Quinoline and quinazoline compounds useful in therapy

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

2001-11-13

2003-02-18

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S307000, C544S283000, C544S284000, C544S292000, C544S293000, C546S001000, C546S139000

Reexamination Certificate

active

06521629

ABSTRACT:

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.
International Patent Application WO 97/23462 (published after the priority date of this application) discloses quinoline and quinazoline compounds having a 5-phenyl substituent. The compounds are indicated in the treatment of benign prostatic hyperplasia.
According to the present invention, there is provided a compound of formula I,
wherein
R
1
represents C
1-4
alkoxy optionally substituted by one or more fluorine atoms;
R
2
represents H or C
1-6
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, C
1-4
alkoxy, C
1-4
alkyl and CF
3
;
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, C
1-4
alkyl, C
1-4
alkoxy, halogen, CONR
8
R
9
, SO
2
NR
8
R
9
, (CH
2
)
b
NR
8
R
9
and NHSO
2
(C
1-4
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 C
1-4
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 SO
2
;
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 C
1-4
alkyl; and
p represents 1, 2 or 3, and in addition, when Z′ represents CH, it may represent 0;
or a pharmaceutically acceptable salt thereof (referred to together herein 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
1-4
may represent or include can be straight chain, branched chain, cyclic, or a combination thereof.
Preferably, R
3
is an aromatic ring, for example pyridinyl, pyrimidinyl, thienyl, furanyl or oxazolyl.
Heterocyclic groups that R
4
comprises may be saturated or unsaturated. However, it is preferred that the ring attached to L, or when L is absent, to the quinoline or quinazoline ring, is saturated.
The compounds of the invention may be optically active. In particular, they may exhibit atropisomerism about the bond joining R
3
to the rest of the molecule when an R
3
substituent is in the ortho-position of the 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:
(a) R
1
represents methoxy;
(b) R
2
represents methoxy;
(c) R
3
represents 2-pyridinyl or 2-pyrimidinyl;
(d) R
4
comprises a saturated 6-membered N-containing ring which is fused to a benzene or pyridine ring; for example R
4
may be a saturated 6-membered N-containing ring which is fused to a benzene ring substituted by NHSO
2
(C
1-4
alkyl);
(e) X represents N; and
(f) L is absent.
According to the invention, there is also provided a process for the production of a compound of the invention, which comprises:
(a) when X represents CH, cyclizing a compound of formula X,
 in which R
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,
 in which R
1-3
, R
6
, R
7
, X, m, n and p are as defined above, with a compound of formula XIV,
 in which R
4
is as defined above, A″ represents CO or SO
2
and Lg represents a leaving group;
(c) reacting a compound of formula XVIII,
 in which R
1
, R
2
, R
4
, X and L are as defined above, with a compound of formula XIX,
R
3
—M  XIX
 in which R
3
is as defined above and M represents substituted boron, zinc or tin, in the presence of a palladium catalyst;
(d) when X represents N, reacting a compound of formula XXII,
 in which R
1-3
are as defined above, with a compound of formula XXIIIa or XXIIIb, as appropriate,
 in which R
4
, R
6
, R
7
, A, A′, Z, Z′, m, n and p are as defined above;
(e) when A or A′ represents CO and R
4
comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to L, reacting a compound of formula XXVIIIa or XXVIIIb, as appropriate,
 in which R
1-3
, R
6
, R
7
, X, Z, Z′, m, n and p are as defined above, and Lg is a leaving group, with a compound of formula XXIX,
HR
4a
  XXIX
 in which R
4a
represents the groups defined by R
4
above which contain a nucleophilic nitrogen atom in the ring, this nucleophilic nitrogen atom being attached to H;
(f) conversion of a compound of formula I in which L represents a cyclic group of formula Ia, to a corresponding compound of formula I in which L represents a chain of formula Ib in which R
6
and R
7
each represent H, by the action of a strong base;
(g) when A or A′ is absent and Z or Z′ represents N, reacting a compound of formula XIIIa or XIIIb, as defined above, with a compound of formula XXX,
R
4
—Hal  XXX
 in which R
4
is as defined above and Hal represents a halogen atom attached to the ring; or
(h) when X represents N, L is absent and R
4
comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to the quinoline or quinazoline ring, reacting a compound of formula XXII, as defined above, with a compound of formula XXIX, as defined above;
and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable salt or vice versa.
In process (a), the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent which does not adversely affect the reaction (for example tetrahydrofuran) around room temperature and quenched with water. In a variation, it may be performed using potassium hydroxide in a solvent such as DMSO at an elevated temperature. Alternatively, it may be performed using zinc chloride in a solvent which does not adversely affect the reaction (for example tetrahydrofuran), at the reflux temperature of the solvent.
In process (b), suitable leaving groups are OH and Cl. When the compound of formula XIV is a carboxylic acid, the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH
2
Cl
2
) at or around room temperature. When the leaving group is Cl, the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH
2
Cl
2
) around 0° C.
In process (c), the palladium catalyst may be tetrakis(triphenylphosphine)palladium. M may be B(OH)
2
, B(CH
2
CH
2
)
2
, Sn(CH
2
CH
2
CH
2
CH
3
)
3
or ZnCl. The reaction may be carried out in a solvent which does not adversely affect the reaction

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