AU738735B2 - Compounds and compositions for delivering active agents - Google Patents

Description

1 1946/2C892 COMPOUNDS AND COMPOSITIONS FOR DELIVERING ACTIVE AGENTS FIELD OF THE INVENTION The present invention relates to compounds for delivering active agents, and particularly biologically or chemically active agents.-These compounds are used as carriers to facilitate the delivery of a cargo to a target. The carrier compounds are well suited to form non-covalent mixtures with biologically-active agents for oral 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, o *these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself. Biologically or chemically active agents are particularly vulnerable to such barriers.

For example in the delivery to animals of biologically active or chemically active pharmacological and therapeutic agents, barriers are .i imposed by the body. Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target. Chemical WO 98/34632 PCT/US98/02619 2 barriers include, but are not limited to, pH variations, lipid bi-layers, and degrading enzymes.

These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers such as varying pH in the gastrointestinal (GI) tract, powerful digestive enzymes, and active agent impermeable gastro-intestinal membranes. 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 are rapidly rendered ineffective or are destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, or the like.

Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants 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 pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation.

Liposomes have also been described as drug delivery systems for insulin and heparin. See, for example, U.S. Patent No. 4,239,754; Patel et al. (1976), FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979), Endocrinology Japan, Vol. 26, pg. 337.

However, broad spectrum use of such drug delivery systems is precluded because: the systems require toxic amounts of adjuvants or inhibitors; suitable low molecular weight cargos, i.e. active agents, are not SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCTIIUS98/02619 3 available; the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; the systems fail to protect the active agent (cargo); the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.

More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals. For example, U.S. Patent No. 4,925,673 describes drug-containing proteinoid microsphere carriers as well as methods for their preparation and use. These proteinoid microspheres are useful for the delivery of a number of active agents.

There is still a need in the art for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents.

SUMMARY OF THE INVENTION Compounds and compositions which are useful in the delivery of active agents are provided. These compositions include at least one active agent, preferably a biologically or chemically active agent, and at least one of the following compounds 1-193, or salts thereof.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIUS98/02619 4 0

CI

Y-(

3 .5-dichtoro-2-hydroxybenzoyl)aminocaproic acid

OH

II 0 a.NH 2 8( 2 -aminobenzoylamino)caprylic acid F3 M 3 8(2-trifluoromethoxy)benzoylamino caprylic acid 04

OH

OH

0 N-(2-hydroxybenzoyl)isonipecotic acid

NH-

2 0 0

H

4 4 -(2-aminobenzoyamino)phnyIbutyryihydroxamic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 PTU9IZ1 PCTftJS98/02619 4-(4-(3-anisoyl)aminopheny)butyric acid 0 CHO N1 8-(3-anisoyt)aminocaprylic acid 0 1 4 4 -(Phenoxyacetylaminophenyl)butyric acid 0O 444-(2-nitrobonzenesulfonyl)aminophenyl)butyric acid 0

NOZ

8-(2-riitrobenzenesulfoflyl)aminocaprylic acid 11 SUBSTITUTE SHEET (RULE 26) OH 0 12 0 6-(4.(salicyloylamilophelfhexaflaic acid 0 13 H 0 8-(2-mnethoxylbenzoyl)amino caprylic acid H 14 OH 011,CH 2-[(4-salicyloyl)aminophenyllethyl methyl sulfone H HO N, N)

COOH

:OH 0 H 1 -Saticyloyl-2-succinyl hydrazide 016 *0

OH

H

3.(4-(2.5dimethoxycnal)amlophellpfopiofiC acid CO 0

CHIH

44(4-(2-5-dimethoxvclnnamovYUmiopheylYbutyric acid 18 19 1 -salicyloyt-2-guta'yl hydrazide HO NN

HOOOH

4-(4-((4-carboxyl-3-hydroxy phenyl)amiino)succinyl)ami nosalicyclic acid 0 8-(2-pyrazinecarbonyl)amnocpryic acid 21 22 4 4-(4-(2-pyrazinecarbony)aminophenyl)butyric acid 6G1 4 2 -Nitrobenzoyl)aminophenyl)hexanoic acid

*OH

1 0 6-(4-(N-2-aminobenzoyl)aminophenylihexanoic acid 23 24' 0 OiOl -(6-carboxyl-2,5-pyrazinylcarboxyl)aminophenyl)butyi ic acid U. U

U

U

U

U

U

A

U

U.

26 27 4(2-NitrobenzoVl)aminophenylsuccinic acid Q-YH

OH

OCF

3 0 I. i 8-( 2 -(tifuoromethoxy)benzoyl)aminocapryic acid H 28 OH 0 29 8-(benzyloxycarbonylaino)Caprylic acid laoi OH H 0 8-(phenoxycarbonylamino)capryic acid H 31 N 0

OH

2.4(-ohxbnolniopeyity

H

2 P0 4 0 0 32 1 -salicyloyI-2-subegyl hydrazide 33 0 4-(4-benhyoxycarboflytfmiopheylbutyfiC acid 34 36 9 -SalicYloy1aminononanic acid 4-(4-phenyloxycarbonylaminophenyhlbutric acid 9 37 38 39 6 2 -methoxybenzoyljamino nicotinic acid WO 98/34632 WO 9834632PCTIUS98/02619 salicyloylglycine C'N N 0 0 4-(1 2 -pyrimidyl)piperazinoyl)butric acid o o 1-NH-

OH

0) 0 41 42 43 44 8-(chromone-3-carbonylaminocaprylic acid 0

QN

Off 8-(vinylbenzoyl)aminocaprylic acid 4-(4-(chronione-3-carbonylainophenyl)butyric 01 8-cinnamoylaminocaprylic acid SUBSITrUTE SHEET (RULE 26) 12 0H H 46 N OH O 0 acid OH H 4 O47 9-(Z-hydroxybenzamido)nonanilc acid 48 0

HY

H 0* OH 0 6-(N-4-(N-salicyloyl)aminobenzoyl)aminocaproic acid 0 49 0 4-flavanic acid -cinnamoylaminoundecanoic acid OH H HO Y&0 0 4-c ctanoylaniino-3-hydroxybenzoic acid WO 98/34632 WO 9834632PCTIUS98/02619

OH

(3Phenyl2,3dihydroxypropanoyl)8aminocaprylic acid 52 8 3 -coumarincarbonylllaminocaprylic acid 8-[N-(4-chlorobenzoyl)Iaminocaprylic acid 53 54 56 57 OH 0

HO

OH

8-(N-2.5-Dihydroxybenzoyl)aminocaprylic acid! 8-(N-2.3-Dimethoxybenzoyl)aminocaprylic acid SUBSTITUTE SHEET (RULE 26) CH0 8-(N-2.4-Dihydroxybenzoyl)aminocaprylic acid

OH

N

CH

3 0 8-(N -2.5-Oimethoxybenzoy)aninocaprylic acid 58 59 61 *so.

84(8-(4-hydroxybenzoyt)aminooctanoyl)anunocaprylic add I

OHOH

1140bo--"tt0 di mer) 62 63 8.(N-2.4-DihydrOXYbezoyI)minOcapry~ic acid Sa* a..

l'Ct-(N4-2-Methoxyanhlinoisebaic acid 9 OH H 0 .1O-(N-2-hydroxyanilino) sebacic acid

CH

3 H 0 o

OH

2-Methoxybenzelamfltodecafloic acid 0

OH

0 H 0 64 66 67 8-(N-benzoyI)amilocapryric acid

S

.5 I>*u S 7' OPF~C OH 0l

OOO

pu~0 acid 68 69 -8-IN-(4-fluorobnzoAl)ainocflryic acid rt 8.EN.43bronobeoyl)afhinocapric acid WO 98/34632 WO 9834632PCTIUS98/02619

OH

HO

0 .2-dihydroxyethy)benzoyl)aminocaprylic acid NH, .o 71 72 8 -IN-(4-bromobenzoyl)Jaminocaprylic acid

NH-._NCOOH

8-[N-(4-iodobenzoylaminocaprylic acid 4 4 fN(2iodobenzoy)aminophenyljlbutyric acid OH 0H N,'l

H

4-{4-IN.(l l 4 ydroxy- 2 -naphthoyI)aminophenyIIlbutric acid 73 74 SUBSTITUTE SHEET (RULE 26) acid 76 77 4 -1o-anisoyl)aminophenylacatic acid 0 4-dimethoxybenzoyQ) aminophenyll proplonic acid (4-[N-(4-iodobenzoylli amninophenvfl butric~ acid 78 4- Olt 79 3-4-1 2.3-dimethoxybienzoytl aminoolienvil orooionic acid I OOH Or 4 4 4N-(2-broanobenzoyl)Jamlnopheayl) butyric acd 4- (4-[N-(3-bromobenzoyl)aminophenyl]) butyric acid 0 Ito 0 C) 0 HO0 81 82 83 84 4-(4-(N-(4-bromobenzoy)apfinophenyIJ)butyric acid

COOH

B.(2-hydroxy-4-chlorobenzoyllaminocapgc acid 86 WO 98/34632 WO 9834632PCT/US98/02619 OH 0 0 NH- 0

OH

8-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid 87 88 89 8 5 -chloro-o-anisoyl)aminocaprylic acid 4-(4-(23-dimethoxybenzoyl)amifophel)butyric acid

OH

00 CQC0 0HO CI

OCH

3 4-(4-(-chloro-o-anisoyl )aminophenyl)butyric acid 91 92 SUBSTITIUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIUS98/02619 0 Cl

OCN

3 93 94 8 4 -chloro-o-anisoyl)aminocaprylic acid (o 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid I jo OOH

H.

4-{N-[4-(3-iodobenzoyl)aminophenyllbutyric acid 96 97 98 8-N-(4-methoxy-3-nitrobenzoyl)aminocapryic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 PTU9121 PCTIUS98/02619 21 O*A~ 99 8-N-(2-methoxy-4-nitrobenzoyl)aminocaprylic acid 1100 4 -{N-f4-(2-nmethoxy-4-nitrobenzoy)aminophenylJ~butyric acid 0 OH 101 I H 4-(4-(2,5-dimethoxybenzoyl)aminphenyl)butyric acid 102 Br HiI 8-(N-2-hydroxy-5-bromobenzoyl)aminocaprylic acid OH 103 DN 0

H

3 -Indolebutyric acid 104 SUBSTITUTE SHEET (RULE 26) 105 106 107 108 109 acid 110 8-AN-2-hydroxy-5iodobenzoyI)aiOcapfric acid WO 98/34632 PTU9/21 PCTIUS98/02619 111 1 12 8-(N- 2 -hydroxy-4-nritrobenzoyi)aminocaprylic acid 4 -1N-( 2 -hydroxy4bromobenzoy)aminophenylbutyi.ic acid

I

HO'e lN-

OH

0 113 114' 115 8-(N- 2 3 -Dihydroxybenzoyl)aminocaprylic acid II3C.%~OH 8-(N -3-methylsalicyloyl)aminocaprylic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIUS98/02619 0O-1 0 I-f 0 8 5 -methysalicyloyl)aminocaprylic acid 116 117 11-8 119 9 -(cinnamoylamino)noo. acid

CI

oiY off acid N~ ~~-CC 2

H

H

H

120 121 fJ- 2 -nitrophepyI.N'48..octanoic acid) urea

H

N-(

2 -mthoxY..5-nlropheny) sebecoyl amide acid SUBSTITUTE SHEET (RULE 26) 8{N-(2-hydroxy-3,5-dibromobenzoyl)]aminocaprylic acid 8-fI-(2-chioro-6-fluorobenzoyl)aminocaprylic acid 122 123 124 125 126 127 00* **o 00.0.

409.

8-f (4-hydroxy-3-nitrobezoylicapryic -acid 4 4 -Salicytoyiaminophenyl)-4-oxobutyric acid 128 129 4-f 4 4N-(3-hydroxy-2-naphthoyl)anpanophenylj Ibutyric acid 0 8-(4-chloro-3..niu'obenzoyl~amnocapryic acd 0 I

N

QZ: 0 130 131 9e S S S S

S.

S S 5 5 5.

