Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-07
2002-07-09
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S259500, C544S297000, C544S283000, C544S291000, C546S139000, C546S259000
Reexamination Certificate
active
06417194
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 that are indicated as inhibitors of gastric acid secretion.
Co-pending International Patent Application No. PCT/EP96/05609 discloses a number of quinoline and quinazoline compounds indicated in the treatment of benign prostatic hyperplasia, and discloses 4-amino-6-benzyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline as an intermediate [see Example 49, step (f), therein]. This is the compound of Example 1 of the present application, which is excluded from claim
1
by proviso (b).
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
and R
3
independently represent H, C
1-6
alkoxy (optionally substituted by one or more fluorine atoms, or by phenyl which may in turn be substituted by one or more fluorine atoms), cyclobutyloxy or CF
3
CH
2
O.
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 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;
X represents CH or N; and
L is absent,
or represents a cyclic group of formula Ia,
in which A is attached to R
4
;
A 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 A is attached to R
4
;
A and Z are as defined above;
R
5
and R
6
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;
provided that:
(a) R
2
and R
3
do not both represent H;
(b) when R
1
represents methoxy, R
2
represents benzyloxy, R
3
represents H, R
4
represents morpholinyl, and X represents N, then L is not
(c) when X represents N and L is absent, then R
4
is not naphthyridine;
or a pharmaceutically acceptable salt thereof (referred to together herein as “the compounds of the invention”).
Alkyl groups may be straight chain, branched, cyclic or a combination thereof. Similarly, the alkyl portion of alkoxy groups may be straight chain, branched, cyclic or a combination thereof.
Preferably, heterocyclic rings represented or comprised by R
4
are saturated. Examples include morpholine, tetrahydrofuran and piperidine.
The compounds of the invention may be optically active. 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 H or methoxy;
(c) R
3
represents cyclobutyloxy or CF
3
CH
2
O;
(d) L is absent, in which case R
4
preferably represents a piperidine ring which is fused to a pyridine ring or to a benzene ring which is substituted by NHSO
2
(C
1-4
alkyl); and
(e) L represents
in which case R
4
preferably represents morpholinyl.
When R
3
represents H, R
2
is preferably benzyloxy or cyclobutyloxy.
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 II,
in which R
1-4
and L are as defined above;
(b) when Z represents N, and L is present, reacting a compound of formula IIIa or IIIb, as appropriate,
in which R
1
, R
2
, R
3
, R
5
, R
6
, X, m, n and p are as defined above, with a compound of formula IV,
Lg—A—R
4
IV
in which R
4
and A are as defined above, and Lg represents a leaving group;
(c) reacting a compound of formula V,
in which R
1
, R
4
, X and L are as defined above, and R
a
and R
b
independently represent H or OH, provided that they do not both represent H, with a compound of formula VI,
R
c
—Lg VI
in which R
c
is alkyl (optionally substituted by one or more fluorine atoms, or by pheny which may in turn be substituted by one or more fluorine atoms), and Lg represents a leaving group, in the presence of a base;
(d) when X represents N, reacting a compound of formula VII,
in which R
1
, R
2
and R
3
are as defined above, with a compound of formula VIIIa, VIIIb or VIIIc, as appropriate,
in which R
4-6
, A, Z, m, n and p are as defined above; and R
4a
has the same significance as R
4
above except that it contains a nucleophilic nitrogen atom in the heterocyclic ring which is attached to the H in formula VIIIc;
(e) when A represents CO and R
4
comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to L, reacting a compound of formula IXa or IXb, as appropriate,
in which R
1-3
, R
5
, R
6
, X, Z, m, n and p are as defined above, and Lg is a leaving group, with a compound of formula VIIIc, as defined above; or
(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
5
and R
6
each represent H, by the action of a strong base; 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 that does not adversely affect the reaction (for example tetrahydrofuran), around room temperature. Alternatively, it may be performed using potassium hydroxide or potassium tert-butoxide in a solvent which does not adversely affect the reaction (for example dimethylsulphoxide or 1,2-dimethoxyethane), at an elevated temperature (for example 80&thgr;C). In addition, it may be performed using zinc chloride either without a solvent at an elevated temperature (for example 190&thgr;C), or in a solvent which does not adversely affect the reaction (for example dimethylformamide at the reflux temperature of the solvent).
In process (b), suitable leaving groups are OH and Cl. When the compound of formula IV 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
or tetrahydrofuran), around 0&thgr;C or up to the reflux temperature of the solvent.
In process (c), suitable leaving groups include halogens such as bromine or iodine, and suitable bases include sodium hydride. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example dimethylformamide) at room temperature or up to 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 the reflux temperature of the solvent).
In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent that 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 compo
Collis Alan John
Fox David Nathan Abraham
Mantell Simon John
Patel Sudhaker B.
Pfizer Inc.
Shah Mukund J.
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