Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
Dane Holte
NaBH4,
NO2
O
DMSO, 85 ºC
via
– Discovered topiramate >$2 billion
in sales/year
– Has produced 13 new chemical
entities to enter human clinical trials
– 275 publications
– nearly 100 patents
Ph
N
O
Ph
Ph
N
N
Ph
Ph
N
N
Ph
BH3 ?
Ph
NH2
NO2 ?
Ph
H
N
condense
OH
Education
B.S. Chemistry, Drexel University, 1969
Ph.D. Organic Chemistry, Drexel University, 1973 (w/ Prof. Robert Hutchins)
Postdoctoral Fellow, Princeton University, 1972–1974 (w/ Prof. Kurt Mislow)
Employment
McNeil Laboratories/Pharmaceutical, 1974–1987
Janssen/Johnson/J&J,1987–2010
TSRI, Visiting Investigator, 2008–present
Institute or Hepatitis and Virus Research, 2009–present
Pennsylvania Drug Discovery Institute, 2010–present
N
O
J. Org. Chem. 1971, 36, 803
NHTs
TsNHNH2
NaBH3CN,
pTsOH
EtOH, !
("good%)
DMF, Sulfolane,
110 ºC (92%)
Wolff-Kishner modification
doesn't affect ester, amide, nitro, cyano, chloro
hindered work well
aryl ketones can be resistant
J. Am. Chem. Soc. 1971, 93, 1793
J. Am. Chem. Soc. 1973, 95, 3662
NaBH3CN in HMPA can be used to mildly and selectively reduce alkyl halides
and tosylates: J. Chem. Soc. D, Chem. Commun. 1971, 1097; J. Org. Chem.
1977, 42, 82
Ph.D/Postdoctoral work not discussed:
– Structural and conformational analyses of boron and phosphorous
containing heterocycles
– Studies on thiabenzenes
Baran Group Meeting
Apr. 20, 2013
H
Me
N
Bruce E. Maryanoff
CO2Et
N2
Ferrocene as a bioisostere:
Me
Me
cycopropane
not observed
+
Cu(II)
CO2Et
known pdt,
maximized w/
Cu(acac)2 ~60%
O
CO2Et
unknown pdt,
until publication,
maximized w/
Cu(BF4)2 ~40%
Cl
NH2
CN
R3P H
R3P H
R''
+
R'
H
HO
R''
R' O
betaines
R''CHO
N
H
(50%)
CH2CO2H
+
– Novel reducing agent: (F3CO2)2BH-THF
– reduces indoles, enamines, diazaheterocycles, carbocation precursors,
ketones, aldehydes, imines, oximes, tosyl hydrazones
– hydride stable to excess acid
J. Org. Chem. 1978, 43, 2733
J. Org. Chem. 1981, 46, 355
+
O
PR3 CHR'
(84%)
Ac2O;
then, "
N
Me
Fe
Studies on the mechanism of the Wittig Reaction:
BH3!THF, TFA
CN
CH2CO2H
N
Me
"Our work [...] indicates that bioisosterism of the ferrocene unit is generally poor."
mechanism - electrophilic substitution in which reactivity of electrophile is
modified by the metal - more reactive are less discriminate
J. Heterocycl. Chem. 1977, 14, 177
J. Org. Chem. 1979, 44, 4410
CO2H
J. Med. Chem. 1983, 26, 226.
N
N
N
H
Dane Holte
Me
NC
J. Org. Chem. 1989, 54, 3790.
H
N
R3P O
R'
+
R''
CR'H CR''H
R3P O
R'
+
Ph3P O
R''
oxaphosphetanes
R3P O
H
CN
Cl
R'
R3P O
R'
R''
H
R''
zwitterions
Maryanoff made fundamental contributions to the mechanism of the Wittig
reaction: as with many things, its complex
– E/Z ratios alone do not explain the mechanism
– mechanism differs for aromatic/aliphatic aldehydes/ylides
–stabalized, semistabilized, nonstabilized ylides
– salt/salt free changes mechanism
–cis/trans oxaphosphetanes have differing rates of reactivity
Be aware that its complicated, but in general, its good enough to know that
simple ylides give Z, Schlosser modification gives E.
