Isoxazole and crotonamide derivatives and their use as...

Details Isoxazole and crotonamide derivatives and their use as... Isoxazole and crotonamide derivatives and their use as...

2000-05-30

2001-07-24

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C536S004100, C536S022100, C536S123100, C528S220000, C528S228000, C528S271000, C525S007100, C525S008000, C525S011000, C525S030000, C525S054100, C525S540000, C524S017000, C524S056000

Reexamination Certificate

active

06265588

ABSTRACT:

The invention relates to novel isoxazole and crotonamide derivatives, their preparation and use as pharmaceuticals, and their use as an antigen for the production of antibodies and their use in diagnosis and purification processes.
BACKGROUND OF THE INVENTION
Isoxazole and crotonamide derivatives having antiinflammatory, immunosuppressant, or antiproliferative action have been disclosed (EP 0 013 376; EP 0 217 206; EP 0 527 736). The analytical determination of these compounds in animal and human sera is possible with the aid of conventional chromatographic processes. The disadvantage of these chromatographic processes is a high outlay in terms of apparatus, complicated sample preparation steps and low sample throughput.
Immunological determination and analysis processes are a rapid and reliable alternative to chromatographic processes. The production of suitable antibodies is crucial for carrying out these alternative processes.
SUMMARY OF THE INVENTION
The invention aims, by modification of isoxazole and crotonamide derivatives, to make available compounds which are suitable for antibody production, can be coupled to polymers and can be employed as tracers in radioimmunoassays.
It has been found that compounds of the formula I are suitable for achieving this object where, on the aromatic ring of the aniline moiety, there are one or more functional groups which can be coupled covalently to polymers as such or via a spacer function.
The invention therefore relates to compounds of the formula I
and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where R
1
is the radical of the formula II or III
and R
2
is
a) —O—(CH
2
)
n
—CH═CH
2
, in which n is the integer 1, 2, or 3,
b) —O—(CH
2
)
m
—CH
2
-halogen, in which m is the integer 1, 2, or 3 and halogen is fluorine, chlorine, bromine, or iodine,
c) the radical of the formula V
 in which
R
3
is
1) halogen or
2) —NH
2
and
R
4
is
1) a hydrogen atom or
2) a radical of an amino acid, or
d) —NH
2
.
DETAILED EMBODIMENTS OF THE INVENTION
Preferred compounds of the formula I are those wherein
R
1
is the radical of the formula II or III and
R
2 is a) —O—(CH
2
)
m
—CH
2
-halogen, in which m is the integer 2 and halogen is bromine or iodine,
b) —O—CH
2
—CH═CH
2
or
c) —NH—C(O)—CH(R
3
)(R
4
),
in which R
3
is bromine, —NH
2
, or chlorine and
R
4
is a hydrogen atom.
Particularly preferred compounds of the formula I are those such as
2-cyano-3-hydroxybut-2-enecarboxylic acid (4-allyloxyphenyl)amide,
2-cyano-3-hydroxybut-2-enecarboxylic acid (4-(3-iodopropoxy)phenyl)amide,
2-cyano-3-hydroxybut-2-enecarboxylic acid (4-(2-aminoacetylamino)phenyl)amide,
5-methylisoxazole-4-carboxylic acid (4-(2-aminoacetylamino)phenyl)amide,
2-cyano-3-hydroxybut-2-enecarboxylic acid (4-(2-bromoacetylamino)phenyl)amide, or
5-methylisoxazole-4-carboxylic acid (4-(2-bromoacetylamino)phenyl)amide.
The radical R
2
in formula I can be in the meta-, ortho-, or para-position relative to the “NH” group on the phenyl ring, preferably in the para-position.
The compounds of the formula I can optionally be present as optical isomers, diastereomers, racemates, or as mixtures thereof. The term “amino acid” is understood as meaning the stereoisomeric forms, e.g., D and L forms, of the following compounds: asparagine, valine, arginine, aspartic acid, glutamine, glutamic acid, tryptophan, &bgr;-alanine, lysine, proline, glycine, &ggr;-aminobutyrate, N&egr;-acetyllysine, N&dgr;-acetylornithine, N&ggr;-acetyldiaminobutyrate, N&agr;-acetyidiaminobutyrate, histidine, isoleucine, leucine, methionine, phenylalanine, serine, cysteine, threonine, alanine, and tyrosine. L-Amino acids are preferred. The amino acid residue Gly is particularly preferred.
