Synthesis and structure-activity relationships of β- and α-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy

J. Med. Chem. 2005, 48, 6713-6730

6713

Synthesis and Structure-Activity Relationships of â- and r-Piperidine Sulfone

Hydroxamic Acid Matrix Metalloproteinase Inhibitors with Oral Antitumor

Efficacy

Daniel P. Becker,* Clara I. Villamil,^†Thomas E. Barta,^‡Louis J. Bedell,^§Terri L. Boehm, Gary A. DeCrescenzo,

John N. Freskos, Daniel P. Getman, Susan Hockerman, Robert Heintz, Susan Carol Howard,^|Madeleine H. Li,

Joseph J. McDonald, Chris P. Carron, Chris L. Funckes-Shippy, Pramod P. Mehta, Grace E. Munie, and

Craig A. Swearingen

Pfizer Research, 4901 Searle Parkway, Skokie, Illinois 60077, and Pfizer Research, 700 Chesterfield Village Parkway,

St. Louis, Missouri 63198

Received January 30, 2005

R-Piperidine-â-sulfone hydroxamate derivatives were explored that are potent for matrix

metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the

â-sulfones subsequently led to the discovery of hitherto unknown R-sulfone hydroxamates that

are superior to the corresponding â-sulfones in potency for target MMPs, selectivity vs MMP-

1, and exposure when dosed orally. R-Piperidine-R-sulfone hydroxamate 35f (SC-276) was

advanced through antitumor and antiangiogenesis assays and was selected for development.

Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when

dosed orally as monotherapy or in combination with paclitaxel.

Introduction

Matrix metalloproteinases (MMPs) are zinc-depend-

ent enzymes responsible for the remodeling and degra-

dation of all components of the extracellular matrix.¹

The upregulation of MMPs has been implicated in

numerous disease states^2-6including osteoarthritis⁷and

cancer.^8-11Protease inhibitors including MMP inhibi-

tors (MMPis) have been explored as anticancer, anti-

inflammatory, and antiviral agents.^12-14A key thera-

peutic target for MMPis is cancer, as MMPs are

essential for tumor growth and metastasis,¹⁵and inhibi-

tion of MMP-9 in particular can block metastasis.^16,17

Figure 1. Selected MMPis.

Until recently, however, clinical trials with MMPis

for advanced cancer had not been successful in demon-

strating efficacy.^18,19Bramhall has now reported the

first placebo-controlled double blind study reporting

success in treating cancer with an MMPi in a study

treating gastric cancer patients with the broad spectrum

inhibitor marimastat.²⁰A survival benefit has also been

recently demonstrated in glioblastoma multiforme pa-

tients on marimastat in combination with temozolomide,

providing additional support that MMPis can improve

the outcome of cancer patients.²¹Marimastat afforded

a survival rate similar to gemcitabine in patients with

unresectable pancreatic cancer.²²Thus, the proof-of-

principle for efficacy in treating human cancers with

MMPis has now been demonstrated. Prinomastat has

been in phase III clinical trials for the treatment of

cancer,¹⁰and phase III clinical studies are presently

underway with mercaptan 1A (Figure 1).²³

Broad spectrum inhibition of MMPs in patients gives

rise to stiffening of the joints referred to as musculo-

skeletal syndrome (MSS). Inhibition of MMP-1 has been

hypothesized to be the cause of MSS observed clinically

with broad spectrum inhibitors including marimastat,

and marimastat induces musculoskeletal side effects in

rats.²⁴We therefore have concentrated our efforts on

potently inhibiting selected MMPs including MMP-2, -9,

and -13 while sparing MMP-1. The strategy of avoiding

inhibition of MMP-1 has been applied to the succinate

class of MMP inhibitors by British Biotech.²⁵Cross-

inhibition of ADAMs and ADAMTSs may also partially

account for side effects observed in long-term MMPi

therapy.²³

We have previously described the synthesis and MMP

inhibitory activity of a series of R-amino-â-sulfone

hydroxamates²⁶and R-alkyl-R-amino-â-sulfone hydrox-

amates²⁷as potent inhibitors of MMP-2 and MMP-13

that spare MMP-1. These compounds had moderate

pharmacokinetic parameters and required enantio-

selective syntheses to access the individual enantiomers.

* To whom correspondence should be addressed. Current address:

Loyola University, 6525 North Sheridan, Chicago, IL 60626. Tel: 847-

525-2642. Fax: 847-730-3181. E-mail: dbecke3@luc.edu.

^†Current address: Abbott Labs, 100 Abbott Park Road, Abbott Park,

IL 60064-6099.

^‡Current address: Serenex, 323 Foster Street, Durham, NC 27701.

^§Current address: deCODE Genetics, 2501 Davey Rd., Woodridge,

IL 60517.

^|Current address: Mallinckrodt, 675 McDonnell Blvd. Hazelwood,

MO 63042.

Published on Web 09/21/2005

6714 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

Scheme 1. General Method to Synthesize R-Piperidine-â-sulfones 7a-f

We wanted to remove the chirality and improve the

pharmacokinetic profile by incorporating a spiro ring R

to the hydroxamate, reasoning that the neopentyl center

should inhibit metabolic degradation of the hydrox-

amate moiety without affecting the binding of the

molecules. It should be noted in this context that the

R-tetrahydropyran â-sulfone 1B (Figure 1)²⁸synthesized

by Roche Bio-Science was advanced to phase II clinical

trials for osteoarthritis.²⁹During our examination of the

â-sulfones series, we discovered R-sulfone hydroxamate

inhibitors, which are superior to the â-sulfone series in

both enzyme profile and ADME properties.^30,31A series

of R-sulfone hydroxamates has also recently been re-

ported by the Wyeth group.^32,33

The R,R-dimethyl-R-sulfone 17 was prepared as shown

in Scheme 3. Alkylation of 4-phenoxythiophenol with

tert-butyl bromoacetate and oxidation of the resulting

sulfide gave the sulfone 14. Dialkylation with methyl

iodide and sodium hydride gave the dimethyl sulfone

15. Removal of the tert-butyl ester with TFA gave the

carboxylic acid 16, which was coupled with hydroxyl-

amine in the presence of EDC to give the R,R-dimethyl

hydroxamic acid 17.

The R-THP sulfone 21 was prepared as illustrated

in Scheme 4. Alkylation of 4-fluorothiophenol with

methyl bromoacetate gave the sulfide, which was oxi-

dized with potassium hydrogen persulfate to afford

sulfone 18. The acidic methylene was dialkylated with

bis(2-bromoethyl)ether to afford the R-sulfone 19. Sa-

ponification of the methyl ester with potassium tri-

methylsilanoate and subsequent coupling of the car-

boxylic acid with O-(tetrahydro-2H-pyran-2-yl)hydroxyl-

amine (THP-hydroxylamine) utilizing the water soluble

carbodiimide reagent (EDC) gave the THP protected

hydroxamate 20. Displacement of the fluoride with

4-chlorophenolate anion and subsequent treatment with

HCl gave the free hydroxamate 21.

N-Alkylpiperidine phenyloxyphenyl R-sulfones were

synthesized as described in Scheme 5. Ethyl isonipeco-

tate N-tert-butyl carbamate³⁴was deprotonated with

LDA and sulfinylated with the disulfide of 4-mercapto-

diphenyl ether to give the sulfide 22, and oxidation with

MCPBA afforded the corresponding R-sulfone 23. Re-

moval of the BOC protecting group under acidic condi-

tions gave the free piperidine 24, which was either

directly alkylated or reductively alkylated to afford 25.

Saponification of the hindered ethyl ester proceeded

This manuscript highlights our initial efforts in the

â-sulfone and R-sulfone aryl ether and thioether hy-

droxamate series resulting in the discovery of 35f (SC-

276), an MMP-1 sparing inhibitor that shows excellent

efficacy in tumor xenograft models.

Chemistry

The â-sulfone derivatives were prepared from ethyl

isonipecotate N-tert-butyl carbamate³⁴as illustrated in

Scheme 1. Deprotonation of ethyl isonipecotate N-tert-

butyl carbamate with LDA and quenching with meth-

ylene diiodide gave iodomethyl derivative 2. Alkylation

of the sodium salt of 4-mercapto-diphenyl ether with 2

gave the corresponding sulfide, which was oxidized

directly with MCPBA to afford the sulfone 3. Removal

of the BOC group with HCl gave amine 4, and alkylation

of the piperidine with an alkylating agent or via

reductive amination gave the N-alkylamine 5. Saponi-

fication of the ethyl ester with sodium hydroxide gave

the carboxylic acid 6, which was coupled with O-(tetra-

hydro-2H-pyran-2-yl)hydroxylamine utilizing EDC as

the coupling reagent. Deprotection under acidic condi-

tions gave the â-sulfone hydroxamate 7.

We targeted the dimethyl ketal 8 (Figure 2) as an

intermediate for facile elaboration of the R-position via

the ketone moiety to afford various R-substituted â-

sulfone hydroxamates. Toward this end, we alkylated

4-mercapto diphenyl ether 10 with bromopyruvic acid

in methanol (Scheme 2) to afford the R-keto acid 11.

Oxidation of the sulfide to the sulfone followed by

conditions of esterification with thionyl chloride in

methanol proceeded with an unexpected decarbonyl-

ation to afford the R-sulfone 12. Direct treatment of the

methyl ester 12 with hydroxylamine gave the corre-

sponding hydroxamic acid 13.

Figure 2. Initial R-ketal-â-sulfone target 8 and new R-sulfone

scaffold 9.

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6715

Scheme 2. Original Synthesis of R-Sulfone 13

Scheme 3. Synthesis of R,R-Dialkyl-R-sulfone 17

Scheme 4. Preparation of R-Tetrahydropyran-R-sulfone 21

Scheme 5. Synthesis of N-Alkylpiperidine-phenyloxyphenyl-R-sulfones 27a-i

under basic conditions, and the resulting carboxylic acid

26 was coupled with THP-hydroxylamine employing

ECD. Acidic deprotection of the hydroxamate moiety

afforded the requisite hydroxamate 27 as the hydro-

chloride salt.

gave the desired R-sulfone hydroxamates 35 as the

hydrochloride salt for basic amines. Alternatively, as

shown in Scheme 7, the fluoro of N-BOC sulfone 30 was

displaced with thiophenol to afford thioether 36. Re-

moval of the BOC with HCl gave the amine hydro-

chloride 37, which was alkylated to give various

tertiary amines 33, which were then converted to

the corresponding hydroxamates 35 as described in

Scheme 6.

N-Alkylpiperidine phenylthiophenyl R-sulfones 35a-h

were prepared as exemplified in Scheme 6. Ethyl

isonipecotate N-tert-butyl carbamate³⁴was sulfinylated

with p-fluorophenyl disulfide after deprotonation with

LDA to afford the sulfide 29, and subsequent oxidation

with MCPBA gave the corresponding R-sulfone 30.

Acidic removal of the BOC group gave the free amine

31 as the hydrochloride salt, which was then alkylated

with an alkyl halide or via reductive amination to yield

32. The p-fluoro was then displaced via a nucleophilic

aromatic substitution reaction with thiophenol to yield

thioether 33. Basic saponification of the hindered ethyl

ester gave the carboxylic acid, which was coupled with

THP-hydroxylamine utilizing EDC to give the protected

hydroxamate 34. Removal of the THP group with HCl

Results and Discussion

Selected R-sulfone and â-sulfone hydroxamates were

tested for inhibitory potency vs MMP-1, -2, -3, -8, -9,

and -13. Table 1 summarizes the MMP inhibitory

potency of â-sulfone analogues and includes 1B as a

direct comparator. We utilized the diphenyl ether P₁′

moiety that we had utilized in our earlier â-sulfone

work, as it had enabled the production of analogues that

were potent for MMP-2 and MMP-13, typically with

6716 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

Scheme 6. Synthesis of N-Alkylpiperidine-phenylthiophenyl-R-sulfones 35a-h

Scheme 7. Alternate Synthesis of N-Alkyl Piperidine Ethyl Esters Intermediates 33a-h

Table 1. In Vitro MMP Inhibitory Data [IC₅₀Values (nM)] and Oral Rat PK Data [C_maxand C_6h(ng/mL)] of â-Sulfones 7

K_i(nM)^a

compd

X

Ar

MMP-1

MMP-2

MMP-3

17.5

MMP-8

1.8

MMP-9

1.0

MMP-13

C_max

C_6h

1B

7a

7b

7c

7d

7e

7f

O

p-ClPh

800

475

2400

330

700

417 ( 96

7700

0.4

0.2

0.6

0.2

1372

537

NBOC

Ph

NH

Ph

2.8

158

2.4

0.40

3.0

0.60

0.70

30.0

1.1

9.0

4.5

7.0

8.0

1095

22

452

8038

1455

12

5

105

49

11

N-(3-MeOBn)

NCH₂CH₂Ph

N-propargyl

Ph

0.2

18.1

42.5

35.0

18.1

0.4

Ph

0.3

1.1

Ph

0.25 ( 0.07

0.9

0.55 ( 0.07

0.8

3,4-diMePh

^aK_i( SEM for n ) 3; other values n ) 1.

>1000-fold selectivity vs MMP-1.^26,27Compounds 7a-e

are phenyloxyphenyl ethers with varying substituents

on the R-piperidine nitrogen, and compound 7f employs

a 3,4-dimethylphenyloxyphenyl sulfone to drive deeper

into the P₁′ selectivity pocket in order to enhance the

selectivity vs MMP-1. The MMP-2/MMP-1 selectivity

ratio of 7a-e is maintained between 860× (example 7b)

and 2400× (example 7a), consistent with the identical

P1′ moiety and comparable to the selectivity ratio of

2000× for 1B. A somewhat higher selectivity (8500×)

was attained with 3,4-dimethylphenyl analogue 7f,

although the potency for MMP-2 was attenuated 3-4-

fold relative to the other analogues in Table 1. The free

NH compound 7b was roughly an order of magnitude

less potent vs all enzymes tested, which was surprising.

It is possible that the compound was unstable under

the conditions of the assay leading to diminished

potency. We were hoping for an enhancement in oral

exposure in the rat for these R-piperidine derivatives

vs the R-tetrohydropyran 1B. Propargyl compound 7e

did exhibit a substantially higher C_maxof 8038 ng/mL,

but the concentration at 6 h was lower for all of these

analogues relative to the neutral compound 1B sug-

gesting a more rapid rate of elimination.

As noted above, we originally targeted ketal 8 to

further our exploration of â-sulfone hydroxamates via

elaboration of the ketone derived from the ketal, but

potassium hydrogen persulfate oxidation of R-keto acid

11 followed by standard conditions to form the methyl

ester afforded the decarbonylated methyl ester 12.

When R-sulfone hydroxamate 13 was subsequently

prepared and tested, we were not expecting particularly

potent inhibition of the target MMPs because the

hydroxamate is known to serve as a tight chelator for

the zinc in the active site, and one of the sulfone oxygen

atoms forms an energetically favorable H-bond with the

NH of Ala-161 in the enzyme. This is analogous to the

binding of amino acid sulfonamide hydroxamates and

corresponds to those well-known MMP inhibitors in

terms of digitization. Thus, we were surprised and

delighted to find that the unsubstituted R-sulfone 13

maintained good inhibitory potency of 5 nM vs MMP-

13, 2.6 nM vs MMP-2, and was selective vs MMP-1 (IC₅₀

) 6600 nM). Indeed, we were then the first to report

R-sulfone hydroxamates as potent MMP inhibitors.^30,31

Aranapakam and co-workers at Wyeth have recently

reported novel series of R-sulfones that are potent for

MMP-13 and sparing of MMP-1, including a compound

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6717

Table 2. In Vitro MMP Inhibitory Data (IC₅₀Values, nM) and Oral Rat PK of 1B and the Corresponding R-Sulfone 21

K_i(nM)^a

compd

MMP-1

MMP-2

MMP-3

MMP-9

MMP-13

C_max

C_6h

t_1/2(h)

BA (%)

1B

21

800

435

0.4

<0.1

17.5

18.1

1.0

0.3

0.60

0.15

1372

3119

537

506

1.5

22.1

45.8

^aK_ivalues n ) 1.

Table 3. In Vitro MMP Inhibitory Data [IC₅₀Values (nM)] and Oral Rat PK Data [C_maxand C_6h(ng/mL)] of Phenyloxyphenyl

R-Sulfones 27a-i

K_i(nM)^a

C_max

C_6h

t_1/2BA

compd

R

MMP-1

1140

MMP-2

0.2

MMP-3

59

MMP-8

3.5

MMP-9

MMP-13 (ng/mL) (ng/mL) (h) (%)

27a BOC

27b

27c

27d methoxyethyl

27e

27f

27g propargyl

27h acetyl

27i

0.3

0.37 ( 0.06

0.1

H

1060 ( 216 0.22 ( 0.03

5.0

0.29

0.7

1839

4130

3111

15720

254

102

97

1.8 16

1.25 59

CH₃

464

350

400

770

<0.1

0.1

0.2

<0.1

0.3

9.4

12.1

0.1

0.3

<0.1

cyclopropyl

cyclopropylmethyl

0.6

135

0.74 36

274 ( 70 0.13 ( 0.03 12.6 ( 1.8 0.85 ( 0.64 0.40 ( 0.14 0.22 ( 0.07 22882

345

121

1.19 35.5

0.86 11.1

464

800

<0.1

0.3

<0.1

0.5

998

mesyl

1.0

^aK_i( SEM for n ) 3; other values n ) 1.

that is efficacious in an advanced rabbit osteoarthritis

model.^32,33

(22%) in this direct head-to-head comparison. This

higher bioavailability and C_maxmay be due to greater

steric bulk around the hydroxamate, protecting it from

the usual modes of hydroxamate metabolism including

N-O bond cleavage, hydrolysis, and glucuronidation.

It is interesting to note that the R-sulfone 21 is of

slightly lower molecular weight relative to â-sulfone 1B

and has one less rotatable bond. Veber has demon-

strated improved BA for compounds with fewer rotat-

able bonds.³⁵

Table 3 summarizes the MMP inhibitory potency for

diphenyl ether R-sulfone analogues and includes rat pk

data for selected analogues. It should be noted for the

rat pk in Tables 1-4 that plasma concentrations were

measured only out to 6 h. This protocol enables a higher

throughput of compounds for rat pk but leads to an

underestimation in particular of the half-life (t_1/2) of the

compounds. It nonetheless allows a direct comparison

among analogues for advancement selection criterion.