For the deeply interested, here are some papers to start you off:
J. Am. Chem. Soc. 1986, 108, 7664
Chem. Rev. 1989, 89, 863
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
O
R
R'
1,5-diastereoseletive reduction
N
H
H2N
O
Dane Holte
NH2
then, SeO2
R
N N
Se
Ph
BuLi, –70 ºC
or "
R'
R
OH
N
Bn
Ph
Ph
O
OH
BnN
SeO2
NH2
O
Se
BnN
N
N
N
+
N
Se
BnN
20:1
>25:1
2:1
1.2:10
dioxane/water (5:1)
AcOH
THF-d8
THF
Ph
Ph
+
OH
OH
dl (anti)
R'
N NH
N
Bn
N
Bn
Ph
OH
meso (syn)
Red. agent
solvent
dl/meso
Pd(OH)2, H2
NaBH(OAc)3
(iBu)2AlH
LAH
A
B
MeOH
THF
CH2Cl2
Et2O
THF
THF
1:1
1:1
1:1
1:1
2:1
7:1
H
J. Org. Chem. 1991, 56, 5203.
H
B
Li
Li
B
recall that:
A
Ac2O
N
N
O
NH
OAc
...but:
O
0 ! 45 ºC
O
high level of 18O retention from N-oxide
consistent with tight ion pair mechanism
OTs
N
N
OTs
Cl
OTs
Cl
OTs
O Ts
N
53%
1,6-diastereoseletive reduction also works with R-alpine hydride, although
1,7- is significantly less selective; later systems switch to DCM - non
coordinating solvent is better
The authors state: "Despite the absence of a clear structural understanding of the
mechanism for high 1,5- and 1,6-anti stereocontrol in these reductions, one can still
draw consolation from the exciting stereochemical results."
TsCl, CHCl3
N
B, R-alpine hydride
N
N
Cl
Cl
Tetrahedron Lett. 1993, 34, 7247.
I will refer you to the following papers:
Tetrahedron Lett. 1994, 35, 4891; Tetrahedron Lett. 1997, 37, 7897; J. Org.
Chem. 1998, 63, 7964
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
slightly more complex:
Pyrroloisoquinoline antidepressants
R2
H
R1
H
N
R
Ph
Cl
1. NaBH4
H
R
O
CONH2
R
Ph
Ph
CO2
R
R
O
then, AcCl
O
R
R
BH3!THF
N
R
Ph
OEt
Ph
SMe
R
Cl
N
100 ºC
H
+
N
O
H
A
Simplistic
working model:
H
R
H
O
N
H
B
N
H
J. Med. Chem. 1987, 30, 1433
R
A rearrangement:
should
favor
N
N
O
A-1,3 minimized
H
Two pharmacologically relevant molecules that came out of the medicinal
chemistry campaign:
PPA
OEt
N
O
N
EtOH
R
N
H
R
H
NaBH4
O
J. Org. Chem. 1986, 51, 1341
2. NH4OH
O
N
Ph
1. SOCl2
O
Ph
R
CO2H
Mg; then,
O
NH2
LAH
Stereochemical outcome determined by:
A-1,3 strain and diaxial interactions which are
minimized by an early, boat-like transition state
N
O
R
Ph
2. SOCl2
NMR studies support a boat-like transition state
H
R3
O
Dane Holte
H
A
O
R
A:B
Ph
Me
Et
cHx
tBu
93:7
72:28
39:61
12:88
15:85
yield (%)
84
50
88
91
74
Ph
Ph
COCl2;
N
H
NHPh
then, CF3CH2NH2
N
H
O
N
Ph
Cl
Tetrahedron Lett. 1982, 23, 2829
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
J. Med. Chem. 2009, 52, 3431.
O
O
O
O
S NH2
O CH2OH
O
O
O
O
O
Dane Holte
O
O
1. SO2Cl2, py.,
DCM
2. NaN3, MeCN
OMe
O
HOH2C
(PhO)2POCl
CH2OSO2N3
OH
HO
PtO2
H2O3PH2C
O
HO
OH
HO
H2SO4
O
acetone, !
OH
R2NSO2Cl
O
O
NaH, DMF
R = Me, H
O
O
S NR2
MeOH
O
O
HOH2C
OMe
O
OH
HO
O
O
Topiramate (R = H)
O
PhO P O
PhO
O
OMe
CH2OSO2NMe2
HO
OH
PtO2
H2O3PH2C
H2, MeOH
PhO P O
PhO
CH2OSO2N3
OH
HO
OMe
OSO2NH2
O
3N HCl
O
O
EtOAc, py.
