Patent EA-002851-B1 (EA)
Title: Quinoline and quinazoline compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia
Inventor: FOX DAVID NATHAN ABRAHAM
IPC: C07D413/04
Filed: 1998-01-06
Abstract: 1. A compound of formula I,   wherein R<1> represents C1-4 alkoxy optionally substituted by one or more fluorine atoms; R<2> represents H or C1-6 alkoxy optionally substituted by one or more fluorine atoms; R<3> represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C1-4 alkoxy, C1-4 alkyl and CF3 ; R<4> represents a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen, CONR<8>R<9>, SO2 NR<8>R<9>, (CH2)b NR<8>R<9> and NHSO2 (C1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms; R<8> and R<9> independently represent H or C1-4 alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S; b represents 0, 1, 2 or 3; X represents CH or N; and L is absent, or represents a cyclic group of formula Ia,   in which N is attached to the 2-position of the quinoline or quinazoline ring; A is absent or represents CO or SO2; Z represents CH or N; m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5; or represents a chain of formula Ib,   in which N is attached to the 2-position of the quinoline or quinazoline ring; A' and Z' have the same significance as A and Z above, respectively; R<6> and R<7> independently represent H or C1-4 alkyl; and p represents 1, 2 or 3, and in addition, when Z represents CH, it may represent 0; or pharmaceutically acceptable salts thereof. 2. A compound as claimed in Claim 1, wherein R<1> and R<2> each represent methoxy. 3. A compound as claimed in Claim 1 or Claim 2, wherein R<3> represents 2-pyridinyl or 2-pyrimidinyl. 4. A compound according to any of preceding Claims, wherein X is N. 5. A compound according to any of preceding Claims, wherein L is absent. 6. A compound according to any of preceding Claims, wherein R<4> comprises a saturated 6-membered N-containing ring which is fused to a benzene or pyridine ring. 7. A compound as claimed in Claim 6, wherein the benzene ring is substituted by NHSO2 (C1-4 alkyl). 8. A pharmaceutical formulation including a compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 9. A use of a compound of formula I according to Claim 1, or a pharmaceutically acceptable salt thereof, as a pharmaceutical. 10. A use of a compound of formula I according to Claim 1, or a pharmaceutically acceptable salt thereof for producing a medicine for treatment of benign prostatic hyperplasia. 11. A method for treatment of benign prostatic hyperplasia, which comprises administration of a compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. 12. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises cyclization the compound of formula X,   wherein R<1-4> and L are such as defined in Claim 1, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 13. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting the compound of formula XIIIa or XIIIb,       wherein R<1-3>, R<6>, R<7>, X, m, n and p are such, as defined in Claim 1, with a compound of formula XIV   wherein R<4> is such, as defined in Claim 1, A" is CO or SO2 and Lg is a leaving group, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 14. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting the compound of formula XVIII,   wherein R<1>, R<2>, R<4>, X and L are such, as defined in Claim 1, with a compound of formula XIX,   wherein R<3> is such, as defined in Claim 1, and M is substituted boron, zinc or tin, in presence of palladium catalyst, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 15. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting the compound of formula XXII,   wherein R<1-3> are such, as defined in Claim 1, with a compound formula XXIIIa or XXIIIb, correspondingly,       wherein R<4>, R<6>, R<7>, A, A', Z, Z', m, n and p are such, as defined in Claim 1, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 16. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting the compound of formula XXVIIIa or XXVIIIb, correspondingly,       wherein R<1-3>, R<6>, R<7>, X, Z, Z', m, n and p are such, as defined in Claim 1, and Lg is a leaving group, with a compound of formula XXIX   wherein R<4a> is the groups, as defined in Claim 1 with the help of R<4>, which comprise nucleophilic nitrogen atom in the ring, at that said nitrogen atom is attached to H, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 17. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises converting the compound of formula I, wherein L is a cyclic group of formula Ia, into a corresponding compound of formula I, wherein L is a chain of formula Ib, wherein each of R<6> and R<7> is H, by forcing of strong base, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 18. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting the compound of formula XIIIa or XIIIb, as determined above, with a compound of formula XXX,   wherein R<4> is such, as defined in Claim 1, and Hal is halo atom, attached to ring, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 19. A process for preparation the compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting the compound of formula XXII, as determined above, with a compound of formula XXIX, as determined above, and, if desired or necessary, converting of the obtained compound of formula I into a pharmaceutically acceptable salt thereof, or vice versa. 20. The compound of formula X,   wherein R<1-4> and L are such, as defined in Claim 1. 21. The compound of formula XIIIa   wherein R<1-3>, R<6>, R<7>, X, m, n and p are such, as defined in Claim 1. 22. The compound of formula XIIIb   wherein R<1-3>, R<6>, R<7>, X, m, n and p are such, as defined in Claim 1. 23. The compound of formula XXII   wherein R<1-3> are such, as defined in Claim 1. 24. The compound of formula XXVIIIa   wherein R<1-3>, R<6>, R<7>, X, Z, Z', m, n and p are such, as defined in Claim 1. 25. The compound of formula XXVIIIb   wherein R<1-3>, R<6>, R<7>, X, m, n and p are such, as defined in Claim 1.