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
2000-04-07
2001-01-30
Russel, Jeffrey E. (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
C530S332000, C530S338000, C546S185000, C546S233000, C546S247000, C560S040000, C562S443000, C562S507000, C564S152000, C564S153000, C564S157000
Reexamination Certificate
active
06180759
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to a process for convergently preparing azacycloalkanoylpseudotetrapeptides comprising coupling a dipeptide with a psuedodipeptide. This invention is also directed to intermediates and processes for preparing the intermediates useful in preparing the pseudotetrapeptide.
BACKGROUND OF THE INVENTION
Azacycloalkylalkanoyl pseudotetrapeptides, as exemplified by N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-&bgr;-cyclohexyl-alanine amide, have antithrombotic activity, including the inhibition of platelet aggregation and thrombus formation in mammals, and are useful in the prevention and treatment of thrombosis associated with disease states such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation. See PCT Patent Application Publication No. WO95/10295.
These pseudotetrapeptides have heretofore been prepared by sequential synthesis from the C-terminal amino acid using standard solid phase or solution phase peptide synthesis procedures. However, sequential coupling of amino acids is less desirable for the production of bulk drug as it constrains manufacturing to a linear schedule.
Thus, an alternative preparative approach to the pseudotetrapeptides is needed. Such an approach should substantially increase production versatility and efficiency. A convergent approach should provide for specialized modifications of the pseudotetrapeptide by performing specialized chemistry on one of the synthons rather than on the whole pseudotetrapeptide, and should provide for the simultaneous preparation of a number of pseudotetrapeptide analogs.
SUMMARY OF THE INVENTION
This invention is directed to a process for the preparation of a pseudotetrapeptide of formula I
or a salt or prodrug thereof
wherein
is optionally N-protected azaheterocyclyl;
is a single or double bond;
q is 1-5;
B is alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl, or alkylaralkyl;
Q
2
is H or a carboxylic acid protecting group;
J is —H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
L is OR
1
, or NR
1
R
2
, where R
1
and R
2
are independently —H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl, or alkylaralkyl; and
p is 1 or2,
comprising
(a) coupling a azabeterocyclyl pseudodipeptide of formula
or a salt thereof wherein K is OH or an acyl activating group,
with a carboxylic acid substituted dipeptide of formula
or a salt thereof,
(b) optionally removing the nitrogen protecting group or carboxylic acid protecting group to prepare the pseudotetrapeptide, and
(c) optionally converting the pseudotetrapeptide to the salt or prodrug.
DETAILED DESCRIPTION OF THE INVENTION
Definitions of Terms
As used above, and throughout the description of this invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
“Azaheterocyclyl” means a 4-8 membered saturated, unsaturated, or aromatic carbocyclic ring system in which one of the carbon atoms other than the carbon of the
moiety is replaced with a nitrogen atom. When the nitrogen atom is incorporated in the ring system through two single bonds, it is optionally substituted by a nitrogen protecting group P
1
. Representative azaheterocyclyl groups include piperidinyl, N-tert-butoxycarbonylpiperidinyl, N-benzyloxycarbonypiperidinyl, pyrrolidinyl, N-tert-butoxycarbonylpyrrolidinyl, N-benzyloxycarbonypyrolidinyl, pyrrolyl, pyridinyl, and the like. Preferred azaheterocyclyl groups are pyridyl, N-tert-butoxycarbonylpiperidin-4-yl and N-benzyloxycarbonypiperidin-4-yl.
“Alkyl” means a saturated aliphatic hydrocarbon group, which may be straight or branched, having about 1 to about 20 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain. Preferred straight or branched alkyl groups are the “lower alkyl ” groups which are those alkyl groups having from 1 to about 10 carbon atoms. More preferred lower alkyl groups have from 1 to about 6 carbon atoms.
“Cycloalkyl” means a saturated carbocyclic group having one or more rings and having about 3 to about 10 carbon atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and decahydronaphthyl.
“Cycloalkylalkyl means an alkyl group substituted with a cycloalkyl group. Preferred cycloalkylalkyl groups include cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, decahydronaphth-1-ylmethyl and decahydronaphth-2-ylmethyl.
“Alkylcycloalkyl” means a cycloalkyl group substituted with an alkyl group. Exemplary alkylcycloalkyl groups include 1-, 2-, 3-, or 4- methyl or ethyl cyclohexyl.
“Alkylcycloalkylalkyl” means an alkyl group substituted by an alkylcycloalkyl group. Exemplary alkylcycloalkyl groups include 1-, 2-, 3-, or 4- methyl or ethyl cyclohexylmethyl or 1-, 2-, 3-, or 4- methyl or ethyl cyclohexylethyl.
“Aryl” means a phenyl or naphthyl group.
“Substituted aryl” means a phenyl or naphthyl group substituted by one or more aryl group substituents which may be the same or different, where “aryl group substituent” includes alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, hydroxyalkyl, acyl, formyl, carboxy, alkenoyl, aroyl, halo, nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, or —NR
a
R
b
where R
a
and R
b
are independently hydrogen, alkyl, aryl, or aralkyl. Preferred aryl group substituents are alkyl, hydroxy, alkoxy, halo and trihalomethyl.
“Aralkyl” means an alkyl group substituted by an aryl radical. Preferred aralkyl groups include benzyl, naphth-1-ylmethyl naphth-2-ylmethyl, and phenethyl.
“Substituted aralkyl” means an aralkyl group substituted on the aryl portion by one or more aryl group substituents. “Alcohol” means an alkyl group as defined herein of from1 to about 10 carbon atoms which is substituted with one or more hydroxyl groups. The term “lower alcohol” means an alcohol of from1 to about 4 carbon atoms substituted by a single hydroxyl group. Representative lower alcohols include methanol, ethanol, 2-propanol,1-butanol, and the like. “Glycol” means an alkyl substituted by two or more hydroxyl groups. Representative glycols include ethylene glycol, propylene glycol, and the like.
The term “ether” means a compound of formula R-O-R′ wherein R and R′ are lower alkyl. R and R′ may be connected through one or more methylene groups atoms or through an additional oxygen atom. Representative ethers include diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, and the like.
“Polar aprotic” means solvents which do not contain hydroxy groups but have a relatively high dipole moment. Representative polar aprotic solvents include acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1-dimethoxyethane (DME), hexamethylphosphoric triamide (HMPA), and the like.
“Alkoxide” means a base of formula M—OH wherein M is an alkali metal selected from sodium, calcium, lithium and potassium.
“Carbonate” means a base of formula M
2
CO
3
wherein M is selected from magnesium, sodium, calcium, lithium and potassium.
“Bicarbonate” means a base of formula MHCO
3
wherein M is selected from sodium, calcium, lithium and potassium.
“Natural amino acid” means a carboxylic acid compound having an amino group &agr; to the carboxylate group, i.e., a compound of formula H
2
N—CHR—CO
2
H wherein R is —H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, or —CH
2
CO
2
Q wherein Q is defined herein. Preferred natural amino acids are those wherein R is cyclohexylmethyl. Preferred amin
D'Netto Geoffrey A.
Daubie Christophe
Lavigne Michel
Leon Patrick
Liu Robert C.
Aventis Pharmaceuticals Products Inc.
Newman Irving
Russel Jeffrey E.
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