Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Reexamination Certificate
2001-02-26
2003-09-02
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
C530S329000, C514S017400
Reexamination Certificate
active
06613880
ABSTRACT:
FIELD OF THE INVENTION
Non-peptidic compounds are described for treatment of autoimmune diseases. Of particular interest are pipecolic acid derivatives compounds incorporating a characterizing segment condensed from pipecolic acid, aspartic acid, proline and threonine, or derivatives thereof, which compounds are useful to treat rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovium. This disease is triggered by an immune response generated via the molecular recognition of the T-cell receptor on CD4-positive T cells with a complex of disease-inducing peptides bound to Human Leukocyte Antigen (HLA) class II molecules.
Rheumatoid arthritis (RA) is associated with the expression of certain HLA class II molecules, particularly the DR4-dw4, as well as DR1 and DR4-dw14. It is known that blockade of the interaction between a given class II molecule, peptide ligand, and T cell receptor inhibits specific T cell responses both in vitro and in vivo. It is further known that blockade of the above interaction in animal models of autoimmunity prevents or ameliorates autoimmune disease. Inhibitor compounds which block the binding of disease-inducing peptides to an RA-associated HLA molecule, but which will not interfere with a patient's ability to generate other class II-restricted immune responses, constitutes a selective immunosuppressive anti-RA therapy. Compounds which compete with disease-inducing endogenous peptides for binding to RA-associated HLA molecules and may thereby inhibit disease.
Other therapeutic strategies which are directed at the T cell, such as total lymphoid irradiation, thoracic duct drainage, cyclosporin A, anti-CD4 monoclonal antibody, and other monoclonal antibodies directed at T cell determinants, result in some cases in clinical improvement of rheumatoid arthritis, but these therapies are also associated with side effects. For instance, conventional general immunosuppressives increase the risk of opportunistic infections and cancer.
PCT App Pub #WO 93/05011, published Mar. 18, 1993, describes a series of oligopeptides, typically comprised of ten or more amino acids, which bind to HLA Class II molecules for indication against autoimmune diseases These larger peptides incorporating proteogenic amino acids can have poor oral bioavailability and poor plasma stability, as well as difficulty in penetrating cell membranes for proper tissue distribution.
A series of heptapeptides, such as recently reported to bind to HLA Class II molecules, similarly comprising natural, mammalian amino acids, unblocked at the C and N termini, are likely to be unstable in vivo and to possess poor bioavailability [Hammer et al,
PNAS,
91, 4456-4460 (1994)].
DESCRIPTION OF THE INVENTION
Treatment of an autoimmune or inflammatory disease, or a hypersensitive reaction of the acute or delayed type, or an allergic reaction or asthmatic disorder, or treatment of dermatitits, arthritis, meningitis, granulomas, vasculitis or septic shock, may be accomplished by preventing or suppressing an immume response in a treatment subject by use of a pipecolic acid derivative of a proline threonine amide selected from a family of compounds of general Formula I:
wherein R
1
is selected from alkyl, phenyl, cycloalkyl rings having four to ten ring-member carbon atoms, bicycloalkyl fused ring systems having seven to nine ring-member carbon atoms, heteroaryl, heteroarylalkyl, benzo-fused-heteroaryl and benzo-fused-heteroarylalkyl wherein said heteroaryl moiety or fragment is a 5- or 6-ring-member fully-unsaturated ring system having one hetero atom as a ring member, said hetero atom selected from oxygen, nitrogen and sulfur atoms, and wherein any of said heteroaryl, heteroarylalkyl, benzo-fused-heteroaryl and benzo-fused-heteroarylalkyl may be attached to the nucleus of Formula I as an R
1
