Quinoline and quinazoline compounds useful in therapy

Details Quinoline and quinazoline compounds useful in therapy Quinoline and quinazoline compounds useful in therapy

1998-06-17

2000-08-15

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514299, 546152, A61K 31495, C07D21542

Patent

active

061037389

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia.
International Patent Application WO 89/05297 discloses a number of substituted quinazoline compounds which are indicated as inhibitors of gastric acid secretion.
According to the present invention, there is provided a compound of formula I, ##STR2## wherein R.sup.1 represents C.sub.1-4 alkoxy optionally substituted by one or more fluorine atoms; more fluorine atoms; halogen, C.sub.1-4 alkoxy and CF.sub.3 ; --OCH.sub.2 --, the methylene group being attached to the ortho-position of the pendant phenyl ring; 2 heteroatoms selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, SO.sub.2 NR.sup.8 R.sup.9 and NHSO.sub.2 (C.sub.1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms; ##STR3## in which N is attached to the 2-position of the quinoline or quinazoline ring; represent 0; and ##STR4## in which N is attached to the 2-position of the quinoline or quinazoline ring; represent 0; as "the compounds of the invention").
Pharmaceutically acceptable salts include acid addition salts, such as hydrochloride and hydrobromide salts, and phosphate salts.
Alkyl and alkoxy groups that R.sup.1-4 may represent or include can be straight chain, branched chain, cyclic, or a combination thereof.
The Heterocyclic groups that R.sup.4 represents may be saturated or unsaturated.
The compounds of the invention may be optically active. In particular, they may exhibit atropisomerism about the bond joining the pendant phenyl ring to the rest of the molecule when an R.sup.3 substituent is in the 2- or 3-position of the phenyl ring. The invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof.
Preferred groups of compounds that may be mentioned include those in which: ##STR5## wherein Y represents O, CH.sub.2, SO.sub.2, NR.sup.5 or CHF; and represents O; and ##STR6## or is absent, this latter preference being of particular interest when R.sup.4 represents a group of formula V or VI.
According to the invention, there is also provided a process for the production of a compound of the invention, which comprises: ##STR7## in which R.sup.1-4 and L are as defined above; (b) when A or A' is present, and Z or Z' represents N, reacting a compound of formula XIIIa or XIIIb, as appropriate, ##STR8## in which R.sup.1-3, R.sup.6, R.sup.7, X, m, n and p are as defined above, with a compound of formula XIV, ##STR9## in which R.sup.4 is as defined above, A' represents CO or SO.sub.2 and Lg represents a leaving group; ##STR10## in which R.sup.1, R.sup.2, R.sup.4, X and L are as defined above, with a compound of formula XIX, ##STR11## in which R.sup.3 is as defined above; or (d) when X represents N, reacting a compound of formula XXII, ##STR12## in which R.sup.1-3 are as defined above, with a compound of formula XXIIIa or XXIIIb, as appropriate, ##STR13## in which R.sup.4, R.sup.6, R.sup.7, A, A', Z, Z', m, n and p are as defined above; XXVIIIb, as appropriate, ##STR14## in which R.sup.1-3, R.sup.6, R.sup.7, X, Z, Z', m, n and p are as defined above, and Lg is a leaving group, with a compound of formula XXIX, contain a nucleophilic nitrogen atom in the ring, this nucleophilic nitrogen atom being attached to H; group of formula Ia, to a corresponding compound of formula I in which L represents a chain of formula Ib in which R.sup.6 and R.sup.7 each represent H, by the action of a strong base; formula XIIIa or XIIIb, as defined above, with a compound of formula XXX, attached to the ring; or cyclization of a compound of formula XXXI, ##STR15## in which R.sup.1, R.sup.4, X and L are as defined above, and R.sup.3a has the same meaning as R.sup.3 above except that R.sup.2 and an

REFERENCES:
patent: 5112832 (1992-05-01), Crossley et al.
Journal of Medicinal Chemistry, vol. 38, No. 18, Sep. 1, 1995, Washington US, pp. 3415-3444, XP00200720, J.P. Hieble et al., Alpha-and beta-adrenoceptors: from the gene to the clinic.1.Molecular biology and adrenoceptor subclassification, p. 3415, 3416, 3418, and 3429.

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