Claims
- 1. A compound of formula I,
- 2. The compound, or salt thereof, of claim 1 wherein halo is fluoro, chloro or bromo; (1-3C)alkyl is methyl, ethyl, propyl or isopropyl; (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; (1-4C)alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy; and (1-3C)acyl is formyl, acetyl or propionyl.
- 3. The compound, or salt thereof, of claim 1 or 2 wherein
when Q is QA, R3 is hydrogen; one of R4 and R5 is hydrogen, (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxymethyl, (1-3C)acyl, RfO—, RfO2C—, RfO2C—CH2—, RfO2C—CH2—O—, methylthio or RgNH— in which Rg is hydrogen, (1-3C)acyl, or RhSO2—; and Rh is (1-4C)alkyl, trifluoromethyl, amino, methylamino or dimethylamino; the other of R4 and R5 is hydrogen, halo or methyl; and R6 is hydrogen; or A6 is N, and each of the others is CR3, CR4and CR5, respectively, in which R3 and R4 is each hydrogen and R5 is hydrogen or methyl; and when Q is QB, Q1L1 is trans-styryl (which may bear one or more halo, methoxy or methyl substituents on the aromatic ring), benzo[b]thiophen-2-yl (which may bear one or more halo, methoxy or methyl substituents at the 5- and/or 6-position) or naphthalen-2-yl (which may bear one or more halo, methoxy or methyl substituents at the 6- and/or 7-position); and R is hydrogen, (1-3C)alkyl, (1-3C)acyl, acetyloxy-acetyl, hydroxyacetyl, methoxycarbonyl, ethoxycarbonyl, {(1-4C)alkoxy}carbonylmethyl, RaRbN—CO— or RjSO2—, wherein each of Ra and Rb is independently hydrogen or (1-3C)alkyl, or RaRbN— is 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or 4-thiomorpholinyl; and Rj is (1-4C)alkyl, trifluoromethyl, amino, methylamino or dimethylamino.
- 4. The compound, or salt thereof, of claim 1, 2 or 3 wherein
when Q is QA, A3 is CR3, A4 is CR4, A5 is CR5, and A6 is CR6; wherein each of R3, R4 and R6 is hydrogen and R5 is fluoro, chloro, methyl, acetyl, methoxycarbonyl or carboxy; or each of R3, R5 and R6 is hydrogen and R4 is methoxycarbonyl or carboxy; or each of R3 and R6 is hydrogen and each of R4 and R5 is fluoro; or A6 is N, and each of A3, A4 and A5 is CH; and R1 is 2-pyridinyl which bears a fluoro, chloro or methyl substituent at the 5-position; and when Q is QB, Q1 is 6-chloronaphthalen-2-yl and L1 is a direct bond; each of X1 and X2 is N; and each of X3 and X4 is CH; or each of X1 and X3 is N; and each of X2 and X4 is CH; or each of X1 and X4 is N; and each of X3 and X4 is CH; or X1 is N and each of X2, X3 and X4 is CH; or X2 is N and each of X1, X3 and X4 is CH; and R is hydrogen, methyl, ethyl, acetyl, acetoxyacetyl, hydroxyacetyl, t-butoxycarbonylmethyl, methylsulfonyl or dimethylaminosulfonyl.
- 5. The compound, or salt thereof, of any one of claims 1-4 wherein Q is QA.
- 6. The compound, or salt thereof, of claim 1 wherein
Q is QA; L is carbonyl; A3 is CR3, A4 is CR4, A5 is CR5, and A6 is CR6; wherein each of R3, R4 and R6 is hydrogen and R5 is fluoro, chloro, methyl, acetyl, methoxycarbonyl or carboxy; or each of R3, R5 and R6 is hydrogen and R4 is methoxycarbonyl or carboxy; R1 is 2-pyridinyl which bears a fluoro, chloro or methyl substituent at the 5-position; and each of X1 and X3 is N; and each of X2 and X4 is CH; or each of X1 and X4 is N; and each of X3 and X4 is CH; or X1 is N and each of X2, X3 and X4 is CH; or X2 is N and each of X1, X3 and X4 is CH; and R is hydrogen, methyl, ethyl, acetyl, acetoxyacetyl, hydroxyacetyl, methylsulfonyl or dimethylaminosulfonyl.