substituent through a bond formed at any said ring-member atom or any atom of the alkyl portion of said R
1
substituent where said bond is capable of forming a stable compound;
wherein R
2
is selected from hydrido, lower alkyl, cyclohexyl and phenyl;
wherein R
3
is selected from hydrido, hydroxy, lower alkyl, phenyl, acetyl(Lys)NH—, acetyl(Tyr)NH—, acetyl(Thr)NH—, acetylamino, propionylamino and benzyloxycarbonylamino;
wherein R
4
is selected from hydrido, lower alkyl and phenyl;
wherein R
5
is selected from hydrido, lower alkyl, phenyl, benzyl, hydroxyphenyl, hydroxybenzyl, aminoalkyl, mono-alkyl-substituted-aminoalkyl and radicals provided by B-Het-A;
wherein Het is selected from heteroaryl moieties consisting of monocyclic and fused bicyclic ring systems having a total of five to fourteen ring members and with one to six ring members being selected from hetero atoms provided by oxygen, nitrogen and sulfur atoms, wherein said monocyclic ring system and at least one ring system of said fused bicyclic ring system is fully unsaturated, and
wherein Het is further selected from heterocyclic moieties consisting of monocyclic and fused polycyclic ring systems having a total of four to twelve ring members and with one to six ring members selected from hetero atoms provided by oxygen, nitrogen and sulfur atoms, wherein said monocyclic ring-system and at least one ring system of said fused polycyclic ring system is fully saturated or partially unsaturated,
wherein A is a single covalent bond or is a divalent radical selected from
wherein R
13
is lower alkyl;
wherein B is one or more substituents attached at a substitutable position on Het of Het-A, said substituent selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, alkenyl, alkynyl, halo, haloalkyl, oxo, cyano, benzyl and phenyl;
wherein R
6
is selected from hydrido, lower alkyl, hydroxy, alkoxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonyloxy, aminoalkyl, mono-alkyl-substituted-aminoalkyl, amido and amidoalkyl;
wherein R
7
is selected from carboxyl, lower alkyl, amido and methylthiomethyl;
wherein R
8
is selected from hydrido, methyl and ethyl;
wherein R
9
is selected from hydrido, lower alkyl, alkoxy and phenyl;
wherein R
10
is hydrido or hydroxy;
wherein R
11
is hydrido or methyl;
wherein R
12
is selected from lower alkyl, phenyl, phenylalkyl, cycloalkyl, cycloalkylalkyl,
wherein each of R
14
through R
17
is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, cyano, benzyl and phenyl;
wherein each of R
18
and R
19
is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, benzyl and phenyl;
or a pharmaceutically-acceptable amide, ester or salt thereof.
Examples of heteroaryl 5- or 6-ring member monocyclic ring systems and benzo-fused bicyclic ring systems, having one hetero atom as a ring member selected from oxygen, nitrogen and sulfur atoms, and which ring systems are fully unsaturated, i.e. “aromatic” in character, in at least one ring, are as follow:
Examples of heterocyclic-type monocyclic or polycyclic ring systems having four to twelve ring members with one to six hetero atoms as ring members, said hetero atoms selected from oxygen, nitrogen and sulfur atoms, and wherein at least one of such ring systems is fully saturated or partially unsaturated, and wherein the polycyclic ring system may be composed of a benzo-fused ring, are as follow:
Examples of heteroaryl monocyclic and bicyclic ring systems and benzo-fused polycyclic ring systems, having one to six hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which ring systems are fully unsaturated, i.e. “aromatic” in character, in at least one of the ring system, are as follow:
A preferred family of compounds consists of compounds of Formula I:
wherein R
1
is selected from cyclopentyl, cyclohexyl, cycloheptyl, norbornanyl, phenyl, furyl, pyrrolyl, thienyl, chromanyl, isochromanyl, benzothienyl, pyridyl, indolizinyl, isoindolyl, indolyl, 3H-indolyl, quinolizinyl, quinolyl, isoquinolyl
Keane J. Timothy
Low Christopher S. F.
Lukton David
Pharmacia Corporation
Schuh Joseph R.
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