–60 ºC " rt
THF, 40 ºC
O
O
HO
O
OSO2NH2
ClO2SO
ClO2SO
O
O
OSO2NH2
HO
NaHCO3
MeOH
O
O
H2NO2SO
O
O
O S
O
O
O
O
"super topiramate"
(RWJ-37947)
py., –20 "
"increased potency and enhanced duration of action"
–5 ºC
but "rejected because of its lack of differentiation from topiramate"
rxn didn't work
when R = H
"A large scale synthesis involving inexpensive starting materials and
reagents (D-fructose, acetone, H2SO4, sulfuryl chloride, and ammonia) was
OMe
eventually developed. Not quite earth, fire, and water but close enough."
See U.S. Patent 5,387,700.
CH2OSO2NR2
HCl
O
(PhO)2POCl
OMe
O
Y
SO2Cl2
O
O
OH
HO
D-fructose
O
O
CH2OSO2NH2
H2, MeOH
O
O CH2OH
py., –20 "
–5 ºC
HCl
O
O
see also: J. Med. Chem. 1998, 41, 1315.
CH2OH
O
O
Initial goal: discover a fructose-1,6-bisphosphatase inhibitor as an antidiabetic
using monosaccaride derivatives
1978 - Project initiated by Maryanoff, Tutwiler, and Steve Benkovik (Penn State)
1986, June - Investigational new drug application filed
1986, Aug. - first human volunteer dosed
1987, July - first epileptic dosed
1994 - Federal regulatory filings submitted
1997 - Topamax national launch
2009 - Last patent expired
MeOH
O
O
Topiramate (Topamax)
O
O
O
S N3
O
CH2OSO2NMe2
OH
HO
X
Has also been used for prophylaxis of migrane, eating disorders, alcohol and
drug dependence, nerve injury, nueropathies, restless leg syndrome, PTSD,
bipolar, and schizophrenia.
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
Ph
Serine protease inhibitors J. Med. Chem. 2004, 47, 769:
Structure-based drug discovery - we know the target, can "rationally" design
Thrombin - keeps us from bleeding to death (hemostatis and thrombosis),
but an excess can lead to pulmonary embolism, myocardial infarction, or
stroke - thus, thrombin inhibitors could be good drugs
OH
O
Cl
O
NH
PPACK - Early Target
R
NH
NH
O
O
N
H
HO
TsHN
2. KCN
(3:2 dr)
O
H2N
NH
OH
HCl! H2N
Ph3P
NPhth C
CF3CO2H
+
(81%)
TsHN
D-PheOtBu,
2. LiOH
(35% overall)
HN
NH
B
DCC, HOBt
(77%)
HN
TsHN
H2N
CO2H
NH
NH2 !HCl
H2N
CO2H
1. PhthNCO2Et (80%)
2. H2, Pd(OH)2
1. Cbz-Cl
2. CH2=CMe2,
H2SO4
(41%)
to next page
CO2tBu
NHCbz
SEMO
CO2tBu
OTBDMS
CO2H
1. SEM-Cl, 2,6lutidine
FmocHN
(73%)
ii. NaHCO3
iii. AcOH to pH 4
NH
OTBDMS
1. Fmoc-Cl, K2CO3
2. TBDMS-Cl
3. DIBAL
4.
