CA2052073C - Sulfonamide fibrinogen receptor antagonists - Google Patents

Abstract

A series of non-peptide derivatives that are antagonists of the fibrinogen IIb/IIIa receptor and thus are platelet anti-aggregation compounds useful in the prevention and treatment of diseases caused by thrombus formation, having the following structure:

(see fig. I) wherein R1 is a piperidinyl moiety R4 is aryl selected from the group consisting of phenyl, pyridyl, thienyl, tetrazole or oxazole, or C1-10 alkyl, or C4-10 aralkyl;
Z is 0, (see fig. II), or (see fig. III), where m is an integer from two to six, and pharmaceutically acceptable salts thereof.

Description

58/RSP35 205~07~

s - l - 18197Y

TITL~ OF T~E T~VE~TION
NOVEL SULFONAMIDE FIBRINOGEN REC~OR ANTAGONISTS

BACKGROUND OF ~ v~ ON

The pre~ent invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds being generally pharmacologically u~eful as anti-platelet aggregation agents in various vascular pathologies. The aforementioned pharmacologic activities are useful in the treatment of mammals.
More specifically, the sulfonamide compounds of the present invention act by blocking the molecular receptor site of the protein fibrinogen. Fibrinogen is a glycoprotein that circulates in the blood plasma, and whose platelet receptor site is glycoprotein IIb/IIIa. By blocking the action of fibrinogen at the receptor (glycoprotein IIb/IIIa), the compounds of the present invention interfere with platelet aggregation, which is a cause of many vascular pathologiés. At the present time, there is a need in the area of vascular therapeutics for such a fibrinogen receptor blocking agent. By interfering lO with hemostasis, such therapy would decrease the morbidity and mortality of thrombotic disease.
Hemostasis is the spontaneous process of stopping bleeding from damaged blood vessels.
Precapillary vessels contract immediately when cut.
15 Within seconds, thrombocytes, or blood platelets, are bound to the exposed matrix of the injured vessel by a process called platelet adhesion. Platelets also stick to each other in a phenomenon known as platelet aggregation to form a platelet plug. This platelet 20 plug can stop ~bleeding quickly, but it must be reinforced by the protein fibrin for long-term effectiveness, until the blood vessel tear can be permanently repaired by growth of fibroblasts, which are specialized tissue repair cells.
An intravascular thrombus (clot) results from a pathological disturbance of hemostasis. The thrombus can grow to sufficient size to block off arterial blood vessels. Thrombi can also form in areas of stasis or slow blood flow in veins. Venous 30 thrombi can easily detach portions of themselves called emboli that travel through the circulatory system and can result in blockade of other vessels, 2~0~7~

such as pulmonary arteries. Thus, arterial thrombi cause serious disease by local blockade, whereas venous thrombi do so primarily by distant blockade, or embolization. These diseases include venous thrombosis, thrombophlebitis, arterial embolism, coronary and cerebEal arterial thrombosis and myocardial infarction, stroke, cerebral embolism, kidney embolisms and pulmonary embolisms.
There is a need in the area of lO cardiovascular and cerebrovascular therapeutics for an agent which can be used in the prevention and treatment of thrombi, with minimal side effects, including unwanted prolongation of bleeding in other parts of the circulation while preventing or treating 15 target thrombi. The compounds of the present invention meet this need in the art by providing therapeutic agents for the prevention and treatment of thrombi.
The cpmpounds of the present invention show 20 efficacy as antithrombotic agents by virtue of their ability to block fibrinogen from acting at its platelet receptor site and thus prevent platelet aggregation.

~;
2~5~0t73 SUMMARY OF THE INVENTION
The present invention relates to novel compounds having the general structural formula I:

:. 2 R6 R ¦
)n ~¦,N~SO'R
~ (CH2)p /(CH2)~X~Y~Z R7 Rl R5 and the pharmaceutically aceptable salts thereof, wherein Rl is a four to eight member heterocyclic ring containing 1, 2 ,3 or 4 heteroatoms wherein said hetero atoms are N, O or S and wherein said hetero ring is optionally substituted at an~ atom by H, R6 or R7; NR6R7 R6R7N-C-; R6R7N-C-NH-; or R6-C-NR7-;

~CH~; or wherein R6 and R7 are independently 30 hydrogen and unsubstituted or substituted Co_lo alkyl and cycloalkyl wherein said substituents are Cl_l0 alkoxy, Cl_10 alkoxyalkyl, Cl_10 alkoxyalkyloxy.

2(:~5~

Cl_10 alkoxycarbonyl, Cl_10 alkylcarbonyl~
C4_10 aralkylcarbonyl, Cl_10 alkylthiocarbonyl, Cl_10 aralkylthiocarbonyl, thiocarbonyl, Cl_10 alkoxythiocarbonyl, aryl, a 5 to 6 membered saturated heterocyclic ring containing 1,2,3 or 4 hetero atoms wherein said heteroatoms are taken from the group consisting of N, 0 and S, Cl_4 alkanoylamino, Cl_6 alkoxycarbonyl-C0_6 alkylamino, Cl-10 alkylsulfonylamino, C4_10 aralkylsulfonylamino, C4_10 aralkyl, Cl_10 alkaryl, Cl_lO~alkylthio~
C4_10 aralkylthio~
Cl_10 alkylsulfinyl, C4_10 aralkylsulfinyl~
Cl_10 alkyl~ulfonyl, C4_10 aralkylsulfonyl, aminosulfonyl, Cl_10 alkylaminosulfonyl, = C4_10 araikylsulfonylamino, oxo, thio, unsubstituted and mono- and di-substituted l-ethenyl, 2-ethenyl and 3-propenyl wherein 2 ~ 7 said substituents are selected from the group consisting of hydrogen, Cl_lo alkyl and C4_10 aralkyl, carboxy, hydroxy, amino, Cl_6 alkyiamino, Cl_6 dialkylamino, halogen, where halogen i8 defined as F, Cl, Br or I, nitro, and cyano, and further wherein said N can additionally be 15 substituted to form a quaternary ammonium ion wherein said substituent i8 as previously defined for R6 and R7;

20 R2 and R3 are Independently hydrogen, aryl and unsubstituted and substituted C0_lO alkyl and cycloalkyl wherein said substituent i8 Cl_10 alkoxyalkyl, aryl a 4 to 8 membered ~aturated heterocyclic ring system containing l, 2, 3 or 4 heteroatoms, wherein said heteroatoms are taken from the group consisting of N, 0 and S, C4_10 aralkyl, Cl_10 alkaryl, Cl_10 alkylthio, -2~5~Q7;~

C4_10 aralkylthiO, Cl_10 alkylsulfinyl.
C4_10 aralkylsulfinyl, Cl_10 alkylsulfonyl, C4_10 aralkylsulfonyl, carboxy, ~;i-10 alkylcarbonyl, Cl_10 alkylthiocarbonyl, C4_10 aralkylcarbonyl, C4_10 aralkylthiocarbonyl, Cl_6 alkoxycarbonyl, C4_10 aralkoxycarbonyl, Cl_6 alkoxy, Cl_6 alkoxycarbonyl-Cl-4 aikyi, C4_10 aralkoxycarbonyl-Cl_4 alkyl, C4_10 aralkoxy~
Cl_6 alkylamino, Cl_l2 dialkylamino, Cl_6 alkanoylamino, ~4-10 aralkanoylamino~
C4_10 aralkylamino, R iS

aryl, Cl_10 alkyl or cycloalkyl, C4_10 aralkyl, Cl_lo alkoxyalkyl, Cl_10 alkaryl, Cl_10 alkylthioalkyl, Cl-10 alkoxythioalkyl, Cl_lo alkylamino, C4_10 aralkylamino, 2~5~07~

Cl_10 alkanoylamino, C4_10 aralkanoylamino Cl_lo alkanoyl~
C4_10 aralkanoyl, and unsubstituted or substituted Cl_10 carboxyalkyl wherein said substituent is aryl or Cl_lo aralkyl; furthér wherein any of the substituents for R4 may be substituted by substituents selected from the group as defined for R6;

R5 is a four to eight member saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heterocyclic atoms wherein said heteroatoms are N, O and S and o ~1 0 -C-R~, IS
-C-R8, wherein R8 is hydroxy, Cl_10 alkyloxy, Cl_10 alkaryloxy, C4_10 aralkyloxy, C4_10 aralkylcarbonyloxy, Cl_10 alkoxyalkyloxy, Cl_10 alkoxyalkylcarbonyloxy, Cl_10 alkoxycarbonylalkyl, Cl_10 alkylcarbonyloxyalkyloxy, an L- or D-amino acid joined by an amide linkage or 2(~0~

an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is esterified by C1-6 alkyl or C4_10 aralkyl, o -P-OR9, -P-oR9, ORl O, wherein R9 and R10 are selected from the group consisting of hydrogen, Cl_10 alkyl and C4_10 aralkyl;

15 X and Y are independently O, O S OH
S, SO, -C-; -C-; -CH-S02, ' --C=C--, -C_C-, a 4- to 8-membered ring containing 0,1,2,3, or 4 heteroatoms chosen from N, O and S, wherein said ring is independently substituted at any atom~0 with R6, aryl, ZC~5~

~C'NR6 ~ NR6S02-; -S02NR6-; or o ~6,~C

lO Z is an optional substituent that, when present, is independently chosen as defined for X and Y;
m is an integer of from zero to ten;
n is an integer of from zero to ten; and p is an integer of from zero to three.
A preferred group of compounds of the present invention are those defined for general structural formula II as:

R2l (CH2)p ( CH2) m~X Z 1 11 wherein Rl is a five to six member heterocyclic ring wherein said heteroatoms are N, 0 or S and wherein said heterocyclic ring is optionally substituted by 2~
43/RSP24 ~ 18197IA

Cl_5 alkyl; or NR6R7 wherein R6 and R7 are independently hydrogen, unsubstituted or substituted Cl_lo alkyl wherein said substituent is Cl_10 alkoxycarbonyl, aryl, C0_5 dialkylamino-Cl_10 alkyl, C4_10 aralkyl, 10 and further wherein said N can additionally be substituted to form a quaternary ammonium ion wherein said substituent is as previously defined for R6 and R7;

15 R2 and R3 are hydrogen and C1_4 alkyl, C4_10 aralkyl;
R4 is aryl, Cl_10 alkyl or cycloalkyl, C4_10 aralkyl, Cl-lo alkoxyalkyl, Cl_lo alkaryl, unsubstituted or substituted Cl_lo carboxyalkyl wherein said substituent is aryl, Cl_6 alkyl, or C4_10 aralkyl;

Rll iS
hydrogen or Cl_lo alkyl;
X and Y are independently aryl, 43/RSP24 - 12 - 181~ ~ ~ 0 ~~ S~2~
O O
-CE=CE-; -CNR6-; -NR6~-; S02NR6-; or -NR6S02 a 5 or 6-membered ring containing 0,1 or 2 heteroatoms chosen from N or 0;
., , Z is an optional substituent that, when present, is ~~ S~2. -NR6CO-, -CONR6-, Cl_10 straight or branched alkyl;

m is an integer of from zero to eight;
n is an integer of from zero to two; and p is an integer of from zero to two.

A more preferred group of compounds of the present invention are those defined for general structure formula III as ~,NE~02- R4 R1-(CH2)m-X-Y-Z CO2H

whereln Rl is a five or six membered heterocyclic ring wherein said heteroatoms are N and 0 and wherein said heterocyclic ring is optionally substituted by Cl_5 alkyl;

~' 2~0~3 NR6R7 wherein R6 and R7 are independently Cl_10 alkyl, or C4_10 aralkyl and further wherein said N can additionally be substituted to form a quaternary ammonium ion wherein said stubstituent is as previously defined for R6 and R7;

R4 is aryl, Cl_10 alkyl or cycloalkyl, or C4_10 aralkyl;

X and Y are independently phenyl ~ ~ SO2 O O
-CNR6-; -NR6C-or a 5- or 6- membered ring.containing O or 1 heteroatoms chosen from N or O;

Z is an optional substitutent that, when present, is 0, S02, -NR6CO-, -CONR6-, or -CH2-; and 25 m is an integer of from zero to six.