S

5* 0 S S 5e

S

S S S S 5505 8-( 2 -chloronicotinoyljaminocaprylic acid -0 0H 00 0 CO 2

H

*4-(4-phthalromidophenyllbutyric acdd 132 ease .00.

0 0 133 ho

H

HMO Y 0 0 134 4-141 -3 hvrox 2-nphtoyl~rniopheyljpropanoic acidi 0 oct 0 3 4 -(2.6-dimthoxybelzoyl)amilophenyhIpropbonic acia 135 136 137 V 8-(N-2-hydroxy-3.5diiodobelzoyI~amiflocapryti acid

C'

COOH

8-N2clrAfurbezy~mnc~~i acid C0 2 H4 8-(2(1 .2-dihydroisoindole-1 -one))octanoic acid OH1 0

HO

8-(N-1 -hydroxy-2-naphtoyamiocBpryic acid 138 139 WO 98/34632 WO 9834632PCTIUS98/02619 28 140 0 Coj4 8-(phthalimido)caprylic acid 0" H 0 141

N

1 O-(4-chloro-2-hydroxyanilino)sebacic acid monoamide 0 142 H OH

OCH

3 0 6-(anisoyl)aminocaproic acid 0 rO 143 4-(4-(4-chloro.3-nitrobenzoyl)aminophenyt)butyric acid I I 1144 11 -N-(l1-hydroxy-2-naphthoyl)aminoundecanoic acid SUBSTITUTE SHEET (RULE 26) 29 m)4wQ145 HOZC 1 CO 2

H

0 0 Bis(N-2carboxylphenyl-N-(N-8.octanoic acidlureal)oxatyl diamide Cl 146 2-(2-N-(2-chlorobenzoylaminoethoxyjethanoI 147 2-12-N-(4-chlorobenzoy)anmnoqthoxylethanoI 0 *:0 0 4 -{Z-methoxybcnzoylamino)phenyl 2-carboxyethyl sulfoxie 0 0 149.

0.0 0 Q0 2

H

4-(4-(3-hydroxyphthatimido)phenyl~butric acid 151 2-{[2-N-(2-methoxybenzoyl)amninoethloxyjI ethaol 152 0~0 2 2-12-N-(3-chlorobenzoyl)amninoethoxy]ethanoI 0 153

NHN

0 0 0

*OH

Bis(N-2-carboxyplienyl-N-(N*-3(4-aminoplienyllpropionic acid~urealloxaytyl diamide N~-/h~II2~154 trans-4-(2-aminobenzamiAdonmethyl)cyclobexaaocaboxylic acid 0 015 c rH 155

*H

11 -N-(3.5-dichloro-2-hydroxybenzoylaminoundecanoic acid WO 98/34632 WO 9834632PCT/US98/02619 156 157 acid 158 acid 159 acid 160 N-13.5-dichtoro-2-hydroxybenzoyl-3-(4-aminophenyl)]Propionic acid 0

C

CI

161 1 2-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecaloic acid SUBSTITUTE SHEET (RULE 26) O(-i H

N

HO&

0 N-(2-hydroxy-4-carboxyphenyl)-6-hetenamide Or 0 N-(2-bromobenzayfmorphoflne 0 OH

H-

1 62 163 164 165 166 8-N-cydohexanoylaminocaprylic acid 2-(N-A24odobenzoyl)aminoethoxylothanoI OH H 0 1

N

OH

-(-ho2-hydroxynleyminocayligec acid 167 WO 98/34632 WO 9834632PCTIUS98/02619 O N o

CO

2

H

OH

OHH

4--Salioyl-5-(3.aminophenyl)aleric acid OH H0

ON

9-[ 2 -(3-hydroxy)pyridylamilocarbonyll nananic acid 168 169 170 171 172 2-tN-(2-hydroxYbenzoviamilo)ethoxylethanoI SUBSTITUTE SHEET (RULE 26) OK 0

H

4 4

N-(

3 5 -dichloro-2-hydraxybenzoy)Iaminophenylacetic acid -0 0 8-(2-hydroxy5-chtoroantinocarbonyl)otalolc acid 173 174 175 176 177 9-(Z2 hydroxy-5-methylanilinocarbonyl)nonanoic acid 1 I 5-(2-hydroxy-5-methyalinocrboyl)vaIeric acid 178 179 180 181 S S S S

S.

S..

S

5*55

S

5* S S 55 5*55

S

*SS*

S S

S

(CH N

OH

4-(4-(2-dimiethylaminobenzoyl)axninophenyl)butyric acid

COOH

8-(3-Phenoxylprapionylamino)caprylic acid 182

ST

N-N

NV

H

4-(Salicytoyl)amfinophenylethyltetrazole- 183 184 185 186 8 4 4 -N-saicyloyl)aniinophenyl)butyric) aminocaprylic acid

H

0 00 ~OH 4-(4-N-(4-(4-N-(2-Fluorocinnamoyl)aminophenyl)butyric)aminophenyl)butyric acid 0 0** 00 0 0* 0000 0000 0 00*0 00 00 0000 0 0000 00 00 0 **0 00 44-(~N-8(N Saticyloyt)amiflocaprylic)amiflophelyi)buWyi~c acdd 187 4 4 0 H d o ~zy i a i o a r acd 1 8 8 8-(-IdroxybenzoYI)arnino8'ryri acid OR 19 0

O

4 3 .4.5-Tdmethoxyuenzoy)aminoap~r. acid 191 **etysliyol~mncaryi acid 1 0 *.NO H 192 4w.

NO

2 I N(2hdrx--ntoaiio).. I-oxodecanoic acid ~~~yO~l193 N0 4 4 -(Z-Choronicatinoyiamino~pienlbt acid WO 98/34632 PCT/US98/02619 38 Compositions comprising the carrier compounds discussed above and active agents are effective in delivering active agents to selected biological systems.

DETAILED DESCRIPTION OF THE INVENTION The specific compositions of the present invention include an active agent and a carrier. These compositions may be used to deliver various active agents through various biological, chemical, and physical barriers and are particularly suited for delivering active agents which are subject to environmental degradation. The compositions of the subject invention are particularly useful for delivering or administering biologically or chemically active agents to any animals such as birds including, but not limited to, chickens; mammals, such as primates and particularly humans; and insects.

Other advantages of the present invention include the use of easy to prepare, inexpensive raw materials. The compositions and the formulation methods of the present invention are cost effective, simple to perform, and amenable to industrial scale up for commercial production.

Subcutaneous, sublingual, and intranasal coadministration of an active agent, such as, for example, recombinant human growth hormone (rhGH); salmon calcitonin; heparin, including, but not limited to, low molecular weight heparin; parathyroid hormone; and compounds in compositions as described herein result in an increased bioavailability of the active agent compared to administration of the active agent alone.

SUBSTITUTE SHEET (RULE 26) 39 Active Agents Active agents suitable for use in the present invention include biologically or chemically active agents, chemically active agents, including, but not limited to, fragrances, as well as other active agents such as, for example, cosmetics.

Biologically or chemically active agents include, but are not limited to, pesticides, pharmacological agents, and therapeutic agents. For example, biologically or chemically active agents suitable for use in the present invention include, but are not limited to, peptides, and particularly small peptides; hormones, and particularly hormones which by themselves do not or only a fraction of the administered dose passes through the gastrointestinal mucosa and/or are susceptible to chemical cleavage by acids and Senzymes in the gastro-intestinal tract; polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates; lipids; or any combination

S**

thereof. Further examples include, but are not limited to, human growth hormones; bovine growth hormones; growth releasing hormones; interferons; interleukin-1; interleukin-Il; insulin; heparin, and particularly low molecular weight heparin; calcitonin; erythropoietin; atrial naturetic factor; angtigens; monoclonal :'"antibodies; somatostatin; adrenocorticotropin, gonadotropin releasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroid hormone; se..

anti-microbials, including, but not limited to anti-fungal agents; or any combination thereof.

Carriers Although compounds 1-193 above have been found to act as carriers for the oral delivery of biologically or chemically active agents, special mention is made of compounds 9, 35, 64, 67, 79, 102, 109, 111, 117, 122, 136, and 141, above.

WO 98/34632 PCTIUS98/02619 Properties of compounds 1-193 are listed in Table 1, below.

TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point (oc) C H N S C H N S 1 48.8 4.70 4.40 48.81 4.64 4.39 2 64.73 7.97 10.06 64.54 7.81 10.19 3 55.33 5.80 4.03 55.40 5.79 3.96 69-71 4 62.64 6.06 5.62 62.75 6.08 5.51 151-154 65.16 6.11 13.40 65.29 6.03 13.29 144-145 6 54.70 3.24 3.75 54.29 3.24 3.54 165-169 7 69.00 6.11 4.47 69.09 6.24 4.43 126-129 8 65.51 7.90 4.78 65.60 8.25 4.83 89-90 9 68.99 6.11 4.47 69.01 6.08 4.47 104-107 52.74 4.42 7.69 52.91 4.45 7.49 142-145 11 48.83 5.85 8.14 48.95 5.89 8.02 120-122 12 69.71 6.47 4.28 69.56 6.47 4.38 144-146 13 65.51 7.90 4.77 65.23 7.88 4.72 72.5- 74.5 14 60.17 5.36 4.39 10.04 60.09 5.36 4.35 9.99 155-156 52.38 4.79 11.11 52.45 4.94 11.08 220-222 16 67.60 5.95 3.94 67.34 6.01 3.91 219-222 17 68.09 6.53 3.78 67.77 6.24 3.81 130-133 18 54.13 5.30 10.52 54.12 5.24 10.54 192.5- 195.5 19 55.26 4.21 7.16 54.48 4.32 6.86 >280 dec 65.51 7.90 4.77 65.52 7.90 4.77 75-80 21 58.85 7.21 15.84 58.86 7.16 15.69 120-122 22 63.15 5.30 14.73 63.30 5.43 14.18 197-201 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point C H N S C H N S 23 64.04 5.66 7.86 64.17 5.67 7.75 188-190 24 69.91 6.88 8.46 69.98 6.79 8.58 131-134 58.36 4.56 12.76 58.20 4.63 12.61 138-141 26 56.98 3.94 7.82 56.39 3.92 7.74 221-223 27 55.33 5.80 4.03 55.47 6.10 4.04 70-72 28 29 65.74 7.58 4.79 65.51 7.89 4.78 52-55 64.50 7.57 5.02 64.07 7.81 5.40 70-74 31 54.70 5.17 3.99 54.50 4.99 3.95 173-174 32 58.63 5.94 9.12 58.73 6.20 10.34 125-129 33 69.00 6.10 4.47 69.18 6.08 4.54 100-102 34 63.99 5.37 9.33 63.46 5.35 9.06 218- 221c 65.5 7.90 4.78 65.37 8.00 4.66 96-97C 36 68.22 5.72 4.68 67.88 5.65 4.55 134-137 37 63.14 7.23 6.69 63.15 7.29 6.58 53.5-56 38 60.00 7.14 10.00 59.78 7.31 9.94 135-138 39 61.67 4.41 10.29 61.69 4.41 10.12 225 55.39 4.65 7.18 55.52 4.77 7.30 162.5- 166 41 56.10 6.52 20.14 55.66 6.71 19.69 129-131 42 65.24 6.39 4.23 65.42 6.16 3.78 130- 133.5 43 70.59 7.96 4.84 70.35 8.13 4.79 111-113 44 68.37 4.88 3.99 68.61 4.89 3.79 120-123 70.59 7.96 4.84 70.48 7.97 4.71 108-110 46 60.75 6.37 5.90 60.97 6.18 5.80 100.5- 103 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 1- Carrier Properties Melting Compound Anal. Calculated For Found Point C H N S C H N S 47 64.50 7.57 5.02 64.42 7.58 5.01 97-100 48 64.86 5.98 7.56 64.50 6.01 7.52 165-169 49 72.18 3.76 0.00 72.13 3.84 0.00 >225 72.51 8.76 4.23 72.39 8.84 4.12 120-122 51 64.50 7.58 5.01 64.75 7.65 4.69 200.5- 204 52 7.74 4.33 7.82 4.30 88-89 53 65.24 6.39 4.23 65.15 6.46 4.23 93-97 54 60.49 6.77 4.70 60.54 6.76 4.65 114-116 64.04 7.17 4.98 63.90 7.11 4.93 105-106 56 61.00 7.17 4.74 60.49 6.92 4.65 146-148 57 63.14 7.79 4.33 63.22 7.82 4.36 59-61 58 63.14 7.79 4.33 63.17 7.86 4.26 102-104 59 63.14 7.79 4.33 63.35 7.68 4.20 89-90 60.15 6.64 3.69 59.84 6.66 3.64 112-113 61 65.53 8.85 6.65 65.34 8.73 6.67 89-92 62 61.00 7.17 4.74 60.94 7.12 4.49 104-108 63 66.43 8.20 4.56 66.29 8.23 4.36 77-78 64 65.51 7.90 4.77 65.52 8.06 4.54 97-98 69.59 9.28 4.77 69.64 9.35 4.86 62-65 66 68.41 8.04 5.32 68.41 8.06 5.28 88-89 67 62.12 7.49 4.53 61.94 7.45 4.43 98-99 68 64.04 7.17 4.98 64.07 7.16 4.95 106-107 69 52.64 5.89 4.09 52.63 5.85 4.03 109-110 63.15 7.74 4.33 63.26 7.90 4.14 97-100 71 52.64 5.89 4.09 52.67 5.99 3.97 114-115 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCTfUS98/02619 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point (oc) C H N S C H N S 72 46.31 5.18 3.61 46.25 4.86 3.52 143-144 73 49.89 3.94 3.42 49.92 3.85 3.39 170-171 74 72.19 5.48 4.01 71.51 5.33 3.75 180 66.46 6.16 4.08 66.47 6.26 4.06 168.5- 76 67.37 5.26 4.91 67.31 5.25 5.07 130-133 77 65.65 5.78 4.26 65.49 6.04 4.26 179-183 78 49.89 3.94 3.42 49.8 3.71 3.29 237-238 79 65.65 5.78 4.26 65.21 6.05 4.24 156-158 56.38 4.45 3.87 56.4 4.21 3.91 130-131 81 56.38 4.45 3.87 56.46 4.5 3.84 197-198 82 56.6 7.49 4.4 56.3 7.49 4.14 58-62 83 57.03 8.2 3.91 57.17 7.8 3.7 138-140 84 57.58 7.11 3.95 57.52 7.7 3.94 56.38 4.45 3.87 56.31 4.25 3.64 230-231 86 57.42 6.42 4.46 57.14 6.45 4.2 116-117 87 61 7.17 4.74 61.18 7.05 4.65 108-109 88 62.12 7.49 4.53 62.34 7.21 4.39 107-109 89 58.63 6.76 4.27 58.53 6.81 4.2 117-118 66.46 6.16 4.08 66.18 6.15 3.84 100-104 91 62.16 5.21 4.03 61.93 4.97 3.86 183-185 92 62.16 5.21 4.03 62.2 5.14 3.98 167-170 93 58.63 6.76 4.27 58.64 6.83 4.19 106-108 94 65.65 5.81 4.25 65.56 5.64 4.2 153-156 49.89 3.94 3.42 49.9 3.81 3.18 216-217 96 69.82 7.64 5.09 69.91 7.66 5.02 129-131 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 1 Carrier Properties Compound Melting Compound Anal. Calculated For Found Point (oc)