In general, these analogues are very potent vs the target

enzymes MMP-2, MMP-9, and MMP-13, and quite

sparing of MMP-1. N-Methyl analogue 27c, for example,

is 4600× selective for MMP-2 and MMP-13 over MMP-

1. Comparable potency and selectivity would be expected

for most of these analogues, given that the P₁′ substitu-

ent is held constant, which occupies the S₁′ selectivity

pocket. As in the â-sulfone series, the secondary amine

27b was notably less potent than the other analogues

in the series, and methanesulfonyl compound 27i was

somewhat less potent as well. Secondary amine 27b did

have the longest t_1/2of 1.8 h among these compounds

With the potency of R-sulfone 13 established, we

prepared the R,R-dimethyl analogue 17, which boosted

the potency back to subnanomolar values and actually

exceeded the potency of the â-sulfones with IC₅₀values

for MMP-13 and MMP-2 of 0.25 and 0.1 nM, respec-

tively. The R-sulfone 17 is also more potent for MMP-1

(IC₅₀) 220 nM) but is still >2000× sparing of MMP-1

relative to MMP-13. We thus determined to make the

corresponding R-piperidine diaryl ethers and diaryl

thioethers 9 (X ) O and X ) S, respectively; Figure 2).

We also prepared the R-THP 21 corresponding to the

Roche R-THP sulfone hydroxamate 1B for a direct

comparison of the â- and R-sulfones (Table 2). We have

found, in general, that R-sulfones are more potent vs

target MMP isozymes and also have superior pharmaco-

kinetics relative to the â-sulfones. Specifically, relative

to 1B, compound 21 is approximately 4× more potent

vs MMP-2, 3× more potent against MMP-9, and 4×

more potent vs MMP-13. Compound 21 is twice as

potent vs MMP-1, so the selectivity ratio vs MMP-1 is

actually improved. Potency for MMP-3 remains es-

sentially unchanged relative to the â-sulfone. When

administered orally to the rat, compound 21 has twice

the C_maxof 1B, although the concentration at 6 h is

comparable. The t_1/2of 1.5 h is identical for hydrox-

amates 1B and 21. (Data were only collected to 6 h;

hence, the t_1/2is less that would be measured for a full

24 h data collection.) Strikingly, the bioavailability for

R-sulfone 21 (45.8%) is double the value for RS-130830

6718 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

Scheme 8. â-Sulfone vs R-Sulfones (MMP IC₅₀Values, nM; Rat PK 20 mpk Suspension, ng/mL)

Table 4. In Vitro MMP Inhibitory Data [IC₅₀Values (nM)] and Oral Rat PK Data [C_maxand C_6h(ng/mL)] of Phenylthiophenyl

R-Sulfones 35a-g

K_i(nM)^a

C_max

C_6h

t_1/2

(h)

BA

(%)

compd

R

MMP-1

MMP-2

MMP-3 MMP-8 MMP-9

MMP-13

(ng/mL) (ng/mL)

35a

35b

35c

35d

35e

35f

CH₃

Et

methoxyethyl

cyclopropyl

allyl

propargyl

acetyl

mesyl

>10000

0.5

0.8

39.3

11.4

9.4

0.68 ( 0.18

3330

543

1.91 27.5

0.8

0.5

0.3

20.0

23.5

4.0

3.5

3.0

2.5

12589

7647

10015

13630

162

1237

529

537

281

72

0.1

0.15

0.2

0.3

1.03 34.6

8660 ( 1656 0.33 ( 0.09

13.0

23.0

32.0

1.8

5.0

4.0

1.5

8.0

14.7

0.40 ( 0.10

0.6

1.1

28

35g

35h

7300

>10000

0.4

2.0

0.65 12.7

2.6

^aK_i( SEM for n ) 3; other values n ) 1.

but suffers from a lower BA of 16% as compared with

the tertiary amine compounds tested. N-Methyl piperi-

dine 27c showed good exposure and the highest bio-

availability (59%) of the series, while N-cyclopropyl

piperidine 27e had a C_maxof 15720 ng/mL and a good

BA of 36%. N-Propargyl piperidine 27g exhibited the

highest oral exposure of these analogues, with a very

high C_maxof 22882 ng/mL and a significant concentra-

tion (345 ng/mL) remaining after 6 h. The N-propargyl

analogue also had an acceptable BA of 35.5%.

The chronological and conceptual progression from

â-sulfones to R-sulfones is summarized in Scheme 8,

beginning with N-propargyl R-piperidine-â-sulfone 7e

and proceeding via R-sulfone 13 and R,R-dimethyl-R-

sulfone 17 to the N-propargyl R-piperidine R-sulfone

27g, which shows the improvement from good to excep-

tional potency, selectivity, and pk in the rat. The

improvement of the R-sulfones over the â-sulfones is

again clearly borne out in the direct comparison of

N-propargyl piperidine phenyloxyphenyl â-sulfone 7e

and the corresponding R-sulfone 27g. The R-sulfone 27g

is almost twice as potent at MMP-1 than the â-analogue,

but it is 3× as potent at MMP-2, 9× as potent at MMP-

9, and over 2× as potent at MMP-13. The exposure in

rat after an oral suspension dose of 20 mpk was

substantially greater for 27g, with a C_maxof 22882 ng/

mL and a concentration at 6 h of 345 ng/mL, as

compared with a C_maxof 8038 ng/mL and C_6hof 49 ng/

mL for 7e.

longer C-S bond lengths would enhance the selectivity

vs MMP-1. We reasoned that the phenylthiophenyl

moiety would probe deeper into the S₁′ pocket than the

phenyloxyphenyl group and improve the level of selec-

tivity. These compounds were still highly potent, al-

though slightly less potent relative to the phenyl-

oxyphenyl ethers of Table 3. These thioethers have the

advantage of exquisitely sparing MMP-1, with all

examples shown having selectivity ratios of >10000×

for MMP-2 over MMP-1, with the exception of N-mesyl

piperidine 35h, being limited by the accuracy of the

MMP-1 value and the compound’s lower potency for

target enzymes. N-Cyclopropyl piperidine 35d, for ex-

ample, is very potent for MMP-2 (IC₅₀) 0.1 nM) with

an IC₅₀for MMP-1 of >10000 nM. Cyclopropyl com-

pound 35d is also very potent for MMP-13 (0.2 nM) and

has good potency for MMP-9 (2.5 nM). The tertiary

amines tested exhibit very good pk in the rat after

dosing as an oral suspension. N-Cyclopropyl derivative

35d has a significant C_maxof 7647 ng/mL with a

substantial concentration remaining after 6 h (529 ng/

mL) and a good BA of 34.6%. N-Methoxyethyl piperidine

35c also enjoyed good exposure, as did N-propargyl

piperidine 35f, with a C_maxof 13630 and 281 ng/mL

remaining after 6 h. Compound 35f was selected for

further study based on its excellent in vitro and in vivo

pharmacokinetic parameters.

Antiangiogenic and Antitumor Properties of 35f.

The growth of solid tumors has been shown to be

dependent on the development of new blood vessels.³⁶

Avascular, microscopic growing tumors produce diffus-

ible angiogenic factors that induce host capillary endo-

We then prepared the phenylthiophenyl ether R-

sulfones summarized in Table 4, hoping that the greater

size of the sulfur relative to oxygen and the slightly

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6719

Figure 4. Compound 35f extends the survival of MX-1 breast

tumor-bearing mice treated with paclitaxel and/or 35f. Mice

were implanted with MX-1 tumor fragment and then pair-

matched on day 1 when the tumors reached approx 60 mg.

Groups were administered vehicle, 35f, paclitaxel, or the

combination of paclitaxel and 35f from day 1 until the end

point was reached.

Figure 3. Compound 35f inhibits angiogenesis in the mouse

cornea. Neovascularization was initiated in the mouse cornea

by implanting a Hydron pellet containing basic FGF pellet.

Compound 35f, at doses of 1-50 mg/kg in 0.5% methylcellose/

0.08% tween 80, was administered orally twice a day for 5

days. Neovascularization in the control and treated groups was

measured, and the extent of neovascularization in treatment

groups was normalized to vehicle-treated control (set at 100%).

These are representative data from two independent experi-

ments.

Table 5. Summary of MX-1 Treatment Response to Paclitaxel

and/or 35f

drug 1

drug 2

MDS

P value

vehicle

25.3

31.0

32.1

46.7

paclitaxel

p ) 0.036^a

p < 0.04^b

p ) 0.005^c

p ) 0.007^d

thelial cells to proliferate, migrate, and form new vessels

in a process called tumor-induced angiogenesis. Once

vascularized, tumor size can increase almost exponen-

tially.^37-39To address the question of whether 35f is

antiangiogenic in vivo and therefore might inhibit tumor

growth by inhibiting angiogenesis, we tested 35f in a

mouse model of corneal neovascularization.

The mouse corneal micropocket assay is a widely used

model of angiogenesis useful for in vivo testing of

antiangiogenic agents. Hydron pellets containing basic

fibroblast growth factor (bFGF) were implanted into the

corneas of mice. Pronounced neovascularization oc-

curred in the tissue surrounding the pellet of the course

of 4 days. Mice were administered vehicle or 35f, orally,

twice a day beginning the evening of pellet implantation.

On day 5, animals were sacrificed and corneal neovas-

cularization was determined by computer-aided image

analysis. Compound 35f inhibited bFGF-induced corneal

neovascularization in a dose-dependent manner (Figure

3). Compound 35f reduced corneal neovascularization

approximately 50% at a dose of 50 mpk and supports

the hypothesis that the antitumor activity of 35f de-

scribed below is due, at least in part, to inhibition of

tumor angiogenesis.

Inhibition of Tumor Growth by 35f. MMPis may

be most useful in the human clinical setting when used

in combination with chemotherapy. We tested 35f as a

single agent and in combination with paclitaxel, a

chemotherapeutic used in the treatment of breast

cancer. The Kaplan-Meier survival curves for the

various treatment groups are presented in Figure 4.

MX-1 carcinomas grew progressively and rapidly in mice

that received vehicle only; the median survival time

(MDS) was 25.3 days. A MDS value of 32.1 days was

calculated for the mice treated with 100 mg/kg of 35f.

All tumors in this group reached the cutoff size of 1.5

g. The 27% increase in the MDS of the 35f -treated mice

was statistically significant when compared to the MDS

of vehicle-treated mice (p ) 0.04). Eight of the nine mice

treated with paclitaxel had a MDS of 30.1 days. The

19% increase in survival as compared to vehicle-treated

mice was statistically significant (p ) 0.036). One mouse

35f

paclitaxel

^ap, Vehicle vs paclitaxel. ^bp, Vehicle vs 35f. ^cp, Paclitaxel vs

combination paclitaxel/35f. ^dp, 35f vs combination paclitaxel/35f.

died from unknown causes on day 13 and was not

included in the analysis.

Excellent activity was seen when paclitaxel and 35f

were combined. The MDS of the mice treated with

paclitaxel and 35f was 46.7 days and represents a

survival increase of 53% over the MDS of the mice

treated with paclitaxel alone. These results clearly show

that the combination of paclitaxel and 35f exceeds the

efficacy of paclitaxel alone as demonstrated by the

increased median survival time of mice bearing MX-1

tumors. Moreover, the survival benefit appears to be

more than additive when compared to the efficacy of

monotherapy with either agent (Table 5).

Conclusions

The â-sulfone hydroxamate series summarized in

Table 1 provided potency for the targeted MMPs and

selectivity vs MMP-1 but generally exhibited poor oral

exposure. In addition, we have observed that some

â-sulfones with R-hydrogens can undergo â-elimination.

In contrast, the R-sulfones summarized in Tables 2-4

possess both potency and selectivity and provide an

improvement in oral exposure demonstrated by higher

C_maxvalue and bioavailability relative to the â-sulfones.

Both the aryl ether and the thioether P₁′ moieties

provide excellent potency (Tables 3 and 4, respectively),

and the thioether moiety exhibits enhanced selectivity

over the phenyloxyphenyl sulfones. The R-piperidine

nitrogen substituents provide improved ADME proper-

ties, and compounds exhibiting the highest oral expo-

sures are those with the methoxyethyl, cyclopropyl,

allyl, and propargyl groups (35c, 35d, 35e, and 35f).

This work culminated in the discovery of 35f, a thioether

sulfone hydroxamate that shows excellent efficacy in

murine xenograft tumor models and antiangiogenesis

assays.

6720 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

t, J ) 8.5 Hz), 4.19 (2H, q, J ) 7 Hz), 3.69 (2H, s), 3.32 (2H,

m), 3.16 (2H, td, J ) 10, 3 Hz), 2.39 (2H, m), 2.00 (2H, m),

1.31 (3H, t, J ) 7 Hz). IR (MIR): 1722, 1583, 1486, 1246, 1146

cm^-1. Anal. calcd for C₂₁H₂₅NSO₅‚HCl: C, 57.33; H, 5.96; N,

3.18; Cl, 8.06. Found: C, 57.29; H, 5.87; N, 3.17; Cl, 8.17.

Compound 35f exhibits excellent potency for target

enzymes, selectivity vs MMP-1, good pk in multiple

species, and excellent efficacy in tumor xenograft mod-

els. Primate pk for 35f was excellent, with BA ) 88%

in cyno and a t_1/2of 3.8 h. The compound has been slated

for development and has been prepared on a multikilo

scale. Additional results of our work on highly selective

R-sulfone hydroxamate MMP inhibitors will be reported

in due course.

tert-Butyl 4-[(Hydroxyamino)carbonyl]-4-{[(4-phen-

oxyphenyl)sulfonyl]methyl}piperidine-1-carboxylate (7a).

To a solution of ethyl ester 3 (250 mg, 0.496 mmol) in 1:1

EtOH/THF (6 mL) was added NaOH (198 mg, 4.96 mmol) in

water (2 mL), and the solution was heated at 60 °C for 18 h.

The reaction was diluted with water (20 mL) and acidified with

2 N HCl. The mixture was then extracted with CH₂Cl₂(3×).

The combined extracts were washed with brine and dried over

MgSO₄and concentrated to afford the carboxylic acid 6a (236

Experimental Section

All solvents and reagents were used without further puri-

fication unless otherwise noted. All reactions were performed

under an atmosphere of nitrogen or argon. Merck silica gel 60

(230-400 mesh) was used for flash chromatography. Merck

Kieselgel 60 F254 DC-Fertigplatten (0.25 mm, Art. 5719) were

used for TLC. High-performance liquid chromatograms (HPLC)

were obtained from YMC AQ C-18 reverse phase columns. ¹H

NMR spectra were obtained from either General Electric QE-

300 or Bruker-400 MHz Ultrashield spectrometers with tetra-

methylsilane (TMS) as an internal standard. Noise-decoupled

and APT ¹³C NMR spectra were recorded at 75 MHz on a

General Electric QE-300 spectrometer. IR spectra were re-

corded on a Perkin-Elmer 685 spectrophotometer. DSC refers

to differential scanning calorimetry. MIR refers to multiple

internal reflectance infrared spectroscopy. High-resolution

mass spectra were recorded on a Finnigan MAT8430 instru-

ment. Elemental analyses were conducted on a Control Equip-

ment CEC240-XA instrument. Melting points were obtained

by DSC.

1-tert-Butyl 4-Ethyl 4-(iodomethyl)piperidine-1,4-di-

carboxylate (2). To a solution of ethyl isonipecotate N-tert-

butyl carbamate³⁴(1.00 g, 3.89 mmol) in dry THF (10 mL) at

-40 °C was added 1.8 M LDA (2.2 mL, 3.9 mmol) dropwise.

After 0.5 h at -40 °C, the reaction was quenched with water

and extracted with diethyl ether (3×). The combined extracts

were washed with water and brine and dried over MgSO₄.

Concentration gave the desired iodide 2 (1.5 g, 96.8%) as an

oil. ¹H NMR (400 MHz, CDCl₃): δ 4.23 (2H, t, J ) 7 Hz), 3.83

(2H, m), 3.30 (2H, s), 3.00 (2H, m), 2.18 (2H, m), 1.42 (9H, s),

1.28 (3H, t, J ) 7 Hz).

1

mg, 100%). H NMR (400 MHz, CDCl₃): δ 7.84 (2H, d, J ) 8

Hz), 7.41 (2H, t, J ) 8 Hz), 7.22 (1H, t, J ) 7 Hz), 7.06 (4H, d,

J ) 7 Hz), 3.68 (2H, m), 3.48 (2H, s), 3.32 (2H, m), 2.21 (2H,

m), 1.71 (2H, m), 1.45 (9H, s).

To a solution of the carboxylic acid 6a (850 mg, 1.79 mmol)

in DMF (7 mL) was sequentially added HOBT (290 mg, 2.1

mmol), EDC (480 mg, 2.5 mmol), NMM (0.59 mL, 5.37 mmol),

and 50% aqueous hydroxylamine (0.35 mL, 5.37 mmol), and

the solution was stirred at room temperature for 16 h. Water

(35 mL) was added, and the mixture was extracted with EA

(4 × 50 mL). The combined extracts were washed successively

with water and brine and dried over MgSO₄. Concentration

gave a residue (900 mg), which was chromatographed on

reverse phase eluting with MeCN/H₂O (gradient from 30/70

to 80/20) to afford the desired hydroxamate 7a (300 mg, 34%)

1

as a colorless solid. H NMR (400 MHz, CDCl₃): δ 7.85 (2H,

d, J ) 8 Hz), 7.48 (2H, t, J ) 8 Hz), 7.28 (1H, t, J ) 7 Hz),

7.15 (4H, d, J ) 7 Hz), 3.66 (2H, s), 3.42 (2H, m), 3.18 (2H,

m), 1.91 (2H, m), 1.65 (2H, m), 1.38 (9H, s). Anal. calcd for

C₂₄H₃₀N₂SO₇: C, 58.76; H, 6.16; N, 5.71; S, 6.54. Found: C,

58.64; H, 6.24; N, 5.66; S, 6.66.

N-Hydroxy-4-{[(4-phenoxyphenyl)sulfonyl]methyl}-

piperidine-4-carboxamide Hydrochloride (7b). Through

a solution of N-BOC hydroxamate 7a (499 mg, 1.02 mmol) in

EA (20 mL) at 0 °C was bubbled HCl gas for 2 min. The

solution was then stirred for 0.5 h at 0 °C and then concen-

trated to dryness. The residue was triturated with ether and

dried to afford the hydrochloride salt of hydroxamate 7b (432

1

mg, 99%) as a colorless solid. H NMR (400 MHz, d₆-DMSO):

1-tert-Butyl 4-Ethyl 4-{[(4-Phenoxyphenyl)sulfonyl]-

methyl}piperidine-1,4-dicarboxylate (3). To a suspension

of sodium hydride (600 mg of a 60% dispersion, 15.0 mmol) in

dry DMF (9 mL) at 0 °C was added 4-phenoxy thiophenol (3.03

g, 15.0 mmol) in dry DMF (1 mL) and stirred for 15 min at 0

°C. The sodium thiolate solution was then added to a solution

of iodide 2 (5.96 g, 15.0 mmol) in DMF (9 mL) at 0 °C, and the

solution was stirred for 1 h at 0 °C and 3 h at room

temperature. The reaction was quenched with the addition of

water (100 mL), and the resulting mixture was extracted with

EA (3×). The combined extracts were washed successively with

water, 1 N KHSO₄, water, and brine and dried over MgSO₄.

