AU2004202745A1 - Compounds and compositions for delivering active agents - Google Patents

Compounds and compositions for delivering active agents Download PDF

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Publication number
AU2004202745A1
AU2004202745A1 AU2004202745A AU2004202745A AU2004202745A1 AU 2004202745 A1 AU2004202745 A1 AU 2004202745A1 AU 2004202745 A AU2004202745 A AU 2004202745A AU 2004202745 A AU2004202745 A AU 2004202745A AU 2004202745 A1 AU2004202745 A1 AU 2004202745A1
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Australia
Prior art keywords
acid
active agent
butyric
hydroxy
biologically active
Prior art date
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AU2004202745A
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Emisphere Technologies Inc
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Emisphere Technologies Inc
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Filing date
Publication date
Priority claimed from AU72260/00A external-priority patent/AU771434B2/en
Application filed by Emisphere Technologies Inc filed Critical Emisphere Technologies Inc
Priority to AU2004202745A priority Critical patent/AU2004202745A1/en
Publication of AU2004202745A1 publication Critical patent/AU2004202745A1/en
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  • Medicinal Preparation (AREA)

Description

Our Ref: 12262061 P/00/011 Regulation 3:2
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Emisphere Technologies, Inc 765 Old Saw Mill River Road Tarrytown New York 10591 United States of America Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street Sydney, New South Wales, Australia, 2000 Compounds and compositions for delivering active agents The following statement is a full description of this invention, including the best method of performing it known to me:- 5951
I
P:\WPDOCS\CAB\CHEMCAL\SPECI\7562890.dc-22106/04 -1- COMPOUNDS AND COMPOSITIONS FOR DELIVERING ACTIVE AGENTS This application is a divisional of application No. 72260/00, in turn a divisional of parent application No. 62756/98 (now patent No. 738735).
The ensuing description is substantially identical to the description of the specification of the parent application. The "parent" description has been readopted to facilitate identification of the parent/divisional relationship. The scope of the invention of this divisional application is set forth in the claims of this specification.
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, 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 imposed by the body.
Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target. Chemical
I
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 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.
OH
CI
G-N-(3.5-dichloro-2-hydroxybenzoyl)aminocaproic acid
OH
aNH 2 8(2-aminobenzoylamino)caprylic acid 121 OH FfPO 0 8(2-trifluoromethoxy)benzoylamino caprylic acid 04
N
OH OH 0 N-(2-hydroxybenzoylisonipecatic acid H1 F 0 joif F F
F
4 4 -(pentafluorobenzoyl)aminophnyl)butric acid 0 H c~ou 4-(4-(3-anisoyl)aminophenyl)butyric acid 01 0 8-(3-anisoyl)aminocaprylic acid
H
4 4 -(phenoxyacetyl)aminopheny)butyric acid 0 Is, 4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid 0
HOH
NO
2 8-(2-nitrobenzenesulfonyl)aminocaprylic acid 6 OH 0 12 0 6-(4.Isaticyloyl)aminophenyl)hexanoic acid 0 13
OH
H 0 8-(2-wnethoxylberizoyI)amino caprylic acid 1H 14 OH 0 II CH 2-[(4-salicyloyl)aminophenyl]ethyI methyl sulfone H 0 N ,N'J
COOH
OH 0 H 1 Slclyl2sciy hydrazide 0 16 0 OH
CH),O
~U2 H acid I too HI 17 acid~ 0OH 18 N
O
H 0 0
OH
1 -salicyoyI-2-gltryI hydrazide 0 Cooli19 4-(4-((4-carbaxyl-3-hydroxy phenyl)arnino)succinyl)aminosalicyclic acid 0OH 84(Phenoxyacetylamino)caprylic acid 0 21
CNIN
N H OH 0 8-(2-pyrazirlccarbonyl)aminocapryic acd N 22 N N 0
OH
4-(4-(2-pyrazinecarbonyl)amilophelyl)butyric acid Noz 0OH G-1 4 2 -Nitirobenzoyl)aminophenyl)hexanoic acid .0
N
OilK 4-(4-(N-(6-carboxyl-2,5-pyrazinylcarboxyl)aminophenyl)butyric acid 23 24' 26 27 412-Nitrobenzoy)aminophenyisuccinic acid 0 H OH
II
8 2 -(trifluoromethoxy)benzoyl)aminocaprylic acid
H
cis &trans OH 0 28 29 31 32 33 8-(phenoxycarbonyaio)capryic acid 00 44t4-beruIoxVcarboflamiflophenyl~butyric acid H1 OR 0 1 34 36 37 38 39 O H 3-(2-mnethoxybenzoylamino)-l -propanol 0 N OH0 8 2 -Hydroxynicotinoyl)aminocaprylic acid- 6 2 -mnethoxybenzoyl)amino nicotinic acid 0 NH-yOH 0
OH