S

97 T I 46.31 5.18 3.61 46.54 4.95 13.64 122-123 98 99 I 56.8 6.55 8.28 56.69 6.67 18.1 I I I I6 I 56.8 6.55 8.28 57.37 6.57 8.33 1 1 7-1 1 100 60.33 5.06 7.82 59.98 4.97 7.67 207-209 101 66.46 6.16 4.08 66.37 6.32 3.96 126-128 102 50.29 5.63 3.91 50.14 5.7 3.76 129-131 103 70.93 5.95 6.89 70.94 6.44 6.89 104 65.84 6.14 8.53 65.94 6.19 8.54 228-231 105 64.96 5.77 8.91 64.89 5.82 8.82 106 66.65 6.48 8.18 66.39 6.49 8.05 140-142 107 66.47 6.12 4.07 66.5 6.26 4.08 140-142 108 60.33 5.06 7.82 60.32 4.99 7.78 150-151 109 57.41 6.42 4.46 57.07 6.44 4.39 121-123 110 44.46 4.97 3.46 133-135 111 69.28 7.03 4.25 68.86 7.07 4.11 147-149 112 55.55 6.22 8.64 55.27 5.99 8.5 120-121 113 53.99 4.26 3.7 53.98 4.25 3.63 210 decom 114 57.49 7.39 4.74 57.72 7.57 4.43 80-83 115 65.5 7.9 4.77 64.97 7.79 4.75 90-92 116 65.5 7.9 4.77 65.11 8.03 4.71 125-127 117 71.26 8.3 4.2 70.6 7.89 4.83 94-96 118 56.29 4.17 7.72 56.23 4.01 7.6 173-175 119 47.89 3.81 3.29 47.52 3.71 3.16 236-237 120 55.7 6.55 13 55.71 6.58 13.05 123-5 121 57.98 5.81 7.95 157.9 17.11 7.82 )131_133 1.17.82 1131-133 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 1- Carrier Properties Melting Compound Anal. Calculated For Found Point 0 c) C H N S C H N S 122 51.74 5.5 4.02 51.41 5.43 3.61 118- 119.5 123 41.22 4.38 3.2 41.45 4.36 2.94 143- 144.5 124 57.06 6.06 4.44 57.02 6.12 4.35 57-58 125 61.18 4.83 4.2 60.71 4.76 3.89 214 decom 126 55.55 6.22 8.64 55.4 6.24 8.53 150-151 127 65.17 4.83 4.47 65.27 4.87 4.48 208-209 128 73.03 8.99 4.06 72.92 9.36 4.1 99-101 129 72.25 5.44 4 72.14 5.24 4.01 216-217 130 52.56 5.58 8.17 52.66 5.44 8.21 96-100 131 56.28 6.41 9.38 56.32 6.42 9.28 98-100 132 52.56 5.58 8.17 52.46 5.65 7.86 150-153 133 69.89 4.89 4.53 69.64 5 4.54 136-9 134 71.68 5.2 4.2 71.24 5.1 4.13 251-253 135 65.64 5.78 4.25 65.3 5.91 4.04 79-83 136 33.92 3.61 2.64 34.48 3.84 2.48 164-165 137 57.06 6.06 4.44 57.09 6.17 4.45 88-89 138 69.79 7.69 5.09 69.68 7.78 5.08 102-3 139 69.28 7.04 4.25 68.99 7 4.1 107-108 140 66.42 6.62 4.84 66.2 6.49 4.81 88-9 141 58.62 6.76 4.27 58.66 6.93 4.18 134-135 142 63.38 7.21 5.28 63.22 7.28 5.24 71-73 143 56.29 4.17 7.72 56.19 4.04 7.65 156-160 144 71.13 7.88 3.77 70.39 7.91 3.64 95-97 145 58.44 6.06 8.02 58.25 6.38 7.84 165-8 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 1- Carrier Properties Melting Compound Anal. Calculated For Found Point (oc) C H N S C H N S 146 54.22 5.79 5.75 54.26 5.65 5.69 77-78.5 147 54.22 5.79 5.75 54.21 5.85 5.61 80-81 148 58.78 4.93 40.3 58.64 4.89 3.97 172-173 149 56.19 4.72 3.85 56.31 4.67 3.86 177 150 66.46 4.65 4.31 66.41 4.56 4.23 158-160 151 58.61 7.24 5.69 58.79 7.35 5.66 152 54.22 5.79 5.75 54.21 5.72 5.62 54-55 153 60.85 4.25 7.89 60.27 4.37 7.89 >260 154 62.5 7.3 10.14 64.77 7.27 9.9 187-190 155 55.4 6.5 3.6 55.56 6.51 3.5 114-116 156 45.85 4.9 4.86 46.06 4.78 4.71 67-68 156 48.8 4.7 4.4 48.81 4.64 4.39 144-146 157 50.3 5.1 4.2 50.25 5.12 3.99 141-143 158 55.5 4.1 3.8 55.55 3.88 3.75 190-192 159 64.97 6.9 5.05 64.7 6.82 5.02 171-174 160 54.3 3.7 4 54.31 3.58 3.83 222-224 161 56.4 6.7 3.5 56.69 6.98 3.11 76-78 162 63.63 6.47 5.3 64.76 6.84 4.74 188-191 163 48.91 4.48 5.19 48.89 4.31 5.10 88.5-90 164 66.66 10.0 5.18 66.69 10.7 5.16 67.5- 4 7 70.5 165 39.42 4.21 4.18 39.19 4.35 3.88 oil 166 53.05 5.19 5.16 53.06 5.03 4.86 151-152 167 65.53 7.85 4.78 65.4 7.84 4.57 85-89 168 68.99 6.11 4.47 68.62 5.87 4.49 162-6 169 69.71 6.47 4.28 69.67 6.58 4.50 132.5- 135 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point (oc) C H N S C H N S 170 61.21 7.53 9.52 61.21 7.68 9.46 134-135 171 62.14 7.44 4.53 61.96 7.52 4.57 101-104 172 58.63 6.71 6.22 58.15 6.83 6.04 173 52.96 3.26 4.12 52.96 3.28 4.02 225-227 174 57.42 6.42 4.46 57.3 6.38 4.39 119-120 175 68.99 6.11 4.47 68.84 6.08 4.51 131-4 176 66.43 8.2 4.56 66.42 8.16 4.51 109-110 177 62.14 6.82 5.57 61.96 6.66 5.52 127-128 178 51.00 4.56 3.97 51.09 4.61 3.93 179 67.36 5.30 4.90 67.26 5.24 4.91 185-186 180 66.43 8.20 4.56 66.32 8.60 5.12 51.5-55 181 69.92 6.79 8.58 67.02 6.93 8.20 81-84 182 66.46 8.14 4.56 66.43 8.34 4.47 82-84 183 62.13 4.89 22.64 62.05 4.88 22.45 271-272 184 68.16 7.32 6.36 67.73 7.44 6.70 114-117 185 71.30 5.98 5.73 71.10 5.97 5.74 146-149 186 68.16 7.32 6.36 67.94 7.31 6.41 105-108 187 65.51 7.90 4.77 65.35 7.63 4.59 102-103 188 64.50 7.58 5.01 64.19 7.69 4.83 133-134 189 64.5 7.58 5.01 64.5 7.57 4.90 116-118 190 61.15 7.71 3.97 61.27 7.79 4.08 124-127 191 65.5 7.9 4.77 65.32 7.94 4.7 114-115 192 56.77 6.51 8.28 56.83 6.76 8.21 141-143 193 60.29 4.74 8.79 60.17 4.58 8.74 202-205 194 48.8 4.7 4.4 48.81 4 4.39 144-146 SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 48 These carrier compounds or poly amino acids, and peptides, including the amino acids, may be used to deliver active agents including, but not limited to, biologically or chemically active agents such as for example, pharmacological and therapeutic agents.

An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids.

Poly amino acids are either peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g. an ester, anhydride, or an anhydride linkage.

Peptides are two or more amino acids joined by a peptide bond.

Peptides can vary in length from dipeptides with two amino acids to poly peptides with several hundred amino acids. See Chambers Biological Dictionary, editor Peter M. B. Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of di-peptides, tri-peptides, tetra-peptides, and penta-peptides.

Salts such as, for example, sodium salt of these carrier compounds can be used as well.

Many of the compounds described herein are derived from amino acids.

Many of the compounds of the present invention can be readily prepared from amino acids including, but not limited to, aminocaprylic acid, butyrylhydroxaminic acid, aminophenylbutyric acid, aminophenylhexanoic acid, aminophenylpropionic acid, amino salicylic acid, aminophenylsuccinic acid, aminononanic acid, aminonicotinic acid, amino valenic acid, aminophenylacetic acid, aminocaproic acid, aminoundecanoic acid, aminoheptanoic acid, aminohydroxybenzoic acid, and aminodecanoic acid by methods within the skill of those in the art based upon the present disclosure and the methods described in U.S. patent application serial nos. 60/017,902, SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 49 filed March 29, 1996; 08/414,654, filed March 31, 1995; 08/335,148, filed October 25, 1994; and 60/003,111, filed September 1, 1995.