Concentration gave a residue (7.42 g), which was purified by

chromatography on silica gel eluting with EA/hexane (20/80)

to afford the desired sulfide (6.27 g, 89%) as a solid. HRMS

calcd for C₂₆H₃₃NSO₅, 471.2063; found, 471.2052. To a solution

of the sulfide (6.2 g, 13.1 mmol) in CH₂Cl₂at 0 °C was added

85% MCPBA (5.65 g, 27.8 mmol), and then, the reaction was

stirred for 2 h at 0 °C. The solution was then washed

successively with water, saturated NaHCO₃, water, and brine

and then dried over MgSO₄. Concentration gave a residue (7.86

g), which was chromatographed on silica gel eluting with EA/

hexane (30/70) to afford the â-sulfone 3 (6.4 g, 97%) as a

colorless solid.

δ 8.78 (1H, s), 8.65 (1H, br s), 3.18 (2H, m), 2.91 (2H, m), 2.16

(2H, m), 1.95 (2H, m). HRMS calcd for C₁₉H₂₂N₂SO₅: 391.1328;

found, 391.1349. Anal. calcd for C₁₉H₂₂N₂SO₅‚HCl‚H₂O: C,

51.29; H, 5.66; N, 6.30; Cl, 7.97; S, 7.21. Found: C, 50.87; H,

5.24; N, 6.22; Cl, 8.24; S, 7.07.

N-Hydroxy-1-(3-methoxybenzyl)-4-{[(4-phenoxyphenyl)-

sulfonyl]methyl}piperidine-4-carboxamide Hydrochlo-

ride (7c). To a solution of the ethyl ester piperidine mono-

hydrochloride 4 (748 mg, 1.70 mmol) in methanol (7 mL) was

added anisaldehyde (242 mg, 1.78 mmol) followed by borane-

pyridine complex (106 µL of a ca. 8 M solution in pyridine,

0.85 mmol). After 18 h at room temperature, additional

quantities of anisaldehyde (112 mg, 0.82 mmol) and borane-

pyridine (106 µL, 0.85 mmol) were added, and the solution was

stirred for an additional 18 h at room temperature. Saturated

aqueous sodium bicarbonate (10 mL) was then added, and the

reaction was extracted with ethyl acetate (3×). The combined

extracts were washed with water and brine, dried over Na₂SO₄,

and concentrated to afford a colorless oil (1.03 g). Chromatog-

raphy on silica gel eluting with EA/hexane (1:1) afforded the

N-methoxybenzylamine 5c (0.82 g, 92%) as a colorless oil. IR

(MIR): 1731, 1581, 1486, 1242, 1140 cm^-1. ¹H NMR (300 MHz,

CDCl₃): δ 7.81 (2H, d, J ) 8.7 Hz), 7.42 (2H, t, J ) 8 Hz),

7.22 (2H, q, J ) 8 Hz), 7.05 (5H, m), 6.85 (2H, m), 6.75 (1H, d,

J ) 8 Hz). MS MH+ calcd for C₂₉H₃₃NO₆S, 524; found, 524.

Anal. calcd for C₂₉H₃₃NO₆S‚0.75H₂O: C, 64.84; H, 6.47; N,

2.61. Found: C, 64.89; H, 6.72, N, 2.51.

Ethyl 4-{[(4-Phenoxyphenyl)sulfonyl]methyl}piper-

idine-4-carboxylate Hydrochloride (4). Through a solution

of sulfone BOC amine 3 (1.11 g, 4.03 mmol) in EA (30 mL) at

0 °C was bubbled HCl gas for 5 min. Concentration gave a

colorless solid, which was triturated with ether, filtered, and

dried to afford the amine hydrochloride 4 (774 mg, 80%) as a

colorless solid. ¹H NMR (300 MHz, CD₃OD): 7.88 (2H, d, J )

9 Hz), 7.46 (2H, t, J ) 8 Hz), 7.27 (1H, t, J ) 8 Hz), 7.12 (4H,

To a solution of 3-methoxybenzylamine 5c (800 mg, 1.53

mmol) in EtOH (10 mL) and THF (15 mL) was added an

aqueous solution of NaOH (612 mg, 15.3 mmol) in water (15

mL), and the solution was heated under reflux for 16 h. The

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6721

C₂₇H₃₀N₂SO₅‚HCl‚0.75H₂O: C, 59.55; H, 6.02; N, 5.14. Found:

reaction mixture was concentrated, and 5.5 N aqueous HCl

(15 mL) was added followed by MeOH (20 mL) to affect

dissolution of the resulting gum. Purification on a Waters

reverse phase instrument eluting with 15/85 MeCN/H₂O with

0.5% HCl afforded the corresponding carboxylic acid 6c as a

yellow-orange oil. IR (MIR): 3500 (br), 3200-2300 (br), 1581,

1486, 1244, 1142 cm^-1. HRMS calcd for C₂₇H₂₉NO₆S, 496.1798;

C, 59.29; H, 6.04; H, 5.19. IR (MIR): 1647, 1580 cm^-1

.

N-Hydroxy-4-{[(4-phenoxyphenyl)sulfonyl]methyl}-1-

prop-2-ynylpiperidine-4-carboxamide Hydrochloride (7e).

To a solution of amine hydrochloride 4 (750 mg, 1.70 mmol)

in DMF (10 mL) was added K₂CO₃(469 mg, 3.4 mmol) followed

by 80% propargyl bromide in toluene (0.25 mL, 1.7 mmol). The

reaction was stirred at room temperature for 5 h and then

diluted with EA (40 mL) and washed successively with water

and brine and dried over MgSO₄. Concentration gave a residue

(730 mg), which was chromatographed on silica gel eluting

with EA to afford the N-propargylamine ethyl ester 5e (620

mg, 82%) as a solid. IR (MIR): 3278, 1733, 1581, 1467, 1242,

1

found, 496.1794. H NMR (300 MHz, CD₃OD): δ 7.87 (2H, d,

J ) 8.7 Hz), 7.45 (2H, t, J ) 8 Hz), 7.39 (1H, t, J ) 8 Hz), 7.26

(2H, m), 6.92 (1H, m), 4.29 (2H, s), 3.83 (3H, s), 3.78 (2H, s),

3.38 (2H, br m), 3.23 (2H, br m), 2.45 (2H, br m), 2.12 (2H, br

m).

To a solution of this carboxylic acid 6c (841 mg, 1.62 mmol)

in dry DMF (6 mL) were added HOBT (263 mg, 1.94 mmol)

and NMM (655 mg, 6.5 mmol). The solution was then cooled

to 0 °C, and 50% aqueous hydroxylamine (128 µL, 194 mmol)

was added followed by EDC (372 mg, 1.94 mmol). After 20 h

at room temperature, additional quantities of HOBT, NMM,

hydroxylamine, and EDC (same quantities as original) were

added and the solution was stirred for an additional 16 h at

room temperature. The reaction mixture was then concen-

trated. Saturated aqueous NaHCO₃(50 mL) was added, and

the mixture was extracted with EA (4×). The combined

extracts were washed with water and brine, dried over Na₂SO₄,

and concentrated to afford a yellow-orange oil (308 mg), which

was purified on a Waters reverse phase instrument eluting

with 15/85 MeCN/H₂O with 0.5% HCl afforded the requisite

hydroxamic acid 7c as a colorless solid. IR (MIR): 1737, 1656,

1583, 1487, 1245, 1144 cm^-1. ¹H NMR (300 MHz, CD₃OD): δ

7.89 (2H, d, J ) 8 Hz), 7.5-6.9 (11 H, m), 4.27 (2H, s), 3.84

(3H, s), 3.55-3.25 (4H, m), 3.06 (2H, m), 2.62 (2H, m), 2.16

(2H, m). HRMS calcd for MH+ C₂₇H₃₁N₂O₆S, 511.1903; found,

511.1907. Anal. calcd for C₂₇H₃₀N₂O₆S‚HCl‚1.5H₂O: C, 56.49;

H, 5.97; N, 4.88. Found: C, 55.92; H, 5.32; N, 4.72.

1

1142 cm^-1. H NMR (400 MHz, CDCl₃): δ 7.84 (2H, d, J ) 9

Hz), 7.42 (2H, t, J ) 9 Hz), 7.23 (1H, t, J ) 7 Hz), 7.06 (4H, d,

J ) 9 Hz), 4.21 (2H, q, J ) 7 Hz), 3.47 (2H, s), 3.41 (1H, m),

2.83 (2H, m), 2.69 (2H, m), 2.37 (2H, m), 1.96 (2H, m), 1.33

(3H, t, J ) 7 Hz).

To a solution of N-propargylamine ethyl ester 5e (620 mg,

1.4 mmol) in 1:1 EtOH/THF (20 mL) was added NaOH (560

mg, 14.0 mmol) in water (10 mL), and the reaction was heated

to 60 °C for 18 h. The reaction mixture was then concentrated

to a residue. Water (40 mL) was added, and the mixture was

acidified with 2 N HCl to pH 4. The resulting precipitate was

filtered and dried to afford carboxylic acid 6e (473 mg, 82%)

1

as a solid. H NMR (300 MHz, CDCl₃): δ 7.85 (2H, d, J ) 9

Hz), 7.48 (2H, t, J ) 8 Hz), 7.28 (1H, t, J ) 6 Hz), 7.16 (4H, d,

J ) 9 Hz), 3.53 (2H, s), 3.20 (2H, s), 3.09 (1H, s), 2.48 (2H, m),

2.33 (2H, m), 2.01 (2H, m), 1.06 (2H, m). HRMS calcd for

C

₂₂H₂₄NSO₅, 414.1375; found, 414.1382. Anal. calcd for

C₂₂H₂₃NSO₅‚HCl‚0.5H₂O: C, 57.57; H, 5.49; N, 3.05; S, 6.99.

Found: C, 57.59; H, 4.91; N, 2.72; S, 6.76.

To a solution of solution of carboxylic acid 6e (460 mg, 1.10

mmol) in DMF (10 mL) was added sequentially HOBT (180

mg, 1.33 mmol), EDC (299 mg, 1.56 mmol), NMM (0.49 mL,

4.45 mmol), and 50% aqueous hydroxylamine (0.22 mL, 3.3

mmol), and the reaction was stirred on at room temperature.

The reaction was then charged again with identical amounts

of HOBT, EDC, NMM, and aqueous hydroxylamine and stirred

an additional 48 h. Water (30 mL) was added, and the reaction

was extracted with CHCl₃(3×), and the combined extracts

were washed with brine, dried over MgSO₄, and concentrated

to afford a residue (500 mg), which was chromatographed on

reverse phase eluting with MeCN/H₂O (20/80) to afford the

N-propargyl hydroxamic acid free base of 7e (173 mg, 36%)

as a colorless solid. ¹H NMR (400 MHz, d₆-DMSO): δ 8.63 (1H,

s), 7.82 (2H, d, J ) 9 Hz), 7.48 (2H, t, J ) 9 Hz), 7.27 (1H, t,

J ) 8 Hz), 7.14 (4H, d, J ) 9 Hz), 3.57 (2H, s), 3.19 (2H, s),

3.11 (1H, s), 2.47 (2H, m), 2.32 (2H, m), 201 (2H, m), 1.72 (2H,

m). HRMS calcd for C₂₂H₂₅N₂SO₅, 429.1484; found, 429.1480.

Anal. calcd for C₂₂H₂₄N₂SO₅: C, 61.66; H, 5.64; N, 6.54; S, 7.48.

Found: C, 61.33; H, 5.68; N, 6.36; S, 7.35. To a solution of

this free base hydroxamate in MeOH (5 mL) was added a

solution of HCl in MeOH [prepared by adding 46 mg (0.66

mmol) of acetyl chloride to MeOH (2 mL) at 0 °C]. Concentra-

tion and trituration with ether afforded the hydroxamic acid

amine hydrochloride salt 7e (153 mg, 100%) as a colorless solid.

Anal. calcd for C₂₂H₂₄N₂SO₅‚HCl‚0.5H₂O: C, 55.75; H, 5.53;

N, 5.91; Cl, 7.48. Found: C, 55.42; H, 5.63; N, 5.79; Cl, 8.00.

N-Hydroxy-4-{[(4-phenoxyphenyl)sulfonyl]methyl}-1-

(2-phenylethyl)piperidine-4-carboxamide Hydrochlo-

ride (7d). To a suspension of amine hydrochloride 4 (750 mg,

1.70 mmol) in EtOH (30 mL) was added phenyl acetaldehyde

(414 mg, 3.4 mmol) followed by borane-pyridine (0.44 mL, 3.4

mmol), and the reaction was stirred at room temperature for

3 days. The solvent was removed in vacuo, and the residue

was resuspended in H₂O (40 mL). The mixture was extracted

with CH₂Cl₂(3×), and the combined organic extracts were

washed successively with water and brine and dried over

MgSO₄. Concentration gave a residue, which was chromato-

graphed on silica gel eluting with EA/hexane (60/40 to neat

EA) to afford the phenethylamine ethyl ester 5d. ¹H NMR (400

MHz, CDCl₃): δ 7.81 (2H, d, J ) 9 Hz), 7.44 (2H, t, J ) 9 Hz),

7.31 (1H, m), 7.24 (5H, m), 7.09 (4H, m), 4.30 (2H, q, J ) 7

Hz), 3.50 (2H, m), 3.45 (2H, s), 3.24 (2H, m), 3.12 (2H, m),

2.94 (2H, m), 2.55-2.45 (4H, m), 1.36 (3H, t, J ) 7 Hz). HRMS

calcd for C₂₉H₃₄NSO₅, 508.2158; found, 508.2161.

To a solution of phenethylamine ethyl ester 5d (680 mg, 1.30

mmol) in 1:1 EtOH/THF (16 mL) was added an aqueous

solution of NaOH (520 mg, 13.0 mmol) in water (3 mL), and

the reaction was heated to 60 °C for 16 h. The reaction was

then concentrated to dryness and acidified with 2 N HCl.

Trituration with ether afforded the carboxylic acid 6d as a

beige solid (894 mg). MS MH+ calcd for C₂₇H₂₉NSO₅, 480;

found, 480.

4-({[4-(3,4-Dimethylphenoxy)phenyl]sulfonyl}methyl)-

N-hydroxy-1-prop-2-ynylpiperidine-4-carboxamide Hy-

drochloride (7f). To a suspension of 60% NaH (600 mg, 15.0

mmol) in DMF (10 mL) at 0 °C was added 4-(3,4-dimethyl-

phenoxy)thiophenol (3.45 g, 15.0 mmol). To this solution of

sodium thiolate was then added a solution of iodide 2 in DMF

(10 mL). The reaction, which became thick, was stirred for 0.5

h at 0 °C and then warmed to room temperature for 4 h. Water

(100 mL) was then added, and the mixture was extracted with

EA (3×). The combined extracts were washed with brine and

dried over MgSO₄. Concentration gave a viscous oil, which was

purified by chromatography on silica gel eluting with EA/

hexane (15/85) to afford the corresponding sulfide (6.45 g, 86%).

HRMS calcd for C₂₈H₃₇NSO₅, 400.1946; found, 400.1948. Anal.

To a suspension of the carboxylic acid 6d (850 mg) in DMF

(10 mL) was added sequentially HOBT (267 mg, 1.98 mmol),

EDC (429 mg, 2.24 mmol), NMM (485 mg, 4.8 mmol), and 50%

aqueous hydroxylamine (1.06 mL, 16 mmol). After 16 h, the

reaction was charged with identical quantities of HOBT, EDC,

NMM, and hydroxylamine and stirred for an additional 24 h.

To the reaction was then added H₂O (50 mL), and the mixture

was extracted with CHCl₃(3×). The combined extracts were

washed successively with water and brine, dried over MgSO₄,

and concentrated to afford a residue (380 mg), which was

chromatographed on reverse phase eluting with a gradient of

MeCN/H₂O/HCl to afford the hydroxamic acid hydrochloride

salt 7d (104 mg, 14% from amine 4) as a colorless solid. MS

MH+ calcd for C₂₇H₃₀N₂SO₅, 495; found, 495. Anal. calcd for

6722 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

calcd for C₂₈H₃₇NSO₄‚1.75H₂O: C, 63.31; H, 7.68; N, 2.64; S,

followed by removal of excess potassium hydrogen persulfate

by filtration. The filtrate was concentrated, and the residue

was dissolved into EA and washed with saturated NaHCO₃

and brine and dried over MgSO₄. After concentration in vacuo,

the resulting residue was dissolved into MeOH and thionyl

chloride (1.9 mL, 26 mmol) was added. Chromatography (on

silica, EA/hexane) provided the decarbonylated sulfone 12 as

a solid (350 mg, 44%). MS(CI) MH+ calculated for C₁₅H₁₄0₅S,

307; found, 307. To a solution of the sulfone 12 (350 mg, 1.1

mmol) in MeOH (2 mL) and THF (2 mL) was added 50%

aqueous hydroxylamine (1 mL). The solution was stirred

overnight. Trituration with EA provided the hydroxamic acid

13 as a white solid (270 mg, 77%). HPLC purity: >97%. HRMS

MH⁺calculated for C₁₄H₁₃NO₅S, 308.0587; found, 308.05998.

¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (2H, d, J ) 8.9 Hz),

7.46 (2H, m), 7.25 (1H, t, J ) 7.4 Hz), 7.12 (4H, m), 4.07 (2H,

s).

6.04. Found: C, 63.36; H, 7.49; N, 2.86; S, 5.59.

To a solution of this sulfide (6.45 g, 13.0 mmol) in CH₂Cl₂

(100 mL) at 0 °C was added 3-chloroperbenzoic acid (4.45 g,

26.0 mmol), and the reaction was stirred at 0 °C for 3 h. The

solution was then washed with water (2×) and brine and dried

over MgSO₄. Concentration gave a residue (10.5 g), which was

chromatographed on silica gel eluting with EA/hexane (20/80)

to afford the corresponding sulfone 3f (5.7 g, 98%) as a colorless

solid. Anal. calcd for C₂₈H₃₇NSO₇‚H₂O: C, 61.18; H, 7.15; N,

2.55; S, 5.83. Found: C, 61.32; H, 7.11; N, 2.44; S, 5.16.

Through a solution of the sulfone 3f (5.7 g, 13.0 mmol) in

EA (120 mL) at 0 °C was bubbled HCl gas for 15 min.

Concentration and trituration of the residue with ether af-

forded the hydrochloride salt of the secondary amine 4f (5.4

g, 89%) as a colorless solid. HRMS calcd for C₂₃H₃₀NSO₅,

432.1845; found, 432.1828.