DETAILED DESCRIPTION 0~ THE I~v~NllON
The term "pharmaceutically acceptable salts"
shall mean non-toxic salts of the compounds of this 30 invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following 2C~S~Q~7~

salts:

Acetate Benzenesulfonate Benzoate Bicarbonate Bisulfate Bitartrate Borate Bromide Calcium Edetate Camsylate Carbonate Chloride Clavulanate Citrate Dihydrochloride Edetate Edisylate Estolate Esylate Fumarate Gluceptate Gluconate Glutamate Glycollylarsanilate Hexylresorcinate Hydrabamine Hydrobromide Hydrochloride Hydroxynaphthoate Iodide . ~ 2~5~0~3 Isothionate Lactate Lactobionate Laurate Malate Maleate Mandelate Mesylate Methylbromide Methylnitrate Methylsulfate Mucate Napsylate Nitrate Oleate Oxalate Pamaote Palmitate Pantothenate Phosphate/diphosphate Polygalacturonate Salicylate Stearate Subacetate Succinate Tannate Tartrate Teoclate Tosylate Triethiodide Valerate 2~ 73 The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical reponse of a tissue, system or animal that is being sought by a researcher or clinician. The term "anti-coagulant agent" shall include aspirin, heparin and warfarin. The term "fibrinolytic agent"
shall include streptokinase and tissue plasminogen activator.
The term "aryl" shall mean a mono- or polycylic ring system composed of 5- and 6- membered aromatic rings containing 0, 1, 2, 3, or 4 heteroatoms chosen from N, 0, and S and either unsubstitutued or substituted with R6.
The term "alkyl" shall mean straight or branched chain alkane, alkene or alkyne.
The term "alkoxy" shall be taken to include an alkyl portion where alkyl is as defined above.
The terms "aralkyl" and "alkaryl" shall be 20 taken to include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
The term "halogen" shall include fluorine, chlorine, iodine and bromine.
The term "oxo" shall mean the radical =0.
The term "thio" shall mean the radical =S.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the 30 platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid 2~5~C~7;~

endarterectomy) and in cardivascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. They may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used lO for cardivascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of 15 the circuit. (Gluszko et. al., Amer. J. Physiol., 1987, 252:H, pp 615-621). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
Other~application of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of 25 coronary and other arteries and after coronary artery bypass procedures. They may also be used to prevent mycocardial infarction.
The compounds of the present invention can be administered in such oral dosage forms as tablets, 30 capsules, pills, powders~ granules, elixers, tinctures, suspensions, syrups and emulsions.
Likewise, they may also be administered in ~' ZC~5~0~3 intravenous, intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
The dosage regimen utilizing the compounds of the present~lnvéntion is ~elected in accordance with a variety of factors including type, ~pecies, age, weight, sex and medical condition of the 10 patient; the severity of the condition to be treated;
the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and 15 prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between 20 about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day and most preferably 1.0 to 50 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute 25 during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, 30 preferred compounds for the present invention can be ' 2~5~0~
43/~SP24 - 19 - 18197IA

administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the 10 compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with 15 respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the 20 form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesuim stearate, dicalcium phosphate, calcium 25 sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, 30 when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable ~ 2~S~0~3 binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms includ~e sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl 10 cellulose, agar, bentonite, xanthan gum and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
15 Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as 20 individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, 25 polyhydroxypropylmethacrylamide-phen polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of 30 biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and ' ~ . 21~S~73 polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The compounds of the present invention can also be co-administered with suitable anti-coagulant agents or thrombolytic agents to achieve synergistic effects in the treatment of various vascular 10 pathologies.
The compounds of formula I can be prepared readily according to the following reaction Schemes and Examples or modifications thereof using readily available starting materials, reagents and 15 conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any 25 combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations 30 of the conditions and processes of the following preparative precedures can be used to prepare these compounds. All temperatures are degrees Celsius - =

2~S~0~73 unless noted otherwise.
Reagent symbols have the following meanings:
BOC: t-butyloxycarbonyl Pd-C: Palladium on activated carbon catalyst DMF: Dimethylformamide DMSO: Dimethylsulfoxide CBZ: Carbobenzyloxy CH2C12: Methylene chloride CHC13: Chloroform EtOH: Ethanol MeOH: Methanol EtOAc: Ethyl acetate HOAc: Acetic acid THF: Tetrahydrofuran The source for the following compounds is as shown:

1. BocN

25 is described below.

~ H ~ H
HN Boc-N

2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol 2(~5~0~73 4-Piperidine-2-ethanol (Available from Aldrich) (130 g, 1.0 mole) was dissolved in 700 mL
dioxane, cooled to 0~ C and treated with 3 N NaOH
(336 mL, 1.0 mole), and di-t-butylcarbonate (221.8 g, 1.~ mole). The ice bath wa~ removed and the reaction stirred overnight. The reaction was concentrated, diluted with water and extracted with ether. The ether layers were combined, washed with brine, dried over MgS04, filtered and evaporated to give 225.8 g lO ~f product (98%).

Rf = 0.37 in 1:1 EtOAc/Hexanes, ninhydrin stain lH NMR (300MHz, CDC13) ~ 4.07 (bs, 2H), 3.7 (bs, 2H), 15 2.7 (t, J = 12.5 Hz, 2H), 1.8-1.6 (m, 6H), 1.51 (s, 9H), 1.1 (ddd, J = 4.3, 12.5, 12 Hz, 2H).

1.DMSO, Oxalyl Chloride 2.Carbonethoxy-triphenylphos-Boc-N ~ H phorane Boc-N ~ CO2CH3 Methyl 4-(4-N-t-butyloxycarbonylpiperidinyl)-but-2-enoate Oxalyl chloride (55.8 mL, 0.64 mole) was dissolved in 1 L CH2C12 and cooled tG -780 C under ~ 205;~073 N2. DMSO (54.2 mL, 0.76 mole) was added dropwise.
After gas evolution had ceased, 2-(4-N-t-butyloxy-carbonylpiperidinyl)ethanol (102.5 g, 0.45 mole) dissolved in 200 mL CE2C12 was added over 20 minutes. After stirring an additional 20 minutes, triethylamine (213 mL, 1.53 mole) was added dropwise and the cold bath removed. After 1 and 1/2 hours TLC
showed starting material gone. Carbomethoxytri-phenylphosphorane (179 g, 0.536 mole) was added and 10 the reaction stirred overnight. The solution was diluted with 300 mL Et2O, extracted once with 800 mL
H20, twice with 300 mL 10% KHSO4 solution, then once with 300 mL brine. The organic layer was dried over MgSO4, filtered and evaporated. Column 15 chromatography (SiO2, 5% EtOAc/Hexanes) yielded 78.4 g (62%) of pure methyl 4-(4-N-t-butyloxy-carbonylpiperidinyl) but-2-enoate.
lH NMR (300MHz, CDC13) ~ 6.9 (ddd J = 15.6, 7,6, 7.6 Hz, lH), 5.8 (d, J = 15.6 Hz, lH), 4.0 (bs, 2H), 3.7 20 (s, 3H), 2.6 (t, J = 12.6 Hz, 2H), 2.1 (t, J = 7.4 Hz, 2H), 1.7-1.4 ~m, 3H), 1.4 ~s, 9H), 1.1 (m, 2H).

1. Hz~ on C
2. NaOH

N~CO2CH3 4 (C~ P. C~r~ N~r ~ E~oc-- E~oc-~ o 5 ~ ~ 7 3 4-(4-N-t-Butyloxycarbonylpiperidinyl)butyl bromide Methyl 4-(4-N-t-butylo~ycarbonylpiperidin-yl)but-2-enoate (36.2 g, 0.128 mole), wa~ dissolved in 500 mL EtOAc. 10Z Palladium on carbon (10 g) was 5 added as a slurry in EtOAc and the reaction was placed under H2 (in a balloon) overnight The reaction was filtered through Sol~a-Floc, the cake washed with EtOAc and the ethyl acetate evaporated to give 34.7 g (90%) of methyl 4-(4-N-t-butyloxycarbonyl-lO piperidin-4-yl)butanoate. TLC Rf = 0.69 in 30Z
EtOAc/Hexanes.

lH NMR (300MlIz, CDC13) ~ 4.0 (bs, 2H), 3.6 (8, 3H), 2.60 (t, J = 12.3 Hz, 2H), 2.20 (t, J = 7.4, 2H), 1.6 15 (m, 4H), 1.40 (8, 9H), 1.40 (m, lH), 1.20 (m, 2H), l.O (m, 2H).

The butanoate ester (45.3 g, 0.159 mole) was dissolved in CH30H and treated with 1 N NaOll (500 20 mL, O.5 mole) overnight. The ~olvent was removed in vacuo, water was added and the solution washed with ether, then acidified with 10% KHSO4 solution. l'he aqueous layer was washed with ether, the ether layers were combined, washed with brine, dried (MgSO4), and 2s concentrated to give the corresponding acid a~ a clear oil (41.85 g, 97Z yield).

lH NMR (300MHz, CDC13) ~ 4.0 (bs, 2H), 2.6 (m, 2H), 2.25 (m, 2H), 1.6 (bs, 4H, 1.4 (8, 9E), 1.3-0.9 (9H).
This acid (20.4 g, 0.077 mole) was treated with borane (BH3/THF, 235 mL, 235 mmole) in THF at 0~
* Trademark B

~' 2~5~0~7;3 43/RSP2~ - 26 - 18197IA

for 1 hour. NaOH (lN, 250 mL) was added dropwise and the solution stirred overnight. The resulting reaction mixture was concentrated to remove THF and extracted with ether. The ether extracts were combined, dried over MgS04, filtered and evaporated to give the corresponding alcohol as 19.7 g of a colorless oil.

Rf = 0.7 in 2:1 ethyl acetate/hexanes.

lH NMR (300MHz, CDC13) ~ 4.1 (bs, 2H), 3.6 (t, 2H), 2.65 (t, 2H), 2.1 (bs, lH), 1.65 (bs, 2H), 1.55 (m, 2H), 1.4 (s, 9H), 1.35 (m, 3H), 1.25 (m, 2H), 1.1 (m, 2H).
This alcohol (19.7 g, 76.5 mmole) was dissolved in THF and treated with triphenylphosphine (23.1 g, 88 mmole) and cooled to 0~ C. Carbon tetrabromide (29.8 g, 89.9 mmol) was added in one 20 portion, the cold bath was removed and the reaction stirred overnight. Additional triphenyl phosphine (11.71 g) and carbon tetrabromide (14.9 g) was added to drive the reaction to completion. The mixture was filtered and the liquid was diluted with ether and 25 filtered again. After solvent removal the resulting liquid was adsorbed onto SiO2 and chromatographed with 5~/0 ~tOAc/~e~nes to yield 4-(4-N-t-butyloxy-carbonylpiperidin-4-yl)butyl bromide as a clear colorless oil (20.7 g, 85% yield).
Rf = 0.6.in 1:4 ethyl acetate/hexanes ~ 2C~5;~07;~

lH NMR (300MHz, CDC13) ~ 4.1 ~bs, 2H), 3.4 (t, 2H), 2.65 (t, 2H), 1.85 (m, 2H), 1.65 (bd, 2H), 1.4 (s, 9H), 1.35 (m, 2H), 1.3 (m, 3H), 1.1 (m, 2H).

2.BocNH(CH2)6Br Commercial H2N(CH2)5CH20H was protected as the N-Boc derivative in standard fashion and this was converted to the bromide with Ph3P/CBr4 in THF. Utilization of starting amino alcohols of varying chain lengths provides the analogous halides in this manner.

3. ~ ~ O~H Purchased from Signa.
HO

4. ~oc ~ OH HN ~ H (Aldrich) w~s N-~oc protected in the stand~rd nanner.

5. CEZN ~ C02CH3 HN ~ w~s N-Cbz protected in the standard fashion and ~ converted to final product a~
described in US Serial No. 589,145.

~' Z05~073 S CHEME

~NH~b~
COOH N~H, DME
130C- ~ Br H ,,U~
~ CH2) ~ ~I~OH --13 BOC- N

1 5 J~DSMFCO3 2 0 ~ CH2); ,1~ CH3 --13 ¦HZ Pd/C
Et OH

~(CHz)~ ~I~H3 ~30C-N 1-4 O

Cl-S-R NaHCO3 1 - ~Bt OAc ~ ~ Z~S~0~73 N~( CHZ) 4 ~ ~COOCH3 BOC- LiOH
;1 - 5THE' CH3oHl H20 ~N~ ~2 R
~C CH2) 4 ~ ~ COOH
BOC- HCl 1 - 6 _ EtOAc H
~N~ ~2 R
~( CH2~ 4 ~,~ COOH
HCl ~ Z~S~073 CBZ
~ CH2)4_o ~ CO2H

2-S-(Benzyloxycarbonylamino)-3-[4-(N-t-butyloxy-carbonylpiperidin-4-yl)butyloxyphenyl]propionic acid ~1-2) 15 N-CBZ-L-tyrosine (1-1) (17.58 g, 0.055 mmole) was dissolved in DMF (75 mL), cooled to 0-10~
C and treated with sodium hydride (2.88 g, 0.12 mole). This suspen~ion was stirred at 0-10~ C for 1 hour and then ~-t-butyloxycarbonylpiperidin-4-20 ylbutyl bromide (17.70 g, 0.055 mole) in 25 mL DMFwas added dropwise over 15 minutes. The reaction mixture was then stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up in a mixture of 500 mL EtOAc/100 25 mL 10% KHSO4. The organic phase was washed with brine, dried (Na2SO4) and the solvent was removed to give a viscous oil. This was purified by flash chromatography on silica gel eluting with 98:2:0.5 CHC13/CH30H/HOAc to give pure 1-2 (23.75 g), Rf =
30 0.35, as a pale yellow oil.
H NMR (300MHz, CDC13) ~ 1.00-1.15 (2H, m), 1.20-1.80 (16H, m), 2.62 (2H, t), 3.10 (2H, m), 3.91 (2H, t), 4.04 (2H, m), 5.10 (2H, m), 5.22 (lH, d), 6.78 ( 2, d), 7.04 (2H, d), 7.35 (5H, m).

