(3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting...

Details (3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting... (3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting...

2000-02-07

2003-07-15

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S019300, C530S330000, C530S331000, C530S351000, C424S085100, C424S085200

Reexamination Certificate

active

06593300

ABSTRACT:

This invention relates to new (3R)-3-amino-4-carboxy-butyraldehyde derivatives of general formula (I),
wherein
X represents a C
1-4
alkyloxycarbonyl, an optionally substituted phenyl-(C
1-2
alkyloxy)carbonyl, a C
1-4
alkylcarbonyl or an optionally substituted phenylC
1-3
alkyl)-carbonyl group, n represents 1 or 0,
Y represents, in the case when n=1, a tetrapeptide of general formula Y
4
-Y
3
-Y
2
-Y
1
, a tripeptide of general formula Y
3
-Y
2
-Y
1
or a dipepbide of general formula Y
2
-Y
1
or an amino acid residue of general formula Y
1
, or in the case when n=0, an &agr;-hydroxyacyl-tripeptide of general formula Q
4
-Y
3
-Y
2
-Y
1
, an &agr;-hydroxyacyl-dipeptide of general formula Q
3
-Y
2
-Y
1
or an &agr;-hydroxyacyl-aminoacyl residue of general formula Q
2
-Y
1
,
 wherein
Y
1
-Y
4
represent a residue selected from the group comprising the following L- or D-amino acids: alanine, alloisoleucine, cyclohexyl-glycine, phenylalanine, glutamine, histidine, isoleucine, leucine, lysine, methionine, pipecolic acid, proline, tyrosine and valine, and
Q
2
-Q
4
represent an acyl group selected from the following &agr;-hydroxyacids of R or S configuration: 2cloheptyl-2-hydroxyacetic acid, 2-cyclohexyl-2-hydroxyacetic acid, 3-cyclo-hexyllactic acid, 3-phenyllactic acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxy-3-methyl-valeric acid, mandelicacid or lactic acid,
and salts thereof formed with organic or inorganic bases, and pharmaceutical compositions containing the same.
The compounds of general formula (I) of the invention have valuable therapeutic properties, particularly an inhibitory effect on the interleukin-1&bgr; converting enzyme. Accordingly, they may be applied for the treatment of various inflammatory diseases such as arthritis, colitis, hepatitis, glomerulonephritis and myocarditis, as well as septic shock.
Particularly valuable representatives of the compounds of general formula (I) of the invention are the following:
(3R)-3-(acetyl-L-tyrosyl-L-valyi-L-alanylamino)-4-carboxy-butyraldehyde, (3R)-3-(ethoxycarbonyl-L-alanyl-L-tyrosyl-L-valyl-L-alanyl-amino)-4-carboxybutyraidehyde, (SEQ ID NO:1)
(3R)-3-(methoxycarbonyl-L-alanyl-L-tyrosyl-L-valyl-L-alanyl-amino)-4-carboxybutyraldhyde, (SEQ ID NO:1)
(3R)-3-(acetyl-L-tyrosyl-L-valyl-L-histidylamino)-4-carboxy-butyraldehyde,
(3R)-3-(acetyl-L-tyrosyl-L-valyl-L-glutaminylamino)-4-carboxybutyraldehyde,
(3R)-3-(acetyl-L-tyrosyl-L-isoleucyl-L-alanylamino)-4-carboxybutyraldehyde,
(3R)-8-(acetyl-L-tyrosyl-L-alloisoleucyl-L-alaylamino)-4-carboxybutyraldehyde,
(3R)-3-(acetyl-L-tyrosyl-L-leucyl-L-alanylamino)-4-carboxy-butyraldehyde,
(3R)-3-(acetyl-L-tyrosyl-L-methionyl-L-alanylamino)-4-carboxybutyraldehyde,
(3R)-3-(acetyl-L-tyrosyl-L-cyclohexylglycyl-L-alanylamino)-4-carboxybutyraldehyde,
(3R)-3-(acetyl-L-phenylalanyt-L-valyl-L-alany lamino)-4-carboxybutyraldehyde,
(3R)-3[(2S)-(2-hydroxypropionyl)-L-tyrosyl-L-valyl-L-alanyl-amino]-4-carboxybutyraldehyde,
(3R)-3-[(2-hydrxypropionyl)-L-tyrosyl-L-valyl-L-pipecolinylamino]-4-carboxybutyraldehyde,
(3R)-3-[(2S)-(2-hydroxypropionyl)-L-tyrosyl-L-valyl-L-prolylamino]-4-carboxybutyraldehyde,
(3R)-3-[(2S)-(2-hydroxy-3-phenylpropionyl)-L-vayl-L-alanylamino]-4-carboxybutyraldehyde,
(3R)-3-[(2S)-(2-hydroxy-3cyclohexylpropionyl)-L-valyl-L-alanylamino]-4-carboxybutyraldehyde,
(3R)-3-[(2S)-(2-cyclohexyl-2-hydroxyacetyl)-L-alanylamino]-4-carboxybutyraldehyde,
(3R)-3-[(2S)-(2-cycloheptyl-2-hydroxyacetyl)-L-alanylamino]-4-carboxybutyraldehyde,
(3R)-3-[(2S)-(2-hydroxy-3-methylbutiryl)-L-alanylamino)]-4-carboxybutyraldehyde,
(3R)-3-[(2S,3S)-(2hydroxy-3-methylvaleryl)-L-alanylamino)]-4-carboxybutyraldehyde,