Amino acid residues are derived from the corresponding amino acids. The brief notation for the amino acids follows the generally customary notation. The radical (R
4
) represents the side chain of the respective amino acid.
Suitable physiologically tolerable salts of the compounds of the formula I are, for example, alkali metal, alkaline earth metal and ammonium salts, including those of organic ammonium bases and salts of the protonated amino acid residues.
The invention also relates to a process for the preparation of a compound of the formula I and/or a physiologically tolerable salt of a compound of the formula I and/or an optionally stereoisomeric form of a compound of the formula I, which comprises:
a) reacting a compound of the formula VI
where R
6
is the radical OH, Cl, or Br, with a compound of the formula VII
where R
7
is
1) —NH
2
,
2) an —NH—C(O)—CH
2
—NH-protective group, for in which protective group is an amine protective group, for example Boc,
3) —NH—C(O)—CH
2
-halogen or
4) —OH
to give a compound of the formula I in which R
1
is the radical of the formula II and R
2
is —NH
2
, —NH—C(O)—CH
2
—NH-protective group, —OH, or —NH—C(O)—CH
2
-halogen, or
b) reacting a compound prepared by process a), in which R
7
is —OH, with an alkyl halide or a dihaloalkane in which the alkyl moiety has 2, 3, or 4 carbon atoms to give a corresponding compound of the formula I, or
c) reacting a compound prepared by process a), in which R
7
is —OH, with an unsaturated alkyl halide in which the alkyl moiety has 3, 4, or 5 carbon atoms to give a corresponding compound of the formula I, or
d) reacting a compound prepared by process a), in which R
7
is —NH
2
, with a carboxylic acid halide such as bromoacetyl bromide to give a compound of the formula I in which R
2
is the radical of the formula V, R
3
is halogen and R
4
is a hydrogen atom, or
e) reacting an aromatic diamine such as p-phenylenediamine with an amino acid protected on the amino group to give a compound of the formula VII in which R
7
is a radical of the formula V, R
3
is —NH
2
and R
4
is a protected amino acid and then reacting as in process a) to give a corresponding compound of the formula I, or
f) removing the protective group in a compound of the formula I prepared by process a) or e), or
g) converting a compound of the formula I prepared by processes a) through f), where R
1
is the radical of the formula II, into a compound of the formula I where R
1
is the radical of the formula III, or
h) either isolating the compound of the formula I prepared by processes a) through g) in free form or, in the case of the presence of acidic or basic groups, optionally converting it into physiologically tolerable salts.
In the process step according to a), it is possible to convert, for example, an isoxazole-4-carboxylic acid (R
6
is —OH) into an acid chloride by methods known from the literature, e.g., by means of thionyl chloride or phosphorus oxychloride in an aprotic solvent (e.g., toluene, tetrahydrofuran (THF) or a chlorinated hydrocarbon) and then to react it with an aromatic amine which is optionally substituted in a suitable manner with addition of an organic base, e.g., with a tertiary amine (e.g., triethylamine or N-ethyimorpholine), in a dipolar aprotic solvent, for example THF or a chlorinated hydrocarbon. Alternatively, the amide formation can be carried out directly from the carboxylic acid with addition of a condensing reagent known from peptide chemistry, e.g., dicyclohexylcarbodiimide. The second variant is particularly suitable for aromatic amines having further amino or alcohol radicals.
In process steps b) or c), the hydroxyl group introduced by means of the aniline moiety is further functionalized by reacting this:
1) with an alkyl halide or a dihaloalkane such as 1,3-diiodopropane with addition of an organic or inorganic base, e.g., potassium carbonate, to give a correspondingly substituted araliphatic ether, where in the latter case dimerization can be avoided by an appropriately large excess of alkylating agent or use thereof as a solvent, such that in the product an alkyl halide function remains for the further coupling of the product to a stationary phase, or
2) reacting with an unsaturated alkyl halide, e.g., an allyl or propargyl halide,

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