salicylovlglycine 03 41 N N 0 0 4-(1 -(2-pyrimidyl)piperazinoyl)butyric acid 0 0 8-(chromone-3-carbonyl)aminocaprylic acid 0 43 N0 Q N OH 8-(vinylbenzoyl)aminocaprylic acid 0 0 44 o NH 4( 4 -(chromone-3-carbonyl)aminaphenyl)butyric acid NH0 011 8-cinnamoylaminocaprylic acid 46 -salicyloylamino)vateric acid 06H H 9-(2-hydroxybenzamido)nonanic acid Ho N0 OH HO Ha 0 6-(N-4-(N-salicyloyl)aminobenzoyl)anminocaproic acic 47 48 49 4-flavanic acid I1I -cinnamoylaminoundecanoic acid OH H HOy 0 0 4-octanoylamino-3-hydroxybenzoic acid 51 0" O 52 (3PhenyI2.3dihydroxypropanoyl)8aminocaprylic acid NH COOH 8-[N-(3-coumarincarbonylllaminocaprylic acid COOH 54 8-[N-(4-chtorobenzoyt)Jaminocaprylic acid COH
F
84[N-3-fiuorobenzoyl)laminacaprylic acid OH 0 1 N OH lof 0
OH
8-(N-2,5-Dihydroxybenzoyl)aminocaprylic acid Ctso- N-'-OH 8-(N -2,3-Dimethoxyb enzoyl) amino caprylic acid [SOO 58
CH
3 0 8-(N-2.4-Dihydroxybenzoyl)aminocapryac acid C~jOO59 N
OH
00
CH
3 0 8-(N 5-Dimethoxyb enzoylamino cap rylic acid 0 0 0 CHjo 0 B-tN-3.5-Diacetyt0xybenzoyI)aminocaprylic acid 0o 61 N (H o -hydroxYbenzoYl)aminooctanoyl)amiocaprylic acid (dimer) OHO0 0-6 8-(N-2.4-Dihydroxybenol0Y)amliocaprylic acid H,6 8-(8-(4 N
OH
1 C-(N4-2-Mthoxyaniino)sebalic acid OH H 0
N
-10-(N-2-hydroxyanilino) sehacic acid
CH
3 H ,0 o
OH
2-Methoxybelzeamilodecafloic acid 0
OH
Hro 0 8-(N-benzoyI)amiloceprylic acid 64 66 67 acid 68 69 tfo 0 1 2-dihydroxyethyl)benzoyl)aminocaprylic acid OOH71 8-[N-(4-bromobenzoylllaminocaprylic acid xn~-~ocrn72 8-4N-(4-iodobenzoyl)amiocapryic acid 73
N
4 44 N-(2-iodobenzoyl)aminophenylllbutyric acid OH 0 ~H 74 acid 0 t HtjCo OCH~ 4-(4-(2.4-dimethoxylbenzoy)aminopheny~butyric acid o NH 76 OMc 0
OH
4 -(o-anisoyl)aminophenylacatic acid Hf I OC 1 3 7 0 4 -(2.4-dimetlioxybenzoyl) aminophenyll propionic acid 78 4 -{4-[N-(4-.odobenzoylll aminophenyl) butyric acid CH3 79 3-14-(2.3-dimethoxybenzoyQl aminoplienvl orooionic acid
BH
4 4 -[N-(2-hromobenzoyl)IaminophenylI butyric acid 4-{4-[N-(3-bromobeflzoyl)aminophenyll butyric acid 0 Ito
OH
0 8-(N-3.5 Dthydroxybenzoyi)aminocapric acid 0 CH
OH
0 C
H
8-(N-3.5-Dimethoxy 4-hydroxybenzoy)aminocapryllc acid 81 82 83 84 8-(N-2-6-Dimethoxybenzoyl)aminocaprylic acid Br
H
4-{4-(N-14-bromobenzoyl)apninophenyll)butyric acid Cl Off 2-bydroxy-4-chlorobenzoyl)aminocaprynic acid 86 87 88 89 0 0 0 C1 91 92 4 -1 4 4 -chloro-o-anisoyl)aminophenyI)butyric acid 93 94 .(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid 0011
H
4-(N-[4-(3-iodobenzoyl)aminophenyll)butyric acid j4~k~%%~00] 96 7-cinnamoylaminoheptanoic acid
OO
8-N-(3-iodobenzoyl)aminocaprylic acid 97 1 98 8-N -(4-methoxy-3 -nitrob enzol) amin cap ryic acid
OMOO
Q H 8-N-C 2-methoxy-4-nitrobenzoyl)aminocaprylic acid OMe 4 -{N-44-(2-.methoxy.4nitrobenzoyl)aminophenyll~butyic acid 0 11
OHI
99 4 4 2 5 -dimethoxybenzoylaminophenyl)butyric acid
OH
Br 8 2 -hydroxy-5-bromobenzoyl)aminocaprylic acid 100 101 102 103 104 N.
OH
3 -tndalebutyric acid NH INH. 0 OMe 0 oti105
H
0 Otf 106 NH Nil:
OR
Ocl 107 4-[4-(2,6-dimethoxybenzoyl)aminophenylI butyric acid o COOH 4-[4-N-44-methoxy-3-nitrobenzoyl)aminophenyllbutyrio acid 109 8-(N-2-hydroxy-5-chorobenzoyl)aminocapryIIc acid 110 8-(N-2-hydroxy-54iodobelzoylamilocapryic acid 0 N N
OH
H
OH0 111 1 12 8 3 -hydroxy-2-naphthoyl)aminocaprylic acid
JH
8 2 -hydroxy-4.nitrobenzoyI)aminocaprylic acid H
H
0" Be 1 113 4-f-N-C: 2-hdrov...rmobnz *"amJULim( 1, 1- Qj l NH- OH 0 114' 115 8 -(N-2,3-DihydroxybenzoyI)aminocapryic acid 8-(N- 3 -methylsalicyloyl)aminocaprylic acid Q N 0H 116 8-(N -5-m ethylsalicylo yl)amino cap rylic acid 0 0 117 H Q 9 -(cinnamoylamino)nonanoic acid 0 oO0 11-8 C I 2-chloro-5-nitrobenzoyl)aminaphenyl)butyric acid oil Oil 119
II
N-2-nitrophenyl-N'-(8-octanoic acid) urea
H
OzN N __121 sebecoyl amide acid 1122 -8-[-(2hydrxy-,5-dichlorobenzoyl)laminocaprylic ai 123 8-[N-(2-hydroxy-3,5-dibromobenzoyl)]aminocaprylic acid Cl 124 8-N-(2-chtoro-6-fluorobenzoylaminocaprylic acid OR H 125 0 126 127 ~Nr 0 128 129 1 2.cinnamoyiddcaoic acid
HO
H
0 Ho,,
I
4-f 4 -[N-(3-hydroxy-2-naphthoyl)aminophenylj )butyric acid 0 N
C
N N 130 131 132 133 8 2 -chloronicotinoyljaminocapryic acid -0 H 0 8 2 -Chloro.5-nitabenzoylarinocepryrgc acid 0 0 C0Na H 4-(4-phthaimidaphenyl)butyric acid 134 acid 135 136 8-(N-2-hydroxy-3.5-diiodobenzoyI)aminocaprytic acid 137 138 139 8-(N-1 -bydroxy-2-naphthoyt)amilocOPrYlc acid 28 0 CO0 140 141 8-(phthalimido)caprylic acid
N
CI
1 O-(4-chloro-2-hydroxyaliflo)seb8cic acid monoamide 0 OC 0 0 142 143 6-(anisoyl)aminocaproic acid rOH 02N N 0 Ow
H
OH 0 0
H
11 -N-(l1 hydroxy-2.-naphthoy)aminoundecafloic acid 144 I 1 Bis(N-2carb' u v 145 HOzC Z, co 2
H
Nfj 00OJNt HOzC K H CoaH oxylphenyl-N-(N'-S-octanoic acid)ureafloxalyt diamide C1 146 Q N
H
H
2-[2-N-(2-chlorobenzoyl)aminoethoxyI ethanol 147
CI.