N-Hydroxy-2-methyl-2-[(4-phenoxyphenyl)sulfonyl]-

propanamide (17). To a solution of 4-(phenoxy)benzenethiol

(3.8 g, 18.8 mmol) in MeOH (60 mL) cooled to 0 °C was added

tert-butyl bromoacetate (2.8 mL, 18.8 mmol) and triethylamine

(2.6 mL, 19.0 mmol). The solution was stirred for 30 min and

was then concentrated in vacuo. The residue was partitioned

between EA and H₂O, and the organic layer was washed with

brine and dried over MgSO₄. Concentration in vacuo provided

the sulfide as an oil. To a solution of the sulfide in CH₂Cl₂(85

mL) was added m-chloroperbenzoic acid (13.8 g, 43.2 mmol)

over 15 min. The solution was stirred at room temperature

for 2 h. The reaction was quenched by the addition of aqueous

Na₂S0₃. After 30 min, the solution was filtered through Celite.

The filtrate was washed with 25% aqueous ammonia, 1 N HCl,

and brine and dried over MgSO₄. Chromatography on silica

gel eluting with EA/hexane provided the sulfone 14 as a white

solid (4.0 g, 68%).

To a solution of the HCl salt of amine 4f in DMF (70 mL)

was added K₂CO₃(3.17 g, 23.0 mmol) followed by propargyl

bromide (0.98 mL, 23.0 mmol). The reaction was stirred for 4

h at room temperature and then diluted with water (75 mL)

and extracted with EA (3×). The combined organic extracts

were washed successively with water and brine and dried over

MgSO₄. Concentration gave a residue (6.28 g), which was

chromatographed on silica gel eluting with 1:1 EA/hexane to

afford the propargylamine ethyl ester 5f (4.28 g, 82%). ¹H NMR

(400 MHz, CDCl₃): δ 7.79 (2H, d, J ) 9 Hz), 7.15 (1H, d), 7.04

(2H, d, J ) 9 Hz), 6.86 (1H, s), 6.80 (1H, m), 4.19 (2H, q, J )

7 Hz), 3.44 (2H, s), 3.32 (2H, br s), 2.74 (2H, m), 2.69 (2H, m),

2.38-2.30 (3H, m), 2.31 (3H, s), 2.28 (3H, s), 1.86 (2H, m), 1.31

(3H, t, J ) 7 Hz). HRMS calcd for C₂₄H₃₁NSO₅, 469.1923;

found, 469.1908. Anal. calcd for C₂₄H₃₁NSO₅.0.5EA (consistent

with NMR): C, 65.47; H, 6.87; N, 2.73; S, 6.24. Found: C,

65.50; H, 7.02; N, 2.66; S, 6.15.

To a solution of the sulfone 14 (3.2 g, 9.2 mmol) in THF (65

mL) cooled to 0 °C was added sodium hydride (730 mg of a

60% dispersion in mineral oil, 18.4 mmol). After 10 min,

methyl iodide (2.28 mL, 36.8 mmol) was added dropwise and

the mixture was stirred for 18 h at room temperature. The

reaction was quenched with H₂O and concentrated in vacuo.

The aqueous residue was diluted with EA, and the organic

phase was washed with H₂O and dried over Na₂S0₄. Concen-

tration in vacuo provided the dimethyl sulfone 15 as an off-

white solid (3.2 g, 92%). HPLC purity: 95%.

To a solution of the dimethyl sulfone 15 (3.2 g, 8.5 mmol)

in anisole (10 mL) was added trifluoroacetic acid (30 mL), and

the solution was stirred for 30 min. Concentration in vacuo

followed by trituration (ethyl ether) provided the carboxylic

acid 16 as a white solid (750 mg, 28%). HPLC purity: 99%.

MS(CI) MH+ calculated for C₁₆H₁₆O₅S, 321; found, 321.

To a solution of the acid 16 (723 mg, 2.26 mmol) in DMF

(4.5 mL) were added HOBT (366 mg, 2.71 mmol) and EDC

(476 mg, 2.49 mmol). After the solution was stirred for 1 h at

room temperature, 50% aqueous hydroxylamine (0.40 mL, 6.8

mmol) was added. After 15 min, the solution was partitioned

between EA and H₂O. The organic layer was washed with H₂O

and brine and dried over Na₂SO₄. Reverse phase chromatog-

raphy (MeCN/H₂O) provided the hydroxamic acid 17 as a white

foam (434 mg, 57%). HPLC purity: 99%. HRMS MH+ calcu-

lated for C₁₆H₁₇NO₅S, 336.0900; found, 336.0898. ¹H NMR (400

MHz, DMSO-d₆): δ 10.73 (1H, d, J ) 1.9 Hz), 8.99 (1H, d, J )

2.2 Hz), 7.70 (2H, d, J ) 8.9 Hz), 7.46 (2H, dd, J ) 8.6, 7.5

Hz), 7.26 (1H, t, J ) 7.4 Hz), 7.15 (2H, dd, J ) 8.6, 1.1 Hz),

7.08 (2H, d, J ) 9.1 Hz), 1.40 (6H, s).

4-{[4-(4-Chlorophenoxy)phenyl]sulfonyl}-N-hydroxy-

tetrahydro-2H-pyran-4-carboxamide (21). In dry equip-

ment under nitrogen, sodium metal (8.97 g, 390 mmol) was

added to MeOH (1 l) at 0 °C. The reaction was allowed to warm

to room temperature over 45 min by which time the sodium

had completely dissolved. The solution was chilled to 0 °C and

p-fluorothiophenol (41.5 mL, 0.39 mmol) was added, followed

by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction

was stirred at room temperature for 4 h, filtered, and concen-

trated in vacuo to give the desired sulfide (75.8 g, 97%) as a

To a solution of the propargylamine ethyl ester 5f (4.13 g,

8.79 mmol) in 1:1 EtOH/THF (100 mL) was added a solution

of NaOH (3.52 g, 87.9 mmol) in H₂O (30 mL), and the reaction

was heated to 65 °C for 40 h. The reaction was then concen-

trated to dryness, and water (50 mL) was added, which was

then acidified to pH 2 with 2 N HCl. Concentration gave a

residue, which was triturated with ether, filtered, and dried

to afford the carboxylic acid 6f (3.8 g, 100%) as a colorless solid.

HRMS calcd for C₂₄H₂₇NSO₅, 441.1608; found, 441.1651.

To a suspension of carboxylic acid 6f (1.0 g, 2.26 mmol) in

CH₂Cl₂(15 mL) were added triethylamine (0.95 mL, 6.78

mmol) and 50% aqueous hydroxylamine (1.5 mL, 22.6 mmol)

followed by PyBroP (1.16 g, 2.48 mmol). After 3 days, the

reaction was concentrated to afford a residue, which was

chromatographed on a reverse phase column eluting with a

gradient of MeCN/H₂O (30/70 to neat MeCN) to afford the

requisite hydroxamic acid free base 7f (215 mg, 21%) as a solid.

Anal. calcd for C₂₄H₂₈N₂SO₅: C, 63.14; H, 6.18; N, 6.14; S, 7.02.

Found: C, 62.78; H, 6.06; N, 6.17; S, 6.86. To a suspension of

this free base hydroxamic acid (205 mg, 0.449 mmol) in MeOH

(4 mL) at 0 °C was added a solution of HCl in MeOH [prepared

by adding acetyl chloride (35 µL, 0.49 mmol) to MeOH (1 mL)].

The solution was concentrated to afford a solid, which was

triturated with ether and dried to afford the monohydro-

chloride salt of the hydroxamic acid 7f (191 mg, 86%) as a

colorless solid. MS MH+ calcd for C₂₄H₂₈N₂SO₅, 457; found,

457. Anal. calcd for C₂₄H₂₈N₂SO₅‚HCl‚0.5H₂O: C, 57.42; H,

6.02; N, 5.58; Cl, 7.06. Found: C, 57.36; H, 6.32; N, 5.68; Cl,

6.84.

N-Hydroxy-2-[(4-phenoxyphenyl)sulfonyl]acetamide

(13). To a solution of 3-bromopyruvic acid hydrate (1.95 g, 11.7

mmol) cooled to 0 °C in MeOH (50 mL) was added 4-phenoxy-

benzenethiol 10 (2.35 g, 11.7 mmol). The solution was stirred

for 15 min followed by concentration in vacuo. The residue was

partitioned between EA and H₂O, and the organic layer was

dried over MgSO₄. Concentration in vacuo provided the crude

sulfide 11 as a yellow solid that was used without any

additional purification. To a solution of this sulfide of 1.2 g in

methanol/H₂O cooled to 0 °C was added potassium hydrogen

persulfate (3.5 g, 5.72 mmol). The solution was stirred for 1 h

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6723

clear colorless oil. To a solution of this sulfide (75.8 g, 0.38

mol) in MeOH (1 L) were added water (100 mL) and potassium

hydrogen persulfate (720 g, 1.17 mol). An exotherm to 67 °C

was noted. After 2 h, the reaction was filtered and the cake

was rinsed with MeOH. The filtrate was concentrated in vacuo.

The residue was taken up in EA and washed with brine, dried

over MgSO₄, filtered, and concentrated to give the sulfone 18

as a crystalline solid (82.74 g, 94%). HRMS MH⁺calcd for

C₉H₉FO₄S, 233.0278; found, 233.0269. ¹H NMR (400 MHz,

DMSO-d₆): δ 7.96 (2H, m), 7.49 (2H, t, J ) 8.9 Hz), 4.67 (2H,

s), 3.56 (3H, s).

To a solution of the sulfone 18 (28.5 g, 0.123 mol) in DMF

(200 mL) were added K₂CO₃(37.3 g, 0.27 mol), bis-(2-

bromoethyl)ether (19.3 mL, 0.147 mol), DMAP (0.75 g, 6.0

mmol), and tetra-n-butylammonium bromide (1.98 g, 6 25

mmol). The reaction was stirred for 18 h at room temperature.

The reaction was then slowly poured into 1 N HCl (300 mL),

and the resultant solid was filtered and the cake was washed

well with hexanes. The solid was recrystallized from EA/

hexane to give the pyran 19 as a beige solid (28.7 g, 77%). MS

MH+ calcd for C₁₃H₁₅O₅SF, 303; found, 303.

To the pyran methyl ester 19 (8.0 g, 26.5 mmol) in THF

(250 mL) was added a solution of potassium trimethylsilanoate

(10.2 g, 79.5 mmol) in dry THF (15 mL). After 1.5 h, water

(100 mL) was added and the solution was concentrated in

vacuo. The residue was taken up in water and washed with

EA. The aqueous solution was acidified with 6 N HCl to pH 1

and the resulting slurry was extracted with EA. The combined

extracts were washed with water, dried over Na₂SO₄, and

concentrated in vacuo. The residue was triturated with hot

ether, and the resulting solid was filtered and dried to give

the carboxylic acid (5.78 g, 76%) as a crystalline solid. HRMS

MH⁺calcd for C₁₂H₁₃O₅SF, 287.04; found, 287.04. To a solution

of the carboxylic acid (9.1 g, 31.6 mmol) in DMF (70 mL) were

added HOBT (5.1 g, 37.9 mmol), NMM (10.4 mL, 94.8 mmol),

O-tetrahydro-2H-pyran-2-yl-hydroxyIamine (11.5 g, 98 mmol),

and EDC (8.48 g, 44.2 mmol). After 3 h at room temperature,

the reaction was concentrated in vacuo. The residue was taken

up in EA, washed successively with water, 5% KHSO₄,

saturated aqueous NaHCO₃, and brine, and dried over Na₂SO₄.

Concentration gave a residue, which was purified by chroma-

tography on silica gel eluting with EA/hexane to prove the

THP-hydroxamate 20 (9.7 g, 80%) as a crystalline solid. HRMS

MH⁺calculated for C₁₇H₂₂NO₆SF, 388.12; found, 388.12.

To a solution of the THP-hydroxamate p-fluorophenyl sul-

fone 20 (2.9 g, 7.5 mmol) in DMF (15 mL) were added

p-chlorophenol (1.93 g, 15 mmol) and cesium carbonate (7.3

g, 22.5 mmol). The reaction was heated to 90 °C for 1.5 h.

Additional DMF (20 mL) was added, followed by additional

cesium carbonate (2 g, 6.2 mmol). The resulting mixture was

heated to 95 °C for 3 h. The reaction was then diluted with

H₂O and extracted with EA. The organic layer was washed

with brine and dried over Na₂SO₄. Concentration gave a

residue, which was purified by chromatography on silica gel

eluting with EA/hexane to afford the p-chlorophenoxyphenyl

sulfone THP-protected hydroxamate (2.9 g,78%). To a solution

of this THP-protected hydroxamate (2.9 g, 5.7 mmol) in

dioxane (5 mL) was added 4 N HCl in dioxane (5 mL, 20 mmol),

followed by MeOH (7.5 mL). The resulting solution was stirred

at room temperature for 1 h. Concentration and reverse phase

chromatography eluting with MeCN/H₂O provided the p-

chlorophenoxyphenyl sulfone hydroxamic acid 21 (1.35 g, 58%)

as a white solid. HPLC purity: >99%. HRMS MH+ for C₁₈H₁₈-

ClNO₆S, 412.0616; found, 412.0577. ¹H NMR (400 MHz,

DMSO-d₆): δ 10.95 (1H, s), 9.15 (1H, s), 7.68 (2H, d, J ) 9.1

Hz), 7.51 (2H, d, J ) 8.9 Hz), 7.19 (2H, d, J ) 9.1 Hz), 7.13

(2H, d, J ) 9.1 Hz), 3.84 (2H, dd, J ) 11.8, 3.5 Hz), 3.12 (2H,

t, J ) 11.4 Hz), 2.18 (2H, d, J ) 12.9 Hz), 1.86 (2 H, td, J )

12.8, 4.0 Hz).

h and then recooled to -40 °C, whereupon a solution of

4-phenyloxythiophenol disulfide (25.5 g, 63.0 mmol) in THF

(30 mL) was added. The reaction was then stirred at 0 °C for

1 h and then warmed to room temperature for 16 h. Water

(600 mL) was added, and the mixture was extracted with EA

(3 × 500 mL). The combined organic extracts were washed

with brine and dried over MgSO₄. Concentration gave a dark

yellow oil (53 g), which was purified by chromatography on

silica gel eluting with EA/hexane (10/90) to give the desired

sulfide 22 (24.7 g, 86%). MS calcd for [C₂₅H₃₁NSO₅-C₅H₉O₂-

1

(BOC)], 358; found, 358. H NMR (400 MHz, CDCl₃): δ 7.87

(4H, m), 7.16 (1H, t, J ) 7 Hz), 7.03 (2H, m), 6.92 (2H, m),

4.14 (2H, q, J ) 7 Hz), 3.79 (2H, m), 3.12 (2H, m), 2.09 (2H,

m), 1.72 (2H, m), 1.46 (9H, s), 1.23 (3H, t, J ) 7 Hz).

1-tert-Butyl4-Ethyl4-[(4-phenoxyphenyl)sulfonyl]piper-

idine-1,4-dicarboxylate (23). To a solution of sulfide 22 (1.8

g, 3.95 mmol) in CH₂Cl₂(75 mL) at 0 °C was added 3-chloro-

perbenzoic acid (1.7 g, 7.9 mmol). The reaction was stirred for

1 h at 0 °C and then for 0.5 h at room temperature. The

reaction solution was then washed with water and brine and

dried over MgSO₄. Concentration gave a residue, which was

purified by chromatography on silica gel eluting with EA/

hexane (20/80) to afford the sulfone 23 (1.68 g, 87%) as a

colorless solid. DSC 137.1-139.3 °C. MS MH+ calcd for

[C₂₅H₃₁NSO₇-C₅H₉O₂(BOC)], 390; found, 390. Anal. calcd for

C₂₅H₃₁NSO₇: C, 61.33; H, 6.38; N, 2.79; S, 6.55. Found: C,

61.39; H, 6.45; N, 2.77; S, 6.54. ¹H NMR (400 MHz, CDCl₃): δ

7.71 (2H, d, J ) 8 Hz), 7.43 (2H, m), 7.25 (1H, m), 7.12-7.02

(4H, m), 4.21 (2H, q, J ) 7 Hz), 4.16 (2H, m), 2.63 (2H, m),

2.32 (2H, m), 2.03 (2H, m), 1.44 (9H, s), 1.26 (3H, t, J ) 7 Hz).

Ethyl-4-[(4-phenoxyphenyl)sulfonyl]piperidine-4-car-

boxylate, Hydrochloride (24). Through a solution of N-BOC

ethyl ester 23 (3.65 g, 7.00 mmol) in EA (100 mL) at 0 °C was

bubbled HCl gas for 5 min. The solution was concentrated to

give a residue, which was triturated with ether to afford amine

hydrochloride salt 24 (3.1 g, 100%) as a colorless solid. HRMS

calcd for C₂₀H₂₃NSO₅, 390.1375; found, 390.1357. ¹H NMR (400

MHz, d₆-DMSO): δ 7.77 (2H, d, J ) 11 Hz), 7.51 (2H, m), 7.32

(1H, t, J ) 6 Hz), 7.18 (4H, d, J ) 11 Hz), 4.12 (2H, q, J ) 7

Hz), 3.41 (2H, br d, J ) 14 Hz), 2.72 (2H, t, J ) 11 Hz), 2.36

(2H, d, J ) 14 Hz), 2.22 (2H, td, J ) 11, 3 Hz), 1.08 (3H, t, J

) 7 Hz).

1-tert-Butyl 4-[(Hydroxyamino)carbonyl]-4-[(4-phenoxy-

phenyl)sulfonyl]piperidine-1-carboxylate (27a). To a so-

lution of ethyl ester sulfone 23 (800 mg, 1.63 mmol) in 1:1

EtOH/THF (17 mL) was added NaOH (654 mg, 16.3 mmol) in

H₂O (3 mL), and the solution was heated to 65 °C for 16 h.

Concentration gave a beige semisolid. Water (25 mL) was

added, and the mixture was acidified to pH 4 with 2 N HCl

and extracted with EA (2×). The combined organic extracts

were washed with brine and dried over MgSO₄. Concentration

gave the corresponding carboxylic acid 26a (754 mg, 100%)

as a white foam. Anal. calcd for C₂₃H₂₇NSO₇: C, 59.86; H, 5.90;

N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.56.

MS MH+ calcd for [C₂₃H₂₇NSO₇-C₅H₉O₂(BOC)], 362; found,

1

362. H NMR (400 MHz, CDCl₃): δ 7.74 (2H, d, J ) 10 Hz),

7.42 (2H, t, J ) 8 Hz), 7.25 (1H, m), 7.09 (2H, d, J ) 8 Hz),

7.03 (2H, d, J ) 9 Hz), 4.18 (2H, m), 2.73 (2H, m), 2.28 (2H,

m), 2.05 (2H, m), 1.45 (9H, s).

