baran group meeting bruce e. maryanoff dane holte … · dane holte baran group meeting apr. 20,...

Dane HolteBaran Group MeetingApr. 20, 2013 Bruce E. Maryanoff

EducationB.S. Chemistry, Drexel University, 1969Ph.D. Organic Chemistry, Drexel University, 1973 (w/ Prof. Robert Hutchins)Postdoctoral Fellow, Princeton University, 1972–1974 (w/ Prof. Kurt Mislow)

EmploymentMcNeil Laboratories/Pharmaceutical, 1974–1987Janssen/Johnson/J&J,1987–2010TSRI, Visiting Investigator, 2008–presentInstitute or Hepatitis and Virus Research, 2009–presentPennsylvania Drug Discovery Institute, 2010–present

NO2 NaBH4,

DMSO, 85 ºC PhNO

NPh Ph

NN

PhPh

NH2

PhN

O PhHN

OH

via PhNO2

condense?

BH3 ?

J. Org. Chem. 1971, 36, 803O N

NHTs

TsNHNH2

EtOH, !("good%)

DMF, Sulfolane, 110 ºC (92%)

NaBH3CN,pTsOH

Wolff-Kishner modificationdoesn't affect ester, amide, nitro, cyano, chlorohindered work wellaryl ketones can be resistant J. Am. Chem. Soc. 1971, 93, 1793

J. Am. Chem. Soc. 1973, 95, 3662NaBH3CN 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

– Discovered topiramate >$2 billion in sales/year– Has produced 13 new chemical entities to enter human clinical trials– 275 publications– nearly 100 patents


NMe

NMe N

Me

CO2EtCO2Et

Cu(II)

N2

CO2EtH

known pdt, maximized w/

Cu(acac)2 ~60%

unknown pdt, until publication, maximized w/

Cu(BF4)2 ~40%

cycopropane not observed+

mechanism - electrophilic substitution in which reactivity of electrophile is modified by the metal - more reactive are less discriminate

J. Heterocycl. Chem. 1977, 14, 177J. Org. Chem. 1979, 44, 4410

NH

BH3!THF, TFA

NH(84%)

– 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

Studies on the mechanism of the Wittig Reaction:

PR3 CHR'

R''CHO+

H R''

O

R3P

HR'

+

H R''

O

R3P

R'H

R3P O

R' R''

R3P O

R' R''

betaines

+

oxaphosphetanes

R3P O

R' R''

R3P OR'

R''zwitterions

HH

CR'H CR''H

Ph3P O+

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

Cl

CO2H

NH2

CN

CN

Ac2O;then, "

+HN

NC CN

Me

Cl(50%)

J. Org. Chem. 1989, 54, 3790.

Ferrocene as a bioisostere:

ONMe

CH2CO2H

ONMe

CH2CO2HFe

"Our work [...] indicates that bioisosterism of the ferrocene unit is generally poor."

J. Med. Chem. 1983, 26, 226.


N

TsCl, CHCl3

0 ! 45 ºCON

OTsCl

NOTs

Cl

N

Cl

O Ts

N

OTs

Cl

N

OTs

high level of 18O retention from N-oxide consistent with tight ion pair mechanism

53%

Tetrahedron Lett. 1993, 34, 7247.

NO

Ac2ON

OAc

NH

O

recall that:

...but:

R

OR'

H2N

O

NH

NH2

then, SeO2

SeNN

RR'

RR'

BuLi, –70 ºC

or "

J. Org. Chem. 1991, 56, 5203.

BnN

N NH

ONH2

SeO2 BnN NN

Se

BnNSeN

N

+

dioxane/water (5:1)AcOHTHF-d8THF

20:1>25:1 2:1 1.2:10

Ph

OHNBn

O

Ph Ph

OHNBn

OH

Ph Ph

OHNBn

OH

Ph

dl (anti) meso (syn)

+

Red. agent solvent dl/mesoPd(OH)2, H2 MeOH 1:1NaBH(OAc)3 THF 1:1

(iBu)2AlH CH2Cl2 1:1LAH Et2O 1:1

AB

BH

A

BHLi

Li

THF 2:1THF 7:1

B, R-alpine hydride

1,5-diastereoseletive reduction

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."