2-12--N-(4-chlorobenzoyl)aminoethoxylethanoI 148 0 ~yOtH 0 YOCt13I IethoxYbenzoylamnino)phenyl 2-carboxyethyl sulfoxide 0* s 0 OH149 0 0C0 ;ethoxybenzoylamino)pheny1 2-carboxyeffhyi sulfone OH I 1 150 0NQ 0 C0 2
H
4 4 3 -hydroxyphthaimidopheny)butyric acid 2.-[2-N-(2-methoxybenzoyl)aminoetboxy ethanol 151 152 2 2 -N-(3-chlorobenzoy)aminothoxyletbanoI 153 Bis(N-2-carboxyplhenyi-N-(N'-3(4-aminopeny)propionic acid)urealjoxaylyl diamide 0
C
154 trans-4-(2-aminobenzamidomethyl)cyclohexanocarboxylic acid 00 Ct 11 -N-(3.5-dichloro-2-hydroxybenzoylaminoundecanoic acid 155 2-IN-(2-bromobenzoyl)aminoethoxylethanol O 0 V
~OHH
CI
7N 5-dichloro-2-ydroxybenzoylaminohetnouic acid 0 .0C 0
HO
tr--N-[3ali2-ydrxnoyl-44aminopylhene caboyic acid 00 I I~ trns-4-( aicloyfmiomoh ycclheae obx i cd 156 157 158 159 160 N-13,5 -dichloro-2-hydroxybenzoyl-3-(4-amiflaphenyl)]propionic acid 1 5-dichloro-2-hydroxybenzoyl)aminododecaflic acid 32 OH H 1 162
N
HO 0.
0 N-(2-hydroxy-4-carboxyphenyl)-6.heptenamide r o 163 00 N-(2-bromobenzoyl)morpholine 0 164
OH
H
8-N-cyciohexanoylaminocaprylic acid 165 2-[N-(2-iodobenzoyl)aminoethoxylethanoI OH H 016
N
OH
CI-
4 -chloro-2-hydroxyanilinocarbonyljvaleric acid 0 167 1cWINH 0o 8-(2-hydroxyphenyacety)ahifocaprylic acid
OH
N-Salicoyl-5-(3-aminoplienyl)valeric acid o O 4.4-(2-ethioxylbenzyl)aminophenyl)butyric acid OH H 0
N
oN Off .3 hydroxy)pyridylamilocarbonylI nonaniC acid 168 169 170 171 172 2-IN -(2-hydro xYbenzo vlamino) etho x Ie tha no I 4 3 5 -dichloro-2-hydroxybenzoyl)jaminophenylacetic acid 8-(2-hydroxy-5-cbloroanlinocarbonyl)octanoic acid 173 174 175 9 176 177 2-hydroxy-5-methyaniinocarboyl)valeric acid 0 178 179 180 181 3-(3-(salicyloyl)aminophenyl)propionitc acid 0 N.
OH
*OC
2 Hf 8-(2-ethoxybenzoyl)aminocaprylic acid (CH )N
O
00 -(442-dimethylaniinobenzoflaminonhenvflbutvri 4 acid 4 acid 8-(3-Phenoxylprapionyfamino~caprylic acid 182 183 4-(Salicyloyl)aminophenylethyltetrazole- 184 OH 0 8 4 4 -N-saicyloyl)affinopheny)butyric) amninocaprylic acid
H
F0 N"
OH
H
4-(4-N-(4-(4-N-(2-Fluorocinnamoyl)aminophenyl)butyric)amilophelyl)butyric acid 185 186 4-(A N-Saiicyloy)aminocapryic)amiflophenyt)butyric acid .187 0 8 4( 4 -HydroxybenzoYl)rinoca-prluc acid 188 189 190 191 192 1O-N-(2-hydroxy-5-nitroanilino).IO-oxodecanoic acid 193 4 4 (2chloronicatinoy)aminopien~btr acid
I
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.
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 enzymes in the gastro-intestinal tract; polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates; lipids; or any combination thereof. Further examples include, but are not limited to, human growth hormones; bovine growth hormones; growth releasing hormones; interferons; interleukin-1; interleukin-ll; 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; 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.
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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 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point (c) 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 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point I°C) 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
I
TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point 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- 171 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
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TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point (oC) C H N S C H N S 97 46.31 5.18 3.61 46.54 4.95 3.64 122-123 98 56.8 6.55 8.28 56.69 6.67 8.1 99 56.8 6.55 8.28 57.37 6.57 8.33 117-118 100 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 57.9 7.11 7.82 131-133 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point 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 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point 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 TABLE 1 Carrier Properties Melting Compound Anal. Calculated For Found Point 0 c 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 .64 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, 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 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 5 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,
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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. MeO N NHOH Me Actinonin N
HNHOH
0 H 0 HO Me oMe Epiactinonin Derivatives of these compounds are disclosed in U.S. Patent No. 5,206,384.
Actinonin derivatives have the formula: 0 11 R5-- C CH, H 0
N
0 CH
CH
3
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.
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 chemnically 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 111111111 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) g, 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
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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%).