and their salts formed with organic or inorganic bases.
Particularly preferred compounds of general, formula (I) of the invention are (3R)-3-(acetyl-L-tyrosyl-L-valyl-L-alanyl-amino)-4-carboxybutyraldehyde and (3R)-3-(ethoxycarbonyl-L-alanyl-L-tyrosyl-L-valyl-L-alanylamino)-4-carboxy-butyraldehyde and their salts formed with organic or inorganic bases (SEQ ID NO:1)
Definitions
The abbreviations of the amino acids, their substituents and peptides built up therefrom are in accordance with the prior art, e. g. J. Biol. Chem. 264, 668 (1989).
Amino Acids:
Arg=L-arginine [(2R)-2-amino-5-guanidino-pentanoic acid],
Ala=L-alanine [(2S)-2-aminopropionic acid],
Ale=L-alloisoleucine [(2S,3R)-2-amino-3-methylvaleric acid],
Asn=L-asparagine [(2S)-2-amino-3-carbamoylpropionic acid],
Asp=L-aspartic acid [(2S)-2-amino-3-arboxypropionic acid],
hAsp=L-&bgr;-homoaspartic acid [(3R)-3-amino-4-carboxy-butyric acid],
Chg=L-2-cyclohexylglycine [(2S)-2-amino-2-cyclohexyl-acetic acid],
Gln=L-glutamine [(2S)-2-amino-4-carbamoylbutyric acid],
Glu L-glutamic acid [(2S)-2-amino-4-carboxybutyric acid],
Gly=glycine (2-aminoacetic acid),
His=L-histidine [(2S)-2-amino-3-(imidazolyl)propionic acid],
Ile=L-isoleucine [(2S,3S)-2-amino-3-methylvaleric acid],
Leu=L-leucine [(2S)-2-amino-4-methylvaleric acid)],
Lys=L-lysine [(2S)-2,6-diaminocaproic acid],
Met=L-methionine [(2S)-2-amino-4-methylmercapto-butyric acid],
Phe=3-phenyl-L-alanine [(2S)-2-amino-3-phenylpropionic acid],
Pip=L-pipecolic acid [(2S)-piperidine-2-carboxylic acid],
Pro=L-proline [(2S)pyrrolidine-2-carboxytic acid],
Ser=L-serine [(2S)-2-amino-3-hydroxypropionic acid],
Tyr=L-tyrosine [(2S)-2-amino-3-(4-hydroxyphenyl)-propionic acid],
Val=L-valine [(2S)-2-amino-3-methylbutyric acid].
&agr;-Hydroxyacids:
cHga=L-2-cycloheptylglycolic acid [2S)-2-cycloheptyl-2-hydroxyacetic acid],
Hma=L-hexahydromandelic acid [(2S)-2-cyclohexyl-2-hydroxyacetic acid],
Hmb=(2S)-2-hydroxy-3-methylbutyric acid,
Hmv=(2S)(3S)-2-hydroxy-3-methylvaleric acid],
Hpl=L-hexahydrophenyllactic acid [(2S)-2-hydroxy-3-cyciohexylpropionic acid],
Lac=L-lactic acid [(2S)-2-hydroxypropionic acid],
Man=L-mandelic acid [(2S)-2-phenyl-2-hydroxyacetic acid)],
Pla=L-phenyllactic acid [(2S)-2-hydroxy-3-phenylpropionic acid],
Pla(OH)=L-(4-hydroxyphenyl)lactic acid [(2S)-2-hydroxy-3-(4-hydroxyphenyl)propionic acid]
Substituens:
Ac=acetyl,
Boc=t-butoxycarbonyl,
Eoc=ethoxycarbonyl,
DCB=2,6-dichloro-benzoyloxy,
DMB=2,6-dimethyl-benzoyloxy,
Moc=methoxycarbonyl,
PhP=3-phenyl-propionyl,
Z=benzyloxycarbonyl,
Z(OH)=4-hydroxy-benzyloxycarbonyl.
Peptides and Derivatives
The abbreviations of amino acids alone represent the respective L-amino acid. The D-amino acid is marked separately, e. g. 3-phenyl-D-alanine=D-Phe. The hyphen before and after the amino acid abbreviation designates a missing hydrogen atom from the amino group or a missing hydroxy group from the carboxy group, resp. Accordingly, Eoc-Ala-Tyr-Val-Ala-hAsp-H represents ethoxycarbonyl-L-alanyl-L-tyrosyl-L-valyl-L-alanyl-3-amino-4-carboxy-butyraldehyde.
Description of the Known Art
Interleukin-1 (IL-1), a cytokine, formed e.g. in monocytes upon the action of infections, tissue injury or antigens, exerts manifold local and systemic effects [C. A. Dinarello: Blood 77, 1627 (1991)]. It is best known as an inflammation inducing cytokine but it also promotes the proliferation and differentiation of various cells while in other cells it influences the synthesis and release of enzymes, hormones, blood clotting factors and proteins of the acute phase. IL-1 is responsible for triggering inflammatory processes and maintaining inflammations followed by tissue injury [C. A. Dinarello and S. M. Wolff: N. Engl. J. Med., 328, 106 (1993)]. The direct pathologic role of IL-1 has been confirmed in rheumathoid arthritis an

Affiliated with

Also associated with

Rating

(3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with (3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and (3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3101463