Prodrugs via acylation with cinnamate

Details Prodrugs via acylation with cinnamate Prodrugs via acylation with cinnamate

2002-01-31

2004-08-10

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S396000, C514S529000, C514S252120, C514S785000, C514S568000, C514S554000, C514S614000, C514S613000, C564S164000, C564S167000, C560S045000, C548S542000, C544S358000

Reexamination Certificate

active

06774116

ABSTRACT:

BACKGROUND OF THE INVENTION
The present application relates generally to energy-reversible compositions containing drugs or other molecules. In particular, the present application relates to drug moieties and other biologically active moieties, herein denoted —X
1
A, bonded to a cinnamic acid or related molecular core (herein denoted Z—CINN).
In prodrugs, an active drug is typically bonded to another molecule to alter the drug's properties in a reversible manner and regulate the drug's release. The majority of prodrugs have an ester or amide bond formed between a hydroxyl, amino, or thiol group of a drug moiety and the carboxylate group of a carrier molecule, or vice versa. Depending on the chemical properties of the molecules making up the linkage, these prodrugs have hydrolysis rates that range from minutes to days. Temperature, pH and the chemical composition of the solution in which the prodrug is administered can also influence the rate of release of the active ingredient from the prodrug. The very short hydrolysis rates and very long ones are generally not useful. Hydrolysis rates in the range of 0.5-48 hours are generally more desirable. Prodrugs can be designed 1) to change aqueous solubility properties of the drug, 2) to change circulating lifetime of the drug, 3) to be more lipophilic than the parent compound, allowing greater penetration of biological membranes and therefore greater access to diseased sites, 4) to have lower toxicity, for example, by allowing the prodrug to be transported to its site of action in its inactive form, where the inactive prodrug is converted to the active parent compound at its target site, 5) to bind selectively at a target site, because of a specific targeting molecule attached to the prodrug complex, or for other purposes.
Over the years, a large number of prodrugs have been developed. For example, some have suggested preparing amino acid esters of various therapeutic agents. Others have suggested forming polymeric conjugates with ester linkages. In either case, the active compound is released in vivo via hydrolysis. Another approach is described in U.S. Pat. No. 6,071,908 which discloses a method of treating neoplastic disease using a radiation-activated cytotoxin prodrug. The prodrug releases a tumoricidal cytotoxic effector using reducing agents generated by the radiolysis of water.
A still further prodrug approach relies upon the use of light for reversible control of enzyme activity, (see U.S. Pat. Nos. 5,114,851 and 5,218,137 to Porter et al.). Specifically, Porter et al. disclose coupling an enzyme active site amino acid residue to cinnamate (CINN) derivatives to form o-hydroxy cinnamate substituted esters or acyl enzymes, which are inactive. On photolysis, the bond with the active site amino acid residue is cleaved and the active site is exposed. There are a number of potential advantages associated with this concept. In theory, using this technique, the artisan has the ability to control in vivo enzyme activity specifically and rapidly, by exposure to light in vivo or ex vivo.
In spite of the advances of Porter et al., work in this area has continued. There continues to be a need in the art to expand the cinnamate core platform beyond inhibited enzymes. It would also be desirable to provide a means for better targeting non-enzyme therapeutic compounds to sites of interest in the body. In the past, the artisan has had little ability to control when and in what amount a drug can be generated in the therapeutically desired area. Moreover, the ability to reduce the amount of administered drug and/or peripheral organ damage caused by untargeted delivery would be welcomed by those in the art. It would also be advantageous to have the capability to independently initiate or control the hydrolysis of a prodrug. It would also be advantageous to have a means to localize a prodrug or other conjugate to a diseased area. The present invention addresses these and other needs.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide improved compositions designated herein as Z—CINN—X
