Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-27
2001-03-06
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S364000, C548S126000
Reexamination Certificate
active
06197800
ABSTRACT:
The invention relates to compounds of the formula I
in which
R is
X is O or S,
R
1
is H, Hal, OA or A,
R
2
, R
3
, R
5
, R
6
independently of one another are H, Hal, A, OA or R
4
,
R
4
is —O—(CH
2
)
n
—Cy,
Cy is cycloalkyl having 3-8 C atoms,
A is alkyl having 1-6 C atoms, in which one or two CH
2
groups can be replaced by O or S atoms or by —CR
5
═CR
5′
groups and/or 1-7 H atoms can be replaced by F,
R
5
and R
5′
in each case independently of one another are H, F or A,
Hal is fluorine, chlorine, bromine or iodine,
n is 0, 1 or 2,
or a tautomeric ring-closed form, and the (E) isomers and the salts of all isomers.
The tautomeric ring-closed hydroxylactone form
is present if the compounds of the formula I are isolated as carboxylic acids. If the compounds of the formula I are obtained as salts (carboxylates), the open-chain tautomer is obtained.
Similar compounds are disclosed in WO 95/05376.
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability. In particular, they exhibit endothelin receptor-antagonistic properties and can therefore be employed for the treatment of illnesses such as hypertension, cardiac insufficiency, coronary heart disease, renal, cerebral and myocardial ischaemia, renal insufficiency, cerebral infarct, subarachnoid haemorrhage, arteriosclerosis, pulmonary high blood pressure, inflammations, asthma, prostate hyperplasia, endotoxic shock and in complications after the administration of substances such as, for example, cyclosporin, and also other illnesses associated with endothelin activities.
The compounds exhibit, inter alia, a high affinity for the endothelin subreceptors ET
A
and ET
B
. These actions can be determined by customary in vitro or in vivo methods, such as, for example, described by P. D. Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohlstein et al., Proc. Natl. Acad. Sci. USA 91, 1994, 8052-8056.
A suitable method for the determination of the hypotensive action is described, for example by M. K. Bazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 and J. Lange et al., Lab Animal 20, 1991, Appl. Note 1016.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the prophylaxis and/or therapy of cardiac, circulatory and vascular illnesses, especially of hypertension and cardiac insufficiency.
The invention relates to the compounds of the formula I and their salts, and to a process for the preparation of compounds of the formula I according to claim
1
and their salts, characterized in that
a compound of the formula II
in which
R
1
, R
5
, R
6
and X have the meaning indicated in claim
1
, and A is alkyl having 1-4 C atoms or benzyl,
is reacted with a compound of the formula III
in which
R
2
, R
3
, R
4
have the meaning indicated in claim
1
,
and then the ester is cleaved,
and/or a base or acid of the formula I is converted into one of its salts.
For all radicals which occur two or more times, such as, for example, R
3
, R
4
or R
5
, it is a condition that their meanings are independent of one another.
Above and below, the radicals or parameters R, X, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, A and n have the meanings indicated under the formulae I to III, if not expressly stated otherwise.
In the above formulae, A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4, C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and further also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermore trifluoromethyl, pentafluoroethyl, allyl or crotyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Hal is preferably F, Cl or Br, but also I.
R
1
is preferably H, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, methoxymethyl, nitro, amino, formamido, acetamido, sulfonamido, methylsulfonamido, N-methylsulfonamido, cyano and further also formyl.
R
2
, R
3
, R
5
, R
6
in each case independently of one another are H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, alkyl such as, for example, methyl, ethyl, propyl or isopropyl, furthermore hydroxyl, nitro, amino, N-methylamino, dimethylamino, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, N-methylacetamido, N-ethylacetamido, N-propylacetamido, N-butylacetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, N-methylmethylsulfonamido, N-methylethylsulfonamido, N-ethylmethylsulfonamido, N-ethylethylsulfonamido, N-propylmethylsulfonamido, N-propylethylsulfonamido, N-butylmethylsulfonamido, N-butylethylsulfonamido, phenylsulfonamido, (4-methylphenyl)sulfonamido, ureido, methylureido, phenylureido, methoxycarbonylamino, ethoxycarbonylamino, formyl, hydroxymethyl, methoxymethyl, ethoxymethyl, anilino, phenoxycarbonylamino, benzyloxycarbonylamino, benzylsulfonamido, N,N-dimethylureido, 1-piperidinyl-CONH-, 1-pyrrolidinyl-CONH, hydroxyethoxycarbonylamino, methoxyethoxycarbonylamino, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxyethoxy, methoxyethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxymethyl, methoxycarbonylmethyl or ethoxycarbonylmethyl.
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms.
The Z isomers of the formula I are particularly preferred, i.e. the compounds in which the C═C double bond in the radical R is present in the Z configuration.
Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ia to Ie, which correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated under the formula I, but in which
in Ia R
1
is H,
X is S,
R
2
, R
3
, R
4
, R
5
in each case independently of one another are H, Hal, A or OA,
A is alkyl having 1-6 C atoms and
R
4
is cycloalkyl having 3-6 C atoms,
in Ib R
1
is H.
X is O,
R
2
, R
3
, R
4
, R
5
in each case independently of one another are H, Hal, A or OA,
A is alkyl having 1-6 C atoms and
R
4
is cycloalkyl having 3-6 C atoms.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and are suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I. Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III, and then cleaving the ester.
As a rule, the reaction is carried out in an inert solvent, preferably in the presence of a base. A suitable base is, for example, a potassium or sodiu
Christadler Maria
Dorsch Dieter
Mederski Werner
Osswald Mathias
Schmitges Claus Jochen
Gerstl Robert
Merck Patent Gesellschaft mi beschraenkter Haftung
Millen White Zelano & Branigan P.C.
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