ZA200202365B

ZA200202365B - Phenoxy carboxylic acid compounds and compositions for delivering active agents.

Info

Publication number: ZA200202365B
Application number: ZA200202365A
Authority: ZA
Inventors: Andrea Leone-Bay; Kelly Kraft; Destardi Moye-Sherman; David Gschneidner; Maria A P Boyd; Puchin Liu; Pingwah Tang; Jun Liao; John E Smart; John J Freeman Jr
Original assignee: Emisphere Tech Inc
Priority date: 1999-11-05
Filing date: 2002-03-25
Publication date: 2002-10-25

Description

, .

PEENOXY CARBOXYLIC ACID COMPOUNDS AND COMPOSITIONS

°° FOR DELIVERING ACTIVE AGENTS TT , FIELD OF THE INVENTION ; The present invention relates to phenoxy carboxylic acid ¥ . compounds for delivering active agents, such as biologically » 25 or chemically active agents, to a target. These compounds are 5 well suited for forming non-covalent mixtures with active y “agents for oral, intracolonic, pulmonary, and other routes of . administration to animals. Methods for the preparation and administration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, and/or the target itself.

Biologically and chemically active agents are particularly vulnerable to such barriers. 40 In the delivery to animals of biologically active and chemically active pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical o barriers are the skin, lipid bi~layers and various organ 3 membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as ) the circulatory system. Chemical barriers include, but are 5S not limited to, pH variations in the gastrointestinal (GI) : tract and degrading enzymes.

These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many 7 biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These - agents may be rapidly rendered ineffective or destroyed in the ; gastro-intestinal tract by acid hydrolysis, enzymes, and the

N ) like. In addition, the size and structure of macromolecular h 20 drugs may prohibit absorption. : Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e.

—— ——Woms325% —.. ._ _______ ___ PCT/USN/30662 a "active agents, are not avallable; (3) the systems exhibit poor

QO stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the . active agent; or (7) the systems fail to allow or promote absorption of the active agent. CL

More recently, proteinoid microspheres have been used to deliver pharmaceuticals. See, for example, US Patent Nos. 5,401,516; 5,443,841; and Re. 35,862. In addition, certain ‘modified amino acids have been used to deliver pharmaceuticals. See, for example, US Patent Nos. 5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5,866,536.

However, there is still a need for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents by various routes.

SUMMARY OF THE INVENTION

The present invention provides compounds and .compositions : which facilitate the delivery of active agents. Delivery agent compounds of the present invention include those having RX the following formula rR?

R’ R®

RS COOH

2 NRT”

R 0 R

R! em em mee and salts thereof, wherein

. : R!, R?, 2%, and R! are independently H, -OH, halogen, , C1-Cq alkyl, C-Cq alkenyl, C,-C4 alkoxy, -C(O)R?, -NO;, -NR°R!, or -N*R°RIOR!! (R!?)7; - : RS is H, -OH, -NO,, halogen, -CF3, -NRYR!®, -N'RYR!’R!® (R*?)", amide, C,-C;, alkoxy, C;-Cj» alkyl, C;-C;; alkenyl, . carbamate, carbonate, urea, or -C (0) RE; : R® is optionally substituted with halogen, -OH, =-SH, or -COOH; — © ~~" "R® is optionally interrupted by O, N, S, or =C(O)-; -

R® is a C;-C;; alkylene, C,-C;; alkenylene, or arylene;

R® is optionally substituted with a C;-C4 alkyl, C;-C4 alkenyl, Ci-Cs alkoxy, -OH, -SH, halogen, =-NH;, or -CO.R%;

RE is optionally interrupted by O or N;

R’ is a bond or arylene; h 15 R’ is optionally substituted with -OH, halogen, -

C(0)CH3, -NRMORY, or -N'RYRMR¥ (RY)7;

R® is H, C,-C4 alkyl, C;-Cq4 alkenyl, or -NHj; ~ R?, R!?°, R!, and R!? independently H or C;-Cj;o alkyl;

FEI R!? is a halide, hydroxide, sulfate, = 20 tetrafluoroborate, or phosphate; and