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Compounds 2-4, 6-17, 19-29, 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, 0.0101 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 mls) 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 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 1N 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 mls) 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
I
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 250C 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 1400C. The mixture became a clear solution after 5 min at 1400C. 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.
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 40 0 C, diluted with water and extracted with CH 2
CI
2 (2 X 20 rL). The organic phase was washed with water and brine, dried over Na 2
SO
4 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.
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 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 200-250g 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.
L
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
I
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 m I Solutions An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula
OH
O O H 0 for the carrier. This dosing solution is designated as Comparative Example 4C 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
I
H
0 N 0 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 wer'e 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 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.
TABLE 3 In Vivo Recombinant Human Growth Hormone Delivery__ Mean Peak Serum [rHGH] Dosing Solution Standard Deviation (ng/mI) R-9-DS 125 34 (IC) 41 46 (P0) 108 56 (IC) R-36-DS 28 11(10) R-47-DS 0 (IC) R-62-DS 11 12(IC) R-64-DS 72 22 (PO) 19 22 (PO) R-67-DS 88 24 (IC) R-77-DS 34 10 (P0) R-79-DS 62 51 (P0) 9 13 (P0) 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-OD-DS 0 0 (IC) R-0E-DS 0 0 (IC) Example 6 In Vivo Interferon Delivery An intracolonic dosing composition containing 50 mg/kg of carrier 9 and 250/ g/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.
OH
1
HO
0
O
I0 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.
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.
TABLE 4 In Vivo Evaluation of Heparin in Rats Dosing Solution JHeparin APTT (sec) H-9-DS 48 18 (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 27 (P0) H-96-DS 36 ±L 8 (IC) H-102-DS ill 1080(C) H-109-DS 56 28 (IC) H- 11 -DS 37 9 (IC) H-1 11 -DS 71 39 (IC) H-1 17-DS 140 128 (IC) H-122-DS 49 21 207 ±7 (PO) H-1 23-DS 42 14 (PO) H-139-DS 31 11 (IC) H- 141 -DS 59 26 (IC) H-144-DS 26 3 (IC) 61 29 (IC) 51 30 (IC) H-169-DS 23 2 (IC) H-0A-DS 23 2 (PO) H-OB-DS 33 6 (IC 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.
I

Claims (19)

  1. 4-(pentafluorobezoyl)amiophefl)butyric acid 0 N 4-(4-(3-anisoy)amilophe1yt)butyric acid CH 1 O H 8t
  2. 8-(3.anisov)amilocaprytic acid 0 I 4 4-(4-(phenoxyacetyl)aminopheny)butyric acid U0 -N, NO 2 OH 4 4 4 Z2--itrobonzensufoyl)amiflophenyI)butyric acid O0 0 1 S-NH OH N0 2 8.(2-nitrobezslZfUfonyI)am~inocaprylic acid O0 0 12 G- 4 (arBicyloy)mifophenyl)hexanoic acid 0H 13 lo& 0 8412fnethoxylbenzoyI~amino caprylic acid I~NH I 14 16 acid H OCIIb 17 4-(4-(2.5-dimothoxycinnamoyl)aminophenyl)butyric acid~ 18 I -salicyloyl-2.'glutaryl hydrazido 4 4 ((-carboxyl-3-hydroxy phenyl)alniino)succinyl)anmjnosaii 19 N H OH 0 8-(2-pyrazinecarbonyl)amfinocapryric acid 21 76 (N 22 0 OH 4 4 2 -pyrazilScarboflI)8flifophenyl)butyric acid Nb 0 23 0 6-44N2-Nitrobenzoyl)aminophenylhexanoic acid NK 0 24 6-4(--rioezyiaiohnlhxni acid 0 I ~COOK 2 4(2-Nitrobenzoy)amiopheyISiflKcci acid 27 28 29 8-(phenoxycaboflamiflo)caprylic acid 32 33 34 36 37 38 39 41 NH-OH 42 0 8-(chromona-3-carbonyl)aminocaprylic acid o 43 QN Off 8-(vinylbenzoyl)aminocaprylic acid 0 0 44 4-(-(hrmoe-3caboylamnopenl~utr0 acid 0 4 46 OH H 4 N OH
  3. 9-(2-hydroxybenzamido)nonanic acid 48 HO %l',I2Y O0 OH HY0 6-(N- 4 -(N-sahicyloyl)aminobenzuyl)aminocaproic acid 0 49 0, 0 4-flavonic acdd 0- NH OOH I1I -cinnamoylamlaioundecanoic acid OH K 51 HOf0 0 0 4 -bctanoylamin-3-hydroxybnoic acid ORf 52 ORO (3PhenyI2.3dihydroxypropanot)aminocaprygc acid 53 N H COO II 8-[-su-coumarincarbo iyI)laminocap..ijc acid 8 -[N-(4-chlorobenzoyl)]aminocapryiic acid 54 56 CH~o- Q OH 8 2 3 -Dimethoxybenzoy)aminocapryic acid H0 (I OH 8-(N-2.4-DihydroxybenzoyI)aminocaPr~,ic acid 57 58 CH)OO OH H 0 CH 3 0 8-(N-2.5-Dimethoxybenzoyl)amirnocaprylic acid 59 61 (dimer) 62 63 OH- Hl 0 0H~ 1O-(N-2-hydroxyanilino) sebacic acid CH 3 H 0 o OH 2-Methoxybenzenaminodecanoic acid 8-(N-benzoyl)aminocaprylic acid OHO0 N 0OH CHO 0 C I-I 0 HUk%% COOH S-IN-(4-fluorobenzoyl)laminacapryic acid 8-(N-(3-bromob enzoyl)]amino caprytic acid OH 0 2-dihydro xyethyl) benzoyl) amino caprylic acid 67 68 69 0 71 84N 44-bro mob enzoy) Iaiocapryic acid 72 OOH 4-{4-[N-(24odobenzoyI) amino Phenl I butyric