- 7. The compound of claim 1 which is selected from
a. 5-fluoro-2-[5-(hexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-N-(5-chloropyridin-2-yl)benzamide; b. 5-fluoro-2-[6-(hexahydro-1,4-diazepin-1-yl)pyridazin-3-ylcarbonylamino]-N-(5-chloropyridin-2-yl)benzamide; c. 5-fluoro-2-[5-(hexahydro-1,4-diazepin-1-yl)pyrimidin-2-ylcarbonylamino]-N-(5-chloropyridin-2-yl)benzamide; d. 5-fluoro-2-[5-(hexahydro-1,4-diazepin-1-yl)pyridin-2-ylcarbonylamino]-N-(5-chloropyridin-2-yl)benzamide; and e. 2-[6-(hexahydro-1,4-diazepin-1-yl)pyridin-3-ylcarbonyl-amino]-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzamide, or a pharmaceutically acceptable salt thereof.
- 8. The compound, or salt thereof, of claim 4 wherein Q is QB.
- 9. The compound, or salt thereof, of claim 8 wherein each of X1 and X2 is N and each of X3 and X4 is CH, and R is hydrogen or methyl.
- 10. The pharmaceutically acceptable salt of any of claims 1-9 which is the acid addition salt of a basic compound of formula I with an inorganic or organic acid which affords a physiologically acceptable anion or which is the salt formed by an acidic compound of formula I with a base which affords a physiologically acceptable cation.
- 11. A pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of formula I (or a pharmaceutically acceptable salt thereof) as provided in any of claims 1-10.
- 12. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, as provided in any of claims 1-10, wherein a functional group of a starting material which is not involved in the indicated process may be in a form in which the functional group is protected using a protecting group, which comprises:
(A) substituting the group Ya of a compound of formula II, 205in which Ya is a leaving group for nucleophilic aromatic substitution, using an amine of formula III; 206(B) for a compound of formula I in which L is carbonyl, acylating an amine of formula Q—H using a corresponding acid of formula IV, 207or an activated derivative thereof; (C) for a compound of formula I in which R is not hydrogen, substituting the nitrogen of a corresponding compound in which R is hydrogen using a conventional procedure; (D) for a compound of formula I in which L is methylene and Q is QA, substituting the group Ya of a compound of formula V 208in which Ya is a leaving group for nucleophilic aromatic substitution with an amine of formula VI; or 209alkylating an amine of formula Q—H directly, using a compound of formula VII, 210in which Yb is a leaving group for nucleophilic substitution, or indirectly by reductive alkylation using an aldehyde of formula VIII; 211or (E) for a compound of formula I in which Q is QA, acylating an amine of formula H2N—R1, or a deprotonated derivative thereof, using an acid of formula IX or an activated derivative thereof, 212whereafter, for any of the above procedures, when a functional group of a starting material 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, Q, L, X1-X4, and R have any of the values defined in any of claims 1-10.
- 13. A compound of formula II,
- 14. An acid of formula IV,
- 15. An acid of formula IV,
- 16. An amine of formula VI,
- 17. An acid of formula IX,
- 18. The activated derivative of claim 16 which is a compound of formula X,
- 19. (Cancelled on National Stage Entry)
- 20. (Cancelled on National Stage Entry)
- 21. A method of inhibiting factor Xa in a mammal comprising administering to a mammal in need of treatment an effective (factor Xa inhibiting) dose of a compound of formula I (or prodrug or salt) as described in any of claims 1-10.
- 22. (Cancelled on National Stage Entry)
- 23. (Cancelled on National Stage Entry)
- 24. (Cancelled on National Stage Entry)
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application No. 60/221,092, filed Jul. 27, 2000, which is incorporated by reference herein in its entirety.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US01/16528 |
7/18/2001 |
WO |
|