Treatment of T-cell mediated diseases

A method of inhibiting activation of T-cells comprising administering to an animal in need thereof an effective amount of a diketopiperazine having the following formula:

• wherein:
• R1 and R2, which may be the same or different, each is:
• (a) a side chain of an amino acid, wherein the amino acid is glycine, alanine, valine, norvaline, α-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminobutyric acid, leucine, isoleucine, norleucine, serine, homoserine, threonine, lysine, hydroxylysine, histidine, arginine, homoarginine, citrulline, phenylalanine, p-aminophenylalanine, tyrosine, tryptophan, thyroxine, cysteine, homocysteine, methionine, penicillamine or ornithine;
• or
• (b) a derivative of a side chain of an amino acid, wherein the amino acid is one of those recited in (a), and the derivatized side chain has:
• (i) an —NH2 group replaced by an —NHR3 or —N(R3)2 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (ii) an —OH group replaced by an —O—PO3H2 or —OR3 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (iii) an —SH group replaced by —S—S—CH2—CH(NH2)—COOH or —S—S—CH2—CH2—CH(NH2)—COOH;
• (iv) a —CH2— group replaced by a —CH(NH2)— or a —CH(OH)— group;
• (v) a —CH3 group replaced by a —CH2—NH2 or a —CH2—OH group;
• and/or
• (vi) an H which is attached to a carbon atom replaced by a halogen;
• or
• a physiologically-acceptable salt thereof.

A method of treating inflammation or an inflammatory disease involving, caused by or exacerbated by T-cells, the method comprising administering to an animal in need thereof an effective amount of a diketopiperazine having the following formula:

• wherein:
• R1 and R2, which may be the same or different, each is:
• (a) a side chain of an amino acid, wherein the amino acid is glycine, alanine, valine, norvaline, α-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminobutyric acid, leucine, isoleucine, norleucine, serine, homoserine, threonine, lysine, hydroxylysine, histidine, arginine, homoarginine, citrulline, phenylalanine, p-aminophenylalanine, tyrosine, tryptophan, thyroxine, cysteine, homocysteine, methionine, penicillamine or ornithine;
• or
• (b) a derivative of a side chain of an amino acid, wherein the amino acid is one of those recited in (a), and the derivatized side chain has:
• (i) an —NH2 group replaced by an —NHR3 or —N(R3)2 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (ii) an —OH group replaced by an —O—PO3H2 or —OR3 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (iii) an —SH group replaced by —S—S—CH2—CH(NH2)—COOH or —S—S—CH2—CH2—CH(NH2)—COOH;
• (iv) a —CH2— group replaced by a —CH(NH2)— or a —CH(OH)— group;
• (v) a —CH3 group replaced by a —CH2—NH2 or a —CH2—OH group;
• and/or
• (vi) an H which is attached to a carbon atom replaced by a halogen;
• or
• a physiologically-acceptable salt thereof.

A method of treating a T-cell mediated pulmonary disease comprising administering to an animal in need thereof an effective amount of a diketopiperazine having the following formula:

• wherein:
• R1 and R2, which may be the same or different, each is:
• (a) a side chain of an amino acid, wherein the amino acid is glycine, alanine, valine, norvaline, α-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminobutyric acid, leucine, isoleucine, norleucine, serine, homoserine, threonine, lysine, hydroxylysine, histidine, arginine, homoarginine, citrulline, phenylalanine, p-aminophenylalanine, tyrosine, tryptophan, thyroxine, cysteine, homocysteine, methionine, penicillamine or ornithine;
• (b) R1 is —CH2—CH2—CH2— or —CH2—CH(OH)—CH2— and together with the adjacent ring nitrogen forms proline or hydroxyproline, or R3 is —CH2—CH2—CH2— or —CH2—CH(OH)—CH2— and together with the adjacent ring nitrogen forms proline or hydroxyproline;
• or
• (c) a derivative of a side chain of an amino acid, wherein the amino acid is one of those recited in (a), and the derivatized side chain has:
• (i) an —NH2 group replaced by an —NHR3 or —N(R3)2 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (ii) an —OH group replaced by an —O—PO3H2 or —OR3 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (iii) an —SH group replaced by —S—S—CH2—CH(NH2)—COOH or —S—S—CH2—CH2—CH(NH2)—COOH;
• (iv) a —CH2— group replaced by a —CH(NH2)— or a —CH(OH)— group;
• (v) a —CH3 group replaced by a —CH2—NH2 or a —CH2—OH group;
• and/or
• (vi) an H which is attached to a carbon atom replaced by a halogen;
• or
• a physiologically-acceptable salt thereof.

A method of reducing the symptoms, severity or both of a T-cell mediated autoimmune disease comprising administering to an animal in need thereof an effective amount of a diketopiperazine having the following formula:

• wherein:
• R1 and R2, which may be the same or different, each is:
• (a) a side chain of an amino acid, wherein the amino acid is glycine, alanine, valine, norvaline, α-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminobutyric acid, leucine, isoleucine, norleucine, seine, homoserine, threonine, lysine, hydroxylysine, arginine, homoarginine, citrulline, p-aminophenylalanine, tyrosine, thyroxine or ornithine;
• (b) R1 is —CH2—CH2—CH2— or —CH2—CH(OH)—CH2— and together with the adjacent ring nitrogen forms proline or hydroxyproline, or R3 is —CH2—CH2—CH2— or —CH2—CH(OH)—CH2— and together with the adjacent ring nitrogen forms proline or hydroxyproline;
• or
• (c) a derivative of a side chain of an amino acid, wherein the amino acid is one of those recited in (a), and the derivatized side chain has:
• (i) an —NH2 group replaced by an —NHR3 or —N(R3)2 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (ii) an —OH group replaced by an —O—PO3H2 or —OR3 group, wherein each R3 may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl;
• (iii) a —CH2— group replaced by a —CH(NH2)— or a —CH(OH)— group;
• (iv) a —CH3 group replaced by a —CH2—NH2 or a —CH2—OH group;
• and/or
• (v) an H which is attached to a carbon atom replaced by a halogen;
• or
• a physiologically-acceptable salt thereof.