For example, these compounds may be prepared by reacting the single acid with the appropriate agent which reacts with free amino moiety present in the amino acids to form amides. Protecting groups may be used to avoid unwanted side reactions as would be known to those skilled in the art.

The carrier compound may be purified by recrystallization or by fractionation on solid column supports. Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation may be performed on a suitable solid column supports such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. When anion exchange chromatography is performed, preferably a subsequent 0-500 mM sodium chloride gradient is employed.

Delivery Systems The compositions of the present invention may include one or more active agents.

In one embodiment, compounds or salts of compounds 1-193 or poly amino acids or peptides that include at least one of these compounds or salts may be used directly as a delivery carrier by simply mixing one or more compound or salt, poly amino acid or peptide with the active agent prior to administration.

The administration mixtures are prepared by mixing an aqueous solution of the carrier with an aqueous solution of the active ingredient, just prior to administration. Alternatively, the carrier and the biologically or chemically active ingredient can be admixed during the manufacturing SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 process. The solutions may optionally contain additives such as phosphate buffer salts, citric acid, acetic acid, gelatin, and gum acacia.

Stabilizing additives may be incorporated into the carrier solution.

With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution.

The stabilizing additives may be employed at a concentration ranging between about 0.1 and preferably about 0.5 Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are gum acacia, gelatin and methyl cellulose.

The amount of active agent is an amount effective to accomplish the purpose of the particular active agent. The amount in the composition typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than a pharmacologically, biologically, therapeutically, or chemically effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, because the dosage unit form may contain a multiplicity of carrier/biologically or chemically active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount. The total effective amounts can then be administered in cumulative units containing, in total, pharmacologically, biologically, therapeutically or chemically active amounts of biologically or pharmacologically active agent.

The total amount of active agent, and particularly biologically or chemically active agent, to be used can be determined by those skilled in the art. However, it has surprisingly been found that with some biologically or chemically active agents, the use of the presently disclosed carriers provides extremely efficient delivery, particularly in oral, intranasal, sublingual, SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 51 intraduodenal, rectal, vaginal, buccal, ophthalmic, or subcutaneous systems as well as systems for crossing the blood/brain barrier. Therefore, lower amounts of biologically or chemically active agent than those used in prior dosage unit forms or delivery systems can be administered to the subject, while still achieving the same blood levels and therapeutic effects.

The amount of carrier in the present composition is a delivery effective amount and can be determined for any particular carrier or biologically or chemically active agent by methods known to those skilled in the art.

Dosage unit forms can also include any of excipients; diluents; disintegrants; lubricants; plasticizers; colorants; and dosing vehicles, including, but not limited to water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.

Administration of the present compositions or dosage unit forms preferably is oral or by intraduodenal injection.

The delivery compositions of the present invention may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof. These compounds have the formulas below: Me. Me N NHOH S H0 HO 0 Me Actinonin SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 52 M Me N NHOH HO 0 H 0 HO Me Me Epiactinonin Derivatives of these compounds are disclosed in U.S. Patent No. 5,206,384.

Actinonin derivatives have the formula: 0

C

CH

2 H 0

N

O CH CH CH 3 R6 wherein R 5 is sulfoxymethyl or carboxyl or a substituted carboxy group selected from carboxamide, hydroxyaminocarbonyl and alkoxycarbonyl groups; and R 6 is hydroxyl, alkoxy, hydroxyamino or sulfoxyamino group.

Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 53 The compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals such as birds; mammals, such as primates and particularly humans; and insects. The system is particularly advantageous for delivering chemically or biologically or chemically active agents which would otherwise be destroyed or rendered less effective by conditions encountered before the active agent its target zone the area in which the active agent of the delivery composition are to be released) and within the body of the animal to which they are administered. Particularly, the compounds and compositions of the present invention are useful in orally administering active agents, especially those which are not ordinarily orally deliverable.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples illustrate the invention without limitation.

All parts are given by weight unless otherwise indicated.

Example 1 Carrier Preparation General Preparations of Carriers. The following procedures were used to prepare the compounds described herein. Many of the compounds were prepared by reaction of the appropriate amino acid with the appropriate acid chloride. The preparation of compound 79 is given as a representative example of the compounds prepared in this. manner.

Preparation of Compound 79. Method A. A 1 L round bottom flask fitted with a magnetic stirrer was charged with 3-(4aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) and 2 M aqueous sodium hydroxide (300 mL). 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) was added portionwise over 1 h to the stirred solution. After the addition, the reaction was stirred for 2.5 h at ambient SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 54 temperature, and the pH of the solution was kept at ca 10 by the addition of M sodium hydroxide. The solution was then acidified with 1 M hydrochloric acid (3 x 100 mL), water (100 mL), and air dried. It was redissolved in boiling acetone (ca 500 mL), decolorized with activated charcoal and filtered. Water (1.5 L) was added to the filtrate to induce the formation of a brown oil. The brown oil solidified upon stirring at room temperature for 10 min. The crude solid was collected by filtration and recrystallized from 70% methanol-water to afford compound 79 as a tan solid (39.5) Compounds 1, 5, 30, 31, 33, 36, 53-66, 68, 69, 71-74, 78, 88, 95, 97-99, 102, 108-110, 112-115, 119, 121-126, 136, 137,139, 141, 144, 146, 147, 151, 152, 155-158, 160, 161, 163, 165, 166, 170, 172- 174, 176, 177, 184-186, 188, 189, 191 and 192 were also prepared by this process.

Preparation of Compound 79. Method B. A 2 L three-neck round bottom flask was fitted with a magnetic stirrer and two addition funnels under an argon atmosphere. A suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in ethyl acetate (700 mL) was added to the flask. A solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) in ethyl acetate (250 mL) was charged to one of the addition funnels and added dropwise over 1 h. Triethylamine (28.20 g, 0.28 moles, 1.00 equiv.) was subsequently charged to the second funnel and added dropwise over 15 min. The reaction was stirred at ambient temperature for 3 h, and the solvent was evaporated in vacuo giving a residual brown oil. Water (600 mL) was added to the residue followed by sodium hydroxide (2 M, 500 mL), and the mixture was stirred at ambient temperature for 3 hours. The resultant brown solution was acidified with 2 M hydrochloric acid (ca 1 L).

After cooling the mixture in an ice bath for 1 h, a yellow solid formed and SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 was collected by filtration. The solid was washed with water (3 x 1.5 L) and recrystallized from 50% ethanol-water to give compound 79 as a tan solid (59.2 g, 68%).

Compounds 18, 32, 37, 41, 168, 175, and 183 were also prepared by this process.

Preparation of Compound 79. Method C. A 2 L round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with a suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in dichloromethane (560 mL). Chlorotrimethylsilane (62.36 g, 0.57 moles, 2.05 equiv.) was added in one portion, and the mixture was heated to reflux for 1 h under argon. The reaction was allowed to cool to room temperature and was placed in an ice bath (internal temperature 0 The reflux condenser was replaced with an addition funnel containing triethylamine (42.50 g, 0.42 moles, 1.50 equiv.). The triethylamine was added dropwise over 15 min, and a yellow solid formed during the addition. The funnel was replaced by another addition funnel containing a solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv. in dichloromethane (100 mL). The solution was added dropwise over 30 min. The reaction was stirred in the ice bath for another 30 min and at ambient temperature for 1 h. The dichloromethane was evaporated in vacuo to give a brown oil. The brown oil was cooled in an ice bath, and an ice-cold solution of 2 M sodium hydroxide (700 mL) was added. The ice bath was removed, and the reaction was stirred for 2 h to afford a clear brown solution. The solution was acidified with 2 M sulfuric acid (400 mL) and stored at ca 5 0 C for 1 hour. A yellow solid formed and was collected by filtration. The solid was washed with water (3 x 100 mL) and recrystallized from 50% ethanol-water to afford compound 79 as tan needles (64.7 g, 82%).

SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 56 Compounds 2-4, 6-17, 1 9-29, 34, 38-40, 42-48, 50-52, 67, 75-77, 89-94, 96, 100, 101, 107, 111, 116-118, 127-132, 134, 135, 193, 142, 143, 148, 149, 159, 162, 164, 169, 178-182, 187, and 190 were also prepared by this process.

Preparation of Compound 35. A solution of O-acetylsalicyloyl chloride (24.68 g, 124 mmol, 1 equiv) in tetrahydrofuran (300 mL) was cooled in an ice bath. Triethylamine (25 g, 249 mmol, 2 equiv) was added dropwise via an additional funnel. The methyl 9 -aminononanoate hydrochloride was dissolved in DMF (190 mL, slightly warm to dissolve), charged to an addition funnel and added dropwise to the above mixture. The reaction was stirred in the ice-bath for 20 min and at room temperature for 2 h. Evaporation of the THF under reduced pressure gave a pink DMF solution. The pink solution was cooled in an ice-bath, and 2 M aqueous sodium hydroxide (300 mL) was added. After being stirred at room temperature for 12 h, the mixture was acidified with 2 M hydrochloric acid (500 mL). The solution was cooled in an ice-bath, and a solid formed. The solid was collected by filtration and was recrystallized from ethanol/water to give compound 35 (32 g, 87%) as an off-white solid.

Preparation of Compound 49. 1-(2-hydroxyphenyl)-3-(4-methyl benzoate)-1,3-propane dione (3.00 g, 0.0301 mil.) is placed in a 100 ml round bottomed flask fitted with argon purge, magnetic stir bar and cold water condenser. Glacial acetic acid (20 mis) and concentrated sulfuric acid (5 mis) were added, and heating of the reaction mixture was initiated. The reaction mixture was allowed to heat at reflux for 6 h before heating was discontinued. The reaction mixture was allowed to come to room temperature, and then was poured into 100 mis of ice/water. This was stirred for approximately 1/2 h before the mixture was filtered, and a brown SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 57 solid was isolated. The brown solid was recrystallized twice from acetic acid, yielding compound 49 as a tan solid (1.44 g, 53.8%).

Preparation of Compound 167. 2-coumaranone (4.21 g, 0.0314 mol) was dissolved, with stirring, in acetonitrile (75 mis) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser. Triethylamine (3.18 g, 0.0314 mol) and 8-aminocaprylic acid (5.00 g, 0.0314 mol) were added, and a tan slurry was formed. Heating was started, and the reaction, mixture was allowed to reflux overnight. After heating overnight, thin layer chromatography of the reaction mixture ethyl acetate 50% hexane) indicated that the reaction had gone to completion. Heating was stopped, the reaction mixture was allowed to cool to room temperature, and was concentrated in vacuo. The resulting residue was taken up in methylene chloride, and was washed with two, 100 ml portions of 1 N hydrochloric acid solution. The methylene chloride layer was dried with sodium sulfate and was concentrated in vacuo. The resulting tan solid was allowed to dry in vacuo overnight, yielding compound 167 as a tan solid (8.35 g, 70.4%).

Preparation of Compound 171. 1,4-benzodioxan-2-one (3.93 g, 0.0262 mol) was dissolved, with stirring, in acetonitrile (70 mis) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser. Triethylamine (2.64 g, 0.0262 mol) and 8-aminocaprylic acid (500 g, 0.0262 mol) were added and a tan slurry was formed. Heating was started, and the reaction mixture was allowed to reflux for approximately 3 hours. At this time, thin layer chromatography of the reaction mixture ethyl acetate /50% hexane) indicated that the reaction had gone to completion. Heating was discontinued, and the reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The resulting SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 58 residue was taken up in methylene chloride and was washed with a 100 ml portion of 1N hydrochloric acid solution. At this time, a tan solid was noted to precipitate, and it was isolated by filtration. This tan solid was washed further with an additional 100 ml portion of 1 N hydrochloric acid solution, and then with 100 ml of water. The resulting tan solid was allowed to dry in vacuo overnight yielding Compound 171 as a tan solid (7.73 g, 95.6%).