CO2tBu
CO2Me
FmocHN
CO2Me
NH
O
HN
TsHN
A
TsHN
NHCbz i. HCl, MeOH
HO
O
NH
Cyclotheonamide A: R = H
Cyclotheonamide B: R = Me
1. (im)2CO;
then, DIBAL
NHCbz
FmocN
H
N
HN
NH
NHCbz
HO
NH
O
1. H2, Pd(OH)2
2. Fmoc-Pro, DCC
HN
CN
NH
CO2H
HN
O
N
O
TsHN
NHCbz
SEMO
Ph
O
N
H
CtA and B looks kind of like native
protease inhibitor proteins - can
be used as a tool to learn more
about interactions w/in active site
HN
NH
O
NH2
N
HO
Ph
CO2tBu
3. CF3CO2H
(56%)
O
MeHN
Ph
3
HN
O
H
N
Dane Holte
NH2
CbzHN
CO2tBu
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
Dane Holte
OTBDMS
OTBDMS
BOP-Cl
1. EDC, HOBt
B+C
+A
O
2. Et2NH, DMF
(68% overall)
N
H
NH2
O
NEt3
(65%)
CO2tBu
NPhth
OHC
TBDMSO
NH
Phth N
1. Et2NH
2. CF3CO2H
Ph
O
HN
CO2tBu
H
N
N
Fmoc
O
N
H
NH
H2N
NHTs
NH
O
N
Ph
OTBDMS
O
O
HN
HO
N
H
HN
NH
OH
O
NH
NH
3. DCC, HOBt Phth N
(41%)
O
HO
N
H
O
NH
CtA
2. HF, PhOMe
(33%)
HN
O
N
OTBDMS
O
1. DMP, MeCN
O
O
N
H
Ph
NH
NH
O
NH
O
O
3
N
H
TsHN
~10% macrolactonization
Ph
NH
NH
O
1. DMP, DCM,
tBuOH
CtB
O
2. HF, anisole
(33%)
HN
O
HO
N
O
H2N
N
H
OTBDMS
NH
HCO2Et
HO
(88%)
O
1. NH2NH2,
2-butenol
NH
NH
NH
O
H2N
N
Ph
O
O
HO
N
H
O
O
HN
C6F5
O
H2N
NH
(90%)
NH
See: J. Am. Chem. Soc. 1995, 117, 1225 and Tetrahedron Lett. 1996, 37, 3667.
CtA
NaHCO3
NH
NH
MeCN, H2O
OHC
(65%)
N
H
O
Ph
O
HN
O
O
HO
N
N
H
N
NH
NH2
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
Following that foray into tryptase inhibitiors... What about other compounds that
could be used to treat asthma or chronic obstructive pulmonary disease?
OH
(E)
O
(S)
H
N
H
Ph
O
(R)
Ph
NH
O
NH
O
O
O
N
(S)
N
(R)
O
N
H
O
N
H
N
(S)
(S)
N
H
HN
O
Cathepsin G (Cat G) inhibitor? [... onward to the high throughput screen...]
S
MeHN
(S)
O
NH2
NH
O
(HO)2(O)PO
IC50 = 4.1 ± 0.3 µM
H2N
(S)
Dane Holte
NH
Moderate potency, but:
1. Easy to make analogues
2. Non-peptide
-rare among Cat G inhibitors
-!-ketophosphonic acid is novel
3. Reversible inhibitor
NH
crystallographic studies
computer modelling
medicinal chemistry
Cyclotheonamide A
RWJ-50353
Ki = 4.1 nM
Ki = 0.20 nM
CtA SAR
crystallographic studies
medicinal chemsitry
O
RWJ-50353 was eventually abandoned due to pronounced hypotension and
electrocardiogram effects in guinea pigs.
N
Me
N
Whats the minimum structure required for potent thromin ihibtion (<10 nM)?
O
[...some med chem later...] A potent tryptase inhibitor!
O
HO
HO
N
Ac
H
N
O
S
N
O
RWJ-56423
NH
HN
NH2
N
Ac
H
N
(HO)2(O)PO
O
S
N
O
benzthiazole 8x more
potent than thiazole!
NH
HN
NH2
Benzthiazole RWJ-56423 was tested in sheep for antiasthma studies and was
advanced to preclinical studies. Eventually, it entered human clinical trails.
J. Med. Chem. 2005, 48, 1984.
Inhibits Cat G (IC50 = 38 ± 8 nM) and bonus
inhibition of chymase (IC50 = 17 ± 5)
Yet, still selective for these two (poorly inhibits
many other serine proteases)
To summarize some biology - this molecule
could treat asthma / other inflammatory
diseases by two mechanisms of action
Sheep as well as other animal model studies have been positive.
Stories about serine protease inhibitors:
Thrombin inhbitor " Tryptase inhibitor " Cat G/Chymase dual inhibitor
Using natural products total synthesis, SAR, computer modelling,
crystallography, medicinal chemsitry, high throughput screening, intuition,
and luck
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
But wait, theres more about thrombin! En route to RWJ-58259 we stumble
upon an unsuspecting mechanism, lets watch and see what she does...
Some interesting things from the work on Cat G and Chymase:
O
O
R
R'
!
P ONa
OH
Dane Holte
CHO
O
H2O, MeCN
NaNO2, 6 N HCl
R'
R
Org. Lett. 2006, 8, 3249.
