Pyrimidine derivatives and processes for the preparation...

Details Pyrimidine derivatives and processes for the preparation... Pyrimidine derivatives and processes for the preparation...

1999-09-24

2002-03-05

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...

C514S272000, C544S298000, C544S320000, C544S321000, C544S330000, C544S331000, C544S332000

Reexamination Certificate

active

06352993

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel pyrimidine derivatives or pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing same as an active ingredient, their novel intermediates, and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
For the treatment of peptic ulcer disease, various drugs such as antacid, anticholinergic agent, H
2
-receptor antagonist and proton pump inhibitor have been used. The advent of omeprazole useful as a proton pump inhibitor has rekindled research activities in this field.
However, it has been pointed out that the proton pump inhibition by omeprazole is irreversible, which may induce side effects. Accordingly, various attempts to develop a reversible proton pump inhibitor are being actively made. For example, European Patent Nos. 322133 and 404322 disclose quinazoline derivatives, European Patent No. 259174 describes quinoline derivatives, and WO 91/18887 offers pyrimidine derivatives, as a reversible proton pump inhibitor. Further, the present inventors have also reported quinazoline derivatives in WO 94/14795 and pyrimidine derivatives in WO 96/05177.
SUMMARY OF THE INVENTION
The present inventors have carried out extensive research to develop a reversible proton pump inhibitor with improved efficacy, and as a result have discovered that pyrimidine derivatives having a substituted tetrahydroisoquinoline group at 4-position of the pyrimidine nucleus or substituents at the 2-, 5-, or 6-positioni of the pyrirnidine nucleus exhibit excellent proton pump inhibition effects and possess the ability to attain a reversible proton pump inhibition.
Accordingly, it is a primary object of the present invention to provide novel pyrimidine derivatives having a substituted tetraydroisoquinoline group at 4-position of the pyrimidine nucleus or substituents at the 2-, 5-, or 6-position of the pyrirnidine nucleus, or pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide processes for preparing said compounds.
It is a further object of the present invention to provide pharmaceutical compositions for treating peptic ulcer containing the same as active ingredients. it is still another object of the, invention to provide novel intermediate compounds useful for the preparation of the novel pyrimidine derivatives.
In accordance with on aspect of the present invention, there are provided novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof:
wherein:
when A is piperidin-1-yl or —NH—B, wherein B is C
3
-C
4
alkenyl, C
3
-C
7
cycloalkyl, C
1
-C
3
alkoxyethyl, phenylethyl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, 1-naphthyl-methyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl,
R
1
is hydrogen or methyl; and
R
2
, R
3
, R
4
and R
5
are hydrogen; or
when A is a group of formula (II):
when R
1
is hydroxymethyl or C
1
-C
3
alkoxymethyl,
R
2
, R
3
, R
4
, R
5
and R
6
are hydrogen; and
R
7
is hydrogen or halogen; or
when R
1
is hydrogen or methyl,
R
7
is hydrogen or halogen; and
one or two of R
2
, R
3
, R
4
, R
5
and R
6
is hydroxy, methoxy, or a group of formula (III):
wherein Z is C
1
-C
4
alkyl, substituted or unsubstituted C
2
-C
4
alkenyl, cycloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazine-methyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiopen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR
8
NHR
9
, wherein R
8
is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxy-carbonylmethyl, carbamoylmethyl, carbamoylethyl, or 1-benzyl imdazol-4-ylmethyl and R
9
is hydrogen or t-butoxycarbonyl; and the others are hydrogen or methyl.
DETAILED DESCRIPTION OF THE INVENTION
Among the compounds of formula (I), preferred are the compounds of the following formula (I-1):
wherein R
1
is hydrogen or methyl; and A′ is piperidin-1-yl or —NH—B, wherein B is C
3
-C
4
alkyl, C
3
-C
4
alkenyl, C
3
-C
7
cycloalkyl, C
1
-C
3
alkoxyethyl, phenylethyl which may be substituted or unsubstituted, 3-trifluoromethyl phenylmethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl.
Among the compounds of the formula (I), also preferred compounds are the compounds of the following formula (I-2):
wherein R
1
is hydrogen or methyl; R
7
is hydrogen or halogen; one or two of R
2
′, R
3
′, R
4
′, R
5
′ and R
6
′ is hydroxy or methoxy and the others are hydrogen or methyl.
Similarly preferred compounds are those of the following formula (I-3)
wherein R
1
is hydrogen or methyl; R
7
is hydrogen or halogen; one or two of R
2
″, R
3
″, R
4
″, R
5
″ and R
6
″ is a group of formula (III):
wherein Z is C
1
-C
4
alkyl, substituted or unsbstituted C
1
-C
4
alkenyl, C
3
-C
6
cycloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazinomethyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiophen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR
8
NHR
9
, wherein R
8
is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxycarbonylmethyl, carbamoylmethyl, carbamoylethyl, or 1-benzyl imdazol-4-ylmethyl and R
9
is hydrogen or t-butoxycarbonyl; and
the others are hydrogen or methyl.
Similarly preferred compounds are those of the following formula (I-4)
wherein R
1
is hydroxymethyl or C
1
-C
3
alkoxymethyl; and R
7
is hydrogen or halogen.
The pyrimidine derivatives of formula (I) in the present invention may exist in the form of an optical isomer, (R) or (S), or a mixture thereof. Both types of the isomeric compounds are found to exhibit excellent anti-secretory activity.
The compounds of the formula (I-1), (I-2), (I-3), and (I-4) may be prepared in accordance with the following methods.
Method for Preparation of the Formula (I-1)
The compound of formula (I-1a) may be prepared by reacting the compound (IV) with A″H in accordance with Scheme 1 described below.
wherein R
1
is hydrogen or methyl; and A″ is piperidin-1-yl or —NH—B, wherein B is C
3
-C
4
alkyl, C
3
-C
4
alkenyl, C
3
-C
7
cycloalkyl, C
1
-C
3
alkoxyethyl, phenylethyl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, or 1-naphthylmethyl.
In the process of Scheme 1, the compound of formula (IV) may be prepared by the same method as described in WO96/05177. The compound of A″H is commercially available (for example, from Aldrich Co. in U.S.A.).
As shown in Scheme 1, the pyrimidine compounds (IV) are reacted with A″H in the presence of an appropriate solvent and a base for 2 to 5 hours to give the compounds of formula (I-1a). Suitable solvents for this reaction may include dimethylformamide, p-dioxane, dimethylsulfoxide, and propyleneglycol. Suitable base for this reaction may include triethylamine, N,N-dimethylaniline, and pyridine. The reaction temperature preferably ranges from 80° C. to 140° C.
The compound of formula (I-1b) may be prepared by a process which comprises: chlorinating the compound of formula (V) to give a compound of formula (VI); and reacting the compound of formula (VI) with 1-R
1
-1,2,3,4-tetrahydroisoquinoline in accordance with Scheme 2 described below.
wherein R
1
is hydrogen or methyl; and R
10
is methyl or phenyl.
In the process of Scheme 2, the compound of formula (V) may be prepared by using a known process [see, e.g.,
J. Med. Chem
., 33, 543, (1990); and
J. Heterocyclic. Chem
., 28, 231 (1991)].
The compound of formula (V) is chlorinated with chlorinating agent, e.g. phosphorous oxychloride, to give a compound of formula (VI). And then the compound of formula (VI) is reacted with 1-R
1
-1,2,3,4-tetrahydroisoquinoline to give compounds of formula (I-1b).
Method for Preparation of the Formula (I-2)
The compound of formula (I-2a) may be prepared by reacting the compound (VII) with a compound

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