Preparation of Compound 120. A solution of 3.00 g (18.3 mmol) of 2-nitrophenylisocyanate and 5 mL of tetrahydrofuran was dropwise over 10 min to an ice bath-cooled solution of 2.08 g (13.1 mmol) of 8aminocaprylic acid, 1.40 mL of 10 N NaOH and 40 mL of water. The reaction mixture was stirred an additional 30 min, warmed to 25 0 C and treated with 3% HCI solution until the pH was 5. The yellow precipitate was filtered off and rinsed with 100 ml of water. The yellow solid was recrystallized in 2-propanol and water to give 3.7 g of compound 120 as pale yellow crystals.

Compounds 104-106 were also prepared by this procedure.

Preparation of Compound 133. A suspension of 2.40 g (16.3 mmol) and 2.80 g (15.6 mmol) of 4-(4aminophenyl)butyric acid in 20 mL of propylene glycol, 2.40 mL (1.74 g, 17.3 mmol) of triethylamine and 10 mg (0.08 mmol) of dimethylaminopyridine was heated to 140 0 C. The mixture became a clear solution after 5 min at 140 0 C. After stirring for 330 min, the reaction mixture was cooled to 25 0 C and diluted with 20 mL of water. The solid phthalimide which had formed was filtered off. The filtrate was acidified with 3% HCI solution. The resulting solid was filtered off and was recrystallized from 2-propanol and water to give 0.62 g of compound 133 as a tan solid.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 59 Preparation of Compound 138. A solution of 1.73 g (12.9 mmol) of phthalic dialdehyde, 2.04 g 8-aminocaprylic acid and 20 mL of acetic acid was heated to reflux for 10 min. The reaction mixture was cooled to 400C, diluted with water and extracted with CH 2

CI

2 (2 X 20 mL). The organic phase was washed with water and brine, dried over Na 2 SO4 and evaporated. The residue was dissolved in ether and extracted with 2N NaOH.

The layers were separated. The aqueous layer was made acidic with 3% HCI and extracted with CH 2

CI

2 The organic phase was dried over Na 2

SO

4 and evaporated. The yellow residue was crystallized from acetonitrile and water to give 1.25 g of compound 138 as a yellow solid.

Preparation of Compound 140. A mixture of 1.40 g (9.48 mmol) of phthalic anhydride and 1.51 g (9.48 mmol) of 8-aminocaprylic acid was heated to 150 0 C for 5 min. Upon cooling, 2.61 g of solid compound 140 was received.

Compound 150 was also prepared by this procedure.

Preparation of Compound 145. A suspension of 2.11 g (10.1 mmol) ethyl carbamoylanthranilic acid and 5 mL of CH 2

CI

2 was treated with 2.20 mL of oxalyl chloride. After stirring for 1 h the volatiles were stripped off. At that same time, a suspension of 1.60 g (10.1 mmol) of 8aminocaprylic acid and 15 mL of CH 2

CI

2 was treated with 2.60 mL (2.23 g, 20.5 mmol) of TMSCI. This mixture was heated to reflux for 90 min, cooled in an ice bath and treated with 4.30 mL (3.12 g, 30.9 mmol) of triethylamine.

Five min later, a slurry of the residue from the oxalyl chloride reaction in mL of CH 2

CI

2 was added. The reaction mixture was warmed to 250C and stirred overnight. Upon acidification of the mixture with 3% HCI, a white solid formed. The solid was filtered off and recrystallized from EtOH and water to give 1.88 g of compound 145.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 Compound 153 was also prepared by this procedure.

Preparation of Compound 154. A suspension of 4.02 g(25.6 mmol) of trans-4-aminomethylcyclohexane-carboxylic acid, 4.18 g (25.6 mmol) of isatoic anhydride, 20 mL of CH 2

CI

2 20 mL of dioxane, and 4 mL of water was heated to reflux for 12 h. The solution was cooled to 25 0 C and extracted with ether (4 x 20 mL). The organic layer was dried over Na 2

SO

4 and concentrated. The resulting solid was recrystallized from EtOH and water to give 4.95 g of compound 154.

Compound 103 is available from Aldrich Chemical Company, Inc., Milwaukee, WI.

Example 2 Parathyroid Hormone Dosing Solutions Intracolonic dosing compositions containing 100 mg/kg of carrier and 25 pg/kg of parathyroid hormone in 25% aqueous propylene glycol or oral gavage dosing solution containing 400 mg/kg of carrier and 100 pg/kg of parathyroid hormone in water, were prepared with carriers 9, 33, 77, 79, 109, 110, 123, 136, 141, and 169. The dosing solutions are designated P- carrier number DS.

Comparative Example 2A Parathyroid Hormone Dosing Solutions An intracolonic dosing composition containing 100 mg/kg of a carrier having the formula SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 61 and 25 ug/kg of parathyroid hormone in 25% aqueous propylene glycol was prepared. The dosing solution is identified as P-9A-DS.

Examples 3 In vivo Parathyroid Hormone Delivery Male Sprague-Dawley rats weighing between 2 00-250g were fasted for 24 hours and were administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of dosing solutions P-9-DS, P-33-DS, P-35-DS, P-77-DS, P- 79-DS, and P-141-DS by oral gavage or intra-colonic instillation Blood samples were collected serially from the tail artery for serum determination of parathyroid hormone concentration. Serum parathyroid hormone concentrations were quantified by a parathyroid hormone immunoaccuracy test host.

Results are illustrated in Table 2, below.

Comparative Example 3A In vivo Parathyroid Hormone Delivery The procedure of Example 3 was followed substituting dosing solution P-9A-DS for dosing solution P-9-DS. Results are illustrated in Table 2, below.

Comparative Example 3B In vivo Parathyroid Hormone Delivery The procedure of Example 3 was followed with a dosing solution (at a dose of 25 pg/kg of parathyroid hormone (intra-colonic) or 100 pg/kg of parathyroid hormone (oral)), P-0A-DS, that omitted the carrier.

Results are illustrated in Table 2, below.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 TABLE 2 In vivo Parathyroid Hormone Delivery Mean Peak Serum [PTH] Dosing Solution Standard Deviation (pg/ml) P-9-DS 155 105 (IC) P-33-DS 58 18(IC) 50 27 (IC) P-77-DS 358 274 (PO) P-79-DS 521 128 (PO) P-109-DS 128 25 (IC) P-110-DS 35 11 (IC) P-123-DS 49 22 (IC) P-136-DS 106 72 (IC) P-141-DS 120 120 (PO) P-169-DS 19 33 (IC) P-9A-DS 116 48 (IC) P-0A-DS 11 2 27 27 (IC) Examples 4 Recombinant Human Growth Hormone Dosing Solutions Intracolonic dosing compositions containing 25 mg/kg of carrier and 1 mg/kg of rHGH in phosphate buffer or oral gavage dosing solutions containing 600 mg/kg of carrier and 3 mg/kg of rHGH in phosphate buffer were prepared with carriers 9, 35, 36, 47, 62, 64, 67, 77, 79, 90, 94, 107, 109, 136, and 141.

The dosing solutions are designated R- carrier number DS.

Comparative Example 4A Recombinant Human Growth Hormone Dosing Solutions SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 63 An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula for the carrier. This dosing solution is designated as Comparative Example 4B Recombinant Human Growth Hormone Dosing Solutions An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula

OH

H 0 O O for the carrier. This dosing solution is designated as Comparative Examole 4C Recombinant Human Growth Hormone Dosinq Solutions An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 64

H

0 N 0 0OH for the carrier. This dosing solution is designated as R-9A-DS.

Example 5 In Vivo Recombinant Human Growth Hormone Delivery Male Sprague-Dawley rats weighing 200-250g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine mg/kg) 15 minutes prior to dosing. The rats were administered one of the dosing solutions of Example 3 by either oral gavage or intracolonic instillation.

Blood samples were collected serially from the tail artery for determination of serum rHGH concentrations. Serum rHGH concentrations were quantified by an rHGH immunoassay test kit.

Results are illustrated in Table 3, below.

Comparative Example 5A In Vivo Recombinant Human Growth Hormone Delivery The procedure of Example 5 was followed, substituting the dosing solutions of Comparative Examples 3A-3C for the dosing solutions.

Results are illustrated in Table 3, below.

Comparative Example 5B In Vivo Recombinant Human Growth Hormone Delivery The procedure of Example 5 was followed, with dosing solutions of 'active agent (at a dose of 1 mg of rHGH/kg (intracolonic) or 3 mg of SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 rHGH/kg (oral) and no carrier. These dosing solutions are designated R-0D- DS and R-0E-DS, respectively. Results are illustrated in Table 3, below.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIUS98/02619 TABLE 3 -In Vivo Recombinant Human Growth Hormone Delivery IMe an Peak Serum [rHGH] Dosing Solution j Standard Deviation (ng/mI) R-9-DS 125 34 (IC) 41 46 (PO) 108 ±56 (IC) R-36-DS 28 ±11 (IC R-47-DS 0 (IC) R-62-DS 11 12(IC) R-64-DS 72 22 (P0) 19 22 (PO) R-67-DS 88 24 (IC R-77-DS 34 10 (P0) R-79-DS 62 51 (PO) 9 13 (PO) R-94-DS 39 35 (PO) R- 107-DS 0 0 (PO) R- 109-DS 128 25 (IC R-136-DS 106 72 (IC) R-141 -DS 95 14 (IC 17 3 (IC) 42 28 (IC R-9A-DS 55 17 (IC R-D-DS 0 k 0 (IC R-0E-DS 0 0 (IC SUBSTITU TE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 67 Example 6 In Vivo Interferon Delivery An intracolonic dosing composition containing 50 mg/kg of carrier 9 and 250 pg/kg of interferon in 50% propylene glycol was prepared.

Rats were administered the dosing composition by intracolonic instillation.

Delivery was evaluated by use of an ELISA assay for human interferon a from Biosource, Inc. Mean peak serum interferon concentration was 2611 695.

Comparative Example 6A In Vivo Interferon Delivery Rats were administered, orally and by intracolonic instillation, dosing solutions of 1 mg/kg of interferon and no carrier. Delivery was evaluated according to the procedure of Example 6. Mean peak serum interferon concentration was 1951 1857 (PO) and 79 100 (IC).

Example 7 Heparin Dosing Solutions Intracolonic dosing compositions containing 50 mg/kg of carrier and 25 mg/kg of heparin in 25% aqueous propylene glycol or oral gavage dosing solutions containing 300 mg/kg of carrier and 100 mg/kg of heparin in 25% aqueous propylene glycol were prepared with carriers 9, 35, 47, 58, 62, 64, 67, 76, 96, 102, 109, 110, 111, 117, 122, 123, 139, 141, 144, and 169. The dosing solutions are designated H-carrier number-DS.

Comparative Example 7A Heparin Dosing Solutions Comparative intracolonic dosing compositions were prepared according to the procedure of Example 7, substituting the following carriers for the carrier.

H

HO N Y 0 0 OH SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 68

OH

HO

0 0 These dosing solutions are designated H-35A-DS, H-35B-DS, and H-109A-DS, respectively.

Examples 8 In Vivo Evaluation of Heparin in Rats The dosing solutions of Example 7 were administered to fasted rats either by oral gavage or intracolonic instillation.

Blood samples were collected by cardiac puncture following the administration of ketamine (44 mg/kg). Heparin activity was determined by utilizing the activated partial thromboplastin time (APTT) according to the method of Henry, Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; W.B. Saunders (1979).

Results are in illustrated in Table 4, below.

Comparative Examples 8A In Vivo Evaluation of Heparin in Rats The dosing solutions of Comparative Example 7A were administered to fasted rats by intracolonic instillation. Blood samples were collected and heparin activity was determined by the method of Example 8.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 PCT/US98/02619 69 Results are illustrated in Table 4, below.

Comparative Example 8B In Vivo Evaluation of Heparin in Rats An intracolonic dosing solution of 25 mg/kg of heparin and an oral gavage dosing solution of 100 mg/kg of heparin were administered to fasted rats. These dosage solutions were designated H-0A-DS and H-0B-DS, respectively.