I will refer you to the following papers:Tetrahedron Lett. 1994, 35, 4891; Tetrahedron Lett. 1997, 37, 7897; J. Org. Chem. 1998, 63, 7964


Pyrroloisoquinoline antidepressants

N

R2

R3

R1

Ph R

O 1. NaBH4

2. SOCl2 Ph R

Cl Mg; then,

CO2 Ph R

CO2H 1. SOCl2

2. NH4OH

Ph R

CONH2 LAH

Ph R

NH2OO

O

then, AcClPh R

N

O

O

Ph R

N

OEt

O

NaBH4

EtOH

R Ph

N

OEt

O

N

R

HO

N

R

HO

+PPA

100 ºC

A B

N

OH

HR

H

A-1,3 minimized

Simplisticworking model:

N

R

HO

A

shouldfavor R A:B yield (%)

Ph 93:7 84Me 72:28 50Et 39:61 88cHx 12:88 91tBu 15:85 74

N

O

H

HR

H

slightly more complex:

Stereochemical outcome determined by:A-1,3 strain and diaxial interactions which are minimized by an early, boat-like transition state

NMR studies support a boat-like transition state

N

R

HO

N

R

H

BH3!THF

NH

Cl

NH

SMe

Two pharmacologically relevant molecules that came out of the medicinal chemistry campaign:

J. Org. Chem. 1986, 51, 1341

J. Med. Chem. 1987, 30, 1433A rearrangement:

N

Ph

N

Ph

H

NHPh

COCl2;

then, CF3CH2NH2

N

O

Cl

HPh

Tetrahedron Lett. 1982, 23, 2829

H


OO

O O

O

OS NH2

OO

Topiramate (Topamax)Initial goal: discover a fructose-1,6-bisphosphatase inhibitor as an antidiabetic using monosaccaride derivatives1978 - Project initiated by Maryanoff, Tutwiler, and Steve Benkovik (Penn State)1986, June - Investigational new drug application filed1986, Aug. - first human volunteer dosed1987, July - first epileptic dosed1994 - Federal regulatory filings submitted1997 - Topamax national launch2009 - Last patent expired

OHO

HO OH

OHCH2OH

D-fructose

OO

O O

OCH2OH

H2SO4

acetone, !

R2NSO2Cl

NaH, DMF

OO

O O

O

OS NR2

OO

MeOH O

CH2OSO2NR2

OMeHOH2C

HO OH

(PhO)2POCl

py., –20 " –5 ºC

O

CH2OSO2NMe2

OMe

HO OH

OPO

PhOPhO

O

CH2OSO2NMe2

OMeH2O3PH2C

HO OH

PtO2

H2, MeOH

Topiramate (R = H)

HCl

OO

O O

OCH2OH 1. SO2Cl2, py.,

DCM

2. NaN3, MeCNO

O

O O

O

OS N3

OO

MeOH

HCl

O

CH2OSO2N3

OMeHOH2C

HO OH

(PhO)2POCl

py., –20 " –5 ºC

O

CH2OSO2N3

OMe

HO OH

OPO

PhOPhO

O

CH2OSO2NH2

OMeH2O3PH2C

HO OH

PtO2

H2, MeOH

R = Me, H

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 eventually developed. Not quite earth, fire, and water but close enough." See U.S. Patent 5,387,700.

OO

O O

OOSO2NH2 3N HCl

THF, 40 ºC

OHO

HO O

OOSO2NH2

SO2Cl2

EtOAc, py.–60 ºC " rt

OClO2SO

ClO2SO O

OOSO2NH2 NaHCO3

MeOH

O

O

O

H2NO2SO

OS OO

O"super topiramate"

(RWJ-37947)"increased potency and enhanced duration of action"but "rejected because of its lack of differentiation from topiramate"

Has also been used for prophylaxis of migrane, eating disorders, alcohol and drug dependence, nerve injury, nueropathies, restless leg syndrome, PTSD, bipolar, and schizophrenia.

J. Med. Chem. 2009, 52, 3431.

see also: J. Med. Chem. 1998, 41, 1315.