21~5;~0~

~ CBZ
~ ~ CH2)4_o ~ CO2CH3 Methyl 2-S-(Benzyloxycarbonylamino)-3-[4-(N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]-15 propiQnic acid (1-3~
1-2 (10.05 g, 18.1 mmole) was dissolved in CH30H (150 mL) at room temperature and cesium carbonate (2.95 g, 9.06 mmole) was added and the resulting mixture stirred for 15 minutes to give a 20 clear solution The CH30E was removed at reduced pressure and the residue was then dissolved in DMF
(150 mL) and treated dropwise with methyl iodide (2.57), 18.1 mmole). The resulting solution was stirred overnight at room temperature. The solvent 2s was removed in vacuo and the residue was taken up in 400 mL ether and washed with 3 x 50 mL portions of H20, 50 mL brine and dried (Na2S04). Solvent removal provided 1-3 as an oil.
lH NMR (300 MHz, CDC13) ~ 1.0-1.15 (2H, m), 1.30-1.70 30 (16H, m), 2.68 (2E, dt), 3.05 (2H, m), 3.72 (3H, s), 3.91 (2H, t), 4.08 (2H, d), 4.61 (lH, m), 5.10 (2H, m), 5.18 (lH, m), 6.79 (2H, d), 6.98 (2H, d), 7.35 (5H, m).

2(~S~Q73 ~NH2 ~ CH2) 4 _o CO2CH3 Methyl 2-S-Amino-3-[4-(N-t-butyloxycarbonylpiperidin-4-yl)-butyloxyphenyllpropionate (1-4~
To 1-3 (5.0 g, 8.79 mmole) dissolved in absolute ethanol (150 mL) wa~ added 10% Pd/C (0.5 g) and the resulting suspension was hydrogenated under balloon pressure for 12 hours. The catalyst was then filtered off and the solvent was removed in vacuo to 20 give 1-4 (3.6 g) as an oil.

lH NMR (300 MHz, CDC13) ~ 1.00-1.20 (2E, m), 1.22-1.55 (12H, m), 1.60-1.75 (4H, m), 2.00 (2H, bs), = 2.68 (2H, t), 2.87 (lH, dd), 3.05 (lH, dd), 3.72 (3H, 25 s), 3.93 (2H, t), 4.09 (2H, m), 6.82 (2H, d), 7.10 (2H, d).

ZOS~Q73 N ~ CHz)4_o ~ COzCH3 ~NHSO2C4~
~( CH2) 4 o/~ CO2CH3 Methyl 2-S-(n-Butylsulfonylamino)-3-[4-(N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]-propionate (1-8) 1-4 (4.59 g, 1.36 mmole) was dissolved in ethyl acetate (10 mL) and NaHCO3 (0.7 g, 8.68 mmole) was added with stirring at room temperature followed by butanesulfonyl chloride (0.36 mL, 2.76 mmole) and the resulting mixture was refluxed for 26 hours. The 25 cooled reaction mixture was filtered and concentrated and the residue was purified by flash chromatography on silica gel eluting with 4:1 hexane/EtOAc to give pure 1-8 (0.305 g) Rf = 0.7 in 1:1 hexane/EtOAc, ninhydrin stain.

lH NMR (300 MHz, CDC13) ~ 0.82 (3H, t), 1.05 (2H, ddd), 1.45 (9E, s), 1.1-1.6 (lE, m), 1.7 ( 4H, m), 2.6 (2H, t), 2.6-2.8 (2H, m), 2.78 (lH, dd), 3.05 (lH, dd), 3.7 (3H, s), 3.93 (2H, t), 4.05 (2H, bd), 4.15 (lH, dd), 6.85 (2H, d), 7.15 (2H,d).

~ 205~

~,,N~02C4 N ~ CH2)4--o "i~" CO2CH3 BOC- , 1-8 ~N~02C4E~
~( CH2 ) 4 _o~J C~2 H

2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl~butyl-oxyphenyllpropionic acid hydrochloride (1-9) 1-8 (0.325 g, 0.59 mmole) was dissolved in 1:1:1 CH30H/~20/THF and LiOH-H20 (0.157g, 3.76 mmole) wa~ added. The resulting solution was stirred at room temperature for 3 hours, then concentrated, diluted with lp% KHSO4 and extracted with EtOAc.
20 This provided 2-S-(n-butylsulfonylamino)-3~4-(N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]-propionic acid. This acid (0.315 g, 0.59 mmole) was dissolved in EtOAc (20 mL) and treated with HCl gas at -20~ C for 15 minutes. The reaction mixture was 25 then stoppered and was stirred at -5~ C for 1 hour at which time all starting material was consumed. Argon gas was bubbled through the reaction mixture for 1~
minutes and the solvent was removed to give a residue that was triturated with ether to provide pure 1-9 (0.29 g) as a pale yellow solid.

" 205;~0~3 lH NMR (300 MHz, CD30D) ~ 0.85 (3H,t), 1.2 (2H,dd), 1.2-1.7 (9H,m), 1.7 (2H, m), 1.95 (2H, bs), 2.65 (2~, t), 2.8 (lH, dd), 2.95 (2H, bt), 3.10 (lH, dd), 3.83 (2H, bs), 3.95 (2H, t), 4.1 (lH, dd), 6.85 (2H, d), 7.2 (2E, d).

Analysis for C22H36N20slS-HC1~0.8 H20 Calculated: C = 53.76, H = 7.92, N = 5.70 lO Found: C = 53.76, H = 7.66, N = 5.44.

~ NH2 N ~ CHz)4_o ~ C02CH3 ,~,N~ ~2 CH2 C6 H5 N ~ CH2)4 o ~ C02CH3 25 Methyl 2-S-(Benzylsulfonylamino)-3-[4-(N-t-butyloxy-carbonylpiperidin-4-yl~butyloxyphenyl]propionate ~1-10~
1-4 (0.59g, 1.36 mmole) was treated with benzylsulfonyl chloride (0.263 g, 1.38 mmole) as 30 described abo~e for 1-8. The crude reaction product was purified by flash chromatography on silica gel eluting with 3:1 hexane/EtOAc to give pure 1-10 (0.35 g) as an oil.

205~073 lH NMR (300 MHz, CD30D) ~ O.85-1.10 (2H, m), 1.10-1.23 (2H,m), 1.35-1.52 (llH, m), 1.61-1.80 (4H, m), 2.65-3.00 (4H, m), 3.65 (3H, 8), 3.90-4.14 (5H, m), 6.85 (2H, d), 7.08 (2H, d), 7.22 (2H, m), 7.30 (3H, m).

1 0 NH~O2CH2C6H~i 2)4_o CO2cH3 -N~_~ 1-1o I

~ NH~
~( CH2) 4 _o/~ CO~H

2-S-(Benzylsulfonylamino)-3-[4-(piperidin-4-yl)butyl-20 oxyphenyllpropiQnic acid hydrochloride (1-11) Treatment of 1-10 (0.354 g, 0.60 mmole) with LiOH (0.15 g, 3.7 mmole) as described for 1-8 gave 2-S-(benzylsulfonylamino)-3-[4-(N-t-butyloxy-carbonylpiperidin-4-yl)butylo~yphenyl]propionic acid 25 (0.35 g) as a vi~cous oil.

lH NMR (300MHz CD30D) ~ 0.84-1.06 (3H, m), 1.23 (4H, m), 1.34-1.50 (llH, m), 1.60-1.78 (5H, m), 2.65 (2H, bt), 2.82 (lH, m), 3.02 (lH, m), 3.91 (2H, m), 30 3.96-4.12 (5H, m), 6.83 (2H, d), 7.15 (2H, d~, 7.22 (2H, m), 7.29 (3H, m).

" Z05~07~

This acid (0.35 g, 0.60 mmole) was dissolved in 20 mL EtOAc and treated with HCl gas as described for 1-9 to give pure 1-11 as a white solid (0.30 g).

lH NMR (300MHz, CD30D) S 1.32 (4H, m), 1.40-1.65 (3H, m), 1.72 (2H, m), 1.92 (2H, d), 2.77-3.08 (4H, m), 3.33 (3H, m), 3.95-4.14 (5H, m), 6.86 (2H, d), 7.17 (2H, d), 7.28 (2H, m), 7.31 (3E, m).

~ rT~-r~r 8cc N3(CH~)~o C4CH, ~oc N3CC*)~o CO,CH, t--4 1 -1 2 ~) ~OH
2) HCl ~o~r~C~r HN~ CH3) ~O CO,H

25 Methyl 2-S-(2-Styrylsulfonylamino)-3-[4-(N-t-butyl-oxycarbonylpiperidin-4-yl)butyloxyphenyl]propionate (1-12~
1-4 (0.647 g, 15 mmoles) was dissolved in ethyl acetate (20 ml), and NaHC03 (0.454 g, 5.4 30 mmoles) was added followed by ~-styrenesulfonyl chloride (0.365 g, 18.0 mmoles) and the resulting reaction mixture was heated at reflux with stirring ~' 2(~5~0~3 for 16 hours. The cooled reaction mixture was filtered, the solvent removed and the residue was purified by flash chromatography on silica gel eluting with hexane (3)/ethyl acetate (1) to give pure 1-12.

H NMR (300 MHz, C~C13) ~ 1.10 (2H, m), 1.30-1.55 (14 E, m), 1.65-1.80 (4H, m), 2.68 (2H, t), 3.01 (2H, dt), 3.62 (3H, s), 3.88 (2E, t), 4.09 (2H, m), 4.22 (lH, m), 4.98 (lH, d), 6.45 (lH, d), 6.80 (2H, lO d), 7.06 (2H, d), 7.40 (4H, s).

2-S-(2-Styrylsulfonylamino)-3-4-[4-piperidinylbutyl-oxyphenyl~ propionic acid hydrochloride (1-13~
1-12 (0.58 g, 0.97 mmole) was dissolved in 15 THF(l)-H20(1)-MeOH(1) (15 ml) and lithium hydroxide (0.12 g, 5.0 mmole) was added and the resulting clear solution was stirred overnight at room temperature.
The reaction mixture was diluted with 75 ml H20, acidfied to pH 2-3 with 10% KHS04 solution and 20 then extracted with 3 x 50 ml EtOAc. The organic extract was dried, the solvent removed, and the residue purified by flash chromatography on silica gel eluting with CHC13(97)-MeOH(3)-HOAc(l) to give the desired acid (Rf=0.2).
This acid was dissolved in EtOAc and treated with HCl gas as described for 1-9 to give 1-13.
1H NMR (300 MHZ, CD30D) ~ 1.15-1.70 (lOH, m), 1.70-1.82 (2H, t), 1.97 (2H, t), 2.78-3.12 (5H, m), 3.35 (3H, m), 3.87 (2H, t), 4.03 (lH, m), 6.50 (lH, 30 d), 6.69 (2H, m), 7.18 (3H, m), 7.41 (5H, bs).

~ Z ~ S~ 07 ~,C,s~s ~150l ~,Co~
CO~N ~ ~5C}~ O~ CO~
~D~
1-12n 1-14 ~5 C~) ,0 2-S-(2-Phenethyl~ulfonylamino)-3-[4-(N-t-butyloxycar-20 bonylpiperidin-4-yl)butyloxyphenyl]propionic acid (1-14~
1-12a (0.21 g) was dissolved in 20 ml absolute ethanol, 0.1 g 10% Pd/C was added and the stirred suspension was hydrogenated under balloon 25 pressure. After 4 hours the reaction was stopped and the solvent was removed to give the desired product 1-14 (0.194 g).
H NMR (300 MHz, CD30D) ~ 1.05 (2H, m), 1.30-1.40 (3E, m), 1.47 (14H, m), 1.72 (5H, m), 2.67-2.93 (8H, 30 m), 3.13 (lH, m), 3.31 (2H, m), 3.82 (2H, m), 4.00-4.20 (4H, m), 6.82 (2H, d), 7.07 (2H, d), 7.21 (5H, m).

' ~ Z~5~07~

2-S-(2-Phenethylsulfonylamino)-3-4-[4-piperidinyl-butyloxyphenyllpropionic acid hydrochloride (1-15) 1-14 (0.194 g) was dissolved in EtOAc and treated with HCl gas as described for 1-9 to provide pure 1-15 (0.145 g).
H NMR (300 MHz, CD30D) ~ 1.25-1.68 (8H, m), 1.73 (2H, m), 1.93 (2H, m), 2.78 (3H, m), 2.91 (4H, m), 3.13 (lH, m), 3.33 (4H, m), 3.86 (2H, m), 4.18 (lH, m), 6.80 (2H, d), 7.09 (2H, d), 7.22 (5H, m).

~( CH~ O~C4B, ~5 CE~ ~~CO,CI~, ~oc N

~O~C~,H, ~,5CE~)~o~ crJ2H

HCl ~ HN~J

205~07;~

Methyl 2-S-(Phenylsulfonylamino)-3-[4-(N-t-butyloxy-carbonylpiperidin-4-yl)butyloxyphenyl]propionate ~1-16~.
1-4 (0.647 g, 1.5 mmoles) was treated with phenylsulfonyl chloride (0.318 g, 1.8 mmoles ) as described for 1-8. The crude product was purified by flash chromatography on silica gel eluting with CHC13(98)-MeOH(2) to give pure 1-16 (0.67 g).
lH NMR (300 MHz, CDC13) ~ 1.09 (2H, m), 1.25-1.40 (3H, m), 1.42 (9H, bs), 1.60-1.85 (6H, m), 2.66 (2H, m), 2.96 (2H, d), 3.55 (3H, s), 3.89 (2H, t), 4.09 (4H, m), 5.12 (lH, d), 6.72 (2H, d), 6.95 (2H, d), 7.40-7.65 (3H, m), 7.75 (2H, m).