acid 73 74 acid acid 76 L 4-(o~anisoy) aminlophenlacetic acid HICI 1 77 0 4-N-(3-bromobenzoyl)amninophenyll I butyric acid 78 4 -{4-[N-14-iodobenzoyl)) aminophenyl) butyric: acid F 00c 1 7 9 001 4 -[N-(2-bromobenzoyl)]aminophenyl) butyric acid 81 -4-(2,6.dimethoxybenzoyl)aminophenyllbutyric acid 110 0H8 N 0 8-(N-3.5 Dthydroxybenzoyl)aminocaprylic acid 87 00 al 00 84N-3. -Dimethoxy rxbenzoyllaminocapgjc acid 84 I1- rmet obenzoyl)aminopnc utri acid lroabnzoyl)aminopylbuic add OR 0 87 0o1-f 0 8-(N- 2 .6-Dihydraxybenzoyl~aminocaprylic acd 1H 88 89 91 92 0 oil 8-(4-chloro -o -aniso yt)amino cap rylic acid 93 94 -dim ethoxyb enzoyl)aminophenyl)pra pio nic acid 4-{N-[4-(3-iodobenzoyl)aminopheny[lbutyric acid 96 97 98 8-N-(3-iodabenzoyl)aminocaprylic acid 8-N-(4-methoxy3-nitrobenzoyl)aminocapryic acid OMe 8 -N -(2-metho xy-4-nitrob enzo yl) amino cap rytic acid 99 ome 100 w~p H -[-2mtoy4ntoezolaiohnl~u~i acid O OH 101 4-(4-(2.S-diamethoxyb enzoyl)aminophenyt)butyric acid Ott o ~~COOH102 I Er NOR 103 3-Indolebutyric acid 104 105 106 107 108 109 110 112 113 8-(N-2-hydroxy-4-fitrobelzoyI)aminocaprytic acid acid 114' 115 8 -(N-3-methyisaicylYI~)ammnocaprylic acid 9-(cinnamoylamino)nonanoic acid 116 117 I118 119 120 acid 121 122 -8[-2hdoy35dclrbnollmnc~y' acid 123 OiO FH 8 2 -chydro643-iUrobenzoY)lamnocapry ic acid ttI 126 127 ON 128 1 2-cinnamoyldodecaloic acid H H 129 0 4- l 4 3 -hydroxy-2naphthoyl)amino~henyII )butyric acid 0 130 0 131 8-(4-choro-ictrfobeY)amflocapri~tc acid 0 132 8-Zcdrretnylr~ncpyi acid -0 133 4 4 -phlthlarfdophelyfbutYflC acid H HO 134 4- l4-IN-(3-hydroxy-2naPhthoy1)anfopheljlIpropano c acid 0 135 CHI 3 2 .6-dimethoxybertzoy)amiflGphenyI)propionic acid H oofl136 8 -(N-2-hydroxy-3.5diiodobenzyI)aminocapfylic acid CI 137 8 -(N-2-chtoro-4fuorobenzoyl)aminocapIVltc acid 0 138 C02H1 84(2-Cl ,2-dihydroisoindole-l -one))Octenoic acid F- 1 139 acid 8-(phthaimido)caprylic acid 1 O-(4-chloro-2-hydroxyalililo )s ebacic acid monoamide ON~~ 0 9YH OH 6-(anisoyl)aminocaproic acid 140 141 142 143 144 (4-(4-chloro-3-nitrobenzoy)amiophelt)butyric acid
  4. 11-N-Cl -hydroxy-2-naphthoylaminouldecafloic acid 145 146 147 2 2 -N 4 -chorobenzoyl) amino eilhoxylethanol 148 149 OH 0 6 1Q 0 C0 2 H 4-(4-(3-hydroxyphthaimido)pheyl)butYric acid 150 151 152 153 8isIN-2-carbo xypleflvl -N-tF4 3 t4-aioplenyt)ProDpionic acid lureaU)O xaylyl diampide 154 155 A1I C .5 _iChtorO-Z-hydroxybenzoYlefinudcro ad 100 156 2-[N-(2-bromob enzoyt)amino etho xylethianol 0O0 157 H OM C" 74'J-(3. 5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid 0 158 C 0 HO CH O1 dichloro-2-hydroxybenzoyl-(4-aminophenyl)Iputrpic acid 00 161 0 CI N413,! N-[3 1 2-N -dichlo ro -2-hyd ro xyb en zoyl) amino do decanoic acid 101 H 162 0 N-(2-hydroxy4caboxyphenl)-6heptenande 0 163 N 2-bromobenzoyl)mophoflfle 0 164 HO 8.N -cyclo hex alo ylamino caprylic acid 1 165 2-LN-{24iodobenzoyi)amiOethoxy]O'thnoI OH iR 0 166 OH Cl0 0 5-(4-chloro -2-hydroxyaniilocarbonl)vaIeric acid 167 102 IO Q 1 6 8 0 HN O OOH 2. 1 0 4 4 -(3-chdoxy~pyriy)amfiocabylI nonan acid 0 170 -12--hydroxypeoyridylamincapryll oic acid OHII 171 F I vI 2 2 -hydrox Ybenzo ylamino )ethox y Ieth anol 103 4N(3 5 -dichoro2ydroxbenoy)aoheyati acid on H N OH 0 0 Ci 8 -(2-hydroxy-5-chloroanifinocarbonyI)octanoic acid 0 CO 2 H O'H OH 173 174 175 176 177 IN-saticoyI-5-(4-aminopheny)vaieric acid OH H 0 o H 9 fZ1-ydroxy-5-rnethylanilinocarbonyI)nonanoic acid 2 -hydroxy-5-methylaniinocarbony~vateric acid 104 F 0oi 178 FF F 8-(pentafluorobenzoyl)aminocaprylic acid OH 0 179 3-(3-(saicyloyl)aminophenyl)propionic acid 0 180 (41 8-(2-ethoxyb enzoyl~aminocap rylic acid 0C[ 181 4-(4-(2-dimethylaminobenzoyl)aminophenyl)butyric acid 0 182 8 (3-Phenoxytpropionytamino ~caprylic acid 105 H 183 4-(SaicyloyI)aminophenylethyltetrazole 184 8-(4-(4-N-salicyloyl)aminophenyl)butyric) aminocaprylic acid H OH 0 H 185 4-(4N-(-(4N-(-Floroinnmoy~amnophnylbutricamiophnylbutricacid 4-4-(N8(N-Sticyoy)amiocpryiclamilaphelylbutyric acid 187 8-(p-anlsoyl)&minocapryroc acid 106 0 188 8-(4-Hydroxybenzoyl)aminocaprylic acid o 189 0 8-(34ydroxybenzoyl)amiocapric acid 0 190 CM 8-(3.4.5-Trimethoxybenzoyl)aminocapryrlc acid 191 OH C 0 8-(N-4-methysaicyloy)arfliflOapFylic acid -OttH 0 192 t4OZ 10N(-yrx--iranln)1-xdcni acid I_ 193 4-(4-(Z-chloronicotinoyl)amiflaphenyl)butyric acid I 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-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. A composition as defined in claim 4, 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. 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. I 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 fromthe group consisting of a biologically active agent, a chemically active agent, or a combination thereof. 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-l, interleukin-l, 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. 109
  5. 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 combinatikns thereof.