To a solution of carboxylic acid 26a (730 mg, 1.58 mmol) in

DMF (9 mL) were added sequentially HOBT (256 mg, 1.90

mmol), EDC (424 mg, 2.21 mmol), NMM (479 mg, 4.70 mmol),

and 50% aqueous hydroxylamine (1.04 mL, 15.8 mmol). After

it was stirred for 16 h at room temperature, the reaction was

recharged with equivalent additional quantities of HOBT,

EDC, NMM, and hydroxylamine. After an additional 20 h at

room temperature, water (50 mL) was added and the mixture

was extracted with EA (2 × 120 mL), and the combined

extracts were washed with brine and dried over MgSO₄.

Concentration gave a residue (820 mg), which was purified

by reverse phase chromatography eluting with a gradient of

MeCN/H₂O (30/70 to 80/20) to afford the desired hydroxamate

27a (460 mg, 61%). MS MH+ calcd for [C₂₃H₂₈N₂SO₇-

C₄H₉O₂(BOC)], 377; found, 377. Anal. calcd for C₂₃H₂₈N₂SO₇:

1-tert-Butyl 4-Ethyl 4-[(4-phenoxyphenyl)thio]piperi-

dine-1,4-dicarboxylate (22). To a solution of ethyl iso-

nipecotate N-tert-butyl carbamate³⁴(26.2 g, 102 mmol) in THF

(470 mL) at -45 °C was added 2 M LDA in THF (60 mL, 120

mmol) with stirring. The solution was warmed to 0 °C over 2

6724 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02;

To a solution of the methoxyethylamine 25d (2.63 g, 5.87

mmol) in THF (18 mL) and ethanol (18 mL) was added NaOH

(2.1 g, 5.25 mmol) in water (6 mL). The solution was heated

to reflux for 12 h. The solution was concentrated in vacuo and

diluted with water. The aqueous layer was extracted with

ether (2 × 100 mL) and was acidified to pH 2. Vacuum

filtration of the resulting precipitation provided the acid 26d

as a white solid (2.4 g, 100%).

To a solution of the acid 26d (2.0 g, 4.33 mmol), also

containing NMM (1.8 mL, 16.4 mmol), and O-tetrahydro-2H-

pyran-yl-hydroxylamine (0.767 g, 6.44 mmol) in DMF (20 mL)

was added EDC (3.1 g, 16.2 mmol), and the solution was

stirred at room temperature for 20 h. The solution was

concentrated under high vacuum, and the residue was dis-

solved in EA. The organic layer was washed with H₂O and

dried over MgSO₄. Concentration in vacuo provided the THP-

hydroxamic acid as an off white foam (1.60 g, 71.1%). To a

solution of this protected hydroxamate (1.58 g, 3.05 mmol) in

MeOH (20 mL) at 0 °C was added acetyl chloride (0.65 mL,

9.15 mmol), and the solution was stirred at 0 °C for 3 h.

Concentration gave a residue, which was purified on reverse

phase chromatography on C-18 eluting with MeCN/H₂O (0.01%

HCl) to afford the hydroxamate HCl salt 27d (0.65 g, 45.5%)

as a white solid. Anal. calcd for C₂₁H₂₆N₂O₆S‚HCl‚0.75H₂O:

C, 52.06; H, 5.93; N, 5.78; S, 6.62. Found: C, 51.94; H, 5.67;

N, 5.91; S, 6.66. HRMS calcd for C₂₁H₂₆N₂O₆S, 435.1590; found,

435.1571.

1-Cyclopropyl-N-hydroxy-4-{[4-(phenoxyphenyl]-

sulfonyl}piperidine-4-carboxamide Hydrochloride (27e).

According to the N-cyclopropanation procedure of Gillaspy,⁴⁰

to a solution of amine hydrochloride 24 (2.13 g, 5.0 mmol) in

MeOH (25 mL) was added 3 Å molecular sieves (2 g) followed

sequentially by acetic acid (2.86 mL, 50 mmol), [(1-ethoxy-

cyclopropyl)oxy]trimethylsilane (6.08 mL, 30 mmol), and so-

dium cyanoborohydride (1.41 g, 22.0 mmol), and the reaction

was heated under reflux for 16 h. The mixture was cooled and

filtered and then concentrated to give a residue (2.08 g), which

was purified by chromatography on silica gel eluting with EA/

hexane (20/80) to afford the N-cyclopropylamine 25e (1.90 g,

86%) as a white solid. DSC 131.4-133.5 °C. HRMS calcd for

C₂₃H₂₇NSO₅, 429.1653; found, 429.1600.

To a solution of N-cyclopropyl ethyl ester 25e (1.9 g, 4.2

mmol) in 1:1 EtOH/THF (25 mL) was added a solution of

NaOH (1.71 g, 4.3 mmol) in H₂O (10 mL) and the reaction was

heated to 65 °C for 16 h. The organic solvents were removed

in vacuo, and the reaction was diluted with additional water

(20 mL). Concentration to pH 5 with 1 N HCl gave a solid,

which was filtered and dried to give the carboxylic acid 26e

(1.49 g, 82%) as a colorless solid. HRMS calcd for C₂₁H₂₃NSO₅,

402.1375; found, 402.1350.

N, 5.81; S, 6.85. IR (MIR): 1637, 1658 cm^-^{1 1}H NMR (400

.

MHz, d₆-DMSO): δ 9.14 (1H, br s), 7.71 (2H, d, J ) 8 Hz),

7.49 (2H, t, J ) 8 Hz), 7.28 (1H, t, J ) 6 Hz), 7.16 (2H, d, J )

6 Hz), 7.11 (2H, d, J ) 10 Hz), 3.96 (2H, m), 2.58 (2H, m),

2.28 (2H, m), 1.69 (2H, m), 1.39 (9H, s).

1-N-Hydroxy-4-[(4-phenoxyphenyl)sulfonyl]piperidine-

4-carboxamide (27b). Through a solution of N-BOC hydrox-

amate 27a in EA (25 mL) at 0 °C was bubbled HCl gas for 5

min. The solution was allowed to stand at 0 °C for 0.5 h and

was then concentrated to give a residue, which was triturated

with ether to afford the hydroxamate hydrochloride salt 27b

(330 mg, 99%) as a light pink solid. HRMS calcd for

C₁₈H₂₀N₂SO₅, 377.1171; found, 377.1170. ¹H NMR (400 MHz,

d₆-DMSO): δ 9.28 (1H, s), 8.98 (1H, br s), 8.65 (1H, br s), 7.72

(2H, d, J ) 10 Hz), 7.51 (2H, m), 7.31 (1H, t, J ) 7 Hz), 7.20-

7.11 (4H, m), 3.38 (2H, m), 2.63 (2H, m), 2.45 (2H, m), 2.10

(2H, m). Anal. calcd for C₁₈H₂₀N₂SO₅‚HCl: C, 52.36; H, 5.13;

N, 6.78; Cl, 8.59; S, 7.77. Found: C, 51.95; H, 5.25; N, 6.55;

Cl, 8.37; S, 7.63.

N-Hydroxy-1-methyl-4-{[4-(phenoxyphenyl]sulfonyl}-

piperidine-4-carboxamide Hydrochloride (27c). To a

solution of N-BOC R-sulfone 23 (2.67 g, 5.5 mmol) in CH₂Cl₂

(5 mL) was added trifluoroacetic acid (5 mL), and the solution

was stirred at room temperature for 2 h. The solution was

concentrated in vacuo, and the residue was triturated with

ethyl ether to provide the crude amine trifluoroacetic acid salt.

To a solution of the crude amine salt in MeOH (10 mL) were

added formaldehyde (37% aqueous solution, 2.0 mL, 27.5

mmol) and borane pyridine (2.2 mL, 22 mmol), and the solution

was stirred at room temperature for 18 h. The solution was

concentrated in vacuo. The residue was dissolved in EA,

washed with H₂O, and dried over MgSO₄. Concentration in

vacuo provided the N-methyl amine 25c as a yellow oil (2.17

g, 98%).

To a solution of the N-methyl R-sulfone 25c (2.17 g, 5.4

mmol) in EtOH (10 mL) and THF (10 mL) was added NaOH

(2.0 g, 50 mmol), and the reaction mixture was stirred at 65

°C for 18 h. The solution was concentrated in vacuo. The

residue was dissolved in H₂O and extracted with ether. The

aqueous solution was acidified to pH 2, and the resulting solid

was collected by vacuum filtration to provide the acid 26c (1.8

g, 90%) as a white solid.

To a solution of the acid 26c (0.5 g, 1.3 mmol) in DMF (10

mL) was added EDC (1.06 g, 5.5 mmol) followed by O-tetra-

hydro-2H-pyran-2-yl-hydroxylamine (490 mg, 4.2 mmol) and

4-methylmorpholine (0.76 mL), and the solution was stirred

at room temperature for 18 h. The solution was concentrated

in vacuo, and the residue was dissolved to EA, washed with

H₂O, and dried over MgSO₄. Concentration in vacuo provided

the crude protected hydroxamate. To a solution of the crude

hydroxamate in MeOH (10 mL) was added acetyl chloride (0.28

mL, 3.9 mmol), and the solution was stirred for 3 h at room

temperature. The solution was concentrated in vacuo. Reverse

phase chromatography eluting with MeCN/H₂O (0.01% HCl)

provided the R-sulfone hydroxamic acid 27c as a white solid

(261 mg, 46%). HPLC purity: 97.6%. HRMS MH⁺calculated

for C₁₉H₂₂N0₅S, 391.1322; found, 391.1315. ¹H NMR (400 MHz,

DMSO-d₆): δ 11.13 (1H, s), 9.29 (1H, s), 7.71 (2H, d, J ) 9.1

Hz), 7.47 (2H, m), 7.28 (1H, t, J ) 7.4 Hz), 7.16 (2H, d, J )

7.5 Hz), 7.10 (2H, d, J ) 9.1 Hz), 3.45 (2H, d, J ) 12.6 Hz),

2.73 (2H, m), 2.67 (3H, s), 2.50 (2H, s), 2.16 (2H, t, J ) 13.0

Hz).

To a solution of N-cyclopropyl carboxylic acid 26e (1.49 g,

3.4 mmol) in CH₂Cl₂(50 mL) was added Et₃N (1.42 mL, 10.2

mmol) followed by 50% aqueous hydroxylamine (2.25 mL, 34.0

mmol) and PyBroP (3.17 g, 6.8 mmol). The reaction was stirred

for 3 days at room temperature. Water (70 mL) was added,

and the reaction was extracted with CH₂Cl₂(3×). The com-

bined organic extracts were washed with brine and dried over

MgSO₄and concentrated to give an oil (4.0 g), which was

chromatographed on reverse phase eluting with MeCN/H₂O

(20/80 to neat MeCN) to afford the free base hydroxamic acid

(830 mg, 58%) as a solid. To a solution of this hydroxamic acid

amine (830 mg, 2.0 mmol) in MeOH (20 mL) was added

methanolic HCl [prepared by the addition of acetyl chloride

(170 µL, 2.0 mmol) to MeOH (2 mL)]. The resulting precipitate

was filtered and dried to give the desired N-cyclopropylamine

hydroxamic acid hydrochloride salt 27e (595 mg, 66%) as a

white powder. HRMS calcd for C₂₁H₂₄N₂SO₅, 416.1407; found,

416.1398. Anal. calcd for C₂₁H₂₄N₂SO₅‚HCl: C, 55.68; H, 5.56;

N, 6.18; Cl, 7.83; S, 7.08. Found: C, 55.39; H, 5.72; N, 6.15;

Cl, 8.17; S, 7.29.

N-Hydroxy-1-(2-methoxyethyl)-4-{[4-(phenoxyphenyl]-

sulfonyl}piperidine-4-carboxamide Hydrochloride (27d).

To a solution of the amine HCI salt 24 (2.5 g, 5.87 mmol) and

K₂CO₃(1.6 g, 11.57 mmol) in DMF (25 mL) was added

2-bromoethylmethyl ether (0.66 mL, 7.0 mmol), and then it

was stirred at room temperature for 18 h. The solvent was

evaporated, and the residue was diluted with EA. The organic

layer was washed with water and dried over MgSO₄. Concen-

tration in vacuo provided the methoxy ethylamine 25d as light

yellow oil (2.63 g, 100%).

1-(Cyclopropylmethyl)-N-hydroxy-4-[(4-phenoxy-

phenyl)sulfonyl]piperidine-4-carboxamide Hydrochlo-

ride (27f). To a solution of amine hydrochloride 24 (2.13 g,

5.0 mmol) in DMF (10 mL) at room temperature was added

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6725

K₂CO₃(1.4 g, 10.0 mmol) followed by bromomethylcyclo-

propane (675 mg, 5.0 mmol), and the reaction was stirred for

16 h. Water (40 mL) was added, and the mixture was extracted

with EA (2×). The combined extracts were washed with water

and brine and dried over MgSO₄. Concentration gave a residue

(2.94 g), which was purified by chromatography on silica gel

eluting with EA/hexane (20/80) to afford the cyclopropylm-

ethylamine 25f (2.09 g, 91%) as an oil, which solidified. MS

MH+ calcd for C₂₄H₂₉NSO₅, 444; found, 444. Anal. calcd for

C₂₄H₂₉NSO₅: C, 64.99; H, 6.59; N, 3.16; S, 7.23. Found: C,

64.99; H, 6.92; N, 3.18; N, 3.11; S, 7.28.

To a solution of cyclopropylmethylamine ethyl ester 25f (2.0

g, 4.4 mmol) in EtOH/THF (25 mL) was added a solution of

NaOH (1.75 g, 4.4 mmol) in water (10 mL), and the reaction

was heated for 16 h at 65 °C. The organic solvents were

removed in vacuo, and additional water (20 mL) was added.

Acidification to pH 4 gave a precipitate, which was filtered

and dried to give the carboxylic acid 26f (1.58 g, 79%) as a

colorless solid. HRMS MH+ calcd for C₂₂H₂₅NSO₅, 414.1375;

found, 414.1334. Anal. calcd for C₂₂H₂₅NSO₅‚HCl‚0.5H₂O: C,

57.32; H, 5.90; N, 3.04. Found: C, 57.44; H, 5.63; N, 3.13.

rinsed successively with water and ether to afford carboxylic

acid 26g (519 mg, 80%) as a colorless solid. DSC 197.6-203.3

°C. HRMS calcd for C₂₁H₂₂NSO₅, 400.1219; found, 400.1210.

¹H NMR (400 MHz, d₆-DMSO): δ 7.75 (2H, d, J ) 10 Hz),

7.49 (2H, d, J ) 8 Hz), 7.28 (1H, t, J ) 6 Hz), 7.18 (2H, d, J )

9 Hz), 7.12 (2H, d, J ) 9 Hz), 3.28 (2H, s), 3.11 (1H, s), 2.80

(2H, m), 2.18 (2H, m), 2.06 (2H, m), 1.90 (2H, m). Anal. calcd

for C₂₁H₂₁NSO₅‚H₂O: C, 60.42; H, 5.55; N, 3.36; S, 7.68.

Found: C, 60.60; H, 4.91; N, 3.33; S, 7.34.

To a suspension of carboxylic acid 26g (485 mg, 1.10 mmol)

in DMF (10 mL) were added sequentially EDC (326 mg, 1.70

mmol), NMM (364 uL, 3.30 mmol), and 50% aqueous hydroxyl-

amine (0.73 mL, 11.1 mmol), and the reaction was stirred for

16 h at room temperature. An additional quantity of EDC (326

mg, 1.70 mmol) and aqueous hydroxylamine (0.73 mL, 11.1

mmol) was added, and the reaction was stirred for another 24

h at room temperature. Water was added, and the mixture

was extracted with CH₂Cl₂. The combined extracts were

washed with brine and dried over MgSO₄and concentrated to

afford a residue (380 mg), which was purified by reverse phase

chromatography eluting with MeCN/aqueous HCl (30/70 to 80/

20) to afford the requisite N-propargylamine hydroxamic acid

hydrochloride salt 27g (275 mg, 57%) as a colorless solid:

HRMS calcd for C₂₁H₂₃N₂SO₅, 415.1328; found, 415.1331. Anal.

calcd for C₂₁H₂₂N₂SO₅‚HCl‚0.5H₂O: C, 54.84; H, 5.26; N, 6.09.

Found: C, 54.90; H, 5.37; N, 6.07.

1-Acetyl-N-hydroxy-4-{[4-(phenoxyphenyl]sulfonyl}-

piperidine-4-carboxamide (27h). To a solution of N-BOC

R-sulfone 23 (2.75 g, 5.6 mmol) in THF (10 mL) and EtOH (10

mL) was added NaOH (2.25 g, 56 mmol), and the solution was

heated to 70 °C for 18 h. The solution was concentrated in

vacuo, and the residue was dissolved into H₂O and extracted

with ethyl ether. The aqueous solution was acidified to a pH

value of 2 and extracted with EA. The organic layer was dried

over MgSO₄. Concentration in vacuo provided the crude acid

as a solid. A solution of the acid in CH₂Cl₂(6 mL) and

trifluoroacetic acid (6 mL) was stirred for 1 h at room

temperature. Concentration in vacuo provided the amine

trifluoroacetate salt as a solid (2.3 g, 100%). To a solution of

this amine trifluoroacetate salt (2.3 g, <5.6 mmol) in acetone

(10 mL) and H₂O (10 mL) cooled to 0 °C were added triethyl-

amine (1.17 mL, 8.4 mmol) and acetyl chloride (0.60 mL, 8.4

mmol), and the solution was stirred at room temperature for

18 h. The solution was concentrated in vacuo to remove the

acetone, and the aqueous solution was extracted with ethyl

ether. The aqueous layer was acidified to pH 2 and extracted

with EA. The organic layer was dried over MgSO₄, and

concentration in vacuo provided the N-acetyl carboxylic acid

26h as a white solid (1.5 g, 65.2%). HRMS MH⁺calcd for

C₂₀H₂₁NO₆S, 404.1180; found, 404.1240.

To a solution of the N-acetyl carboxylic acid 26h (0.6 g,

1.49 mmol) in DMF (10 mL) was added EDC (401 mg, 2.1

mmol) followed by 50% aqueous hydroxylamine (0.9 mL) and

4-methylmorpholine (0.7 mL, 6.4 mmol), and the solution was

stirred for 18 h at room temperature. The solution was

concentrated in vacuo, and the residue was dissolved into EA.

The organic layer was washed with H₂O and dried over MgSO₄.

Reverse phase chromatography eluting with MeCN/H₂O pro-

vided the N-acetyl hydroxamic acid 27h (101 mg, 16%) as a

white solid. HPLC purity: 97.5%. MS MH+ calcd for C₂₀H₂₂-

N2O₆S, 419; found, 419.

