hydrogen, (Ci-C 6 )-straight or branched alkyl, (C 3 -C 5 )-straight or. branched alkenyl, or wherein R 4 and R 5 when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, N(R3), 0, S, or oS(0)2; wherein said alkyl, alkenyl or alkynyl groups in R 4 Sand R 5 are optionally substituted with Z; Seach n is independently 0 to 4; each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 0\ ring atoms independently selected from C, N, N(R 3 0, S, \O IND or S(0) 2 and wherein no more than 4 ring atoms are o selected from N, N(R 3 S or S(0) 2 wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, OC cyano, C(0)OH, (Ci-C 3 )-straight or branched alkyl, O-(CI-C3)-straight or branched alkyl, 0- (Ci-C 3 -straight or branched alkyll, amino, NH[ (Ci-C 3 )-straight or branched alkyl], or N-[(Ci-C 3 )-straight or branched alkyl] 2 J is H, methyl, ethyl or benzyl; K and K 1 are independently selected from (CI-Cs)-straight or branched alkyl, (C 2 -Cs)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E; wherein K and K 1 are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O-(Ci-C 6 )-alkyl, 0-(CH 2 NO 2 C(O)OH, C(0)-0-(Ci-C 6 )-alkyl, C(O)NRR 5 NR 4 Rs and (CH 2 or, J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R3), O, S, S(0), or S(O) 2 wherein 1 to 4 hydrogen atoms in said -71- Sheterocyclic ring are optionally and independently 0 replaced with (C1-Cs)-straight or branched alkyl, S(C2-Cs)-s.traight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any -CH2- group in said alkyl, Salkenyl or alkynyl substituent is optionally and independently replaced by or -N(R 3 and wherein said heterocyclic ring is.. optionally fused with E; G, when present, is -S(O) 2 OC or o Y is oxygen, or N(R 6 C wherein R 6 is hydrogen, E, -straight or branched alkyl, (C3-Cs)-straight or branched alkenyl or alkynyl;: or, wherein R 6 and D are taken together with the. atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, N(R 3 SO, or SO 2 and wherein said ring is optionally benzofused; D is hydrogen, (Ci-C7)-straight or branched alkyl, (C2-C7)-straight or branched alkenyl or alkynyl, (Cs-C7)-cycloaikyl or cycloalkenyl optionally substituted with (Ci-C6)-straight or branched alkyl or (C2-C7)-straight or branched alkenyl or alkynyl, [(CI-C7)-alkyl]-E, [(C2-C7)-alkenyl or alkynyll-E, or E; wherein 1 to 2 of the CH2 groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by or -N(R3); provided that when J is hydrogen or G is selected from S0 2 or C(0)C(O)-Y, wherein Y is 0; then D is not hydrogen; and -72- ox is 0 or.1. c(
2. The compound according to claim 1, wherein: each of A and B is independently selected from -CH 2 -CH 2 -E or -CH 2 -CH 2 -CH 2 and 0 E is a monocyclic or bicyclic aromatic ring system, VO N wherein said ring comprises 5-7 ring atoms independently o selected from C, N, N(R 3 0, S, or S(0)2, and c wherein 1 to 4 ring atoms are independently selected from SN, N(R 3 O, S, or S(0)2; Ci wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro; .SO0H, trifluoromethyl. trifluoromethoxy, (Ci-C 6 )-straight or branched alkyl, (C2-Cs)-straight or branched alkenyl, O-[(Ci-C 6 )-straight or branched alkyl], O-[(C3-C 6 )-straight or branched alkenyl], (CH 2 4 (CH 2 )n-NH(R 4 )-(CH 2 )n-Z, (CH2)n-N(R- (CH2)n-2) (RS- (CH2)n-Z) (CH2) n-Z, O- (CH2)n-Z, (CH 2 S-(CH 2 CH=CH-Z, 1,2-methylenedioxy, C(0)OH, or C(0) (R 5
3. The compound according to claim 1 or 2, wherein D is an aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 0, S, or S(0) 2 and wherein no more than 4 ring atoms are selected from N, N(R 3 0, S, or S(0)2.