  6. 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.
  7. 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.
  8. 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-1, interleukin-Il, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a I 110 monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.
  9. 17. A dosage unit form as defined in claim 16, wherein said biologically active agent comprises an interferon, interleukin-l, interleukin-11, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.
  10. 18. A dosage unit form comprising a composition as defined in claim 7; and an excipient a diluent, a disintegrant, a lubricant, a plasticizer, a colorant, a dosing vehicle, or any combination thereof.
  11. 19. A dosage unit form as defined in claim 1 8, 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 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-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.
  12. 22. A dosage unit form as defined in claim 21, wherein said biologically active agent comprises an interferon, interleukin-1, interleukin-11, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.
  13. 23. A dosage unit form as defined in claim 8, comprising a tablet, a capsule, or a liquid.
  14. 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 diol, ethanol, or any combination thereof. A dosage unit form as defined in claim 13, comprising a tablet, a capsule, or a liquid.
  15. 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. I 112 1
  16. 27. A dosage unit form as defined in claim 18, comprising a 2 tablet, a capsule, or a liquid. 1
  17. 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. A compound selected from the group consisting of 113 5-dichloro-2-hydroxybenzoyl)aminocaproic acid OH Ni2 8 (2-aminob enzoylamirio) cap rylic: acid 0 FOl FfO 0 8(2trifluorometho xy)b elzoyl aminlo caprylic acid 0 OH 0 N-(2-hydroxybenzoyl)isonipecotic acid 114 F Q ON 011" F F F entafluo rob enza ylaminoph enyl)butyric acid CvO 0f 4-(4-(3-anisoyl)aminophenyl)butyric acid 00 8-(3-anisoyl)aminocaprylic acid Y 0 4 4 -(phenoxyacetyl)aminophenyl)butyric acid ,~N-N 0 0 NO 2 4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid 0 N Q0-0 Q 01-H NO 2 8-(2-nitrob enz en esufo nyl) amino caprylic acid 115 0" 0 O 12 6-(4-(salicyloyl)aminophenyl)hexanoic acid 0 13 N OH 8-(2-mnethoxylbenzoyl)amino caprytic acid H 14 Q-lf N 2-f (4-salicyloyl)aminophenyljetbyl methyl sulfone H~ 0 N t" COOH 1 -Salicyloyl-2-succiuyl hydroxide 0 16 HO 2.5-dimethoxycinnamoylainopheyl)propi~lic acid 0 o, 17 CHSO 111AOaCH -dim ethoxycinnamoy)aminopheny)butric acid 116 0o 18 N OH 1 -salicyloyl-2-glutaryl hydrazide 0 OON 4 4 4 -carboxyI-3-hydroxy phenyl)a 'no)succinyl)aminosalicyclic acid *OH 0 8-(Phenoxyacetylaminokcapry~ic acid No 21 N)'jrH OH 0 8-(2-pyrazinecarbonylaminocapryic acid N 22 0NN OH 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid 117 23 24- OH -4(-N(-a~xl25prznycroy~ri-pey~uyi acid 26 27 4 (2-Nitrobenzoyl)aminophenylsuccini-c acid OH OCF 3 0 8 2 tifluorometIhoxy) enzoyIminocri acid 118 0 8-(benzyloxycarbonylarino)caprylic acid aOiN OH 0 S-(phenoxycaz-bonylamiino)caprylic acid N 0 OCR., 0I 0 "O OH 2-4.(2-Mthoxybenzoylamino)phenylethyI HZP0 4 0010 011 0 28 29 31 32 33 1 -selicyoyf.2suberyl hydrazide 0 00 4-(4-benzylaxycarbonylaminophenyl)butyrlc acid 119 NH\ OH N OH 4 4 2 -hydro xynicotino yl)amino ph enyI) b utric acid 34 0 OH QAOt N C4 ,0 H 4-(4-phenyloxycarbonylagminophenyl)butyric acid 0 0fNH' H OCH) E657 3-(2-metho xyb enzoyl amino)- I1 propanol 36 37 38 39 8-(2-Hydroxynicotinoyl)aminocaprylic acid I .COO H 6-(2-methoxybenzoyl)amino nicotinic acid 120 0 NHH *1 0 OH saticyloylglycine 0~N 01- 4-Cl -(2-pyrimidyl)pip erazinoyl )butyric acid 41 42 43 44 acid 00 8-cinnamoylamilocaprylic acid 121 OH H46 N OH 0 0 acid OH H 4 7 rN OR 9-(2-hydroxybenzamido)nonanic acid 48 00 6-(N-4-(N-salicyloyl)aminobenzoyl)aniinocaproic acid 0 49 0 4'-flavonic acid COO I1I -cinnamoylaminoundocanoic acid OK H 51 HO 0 0 4-octanoylamino-3-hydroxybenzolc acid 122 GH OH N Kj0 (3PhenyI2.3dihydroxyprop anoyt)8aminocaprylic acid NH -COO"53 8-EN-(3-coumarincarbonyl~ominocaprylic acid 8-tN-(4-chlorobenzoyl)aTinocaprylic acid F 84IN-3-fluoronzoylllamiinocapryic acd OH 0 OH