ES - RY, R!® and R!® are independently H, C;-Cyo alkyl, C;- . Cio alkyl substituted with -COOH, Cp-Ci; alkenyl, Cp-Ci; alkenyl substituted with -COOH, -C(0)R';

R'’ is -OH, C;-Cyy alkyl, or C;-Cj2 alkenyl; and

R'® is H, C;-Cs alkyl, -OH, -NRMR!®, or N'RMRPR!(R"). with the proviso that when R!, R?, R} RY and R® are H, and R’ is a bond then R® is not a C;-Cg, Cg or Cio alkyl; . when RY, RZ, R3, and RY are H, R® is -OF, R’ is a bond then

R® is not a C;-Ci3 alkyl; when at least one of RY, R?, R? and R® is not H, R® is -

OH, R’ is a bond, then R® is not a C;-C4 alkyl; when R!, R?, and R® are H, R* is -OCHs;, R® is -C(O)CH;, and

— oo -Wooms% — .— —— ___PCTASIB0662. —

R® is a bond then R’ is not a Ci; alkyl; and TT when R!, R?, RY, and R®> are H, R’ is -OH, and R’ is a bond ) then R® is not a methyl.

According one preferred embodiment, R! is hydrogen; R?, -

R? and R’ are independently hydrogen, halogen, -OH, or -OCHj;

I. R® is hydrogen, -OH, or -C(O)CHjs; R® is C,-Cy2 alkylene, and rR’ ] is a bond or para-phenylene. R’ is more preferably a €;-Cg alkyl.

According to another preferred embodiment, at least one of RY, R?, R3} and R?! is hydrogen, -C(O)CH;, -OH, Cl, -OCH,, F, or -NO,. In one more preferred embodiment, R? is -C(O)CHj, -

OH, -OCHj3, or -Cl. In another more preferred embodiment, R? is

Cl, -OCH;, F, or -OH. In yet another more preferred embodiment, R*? is -OCH3 or -NOa.

According to yet another preferred embodiment, R® is -

C(O)CH;, -OH, H, -CH=CHCH;, -NH;, =-NO;, ~NHC(O)CHi;, -CH=CHCO:H, -C (0) CH,CH3, -C(O)NH;, -~C{(O)NHCH3, -COOH, -C(O)NHCH.CHj3, -

C(O) NHCH (CH3) ,, —-OCH3, -C(CH3),0H, -C(OH) (CH3)2, or -CH(OH)CHs.

According to yet another preferred embodiment, R® is a oo } 20 linear C,-C;, alkylene. More preferably, R® is =-(CHz)n-, where n is an integer from 1 to 10. .

According to yet another preferred embodiment, R* and R® are not alkyl or halogen.

According to yet another preferred embodiment, R’ is para- phenylene or a bond.

According to yet another preferred embodiment, R® is -CH,- and R’ is phenylene and, more preferably para-phenylene. More preferably, at least one of R!, R?, R’, and R' is hydrogen. "TTT Nore preferably, B® is “Ci0)CH;, OH or -C(CH3lp0H. © TT "C

According to yet another preferred embodiment, R’ is a bond, R® is -OH, and R}, R?, R’, and R! are hydrogen. R® is preferably C4-Cy; alkylene and, more preferably, C;-Cs alkylene.

According to yet another preferred embodiment, R’ is a

, bond, R® is -OH, and at least one of rR}, R?, R}, and R' is not : hydrogen. R® is preferably C;-Ci; alkylene, more preferably Cs-

C12 alkylene, and most preferably Cs-Cg alkylene. ) According to yet another preferred embodiment, R” is a bond, R® is -C(O)CH3;, and R', R?, R’, and R® are hydrogen. R® is : preferably C;-C;; alkylene, more preferably C3-Cy; alkylene, and most preferably C;3;-C,; alkylene.

According to yet another preferred embodiment, R' is a bond and RY, R?, R}, R'and R® are hydrogen. Pre ferably, R® is B

C;-Cg alkylene.