X

Y


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

MeHN

Ph

N

OHN

O

HN

NH

NH2

OCl

3

PPACK - Early Target

O

NHNH

OH

OHN

Ph

NH

O

NR

O

OO

NH

O

NH

H2NNH

Cyclotheonamide A: R = HCyclotheonamide B: R = Me

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

HO

ONHCbz

HN

NHTsHN

1. (im)2CO; then, DIBAL

2. KCN (3:2 dr)

HO

CNNHCbz

HN

NHTsHN

i. HCl, MeOHii. NaHCO3iii. AcOH to pH 4

HO

CO2MeNHCbz

HN

NHTsHN

SEMO

CO2HNHCbz

HN

NHTsHN

1. SEM-Cl, 2,6- lutidine2. LiOH (35% overall)

D-PheOtBu,

DCC, HOBt(77%)

SEMONHCbz

HN

NHTsHN

NHO

CO2tBuPh

HOHN

HN

NHTsHN

NHO

CO2HPh

1. H2, Pd(OH)22. Fmoc-Pro, DCC

3. CF3CO2H (56%)

A

O

FmocN

H2N CO2Me

OH

HCl!

1. Fmoc-Cl, K2CO32. TBDMS-Cl3. DIBAL4.Ph3P

CO2tBu FmocHN

OTBDMS

CO2tBu

(73%)

FmocHN

OTBDMS

CO2H

CF3CO2H

(81%)

NH2

CO2H

!HClH2N

1. Cbz-Cl

2. CH2=CMe2, H2SO4 (41%)

NH2

CO2tBuCbzHN

1. PhthNCO2Et (80%)2. H2, Pd(OH)2

NPhth

CO2tBuH2N+

B

C to next page


B + C1. EDC, HOBt

OTBDMS

NH2

O

NH

NPhth

CO2tBu2. Et2NH, DMF (68% overall)

+ ABOP-Cl

NEt3(65%)

O

NHNH

OTBDMS

OHN

Ph

NCO2tBuPhth O

OHHN

ONFmoc

NH

NHTs

NH

1. Et2NH2. CF3CO2H

3. DCC, HOBt (41%)

O

NHNH

OHN

Ph

NO

N OHO

NH

OPhth

TBDMSO

NH

TsHN

HN 3

1. NH2NH2, 2-butenol

O

NHNH

OTBDMS

OHN

Ph

H2NO

N OHO

NH

O

NH

H2NNH

~10% macrolactonization

HCO2Et

(88%)

(90%)

O

C6F5

O

NHNH

OTBDMS

OHN

Ph

NH

O

N OHO

NH

O

NH

H2NNH

O

NHNH

OTBDMS

OHN

Ph

NH

O

N OHO

NH

O

NH

H2NNH

O

OHCCtA

CtB

1. DMP, MeCN

2. HF, PhOMe (33%)

1. DMP, DCM, tBuOH

2. HF, anisole (33%)

CtA

O

NHNH

OHN

Ph

NH

O

NO

HO

NH

OOHC

HO

N NH2

NH

NaHCO3

MeCN, H2O(65%)

See: J. Am. Chem. Soc. 1995, 117, 1225 and Tetrahedron Lett. 1996, 37, 3667.


O

NH

(E)(S)(S) NH

OH

O (R)(R)HN

Ph

(S)(S)NH

O

NH

O

(S)(S)

OO

NH (S)(S)

O

NH

H2NNH

Cyclotheonamide AKi = 4.1 nM

N (S)(S) NH

(S)(S) HN NH2

NH

O N

S(R)(R) O

MeHN

Ph O

RWJ-50353Ki = 0.20 nMCtA SAR

crystallographic studiesmedicinal chemsitry

Whats the minimum structure required for potent thromin ihibtion (<10 nM)?

[...some med chem later...] A potent tryptase inhibitor!

HNN

AcO

O

NH

NH2HN

N

S

HO

HNN

AcO

O

NH

NH2HN

N

S

HO

benzthiazole 8x more potent than thiazole!

RWJ-50353 was eventually abandoned due to pronounced hypotension and electrocardiogram effects in guinea pigs.

Benzthiazole RWJ-56423 was tested in sheep for antiasthma studies and was advanced to preclinical studies. Eventually, it entered human clinical trails.

RWJ-56423

Following that foray into tryptase inhibitiors... What about other compounds that could be used to treat asthma or chronic obstructive pulmonary disease?

Cathepsin G (Cat G) inhibitor? [... onward to the high throughput screen...]

