Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-19
2003-11-04
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S258100, C514S252160, C514S252170, C514S234500, C514S234200, C514S228500, C514S228200, C514S218000, C514S217050, C514S217060, C514S211150, C514S211080, C544S116000, C544S279000, C544S058200, C544S291000, C544S284000, C544S293000, C540S600000, C540S575000, C540S553000
Reexamination Certificate
active
06642242
ABSTRACT:
This invention relates to novel compounds useful in therapy, particularity 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,
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 one or more groups independently selected from H. halogen, C
1-4
alkoxy and CF
3
;
in addition, R
2
and one R
3
group may together represent —OCH
2
—, the methylene group being attached to the ortho-position of the pendant phenyl ring;
R
4
represents a 4-, 5- or 6-membered heterocyclic ring containing 1 or 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
1-4
alkyl, C
1-4
alkoxy, halogen, SO
2
NR
8
R
9
and NHSO
2
(C
1-4
alkyl), and wherein 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
alkyl;
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.
Heterocyclic groups that R
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 phenol ring to the rest of the molecule when an R
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:
(a) R
1
represents methoxy;
(b) R
2
represents methoxy;
(c) R
2
and an R
3
group together represent —OCH
2
—;
(d) R
3
represents H or 4-fluoro;
(e) R
4
represents a group having the formula II, III, IV, V or VI,
wherein
Y represents O, CH
2
, SO
2
, NR
5
or CHF; and
R
5
represents H or C
1-4
alkyl;
the group of formula II being of particular interest, especially when Y represents O; and
(f) L represents a group of formula VII,
or is absent, this latter preference being of particular interest when R
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:
(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,
in which R
3
is as defined above; or
(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, reacting a compound of formula XXVIIIa or XVIIIb, 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 R
2
and one R
3
group together represent —OCH
2
—, cyclization of a compound of formula XXXI,
in which R
1
, R
4
, X and L are as defined above, and R
3a
has the same meaning as R
3
above except that R
2
and an R
3a
group do not together represent —OCH
2
—;
and where desired or necessary converting the resulting compound of the invention 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 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 reaction may be carried out in the presence of a palladium catalyst [for example tetrakis(triphenylphosphine)palladium] in a solvent which does not adversely affect the reaction (for example a mixture of toluene, ethanol and 1N aqueous sodium carbonate) at an elevated temperature (for example the reflux temperature of the solvent).
In process (d), the reaction may be carried out in a solvent which does not adversely affect the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example 100° C.).
In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature.
The reaction may also be carried out without isolating the compound of formula XVIIIa or XXVIIIb, by reacting a compound of formula XIIIa or XIIIb with triphosgene and a compound of formula XXIX. In this case 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
) in the presence of a base (for example triethylamine) at or around room temperature.
In process (f), suitable strong bases include lithium diisopro
Collis Alan John
Fox David Nathan Abraham
Newman Julie
Benson Gregg C.
Ford John M.
Goddard Carl J.
Pfizer Inc.
Richardson Peter C.
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