Blood samples were collected, and heparin activity was determined by the methods of Example 8.

Results are illustrated in Table 4, below.

SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCT/US98/02619 TABLE 4 In Viva Evaluation of Heparin in Rats Dosing Solution ]Heparin APTT (sec) H-9-DS 48 1 8 (IC) 54 27 177 85 (IC) H-47-DS 30 14 (IC) 40 22 (IC) H-58-DS 24 ±4 (IC H-62-DS 37 ±13 (IC) H-64-DS 59 ±28 168 ±75 (IC) H-67-DS 76 ±36 (IC) H-76-DS 63 2 27 (PO) H-96-DS 36 8 (IC) H-102-DS 111 108 (IC) H-109-DS 56 28 (IC) H-i 110-DS 37 9 (IC) H-1 11-DS 71 39 (IC) H-1 17-DS 140 128 (IC) H-1 22-DS 49 21 207 ±7 (PO) H-i 23-DS 42 14 (P0) H-1 39-DS 31 11 (IC) H-141-DS 59 26 (IC H-i144-DS 26 3 (IC) 61 29 (IC 51 30 (IC) H-169-DS 23 2 (IC) H-OA-DS 23 2 (P0) H-0B-DS 33 6 (IC) SUBSTITUTE SHEET (RULE 26) The above mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety.

Many variations of the present invention will suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations are within the full intended scope of the appended claims.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Amendments have been made to the claims which follow and new ooo claims have been proposed to more closely define the invention. The claim So amendments are based on various preferred embodiments as described and exemplified in the description. However, for the purpose of maintaining integrity of the text of the disclosure, substantial amendments have not been made to the description in light of the claim amendments. It is submitted that there is no disconformity in the specification as a consequence of amendment of the claims given the limitation of claim scope of various preferments of the invention described.

ooo

Claims (17)

1. A composition comprising: at least one active agent; and at least one carrier selected from the group consisting ofI N-(2-hydroxybenzoyt)isonipecotic acid SUBSTITUTE SHEET (RULE 26) H NH- 2 0 OHA H 4 4 4

2-amiobfolZOmio)phaflYIbutyryhydroxamic acid F 0 OH F F F t F

4-(4-(pentafluorobelzoyl)amilaphelyl)butyric acid 0v 1~ 0 1 a a a a a a a a B-(3.anisovI)ailoceprylic acid NO 2 iOH 4 4 -(2-flitrabonzenosulfonylamInophenyl)butyflc acid 0 0 H 00

6. 4 -(saicyloyt)amIflophefl)hexanoic acid 11 12 13 14 S 0 S 09 5* 9 0O S 000 S S. S S.. 0 S. S SS S. 5 9 9 5*SS S @005 0 *5S. 6* S S. S* S 5555 0@ 55 0 S SS S S S S. ST Il 0 0 OH16 H 0cf 3-(4-(2.5-dimethoxycinnhinoyllamidnophenylprpionic acid O400 H117 o H OCIS~ 4-(4-(2.5-dimothoxycinnmoy)aminopeny)butyric acidl 0 H 18 H 0O0 OH 1 .salicylayt-2-glutaryl hydrazido 4 4 -((4-carboxyl-3-hydroxy phenyl)anmino)succinyl)aniinosalicyclic acid H .II

8-(Phonoxyacetylaminokcaprytlc acid o N 2 1 00 N HOH 0. 0..*0 00 84(2 pyrazinecarbonyl)amnocapryic acdd o.0* 0 4 4 2 -pyrazinecarbofl)aminOphenyIbutyric acid 22 23 24 26 4(2-Nitrobenzoy)amilopheyISisucic acid 77 O 27 9 H O OCF 3 0 84 2.(trifuoromthoxy bemYIaI1minocapryiYc acid H 28 0 29 ~0 HO 8(enxyycrbolanino)caprylic acid HO 31 2 4 2 -Mothoxybelzoylamino)phnyllthyI HP0 4 (3 0 0 1 -salicyloyl-2-suberyt hydrazide 4 .(4-benyloxyclrboflailophenyI)butyric acid N OH 4-(4(2-hvdroxvicotinlO)amilophevl)butvric acid 32 33 34 WO 98/34632 WO 984632PT/US98O2619 36 37 38 39 41 SUBSTITUJTE SHEET (RULE 28) o 0 8-(chromone-3-carbonyl)aminocaprylic acid 0 o OHi 8-(vinylbanzoyl)aminocaprylic acid o 0 -NH0 "'OH 4 4 -(chromone-3-carbonyl)aminophenyl)butyric acid 00 8-cinnamoylaminocaprylic acid 42 43 44 9* 81 OH H 4 N OH

9-(2-hydroxybenzarido)nonardjc acid N 48 0 H OH 0 6 4 -(N-salicyloyl)aminobenzoyl)ananocaproic acid 0 49 00 0'faoi d 11 -mfmlanondeani acid 1 0 4-caolmn-3hdoy*i acid (3Phanyl2.3daydoxypronondgcanl rfc acid WO 98/34632 WO 9834632PCT/US98/02619 Q NH 0 8 -WJ-(3coumarincarbonygJlaminocayic acid 0 8 -IN-( 4 -chloroberizoyl)]aminocaP,.ylic acid 53 54 56 57 58 8 -(N-2.4-DihydroxybenzoyI)aminocapryic acid SUBSTITUTE SHEET (RULE 26) H 0 CH 3 0 8-(N-2.5-Dimethoxybenzoyllaminocaprylic acid CH 3 C Nl* OH 0 0 N-8acid HW& I 59 61 8 8 -(4-hydroxybenzoyl)anuinooctaioyl)anminocaprylic acid (dimer) I 0H 0 WH- O II tII t 0 1 62 s-(N-2.4-Dwdroxybenzoflamnocapryluc acd Q OH 1i-~-Muthoxyaninoebalic acid 63 OH H 0 ~0 1O-(N-2-hydroxyanilino) sebacic acid CH 3 H 0 N 2-Methoxybelleamilodecaloic acid 0 OH~ 8-(N-benzlY)a8fmfocspryhic acid S @5 S S S S a.. a. S a 5* 55 S 'S S S S S *5*55* S *955 S S S N. 55 S S *S S S 5e55 COOH 0 66 68 69 -84[N-(4-fluorobenzoyl)Iaminocaprylic acid KH 0 8.[N.(3-bromobezoyDIlmfloc8pryrlc acid OH 0 8-(44(1 2-dihydroxythyI)belzoyI)amliocapryic acid WO 98/34632 WO 9834632PCT/UJS98/02619 o m~~-~COOH71 r- 8-[N-(4-bromobenzoy) amio capryic acid Q COOH72 8-(N-(4-iodobenzoyl)Iaminocaprylic acid 73 ItOOH 4-{4-[N-(2iodobnzoy)amaiophofli)butyflic acid Ot 0OH 74 I H 1 hydroxy-2-naphthoyI)flmiflophanyIJ)butyrlc acid 0' off Ely 0 KHOH 4.(o-ansoyl)arnifopheyleiScO acid SUBSTITUTE SHEET (RULE 26) 77 78 4 -LN-(3-bromobenzoyl)aminophenylfl butyric acid 4 -t4-IjN-(4-iodobenzoyl)J aminophenyl) butyric acid [cr± OOH] 4-f 4 4N-( 2 -bromobenzoyl)]aiinophenyl) butyric acid 79 81 H -4-(2,6dfimtboxenzoy)aminopbenybuyic a.dd 0 0 H 0 82 8-(N-3.5 Dihydroxybenzoyt)aminocapryjc acid 87 Clfj 0 H 83 HO) C%~ 8-(N-3.5-Dimetuoxy 4 -hydroxybenzoII,,.inocapryric acid 84 IOCH 3 0 8-(N- 2 -6-Dimethoxybenzoyl)arinocap.ylir, acid BE 4-(44N-(4-bramobenzoylaminopheny(IJ)butyric acid 86 *-4 2 -hydroxy4horobnz~nocapry.;. aci 00". H 0 0 0 0 0 0* 0. 0. *N2H doy oh xb no lw iaarrcai WO 98/34632 WO 9834632PCTIUS98/02619 88 0 11* H 89 acid 0 H~qn 0 0~~c 2,3-dimethoxybenzoylaiophel)btyric acid 0OH 91 H WOCH 3 acid OH0 92 N Ct OCH 3 -(4-(4-chloro-o-anisoyI)aminophenyI)butyric acid ce 0C4 8 -(4-chtoro-o-anisoyl)aminocaprylic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 PTU9IZ1 PCTIUS98/02619 94 .(4-(2,5-dimethoxybenzoy)aminopheny)propionic acid Ho 4*N[4-(3-lodobenzoyl)aminophenyll~butyric acid lo o 0 7 -cinnanioylaminoheptanoic acid 8-N-(3-odobenzoyl)aminocaprylic acid 8-N-(4-niathoxy-3-nitrobenzoyl)aminocaprylic acid OMe 0 H 8-N-(2-methoxy-4-nitrobenzoy)aminocaprylic acid 96 97 98 99 b SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCT/US98/02619 omc 100 1I 4-{N-14-{2-methoxy-4-nitrobenzoy)aminopheny1butyric acid 0.01 101 F Nf 0C10 4-(4-(2,5-.dimethoxybenzoyl)aminophenyl)butyric acid OR o COOH 102 OH 103 C N H 3 -Indolebutyric acid 0OH 104 o NH NH0 105 SUBSTITUTE SHEET (RULE 26) 91 0OH 106 NH N4 ORf OCH 3 q 0 107 00H 3 0 OH 4-4(2,6-dimthoxybenzoy)miophel] butyric acid 108 4 4 4 -N4mthoxy-31itrObezovI)amnoDhenvilbutlir- ar~id *H 01 WO 98/34632 WO 9834632PCT/US98/02619 0 OH OC OH 111 1 12 8-(34iydroxy-2-naphthoy)amilocapIylic acid H H 8-(N-2-hydroxy4-nitrobenzoy)miocapryic acid 113 acid 114' 115 8-(N-3-methyIsaicyloyt)amilocapryic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIUS98/02619 116 117 9 cinnamoytamino)no nano ic acid 118 119 acid 120 121 SUBSTITUE SHEET (RULE 26) 122 123 8-[N(2-ydrxy-,5-ibrmobezoy~lainoaprlicacid 124 125 9 9 9 9**9 9* Jo 9 9 9 9 9* 9*9 99 9 9* 0* 9 9 9 0 9 *099 009. 9 0999 0 9009 99 9 0 90 9900 0 9009 99 09 9 9 0 09 0 90 *9 126 127 0 FF\C~ 1 2-cinnamoyldodecaloic acid HO 0 HO 4- 4 -{N-(3-hydroxy-2-flaphtboy1)amiinophenylI )butyric acid 128 129 130 131 132 133 S. S 5 0 500 S S. S S.. S. S 9S S. S S S 0 0 5555 S 5.5. S SOSS 55 S S 5.5. S. S S S S. S eS 0 1w, N 0 C02H1 4 4 -phthrmildophelytbutyflc acd HO H HMO 0 0 4-(4 .[N-(3-hydroxy-2-naphthoyl)aminophenyll)propanoic acid 134 135 136 8-(N-2-hydroxy-3.S -diiodobenzoyt)aminocaprylic acid 0 0 CI COOH P" Ii ,*S.d..,A-mairhnzv~fmfaDIVcpryC acid E~. O-All- w 0 cozi 137 138 139 ,2-dithydroisoindote-l-orte))octanoic acid OH 00 8-(N-1 .hydroxy-2-naphthoy)aminocnPrYlic add WO 98/34632 WO 9834632PCT/US98/02619 140 141 8-(phthalimido)caprylic acid 1 O-(4-chloro-2-hydroxyaflitilo )sebacic acid mono amide 142 143 144 (-(4chlro--nirobnzol~aincpheyt~ut~icacid 11 -N-01 -hydroxy-2-naphthoy)amioufdecafloic acid SUBSTITUTE SHEET (RULE 98 0 0* 145 F, 9 C0 2 H 00 0 Bis(N-2crboxyIphelYI-(N 8 ctanoic acid )urealloxatyI diamide ci 146 2 2 -N42-chlorobefzlZt)a inoetoxyI8et1anol 147 010 00 0c~0 4-(2-mthoxybeflZyflmIio)pheflyl 2-carboxyethyl sulfoxide Odmi 149 4-(2-Inthoxybenzoyanino)phenyI 2-crboxythy1 sulfole 4-(4-(3-hydroxyphtherimido)pteylbutyrc acid 99 mve 151 en OainoehOXYethanol 152 0 153 0 0 Bist~ 2~crbOX PI~elYI (N 3 (4amfltoplenylipropionic acidurallo ayyl diamide 0 C02H154 .N3 H 4 a§155 WO 98/34632 WO 9834632PCT/US98/02619 100 156 2 2 -bromobenzoyl)ammnoethoxyletjhanoI 0 0 157 ~H CI 7-N-(3,5 dichloro-2-hydroxybenzoyl)aminoheptanoic acid 0 159 C160 H ON -dichloro-2-hydroxbenzoyl-3(4aminophenyl) Iptrpic acid 0 161 N-13 N- SUBSTITUTE SKEET (RULE 26) 101 OH H16 HO1 Y-6 0 0 o 163 ON 0 lJ-(2-bromobenzoy)morphoflfle