According to yet another preferred embodiment, R? is a } bond, R® is hydrogen, and at least one R!, R?>, R’, and R' are not hydrogen. R® is preferably C;-Cj; alkylene, more preferably

C4-Co alkylene, and most preferably C;-Cs alkylene. - 15- According to yet another preferred embodiment, R? is -OH.

More preferably, R’ is a bond and R® is hydrogen. Preferably, ¢ R® is C;-Ci alkylene, more preferably C3-Cy alkylene, and most - preferably C,; alkylene.

Reon According to yet another preferred embodiment, R? is -OH. oe 20 More preferably, R” is a bond and R® is hydrogen. R® is : preferably C,-Cjy; alkylene, more preferably C;-Cg alkylene, and y most preferably C; alkylene.

Preferred delivery agent compounds include, but are not limited to, those described in Table 1 below, and salts thereof.

TABLE 1

EZ LL EE ES I

[4 [Hmm |H Jou ~~ (CH), |bond [6 [a [wm [a [m Jon = [(CHjs [bond |]

CL WOOMR8% PCTS —

SG el - (CH3) 2

I

EEE CA EE ER CE EN

‘ oo oH |H : H . Tw Tn ww [clon licks [bona =

CH; -— 63 _lH. H jC(Q) |H _ _|H | (CHz2)y bond — ET -.- 3 - - = Ti for Te m5 lichiny; [bond [72 w |m [A [A [oH ~~ [(CH)y [bond

CT 17s [nu |H

Sa. i i : CH,CH (OH) wr H H OCH3 H H (CH) 6- bond a ER . CH (CH3) .| 82 H H OH H H (CH) s-— bond

A ll

Hs) 88 H H H H ~C (0) NH- CH» bond

ET

H H H C(0)- | O-(CHp)1- -{CH>)q- bond

I Fl = a

TT NOMS a Resse * - The term “para-Ph” represents para-phenylene.

More preferred compounds include, but are not limited to, . . 5 compound nos. 5, 7, 11, 12, 43, and 47.

The invention also provides a composition comprising at . - one of the delivery agent compounds of the formula above, including those compounds excluded by proviso, and at least - one active agent. These compositions deliver active agents to ; 10 selected biological systems in increased or improved - bicavailability of the active agent compared to administration -of the active agent without the delivery agent compound.

Also provided are dosage unit forms comprising the

R compositions. The dosage unit may be in the form of a liquid . 15 or a solid, such as a tablet, capsule or particle, including a . - powder or sachet. - - - . Another embodiment is a method for administering an active agent to an animal in need of the active agent, by — _administering a composition comprising at one of the delivery - agent compounds of the formula above, including those i . compounds excluded by proviso, and the active agent to the . .animal. Preferred routes of administration include the oral, intracolonic and pulmonary routes. : Yet another embodiment is a method of treating a disease 25 .or for achieving a desired physiological effect in an animal by administering the composition of the present invention.

Yet another embodiment is a method of preparing a composition of the present invention by mixing at least one

TT TTT TT delivery agent compound of the formula above, including thosé Si compounds excluded by proviso, and at least one active agent. -Q-

DETAILED DESCRIPTION OF THE INVENTION

Delivery Agent Compounds ; The terms “alkyl” and “alkenyl” as used herein include linear and branched alkyl and alkenyl substituents, . respectively.

The delivery agent compounds may be in the form of the carboxylic acid or salts thereof. Suitable salts include, but 7 "are not limited to, organic and inorganic salts, for example ~~ ~~ alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids, such as lysine or arginine; and organic amines, such as dimethylamine or : pyridine. Preferably, the salts are sodium salts. The salts : 15 may be mono- or multi-valent salts, such as monosodium salts and di-sodium salts. A preferred disodium salt is the disodium salt of compound 47. The salts may also be solvates, including ethanol solvates, and hydrates. be ’ - Salts of the delivery agent compounds of the present = 20 invention may be prepared by methods known in the art. For

L LC . example, sodium salts may be prepared by dissolving the . delivery agent compound in ethanol and adding aqueous sodium : hydroxide.