To a solution of carboxylic acid 26f (1.58 g, 3.50 mmol) in

CH₂Cl₂(50 mL) was added Et₃N (1.46 mL, 10.5 mmol) followed

by 50% aqueous hydroxylamine (2.31 mL, 3.50 mmol) and

PyBroP (3.26 g, 6.99 mmol). After 3 days at room temperature,

the reaction was still a suspension so DMF (20 mL) was added

and the reaction was charged again with equivalent quantities

of Et₃N, aqueous hydroxylamine, and PyBroP. After 24 h at

room temperature, water was added and the mixture was

extracted with CH₂Cl₂. The combined extracts were washed

with water and brine and dried over MgSO₄. Concentration

gave an oil (5.0 g), which was purified by reverse phase

chromatography eluting with MeCN/H₂O to afford the free

base of the hydroxamate (3.2 g; theo ) 1.51 g) contaminated

with phosphoramide. To a solution of this free base in MeOH

(5 mL) was added a methanolic solution of HCl [prepared by

adding acetyl chloride (0.25 mL, 3.5 mmol) to MeOH (20 mL)

at 0 °C]. Concentration gave an oil, which was dissolved in a

minimum amount of MeOH (2.5 mL) and added slowly to ether

(300 mL) with rapid stirring. The resulting solid was filtered

and dried to afford the requisite hydroxamic acid 27f (677 mg,

42% from 25) as a colorless powder. HPLC purity: >95%.

1

HRMS calcd for C₂₂H₂₆N₂O₅S, 431.1635; found, 431.1601. H

NMR (400 MHz, DMSO-d₆): δ 11.16 (1H, s), 9.31 (1H, s), 7.72

(2H, d, J ) 8.6 Hz), 7.48 (2H, t, J ) 7.6 Hz), 7.28 (1H, t, J )

7.3 Hz), 7.16 (2H, d, J ) 8.3 Hz), 7.11 (2H, d, J ) 8.9 Hz),

3.62 (2H, d, J ) 10.5 Hz), 2.94 (2H, m), 2.69 (2H, m), 2.53

(2H, m), 2.20 (2H, m), 0.98 (1H, m), 0.57 (2H, d, J ) 6.7 Hz),

0.29 (2H, d, J ) 4.3 Hz).

N-Hydroxy-4-{[4-(phenoxyphenyl]sulfonyl}-1- (2-pro-

pynyl)-4-piperidinecarboxamide, Monohydrochloride

(27g). To a solution of amine hydrochloride salt 24 (850 mg,

1.99 mmol) in DMF (20 mL) was added K₂CO₃(300 mg, 2.0

mmol) followed by 80% propargyl bromide in toluene (300 µL,

238 mg, 2.00 mmol), and the reaction was stirred for 4 h at

room temperature. The reaction was quenched with the

addition of water and extracted with EA (3×). The combined

organic extracts were washed with water and brine and dried

over MgSO₄. Concentration gave a residue, which was purified

by chromatography on silica gel eluting with EA/hexane (20/

80) to afford N-propargylamine 25g (740 mg, 86.5%) as

colorless crystals. DSC 94.4-98.3 °C. IR (MIR): 3278, 1729

cm^-1. Anal. calcd for C₂₃H₂₅NSO₅: C, 64.62; H, 5.89; N, 3.28;

N-Hydroxy-1-(methylsulfonyl)-4-{[4-(phenoxyphenyl]-

sulfonyl}piperidine-4-carboxamide (27i). To a solution of

amine hydrochloride 24 (2.13 g, 7.5 mmol) in CH₂Cl₂(35 mL)

was added triethylamine (2.34 mL, 16.5 mmol) followed by

methanesulfonyl chloride (0.70 mL, 9.0 mmol). After 16 h at

room temperature, the solution was washed with water (2×)

and dried over MgSO₄. Concentration gave a dark oil (3.6 g),

which was chromatographed on silica gel eluting with EA/

hexane (20/80 to 50/50) to afford the N-methanesulfonamide

25i (58%). MS calcd for C₂₁H₂₅NS₂O₇, 468; found, 468. Anal.

calcd for C₂₁H₂₅NS₂O₇: C, 53.95; H, 5.39; N, 3.00. Found: C,

53.97; N, 5.43; N, 3.09.

1

S, 7.50. Found: C, 64.41; H, 5.65; N, 3.11; S, 7.27. H NMR

(400 MHz, CDCl₃): δ 7.73 (2H, d, J ) 10 Hz), 7.42 (2H, t, J )

9 Hz), 7.23 (1H, m), 7.11 (2H, d, J ) 7 Hz), 7.06 (2H, d, J ) 9

Hz), 4.24 (2H, m), 3.28 (2H, m), 3.13 (2H, m), 2.52 (2H, m),

2.39 (2H, m).

To a solution of N-propargylamine ethyl ester 25g (660 mg,

1.50 mmol) in 1:1 EtOH/THF (20 mL) was added NaOH (600

mg, 15.0 mmol) in water (10 mL), and the reaction was heated

to 65 °C for 18 h. Water (40 mL) was added, and the aqueous

layer was washed with EA. Acidification of the aqueous layer

to pH 5 with 2 N HCl gave a solid, which was filtered and

6726 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

To a solution of N-mesyl ethyl ester 25i (2.0 g, 4.15 mmol)

in 1:1 EtOH/THF (25 mL) was added a solution of NaOH (1.66

g, 41.5 mmol) in water (10 mL), and the reaction was heated

to 65 °C for 16 h. The organic solvents were removed in vacuo,

and then, additional water (20 mL) was added. The aqueous

solution was then acidified to pH 4 and extracted with EA (3×).

The combined extracts were washed with brine, dried over

MgSO₄, and concentrated to give the desired carboxylic acid

26i (1.46 g, 80%) as a light yellow foam. HRMS calcd for

C₁₉H₂₁NS₂O₇, 440.0838; found, 440.0820. Anal. calcd for

C₁₉H₂₁NS₂O₇: C, 51.92; H, 4.82; N, 3.19; S, 14.59. Found: C,

52.62; H, 5.18; N, 3.02; S, 13.85.

To a solution of N-mesyl carboxylic acid 26i (1.46 g, 3.38

mmol) in CH₂Cl₂(50 mL) were added sequentially Et₃N (1.41

mL, 10.1 mmol), 50% aqueous hydroxylamine (2.2 mL, 33.8

mmol), and PyBroP (3.16 g, 6.76 mmol). The reaction was

stirred at room temperature for 3 days. Water (70 mL) was

added, and the mixture was extracted with CH₂Cl₂(3×). The

combined extracts were washed with brine and dried over

MgSO₄. Concentration gave a residue (3.5 g), which was

purified by reverse phase chromatography to afford the desired

methanesulfonamide hydroxamic acid 27i (215 mg, 14%) as a

colorless solid. Anal. calcd for C₁₉H₂₂N₂S₂O₇‚H₂O: C, 48.29;

H, 5.12; N, 5.93; S, 13.57. Found: C, 48.72; H, 5.36; N, 5.61;

S, 12.81.

bis(4-Fluorophenyl) Disulfide (28). A solution of 4-fluoro-

thiophenol (50.29 g, 390 mmoL) in DMSO (500 mL) was heated

to 65 °C for 6 h. The reaction was quenched by pouring into

ice, and the resulting solid was collected by vacuum filtration

to provide the disulfide 28 as a white solid (34.4 g, 68.9%). ¹H

NMR (300 MHz, CDCl₃): δ 7.44 (4H, m), 7.01 (4H, m).

1-tert-Butyl 4-Ethyl 4-[(4-Fluorophenyl)thio]piperi-

dine-1,4-dicarboxylate (29). To a solution of ethyl isonipeco-

tate N-tert-butyl carbamate³⁴(16.0 g, 62 mmoL) in THF (300

mL) at -50 °C was added LDA (41.3 mL, 74 mmol), and the

solution was stirred for 1.5 h at 0 °C. To this solution was

added p-fluorophenyl disulfide 28 (15.8 g, 62 mmoL), and the

resulting solution was stirred at ambient temperature for 20

h. The reaction was quenched with the addition of H₂O, and

the solution was concentrated in vacuo. The aqueous residue

was extracted with ethyl acetate, and the organic layer was

washed with 0.5 N KOH, H₂O, and brine. Chromatography

on silica eluting with hexane/ethyl acetate provided the sulfide

29 as an oil (18.0 g, 75%). Anal. calcd for C₁₉H₂₆NO₄: C, 59.51;

H, 6.83; N, 3.65; S, 8.36. Found: C, 59.49; H, 7.03; N, 3.69; S,

8.28.

1-tert-Butyl 4-Ethyl 4-[(4-Fluorophenyl)sulfonyl]pip-

eridine-1,4-dicarboxylate (30). To a solution of the sulfide

29 (16.5 g, 43 mmoL) in dichloromethane (500 mL) cooled to

0 °C was added MCPBA (18.0 g, 86 mmoL), and the solution

was stirred for 20 h. The solution was diluted with H₂O and

extracted with dichloromethane. The organic layer was washed

with 10% Na₂SO₃, H₂O, and saturated NaCl and dried over

magnesium sulfate. Chromatography on silica gel eluting with

EA/hexane provided the sulfone 30 as a solid (10.7 g, 60%).

Anal. calcd for C₁₉H₂₆O₆NSF: C, 54.93; H, 6.31; N, 3.37; S,

7.72. Found: C, 54.89; H, 6.43; N, 3.15; S, 7.57.

Ethyl 4-[(4-Fluorophenyl)sulfonyl]piperidine-4-car-

boxylate (31). Into a solution of the sulfone 30 (10 g, 24.0

mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10

min followed by stirring at ambient temperature for 4 h.

Concentration in vacuo provided the amine hydrochloride salt

31 as a white solid (7.27 g, 86%). Anal. calcd for C₁₄H₁₈O₄NSF‚

HCl: C, 47.80; H, 5.44; N, 3.98; Cl, 10.08; S, 9.11. Found: C,

47.85; H, 5.65; N, 3.87; Cl, 10.35; S, 9.42.

N-Hydroxy-1-methyl-4-{[4-(phenylthio)phenyl]sulfonyl}-

piperidine-4-carboxamide Hydrochloride (35a). To a

solution of amine salt 37 (2.67 g, 5.14 mmol) and 37% aqueous

formaldehyde (2.0 mL, 25.7 mmol) in MeOH (20 mL) was

added borane-pyridine complex (2.6 mL, 25.7 mmol). The

solution was then stirred at room temperature for 18 h. The

solution was acidified and then concentrated to afford a residue

that was partitioned between aqueous NaHCO₃and EA. The

aqueous layer was extracted with EA, and the combined

organic layers were washed with H₂O and dried over MgSO₄.

Concentration gave the N-methyl amine 33a as an off-white

foam (1.6 g, 76%).

To a solution of the methylamine 33a (1.63 g, 3.88 mmol)

in EtOH (20 mL) was added KOH (1.31 g, 23.2 mmol) in water

(4 mL), and the resulting solution was heated to 50 °C for 8 h

and then 70 °C for 4 h. The solution was acidified and

concentrated providing the acid as a white solid. To a solution

of the crude acid in DMF (50 mL) were added O-tetrahydro-

2H-pyran-2-yl-hydroxylamine (0.92 g, 7.76 mmol), NMM (1.05

mL, 7.76 mmol), and EDC (1.5 g, 7.76 mmol). The solution

was stirred at room temperature for 72 h and then concen-

trated. The residue was dissolved in EA and washed with

aqueous NaHCO₃, H₂O, and dried over MgSO₄. Concentration

in vacuo and chromatography on silica gel eluting with CH₂Cl₂/

MeOH provided the THP hydroxamic acid 34a as a white solid

(0.46 g, 24.2%).

To a solution of the THP hydroxamic acid 34a (0.22 g, 0.45

mmol) in MeOH (5 mL) cooled to 0 °C was added acetyl

chloride (0.096 mL, 13.5 mmol), and the resulting solution was

stirred at room temperature for 3 h. The solution was

concentrated in vacuo and chromatographed on reverse phase

eluting with MeCN/H₂O (0.01% HCl) to afford the hydroxam-

ate N-methyl amine hydrochloride salt 35a (0.12 g, 60.6%) as

a white solid. HPLC purity: >99%. HRMS calculated for

C₁₉H₂₂N₂0₄S₂, 407.1099; found, 407.1105. ¹H NMR (400 MHz,

DMSO-d₆): δ 11.14 (1H, s), 9.28 (1H, s), 7.61 (2H, d, J ) 8.6

Hz), 7.56 (2H, m), 7.52 (3H, m), 7.24 (2H, d, J ) 8.6 Hz), 3.45

(2H, d, J ) 11.8 Hz), 2.68 (7H, m), 2.11 (2H, m).

1-Ethyl-N-hydroxy-4-{[4-(phenylthio)phenyl]sulfonyl}-

piperidine-4-carboxamide Hydrochloride (35b). To a

solution of amine hydrochloride 37 (6.2 g, 14 mmol) in DMF

(20 mL) were added K₂CO₃(3.87 g, 28 mmol) and iodoethane

(2.4 g, 15.4 mmol), and the reaction was stirred at room

temperature for 3 h. The mixture was then diluted with EA

(100 mL), washed with water and brine, and dried over MgSO₄.

Concentration gave the N-ethyl amine 33b (6.1 g, 100%) as a

solid. HRMS calcd for C₂₂H₂₇NS₂O₄, 434.1460; found, 434.1452.

To a solution of the N-ethylamine 33b (2.98 g, 6.9 mmol) in

1:1 EtOH/THF (40 mL) was added a solution of NaOH (2.76

g, 69 mmol) in H₂O (15 mL), and the reaction was heated to

65 °C for 18 h. The reaction was concentrated, resuspended

in H₂O (30 mL), and acidified to pH 3. The resulting solid was

filtered and dried to afford the carboxylic acid (1.7 g, 61%) as

a solid. HRMS calcd for C₂₀H₂₃NS₂O₄, 406.1140; found, 406.1147.

To a suspension of the carboxylic acid (5.3 g, 11.8 mmol) in

DMF (45 mL) were added sequentially HOBT (1.94 mg, 1.44

mmol), NMM (3.90 g, 35.4 mmol), O-tetrahydro-2H-pyran-2-

yl-hydroxylamine (2.07 g, 5.7 mmol), and EDC (3.17 g, 16.3

mmol). The reaction was stirred for 6 days and then filtered

to recover unreacted starting material. The filtrate was

concentrated, then water was added, and the solution was

extracted with EA. The combined extracts were washed with

brine and dried over MgSO₄and concentrated to give a residue

(970 mg), which was purified by chromatography on silica gel

eluting with MeOH/EA (3/97) to give the THP-hydroxamate

34b (2.33 g, 39%) as a white solid. HRMS calcd for C₂₅H₃₂-

N₂S₂O₅, 505.1831; found, 505.1831.

To a solution of THP-hydroxamate 34b (2.33 g, 4.6 mmol)

in 1/3-MeOH/1,4-dioxane (20 mL) was added 4 N HCl/1,4-

dioxane (10 mL, 40 mmol). After it was stirred for 2 h at room

temperature, the reaction was concentrated to a semisolid,

which was purified by reverse phase chromatography eluting

with MeCN/H₂O (HCl) (5/95 to 100% MeCN) to afford the

hydroxamic acid 35b (1.29 g, 55%) as a colorless foam. MS

calcd for C₂₀H₂₄N₂S₂O₄, 421; found, 421. Anal. calcd for

C₂₀H₂₄N₂S₂O₄‚HCl‚0.5H₂O: C, 51.55; H, 5.62; N, 6.01; S, 13.76;

Cl, 7.61. Found: C, 51.59; H, 5.73; N, 5.70; S, 13.71; Cl, 7.60.

N-Hydroxy-1-(2-methoxyethyl)-4-{[4-(phenylthio)-

phenyl]sulfonyl}piperidine-4-carboxamide Hydrochlo-

ride (35c). To the solution of the amine hydrochloride salt 37

(4.3 g, 9.43 mmol) and K₂CO₃(2.62 g, 19.0 mmol) in DMF (40

mL) was added 2-bromoethyl methyl ether (1.9 mL, 20.2

mmol). The solution was stirred at room temperature for 48

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6727

h. Then DMF was evaporated, and the residue was diluted

with EA. The organic layer was washed with water and dried

over MgSO₄. Concentration in vacuo provided the methoxy-

ethylamine 33c (4.26 g, 95.3%) as a white foam.

MgSO₄. Concentration gave an oil, which was purified by

chromatography on silica gel eluting with EA/hexane (40/60)

to give the desired N-allylamine 33e (4.80 g, 99%) as an oil.

MS MH+ calcd for C₂₃H₂₂NS₂O₄, 446; found, 446. Anal. calcd

for C₂₃H₂₂NS₂O₄: C, 62.00; H, 6.11; N, 3.14; S, 14.39. Found:

C, 62.22; H, 6.28; N, 3.04; S, 4.09. ¹H NMR (400 MHz,

d₆-DMSO): δ 7.64 (2H, d, J ) 8 Hz), 7.58 (2H, m), 7.53 (3H,

m), 7.31 (2H, d, J ) 8 Hz), 5.74 (1H, m), 5.13 (1H, d, J ) 15

Hz), 5.10 (1H, d, J ) 11 Hz), 4.07 (2H, q, J ) 7 Hz), 2.92-2.85

(4H, m), 2.17 (2H, m), 1.94 (2H, m), 1.72 (2H, m), 1.08 (3H, t,

J ) 7 Hz).

To a solution of the methoxyethylamine 33c (4.26 g, 9.2

mmol) in 1:1 EtOH/THF (10 mL) was added NaOH (3.7 g, 92.5

mmol) in water (9 mL). The solution resulting was heated to

60 °C for 12 h. The solution was concentrated in vacuo, diluted

with water, washed with ether, and acidified to pH 2. Filtra-

tion of the resulting precipitate provided the corresponding

carboxylic acid (3.5 g, 87.5%) as a while solid. To a solution of

this carboxylic acid (3.4 g, 7.8 mmol) in DMF (20 mL) were

added NMM (2.6 mL, 23.4 mmol), HOBT (3.16 g, 23.4 mmol),

O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.85 g, 15.5 mmol),

and EDC (4.47 g, 23.4 mmol). The solution was stirred at room

temperature for 36 h. The solution was concentrated, and the

residue was dissolved in EA. The organic layer was washed

with saturated NaHCO₃, H₂O, and dried over MgSO₄. Con-

centration provided the THP-protected hydroxamic acid 34c

as an off-white solid (2.98 g, 71.5%). To this free base (2.98 g,

5.6 mmol) in MeOH (40 mL) at 0 °C was added acetyl chloride

(1.19 mL, 16.8 mmol), and the resulting solution was stirred

at room temperature for 3 h. The solution was concentrated

and purified on reverse phase chromatography eluting with

MeCN/H₂O (containing 0.01% HCl) provided the desired

hydroxamate N-methoxyethyl monohydrochloride salt 35c

(2.29 g, 84.6%) as a white solid. Anal. calcd for C₂₁H₂₆N₂O₅S₂‚

HCl‚0.9H₂O: C, 50.12; H, 5.77; N, 5.57; S, 12.74. Found: C,

50.41; H, 5.85; N, 5.73; S,12.83.