15 2-s-(phenylsulfonylamino)-3-(4-piperidin-4-ylbut phenyl)propionic acid hydrochloride (1-17).
1-16 (0.525 g) was treated with lithium hydroxide as described for 1-8 to give crude product that was purif~ied by flash chromatography on silica 20 gel eluting with CHC13(97)-MeOH(3)-HOAc(l) to provide pure acid (Rf = 0.2).
This acid was treated with HCl gas in EtOAc as described for 1-9 to provide pure 1-17.

25 lH NMR (300 MHz, CD30D) ~ 1.28-1.47 (6H, m), 1.50-1.70 (3H, m), 1.75 (2H, m), 1.97 (2H, d), 2.77 (lH, m), 2.95 (3H, m), 3.35 (4H, m), 3.93 (3H, m), 6.72 (2H, d), 7.02 (2H, d), 7.41 (2H, m), 7.52 (lH, m), 7.67 (2H, m).

2~S~Q7;3 ~' ~~'~
~(CH,)~O~ CO,CH, 130~: N~{CH2) ,0~ CO2CE~, HN~CC~ ,o ~ ~

Methyl 2-S-(2-Thienylsulfonylamino)-3-[4-(N-t-butyl-oxycarbonylpiperidin-4-yl)butyloxyphenyl]propionate 15 (1-18~.
1-4 (0.304 g, 0.7 mmoles) was treated with 2-thienylsulfonyl chloride (0.155 g, 0.85 mmoles) as described for 1-8 to provide crude product. This was purified by flash chromatography on silica gel 20 eluting with CHC13(98)-CH30H(2) to afford pure 1-18 as a viscous oil, Rf 0.3 [silica gel, CHC13(98)-CH30H(2)]
lH NMR (300 MHz, CDC13) ~ 1.10 (2H, m), 1.31 (4H, m), 1.36-1.80 (16 H, m), 2.68 (2H, bt), 3.03 (2H, d), 25 3.57 (3H, s), 3.91 (2H, t), 4.08 (2H, m), 4.29 (lH, m), 5.16 (lH, d), 6.78 (2H, d), 7.00 (4H, m), 7.55 (2H, dd).

.
' 205~07~3 2-S-(2-Thienylsulfonylamino)-3-[4-(piperidin-4-yl)-butyloxyphenyllpropionic acid hydrochloride (1-19~.
Treatment of 1-18 (0.22 g, 0.38 mmoles) with LiOH (0.045 g, 1.89 mmoles) as described for 1-8 provided the desir~d acid, which was purified by flash chromatography on silica gel eluting with CHC13(97)-CH30H(3)-HOAc(l).

10 lH NMR (300 MHz, CD30D) ~ 1.05 (2H, d t), 1.20-1.40 (5H, m), 1.40-1.60 (12H, m) 1.65-1.80 (5H, m), 2.65-2.82 (4H, m), 2.98 (lH, dd), 3.30 (lH, m), 3.92 (2H, t), 4.00-4.13 (5H, m), 6.75 (2H, d), 7.02 (3H, m), 7.39 (lH, d), 7.67 (lH, d).
Treatment of this acid with HCl gas as described for 1-9 provided 1-19 as a white solid after trituration.

20 AnalySiS Calcd- for C22H30N205S2 HCl 0-5 2 C, 51.60, H, 6.30, N, 5.47.
Found: C, 51.57, H, 6.20, N, 5.51.

lH NMR (300 MHz, CD30D) ~ 1.29-1.45 (4H, m), 25 1.47-1.70 (3H, m), 1.71-1.83 (2H, m), 1.91-2.00 (2H, bd), 2.79 (lH, m), 2.90-3.04 (3H, m), 3.95 (2H, t), 4.04 (lH, m), 6.76 (2H, d), 7.05 (3H, m), 7.40 (lH, m), 7.79 (lH, m).

~ ~ Z~5~(~7~

130c N3~ CH2) ~O/~C02CH3 ~N~2 ElocN~CH2)~0~CO2CH3 1 0 ~N~S2 ~3~ CH2) 40J~CO2H

2-S-(Dansylamino)-3-[4-(N-t-butyloxycarbonyl-15 piperidin-4-yl)butyloxyphenyllprQpionate (1-20).
1-4 (0.304 g, 0.7 mmoles) was treated with dansyl chloride (0.208 g, 0.77 mmoles) as described for 1-8 to provide crude product which was purified by flash chromatography on silica gel eluting with 20 hexane(75)-EtOAc(25) to give pure 1-20. Rf 0.25 (silica gel eluting with hexane(75)-EtOAc(25).

H NMR (300 MHz, CDC13) ~ 1.10 (2H, m), 1.21-1.38 (6H, m), 1.40-1.53 (llH, m), 1.60-1.80 (6E, m), 2.68 2S (2H, bt), 2.89 (6H, s), 3.33 (2H, s), 3.89 (2H, t), 4.05-4.19 (4H, m), 5.24 (lH, m), 6.62 (2H, d), 6.82 (2H, d), 7.18 (lH, d), 7.50 (2H, m), 8.19 (2H, t), 8.51 (lH, d).

2~5~Q~7~

2-S-(Dansylamino)-3-[4-(piperidin-4-yl)butyloxy-phenyllpropionic acid hydrochloride (1-21~.
Treatment of 1-20 (0.275 g, 0.412 mmoles) with LiOH as described for 1-8 gave the desired acid as a highly fluorescent viscous residue.

H NMR (300 MHz, C~30D) ~ 1.09 (2H, m), 1.22-1.40 (3H, m), 1.40-1.57 ~12H, m), 1.65-1.80 (3H, m), 2.60-2.80 (3H, m), 2.90 (6H, s), 3.31 (3H, m), 3.80 lO (2H, t), 3.90 (lH, m), 4.01-4.15 (4H, m), 6.47 (2H, d), 7.21 (lH, d), 7.42 (2H, m), 7.98 (lE, d), 8.20 (lH, d), 8.46 (lH, d).

Treatment of this acid in EtOAc with HCl gas 15 as described for 1-9 provided 1-21 as a white solid upon ethylacetate trituration.

Analysis for C30H3gN30sS-1.8 HCl-H20:
C, 56.53; H, 6.77; N, 6.59; Cl, 10.01.
Found: C,~56.48; H, 6.66; N, 6.36; Cl, 10.21.

lH NMR (300 MHz, CD30D) ~ 1.30-1.51 (7H, m), 1.52-1.80 (4H, m), 1.95 (2H, bt), 2.65 (lH, m), 2.95 (3H, m), 3.30-3.40 (4H, m), 3.45 (6H, s), 25 3-84-3-97 (3H, m), 6.45 (2H, d), 6.77 (2H, d), 7.71 (2H, m), 8.00 (lH, d), 8.16 (2H, d), 8.55 (lH, d), 8.70 (lH, d).

~ ~ Z~S~Q73 ~_~~ C~H ~ C~
~, ~U, ~,~~ ~c~~

~0 ~0 ~ ~ "
m u ~ ~ ~

~ c~ ~O

~~ <~0 ~ o Q n ~' ~ 2~5~0~3 . ~ ~ CBZ

/~ C02H
Boc-NH~ CH2)6O

2-S-(Benzylo~ycarbonylamino)-3-[4-(6-N-t-butyloxy-carbonylaminohexyloxy)phenyllpropionic acid (2-1) 15 N-CBZ-L-tyrosine (15.0 g, 0.045 mole) was dissolved in 75 mL DMF and added at 0-10~ C to a suspension of sodium hydride (2.16 g, 0.09 mole) in 25 mL DMF. The resulting suspension was stirred at 0-10~ C for 1.0 hour and then 6-(t-butyloxycarbonyl-20 amino)hexyl bromide (12.6 g, 0.045 mole) in 25 mL D~F
was added dropwise at 0-5~ C and the clear, dark reaction mi~ture was stirred at room temperature overnight.
After solvent removal, the residue was taken 25 up in EtOAc and this was made acidic with 10% KHS04 solution. The organic phase was separated, washed with brine, dried (Na2S04) and the solvent removed to give an oil. This was purified by column chromatography on silica gel eluting with 98:2:1 30 CHC13/CH30H/HOAc to give pure 2-1 as a clear oil.

lH NMR (300 MHz, CD30D) ~ 1.45 (15E, m), 1.75(2H, m), 2.80-3.15 (6H, m), 3.91(2H, t), 4.38(1H, m), 4.95(6H, m), 6.85(2H,d), 7.06(2H,d) '- ~ 205;~0~7;3 ~z C02H ~ CO2CH3 ~oc - HN( CH2) oO E30C ~ HN~ CH2) ~,0 Methyl 2-S-(Benzyloxycarbonylamino)-3-~4-(6-N-t-butyloxycarbonylaminohexyloxy)phenyllpropionate (2-2) 15 Compound 2-1 (10.0 g, 19.43 mmole) in 75 mL
DMF was treated with cesium carbonate (3.16 g, 9.72 mmole) with stirring at room temperature for 1.9 hours. Then, methyl iodide (2.76 g, 19.43 mmole) was added dropwise and the reaction mixture was stirred 20 overnight at ambient temperature. The solvent was removed at high vacuum (30O C) and the residue was taken up in 300 mL EtOAc and washed with 2 x 40 mL
protions of saturated NaHCO3 solution, brine and dried (Na2SO4). Solvent removal provided 2-2 (8.5 g, 25 83%) as a clear oil.

H NMR (300MHz, CDC13) ~ 1.25-1.53 (16H, m), 1.76 (2H, m), 2.96-3.17 (4H, m), 3.71 (3E, s), 3.90 (2H, t), 4.61 (lH, m), 5.10 (2H, m), 5.19 (lH, m), 6.88 30 (2H, d), 6.98 (2E, d), 7.32 (5E, m).

' 205~07;~

~:13Z ~NH2 C02C~ CO2CEI3 80c-HN(CH2)~sO 13oc-HN(c~ o Methyl 2-S-Amino-3-[4-(6-N-t-butyloxyearbonyl-aminohexyloxy)phenyllpropionate (2-3) Compound 2-2 (8.0 g, 15.1 mmole) was dissolved in 150 mL absolute ethanol and 1.0 g 10%
Pd/ C was added. This suspension was hydrogenated in a Parr apparatus (50 psi) for 3.5 hours. The catalyst was then filtered off and the solvent 20 removed on the rotary evaporator to give pure 2-3 (5.56 g) as a clear oil. Rf = 0.4 on SiO2 with 95:5 lH NMR (300 MHz, CDC13) ~ 1.30-1.55 (16H, m), 1.70 25 (2H, m), 2.80 (lH, m), 3.00-3.17 (3H, m), 3.71 (3H, s), 3.93 (2H, t), 6.82 (2H, d), 7.09 (2H,d).

Z05;~(~73 ~HCH3 ~l~502CH~, E~OC - HN( CH2) ~s~ Boc - }~ CH2) ~0 CO2CH~, 2-S-(Methylsulfonylamino)-3-[4-(6-N-t-butyloxy-15 carbonylaminohexyloxy~phenyllpropionate (2-4) 2-3 (0.40 g, 1.01 mmole) wa~ treated with methanesulfonyl chloride (0.116 g, 1.01 mmole) and NaHCO3 (0.25 g, 3.0 mmole) as described for 1-8. The crude reaction product was purified by flash 20 chromatography on silica gel eluting with 30% EtOAc /hexanes to give pure 2-4 (0.10g) as a clear oil.

H NMR (300MEz, CDC13) ~ 1.36-1.56 (15E, m), 1.77 (2H, m), 2.70 (3H, s), 3.78 (3H, s), 3.92 (2H, t), 25 4.36 (lH, m), 4.90 (lH, d). 6.82 (2E, d), 7.09 (2H, d).

Z05~073 ~iBO,CH, ~NBOzCH3 ~ CO_CH. C02H
13oc-HN(cH2)~o ' EJyN(CH2)~0 2-S-(Methylsulfonylamino)-3-[4-~6-aminohexyloxy)-phenyll propionic acid hydrochloride (2-5) 2-4 (0.1 g, 0.212.mmole) was treated with LiOH (0.026 g, 1.06 mmole) as described for 1-8 to provide 2-S-(methylsulfonylamino)-3-[4-(6-N-t-butyl-oxycarbonylaminohexyloxy)phenyl]propionic acid (0.125g) as a viscous oil.

H NMR (300 MHz, CD30D) ~ 1.30-1.55 (16H, m), 1.75 (2H, m), 2.63 (3H, s), 2.85 (lH, dd), 3.0-3.13 (3H, m), 3.93 (2H, t), 4.17 (lH, m), 6.83 (2H, d), 7.20 (2H, d).