1
—A, that can controllably release the —X
1
A portion thereof at a controlled rate, whether by hydrolysis or by energy input such as light or ultrasound.
It is another object of the present invention to provide means to facilitate the targeting, delivery and binding of a composition containing Z—CINN—X
1
A to a surface or a diseased site, by incorporation of additional molecule(s) attached to Z—CINN, denoted B-L, which are capable of binding to that site, to concentrate the conjugate prior to release of —X
1
A.
It is another object of the present invention to provide an additional site on Z—CINN—X
1
—A compounds which can be derivatized in various ways, including with groups designated herein as “B-L”, to provide compositions designated herein as B-L-Z—CINN—X
1
—A, which have additional properties, such as stability, increased circulation time, targeting capacity, or immobilization to appropriate supports.
It is therefore an object of the present invention to provide a prodrug composition, and the method of preparation thereof, which releases an effective drug at a controlled rate by application of an exogenous stimulus.
It is another object of the present invention to provide means to facilitate the delivery of a prodrug composition to a diseased site by incorporation of a targeting molecule.
It is another object of the present invention to provide means to alter a prodrug composition by incorporation of a molecule(s) to increase circulation time, solubility, or stability.
It is another object of the present invention to provide means to alter a prodrug composition by incorporation of a molecule(s) which can bind to a biological or non-biological surface such as a bead, stent, or other matrix material for purposes of slow release, purification of additional molecules, and the like.
It is another object of the present invention to bind and release biologically active molecules, other than enzymes, in the manner specified above.
These and other objects are provided by the present invention, which in one embodiment provides compounds corresponding to Z—CINN—X
1
—A and the formula:
Formula I
wherein:
X
1
A is a residue of a releasable biologically active moiety;
R
1
and R
2
are individually selected from the group consisting of H, CH
3
, C
2
-C
10
alkyls, C
2
-C
10
alkenyls or C
2
-C
10
alkynyls, each of which can be substituted or unsubstituted; straight or branched, C
2
-C
10
heteroalkyls, C
2
-C
10
heteroalkenyls or C
2
-C
10
to heteroalkynyls and —(CR
15
R
16
)
p
—D;
wherein: R
15
and R
16
are individually selected from the group consisting of H, CH
3
, C
2
-C
10
alkyls, C
2
-C
10
alkenyls or C
2
-C
10
alkynyls, each of which can be substituted or unsubstituted; straight or branched; and
C
2
-C
10
heteroalkyls, C
2
-C
10
heteroalkenyls or C
2
-C
10
heteroalkynyls;
p is a positive integer from 1 to about 12;
D is selected from among —SH, —OH, X
2
, —CN, —OR
19
, NHR
20
,
wherein:
R
17
is H, CH
3
or X
3
;
R
18
is H, a C
1
-C
4
alkyl or benzyl;
R
19
is H, a C
1-4
alkyl, X
2
or benzyl;
R
20
is H, C
1-10
alkyls or —C(O)R
21
,
 wherein R
21
is H, a C
1-4
alkyl or alkoxy, t-butoxy or benzyloxy;
X
2
and X
3
are independently selected halogens;
R
3
is H, CH
3
, or —C(═O)(CR
15
R
16
)
w
—D, where w is 0 or an integer from 1 to about 12, and D is H or as described for R
1
and R
2
J is O, NH or S;
R
4
, R
5
, and R
6
are independently selected from the group consisting of H, CH
3
, C
2
-C
10
alkyls, C
2
-C
10
alkenyls or C
2
-C
10
alkynyls, each of which can be substituted or unsubstituted; straight or branched; C
2
-C
10
heteroalkyls, heteroalkenyls or heteroalkynyls and halogens;
Z is H, NR
7
R
8
or
wherein R
7
is selected from among H, CH
3
, C
2
-C
10
alkyls, alkenyls or alkynyls which can be substituted or unsubstituted; straight or branched; C
2
-C
10
heteroalkyls, heteroalkenyls or heteroalkynyls, or —(CR
23
R
24
)
q
—aryl, or R
8
,
wherein R
23
and R
24
are independently selec

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