1-Cyclopropyl-N-hydroxy-4-{[4-(phenylthio)phenyl]-

sulfonyl}piperidine-4-carboxamide Hydrochloride (35d).

To a solution of the amine TFA salt 37 (6 g, 11.9 mmol) was

added acetic acid (6.8 mL, 119 mmol). After 5 min of stirring

at room temperature, (l-ethoxylcyclopropyl)oxytriomethylsilane

(14.3 mL, 71.4 mmol) was added followed 5 min later by the

addition of sodium cyanoborohydride (3.35 g, 53.6 mmol).

Then, the solution was heated under reflux for 18 h. The

solvent was evaporated, and the residue was dissolved in EA.

The organic layer was washed with 1 N NaOH and H₂O and

dried over MgSO₄. Concentration in vacuo gave the N-

cyclopropylamine 33d as an off-white powder (4.9 g, 92.6%).

To a solution of N-allylamine ethyl ester 33e (4.8 g, 10.8

mmol) in 1:1 EtOH/THF (50 mL) was added a solution of

NaOH (4.3 g, 10.8 mmol) in water (20 mL), and the reaction

was heated at 65 °C for 16 h. The reaction was then

concentrated to dryness and resuspended in water (100 mL).

Acidification with 2 N HCl to pH 3 gave a precipitate, which

was filtered and dried to afford carboxylic acid (4.1 g, 84%) as

a beige solid. MS MH+ calcd for C₂₁H₂₃NS₂O₄, 418; found, 418.

Anal. calcd for C₂₁H₂₃NS₂O₄‚HCl‚H₂O: C, 53.44; H, 5.55; N,

2.97; Cl, 7.51; S, 13.59. Found: C, 53.36; H, 4.71; N, 2.90; Cl,

7.64; S, 14.13. To a suspension of this carboxylic acid (4.1 g,

9.0 mmol) in DMF (90 mL) were added sequentially HOBT

(1.46 g, 11 mmol), EDC (2.42 g, 13 mmol), NMM (2.97 mL, 27

mmol), and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.58

g, 13.5 mmol). The reaction was stirred for 3 days at room

temperature and then concentrated to dryness. The residue

was redissolved in CH₂Cl₂and washed with water and brine

and dried over MgSO₄. Concentration gave a residue (5.97 g),

which was purified by chromatography on silica gel eluting

with MeOH/EA (2/98 to 5/95) to afford the THP-hydroxamate

34e (4.11 g, 88%) as a colorless foam. HRMS MH+ calcd for

C₂₆H₃₂N₂S₂O₅, 517.1831; found, 517.1830. Anal. calcd for

C₂₆H₃₂N₂S₂O₅‚0.25H₂O: C, 59.92; H, 6.29; N, 5.37; S, 12.31.

Found: C, 59.63; H, 6.25; N, 5.79; S, 11.51. ¹H NMR (400 MHz,

d₆-DMSO): δ 7.64 (2H, d, J ) 8 Hz), 7.58 (2H, 2H, m), 7.52

(3H, m), 7.28 (2H, d, J ) 8 Hz), 5.75 (1H, m), 5.12 (1H, d, J )

18 Hz), 5.19 (1H, d, J ) 9 Hz), 4.89 (1H, s), 4.00 (1H, t, J ) 6

Hz), 3.46 (1H, d, J ) 12 Hz), 3.83 (2H, d, J ) 7 Hz), 3.80 (1H,

d, J ) 12 Hz), 2.25 (2H, d, J ) 10 Hz), 1.92-1.74 (4H, m),

1.77 (4H, m), 1.52 (4H, m).

To a solution of THP-hydroxamate 34e (4.11 g, 8.0 mmol)

in EA (100 mL) at 0 °C was added a methanolic solution of

HCl [generated by the addition of acetyl chloride (1.71 mL,

24.0 mmol) to methanol (20 mL)]. The solution was concen-

trated to give a gum, which was triturated with ether to afford

hydroxamate N-allylamine hydrochloride 35e (3.53 g, 95%) as

a colorless powder. MS MH+ calcd for C₂₁H₂₄N₂S₂O₄, 433;

found, 433. Anal. calcd for C₂₁H₂₄N₂S₂O₄‚HCl‚0.5H₂O: C,

52.76; H, 5.48; N, 5.86; S, 13.42; Cl, 7.42. Found: C, 52.57; H,

5.69; N, 6.29; S, 12.59; Cl, 7.80.

N-Hydroxy-4-{[4-(phenylthio)phenyl]sulfonyl}-1-(2-pro-

pynyl)-4-piperidinecarboxamide, Monohydrochloride

(35f, Hydrochloride Salt). To a solution of the amine

hydrochloride salt 31 (5.98 g, 17.0 mmol) in DMF (120 mL)

was added potassium carbonate (4.7 g, 34.0 mmol) followed

by propargyl bromide (2.02 g, 17.0 mmol), and the solution

was stirred for 4 h at ambient temperature. The solution was

partitioned between EA and H₂O, and the organic layer was

washed with H₂O and brine and dried over magnesium sulfate.

Chromatography (on silica, ethyl acetate/hexane) provided the

propargylamine 32f as a yellow oil (5.2 g, 86%).

To a solution of the cyclopropylamine 33d (4.88 g, 10.9

mmol) in THF (12 mL) and EtOH (12 mL) was added NaOH

(4.3 g, 100 mmol) in 45 water (25 mL). The solution was then

heated to 55 °C for 12 h and was stirred at room temperature

for 18 h. The solution was acidified to pH 2 and concentrated

in vacuo to provide the acid as white solid. To a solution of

this crude acid in MeCN (50 mL) were added O-tetrahydro-

2H-pyran-2-yl-hydroxylamine (1.95 g, 16.3 mmol), NMM (2.4

mL, 21.9 mmol), and EDC (3.14 g, 16.3 mmol) in sequence.

The solution was then stirred at room temperature for 18 h.

The solution was concentrated in vacuo, and the residue was

dissolved in EA. The organic layer was washed with H₂O and

dried over MgSO₄. Concentration in vacuo provided the THP-

protected hydroxamate 34d as a white solid (3.0 g, 60 53.1%).

To a solution of the THP-protected hydroxamate 34d (3 g,

5.8 mmol) in MeOH (45 mL) at 0 °C was added acetyl chloride

(1.5 mL, 21.1 mmol), and the solution was stirred at room

temperature for 2.5 h. Vacuum filtration of the resulting

precipitate provided the hydroxamic acid N-cyclopropylamine

monohydrochloride salt 35d as a white solid (1.84 g, 68.3%).

HPLC purity: >95%. MS MH⁺calcd for C₂₁H₂₄N₂O₄S₂,

433.1250; found, 433.1263. ¹H NMR (400 MHz, DMSO-d₆): δ

11.17 (1H, s), 9.29 (1H, s), 7.60 (2H, m), 7.56 (2H, m), 7.52

(3H, m), 7.24 (2H, d, J ) 8.6 Hz), 3.55 (2H, d, J ) 11.0 Hz),

3.43 (3H, m), 2.91 (2H, m), 2.15 (2H, m), 0.92 (2H, d, J ) 1.9

Hz), 0.72 (2H, dd, J ) 6.0, 1.7 Hz).

To a solution of the propargylamine 32f (2.75 g, 7.78 mmol)

in DMF (15 mL) were added thiophenol (0.80 mL, 7.78 mmol)

and CsCO₃(2.79 g, 8.56 mmol), and the solution was heated

to 70 °C for 6 h. The solution was partitioned between ethyl

ether and H₂O. The organic layer was washed with H₂O and

saturated NaCl and dried over magnesium sulfate. Chroma-

tography (on silica, ethyl acetate/hexane) provided the thio-

ether 33f as an oil (1.95 g, 56%). MS MH+ calcd for C₂₃H₂₅-

NO₄S₂, 444; found, 444. Anal. calcd for C₂₃H₂₅NO₄S₂: C, 62.28;

H, 5.68; N, 3.16; S, 14.46. Found: C, 62.27; H, 5.81; N, 3.09;

N-Hydroxy-4-{[4-(phenylthio)phenyl]sulfonyl}-1-(vinyl-

methyl)piperidine-4-carboxamide Hydrochloride (35e).

To a solution of amine hydrochloride 37 (4.78 g, 10.8 mmol)

in DMF (25 mL) was added K₂CO₃(2.98 g, 21.6 mmol) followed

by allyl bromide (0.935 mL, 10.8 mmol). The reaction was

stirred at room temperature for 5 h and then diluted with EA

and washed successively with water and brine and dried over

1

S, 14.32. H NMR (300 MHz, CDCl₃): δ 7.61 (2H, d, m), 7.54

(2H, m), 7.46 (3H, m), 7.20 (2H, m), 4.21 (2H, q, J ) 7 Hz),

6728 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

3.26 (2H, d, J ) 2 Hz), 2.89 (2H, m), 2.34 (2H, m), 2.21 (1H, t,

J ) 2 Hz), 2.17-2.11 (4H, m), 1.23 (3H, t, J ) 7 Hz).

aqueous layer was extracted with EA, and the combined

organic extracts were washed with water and dried over

MgSO₄. Concentration in vacuo provided the N-acetamide

carboxylic acid (5.0 g, 100%) as a light yellow foam. To a

solution of the acetamide (5 g, 11.9 mmol) in DMF (50 mL)

were added NMM (5.3 mL, 47.6 mmol), HOBT (4.8 g, 35.7

mmol), O-tetrahydro-2H-pyran-yl-hydroxylamine (2.8 g, 23.5

mmol), and EDC (6.8 g, 35.7 mmol), and the solution was

stirred at room temperature for 20 h. The reaction was

concentrated under vacuum, and the residue was dissolved in

EA. The organic layer was washed with saturated NaHCO₃,

KHSO₄, and H₂O and dried over MgSO₄. Concentration in

vacuo provided the THP-protected hydroxamic acid 34g (6.07

g, 98.2%) as a colorless foam.

To a solution of the THP-hydroxamate 34g (6.07 g,11.7

mmol) in MeOH (100 mL) at 0 °C was added acetyl chloride

(2.5 mL, 35.1 mmol), and the solution was stirred at room

temperature for 3 h. Concentration gave a residue, which was

purified by chromatography on silica gel eluting with methanol/

CH₂Cl₂to provide the N-acetyl hydroxamic acid 35g (3.3 g,

65%) as a white solid.

To a solution of the ethyl ester 33f (1.81 g, 4.06 mmol) in

ethanol (21 mL) and H₂O (3.5 mL) was added KOH (1.37 g,

24.5 mmol), and the solution was heated to 105 °C for 4.5 h.

The solution was acidified to a pH value of 1 with concentrated

HCl solution and then concentrated to provide the acid as a

yellow residue that was used without additional purification

(1.82 g). To a solution of the carboxylic acid (1.82 g, 4.06 mmol)

in acetonitrile (20 mL) were added O-tetrahydro-2H-pyran-2-

yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67

mL, 4.86 mmol). To this solution was added EDC (1.18 g, 6.17

mmol), and the solution was stirred for 18 h. The solution was

partitioned between H₂O and ethyl acetate. The organic layer

was washed with H₂O, saturated NaHCO₃, and brine and dried

over magnesium sulfate. Chromatography on silica eluting

with ethyl acetate/hexane provided the THP-hydroxamate 34f

(1.32 g, 63%) as a white solid. MS MH+ calcd for C₂₆H₃₁N₂O₅S₂,

515; found, 515. ¹H NMR (300 MHz, CDCl₃): 7.65 (2H, d, J )

8 Hz), 7.55 (2H, m), 7.50-7.43 (3H, m), 7.18 (2H, d, J ) 8

Hz), 4.98 (1H, br s), 3.99 (1H, t, J ) 11 Hz), 3.68 (1H, d, J )

11 Hz), 3.22 (2H, d, J ) 2 Hz), 2.91 (2H, dd, J ) 10, 2 Hz),

2.32 (2H, td, J ) 11, 2 Hz), 2.27-2.16 (4H, m), 1.92-1.73 (3H,

m), 1.68-1.55 (3H, m).

To a solution of the THP-hydroxamate 34f (9.65 g, 18.7

mmol) in methanol (148 mL) cooled to 0 °C was added acetyl

chloride (4.0 mL, 56.2 mmol), and the solution was stirred for

45 min at room temperature. Concentration followed by

trituration with ethyl ether provided 35f as a white solid (8.10

g, 94%). MS(CI) MH⁺calculated for C₂₁H₂₂N₂O₄S₂, 431; found,

431. Anal. calcd for C₂₁H₂₂N₂O₄S₂‚HCl: C, 52.99; H, 5.08; N,

5.88; S, 13.47. Found: C, 53.02; H, 5.21; N, 5.82; S, 13.08. ¹H

NMR (300 MHz, MeOD): δ 7.67 (2H, d, J ) 8 Hz), 7.57 (2H,

m), 7.53-7.47 (3H, m), 7.26 (2H, d, J ) 7 Hz), 4.08 (2H, d, J

) 2 Hz), 3.74 (2H, br d, J ) 3 Hz), 3.39 (1H, t, J ) 2 Hz), 3.02

(2H, br t, J ) 13 Hz), 2.61 (2H, br d, J ) 14 Hz), 2.39 (2H, br

t, J ) 13 Hz).

N-Hydroxy-1-(methylsulfonyl)-4-{[4-(phenylthio)phenyl]-

sulfonyl}piperidine-4-carboxamide (35h). To a solution of

amine hydrochloride 37 (2.0 g, 4.7 mmol) in CH₂Cl₂(35 mL)

was added NMM (1.29 mL, 11.7 mmol) followed by methane-

sulfonyl chloride (0.55 mL, 7.05 mmol). The reaction was

stirred for 2 days at room temperature and then concentrated.

Water was added, and the mixture was extracted with EA

(3×). The combined extracts were washed with water and brine

and dried over MgSO₄. Concentration gave the methane-

1

sulfonamide 33h (2.17 g, 95%) as colorless crystals. H NMR

(400 MHz, CDCl₃): δ 7.62-7.52 (4H, m), 7.47 (3H, m), 7.21

(2H, d, J ) 9 Hz), 4.23 (2H, q, J ) 7 Hz), 3.85 (2H, m), 2.77

(3H, s), 2.63 (2H, t, J ) 11 Hz), 2.46 (2H, d, J ) 13 Hz), 2.17

(2H, m), 1.26 (3H, t, J ) 7 Hz).

To a solution of mesyl ethyl ester 33h (2.1 g, 4.3 mmol) in

1:1 EtOH/THF (50 mL) was added a solution of NaOH (1.72

g, 43 mmol) in H₂O (10 mL), and the reaction was heated on

at 60 °C. Concentration gave a residue, which was acidified

to pH 2 with 2 N HCl and extracted with EA. The combined

extracts were washed with brine and dried over MgSO₄and

concentrated to give the desired carboxylic acid (2.1 g, 100%)

N-Hydroxy-4-{[4-(phenylthio)phenyl]sulfonyl}-1-(2-pro-

pynyl)-4-piperidinecarboxamide, Methanesulfonate (35f,

Mesylate Salt). To a solution of the free base of 35f (1.61 g,

3.7 mmol) in MeOH (10 mL) was added methane sulfonic acid

(395 mg, 4.1 mmol). After 3 h at room temperature, the

precipitate was isolated by filtration to afford the mesylate

salt of 35f (1.60 g, 81%) as a colorless crystalline solid;

crystalline by powder X-ray diffraction. DSC 219.7 °C. Anal.

calcd for C₂₁H₂₂N₂O₄S₂‚CH₃SO₃H: C, 48.51; H, 5.18; N, 5.14;

S, 17.66. Found: C, 48.88; H, 5.15; N, 5.23; S, 17.81.

1

as a solid. H NMR (400 MHz, CDCl₃): δ 7.67 (2H, d, J ) 8

Hz, 7.56 (2H, m), 7.57 (3H, m), 7.24 (2H, d, J ) 11 Hz), 3.89

(2H, dt, J ) 14, 3 Hz), 2.97 (1H, t, J ) 12 Hz), 2.69 (2H, t, J

) 11 Hz), 2.14 (2H, br d, J ) 13 Hz), 1.75 (2H, qd, J ) 11, 3

Hz). To a solution of this carboxylic acid (1.98 g, 4.3 mmol) in

DMF (30 mL) were added HOBT (705 mg, 5.2 mmol), NMM

(1.42 g, 12.9 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxyl-

amine (755 mg, 6.5 mmol), and EDC (1.17 g, 6.1 mmol). The

reaction was stirred for 4 days at room temperature, then

diluted with water, and extracted with EA. The combined

organic extracts were washed with water and brine and dried

over MgSO₄. Concentration gave a yellow oil (3.86 g), which

was purified by chromatography on silica gel eluting with EA/

hexane (30/70) to afford the THP-hydroxamate 34h (1.99 g).

MS MH+ calcd for C₂₄H₃₀N₂S₃O₇, 555; found, 555. ¹H NMR

(400 MHz, CDCl₃): δ 9.49 (1H, s), 7.65 (2H, d, J ) 6 Hz), 7.57

(2H, m), 7.57 (3H, m), 7.19 (2H, d, J ) 7 Hz), 4.98 (1H, s),

3.98 (1H, t, J ) 10 Hz), 3.82 (2H, m), 3.69 (1H, m), 3.86 (2H,

qd, J ) 10, 3 Hz), 2.73 (3H, s), 2.28 (2H, m), 2.19 (2H, m),

1.90-1.76 (3H, m), 1.72-1.58 (3H, m).

1-Acetyl-N-hydroxy-4-{[4-(phenylthio)phenyl]sulfonyl}-

piperidine-4-carboxamide (35g). To a solution of N-BOC

ethyl ester 30 ((40 g, 96 mmol) and K₂CO₃(26 g, 188 mmol) in

DMF (200 mL) at 0 °C was added thiophenol (19.8 mL, 192

mmol), and the reaction was stirred at room temperature for

36 h. Concentration gave a residue, which was dissolved in

EA and washed with water and brine and dried over MgSO₄.