This acid was dissolved in EtOAc (20 mL) and treated with HCl gas as described for 1-9. Solvent removal provided a residue that was triturated with 30 mL ~t2O to provide pure 2-5 as a white solid (0.09 30 g) 205~0~3 lH NMR (300MHz, CD30D), ~ 1.40-1.60 (4H, m), 1.60 (2E, m), 1.69 (2H, m), 2.68 (3H, s), 2.82 (lH, dd), 2.92 (2H, t), 3.10 (lE, dd), 3.30 (2H, m), 3.97 (2H, t), 4.18 (lH, m), 6.83 (2E, d), 7.19 (2H, d).
:. , Analysis for C16H26N2OsS.EClØ25 E2O
Calculated: C = 48.11, H = 6.94, N = 7.01 Found: C = 48.16, H = 6.82, N = 6.98.

H H
~(~NH2 ~NBOzC~H9 ~oc - HN( CHz) ~o CO2CH3 ~3OC- HN( C~5O C~2CH3 2-3 , 2-6 Methyl 2-S-(Butylsulfonylamino)-3-[4-(6-N-t-butyloxy-carbonylaminohexyloxy)phenyllpropionate (2-6) 2-3 (0.40 g, 1.01 mmole) was treated with butylsulfonyl chloride (0.47 g, 3.03 mmole) and 25 NaHCO3 (0.50 g, 6.0 mmole) as described for 1-8.
Crude reaction product was purified by flash chromatography on silica gel eluting with 30~/O
EtOAc/hexanes to give pure 2-6 (0.22 g) as a clear oil .
30 lH NMR (300MHz, CDC13) ~ 0.87 (3H, t), 1.35-1.54 (18 H, m), 1.61 (2H, m), 1.77 (2H, m), 2.74 (2H, t), 2.95 (lH, dd), 3.05-3.18 (3H, M), 3.90 (2H, t), 4.32 (lH, m), 4.72 (lH, m), 6.82 (2E, d), 7.07 (2E, d).

205~0~7~

~,NBO2C~H9 H
~W CO2CH3 , ~ 30zC~H~
E~oc~ CH;~ ~ H2N( CH~ ~ CO2H

2-S-(Butylsulfonylamino)-3-[4-(6-aminohexyloxy)-phenyllpropionic acid hydrochloride (2-7) 2-6 ( O.2 g, O.39 mmole) was treated 15 in THF (l)/H20 (1)/CH30H(l) solution with LiOH
(0.05g, 2.12 mmole) as described for 1-8 to provide Z-S-(butylsulfonylamino)-3-[4-(6-N-t-butyloxycarbonyl-aminohexyloxy)phenyl]propionic acid (0.235 g) as a viscous oil.

E NMR (300 MHz, CD30D) ~ O.83 (3H, t), 1.35-1.56 (16H, m) 1.76 (2H, m), 2.61 (2H, t), 2.79 (lH, ddd), 3.00-3.14 (3H, m), 3.92 (2H, t), 4.11 (lH, m), 6.82 (2H, d), 7.18 (2H, d).

This acid (0.235 g, 0.7 mmole) was dissolved in EtOAc (30 mL) and treated with HCl gas as described for 1-9. The residue was triturated with a solution of ether (40 mL)/EtOAc (lOmL) to provide 2-7 30 (0.17g) as a white solid.

2~5~Q~;3 H NMR (300MHz, CD30D) ~ 0.85 (3H, t), 1.24 (2H, m), 1.35-1.60 (6H, m), 1.70 (2E, m), 1.80 (2H, m), 2.66 (2H, t), 2.78 (lH, dd), 2.92 (2E, t), 3.10 (lH, dd), 3.30 (lH, m), 6.85 (2H, d), 7.20 (2H, d).

Analysis for Ci'9H32N2o5s.Hcl Calculated: C = 52.22, H = 7.61, N = 6.41 Found: C = 51.80, H = 7.61, N = 6.33.

2-S-(Butylsulfonylamino)-3-[4-(6-acetamidinohexy-loxy)phenyllpropionic acid (2-7a) ~,NHSO2C~E~7 NH
HzN(cHz)~5o~ COaH CH3-C-OC2H!i~

NH ~NHSO2C~ H9 CH3 - C- NHi( CH2) ~5~ CO2H
2-7a A solution of 2-7 (1.0 g, 2.29 mmole) in THF
30 (30 ml) is treated with ethyl acetimidate (0.2 g, 2.29 mmol) and the resulting reaction mixture is stirred at room temperature for 16 hours. The solvent is then removed and the residue is recrystallized from ethyl acetate to give pure 2-7a.

-- 2~5~07;~

~- ~,NHSO2C"Hj, NH

HzN(cH2)~o~J CO2EI PhC-OC2H~

NH ~NB~
PhCNH~ CH2 ) 6~ co2 H

2-7b 2-S-(Butylsulfonylamino)-3-[4-(6-benzamidinohe~ylo~y)-phenyl~propionic acid (2-7b) A sol~tion of 2-7 (1.0 g, 2.29 mmole) in THF
20 (30 ml) is treated with ethyl benzimidate (0.34 g, 2.29 mmole) and the resulting solution is stirred at room temperature for 20 hrs. The solvent is removed and the residue is taken up in EtOAc, filtered and recystallized to give pure 2-7b.

~ ZOS~07;~

U NH
J~cozH 1 ) CH3S - CNHNO2 H2N(CH2)60 2) Hz/Pd-C
2-7 ~JHso2c4H9 Il ~ COzH
H2 NCNH( CHZ) 6~
2-7c 2-S-(Butylsulfonylamino)-3-[4-(6-guanidinohexylo~y-phenyllpropionic acid (2-7c~

A mixture of 2-7 (1.0 g, 2.29 mmol) and N-nitrosomethylthioguanidine (0.32 g, 2.29 mmol) is heated at 40~ for 5 minutes in absolute EtOH (15 ml) and then is allowed to stand for 1 day at room 25 temperature. The solvent is removed in vacuo and ~he residue is purified by fla~h chromatography on silica eluting with CHC13(95)-CH30H(5)-HOAc(2) to give the desired nitroguanidino intermediate.
This is dissolved in 10% HCl-CH30H (20 ml) 30 and shaken in a Parr apparatus (50 psi) in the presence of 10% Pd-C (100 mg) at room temperature for 8 hours. The catalyst is then removed by filtration, the solvent is removed in vacuo, and the residue ;~5~73 dissolved in 10% aqueous HCl solution and heated at reflux for 2 hours. The solvent is removed in vacuo and the residue purified by chromatography on a Dowex 1-X2 column eluting with water to give pure 2-7c.
:. , H H
~NH2 ~ ~NBOzCHzC~
Boc-llN(CH2)~0 2 3 13Oc-HN(CH~)~sO ~ CO2CH3 Methyl 2-S-(Benzylsulfonylamino)-3-~4-(6-N-t-butyloxycarbonylaminohexyloxy)phenyllpropionate (2-8) 2-3 (0.29 g, 0.735 mmole) was treated with 20 benzylsulfonyl'chloride (0.14 g, 0.735 mmole) and NaHC03 (0.185 g, 2.2 mmole) as described for 1-8.
The crude reaction product was purified by flash chromatography on silica gel eluting with 1:1 hexanes/EtOAc to give pure 2-8 (0.27 g) as a clear oil.

H NMR (300 MHz, CDC13) ~ 1.47-1.69 (15H, m), 1.~0 (2H, m), 2.18 (2H, s), 3.08 (2H, d), 3.25 (2H, m), 3.85 (3H, s), 4.05 (2H, t), 4.19-4.20 (4H, m), 4.80 (lH, d), 6.83 (2H, d), 7.12 (2H, d), 7.47 (5H, m).

2~5~Q73 H H
~2CHzCoY~ ~,NH502CH2C~H5 Boc- ~C CHz) a~ H21~ CH2) 0O CO2H

2-S-(Benzylsulfonylamino)-3-[4-(6-aminohexyloxy)-phenyllpropionic acid hydrochloride (2-9) 2-8 (0.48 g, 0.875 mmole) was treated with LiOH (0.105 g, 4.37 mmole) as described for 1-8 to give 2-S-(benzylsulfonylamino)-3-[4-(6-N-t-butyloxy-carbonylaminohexyloxy)phenyl]propionic acid (0.4 g) as a foam.

H NMR (300 MHz, CD30D) S 1.30-1.52 (15H, m), 1.72 (2H, m), 2.81 (lH, dd), 3.00 (3H, m), 3.93 (2H, m), 4.06 (2H, m), 6.81 (2H, d), 7.13 (2H, d), 7.20-7.32 (5H, m).

This acid (0.4g, 0.75 mmole) was dissolved in EtOAc (30 mL) and treated with HCl gas as described for 1-9. Crude reaction product was triturated with ether to give pure 2-9 (0.35 g) as a 30 white solid.

205~Q~3 H NMR (300 MHz, CD30D) ~ 1.38-1.57 (4H, m), 1.65 (2H, m), 1.73 (2H, m), 2.71 (lH, dd), 2.89 (2H, t), 3.02 (lH, dd), 3.30 (3H, m), 3.94-4.15 (5H, m), 6.83 (2H, d), 7.15 ~2H, d), 7.29 (5H, m).

EXA~PLE 16 A

NH

~NHSO2CH2C~H5 CH3COC2H5 H2N( CH2) 6~

,~,NHSO2CH2C6Hs NH ~ CO2H

CH3CHN(CH~)6O 2-9a 2-S-(Benzylsulfonylamino)-3-[4-(6-(acetamidinohe~yl-oxy-phenyl)lpropionic acid (2-9a) A solution of 2-9 (1.0 g, 2.1 mmol) in 'l'H~' (30 ml) is treated with ethyl acetimidate (0.18 g, 2.1 mmol) an described in Example 14A to give pure 2-9a after recrystallization from ethyl acetate.

Z(~5~Q7~3 NH

~;~BOzCH2C6H~ 1. CH3S-CNHNO2 ~ C02H 2. H2/Pd-C
HzN( CH2) 6~

~NB02C4Hg NH l Il ~ \~ CO2H
H2NCNH- C CH2) 6 Z-9b 2-S-(Benzylsulfonylamino)-3-~4-(6-(guanidinohexyloxy)-20 phenyllpropionlc acid (2-9b) ~ A mixture of 2-9 (1.0 g, 2.1 mmol) and N-nitrosomethylthioguanidine (0.29 g, 2.1 mmol) is treated as described for Example 14C to give pure 2-9b.

~ 205~0~73 ~f ~;H ~[~,OJ~CH~, ~NHCbz ~NHCbz 3 4 ~,0~ CO2CH~

~3ccN~ H0~ 3-3 ,0~,NE3S02C~,H~
~o CO2CH~
~ ~ 3~5 BocN~) ~,NB02C~,H;, ~[~f ~ C02H

HCl-HNy~ 3-6 Z05~0~3 Methyl 2-S-amino-3-[4-(4-hydroxyphenyl)oxyphenyl]-propionate (3-2).
CH30H (100 ml) was cooled to 0~ and treated with SOC12 (47 mmol) with stirring for 15 minutes at 0~ and then 3-1 (1.5 g, 5.49 mmol) was added with stirring for 1~ hours as the temperature rose to ambient.
The reaction mixture was filtered and the solvent was removed to give an oil that provided 3-2 (1.57 g) after ether washing.
H NMR (300 MHz, CD30D) ~ 3.10-3.30 (2H, m), 3.81 (3H, s), 6.76-6.90 (6H, m), 7.20 (2H, d).

15 Methyl 2-S-(N-Benzyloxycarbonylamino)-3-[4-(4-hydroxy-phenyl)oxyphenyllpropionate (3-3).
A water(l)-dioxane(l) solution (10 ml) of 3-2 (0.2 g, 0.62 mmol) was cooled to 0~C and treated with Na2CO3 (0.131 g, 1.23 mmole) and benzylchloro-20 formate (0.61~ mmol). After 1.5 hours of vigorousstirring, the dioxane was removed at low pressure and the residue diluted with H2O and extracted with EtOAc. The organic extract was washed with brine, dr~ed (M~2SO4) and Lhe sol-vent removed to provide 3-~
25 as an oil.lH NMR (300 MHz, CDC13) ~ 3.06 (2H, m), 3.75 (3H, s), 4.64 (lH, m), 5.10 (2H, m), 5.36 (lH, m), 6.83 (6E, m), 7.00 (2H, d), 7.37 (5H, bs).

30 Methyl-2-S-(N-Benzyloxycarbonylamino)-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)oxyphenyloxy]phenyl-propionate (3-4).
A benzene (40 ml) solution of 3-3 (0.5 g, 1.18 mmol) was treated with N-t-butyloxycarbonyl---~ 2~5~07;3 piperidin-4-ol (0.24 g, 1.18 mmol) and Ph3P (0.310 g, 1.18 mmol) while stirring at room temperature with constant N2 purging. Diethyl azodicarboxylate (1.18 mmol) was added and the resulting solution was stirred at room temperature for 16 hours.
The solvent was then removed and the residue was purified by flash chromatography on silica gel eluting with hexane(70)-EtOAc(30) to provide pure 3-4.
lH NMR (300 MHz, CDC13) ~ 1.48 (9H, s), 1.80 (2H, m), 1.95 (2H, m), 3.08 (2H, m), 3.36 (2H, m), 3.76 (3H, s), 4.40 (lH, m), 4.63 (lH, m), 5.10 (lH, m), 5.25 (lH, m), 6.80-7.04 (8E, m), 7.36 (5H, bs).