The delivery agent compound may be purified by recrystallization or by fractionation on one or more solid chromatographic supports, alone or linked in tandem. Suitable recrystallization solvent systems include, but are not limited to, acetonitrile, methancl, and tetrahydrofuran.

Fractionation may be performed on a suitable chromatographic support such as alumina, using methancl/n-propancl mixtures as the mobile phase; reverse phase chromatography using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water or an

Claims

WHAT IS CLAIMED IS: -

P

1. A compound having the formula . 3 R* R> R® RS COOH ———————————————————————R?%~ f— ZN ES Cee rR! and salts thereof, wherein R!, R?, R’? and R' are independently H, -OH, halogen, : 10 C,-C4 alkyl, Cz-C,4 alkenyl, C;-Cg alkoxy, -C(0)R%, -NO,, -NRPR!?, or -N'RORMRM (R!%)7; RS is H, -OH, -NO,, halogen, -CF3, -NRMR!?, -N'RMRVR'® (RY, amide, C;-Cj» alkoxy, Ci1-Ciz alkyl, C,-Ci2 alkenyl, carbamate, carbonate, urea, or -C(O)RY; R® is optionally substituted with halogen, -CH, -SH, : or -COOH: R® is optionally interrupted by 0, N, §, or -C(O})-; . R® is a C,-C;; alkylene, C3-Ci alkenylene, or arylene; R® is optionally substituted with a C-C4 alkyl, C;-Cq4 alkenyl, Ci1-C; alkoxy, -OH, -SH, halogen, -NH:, or -CO,R%; R® is optionally interrupted by O or N; R’ is a bond or arylene; R’ is optionally substituted with -OH, halogen, C(0)CHs, -NRMR', or -N*RIMRMRY (RY); R® is H, C;-C. alkyl, C,-C4 alkenyl, or -NH;; R®, R!?, R!, and R!? independently H or C;-Cjo alkyl; R}? is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; and

RY, R!® and R!® are independently H, C;-Cyq alkyl, Ci- Cio alkyl substituted with -COOH, C;-C;» alkenyl, C;-C;; alkenyl ) substituted with -COOH, -C(O)R'7; ’ RY is -OKH, C;~Cjp alkyl, or C;-C;; alkenyl; and R® is H, C;-C¢ alkyl, -OH, -NRMR!®, or N'RYMR!°R¢(R!3). : with the proviso that when R!, R?, R3, R*, and R®> are H, and R’ is a bond then R® is not a C;-Cq, Cg or Cy alkyl; — —- — when RY, rZ, RY, -—and" RY are H, R® is =OH, R’ is a bond then a R® is not a C;-C; alkyl; when at least one of R!, R?, R?® and R*! is not H, R’ is - OH, R’ is a bond, then R® is not a C;-C4 alkyl; when R}, R?, and R® are H, R* is -OCH3, R® is -C(O)CH;, and R® is a bond then R’ is not a C3 alkyl; and when R!, R?, R% and R® are H, R® is -OH, and R’ is a bond then R® is not a methyl. no 2. A compound selected from the group consisting of Sa R* : RL RS RS COOH R? 0” “rR R' EE EE EN I EO 6 [ww [mm Jom [(CHy. [bona (6 ~ [uw [uw Ju fou ~~ [(CH)s _ [bond

J -WO.01/32596 om PCT/USN0B30662 [Om [mA [HH |C(O)CH; _ [(CHJ3 [bond Soi Iw [wi [cick [(Chis [bond : ve (19 nu [mH NH, [(CH)s Ibond [mm [mw |H [N0, (CH), [bond 21 {un |H |u| |W, (CH), [bond [22 a |a {cx |W [NH | (CHy)y |bond |] ” 23a |m [ci |W NH, [(CH)s [bond : Ti [nn [iw lci-cicon (chs [bond [27 __|H___|H _|[H |H _|C(O)CHCHs | (CHy)s |bond [26 | |[H |H |H _|C(O)CHCHs [(CHy)y |bond - [29 [m_|H |B |H |C(O)CH,CH; [(CHp)y [bond - [30 [nw |AH [AH |W [C(O)NH, [(CHp)y [bond ) [31 |n_ |B [H |H _|C(O)NHCH; [(CHp)y [bond ” 32 |a |r [WH |B JcOOH | (CHj)y |bond - 3)2 Co : : } (38 |[n|H _|H [OH [C(O)CHy | (CHp)y [bond : a3 fa lom |W |m |W ~~ |(CH), |bond 4a |n_ Jom [H [mH T(CHJ)o |bond - 46m Jom |H Ww Im ~~ |(CH)y [bond a8 [uw |m Jom |H JH (CH), [bond (asm [8 Jou w |H ~~ |(CH)s [bond (56 |H_ |OCH; [H |H _|C(OJCHy _ [(CHp)y [bond [58 |n |H CH, |H [C(O)CHy | (CHp)s [bond

