Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-23
2003-11-18
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...
C514S228200, C514S233800, C514S211080, C514S212010, C514S217060, C514S218000, C514S259500, C540S600000, C540S575000, C540S553000, C544S293000, C544S291000, C544S116000
Reexamination Certificate
active
06649620
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.
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 an aryl group or a heteroaryl group, optionally substituted by C
1-4
alkyl or SO
2
NH
2
;
R
3
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
3
;
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
3
;
A and Z are as defined above;
R
4
and R
5
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 or alkoxy groups that R
1-5
may represent or include can be straight chain, branched chain, cyclic, or a combination thereof.
“Aryl” in the definition of R
2
means an aromatic hydrocarbon, for example phenyl or naphthyl. “Heteroaryl” in the definition of R
2
means an aromatic heterocycle, for example one having 5 or 6 ring members, at least one of which is N, O or S, such as pyridinyl or furanyl.
Preferably, heterocyclic rings represented or comprised by R
3
are saturated. Examples include morpholine, thiomorpholine-1,1-dioxide, 1,4-dioxan, 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.
The compounds of the invention may exist in a number of tautomeric forms. The invention includes all such tautomeric forms.
Preferred groups of compounds that may be mentioned include those in which:
(a) R
1
represents methoxy;
(b) R
2
represents phenyl or 2-pyridinyl;
(c) R
3
represents morpholinyl, or a piperidine ring which is fused to a benzene or pyridine ring;
(d) L is absent or represents 1,4-diazepanylcarbonyl
and
(e) L is absent and R
3
represents a piperidine ring fused to a benzene ring which is substituted by NHSO
2
(C
1-4
alkyl).
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
1-3
and L are as defined above;
(b) when Z represents N, reacting a compound of formula IIIa or IIIb, as appropriate.
in which R
1
, R
2
, R
4
, R
5
, X, m, n and p are as defined above, with a compound of formula IV,
Lg-A-R
3
IV
in which R
3
is as defined above, A represents CO or SO
2
and Lg represents a leaving group;
(c) reacting a compound of formula V,
in which R
1
, R
3
, X and L are as defined above, and Lg is a leaving group, with a compound of formula VI,
R
2
-M VI
in which R
2
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 VII,
in which R
1
and R
2
are as defined above, with a compound of formula VIIIa, VIIIb or VIIIc, as appropriate,
in which R
3-5
, A, Z, m, n and p are as defined above; and R
3a
has the same significance as R
3
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
3
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
, R
2
, R
4
, R
5
, 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
4
and R
5
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 in a solvent which does not adversely affect the reaction (for example dimethylsulphoxide), 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° C. or up to the reflux temperature of the solvent.
In process (c), suitable leaving groups include the trifluoromethylsulphonate (triflate) group. The palladium catalyst may be tetrakis(triphenylphosphine)palladium(0). M may be B(OH)
2
, B(CH
2
CH
2
)
2
, Sn(CH
2
CH
2
CH
2
CH
3
)
3
, Sn(CH
3
)
3
or ZnCl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example, when M is B(OH)
2
, a mixture of toluene, ethanol and 1M 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 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 compound of formula IXa or IXb, by reacting a compound of formula IIIa or IIIb with triphosgene and a compound of formula VIIIc. In this case the leaving group is —Cl. The reaction may be carried out in a solvent that 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 diisopropylamide. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF).
Compounds of formula II [see process (a)] may be prepared by reaction of a compound of formula X,
in which R
1
, R
3
and L are as defined above and Lg is a leaving group (such as a triflate group), w
Collis Alan John
Fox David Nathan
Benson Gregg C.
Ford John M.
Goddard Carl J.
Pfizer Inc.
Richardson Peter C.
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