15 Methyl 2-S-(Butylsulfonylamino)-3-~4-(4-N-t-butyl-oxycarbonylpiperidin-4-yl)oxyphenyloxy]phenyl-propionate ~3-5~.
A solution of 3-4 (0.5 g, 0.082 mmol) in EtOH (40 ml~ was treated with 10% Pd/C (125 mg ) and 20 this suspension hydrogenated in a Parr flask at 50 psi for 1.5 hour. The catalyst was filtered off and the solvent removed to give the de~ired amino ester as a clear oil.
lH NMR (300 MHz, CDC13) ~ 1.48 (9H, s), 1.50-1.80 (8H, m), 1.91 (2H, m), 2.82 (lH, m), 3.04 (lH, m), 3.34 (2H, m), 3.76 (3H, s), 4.20 (lH, m), 7.90 (8H, m), 8.11 (2H, d).
This amino ester (0.36 g, 0.77 mmol) was dissolved in EtOAc (10 ml) and treated with NaHCO3 (0.386 g, 4.6 mmol) and n-butylsulfonylchloride (1.53 mmol) with heating at reflux for 48 hours. The solvent was removed and the residue purified by flash chromatography on silica gel eluting with hexane(65)-EtOAc(35) to provide pure 3-5 as an oil.

~ 205~0~

H NMR (300 MHz, CDC13) ~ 0.88-1.02 (4H, m), 1.25-1.45 (3H, m), 1.50 (9H, s), 1.51-1.80 (2H, m), 1 93 (2H, m), 2.80 (2H, m), 2.95-3.20 (2H, m), 3.21-3.40 (2H, m), 3.72 (2H, m), 3.74 (3H, s), 4.38 (2H, m), 4,80 (lH, d), 6.90 (6H, m), 7.10-7.27 (2H, m).
.
2-S-(Butylsulfonylamino)-3-[4-(piperidin-4-yl)oxy-phenyloxylphenylpropionic acid hydrochloride (3-6).
A solution of 3-5 (0.2 g, 0.34 mmol) in THF(l)-H2O(l)-CH3OH(l) was treated with LiOH (0.075 g, 1.78 mmol) at room temperature for 8 hours. The solvent was removed and the residue was acidfied with 10V/o KHS04 solution and this extracted several times 15 with EtOAc. The organic extracts were combined, washed with brine, dried (NaSO4) and the solvent removed to give the desired acid. Rf = 0.3 [silica gel, 97(CHC13)-3(CH30H)-l(HOAc)].
lH NMR (300 MHz, CDC13) ~ 0.85 (3H, t), 1.20-1.30 (3H, m), 1.46~(9H, s), 1.50-2.0 (6H, m), 2.75 (2H, m), 2.97 (lH, m), 3.18 (lH, m), 3.33 (2H, m), 3.76 (2H, m), 4.35 (2H, m), 5.07 (lH, m), 6.89 (6H, m), 7.13 (2H, m).

This acid (0.15 g, 0.26 mmol) was dissolved in EtOAc and treated with HCl gas as described for 1-9 to give pure 3-6 as a white solid.

lH NMR (300 MHz, CD30D) ~ 0.89 (3H, t ), 1.32 (2H, m), 1.53 (2H, m), 1.97-2.21 (4H, m), 2.75 (2H, m), 2.63 (lH, m), 3.20 (3H, m), 3.40 (2H, m), 4.14 (lH, m), 6.82-7.05 (6H, m), 7.23 (2H, m).

~ 20S~0~3 /~
Cbz N~ CH2) 3C~2cH3 Cbz N~( CH2) 3CC CH3) 2OH

1 5 ~NBO2C4H~
Cbz N3 ( CH2) 3 ~<o CO2CH3 ~NHSOzC4H~
CbZN~( CH2) 3~~~J CO2H

CH3 CH3 4 _ 4 2 5 HN~( CH2) 3 ~O~NE~02C4H~

205~07~3 4[4-(N-Benzyloxycarbonylpiperidin-4-yl)-2-methyl]-pentan-2-ol(4-2).
Methyl 4-(N-Benzyloxycarbonylpiperidin-4-yl)-butanoate (4-1) (10.07 g, 0.032 mol) in THF (200 ml) was cooled to 0~C and treated with CH3MgI (0.095 mol) for 3.0 hours. The reaction mixture was poured i~to ice, acidified with 10% KXS04 and extracted with 3 portions of EtOAc. The combined organic extract was 10 washed with brine, dried (MgS04) and the solvent removed. The residue was purified by flash chromatography on silica gel eluting with hexane(7)-EtOAc(3) to give pure 4-2. Rf = 0.3 (silica gel, hexane (7)-EtOAc(3).
Methyl 2-S-(Butylsulfonylamino)-3-[4-(N-Benzyloxy-carbonylpiperidin-4-yl)-2,2-dimethyl]butyloxyphenyl-propionate (4-3~.
N-n-Butylsulfonyl-L-tyrosine methyl ester (7.21 g, 0.023 mole) was dissolved in a mixture of 4-2(1.0g), CH2C12 (30 ml) and benzene (250 ml).
Triphenylphosphine (5.97 g, 0.023 mole) was added and after purging with N2, diethyl azodicarboxylate (3.6 ml, 0.023 mole) was added at room temperature as the reaction mixture turned red-orange in color.
Reaction mixture stirred at room temperature for 7 days. Solvent was removed and the residue was purified by flash chromatography on silica gel eluting with hexane(60)-EtOAc(40) to give pure 4-3.
H NMR (300 MHz, CDC13~ ~ 0.88 (6H, t), 1.10-1.40 (12H, m), 1.43-1.78 (8H, m), 2.70-2.82 (4~, m), 2.95-3.10 (3H, m), 3.75 (3H, s), 4.18 (2H, m), 4.32 ~ ~ 5 2~ 7 ~

(lH, m), 5.13 (2H, s), 6.88 (2H, d), 7.06 (2H, d), 7.38 (5H, m).

2-S-(Butylsulfonylamino?-3-~4-(N-Benzyloxycarbonyl-piperidin-4-yl)-2,2-dimethyl]butyloxyphenylpropionic acid (4-4).
Dissolved 4-3 (0.64 g, 0.001 mole) in THF/H20/CH3OH mixture and treated with LiOH (0.26 g, 0.0062 mole) at room temperature for 8 hours.
Solvent removal, acidification (KHSO4 solution) and EtOAc extraction provided crude 4-4 which was purified by flash chromatography on silica gel eluting with CHC13(97)-CH3OH(3)-HOAc(l) to give pure 15 4-4.
H NMR (300 MHz, CDC13) ~ 0.86 (6H, s), 1.05-l.S0 (13H, m), 1.55-1.80 (5H, m), 2.77 (4~, m), 3.04 (2~, m), 4.10 (2H, bd), 4.17 (lH, m), 4.85 (lH, d), 5.14 (2E, s), 6.88 (2H, d), 7.13 (2H, d), 7.39 (5H, m).
2-S-(Butylsulfonylamino)-3-[4-(piperidin-4-yl)-2,2-dimethyllbutyl~Yy~h~yl~ro~ionic ~cid (4-5~.
To ammonium formate (O.23 g, 3.65 mmol) in CH30H (5 ml) was added 4-4 (0.22 g, 3.65 mmole) in lO ml CH30H and then 10% Pd/C (100 mg) was added at room temperature. After 15 minutes the reaction mi~ture was passed thru a Sol~a Floc pad and the ~olvent removed. This residue was purified by flash chromatography on silica gel eluting with EtOH(9)-H2O(l)-NH4OH(l) to give pure 4-5.

1~ NMR (300 M~z, CD30D) ~ 0.88 (6H, s), 1.15-1.40 (12H, m), 1.42-1.70 (7H, m) 1.90 (2H, d), 2.78-3.00 (6H, m), 3.06 (1~, dd), 3.35 (3H, m), 3.93 (lH, m), 6.86 (2~, d), 7.20 (2H, d).

* Trademark -Z05~0~73 SC~IEME 5 ~NHCbz ~[3~NHCbz ( CH2~ 4~ CO2H ( CH2) 40 CO2CH3 1 - 2 ~ 5 -1 Boc Boc SO2C4H9 ~NH2 ( CHZ) 40~ ~C02CH3 ~ CH2) ~0~ ~C02CH3 2 0 Boc ¦ 130c ,NB02C4H~ ~NHSO2C4H~
2 5( CH2) ~~J~' CO2H ( CH2~ ~'~~ CO2H
5-4 ~ 5-5 ~oc ~oc 205~073 ~ocN ~ CH2)40 CNoHCb~3 Methyl 3-S-(Benzyloxycarbonylamino)-4-~4-(N-t-butyl-10 oxycarbonylpiperidin-4-yl)butyloxyphenyllbutyrate (5-1).
A solution of compound 1-2 (l.O g, 1.8 mmole) and N-methylmorpholine (0.21 mL, 1.9 mmole) in EtOAc (10 mL) was ~tirred at -15~C and treated with isobutyl chloroformate (0.24 mL, 1.8 mmole). After 15 minutes the heterogeneous mixture was treated portion-wise with an ethereal solution of diazomethane (0.5M:10 mL, 5.0 mmole), followed by continued stirring at 0~ for 1.0 hour. The reaction 20 mixture was t~en purged with argon for 10 minutes to remove excess diazomethane. The organic phase was washed with 2 x 5 mL portions of ~2~~ brine, dried (MgS04), and evaporated. The residue was then dissolved in CH30H (15 mL) and treated se~uentially 25 with triethylamine (0.7 mL, 5.0 mmole) and AgO2CPh (110 mg, 0.5 mmole) while stirring at ambient temperature to effect vigorous gas evolution.

ZOS~0~3 After 30 minutes the solvent was evaporated and then the crude reaction product purified by flash chromatography on silica gel eluting with 4:1 hexane/EtOAc to give 5-1 (0.52 g) as an oil.
TLC Rf = 0.23 ~30% EtOAc/hexane) BocN ~ CH2)4O CO~CH3 Methyl 3-S-Amino-4-[4-(N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyllbutyrate ~5-2).
To 5-1 (0.52 g, 0.9 mmole) dissolved in absolute ethanol (20 mL) was added 10~/o Pd/C (0.25 g) and the resulting suspension was hydrogenated under balloon press~re for 12 hours. The catalyst was then filtered off and the solvent was removed in vacuQ to give 5-2 (0.35 g) as an oil.

TLC Rf = 0.15 (9:1:1 CH2C12/CH3OH/AcOH).

-ZOS~0~3 NHSO2Bu BocN ~ CHz) 40 C02CH3 Methyl 3-S-(Butylsulfonylamino)-4-[4-N-t-butyloxy10 carbonylpiperidin-4-yl)butyloxyphenyllbutyrate (5-3~
To 5-2 (0.36 g, 0.8 mmole), triethylamine (170 ~L, 1.2 mmole), 4-dimethylaminopyridine (12 mg, 0.1 mmole), and THF (5 mL) at 0~C was added n-butyl-sulfonyl chloride (130 ~L, 1.0 mmole) with stirring.
15 The cooling bath was removed and stirring was continued for 6 hours. The reaction mixture was diluted with 10 mL of EtOAc and then washed with 2x5 mL H20, brine, dried (MgS04), and concentrated. The crude reaction product was purified by flash chromatography on silica gel eluting with 4:1 hexane/EtOAc to give 5-3 (180 mg) as an oil.

H NMR (300 MHz, CDC13) ~ 1.12 (2H, m), 1.25-1.83 (13E, m), 1.29 (3H, t), 1.47 (9H, s), 2.68 (6H, m), 2.87 (2H, d), 3.73 (3H, s), 3.93 (2H, t), 4.08 (lE, m), 4.72 (lH, d), 6.87 (2H, d), 7.12 (2H, d).

2~)S~0~3 441~SP25 - 72 - 18197I~

~N~ ~2 Bu BocN ~ CHz) 40 C02H
.,~ J

3-S-(Butylsulfonylamino)-4-[4-N-t-~utyloxycarbonyl-10 piperidin-4-yl)butyloxyphenyl~butanQic acid (5-4).
Compound 5-3 (175 mg, 0.33 mmole~ in C~30H
(4.0 mL) was treated with lN NaOH (1.0 mL, 1.0 mmole) ~ollowed by continued stirring at ambient tempera~ure for 20 hours. The reaction mi~ture was diluted with 15 mL ~tOAc and then washed with 10 mL 5% KHS04 and brine7 dried (MgS04~, and concentrated to give ~-4 (160 mg) as an oil.

T~C Rf = 0.31 (9:0.5:0.5 CH2C12/CH30H/AcOH).

