Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-23
2002-12-17
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...
C544S250000
Reexamination Certificate
active
06495557
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
, R
2
independently of one another are each H, A, OA or Hal,
R
1
and R
2
together are also alkylene having 3-5 carbon atoms, —O—CH
2
—CH
2
—, —CH
2
—O—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
X is R
5
, R
6
or R
4
which is monosubstituted by R
7
,
R
4
is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH
2
groups may be replaced by —CH═CH— groups,
R
5
is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,
R
6
is phenyl or phenylmethyl,
R
7
is COOH, COCA, CONH
2
, CONHA, CON(A)
2
or CN,
A is alkyl having 1 to 6 carbon atoms and
Hal is F, Cl, Br or I,
and their physiologically acceptable salts.
Pyrimidine derivatives are known, for example, from EP 201 188 or WO 93/06104.
The invention was based on the object of discovering new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable
The compounds of the formula I can be employed as medicament active compounds in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active compounds.
The invention accordingly provides the compounds of the formula I and a process for the preparation of compounds of the formula I according to claim
1
, and of their salts, characterized in that
a) a compound of the formula II
in which
X is as defined above
and L is Cl, Br, OH, SCH
3
or a reactive esterified OH group
is reacted with a compound of the formula III
in which
R
1
and R
2
are as defined above,
or
b) a radical X in a compound of the formula I is converted into another radical X, for example by hydrolysing an ester group to a COOH group or converting a COOH group into an amide or a cyano group and/or in that a compound of the formula I is converted into one of its salts.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, X and L have the meanings given for the formulae I, II and III, unless expressly stated otherwise.
A is alkyl having 1-6 carbon atoms. In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, or 6 carbon atoms, and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
X is an R
4
-, R
5
- or R
6
-radical which is monosubstituted by R
7
.
R
4
is a linear or branched alkylene radical having 1-10 carbon atoms, where the alkylene radical is preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene.
R
5
is furthermore, for example, but-2-enylene or hex-3-enylene.
Very particular preference is given to ethylene, propylene or butylene.
R
5
is cycloalkylalkylene having 5-12 carbon atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. R
5
is also cycloalkyl preferably having 5-7 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
Hal is preferably F, Cl or Br, but also I.
The radicals R
1
and R
2
may be identical or different and are preferably in the 3- or 4-position of the phenyl ring. Independently of one another they are in each case, for example, H, alkyl, F, Cl, Br or I, or together they are alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. Preferably, they are also in each case alkoxy, such as, for example, methoxy, ethoxy or propoxy.
The radical R
7
is preferably, for example, COOH, COOCH
3
, COOC
2
H
5
, CONH
2
, CON(CH
3
)
2
, CONHCH
3
or CN.
For the entire invention, all the radicals which occur several times can be identical or different, that is to say independent of one another.
The invention accordingly particularly provides those compounds of the formula I in which at least one of the radicals mentioned has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to Id, which correspond to the formula I and wherein the radicals not defined in more detail have the meaning given for the formula I, but in which
in Ia X is phenyl, phenylmethyl or R
4
which is substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN;
in Ib R
1
and R
2
together are alkylene having 3-5 carbon atoms, —O—CH
2
—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O,
X is phenyl, phenylmethyl or R
4
which is substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN;
in Ic
R
1
, R
2
independently of one another are in each case H, A, OA or Hal,
R
1
and R
2
together are alkylene having 3-5 carbon atoms, —O—CH
2
—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O,
X is phenyl, phenylmethyl or R
4
which is substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN;
in Id R
1
, R
2
independently of one another are in each case H, A, OA or Hal,
R
1
and R
2
together are also alkylene having 3-5 carbon atoms, —O—CH
2
—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
X is cyclohexyl, phenyl, phenylmethyl or alkylene having 2-5 carbon atoms which is monosubstituted by R
7
,
R
7
is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I.
The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the reactions mentioned. For these reactions, it is also possible to utilize variants which are known per. se and are not mentioned here in more detail.
In the compounds of the formulae II and III, R
1
, R
2
, R
3
, R
4
, X and n have the meanings given, in particular the preferred meanings given.
If L is a reactive esterified OH group, this is preferably alkylsulphonyloxy having 1-6 carbon atoms (preferably methylsulphonyloxy) or arylsulphonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulphonyloxy, or furthermore also 2-naphthalenesulphonyloxy).
The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
On the other hand, it is possible to carry out the reaction in stages.
The starting materials of the formulae II and III are generally known. If they are not known, they can be prepared by methods known per se. Compounds of the formula II can be obtained, for example, by reacting POCl
3
with the corresponding hydroxypyrimidines which are synthesized from thiophene derivatives and CN-substituted alkylenecarboxylic esters (Eur. J. Med. Chem. 23, 453 (1988)). The hydroxypyrimldlnes are prepared either by dehydrogenation of the corresponding tetrahydrobenzothienopyrimidine compounds, or after the cyclization of 2-aminobenzothiophene-3-carboxylic acid derivatives with aldehydes or nitriles which is customary for preparing pyrimidine derivatives (for example Houben-Weyl E9b/2).
Specifically, the reaction of the compounds of the formula II with the compounds of the formula III is carried out in the presence or absence of an inert solvent at temperatures between about −20 and about 150°, preferably between 20 and 100°.
The addition of an acid-binding agent, for example an alkyl me
Christadler Maria
Jonas Rochus
Kluxen Franz-Werner
Schelling Pierre
Merck Patent Gesellschaft mit beschraenkter Haftung
Millen White Zelano & Branigan P.C.
Shah Mukund J.
Truong Tamthom N.
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