Compounds and compositions for delivering active agents

Details Compounds and compositions for delivering active agents Compounds and compositions for delivering active agents

2001-08-24

2003-11-11

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C548S543000, C548S346100, C544S222000

Reexamination Certificate

active

06646162

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds for delivering active agents, such as biologically or chemically active agents, to a target. These compounds are well suited for forming non-covalent mixtures with active agents for oral or intracolonic or other routes of administration to animals. Methods for the preparation and administration of such compositions are also disclosed.
BACKGROUND OF THE INVENTION
Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, and/or the target itself. Biologically and chemically active agents are particularly vulnerable to such barriers.
In the delivery to animals of biologically active and chemically active pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical barriers are the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents may be rapidly rendered ineffective or destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs may prohibit absorption.
Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.
More recently, proteinoid microspheres have been used to deliver pharmaceuticals. For example, see U.S. Pat. No. 5,401,516, U.S. Pat. No. 5,443,841 and U.S. RE35,862. In addition, certain modified amino acids have been used to deliver pharmaceuticals. See, e.g., U.S. Pat. No. 5,629,020; U.S. Pat. No. 5,643,957; U.S. Pat. No. 5,766,633; U.S. Pat. No. 5,776,888; and U.S. Pat. No. 5,866,536.
However, there is still a need for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents by various routes.
SUMMARY OF THE INVENTION
Compounds and compositions that are useful in the delivery of active agents are provided. The present invention encompasses compounds having the following formula, or salts thereof, or mixtures thereof.
wherein
Ar is phenyl or naphthyl;
Ar is optionally substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl, aryloxy, a heterocyclic ring, C
5
-C
7
carbocyclic ring, halogen, —OH, —SH, —CO
2
R
6
, —NR
7
R
8
or —N
+
R
7
R
8
R
9
Y;
(a) R
1
is C
1
-C
16
alkylene, C
2
-C
16
alkenylene, C
2
-C
16
alkynylene, C
6
-Cl
16
arylene, (C
1
-C
16
alkyl)arylene, or aryl(C
1
-C
16
alkylene);
R
2
is —NR
3
R
4
or —N
+
R
3
R
4
or —N
+
R
3
R
4
R
5
Y;
R
3
and R
4
are independently hydrogen; oxygen; hydroxy; substituted or unsubstituted C
1
-C
16
alkyl; substituted or unsubstituted C
2
-C
16
alkenyl; substituted or unsubstituted C
2
-C
6
alkynyl; substituted or unsubstituted aryl; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted arylcarbonyl; substituted or unsubstituted alkanesulfinyl; substituted or unsubstituted arylsulfinyl; substituted or unsubstituted alkanesulfonyl; substituted or unsubstituted arylsulfonyl; substituted or unsubstituted alkoxycarbonyl; or substituted or unsubstituted aryloxycarbonyl; and
R
5
are independently hydrogen; substituted or unsubstituted C
1
-C
16
alkyl; substituted or unsubstituted C
2
-C
16
alkenyl; substituted or unsubstituted C
2
-C
16
alkynyl; substituted or unsubstituted aryl; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted arylcarbonyl; substituted or unsubstituted alkanesulfinyl; substituted or unsubstituted arylsulfinyl; substituted or unsubstituted alkanesulfonyl; substituted or unsubstituted arylsulfonyl; substituted or unsubstituted alkoxycarbonyl; or substituted or unsubstituted aryloxycarbonyl;
(b) R
1
R
2
, and R
5
are as defined above; and
R
3
and R
4
are combined to form a 5, 6, or 7-membered heterocyclic ring or 5, 6 or 7-membered heterocyclic ring substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, aryl, aryloxy, oxo group, or carbocyclic ring; or
(c) R
2
and R
5
are as defined above;
R
1
and R
3
are combined to form a 5, 6, or 7-membered heterocyclic ring; or 5, 6, or 7-membered heterocyclic ring substituted with C
1
-C
6
alkyl, alkoxy, aryl, aryloxy, oxo group or carbocyclic ring; and
R
4
is hydrogen; oxygen; hydroxy; substituted or unsubstituted C
1
-C
16
alkyl; substituted or unsubstituted C
2
-C
16
alkenyl; substituted or unsubstituted C
2
-C
16
alkynyl; substituted or unsubstituted aryl; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted arylcarbonyl; substituted or unsubstituted alkanesulfinyl; substituted or unsubstituted arylsulfinyl; substituted or unsubstituted alkanesulfonyl; substituted or unsubstituted arylsulfonyl; substituted or unsubstituted alkoxycarbonyl; or substituted or unsubstituted aryloxycarbonyl;
R
6
is hydrogen; C
1
-C
4
alkyl; C
1
-C
4
alkyl substituted halogen or —OH; C
2
-C
4
alkenyl; or C
2
-C
4
alkenyl substituted with halogen or —OH;
R
7
, R
8
and R
9
are independently hydrogen; oxygen; C
1
-C
4
alkyl; C
1
-C
4
alkyl substituted with halogen or —OH; C
2
-C
4
alkenyl; or C
2
-C
4
alkenyl substituted with halogen or —OH; and
Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, or carboxylate. An example of a suitable carboxylate includes, but is not limited to acetate.
Preferably, at least one of R
3
and R
4
is not hydrogen.
In a preferred embodiment, Ar is phenyl optionally substituted with methyl; methoxy; hydroxy; or halogen. More preferably, Ar is unsubstituted phenyl or phenyl substituted with chlorine, more preferably at the 5 position.
According to another embodiment, R
1
is a C
1
-C
12
substituted or unsubstituted alkylene. Preferably, R
1
is a C
3
-C
8
unsubstituted alkylene. More preferably, R
1
is a C
6
unsubstituted alkylene.
According to another embodiment, R
2
is —NR
3
R
4
; and (i) R
3
is phenyl or cyclohexyl and R
4
is hydrogen; (ii) R
3
and R
4
are both methyl; or (iii) R
3
and R
4
are combined to form a 5- or 6-membered heterocyclic ring containing nitrogen, such as preferably pyrrolidinone, morpholine and imidazole.
According to yet another embodiment, R
2
is —N
+
R
3
R
4

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