205~07~3 ~N~02Bu HN ~ CH2)4O ~ ~CO2H

3-S-(~utylsulfonylamino~-4-[4-piperidin-4-yl)butyloxy-phenyllbutanoic acid (5-5~
To a stirred solution, of compound 5-4 (160 mg, 0.30 mmole), CH2C12 (2.0 mL), and anisole (100 ~L) at 0~C was added CF3CO2H (1.0 mL). After 1.5 hours at 0~C the solvents were evaporated and the crude reaction product purified by flash chromatography on silica gel eluting with 10:0.8:0.8 ethanol/H2O/conc. NH40H to give 5-5 (42 mg) as a solid.

lH NMR (300 MHz, D20/CF3C02D) ~ O~82 (3H, t), 1.10-1.70 (llH, m), 1.80 (m, 2H), 1.98 (m, 2H), 2.48 (2H, t), 2.72 (3H, m), 3.00 (3H, m), 3.43 (2H, m), 3.96 (lH, m), 4.10 (2H, t), 7.01 (2H, d), 7.32 (2H, d).

20S~073 SCH~ME 6 ~ NHCbz ~ NHCbz HO ~ CO2CH3 Cl ~'-~o ~ CO2CH3 1-1 ~ 6-1 ~ NHCbz I'-~'-~O CO2CH3 ~ NHCbz HN N-~CH2)3-O CO2CH3 ~ ~

~ NHCbz HN N-CcH2)3-o CO2H

Z0~073 -Methyl 2-S-(N-Benzyloxycarbonylamino)-3-[4-(3-chloro-propyloxyphenyl)propionate (6-1).

Treatment of a DME solution of 1-1 (0.95 g, 2.9 mmol) and 3-chloro-1-tosyloxypropane (0.84 g, 3.19 mmol) wit~h cesium carbonate (O.47 g, 1.45 mmole) gave a solution that was stirred at room temperature overnight. The reaction mixture was then diluted with H2O and extracted with ether. The ether extract 10 was washed with brine, dried (Na2SO4) and the solvent removed to give an oily residue. This was purified by flash chromatography on silica gel eluting wi~h EtOAc(5)-hexane(95) to afford 6-1 as a clear oil. Rf 0.5 (silica gel eluting with EtOAc(30)-hexane(70).

Methyl 2-S-(Benzyloxycarbonylamino)-3-~4-(3-iodo-propyloxyphenyl~propionate (6-2).

A solution of 6-1 (0.6 g, 1.5 mmol) in acetone was treated with sodium iodide (1.1 g, 7.5 20 mmol) and the resulting solution was heated at reflux for 16 hours. The reaction mixture was then diluted with ether, washed with water, brine and dried (Na2SO4). Solvent removal gave an oil that was purified by flash chromatography on silica gel eluting with hexane(90)-EtOAc(10) to give 6-2 as a clear oil.

- lH NMR (300 MHz, CDC13) ~ 1.85-2.08 (4H, m), 3.04 (2H, m), 3.26 (2H, t), 3.71 (3H, s), 3.95 (2H, t), 4.60 (lH, m), 5.00-5.21 (3H, m), 6.78 (2H, d), 6.99 (2H, d), 7.33 (5H, m).

~ 205~073 Methyl 2-S-(N-~enyzloxycarbonylamino)-3-[4-(2,6-di-methy~piperazin-4-yl~propyloxyphenyl~propionate ~6-3~.
A solution of 6-2 (0.1 g, 0.2 mmol) and 2,6-dimethylpiperazine (0.068 g, O.6 mmol) in 1 ml T~F
was stirred at room temperature for 20 hours. The solvents were removed at low pressure to provide 6-3 as a clear oil.

lH NMR (300 MHz, CDC13) ~ 1.45 (4H, d), 1.82 (3H, m), 2.65 (2H, m), 2.79 (2H, m), 3.05 (lH, m), 3.18 (2H, bd), 3.60 (lH, m), 3.72 (3H, s), 3.96 (2H, m), 4.62 (lH, m), 5.10 (2H, s), 5.21 (lH, m), 6.79 (2H, d), 7.00 (2H, d), 7.35 (5H, bs).
2-(N-Benzyloxycarbonylamino)-3-[4-(2,6-dimethylpiper-azin-4-yl)propyloxyphenyllpropionic acid ~6-4~.
6-3 (0.090 g, 0.2 mmol) in methanol was treated with lN NaOH (0.7 ml) at room temperature for 16 hours. The~solvent was removed to give crude acid which was purified by flash chromatography on silica gel eluting with isopropanol(l0)-NH4OH(l)-H2O(l) to provide pure 6-4, Rf 0.25.

lH NMR (300 MHz, CD30D) ~ 1.65-1.85 (4H, m), 2.60-2.70 (2H, m), 2.80-2.95 (6H, m), 3.11 (8H, m), 3.52 (2H, m), 3.65-3.75 (2H, m), 3.82 (2H, t), 4.17 (lH, m), 4.70 (2H, s), 4.85 (2E, m), 6.63 (2H, d), 6.92 (2H, d), 7.10 (5H, bs).

Z05~0~73 ,NHCbz 1 0 ~/NHCbz BocN3( CH2) 30 C02CH3 1 5 ~NHCbz BocN3~ CH2~ 3~ CO2H

~NHCbz BocN~}( CH2) 30 02CH3 ~ NHCbz HN~ CH2) 30 C02H

2~5;Z 0~3 Methyl 2-S-(N-Benzyloxycarbonylamino)-3-[4-(N-t-butyl-oxycarbonylpiperidin-4-yl)propyloxyphenyl]propionate (7-1).
A solution of 1-1 (4.0 g, 2.6 mmol) and 3-(N-Boc-piperidin-4-yl)propyl iodide (1.1 g, 3.3 mmol) in 40 ml DMF was treated with cesium carbonate (0.4 g, 1.35 mmol) and the resulting solution was stirred at room temperature for 20 hours. The solvent was removed and the residue was taken up in EtOAc, washed with water, brine and dried (Na2S04).
Solvent removal provided a residue that was purified by flash chromatography on silica gel eluting with 4:1 hexane(80)-EtOAc(20) to give pure 7-1 as a clear 15 oil.

H NMR (300 MHz, CDC13) ~ 1.10 (2H, m), 1.37-1.45 (llH, m), 1.65-1.82 (4H, m), 2.68 (2H, m), 3.03 (2H, m), 3.71 (3H, s), 3.90 (2H, t), 4.08 (2H, bd), 4.61 (lH, m), 5.10 (lH, s), 5.18 (lH, m), 6.79 (2H, d), 7.00 (2H, d), 7.35 (5H, bs).

2-(S)-(N-Benzyloxycarbonylamino)-3-[4-(N-t-butyloxy-carbonylpiperidin-4-yl)propyloxyphenyl]propionic acid (7-2).
7-1 (0.5 g, 0.9 mmol) in methanol (12 ml) was treated with lN NaOH (3 ml) at room temperature for 16 hours. The solvent was then removed and the re~idue acidified with 5% KHSO4 solution. This was extracted with EtOAc several times and the combined organic extracts were washed with brine and dried (Na2SO4). Solvent removal gave 7-2 as a clear oil.

Z05~07~

H NMR (300 MHz, CDC13) ~ 1.10 (2H, m), 1.37-1.52 (12H, m), 1.62-1.85 (5H, m), 2.66 (2H, t), 3.10 (2H, m), 4.89 (2E, t), 4.10 (4H, m), 4.62 (lE, m), 5.09 (lH, s), 5.19 (lH, m), 6.79 (2H, d) 7.03 (2H, d), 7.34 (5H, bs).

Methyl 3-S-(N-Benzyoxycarbonylamino)-4-[4-(N-t-butyl-oxycarbonylpiperidin-4-yl)propyloxyphenyl)butanoate (7-3).
To a stirred solution of 7-2 (1.6 g, 2.9 mmol) in EtOAc at -15~C was added isobutyl-chloroformate (2.9 mmol) and N-methylmorpholine (2.9 mmol) and the resulting solution was stirred for 0.5 15 hours at -15~. Then, diazomethane (5.0 mmol in ~t20) was added and the reaction mixture was stirred at 0~
for 20 minutes. The reaction mixture was purged with argon, diluted with EtOAc and washed with water. The organic phase was dried (MgS04) and the solvent removed to provide the desired diazoketone.
H NMR (300 MHz, CDC13) ~ 1.10 (2E, m), 1.35-1.50 (12H, m), 1.55-1.85 (6H, m), 2.68 (2H, bt), 2.95 (2H, d), 3.90 (2E, t), 4.09 (3H, m), 4.42 (lH, m), 5.06 (lH, m), 5.20 (lH, m), 5.35 (lH, m), 6.80 (2H, d), 7-06 (2H, d), 7.35 (5H, bs).

Thi~ diazoketone (1.63 g, 2.9 mmol) was dissolved in CH30H (20 ml) and treated at room temperature with a CH30H solution (5 ml) of silver benzoate (0.22 mg, 0.96 mmoles) and triethylamine (1.25 ml). After a few minutes the reaction became black with gas evolution apparent. After 0.5 hours the solvent was removed and the residue was puri~ied ~05~07~3 by flash chromatography on silica gel eluting with 4:1 hexane(80) EtOAc(20) to give 7-3 as an oil.

lH NMR (300 MHz, CDC13) ~ 1.12 (2H, m), 1.37-1.47 (12H, m), 1.60 (2H, s), 1.65-1.83 (4H, m), 2.49 (2H, m), 2.62-2.91 (4H, m), 3.67 (3H, s), 3.90 (2H, t), 4.03-4.20 (4H, m), 5.08 (2H, s), 5.24 (lH, m), 6.79 (2H, d), 7.05 (2H, d), 7.32 (5E, bs).

3-S-(N-Benzyloxycarbonylamino)-4-[4-(piperidin-4-yl)-propyloxyphenyllbutanoic acid (7-4).
A solution of 7-3 (0.3 g, 0.53 mol) was treated with lN NaOH (1.7 ml? and the resulting 15 mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue acidified with 5% aq KHSO4 solvent and this was extracted several times with EtOAc. The combined organics were washed with brine, dried (NaSO4) and 20 the solvent removed to give the desired acid.

H NMR (300 MHz, CD30D) ~ 1.10 (2H, m), 1.40-1.52 (12, m), 1.65-1.84 (6H, m), 2.54-2.93 (8H, m), 3.92 (2H, t), 4.05-4.12 (3H, m), 5.10 (2H, s), 6.71 (2H, 25 d), 7-08 (2H, d), 7.35 (5H, m).

This acid was dissolved in CH2C12 (4 ml) and anisole (0.41 mmole) was added, followed at 0~ with trifluoroacetic acid (2 ml). After 2.5 hours stirring at 0~, the solvents were removed and the residue purified by flash chromatography on silica gel eluting with EtOH(10)-NH4OH(l)-H2O(l) to give pure 7-4 as a white solid.

20~;~0~73 lH NMR (300 MHz, CD30D) ~ 1.3-1.5 (4H, m), 1.6 (lH, m), 1.75-1.85 (2H, m), 1.95 (2E, d), 2.54 (2E, m), 2.72 (2H, m), 2.93 (2E, t), 3.32 (6E, m), 3.92 (2~, t), 4.11 (lH, m), 4.95 (2H, m), 6.75 (2E, d), 7.05 (2H, d), 7.25 (SH, m).

Z05~073 1 0 ~" o ~7 ~

o=~ ~D7 ~ N
~ Q' ~: t ~
H ~ Z
N I ~ ~
N
o= ~ ~ r7 H

~ ~ W 1 U ~ ,~

_ N ~' ~ Z052073 .

~ MH2 o I CO2CH3 clCC5Hll I cO2CH3 Methyl 2-S-(Hexanoylamino)-3-(4-iodophenyl)propionate (8-2) A suspension of 8-1 (1.01 g, 2.96 mmoles) in 20 ml CHC12 was cooled to 0~ and pyridine (1.43 ml, 17.7 mmoles) was added followed by hexanoylchloride (1.25 ml, 8.88 mmoles). After 20 minutes all 8-1 was consumed. Water (25 ml) was then added carefully and this mixture was e~tracted with EtOAc (150 ml). The separated organic phase was washed with 10% KHSO4, brine, dried (Na2SO4) and the solvent was removed to give a white solid. This was purified by flash chromatography on silica gel eluting with 5%
Et2O/CHC13 to give pure 8-2 (1.07 g) as a white solid.

1H NMR (300 MHZ, CDC13) ~ 0.88 (3H, t), 1.27 (4H, m), 1.60 (2H, m), 2.09 (2H, t), 3.05 (2H, m), 3.75 (3H, s), 4.88 (lH, m), 5.93 (lH, m~, 6.83 (2H, d), 7.60 (2H, d).

-205~07;~
.~

/ -Boc N/~
C HO
~ 8 - 3 [ Ph3P- CH2C= C- TM~] ' Br ~

BocN ~ iM~3 5-(N-t-Butyloxycarbonylpiperidin-4-yl)-1-trimethyl-1-silylpent-3-ene-1-yne ~8-4~.
A suspension of 3-trimethylsilyl-2-propynyl)-triphenyl phosphonium bromide (3.0 g, 6.62 mmoles) (Aldrich) in 50 ml THF was cooled to -78~ and treated with n-BuLi (6.62 mmoles) dropwise. The resulting solution was allowed to warm to -40~ and was then stirred for 0.5 hours to give a deep red solution.
After cooling to -78~C the reaction mixture was treated with 8-3 (1.07 g, 4,73 mmoles) in 15 ml THF
and was allowed to warm to 0~ with stirring for 1 hour. The reaction was quenched with 50 ml H2O and this was extracted with EtOAc (200 ml). The organic phase was separated, dried (Na2SO4) and stripped to provide as residue that was purified by flash chromatography on silica gel eluting with 10%
EtOAc/hexane to provide pure 8-4, (2.02 g), Rf = 0.3.