EIEN EEE EEC CN CE 0 nA Is [a [com | (chy, _ [bond a 62 H H c(o)c |H (CH) 4 bond a H,CH3 Ee -eom— CH 4 ————rA———— }-——— -- —] —— A : p (78 [mm [mw | Jc1 ~~ [CH ___ |para-Ph ” err CH (CHa) ~ 81 H OH H H (CH;) ¢= bond 82 H HB OH H H (CH) 6 bond NA 2 ll Hj) 88 H H H H -C(0O)NH~ CH; bond NE SE = 92 |n__ |CH; |H _[H |CHy ~~ [(CH)s |bond H H H C(O) | O-(CH3)7~- -{CH3) 7- bond I A Ea i and salts thereof.

3. A composition comprising: (A) an active agent; and (B) at least one compound having the formula

—WOM359% —— eee PCT/RISON30662—

R® . R3 RS . RS COOH R 0” “RT - R! and salts thereof, wherein : R!, R?, R’, and R® are independently H, -OH, halogen, C:-C4 alkyl, C2-C, alkenyl, C;-C; alkoxy, -C(0)R®, -NO,, -NR°R!‘, or -N'R°RM@R™ (R!?)"; ) R®> is H, -OH, -NO;, halogen, -CF3, -NRIR!®, -N*RYRI°R!® (R'?)", amide, C;-Ci» alkoxy, C;-C;z alkyl, Cz-C;; alkenyl, carbamate, carbonate, urea, or -C(O)R%; R® is optionally substituted with halogen, -OH, -SH, ’ or -COOH; = R® is optionally interrupted by O, N, S, or -C(0O)-; ee R® is a C;-Ci2 alkylene, C,-C;; alkenylene, or arylene; - R® is optionally substituted with a C,-C, alkyl, C,-C, alkenyl, C;-C4 alkoxy, -OH, -SH, halogen, -NH;, or -CO,R%; R® is optionally interrupted by O or N; R’ is a bond or arylene; R’ is optionally substituted with ~OH, halogen, - C(O)CHs;, -NR'MR!!, or -N'R!RUYMR'? (RY?)"; R® is H, C;-Cq alkyl, C,-C4; alkenyl, or ~-NHj; R%, R!', R!Y, and R!? independently H or C;-Cyp alkyl; R*® is a halide, hydroxide, sulfate, © tetrafluoroborate, or phosphate; and | I To RY, R'® and R'® are independently H, C;-Cjo alkyl, Ci- Cio alkyl substituted with ~COOH, C;-C;; alkenyl, C,-C;» alkenyl substituted with -COOH, -C(O)R'; RY? is -OH, C1-Cyo alkyl, or Cz-Cj;; alkenyl; and

: R'® is H, C;-Cg alkyl, -OH, -NRYR!S, or N*RYRISRIS(R!?). - with the proviso that when R!, R?, R?}, RY, and R® are H, and R’ is a bond then R® . is not a C;-Cq¢, Cg or Cjp alkyl: ] 5 when R!, R?, R?}, and RY are H, R’ is -OH, R’ is a bond then R® is not a C;-C;3 alkyl; ___________ _ _ when at least one of R}, R? R} and R’ is not H, R® is - a OH, R’ is a bond, then R® is not a C1-C4 alkyl; when R!, R?, and R® are H, R® is -OCH;, R® is -C(O)CH3, and R® is a bond then R’ is not a Cj alkyl; and . when R!, R?, R?, and R® are H, R® is -OH, and R’ is a bond then R® is not a methyl.