O

(HO)2(O)PO

Moderate potency, but:1. Easy to make analogues2. Non-peptide -rare among Cat G inhibitors -!-ketophosphonic acid is novel 3. Reversible inhibitorIC50 = 4.1 ± 0.3 µM

crystallographic studiescomputer modellingmedicinal chemistry

O

(HO)2(O)PO

N

O

MeN

O

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 luckJ. Med. Chem. 2005, 48, 1984.


But wait, theres more about thrombin! En route to RWJ-58259 we stumble upon an unsuspecting mechanism, lets watch and see what she does...

O2N NH O2N N

H

N

CHONaNO2, 6 N HCl

J. Med. Chem. 2001, 44, 1021

severalstepslater

Ph NH

HN

NH

NH

O

NH2

O

F

FO

NN

N

Cl

Cl

RWJ-58259 Thrombin Receptor (PAR1-) atagonist

Some interesting things from the work on Cat G and Chymase:

R

O

R'

PO

OHONa

R

OR'

!

H2O, MeCNOrg. Lett. 2006, 8, 3249.

Cl

CO2H PO

N3PhO

PhO !

NEt3, PhMeCl

NCO

J. Med. Chem. 2007, 50, 1727

Cl

HN

O

PO

OHMe

S

Clseveralstepslater

chymase IC50 = 3.5 nM


OO

O

O

N

tol

O

O

N

tol

p-tol CN

CpCo(CO)2,o-xylenes140 ºC, hv

(29%)

(28%)

OO

N

p-tol CCH

CpCo(CO)2,o-xylenes140 ºC, hv

O

O

N

tol

(44%)

N

NH2

O

N

OMe

OO HN

OO

NN

HNO O

N N

N

NMe2

HNO O

N N

NNMe2

10% 9%

KOtBu

THF(63%)

CpCo(CO)2,1,4-dioxane

110 ºC

+

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)

Collogen rigidity provides mechanical strength to tissues. After vascular injury, exposed collogen leads to tissue repair by activating platelets.

R1

NH2 HN

ON

OO N

NH

O

OH

R2

CO2H

n

A: n = 10; R1 = (C6F5)CH2-; R2 = PhCH2B: n = 5; R1 = (C6F5)CH2-; R2 = PhCH2C: n = 10; R1, R2 = PhCH2D: 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, 2202PNAS 2008, 105, 8513.

Co-mediated [2 + 2 + 2] macrocyclizations:J. Am. Chem. Soc. 2005, 127, 3473Bioorg. Med. Chem. Lett. 2007, 17, 2863.


OO

O O

O

OS NH2

OO

Topiramate (Topamax)>$2 billion annually

O

O

O

H2NO2SO

OS OO

O"super topiramate"

(RWJ-37947)

OiPrN

NN

OHO2CCO2H

mazapertine succinate (RWJ-37796)schizophrenia (Phase II clinical)

NH

SMe

McN-5652-Z

NH

Cl

McN-5707

N

O

HN

O

NH

O

OH

Nneurotranmitter uptake inhibitors

elarofiban (RWJ-53308)fibrinogen receptor antagonist (Phase II clinical)

HNN

AcO

O

NH

NH2HN

N

S

HO

RWJ-56423asthma/allergic rhinitis (Phase II clinical)

N

O HN

NMe2

O

NH

O Ph

N

O OH

O

NH

O Cl

OMe

FRWJ-339489 RWJ-676070cogestive heart failure (Phase II clinical)

N

N

O

NH

O Ph

O

H

Cl

RWJ-351647congestive heart failure, edema, liver cirrhosis, hypnoatreama (Phase IIb clinical trials)

O

(HO)2(O)PO

N

O

MeN

O

RWJ-355871asthma and chronic obstructive pulmonary disease (Phase I clinical trials)

F FNH

NN

ONH

OO

NH

NH2

NH

RWJ-671818anticoagulant (Phase I/IIa)

Br

N N

OO N

BrN

HN

SO

ONH

macitentan (Phase III)

S

HN

S NH2O O

JNJ-26990990 epilepsy, migrane, neuropathic pain (Phase IIa)

A small sampling of the (successful) molecules Bruce Maryanoff has been involved with!

baran group meeting bruce e. maryanoff dane holte … · dane holte baran group meeting apr. 20,...

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