Pharmaceutical uses and synthesis of diketopiperazines

Details Pharmaceutical uses and synthesis of diketopiperazines Pharmaceutical uses and synthesis of diketopiperazines

2001-12-28

2004-11-09

Ceperley, Mary E. (Department: 1641)

Chemistry: analytical and immunological testing

Nuclear magnetic resonance, electron spin resonance or other...

C435S008000, C435S007210, C436S057000, C436S098000, C436S501000, C436S503000, C436S504000, C436S804000, C436S815000, C514S249000, C514S252120, C544S349000, C544S360000, C544S362000, C544S364000, C544S366000, C544S367000, C544S383000

Reexamination Certificate

active

06815214

ABSTRACT:

TECHNICAL FIELD
In general, this application is directed to novel diketopiperazines, their use in inhibiting cellular events involving TNF-&agr;, e.g., NFK-&agr; and/or NFK-&bgr;, IL-8, GRO-&agr;, CXCR1, CXCR2 and treatment of inflammation events in general.
BACKGROUND OF THE INVENTION
The process of discovering new therapeutically active compounds for a given indication often involves the screening of compounds from available compound collections. From the compounds tested one or more structures is selected as a promising lead. A number of related analogues are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. Following traditional one-at-a-time synthesis and biological testing of analogues, this optimization process is time consuming and labor intensive. Adding significant numbers of new structures to the compound collections used in this initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of libraries of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as diketopiperazines.
Combinatorial approaches have recently been extended to “organic” or non-peptide, libraries. There is a need in the art for new and diverse organic libraries, which may be used in screening processes.
Although treatment regimens are available for the symptomatic amelioration of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease, allergic inflammation of respiratory pathways, cancer, atherosclerosis, sepsis, adult respiratory distress syndrome, reperfusion injury, graft vs. host disease, multiple sclerosis, severe invasive infections such as fulminant hepatitis, AIDS and bacterial meningitis, there still exists the need for a composition and method for preventing and/or treating the inflammation which is often associated with the disease.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of diketopiperazines, the shortcomings of combinatorial chemistry as directed to diketopiperazines, and provides compounds which are useful in inhibiting TNF-&agr;, TNF-&bgr;, I1-8 and apoptotic mediated processes, and other inflammation-resultant situations. Moreover, this invention provides a library of diverse diketopiperazines useful in elucidating structure-function relationships in biological processes, such as inflammation.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a diketopiperazine (DKP) compound of the structure (I):
and optical isomers, diastereomers, enantiomers and pharmaceutically acceptable salts thereof in isolation or mixture, where, independently at each location: R
1
is an aryl or heteroaryl ring; R
2
and R
3
are selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring, and heterocycle aliphatic ring; n is 1, 2 or 3; R
4
is selected from —OR
5
and —NR
6
R
7
, R
5
is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring; and R
6
and R
7
are independently selected from hydrogen, alkyl heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring or R
6
and R
7
taken together with the nitrogen atom to which they are attached form a heterocycle aliphatic ring.
In other aspects, the present invention provides a DKP compound of structure (1) wherein R
1
is phenyl and the phenyl is substituted with 1-4 substituents independently selected at each occurrence from alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring, heterocycle aliphatic ring. In other aspects, the present invention provides a DKP compound of structure (1) wherein R
1
is phenyl having a substituent at the position para to the site of attachment to the piperazine ring.
In other aspects, the present invention provides a DKP compound of structure (1) wherein R
1
is phenyl having a substituent at the position para to the site of attachment to the piperazine ring, and the substituent has the formula R
10
—R
9
—R
8
—, wherein R
8
is selected from direct bond, alkylene and haloalkylene; R
9
is selected from direct bond and carbonyl, and R
10
is selected from hydrogen, R
11
—O—, (R
11
)
2
N— and R
11
—(C═O)—NH—, wherein R
11
is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen. In a further aspect, R
8
is methylene; R
9
is carbonyl, and R
10
is (R
11
)
2
N— wherein R
11
is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen.
In other aspects, the present invention provides a DKP compound of structure (1) wherein R
1
is phenyl having a substituent at the position para to the site of attachment to the piperazine ring, and the substituent has the formula
wherein R
12
is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen. In a further aspect, R
12
is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring. The R
12
group may, optionally be selected from the following twelve exemplary formulae:
In other aspects, the present invention provides a DKP compound wherein R
1
is phenyl. Optionally, in any of the above-described aspects, n is 1. Optionally, in any of the above-described aspects, R
2
and R
3
are independently selected from groups of the formula R
10
—R
9
—R
8
—, wherein R
8
is selected from direct bond, alkylene and haloalkylene; R
9
is selected from direct bond and carbonyl, and R
10
is selected from hydrogen, R
11
—O—, (R
11
)
2
N— and R
11
—(C═O)—NH—, wherein R
11
is selected from hydrogen and organic groups having 1-20 carbons and optionally containing 1-4 heteroatoms selected from oxygen and nitrogen, with the proviso that two R
11
groups bonded to the same nitrogen may be bonded together so as to form a heterocyclic ring with the common nitrogen. In one further aspect, R
8
is methylene; R
9
is selected carbonyl, and R
10
is (R
11
)
2
N—. For instance, R
10
may be selected from the following twelve exemplary formulae:
Optionally, in any of the above-described aspects, R
4
is —OR
5
. The R
5
may, in one aspect, be selected from hydrogen and alkyl. Optionally, in any of the above-described aspects, and unless otherwise inconsistent, R
4
is —NR R
7
. The R
6
may be hydrogen and R
7
may be R
13
—C(═O)— where R
13
is selected from the following twelve exemplary formulae:
In another aspect, the present invention provides a composition comprising a DKP compound according to any of the aspects described above and herein, and a pharmaceutically acceptable adjuvant, carrier, diluent or excipient.
In another aspect, the present invention provides a method of treating inflammation comprising administering to a subject in need thereof a therapeutically effective amount of a DKP compound as set forth herein.
In another aspect, the present invention provides a method for inhibiting a TNF-&agr; mediated processes, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a DKP compound as set forth herein.
In another aspect, the present invention provides a method for inhibiting a TNF-&agr;. mediated processes, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of a composition comprising a DKP compound as set forth herein, wherein the administering is selected from, for exampl

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