16.5 Ot H016 1 OH H 0O16 0 N 00 o.I :0.:o167 0.0 OH' I WO 98/34632 WO 9834632PCTIUS98/02619 102 o 168 0 OH N-SalicOYI 5.(3aminophel)lic acid 0OH 169 O~hnYIbutricacid NH 170 9-1 2 3 -hydroxy)pyridylaminocarbonylI nonanic acid u 171 OH 0 7 2 -hydroxyphenoxyact)mncpy acid OH~ 172 2 4 2 -hydroxybenzoylamino )ethoxvlethano, SUBSTITUTE SHEET (RULE 26) 103 Cl 173 CII 4 fN 3 .5.dichtoro.2..hydroxyben oy)Ja i o h nyaei acid H 174 8-2hdoy5clrailjoabnlotni acid 0IX~HC 2 175 OH IJ-selicoyt-5-(4-aminophenyl)valeric acid OH H 017 0 177 5 2 -hydroxy-5..methylanilinocarbony)valeric acid 104 178 179 180 181 0 0 0 0 0000 8-42-slhoxybenzoyl)aminocaprytic acid (CIH N OH 0 4 4 -2-dimthYlainobenzoyl)amminophenyl)butyic acid 8 3 -Phenoxylpropionylamino)capryic acid 182 0000 0000 0 0000 00 0 00 *0 0 0000 00 00 0 0 0 00 00 105 N-N N H 4-(Saricyloyl)aminaphenyleithyltetrazole- 183 184 185 8 4 4 -N-salicyloyl)aminophenyl)butyric) aminocaprylic acid. H F J 000O 00 4-(4-N-(4-(4-N-(2-FluorocinnanioyI)aminophenyI)buyric)arinophenly)butyric acid 186 S. S. S 5 0 S S. S S S S 4J14-N.(N-Saicyoy)aminocapylilnopheylibutyic acid S S* S. 5* S S 55 S* 0 8-(p-anisoyiamninocapryric acid .187 106 0 OH 8-(4-Hydroxybonzoyllaminocaprylic acid .0- HoNe 0 84(34ydroxybenzoYIaminocPYic acid 188 189 190 191 192 0* te. SO tee. C C. 0 00 St 10-N(2-ydrxy-5nitoanlin)-10oxoecaoicacid 193 4-(4-(2-chloronicotinoyllaminophenylbutyric acid 107 and salts thereof. 2. A composition as defined in claim 1, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof. 3. A composition as defined in claim 2; wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid. 4. A composition as defined in claim 2, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof. o• 5. A composition as defined in claim 4, wherein said biologically active agent comprises an interferon, interleukin-l, interleukin-ll, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin. vancomycin, DFO, parathyroid hormone, and combinations thereof. 6. A composition as defined in claim 1, wherein said carrier comprises a poly(amino acid). 7. A composition as defined in claim 1, wherein said carrier comprises a polypeptide. SU' OFF\C- 108 8. A dosage unit form comprising a composition as defined in claim 1; and an excipient a diluent, a disintegrant, a lubricant, a plasticizer, a colorant, a dosing vehicle, or any combination thereof. 9. A dosage unit form as defined in claim 8, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof. 10. A dosage unit form as defined in claim 9, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid. 11. A dosage unit form as defined in claim 9, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormome, an interferon, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancornycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof. 109 12. A dosage unit form as defined in claim 11, wherein said biologically active agent comprises an interferon, interleukin-1. interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinatins thereof. 13. A dosage unit form comprising a composition as defined in claim 6; and an excipient a diluent, a disintegrant, a lubricant, a plasticizer, a colorant, a dosing vehicle, or any combination thereof. 14. A dosage unit form as defined in claim 13, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof. A dosage unit form as defined in claim 14, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid. 16. A dosage unit form as defined in claim 14, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormome, an interferon, interleukin-l, interleukin-l, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a 110 monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.

17. A dosage unit form as defined in claim 16, wherein said biologically active agent comprises an interferon, interleukin-l, interleukin-Il, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

18. A dosage unit form comprising a composition as defined in claim 7; and i an excipient a diluent, a disintegrant, a lubricant, a plasticizer, a colorant, a dosing vehicle, or any combination thereof.

19. A dosage unit form as defined in claim 18, wherein said active agent is selected from the group consisting of a biologiqally active agent, a chemically active agent, or a combination thereof. A dosage unit form as defined in claim 19, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid. 111 .21. A dosage unit form defined in claim 19, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormome, an interferon, interleukin-l, interleukin-Il, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.

22. Adosage unit formas defined in claim 21, wherein said biologically active agent comprises an interferon, interleukin-l, interleukin-Il, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

23. A dosage unit form as defined in claim 8, comprising a tablet, a capsule, or a liquid.

24. A dosage unit form as defined in claim 23, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane 9 S. diol, ethanol, or any combination thereof.

25. A dosage unit form as defined in claim 13, comprising a tablet, a capsule, or a liquid.

26. A dosage unit form as defined in claim 25, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof. WO 98/34632 PCTIUS98/02619 112 1 27. A dosage unit form as defined in claim 18, comprising a 2 tablet, a capsule, or a liquid. 1 28. A dosage unit form as defined in claim 27, wherein said 2 dosing vehicle is selected from the group consisting of water, 1,2-propane 3 diol, ethanol, or any combination thereof. 1 29. A method for administering a biologically-active agent to 2 an animal in need of said agent, said method comprising administering orally 3 to said animal a composition as defined in claim 2. 4 30. A compound selected from the group consisting of SUBSTITUTE SHEET (RULE 26) WO 98/34632 PTU9/21 PCTf(JS98/02619 113 0 CI OH CI 5-dichtoro-2-hydraxyb enzoyl)aminocaproic acid 0H 1 2 3 4 0 N OH 0 N-(2-hydroxybenzoylisofipecotic acid acid SUBSTITUTE SHEET (RULE 26) 114 F 0 off 6 F N0y 4 4 -(pentafluorobenzoyl)aminophenyl)butyric acid 0 H 4-(4-(3-anisoyt)aminophenylbutyric acid 0 -(3aninsonyaminopeyl tyi acid 0 N NOZ 8 2 -nitrobenzenesulfonylnaminocaprylic acid WO 98/34632 PTU9121 PCTfUS98/02619 115 0 N HH 0 0cl 8-(2-irethoxylbenzoyt)amino caprylic acid 12 13 14 16 H Iy I OH 0 H 0 IQ ,-COH 1 -Salicyloyl-2-succinyl hydrazide 17 acid SUBSTTUTE SHEET (RULE 28) WO 98/34632 WO 9834632PCTIUS98/02619 116 O H 18 H 00 OH 1 -salicyloyI-2-glutaryI hydrazide 1 19 0 (yOJtOH Ii 0 8-(Phenoxyacetylamino)caprylic acid CN 1o 21 N H OH 0 8-(2-pyrazinecarbonyl)aminocaPryli; acid N 2 rOH 4-(4-(2-pyrazinecarbonyI)aminophenyI)butyric acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 PTU9121 PCTIUS98/02619 117 NOZ 0 OH23 00 6 4 -(N 2 4mifobenzoy)aminophel)ani acid 002 .0 H 0 OH 4 4 2 (3-carboxylpyrazinecaroxy)aminopheny)butrc acid COOH 26 N02 COOH 4 2 -Nitrobenzoyl)aminophenylsuccinic acid H OHI 2 8-( 2 -(trifluoromotJhoxybenzoyI)aminocaPryijc acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIIJS98/02619 118 &OIN OH H 0 8-(phenvicarbonylamino)caprylic acid NH 0 0 0 O OH 2-(4-benzylhoxybarboylaminophenyllbutyI 28 29 31 32 33 SUBSTITUTE SHEET (RULE 26) 119 NEN OR 3 N OH 4 4 -(2-hydroxynicatinolyl)aminopheny )butyric acid 00 4-(4-phenyloxycarbonylaminophenyg)buty c acid 0 37 N OH -(2-Hethoxybnztioyamino1 prylpcacid r 0, cOH3 6 -(2-methoxybenzo A amino nicotinic acid WO 98/34632 WO 9834632PCT/IJS98/02619 120 0 NH OH 0 0OH salicyloylglycine N O 0 0 4-(1 2 -pyrimidyl)piperazinoyl)butyric acid r 11- NH-OH 0 41 42 43 44 8-(cbromone-3-carbonyl)aminocaprylic acid 0 N. 0 NN 8-(vinylbenzoyl)aminocaprylic acid 0 0- 0: N C OH acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCT/US98/02619 121 OH H 46 0 0 acid OH H 4 9-(2-hydroxybenzamido)nonanic acid 48 HO) H 0. OH 0 N-(4-salicyloylamino)-6-caproic acid 0 49 OOOH4 0 4'-flavonic acid 11 -cinnamaylaminoundecanoic acid OH H 51 HO 0 0 4-octanoylamino-3-hydroxybenzoic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCT/US98/02619 1 22 OH Ou 0 3 Phenyi2.3dihydroxypropanoy)aminocapryic acid 52 NH ll .COOH 8 3 -coumarincarbonyI)Jaminocaprylic acid C 8-[N-(4-chlorobenzoytllaminocaprylic acid 53 54 56 57 8-[N-3-fluorobenzoylflaminocapryic acid OH HO 0 OH 8 -(N-2Z5-Dihydroxybenzoyl)aminocaprylic acid! CHO0O CO N 1-1 0 8-4N-2.3-Dimethoxybenzoyl)aminocaprylic acid SUBSTITUTE SHEET (RULE 26) WO 98/34632 WO 9834632PCTIUS98/02619 123 01- CH 3 Oo 0 8-(N-2A4-Dihydroxybenzoyl)aminocaprYlic acid 0O ONH Hl 0 CH 3 0 8-(N-2.5-Dimethoxybenzoyl)aminocaprylic acid 58 59 8-(N-3.5-DiacetytoxybelzoyI)aminocapryic acid N'.07 N, 7 OH Me H 0 8 (NA.-Hydroxybenzoyt)amirnocaprylic acid (dimer) OH 0 O O O HO 0 8-(N-2,4-Dihydroxybenzoyl)aminocaPrYlic acid CH 3 H0 N N 0 OH I C-(N4-2-Methoxyanilino )s'ebalic acid 61 62 63 SUBSTITUTE SHEET (RULE 26) 124 ORH H N OH .10-(N-2-hydroxyanilino) sebacic acid S S** S S S S S SS S *;S S. S ~S *SS* S S S S S S 2-Methoxcybenzenaminodecanoic acid 0 ~OR 0 8-(N-benzoyl)aminoceprylic acid 64 66 68 69 NH,, COOH 8 -(N-(4-fluorobenzayl)Iaminocapryic acid C O 0 KOO 8-IN-(3-bromobenzoyl)Jamrinocaprylic acid WO 98/34632 WO 9834632PCTIUS98/02619 125 GO 0 1 2 -dihydroxyethyl)benzoyI)aminocaprylic acid 8 -[N-(4-bromobenzoylllaminocaprylic acid 0H, CO 71 72 73 8-[IJ-(4-iodobenzoyl)Iaminocapr-ylc acid 4 4 [N(2iodobenzoyl)minophenyI)buty'ic acid OH 0 JDO H 74 4-4[N( hydroxy- 2 -naphthoyi)aminophenylbtric acid SUBSTTUTE SHEET (RULE 126 0. O 1 4-(4*(2.4-dimethoxylbenzoyl)aminopheny)butyric acid 76 OMcO 0 CuOH 4 -(o-ansoyl)aminophenylaceic acid Hf 0 1-7Ct 77 00 3 -12 4 -itmethoxybenzoyUl amninophenyll propionic acid 78 4 -(4--N-4odbenzoy)J aminphenyg) butydc acid OC" 79 a Olt 3-14-(2.3-dimethoxybenzoyl aminophenvll orooionic acid H Bir 4 4 -[N-(2-bromobenzoyl)Janiinophenyl) butyric acid 127 81 H 8-(W-3.5 Dihydroxybenzoyl)aiocapryric acid CHj If 83 HO CH 8-(N-3.5-Dimethoxy 4-hydroxybenzoyl)mlocapryIIc acid' aOH 84 00 OCH3 8-IN-2-6-DimethoxybeOr 8izo l~lncpryrDc acid Br 4-4(-4booezylannpeylbni acid 86 e(2-hydroxy-4-chorobnzoy)aminocapryric acid 128 88 89 91 92 WO 98/34632 WO 9834632PCTIUS98/02619 1 29 rN-rA-13-iodobenzovI)aminophenyflbutyric acid 93 94 96 97 A. o l- o NH 1 7-cinnamoylaminoheptanoic acid 0 O 8.N-(34lodobenzoylamilocapryic acid fJO H B..N (4.metoxy.3.flitrobezoyt)amiocapryic acid 98 SUBSTITUTE SHEET (RULE 26) 130 OfA~ 99 o r COOH WPH 8 2 -methoxy-4-nitrobenzoyl)ainocapryic acid omc 100 4-N14(-ehX--irbnola iohnl~uyi acid OCOH 4 4 2 I 5 -dimethoxybenzoy)ammiopheny)butyric acid OH 102 8-N2hyrx-5boobn l~riocpyi acid OH 104 N* 41NHC *J 131 0OHi 105 0 OH 106 ORL 107 ***OH 4 4 2 ,6-dimethoxybenzoyl)arninophenylI uyric ai 108 o C. CO'OH *NCO 4 4 4 -inetoxy-3tobenzoy)arinophenybutic add ID 110 8 WO 98/34632 WO 9834632PCTIJS98/02619 132 0 Oo0H 0 3 -hydroxy-2-naphthoyl)aminocap.),ic acid H o K cOOH H 8B(N-2hydroxY-4-itobenzoYI)amncpyi acid H H Bt 4 -1N-( 2 -hydroxy4bromobey)inohnlbtii HO o H OH 8-(N23Dihydroxybenzo)icpryi acid OH 8-(N-3-methylsalicyloyI)aminocaprygjc acid 112 113 114 115 SUBSTITUTE SHEET (RULE WO 98/34632 WO 9834632PCTIUS98/02619 1 33 0 0 9- .innmoyiamino)nonaic acid 0 OR 000 IN CI 116 117 11-8 119 120 121 N-2-itrphenl-N-(8-ctaoicacid) urea H OZN -,_COOH N-( 2 -methoxY5nfrophel) sebecoyl amide acid SUBSTITUTE SHEET (RULE 26) 134 I 122 CO123 S-[N( 2 -hydroxy-3,5-dibromrobenzoyl)1aminocapyic acid 12 8 2 -hyoro-,-fluoobenzoyaminocaprylic acid 125 O 126 H HOW 849: flydroxy---nuouenzoycaprycci 0 127 H* K 1 0 Hn Iff~Y~~NW ~0 4-(4-Sicytoyaminopheny)4xobtric acid 135 0 128 1 2 -cinnamoyidodecanoic acid H HO129 0 HO'J 4- 4 4[N-{3-hydroxy-2-naphthoyl)arranophenyl) butyric acid N o"130 8-(4-chloro-3-niltrobenzoy)amnocapryic acid 0