Chromatography on silica gel eluting with EA/hexane gave the

diaryl sulfide (44.3 g, 91%) as a white solid. To a solution of

the diaryl sulfide ethyl ester (7.0 g, 1.29 mmol) in 1:1 EtOH/

THF (50 mL) was added NaOH (5.1 g, 12.9 mmol) in H₂O (50

mL). The solution was heated to reflux for 20 h. The solution

was then concentrated in vacuo, and the residue was dissolved

in H₂O. The aqueous layer was extracted with ether and then

acidified to pH 2 and extracted with EA. The combined organic

extracts were washed with water and brine and dried over

MgSO₄. Concentration provided the carboxylic acid (3.9 g, 60%)

as a white foam. To a solution of this N-BOC carboxylic acid

(2.3 g, 4.98 mmol) in CH₂Cl₂(6 mL) was added TFA (6 mL,

77.8 mmol), and the solution was stirred at room temperature

for 1 h. Concentration in vacuo provided the amine trifluoro-

acetate salt (2.44 g, 100%) as a white foam. To a solution of

this trifluoroacetate salt (5.0 g, 12.1 mmol) and triethylamine

(8.7 mL, 60.4 mmol) in 1:1 acetone/water (20 mL) at 0 °C was

added acetyl chloride (4.6 mL, 36 mmol), and the solution was

stirred at room temperature for 40 h. The mixture was

concentrated, and the aqueous layer was acidified to pH 2. This

To a solution of the THP-hydroxamate 34h (1.86 g, 3.5

mmol) in MeOH/1,4-dioxane (40 mL) was added 4 N HCl in

1,4-dioxane (20 mL, 80 mmol). The reaction was stirred for

2.5 h at room temperature and then concentrated to dryness.

Trituration with ether gave the desired N-mesyl hydroxamic

acid 35h (1.48 g, 91%) as a light pink solid. HRMS calcd for

C₁₉H₂₂N₂S₃O₆, 471.0718; found, 471.0728. Anal. calcd for

C₁₉H₂₂N₂S₃O₆‚Et₂O: C, 50.72; H, 5.92; N, 5.14; S, 17.66.

Found: C, 50.25; H, 5.59; N, 5.12; S, 17.83.

1-tert-Butyl 4-Ethyl 4-{[4-(Phenylthio)phenyl]sulfonyl}-

piperidine-1,4-dicarboxylate (36). To a solution of sulfone

30 (40 g, 96 mmol) and powdered K₂CO₃(26 g, 188 mmol) in

Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6729

DMF (200 mL) cooled to 0 °C was added thiophenol (19.8 mL,

192 mmol), and the resulting composition was then stirred at

room temperature for 36 h. That solution was concentrated

under high vacuum, and the residue was dissolved in EA. The

organic layer was washed with H₂O and dried over MgSO₄.

Chromatography on silica gel eluting with EA/hexane provided

the phenylthiophenyl BOC-sulfone 36 as a white solid (44.3

g, 91%).

Ethyl 4-{[4-(Phenylthio)phenyl]sulfonyl}piperidine-4-

carboxylate Hydrochloride (37, Hydrochloride Salt).

Through a solution of N-BOC ethyl ester 36 (31.2 g, 66 mmol)

in EA (500 mL) at 0 °C was bubbled HCl gas for 0.5 h. The

solution was allowed to stand for an additional 1.5 h and was

then concentrated to afford a residue, which was triturated

with ether to afford amine hydrochloride 37 (26.9 g, 96%) as

a white foam.

Ethyl 4-{[4-(Phenylthio)phenyl]sulfonyl}piperidine-4-

carboxylate Trifluoroacetate (37, Trifluoroacetate Salt).

To a solution of the phenylthiophenyl BOC-sulfone (8.6 g, 17

mmol) in CH₂Cl₂(30 mL) cooled to 0 °C was added TFA (30

mL), and the resulting solution was stirred at room temper-

ature for 2 h. Concentration in vacuo provided the amine TFA

salt as a light yellow gel (8.7 g, 100%).

Enzyme Assays. Inhibitors were assayed against purified

hMMP-1, hMMP-2, hMMP-8, hMMP-9, and hMMP-13 using

an enzyme assay based on cleavage of the fluorogenic peptide

MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂. Human MMP-3 ac-

tivity was measured using a fluorogenic substrate containing

glutamic acid and (S)-2-aminopentanoic acid per Nagase et

al.⁴¹Assay conditions were similar to those described in Knight

et al.⁴²All basic compounds were tested as their hydrochloride

salts unless otherwise indicated.

reached. All drugs were administered starting the day of pair

match (day 1). In the combination group, the oral dose of 35f

immediately followed the paclitaxel injection. The vehicle-

treated mice served as controls and were dosed orally b.i.d.

with vehicle until the study end point was reached.

The median survivals of various groups were compared to

each other and to the median survival time of MX-1 growth

control mice. Mice were euthanized when MX-1 tumors

reached a calculated size of 1.5 g and were considered a cancer

death. The median survival (MDS) is the day at which half

the mice in a group have died. Survival curves were compared

using Graphpad Prism.

Supporting Information Available: Tables with com-

bustion analysis data for the compounds synthesized. This

material is available free of charge via the Internet at http://

pubs.acs.org.

References

(1) Brinckerhoff, C. E.; Matrisian, L. M. Matrix metalloprotein-

ases: A tail of a frog that became a prince. Nat. Rev. Mol. Cell

Biol. 2002, 3, 207-214.

(2) Doherty, T. M.; Asotra, K.; Pei, D.; Uzui, H.; Wilkin, D. J.; Shah,

P. K.; Rajavashisth, T. B. Therapeutic developments in matrix

metalloproteinase inhibition. Expert Opin. Ther. Pat. 2002, 12,

665-707.

(3) Nagase, H.; Woessner, J. F., Jr. Matrix metalloproteinases. J.

Biol. Chem. 1999, 274, 21491-21494.

(4) Wojtowicz-Praga, S. M.; Dickson, R. B.; Hawkins, M. J. Matrix

metalloproteinase inhibitors. Invest. New Drugs 1997, 15, 61-

75.

(5) Skiles, J. W.; Gonnella, N. C.; Jeng, A. Y. The design, structure

and therapeutic application of matrix metalloproteinase inhibi-

tors. Curr. Med. Chem. 2001, 8, 425-474.

Mouse Corneal Neovascularization Model. Animal

work was carried out in accordance with institutional guide-

lines. All animal procedures were approved by the Institutional

Animal Care and Use Committee and conform to the HIH

Guidelines for the Ethical Care and Treatment of Animals. A

Hydron [poly(hydroxyethyl)methacrylate, IFN Sciences, New

Brunswick, NJ] implant containing 60 ng of human recombi-

nant bFGF (Life Technologies, Gaithersburg, MD) and 200 µg

of sucralfate (Carafate, Marion Merrel Dow, Cincinnati, OH)

was prepared and stored at -90 °C. C57BL/6 male mice

(Charles River Laboratories, Raleigh, NC) weighing 200-250

g were anesthetized, and a 2 mm keratotomy was made 1 mm

from the center of the globe with #15 surgical blade. An

intrastromal pocket was tunneled toward the lateral canthus

using a modified corneal knife (1 × 15), and a single Hydron

pellet was inserted ∼2 mm from the conral-scleral junction.

In some cases, mice were implanted with Hydron pellets

prepared without bFGF. Treatment of mice with 35f or vehicle

was initiated the evening of the same day. Compound 35f was

prepared in vehicle (0.5% methylcellulose, 0.1% polysorbate

80 in water; sterile filtered). Seven days later, the mice were

injected in the ipsilateral carotid artery with 50% India ink

to stain the blood vessels. The rats were sacrificed, the corneas

were removed and mounted on microscope slides, and the area

of corneal vascularization was measured using computer-

assisted image analysis.

MX-1 Human Breast Carcinoma Model. Female NCr-

nude mice were implanted subcutaneously with 1 mm³MX-1

human breast carcinoma fragments in the flank. Tumors were

monitored initially twice weekly and then daily as the neo-

plasms approached the desired size. When the majority of the

carcinomas reached a mass of 32-126 mg in calculated tumor

weight, the animals were pair-matched into treatment groups.

Estimated tumor weight was calculated using the formula:

tumor weight (mg) ) [w²× L]/2, where w ) tumor width and

L ) tumor length, measured in mm.

Compound 35f was formulated in vehicle (0.5% methyl-

cellulose, 0.1% polysorbate 80 in water; sterile filtered).

Paclitaxel (Bristol Myers Squibb) was obtained as the mar-

keted pharmaceutical drug. Paclitaxel was given ip on a daily

×5 schedule at a dose of 9 mg/kg. Compound 35f was given

b.i.d. orally at 100 mg/kg until the study end point was

(6) Woessner, J. F., Jr. Matrix metalloproteinases and their inhibi-

tors in connective tissue remodeling. FASEB J. 1991, 5, 2145-

2154.

(7) Martel-Pelletier, J.; Welsch, D. J.; Pelletier, J. P. Metallopro-

teases and inhibitors in arthritic diseases. Best Pract. Res. Clin.

Rheumatol. 2001, 15, 805-829.

(8) Heath, E. I.; Grochow, L. B. Clinical potential of matrix metallo-

protease inhibitors in cancer therapy. Drugs 2000, 59, 1043-

1055.

(9) Hidalgo, M.; Eckhardt, G. Development of matrix metallopro-

teinase inhibitors in cancer therapy. J. Natl. Cancer Inst. 2001,

93, 178-193.

(10) Fingleton, B. Matrix metalloproteinase inhibitors for cancer

therapy: The current situation and future prospects. Expert

Opin. Ther. Targets 2003, 7, 385-397.

(11) Matter, A. Tumor angiogenesis as a therapeutic target. Drug

Discovery Today 2001, 6, 1005-1024.

(12) Supuran, C. T.; Casini, A.; Scozzafava, A. Protease inhibitors of

the sulfonamide type: Anticancer, antiinflammatory and anti-

viral agents. Med. Res. Rev. 2003, 23, 535-558.

(13) Casini, A.; Scozzafava, A.; Supuran, C. T. Sulfonamide deriva-

tives with protease inhibitory action as anticancer, antiinflam-

matory and antiviral agents. Expert Opin. Ther. Pat. 2002, 12,

1307-1327.

(14) Supuran, C. T.; Scozzafava, A. Matrix metalloproteinases (MMPs).

In Proteinase and Peptidase Inhibition: Recent Potential Tartets

for Drug Development; Smith, H. J., Simons, C., Eds.; Taylor &

Francis: London and New York, 2002; pp 35-61.

(15) Stamenkovic, I. Matrix metalloproteinases in tumor invasion and

metastasis. Semin. Cancer Biol. 2000, 10, 415-433.

(16) Yip, D.; Ahmad, A.; Karapetis, C. S.; Hawkins, C. A.; Harper,

P. G. Matrix metalloproteinase inhibitors: Applications in

oncology. Invest. New Drugs 1999, 17, 387-399.

(17) Nelson, A. R.; Fingleton, B.; Rothenberg, M. L.; Matrisian, L.

M. Matrix metalloproteinases: Biologic activity and clinical

implications. J. Clin. Oncol. 2000, 18, 1135-1149.

(18) Coussens, L. M.; Fingleton, B.; Matrisian, L. M. Matrix metallo-

proteinase inhibitors and cancer: trials and tribulations. Science

2002, 295, 2387-2392.

(19) Hidalgo, M.; Eckhardt, S. G. Development of matrix metallo-

proteinase inhibitors in cancer therapy. J. Natl. Cancer Inst.

2001, 93, 178-193.

(20) Bramhall, S. R.; Hallissey, M. T.; Whiting, J.; Scholefield, J.;

Tierney, G.; Stuart, R. C.; Hawkins, R. E.; McCulloch, P.;

Maughan, T.; Brown, P. D.; Baillet, M.; Fielding, J. W. L.

Marimastat as maintenance therapy for patients with advanced

gastric cancer: A randomized trial. Br. J. Cancer 2002, 86,

1864-1870.

6730 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21

Becker et al.

(21) Groves, M. D.; Puduvalli, V. K.; Hess, K. R.; Jaeckle, K. A.;

Peterson, P.; Yung, W. K. A.; Levin, V. A. Phase II trial of

temozolomide plus the matrix metalloproteinase inhibitor,

marimastat, in recurrent and progressive glioblastoma multi-

forme. J. Clin. Oncol. 2002, 20, 1383-1388.

(22) Bramhall, S. R.; Rosemurgy, A.; Brown, P. D.; Bowry, C.;

Buckels, J. A. Marimastat as first-line therapy for patients with

unresectable pancreatic cancer: A randomized trial. J. Clin.

Oncol. 2001, 19, 3447-3455.

(23) Naglich, J. G.; Jure-Kunkel, M.; Gupta, E.; Fargnoli, J.; Hend-

erson, A. J.; Lewin, A. C.; Talbott, R.; Baxter, A.; Bird, J.;

Savopoulos, R.; Wills, R.; Kramer, R. A.; Trail, P. A. Inhibition

of angiogenesis and metastasis in two murine models by the

matrix metalloproteinase inhibitor, BMS-275291. Cancer Res.

2001, 61, 8480-8485.

(24) Renkiewicz, R.; Qiu, L.; Lesch, C.; Sun, X.; Devalaraja, R.; Cody,

T.; Kaldjian, E.; Welgus, H.; Baragi, V. Broad-spectrum matrix

metalloproteinase inhibitor marimastat induced musculoskeletal

side effects in rats. Arthritis Rheum. 2003, 48, 1742-1749.

(25) Brown, P. D. Clinical studies with matrix metalloproteinase

inhibitors. APMIS 1999, 107, 174-180.

(26) Becker, D. P.; Barta, T. E.; Bedell, L.; DeCrescenzo, G.; Freskos,

J.; Getman, D. P.; Hockerman, S. L.; Li, M.; Mehta, P.; Mischke,

B.; Munie, G. E.; Swearingen, C.; Villamil, C. I. R-Amino-â-

sulphone hydroxamates as potent MMP-13 inhibitors that spare

MMP-1. Bioorg. Med. Chem. Lett. 2001, 11, 2719-2722.

(27) Becker, D. P.; DeCrescenzo, G.; Freskos, J.; Getman, D. P.;

Hockerman, S. L.; Li, M.; Mehta, P.; Munie, G. E.; Swearingen,

C. R-Alkyl- R-amino-â-sulphone hydroxamates as potent MMP

inhibitors that spare MMP-1. Bioorg. Med. Chem. Lett. 2001,

11, 2723-2725.

(28) Lollini, L.; Haller, J.; Eugui, E. M.; Womble, S. W.; Martin, R.;

Campbell, J. Disease modification by RS-130830, a collagenase-3

selective inhibitor, in experimental osteoarthritis (OA) [abstract].

Arthritis Rheum. 1997, 40 (Suppl.), S87, abstract 341.

(29) Close, D. R. Matrix metalloproteinase inhibitors in rheumatic

diseases. Ann. Rheum. Dis. 2001, 60, iii62-iii67.

(30) Becker, D.; Barta, T.; Bedell, L.; Boehm, T.; Carron, C.; De-

Crescenzo, G.; Freskos, J.; Funckes-Shippy, C.; Getman, D.;

Hockerman, S.; Li, M.; McDonald, J.; Mehta, P.; Munie, G.; Rico,

J.; Shieh, H.; Stevens A.; Swearingen, C. Design and synthesis

of potent and orally active MMP-1 sparing matrix metallopro-

teinase inhibitors with efficacy in antitumor models. Oral

Presentation at the 222nd ACS National Meeting, Chicago, IL,

August 26-30, 2001. Abstr. Pap. Am. Chem. Soc., Medi 018,

2001.

related compounds as matrix metalloprotease inhibitors. U.S.

Patent 6,541,489, 2003. PCT Int. Appl. WO 9925687 A1 990527

CAN 131:18929; AN 1999:350651.

(32) Aranapakam, V.; Grosu, G. T.; Davis, J. M.; Hu, B.; Ellingboe,

J.; Baker, J. L.; Skotnicki, J. S.; Zask, A.; DiJoseph, J. F.; Sung,

A.; Sharr, M. A.; Killar, L. M.; Walter, T.; Jin, G.; Cowling, R.

Synthesis and structure-activity relationship of R-sulfonyl-

hydroxamic acids as novel, orally active matrix metalloprotein-

ase inhibitors for the treatment of osteoarthritis. J. Med. Chem.

2003, 46, 2361-2375.

(33) Aranapakam, V.; Davis, J. M.; Grosu, G. T.; Baker, J.; Ellingboe,

J.; Zask, A.; Levin, J. I.; Sandanayaka, V. P.; Du, J.; Skotnicki,

J. S.; DiJoseph, J. F.; Sung, A.; Sharr, M. A.; Killar, L. M.;

Walter, T.; Jin, G.; Cowling, R.; Tillett, J.; Zhao, W.; McDevitt,

J.; Xu, Z. B. Synthesis and structure-activity relationship of

N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as

novel, orally active matrix metalloproteinase inhibitors for the

treatment of osteoarthritis. J. Med. Chem. 2003, 46, 2376-2396.

(34) Cignarella, G.; Villa, S.; Barlocco, D. Synthesis and pharmaco-

logical evaluation of a new class of 2-oxo-8-azaspiro (4,5)decan-

1-ones as analogues of the muscarinic agonist RS-86. Farmaco

1993, 48, 1439-1445.

(35) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward,

K. W.; Kopple, K. D. Molecular properties that influence the oral

bioavailability of drug candidates. J. Med. Chem. 2002, 45,

2615-2623.

(36) Folkman, J.; Ingber, D. Inhibition of angiogenesis. Semin. Cancer

Biol. 1992, 3, 89-96.

(37) Blood, C. H.; Zetter, B. R. Tumor interactions with the vascu-

lature: Angiogenesis and tumor metastasis. Biochim. Biophys.

Acta 1990, 1032, 89-118.

(38) D’Amore, P. A. Capillary growth: A two-cell system. Semin.

Cancer Biol. 1992, 3, 49-56.

(39) Sunderkotter, C.; Steinbrink, K.; Goebeler, M.; Bhardwaj, R.;

Sorg, C. Macrophages and angiogenesis. J. Leukocyte Biol. 1994,

55, 410-422.

(40) Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; Hoover, D. J.

Tetracyclopropylmethane: A unique hydrocarbon with S4 sym-

metry. Tetrahedron Lett. 1995, 36, 7399-7402.

(41) Nagase, H.; Fields, C. G.; Fields, G. B. Design and character-

ization of a fluorogenic substrate selectively hydrolyzed by

stromelysin 1 (matrix metalloproteinase-3). J. Biol. Chem. 1994,

269, 20952-20957.

(42) Knight, C. G.; Willenbrock, F.; Murphy, G. A novel coumarin-

labeled peptide for sensitive continuous assay of matrix metallo-

proteinases. FEBS Lett. 1992, 296, 263-266.

(31) Barta, T. E.; Becker, D. P.; Boehm, T. L.; DeCrescenzo, G. A.;

Villamil, C. I.; McDonald, J. J.; Freskos, J. N.; Getman, D. P.

Preparation of arylsulfonyl heterocyclyl hydroxamic acids and

JM0500875

Article Doi

Synthesis and structure-activity relationships of β- and α-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy

DOI: 10.1021/jm0500875

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jm0500875

Full text of DOI:10.1021/jm0500875

Products guided by the article

R&D Labs maybe for 226396-40-3

Relevant to this article

Hot Product