Claims
- 1. A compound of formula I
- 2. The compound of claim 1 wherein halo is fluoro, chloro, bromo or iodo; (1-2C)alkyl is methyl or ethyl; (1-3C) normal alkyl is methyl, ethyl or propyl; (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; (1-6C)alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl; and (3-6C)cycloalkyl is cyclopropyl, cyclobutyl, cyclopenytyl or cyclohexyl.
- 3. The compound as claimed in claim 1 or 2 wherein Q1 is 4-chlorophenyl, 4-methoxyphenyl, 3-fluoro-4-methoxy-phenyl, 5-chlorothiophen-2-yl, 2-pyridinyl or 6-indolyl.
- 4. The compound as claimed in any of claims 1-3 wherein R2 is 4-(4-morpholinyl)benzylamino, [1-(4-pyridinyl)piperin-4-yl-methyl]amino, or (1-isopropylpiperidin-4-ylmethyl)amino.
- 5. The compound as claimed in any of claims 1-4 wherein none of A3-A6 is N, and each of R3-R6 is hydrogen, or each of R3, R4 and R6 is hydrogen and R5 is chloro.
- 6. The compound as claimed in any of claims 1-4 wherein A3 is N and each of A4-A6 is CH.
- 7. The compound as claimed in any of claims 1-7 wherein —L1—Q1 is —CO—NH—Q1.
- 8. The pharmaceutically acceptable salt of a compound of formula I as claimed in any of claims 1-7 which is an acid-addition salt made from a basic compound of formula I and an acid which provides a pharmaceutically acceptable anion or a salt which is made from an acidic compound of formula I and a base which provides a pharmaceutically acceptable cation.
- 9. A pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a novel compound of formula I (or a pharmaceutically acceptable salt thereof) as provided in any of claims 1-8.
- 10. A process for preparing a compound of formula I (or a pharmaceutically acceptable salt thereof) as provided in claim 1 which is selected from
(A) for a compound of formula I in which —L1—Q1 is —NH—CO—Q1, acylating an amine of formula II, 36 using a corresponding acid of formula HO—CO—Q1, or an activated derivative thereof; (B) for a compound of formula I in which —L1-Q1 is —CO—NH—Q1, substituting the group Ya of a compound of formula III 37 in which Ya is a conventional leaving gruop for nucleophilic aromatic substitution with an amine of formula NH2—CH2—Q2; (C) for a compound of formula I in which —L1—Q1 is —CO—NH—Q1, acylating an amine of formula H2N—Q1, or a deprotonated derivative thereof, using an acid of formula IV, or an activated derivative thereof; 38(D) alkylating an amine of formula V 39 directly, using a compound of formula Y—CH2—Q2, or indirectly by reductive alkylation using an aldehyde of formula Q2—CHO; (E) for a compound of formula I in which —L1—Q1 is —CH2—NH—Q1, reducing a corresponding compound of formula I in which —L1—Q1 is —CO—NH—Q1; (F) for a compound of formula I in which R2A is methylsulfonyl, substituting the amino nitrogen of a corresponding compound of formula I in which R2A is hydrogen using an activated derivative of methanesulfonic acid; (G) for a compound of formula I in which R2A is —CHRyRz or —CHRwRx, alkylating the amino nitrogen of a corresponding compound of formula I in which R2A is hydrogen using an alkylating agent of formula Y—CHRyRz or Y—CHRwRx or reductively alkylating the amine using a compound of formula Ry—CO—Rz or Rw—CO-Rx; (H) for a compound of formula I in which R2A is 4-pyridinyl (which is unsubstituted or bears a substituent Rv at the 2- or 3-position), substituting the amino nitrogen of a corresponding compound of formula I in which R2A is hydrogen using a corresponding pyridine reagent bearing a leaving group Y at the 4-position; (I) for a compound of formula I in which R2A is 4-pyridinyl in which Rv is alkoxycarbonyl, esterifying a corresponding compound of formula I in which Rv is carboxy; (J) for a compound of formula I in which R2A is 4-pyridinyl in which Rv is hydroxymethyl, reducing the ester of a corresponding compound of formula I in which Rv is alkoxycarbonyl; (K) for a compound of formula I in which R2A is 4-pyridinyl in which Rv is carbamoyl, amidating the ester of a corresponding compound of formula I in which Rv is alkoxycarbonyl; (L) for a compound of formula I in which R2A is 4-pyridinyl in which Rv is thiocarbamoyl, adding H2S to the nitrile of a corresponding compound of formula I in which Rv is cyano; (M) for a compound of formula I in which R2A is 4-pyridinyl in which Rv is N-hydroxyamidino, adding H2NOH to the nitrile of a corresponding compound of formula I in which Rv is cyano; (N) for a compound of formula I in which R2A is 4-pyridinyl in which Rv is carboxy, decomposing the ester of a corresponding compound of formula I in which Rv is alkoxycarbonyl; (O) for a compound of formula I in which —NRsRt is other than amino, alkylating a corresponding compound of formula I in which —NRsRt is amino using a conventional method; (P) for a compound of formula I which bears —NRsRt, reductively alkylating H—NRsRt using a corresponding compound but in which the carbon to bear the —NRsRt group bears an oxo group; (Q) for a compound of formula I in which Rp is 1-hydroxy-1-methylethyl, adding a methyl group to the carbonyl group of a corresponding compound of formula I in which Rp is acetyl using an organometallic reagent; (R) for a compound of formula I in which Rp is 1-methoxy-1-methylethyl, treating a corresponding compound of formula I in which Rp is 1-hydroxy-1-methylethyl with methanol and an acid catalyst; (S) for a compound of formula I in which R4 or R5 is amino, reducing the nitro group of a compound corresponding to a compound of formula I but in which R4 or R5 is nitro; and (T) for a compound of formula I in which R4 or R5 is RgNH— and Rg is RhSO2—, substituting the amino group of a corresponding compound of formula I in which R4 or R5 is amino using an activated derivative of the sulfonic acid RhSO2—OH; whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group; whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I is required, it is obtained by reacting the basic form of a basic compound of formula I with an acid affording a physiologically acceptable counterion or the acidic form of an acidic compound of formula I with a base affording a physiologically acceptable counterion or by any other conventional procedure; and wherein, unless otherwise specified, A3-A6, L1, Q1 and R2 have any of the values defined in claim 1.
- 11. A method of inhibiting factor Xa comprising administering to a mammal in need of treatment, a compound of formula I as provided in any of claims 1-8.
- 12. The use of a factor Xa inhibiting compound of formula I substantially as hereinbefore described with reference to any of the examples.
- 13. A novel compound of formula I substantially as hereinbefore described with reference to any of the examples.
- 14. A process for preparing a novel compound of formula I substantially as hereinbefore described with reference to any of the examples.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application No. 60/113,778, filed 23 Dec. 1998.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60113778 |
Dec 1998 |
US |
Divisions (1)
|
Number |
Date |
Country |
Parent |
09857747 |
Jun 2001 |
US |
Child |
10377906 |
Feb 2003 |
US |