q. A composition comprising: ) 15 (A) an active agent; and Co (B) at least one compound having the formula : | rR? : Rr’ R® ) _R®___COOH R O R R! ) nd a a ES EN EE ETE (3 [uw Hu jn [wm [oH ~~ [CH _ |bond [a Ju Ju [8 [BH JoH ~~ [(CHy; (CHz) s (6 [uw Jw [nw [nm Joi ~~ [(CHJ)e [bond (Chr), [bond 8 Iw [8H [HH JH JOB [| (CH bond |] (ow fu [uv [8B [croc (CHz) 3 ooo Wess oe -——PCWUSMA0662- EINE EEN EE (10 [Hw fH H Jc(o)CH; [(CHp)s ___ |bond . . (17 ju [WH fH JH Ju [(CHp)yjo |bond = 120 Ju Iw fw JH JwOo, ~~ [(CHp); [bond (21 JH Inu JH INH, ~~ [(CHp)s [bond * 22 [eu Jc1 JH INH, ~~ [(CHp); [bond [24 Ju Iw [H |H [NHC(O)CH; [(CHp); [bond j25 JH [H |H |H [CH=CHCOH | (CH); |bond [26 |H |H |H ~~ |H |C(O)CHxCH3 | (CHp)3 |bond : [27 [HH [H ~~ [H |C(O)CHCHs | (CHp)s _ |bond * [28 [nu [H [H [C(O)CH)CHy [(CHp)y; _ Ibond = (29 |n |H |H |H |C(OJCH,CHs [(CHp)s [bond oh [32 Ia [8 [BH [H JcooH ~~ T(CHp)7; [bond {33 1# 1w TH = [H [C(OJNHCH,CH; | (CH); |bond 3)2 # [36/8 |H [H JH |CH(OH)CH3 | (CH); |bond 38 In [nH ~~ |oH Jc(o)CHy ~~ [(CHpy)y [bond (43 |m Jow JH ~~ fH iH ~~ (CH); |bond (44 JH Jou Ju [BH [HH ~~ 1(CH)g [bond (a5 Jw Jon [WH ~~ |H |H ~~ |(CHp)s |bond 146 [H JoB [HH JH ~~ [(CH)s [bond 47 nn Ju Jou Iu Ju ~~ 1(CHy)s _ [bond (48 [WH [nw fom JH JH ~~ [(CH))s [bond (49 Jn uw Jon |H [H = |(CH)s [bond oie ks0- Iw IH JOH JH [BH J (CH)s [bond [51 |H |H |H |H [C(O)NHCH; |.(CHp)s [bond 154 |v [HH [a [BH [C(O)CH3 [| (CH))s [bond |] [56 [H [oCHs [H ~~ |H |C(OJCHs; | (CH) |bond (57 ju [a [on |H |C(O)CHy | (CH;)» [bond

EINE EEE EE ‘ 60 nH a [# |C(OH _ [(CHjs [bond ’ 61 |n_|H__|H___[H |C(O)H _ [(CHps [bond . 62 H H c(o)C |H (CH3) 5 bond = — H,CH; SS i 5 Ec a LL | CHs es lm |n [A_ [Wm JH (CH), [bond _ es |n_Jci [HH [nH | (CHj, bond %5 |H__JocH; [H [HW [H [(CHj, bond | } ) 4 JH _|NO, |m _ |u _JOH | (CH); bond > eT 8 [nu Jc TcW, __ [parabh CH (CHa) _ : CH (CH3) i 82 H H OH H (CHa) ¢- bond SE A = LL Hi) - [88 H H H H -C (0) NH- CH» bond EE = fc 51 [H_[cHs [A |W __|cHy [(CH;)s [bond Se [= [8 |NH, [m_[H |para-Ph bond (C (CH3) 2) and salts thereof.