  18. 56- 0 OH 8(N-2.5-Dihydroxyb enzoyl) amino caprylic acid ctsp CO0 OH57 H 0H 8-(N-2,3-Dimethoxybenzoy)aminoceprylic acid 123 58 CHiO' 8 2.4 -Dihydro xyb enzoyl)amino cap rylic acid CH 0 01 0 0 CH 3 0 acid 0 0 II 0 8-(N-3.5-DiacetyIoxybenzoyl)aminocaprylic acid 59 61 62 H HO 0 N Q OH 1 -i-2-Methoxyanilinol-sebalic acid 63 124 OH H 64 N 00 O 1O-(N-2-hydroxyanilino) sebacic acid CH 3 H 065 0 OH 2-MethoxybelzenaiodecaflOic acid 0 66 Q N OH 8-(N-benzoy)amilocapryic acid OH 0 6 (N-2-Hydroxy4-rnthoxybenol)miocapryic acid I .O 68 69 125 OH 2 -dihydroxyethy1) benzoyI)amino cap rylic acid NHO S-(N romob enzoyfl)Iamino caprylic acid 84[N-(4-io dob enzo ylamino caprylic acid 71 72 73 OH 0 O I H 74 I I 4-4[N( lhydroxy- 2 -naphthoy)aminophenyf1}butyric acid 126 acid 76 77 4 -(o-anisoyl)aminophenylacetc acid HfCO. OCU 0 3 4 2 -4-dimethoxybenzoyl) aminophenyll propionic acid 4-(4-4N-4todobenzoyl)J aminophenyl) butyric acid 3-r4-( 2.3 -dimethoxybenzoyll aminoptienvi1 oroojonic acid N I OOH BrH 4 -f 4 -[N-(2-bromobenzoyl)]aninophenyl) butyric acid 78 79 127 0011 Hr 4- {4-[N-(3-bromobenzoyI)amilophelII butyric acid I 0 81 82 83 8.(N-3,5 Dihydroxybenzoyl)Smlocapryric acid 0 C H 3 00 140 Cu 8-(N-3.5-Dimethoxy 4-hydroxybenzoI)amiocaprylic acid 011 0 YOCH 3 84 It 8-(N-2-6-Dimethoxybenzli)amifloc8pryic acid N4 C O OH Br 4-4I-4booezylaiohnl~uyi acid 84 2-hydroxy4-chlorobezoyiari~nocapI'ytic acid 86 128 8 2 6 -Dihydro xyb enzo YO amino caprylic acid 87 88 89 91 92 1 29 0 N Oil C1 8-(4-chloro-o-anisoyl)aminocaprylic acid 3 4 -dim ethoxyb ezoyl) aminloph eny)p ropioni c acid 93 94 96 97 98 130 0M~ 99 o COOK iI 8 -N-(2..methoxy-4-nitrobenzoyl )6minocaprylic acid 100 H 0011 4 4 -(2-rnethoxy-4-nitrobenzoyllaminophenyII)butyic acid ocflli 4-4(.-iehxbnoy~mnpey~uyi acid OH 102 Br BA(N- 2 hydroxy-5-bromobenzoy)aThnocap,,,Dc add olH 103 H 3 -indolebutYric acid I g 104 131 0 OH QNH INHi octs 0 OCHO OH 4-[4-(2,6-dimethoxyberizoyl)aminophenylI butyric acid o 0 Q COOH wo, H 4 4 -N-(4-methoxy-3-nitrobenzoyflamninophenyllbutyric acid 8 2 -hydroxy.5..chtorobenzoyl)aminocapric acid 105 106
  19. 107- 108 109 OH cow H 110 8-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid 1 32 0 N O oH 0 H 112 8-(N- 2 h ydroxY-4nirobenzo Aamnocaryi acid H H13 B 2 -hydroxy-4bromobenzoy)aminopheylbutiric acid HO0 114 HO ?HOH 00 S-(N- 2 3-Dihydroxybenzoyl)aminocaprylic acid 0 115 8-(N- 3 -methylsalicyloyI)aminocaprylic acid 133 116 117 118 119 Oil off 0~0 O H I N-( 2 -fmethoxy-5-irophenyl) sebecoYl amide acid 120 121 134 1 122 8 4[N-( 2 -hydroxy-3,5-dichlorobenzoyl)amiocapryIic acid 123 8-[N-(2-hydroxy-3,5-dibromobenzoyl)Iarninocaprylic acid Cl 124 8 2 -chloro-6-fluorobenzoyl)aminocapryic acid OH 125 0 126 0 2 N N" COOH HO H ts-r-~~nyarxy-3-niooezoyacapyie aCRI 0 127 4 4 -Salicyloytaminopheny)-4-oxobutyric. acid 135 128 1 2-cirlnamoytdodecanoic acid 129 4-({4-IIN-(3-hydroxy-2-naphthoyl)aminophenyll )butyric acid 0 8-(4-chloro-3-nitrobenzoylaminocaprVic acid 0 N 4 0 8-(2-chloronicotinoyl)aminocaprylc acid 0 00 4-(4-phthaiimidophenylbutyric acid 130 131 132 133 136 4- 4 -[N-(3-hydroxy-2-naphthoyl)anunophenylj Ipropanoic acid 0 OCI-j 3 0 0H 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)proponic acid 134 135 136 8-(N-2-hydroxy-3.5-diiodabenzoyl)aminocapryic acid 137 138 139 8-1-hdroxy-2-naphtoy)amincaprygc ai 1 37 0 8-(Phthalimi do) cap rylic acid 140 141 1 O-(4-chloro-2-hydroxyanilino)sebacic acid monoamidle 142 143 4 4 4 -chloro.3-nitrobenzoyl)aminopheny)butyric acid 014 0 0 144 11i -N-Cl -hydroxy-2-naphthoy)aminoundecanoic acid 138 0 0 H H C02H 145 Bis (N -2carboxylphenyl-N-(N '-8-octanoic acid)ureal)oxalyl diamide 146 147 2-12-N-(4-chlorobenzoyl)aminoethoxylethanoI 0 4-2mtoxbnolm0opey 2-abxysy sufoi 00 OC14 4-(2-miethoxybenzoylamino)phenyI 2-carboxyethyl sulfonie 0 4-(-(3hdoxybe htyamio)phenyl caboxtyl