131. (Nya 0 18-(2-chloronicotinoylarmlnocpryic acid -0 132 8-(2.chlaro-5-nluraonzoyli~amnocapryrgc ad 0 133 0 COZI- 4-44-phthertimidopheny)butyric acid 136 Ho H HO o 134 I 0 4 3 -hydroy 2 naphthoyl)anrunophenylj Ipropanoic acid 0 3 -(4-(2.6-dimethaxybenzoy)aminopheny)propionic acid 135 136 8 .(N-2-hydroxy-3.5-diiodobenzoylamincapyic acid Cl COOH 8-(N-2-chtoro-4-fluorobenzoyl)am'inocaprylic acid 1 2-dihydroisoindole-.1 ofl.))octanojc acidi 8-WI-i -hydroxy-2-naphtioyl)aminocap.yGc adid 137 138 139 WO 98/34632 WO 9834632PCT/US98/02619 137 140 0 CO,J-( 8 -(Phthalimido)caprylic acid ON lO-( 4 -chlaro-2-hydroxyanilino)sebacic acid monoamide Q0 142 OGH 3 0 G-(anisoyflaminocaproic acid N Kro 143 ONO0 H C 4-4(-hoo3ntoezy~mnpay~uyi acid Ot IR. 0 144 11 -N-f l-hydroxy-2-naphtIhoyI)aminoundecanoic acid SUBSTITUTE SHEET (RULE 26) 138 0 0 145 H-0 2 C H H C6zH Bis(N-2carboxylphenyl-AN'-8-octanoic acid)ureal)oxatvl diamide ci 146 H O 2-(2-N-(2-chlorobenzoy)ainoethOXYIthaloI 147 0 2-12-N-A4-chtorobenzoy)aminoehoxyethaloI 148 0 JO" 0 :4-(2-iuethoxybenzoylamiino)phenyI 2-carboxyethyl suit oxide 4 4-2-iehxyenoya: o~hey 2-carboxyethyI sulfone 0 150 .N 0 C0 2 H 4-(4-(3-hydroxyphtialimido)phenyl)butyrc acid 1 39 Me 151 152 methoxybenzoyl)aminoethoxyI ethanol H 2 2 -N-(3-cblorobenzoyl)arminoethoxyllethanoI 153 Sis(-2-arbxypienM-(*-3(-amnopienlipopinicacid lurealloxaylyl diamidt 0cwt C02H 154 trans-4( 2 -aminobenzanmidozethyl)cyclohexaocbxyijc acid 00 CLOH Av 155 I1I 3 .S-dichloro-2-tlydroxybenzoyllaminoundecanoic acid WO 98/34632 WO 9834632PCTIUS98/02619 140 156 2 -[NA( 2 -bromobenzoylamino ethoxy ethanol oO0 157 Cl C 0 H H OH CI N -13-( 3 loo5.dicro.2xyeroybenzoaminohep~btnic acid 0 159 H OH trans- 4 -(N.salicyloylaminomethyI)cyclohexn carboxylic acid 0 160 0 WAD N-13. 5 -dichloro- 2 -hydroxybenzoyI..3.(4..aminophenyI),poioi acid 0 N 161 C1 l 2 -N-(3.5-dichoro.2hydroxybenzoyg)aminododni acid SUBSTITUTE SHEET (RULE 26) 141 CH H I. N HO& 0 0 r 0 DNO0 N-( 2 -bromobenzovflmorpholine 1 62 163 165 166 167 9 9 9 9* 9 9* 9 9 9 9* 9. 99** 9** 99 9 9 2 2 4odobenzoyiaminoethoxyehanoI OH H 0 1 N 0 5 4 -chloro-2-hydroxyanilinocarbonyIlvaIeric acid WO 98/34632 PCTIUS98/02619 142 N1- C0 2 H N-SaticoYI-5-A3-aminaphenyl)valeric acid 168 169 170 4 4 2 -CthOxYlbnzYl)aminophnYzbutryic acid &H H0 9-12(3-hydroxy)Pyrdylamilocarboflvll nonanic acid 171 172 OH 2-IN-(2-hydroxybenzoylamina )ethoxy lethanol SUBSTITUTE SHEET (RULE 26) 4 143 OH 0 OH N 0 4-4N-(3. 5-dichloro-2-hydroxybenzoyl Rjaminophenylacetic acid H H N OH 8-(2-hydroxy-5-chloroaniinocarboyl)octaIoic acid 00 N-saticoyt-5-48milophenyl)valeric acid OH H 0 H 9-(2-hydroxy-5-mnethylanilinocarbonylnonanoic acid OH 5A(2-hydroxy-5 -methy aliocabonflYvaeric acid 173 174 175 176 S S.. S S S S S 5 5555 177 S 5.55 S

555. S S SS S. 55 S S 144 F 0 WF 0 F 84pentfluorobenzoyl)aminocapryic acid 178 179 180 181 9 9 9 9 99 9 9 9 9 9 9~9 9 9 99*9 .9.9 99.. 99 9. 9999 9 9. 99 9 9 9 9 99 9 99 99 3-13-(salicyloyl)aminophenyl)propionic acid 0 N OH OC 2 H- 8.(2-ethoxybenzoyl)aminocprylic acid (CH .0Of 4-(4-(2-dimethylaminobenzoyl)aninophenyl)butyric acid H 8-(3-Phsnoxypropinyaminoicapryfic acid 182 'xi. C-, ~44i 0' 145 N-N N H 183 4 -(Salicyloyl)aminoPhenylethyltetrazol. 0 OH 184 8 4 -(4-N-salicYlOYI)aniinopheny)buyrd) aminocaprylic acid F N H O 185 see .000 too.0 0.0. 4 4 4 4 2 -Fluorocinnamoy)amhnophenyl)butyric)ainophenyI)butyric acid LI 186 4 4 -(N-8(N-Saicyloyt)aminocasprylic)aminophenyl)butyric acid 8 4 P-anisoyllaminocarylic acid 187 146 0 NH OH 188 189 8 4 -HydroxybenzoyI~aminacapryic acid .0 HOV -Of 8 4(3-Hydroxybenzoyliaminmocaprylic acid 190 191 192 0@ *S0 000 0S*0 0 10-N-(2-bydroxy-5-nitroaniifo)- lO-oxodecanoic acid NHO 4 4 4 2 -chloronicotinoYI)aminophenYgibutyric acid 193 147 and salts thereof. 31. A method for preparing a composition, said method comprising mixing: at least one active agent; at least one compound as defined in claim 30; and optionally, a dosing vehicle. 32. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering intranasally to said animal a composition as defined in claim 2. S33. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering sublingually to said animal a composition as defined in claim 2. I~i an animal in need of said agent, said method comprising administering 0o 34. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering ":si intraduodenally to said animal a composition as defined in claim 2. oooo 1 :B 35. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering ti subcutaneously to said animal a composition as defined in claim 2. ooo° 36. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering rectally to said animal a composition as defined in claim 2. 148 37. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering vaginally to said animal a composition as defined in claim 2. 38. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering bucally to said animal a composition as defined in claim 2. 39. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering ophthalmically to said animal a composition as defined in claim 2. A method for passing a biologically active agent across the blood/brain barrier of an animal in need of said agent, said method comprising administering to said animal a composition as defined in claim 2. 41. Compositions according to claim 1 and/or uses thereof substantially as hereinbefore described with reference to the Examples. oi 42. Methods for the preparation of a compound of claim compositions containing said compound and/or uses of said compound substantially as hereinbefore described with reference to the Examples. *00* DATED this 3rd day of August 2001 EMISPHERE TECHNOLOGIES, INC. By its Patent Attorneys DAVIES COLLISON CAVE 0'