4. The compound according to claim 3, -73- o wherein: CD is phenyl; and x is 1I. eC The compound according to claim 4, wherein G is
6. The compound according to claim 4, wherein o0 G is -SO 2 ci S7. The compound according to claim 4, wherein G is
8. The compound according to claim 4, wherein G is
9. The compound according to claim 1 or.2, wherein: x is 0; D is selected from (Ci-Cs)-straight or branched alkyl, or [(Ci-C 3 )-straight or branched alkyl)]-E; -and E is an aromatic monocyclic or bicyclic ring system, wherein in said ring system each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 0, S, or S(0)2; and wherein no more than 4 ring atoms are selected from N, N(R 3 0, S, or S(0)2. The compound according to claim 9, wherein E is phenyl. -74- o 11. The compound according to claim 2, wherein 0 each of A and B-is independently selected from -CH 2 -CH2-E Sor -CH 2 -CH 2 -CH 2 and E is pyridyl.
12. A composition comprising a compound IND according to claim 1 and a pharmaceutically effective Ci carrier. ci S13. The composition according to claim 12, o further comprising a neurotrophic factor.
14. The composition according to claim 13, wherein said neurotrophic factor is selected from 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 The composition according to claim 14, wherein said neurotrophic factor is nerve growth factor (NGF).
16. A method for stimulating neuronal regeneration or preventing neurodegeneration in a patient or in an ex vivo nerve cell, comprising the step of o administering to said patient or said nerve cell a C compound according to any one of claims 1-12.
17. The method according to claim 16, wherein C said compound is administered to a patient and is formulated together with a pharmaceutically suitable carrier into a pharmaceutically acceptable composition. \O ci S18. The method according to claim 17, comprising the additional step of administering to said patient a neurotrophic factor either as part of a c multiple dosage form together with said compound or as a separate dosage form.
19. The method according to claim 18, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives such as gIGF-1 and Des(l-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 The method according to claim 19, wherein said neurotrophic factor is nerve growth factor (NGF).
21. The method according to claim 16, wherein said method is used to treat a patient suffering from a disease selected from trigeminal neuralgia, -76- o glosspharyngeal neuralgia, Bell's Palsy, myasthenia C gravis, muscular dystrophy, muscle injury, progressive Smuscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae Cq disk syndrome's, cervical spondylosis, plexus disorders, thoracic.outlet destruction syndromes, peripheral h neuropathies, such as those caused by lead, dapsone, VO ticks, or porphyria, other peripheral myelin disorders, ci o Alzheimer's disease, Gullain-Barre syndrome, Parkinson's flf disease and other Parkinsonian disorders, ALS, Tourette's Ssyndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, .motor'neuron diseases, sciatic crush,-neuropathy- associated with diabetes, spinal cord injuries, facial nerve crush and other trauma, chemotherapy- and other. medication-induced neuropathies, and Huntington's disease.
22. The method according to-claim 16, wherein said method is used to stimulate neuronal regeneration in an ex vivo nerve cell.
23. The method according to claim 22, comprising the additional step of contacting said ex vivo nerve cell with a neurotrophic factor.
24. The method according to claim 23, wherein said neurotrophic factor is selected from nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives such as gIGF-1 and -77- 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 The method according to claim 24, wherein said neurotrophic factor is nerve growth factor (NGF).
26. The compound according to claim 1, wherein: is selected from -CH 3 -CH 2 CH 3 -C(=O)-CH 3 CH 2 3i'h; -Ph, -C(=O)-O-CH 2 -Ph or -Ph, wherein Ph is phenyl; and A Zr -~N Sis selected from yrQ -78- N f, or Vertex Pharmaceuticals Incorporated By their patent attorneys CULLEN CO. Date: 24 June 2005
AU2005202769A 1999-07-30 2005-06-24 Acyclic and Cyclic Amine Derivatives Abandoned AU2005202769A1 (en)

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