O
N
H
O2N
J. Med. Chem. 2001, 44, 1021
PhO P
N3
PhO
CO2H
N
N
H
O2N
NCO
!
NEt3, PhMe
Cl
Cl
J. Med. Chem. 2007, 50, 1727
F
several
steps
later
O
Ph
several
steps
later
H
N
Me
O
P OH
N
H
O
H
N
O
NH2
N
H
N
H
N
N Cl
Cl
RWJ-58259 Thrombin Receptor (PAR1-) atagonist
O
Cl
Cl
N
F
S
chymase IC50 = 3.5 nM
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
Co-mediated [2 + 2 + 2] macrocyclizations:
J. Am. Chem. Soc. 2005, 127, 3473
Bioorg. Med. Chem. Lett. 2007, 17, 2863.
p-tol
O
O
tol
O
(29%)
O
CpCo(CO)2,
o-xylenes
140 ºC, hv
Collogen-mimetic peptides:
Collogen has a triple helical structure of repeating peptides: often Gly-X-Y,
where X and Y are largely Pro and Hyp (hydroxyproline)
N
CN
Dane Holte
Collogen rigidity provides mechanical strength to tissues. After vascular
injury, exposed collogen leads to tissue repair by activating platelets.
tol
O
OH
N
(28%)
NH2
O
R1
p-tol
O
O
N
O
O
NH2
tol
O
CCH
N
CpCo(CO)2,
o-xylenes
140 ºC, hv
(44%)
O
O
H
N
OMe
KOtBu
O
O
+
N
O
N
N
N
H
N
O
N
10%
NMe2
THF
(63%)
O
H
N
N
O
9%
NMe2
O
O
N
N
R2
N
H
O
CO2H
n
A: n = 10; R1 = (C6F5)CH2-; R2 = PhCH2
B: n = 5; R1 = (C6F5)CH2-; R2 = PhCH2
C: n = 10; R1, R2 = PhCH2
D: n = 10; R1 = (iPr)CH2-; R2 = PhCH2
– A adopts a triple helix structure (CD spectroscopy), melts (57 ºC) and
anneals, and "crystallization" of melted samples leads to higher order
aggrigates of 1000 nm
– phenyl-pentafluorophenyl stacking is essential
– remarkably, A also had collogen-like function inducing platelet aggrigation!
J. Am. Chem. Soc. 2007, 129, 2202
PNAS 2008, 105, 8513.
N
N
N
N
O
H
N
CpCo(CO)2,
1,4-dioxane
110 ºC
Baran Group Meeting
Apr. 20, 2013
Bruce E. Maryanoff
O
O
A small sampling of
the (successful)
molecules Bruce
Maryanoff has been
involved with!
O
O
O
N
N
O
Ph
O
SMe
CO2H
HO2C
O
"super topiramate"
(RWJ-37947)
Topiramate (Topamax)
>$2 billion annually
OH
O
O S
O
O
O
O
NMe2
H2NO2SO
O
O
O
H
N
O
S NH2
O
Dane Holte
O
O
N
H
O
OMe
Cl
N
H
Cl
N
N
N
OiPr
N
mazapertine succinate (RWJ-37796)
schizophrenia (Phase II clinical)
H
O
N
N
Br
N
Ac
H
N
N
H
O
S
O
N
O
N
NH2
RWJ-56423
asthma/allergic rhinitis (Phase II clinical)
O
Ph
O
N
H
(HO)2(O)PO
RWJ-351647
congestive heart failure, edema,
liver cirrhosis, hypnoatreama
(Phase IIb clinical trials)
RWJ-355871
asthma and chronic obstructive pulmonary
disease (Phase I clinical trials)
S NH2
O O
NH
N
H
N
N
HN
Me
H
N
S
O
Br
N
H
N
O
N
O
Cl
macitentan (Phase III)
O
O
O
OH
elarofiban (RWJ-53308)
fibrinogen receptor antagonist
(Phase II clinical)
HO
N
O
N
H
HN
O
H
McN-5652-Z
McN-5707
neurotranmitter uptake inhibitors
N
O
N
F
RWJ-339489
RWJ-676070
cogestive heart failure (Phase II clinical)
S
JNJ-26990990
epilepsy, migrane, neuropathic
pain (Phase IIa)
N
F F
N
H
NH
O
N
O
RWJ-671818
anticoagulant (Phase I/IIa)
N
H
O
N
H
NH2