oo ——WomMBsee— —. . ___ _ PCTUSWB062_

5. -- The composition of claim 4, wherein the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, and a combination thereof. = 5 6. - The composition of claim 5, wherein the biologically active ro agent comprises at least one protein, polypeptide, peptide, _ hormone, polysaccharide, mucopolysaccharide, carbohydrate, small ve polar organic molecules, or lipid. } on 10 7. ._ The composition of claim 5, wherein the biologically active agent is selected from the group consisting of: growth hormones, human growth hormones (hGH), recombinant human growth hormones - (rhGH), bovine growth hormones, porcine growth hormones, growth : hormone-releasing hormones, interferons, a-interferon, B- interferon, y-interferon, interleukin-1, interleukin-2, insulin, So a porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, - chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, . salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin (EPO), atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, . adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating . hormone, glucocerebrosidase, thrombopoietin, filgrastim, : - prostaglandins, -cyclosporin, vasopressin; - cromolyn: sodium, -- EE sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine, bisphosphonates, alendronate, tiludronate, etidronate, clodronate, pamidronate, olpadronate, incadronate, parathyroid hormone, fragments of parathyroid hormone,

antimicrobials, daptomycin, anti-fungal agents, vitamins; analogs, fragments, mimetics and polyethylene glycol-modified i derivatives of these compounds, and any combination thereof. ] 5 8. The composition of claim 7, wherein the biologically active - agent comprises insulin, unfractionated heparin, low molecular < weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, parathyroid hormone, oo ] erythropoietin, daptomycin, human growth hormones, analogs, - 10 fragments, mimetics or polyethylene glycol-modified derivatives of these compounds; or any combination thereof. EE

9. The composition of claim 8, wherein the biologically active N agent comprises calcitonin. ’ 15 : 10. The composition of claim 8, wherein the compound has the > formula BN : - rR R> R® , _R%_ , COOH R (@) R R! 1 ES ES EN EO CS CN (CHa) 5 © 11. A dosage unit form comprising: (A) the composition of claim 4; and (B) (a) an excipient

To Woes Rese {(b) a diluent, : \ (c} a disintegrant, (d) a lubricant, (e) a plasticizer, ) . 5 {(f) a colorant, (g) a dosing vehicle, or : (h) any combination thereof. ’ 12. The dosage unit form of claim 11, wherein the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, and a combination thereof.

13. The dosage unit form of claim 12, wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, small . polar organic molecules, carbohydrate, or lipid.

14. The dosage unit form of claim 12, wherein the biologically . = active agent is selected from the group consisting of: growth hormones, human growth hormones (hGH), recombinant human . growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone-releasing hormones, interferons, a-. interferon, B-interferon, y-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, oT © ““héparinoids, dermatans, chondroitins, low molecular weight C= heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin (EPO), atrial naturetic factor,

doef antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine, bisphosphonates, alendronate, oo oo tiludronate, etidronate, clodronate, pamidronate, olpadronate, incadronate, parathyroid hormone, fragments of parathyroid hormone, antimicrobials, daptomycin, anti-fungal agents, vitamins, analogs, fragments, mimetics and polyethylene glycol- modified derivatives of these compounds, and any combination thereof. . 15 .

15. The dosage unit form a claim 14, wherein the biologically 5, ; active agent comprises insulin, unfractionated heparin, low molecular weight heparin, very low molecular weight heparin, oo ultra low molecular weight heparin, calcitonin, parathyroid " 20 hormone, erythropoietin, human growth hormones, analogs, , fragments, mimetics or polyethylene glycol (PEG) -modified derivatives of these compounds; or any combination thereof.

16. The dosage unit form of claim 15, wherein the active agent comprises calcitonin.

17. The dosage unit form of claim 12, wherein the dosage unit form comprises a tablet, a capsule, a powder, or a liquid.

18. A composition as claimed in claim 4 for use in a method for administering an active agent to an animal in need of the agent, -104- AMENDED SHEET the method comprising administering the composition orally to the animal.

19. A method for preparing a composition comprising mixing: (A) at least one active agent; (B) at least one compound as claimed in claim 2; and (C) optionally, a dosing vehicle. -105- AMENDED SHEET