1H NMR (300 MHz, CDC13) ~ 0.10 (9H, s), 0.70-1.10 (4E, m), 1.10-1.40 (13E, m), 1.40-1.60 (3H, m), 1.83 38E, m), 2.40-2.60 (3H, m), 3.85 (3H, m), 5.35 (lH, t), 6.00 (lH, m).

~ Z~5~0~;3 BocN ~ = II
s 5-(N-t-Butyloxycarbonylpiperidin-4-yl)pent-3-en-1-yne (8-5) A solution of 8-4 (0.815 g, 2.54 mmoles) in 60 ml THF was treated with 12 ml H20 and lithium hydroxide hydrate (0.96 g, 2.28 mmoles). The reactiorl mlxture was stirred at room temperature ror 6 hours during which time the color became dark orange. The reaction mixture was then diluted with Et2O (75 ml) and the a~ueous phase was separated and washed with 3x75 ml Et20. The combined organic extacts were washed with brine, dried and stripped.
The resulting ~residue was purified by flash chromatography on silica gel eluting with 10%
EtOAc/hexanes to give 0.63 g pure 8-S.

lH NMR (300 MHz, CDC13) ~ 1.0-l.Z5 (3H, m), 1.25-1.60 (llH, m), 1.60-1.75 (3H, m), 2.06 (2H, t), 2.30 (lH, t), 2.60-2.78 (2H, m), 4.07 (2H, m), 5.51 (lH, m), 6.22 (lH, m).

~ 205~0t73 BocN ~ = ~ NHCC5H
. - 8-6 CO2CH3 Methyl 2-S-(Hexanoylamino)-3-[4-(5-N-t-butyloxy-carbonylpiperidin-4-yl)pent-3-ene-1-ynephenyl]-propionate (8-6).
A solution of 8-5 (0. 3 g, 1.2 mmoles) and 8-2 (0.58 g, 1.4 mmoles) in diethylamine (6 ml) was purged with N2 and bis-triphenylphosphine palladium chloride (0.049 g, 0.07 mmoles) was added followed by cuprous iodide (7 mg, 0.035 mmoles) and the suspension was purged again. After several minutes the reaction mixture became homogeneous and this solution was stirred for 16 hours at room temperature.
The solvent was removed at high vacuum and the residue was dissolved in pH 7 buffer and extracted with Et2O. The organic extract was washed with 10~/o KHSO4, brine, then dried (Na2S04) and stripped. The residue was purified by flash chromatography on silica gel eluting with 20%
EtOAc/hexanes to give 0.28 g pure 8-6. Rf = 0.3 (20%
EtOAc, hexanes).

1H NMR (300 MHz, CDC13) ~ 0.90 (3H, m), 1.05-1.40 (9H, m), 1.52 (6H, s), 1.58-1.75 (4H, m), 2.07 (2H, m), 1.70 (2H, m), 3.14 (2H, m), 3.75 (2H, m), 4.10 (2H, m), 4.89 (lH, m), 5.70 (lH, m), 5.94 (lH, m), 6.18 (lH, m), 7.03 (2H, m), 7.38 (2H, m).

7 ~

HN ~ CH2)S ~ MHCCsHl1 2-S-(EIexanoylamino)-3-~4-(5-Piperidin-4-yl)pentyl-10 phenyllpropionic acid (8-7) 8-6 (0.275 g, 0.52 mmoles) was dissolved in EtOH and 2 ml of H2O was added along with 5 drops of HOAc. Pd-C (100 mg) was added and the resulting suspension was hydrogenated on a Paar shaker (50 psi) for 4 hours. The reaction mixture was filtered through Solka-Floc ~nd the resulting solvent was removed. The resulting residue was purified by flash chromatography on silica gel eluting with 35%
EtOAc/hexanes to give 0.22 g of methyl 2-S-hexanoyl amino-3-~4-5-N-t-butyloxycarbonylpiperidin-4-yl)-pentylphenyl propionate.

H NMR (300 MHz, CDC13) ~ 0.85 (3H, t), 1.00-1.35 (12H, m), 1.45 (9H, 8), 1.50-1.65 (6H, m), 2.15 (2H, t), 2.50-2.65 (4H, m), 3.05 (2~, m), 3.71 (3H, ~), 4.04 (2H, m), 4.83 (lH, m), 5.96 (lH, m), 6.98 (2E, d), 7.04 (2~, d).

This ester (0.17 g, 0.32 mmoles) was suspended in 10 ml of 1:1 THF/H2O and CH30H (2 ml), lithium hydroxide hydrate (0.067 g, 1.6 mmoles) was added and the reaction was stirred for 2.0 hours at room temperature. The solvent was then removed and the residue was taken up in H2O. This was acidified * Trademark B

~ Z0~07~3 to pH 2-3 with 10% KHSO4, and extracted with EtOAc.
The organic extract was washed with brine, dried (Na2SO4) and stripped to give 0.050g of the desired acid.

lH NMR (300 MHz, CDC13) ~ O.85 (3H, m), 0.95-1.42 (15 H, m), 1.47 (9~, s~, 1.50-1.70 (7H, m), 2.18 (2H, m), 2.48-2.72 (5H, m), 5.02-5.30 (2H, m), 4.03 (2H, m), 4-84 (lH, m), 6.05 (lH, m), 7.06 (4H, s).

This acid (0.15 g, 0.29 mmoles) was dissolved in EtOAc (25 ml), cooled to -70~ and treated with ECl gas for 10 minutes. The temperature was allowed to rise to -20~ over 0.5 hr. The reaction mixture was purged with N2 and the solvent was removed. The residue purified by flash chromatography on silica gel eluting with 9~
EtOH/H2O/NH4OH to give pure 8-7, 0.040 g as a white solid.

H NMR (300 MHz, CD30D) ~ 0.78 (3H, t), 1.05-1.30 (9H, m), 1.32-1.56 (4H, m), 1.74 (2H, d), 2.03 (2H, m), 2.42 (2H, m), 2.70-2.85 (3H, m), 3.04 (lH, dd), 3-21 (2H, m), 4.38 (lH, m), 6.92 (2H, d), 7.00 (2H, d).

In the above Schemes and Examples, various reagent symbols have the following meanings:
BOC: t-butoxycarbonyl.
Pd-C: Palladium on activated carbon catalyst.
DMF: Dimethylformamide.
CBZ: Benzyloxycarbonyl.

2C~5~073 BOP: Benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate.
EtOAc: ethyl acetate DMF: dimethylformamide CH2C12: methylene chloride CHC13: chloroform MeOH: methanol HOAc: acetic acid Suitable alternative protecting groups that can be used in the preparation of the present invention include benzyl ester, cyclohexyl ester~
4-nitrobenzyl ester, t-butyl ester, 4-pyridylmethyl ester, benzyloxycarbonyl, isonicotinyloxycarbonyl, O-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxyben~yloxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, 2-(4-biphenyl)-2-propyloxy-carbonyl and 9-fluorenylmethoxycarbonyl.
In addition to those compounds specifically exemplified above, additional compounds of the present invention are set forth in tabular form below. These compounds are synthesized by use of the synthetic routes and methods described in the above Schemes and Examples and variations thereof well known to those of ordinary skill in the art, and not requiring undue experimentation. All variables Z05~7;~

listed in the Tables below are with reference to the following generic structure:

Y ~ R2 1 /(CH2)m~X~ ~Z R

~ 205~Qt7;~

P~ ~ U ~ U ~

Ln ~ O O ~ ~
P~ O= OJ O=~ O=~ O= P~ g ~' , . , I ~

1 0 p~ ~ u ~ m Ou ..

1 5 ~ P U ~ X p~

U

20 '~ U u o r ~ ~ N ~ N N

~ 2(~5~(~73 S ~ In r~

1 O--u o--u ~

~ O=~

Z r~
C) u~ ~~ ~ ~--u ~C u~-U _-u U-~ o=~

3 0 ~; ~ U P~ o :~

Ir ~ ~ N N N N

~ Z05~07~3 . , ~

X ~ , U

1 0 o~

U ~ ~ U o=~

~!~ o=~

2 0 I S , ? ~ u~ ~ ~

Iy~ go~ ~u=O bZ-D~

' r ~ cn o ~
~ ~ N N ~ ~ ~r~ tr) ~ 2~5~07;~

u ~ N tT) ~ ~ N N

E~ N ~ N ~ ~ O

N ~ ~ ~ ; U- ~ U- ~;

U--U, ~ U U--U ~ ~ U--U U--U O

Xo o=u U'-~ C~~ ~U' C~~ ~-~

2 5 u ~ N

~ o N N N N N f~ ~ ~

j 205~07.~

U ~ ' ~

n~ ~ ~ZIY U ~ U C U C o ~

U ; d u ~= ~ ~--i 2 0 '~ I ~ I ~1 u ~ U
~ o L I ~ U

~ O r 0 ~~

~ ZOS~Q7~

~ '~ 0 ~ , ~ , In ~0 c ~p ~ , ~ ~ o o N O= U U~= U U o= U U U--U U--U

x q ~3uU--a~ Uu=u~ u-U ~-u--u ~

,~ O~ P:

r 2C~5~073 ~ ", z, ~ q o""

~ o=~ o=~ o=8,0 ~ S

S S ~ Z~

U~ r~

~. o=~

25 , L

205~07~

N
C~ ~ ~ ~ ~ o ~ N N .-N1l7 ~ tr~ N ,- ~ O tr~

N 00- VU~= V ~= ~ ~= ~ V~ = V 0- V

UU7= U C~ U ~-X ~ =U ~ ~, U U o~u ~ u O~, N

~ zos~o~

.,~;5T ~ ~o V,=u :: u~ ul=u ", ~ ' t~~=~ ~=~ o=~
~ o=~
o=y o=u ~ ~r~O U U y~ y~ ,S ,, ~ 5T

h U

~; 8 ~ y 8T U u ~ 2C~S~073 o~ ~ o ,. In ~J N ~r) N ~
~ O ~ O ~ ~ ~ ~ d' 15 t'J

~ ~~

X ~ ~ , o o , , ~, U

U I ~ =U L~ ~ r a ~Q ~ 20 7 3 Blood was drawn into 0.1 volumes of acid-citrate-dextrose (85 mM sodium citrate, 64 mM
citric acid, 110 mM dextro~e) by venipuncture from normal human volunteers. Platelet-rich plasma was prepared by centrifugation at 400 2 g for 12 minutes. PGEl (5 mg/ml) was added and platelets were collected by centrifugation at 800 x g for 12 minutes. The platelet pellet was resuspended into human platelet buffer (140 mM NaCl, 7.9 mM KCl, 3.3 mM Na2~P04, 6 mM HEPES, 2% bovine serum albumin, 0.1 ~Z dextrose, pH 7.2) and filtered over Sepharose 2B
that was previously equilibrated in human platelet buffer. Platelets were counted and adjusted to 2 x 108/ml with human platelet buffer. ~uman fibrinogen (10-100 mg/ml and CaC12 (1 mM) were added and aggregation was initiated by the addition of 10 mM
ADP. Aggregation was monitored by the initial rate of increase of light transmittance.
While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of clotting disorders or emboli, or for other indications for the compounds of the invention indicated above.

*~Trademark B

~ 205~07~3 Likewise, the specific pharmacological responses observed may vary acording to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention.
It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

2s

Claims (13)

1. A compound of the structural formula and pharmaceutically acceptable salts thereof, wherein R1 is piperidine-4-yl R4 is aryl selected from the group consisting of phenyl, pyridyl, thienyl, tetrazole or oxazole, or C1-10 alkyl, or C4-10 aralkyl;

Z is 0, , or , where m is an integer from two to six.

2. A compound as claimed in Claim 1, of the structural formula

3. A compound as claimed in Claim 1, of the structural formula

4. A compound as claimed in Claim 1, of the structural formula

5. A compound as claimed in Claim 1, of the structural formula

6. A pharmaceutical composition comprising the compound as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. The use of a compound as defined in any one of claims 1 to 5 for blocking fibrinogen from acting at its platelet receptor site in a mammal.

8. The use of a compound as defined in any one of claims 1 to 5 for preventing thrombus formation in a mammal.

9. The use of a compound as defined in any one of claims 1 to 5 for treating thrombus formation in a mammal.

10. A use as claimed in claim 8 or 9, wherein said compound is used in association with an anti-coagulant agent.

11. A use as claimed in claim 8 or 9, wherein said compound is used in association with a fibrinolytic agent.

12. The use as claimed in Claim 8 or 9 wherein said compound is used in association with a platelet anti-aggregation agent.

13. The composition as claimed in Claim 6 further comprising compounds selected from the group consisting of platelet anti-aggregation agents, thrombolytic agents and anti-coagulation agents.