acido 148 149 150 1 39 Me 151 2-[N(2-methoxybenzoyl)aminoethoxyl ethanol 152 2-12-N-(3-chlorobenzoyl)aninoethoxyl]ethanoI H4o 153 OHO 0 OH HO Bis(N-2-carboxyph-enyl-N-IfNr-3(4-aminoptienyI~propionic acid lreal loxaylyl diamid( 154 trans--( 2 -aminobenzamnidomethy)cycoexaocwoxyic acid ct-, 0 0155 co t I1I -N-(3.5-dichlaro-2-hydroxybenzoVllaminoundecarioic acid 140 2-[N-(2-bromobenzoyl)aminoethoxylethanoI 0 0 C OH H OH CI 7-N .dichloro -2-hydroxybenzoy) amioheptaloic acid 156 157 158 N-[3.5-dichlaro-24lydroxybenzoyl-4(4-aminophenyl)lbutyric acid 0 H0 OH trans-4-(N -s alicyloylaminometiyl)cyclohexane carbox lic acid 159 160 N-[3.5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)Ipropionic acid 161 1 5-dichloro-2-hydroxybenzoyl)aminododecanoic 141 OH H N 0 N-2hdoy -abxphnl--etnnd 1 62 163 164 165 166 167 2 -[N-(2-idobenzoy)aminoewxyehan, OH H- 0 0 OH ~9H 0 OH OH 8-(2-hydroxyphenylactyl)-amimocaprylic acid 142 00 Q C02H OH N.-Salicoyl-5-(3-aminophenyI)valeric acid 168 169 4 4 -(-7-CthOxYlbenzYl)aminophenyl)butyric acid OH H 0 ON 9-[I2(3-hydroxy)pyridylanocarbonlI nonanic acid 170 ~xyo OH 0 7 (2-h ydro xyphenoxy ace tyl) amino cap rylic acid OH- 2-IN-(2-hydroxybenzoylamnino)ethoxy lethianoI 171 172 143 OH 0 o 173 Cl .40N H 4-IN-(3. 5-dichloro-2-hydroxybenzoyl )Jaminophenylacetic acid OR H 174 N OHf 8-(2-hydroxy-5chloroanlinocarbonyl)octafloic acid o0O~ 175 O'H N-salicoyI-5-(4-zaminophenyI)valeric acid OH H 0 k'O 176 9-(2-bydroxy-5-methylanilinocarbonyl)nonanoic acid IOU H 0117 1 1 it 7 2-hydro xy -5 -m ethyl aniincarbof~lIvfleric acid 144 8-(pentafluorobenzoyl)aminocapyic acid OH 0Q O OH 0 3-(3-(saficyloyl)aminophenyl)propionic acid 0 N OH 0 8.(2-ethoxybenzoylaminocaprylic acid (CH5),J4 H iw0Y 0 178 179 180 181 4-(4-(2-dimethylaminobenzoyl)aniinophenyl)butyric acid H 8-13-Ph enoxylpropionylamino kaprylic acid 182 145 N-N OH O N 183 Q N H I-IH 4 -(Saiicyloyl)aminophenylethyltefrazola 0 OH 0 N 184 O NH- 0 8 4 4 -N-salicyloy1)aminophenyl)butyric) amrinocaprylic acid H18 N 01 OH Q H 4 4 4 4 -N-(2.Rluorocinnamoyi)ariinophenyl)butyric)ar~jnophenyl)butyric acid OH 186 01-0 0OH 4 -(N-8(N-SalicyloyI)aminocaprylic)aminopheny~butyic acid H .187 8 -(p-anisoyl)aminocaprylic acid 146 0 HO 0 8 4 -Hydroxybenzoyl)aminocaprylic acid .0 HOVIN t 0 N11 0 8-43-iydroxybenzoy~arinocaprytic acid 0 CH 1 O 8-( 3 .4.5-Trimethoxybenzoyl)aminocepryic acid 8-.(N-4-methylsalicyloyl)anminocaprylic acid 188 189 190 191 192 1O-N-(2-hydroxy-5-nitroalinfo)- l-oxodecanoic acid 193 4 4 2 -chloronicotinoyl)aminophenyllbutyric acid 147 and salts thereof. 31. A method for preparing a composition, said method comprising mixing: at lea, t 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. 33. 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. 34. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering intraduodenally to said animal a composition as defined in claim 2. A method for administering a biologically active agent to an animal in need of said agent, said method comprising administering subcutaneously to said animal a composition as defined in claim 2. 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. P:\WPDOCS CAB\CHEMICAL\SPEC\7562890.doe22/06/4 -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. 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. DATED this 23rd day of June 2004 Emisphere Technologies, Inc. By its Patent Attorneys DAVIES COLLISON CAVE
AU2004202745A 1997-02-07 2004-06-23 Compounds and compositions for delivering active agents Abandoned AU2004202745A1 (en)

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US08/796338 1997-02-07
US08/796334 1997-02-07
US08/796336 1997-02-07
US08/797817 1997-02-07
US08/796337 1997-02-07
US08/796339 1997-02-07
US08/796340 1997-02-07
US08/797813 1997-02-07
US08/796335 1997-02-07
US08/796341 1997-02-07
US08/797816 1997-02-07
US08/797820 1997-02-07
US08/797100 1997-02-07
AU72260/00A AU771434B2 (en) 1997-02-07 2000-12-14 Compounds and compositions for delivering active agents
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