Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
AssigneePfizer Inc.
InventorsGary Louis Bolton, Kevin James Filipski, Jeffrey Thomas Kohrt, Frances La, Daniele Marie Leonard
Life of this patent
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Abstract
This invention discloses amino acid derivatives which display inhibitory effects on the serine protease factor Xa. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, methods for the preparation of the compounds, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
Claims42
A compound having Formula I:
- 93
- and pharmaceutically acceptable salts thereof, where:
- X1 and X2 are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, —(CH2)m-halogen, —(CH2)m-heteroaryl, —(CH2)m—SOR3, —(CH2)m—OCOR3, —(CH2)m—OSO2R3, —(CH2)m—OSO2NR4R5, —(CH2)m-NR6COR3, —(CH2)m—NR6SO2R3, —(CH2)m—NR3SO2NR4R5, —(CH2)mNR4R5, —(CH2)mOR3, —CN, —NO2, —CF(3-n)Hn, —(CH2)m—O(CH2)mR3 , —(CH2)m—O(CH2)m—OR3 , —(CH2)m—O(CH2)m—NR4R5, —(CH2)mR3, —(CH2)mCO2R3, —(CH2)mCOR3, —(CH2)mCONR4R5, —(CH2)mNR6COR3, —(CH2)mNR6CONR4R5, —(CH2)mSO2R3, —(CH2)mSO2NR4R5,
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- or are joined together to form a substituted or unsubstituted three to eight member ring wherein 0 to 3 atoms of the ring are heteroatoms;
- A is aryl, arylcycloalkyl, heteroaryl, heteroarylcycloalkyl, cycloalkyl, or cycloalkenyl;
- M is arylene, heteroarylene, cycloalkylene, heterocycloalkylene, cycloalkenylene or heterocycloalkenylene;
- Q is —CONR4R5, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;
- R1 is hydrogen, alkyl, aryl, heteroaryl or alkenyl;
- R2 is hydrogen, alkyl, aryl, heteroaryl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, carboxy, —(CH2)mNR4R5, —(CH2)mOR3, —(CH2)mSR3, —(CH2)mCONR4R5, or —(CH2)mNR6COR3;
- R3 is hydrogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aralkyl, or heteroarylalkyl;
- R6 is hydrogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aralkyl, or heteroarylalkyl;
- R4 and R5 are each independently hydrogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroarylalkyl,
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- or joined together to form a 3 to 8 member ring;
- m is 0 to 8;
- n is 0 to 2;
- and
- p is 1 to 3;
- with the proviso that when R1 and R2 are H, neither X1 nor X2 is H.
A process for the preparation of compounds of Formula I, wherein P1 is a protecting group, Y1 is a halogen and X1, X2, A, M, and Q are as defined above, comprising
- (a) contacting an amino acid having Formula III with a reagent capable of forming a protecting group on the amino group of the amino acid to form a compound with Formula IV
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- (b) activating of the carboxylic acid of Formula IV and contacting it with an amino compound of the formula H2N-M-Y1 to form a compound of Formula V
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- (c) coupling the compound of Formula V with a compound having Q to form a compound of Formula VI
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- (d) removing the amino protecting group of the compound of Formula VI and contacting the resulting free amine with an isocyanate having A to form a compound of Formula I
- 116
A process for the preparation of compounds of Formula I, wherein P1 is a protecting group, and X1, X2, A, M, and Q are as defined above, comprising
- (a) contacting an amino acid having Formula X with a reagent capable of forming a protecting group on the amino group of the amino acid to form a compound with Formula XI
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- (b) activating of the carboxylic acid of Formula XI and contacting it with an amino compound of the formula H2N-M-Q to form a compound of Formula XII
- and
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- (c) removing the amino protecting group of the compound of Formula XII and contacting the resulting free amine with an isocyanate having A to form a compound of Formula I
- 119
A process for the preparation of compounds of Formula I, wherein A, M, Q and R2 are as defined above, comprising
- (a) contacting a compound of Formula XVII with a bromoacetyl chloride of the Formula XX to form a compound of Formula XXI
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- (b) contacting a compound of Formula XXI with an amine of Formula XXII to form a compound of Formula XXIII
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- and
- (c) contacting a compound of Formula XXIII with an isocyanate having A to form a compound of Formula I
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A process for the preparation of compounds of Formula I, wherein P1 and P2 are independent protecting groups and A, M, and Q are as defined above, comprising
- (a) base catalyzed ring opening of a compound of Formula XXVIII to form a compound of Formula XXIX
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- (b) contacting a compound of Formula XXIX with a reagent capable of forming a protecting group on the hydroxyl groups followed by contacting the resulting intermediate with a reagent capable of selective deprotection of the carboxylic acid hydroxyl group to form a compound with Formula XXX
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- (c) activating the carboxylic acid of Formula XXX and contacting it with an amino compound of the formula XXXI to form a compound of Formula XXXII
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- and
- (d) removing the amino protecting group of the compound of Formula XXXII and contacting the resulting free amine with an isocyanate having A to from a compound of Formula I
- 126
A process for the preparation of compounds of Formula I, wherein P1 and P2 are independent protecting groups and A, M, and Q are as defined above, comprising
- (a) contacting a compound of Formula XXXIII with a reagent capable of selectively forming a protecting group on the alcohol hydroxyl group to form a compound with Formula XXXIV
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- (b) activating the carboxylic acid of Formula XXXIV and contacting it with an amino compound of the formula XXXV to form a compound of Formula XXXVI
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- (c) removing the amino protecting group of the compound of Formula XXXVI and contacting the resulting free amine with an isocyanate having A to from a compound of Formula XXXVII
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- and
- (d) removing the alcohol hydroxy protecting group of the compound of Formula XXXVII to from a compound of Formula I
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A process for the preparation of compounds of Formula I, wherein P1 and P2 are independently protecting groups and A, M, and Q are as defined above, comprising
- (a) contacting a compound of Formula XXXVIII with acid to form a compound of Formula XXXIX
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- (b) contacting a compound of Formula XXXIX with a reagent capable of forming a protecting group on the amino moiety to form a compound of Formula XL
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- (c) contacting a compound of Formula XL with a reagent capable of forming a protecting group on the heterocycle nitrogen to form a compound of Formula XLI
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- (d) contacting a compound of Formula XLI with a reagent capable of removing the protecting group of the carboxylic acid to form a compound of Formula XLII
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- (e) activating the carboxylic acid of Formula XLII and contacting it with an amino compound of the formula XLIII to form a compound of Formula XLIV
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- and
- (f) removing the amino protecting group of the compound of Formula XLIV and contacting the resulting free amine with an isocyanate having A to from a compound of Formula I
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Dependencies are inferred from the claim text.