Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-19
2002-03-19
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S067000, C544S361000, C540S575000, C514S218000, C514S253030
Reexamination Certificate
active
06358967
ABSTRACT:
The invention relates to novel ergoline amine derivatives with an antihypertensive effect, in particular for use in medicine.
About 10 million people in Germany alone suffer from high blood pressure [E. König, Bluthochdruck, Erste Warnsignale, Gefahren und Behandlung, Wort & Bild Verlag Konradshöhe, GmbH & Co. Baierbrunn, 1995]. There is still a pressing need for novel agents with novel principles of action, in particular without the unwanted side effects frequently occurring with the known products, for treating this disease, which is regarded as a major risk factor for various cardiovascular disorders such as arteriosclerosis, myocardial infarction, stroke and kidney damage.
The ergoline amine derivatives previously disclosed and described in the literature mainly have antisecretory and antiulcer effects. Also known from this class of substances are stimulators of the central nervous system and ergoline thiourea derivatives with antiparkinson activity. Other ergoline derivatives show antiprolactin activity, serotonin antagonistic effects, sympatholytic and oxytocin-like activity. In the search for novel antihypertensives, among the ergot alkaloids which mostly have pressor activity also a few 8&bgr;-aminomethylergoline derivatives with an antihypertensive effect have been found, with urea and thiourea derivatives [A. Temperilli, D. Ruggieri, P. Salvati,
Eur. J. Med. Chem.,
1988, 23, 77.] or organometallic derivatives of 8&bgr;-aminomethylergoline acting as structural elements. It is known that a number of unwanted side effects occur after use of antihypertensives such as, for example, clonidine, reserpine, nifedipine, dihydralazine, and known urea and thiourea derivatives of 8&bgr;-aminomethylergoline, especially nausea, diarrhea, fatigue, depression and edema.
Overall, it is estimated that known drugs with antihypertensive activity do not meet the requirements for adequate hypotensive activity and good tolerability, which makes it necessary to look for novel compounds, especially with novel mechanisms of action.
The invention is based on the object of providing suitable, readily soluble, selectively acting and well tolerated drugs which have high antihypertensive activity after enteral and parenteral administration. The compounds are intended to make effective treatment of hypertensive diseases possible and to be better tolerated than therapeutic agents used to date.
The object is achieved according to the invention by providing novel 8&bgr;-aminomethylergoline derivatives which comprise a diamine structural unit coupled via a dicarboxylic acid. It has been found, surprisingly, that 8&bgr;-aminomethylergoline derivatives which are linked via the aminomethyl group by means of a dicarboxylic acid to a diamine have a pronounced antihypertensive effect, with both the extent of the lowering of blood pressure and the duration of the pharmacological effect being controlled via the diamine/dicarboxylic acid combination, structure-activity relations being derivable. Novel principles of action arise from the molecular structures of the introduced side chain, which differs greatly from conventional peptides.
The tested compounds show on intravenous and enteral (intraduodenal) administration of 0.1 to 5 mg/kg of body weight to anesthetized rats a dose-dependent and persistent, large hypotensive effect and show on isolated vessels a high selectivity on the &agr;
1
receptor.
The hypotensive effect of the compounds of the invention is not caused by an effect on the central nervous system.
Substances in therapeutic use, such as minoxidil and dihydroergocornine, are exceeded in their effect many times by the substances of the invention. The unwanted side effects frequently observed with lysergic acid derivatives can be avoided by very much lower active doses.
The aminoergoline derivatives of the invention have the general formula 1:
in which
R
5
=H, alkyl, aryl, acyl, CN;
R
6
=H, alkyl, halogen;
R
7
, R
8
=H or together a bond;
R
1
together with the two adjacent N atoms is the residue of a diamine,
R
4
together with the two adjacent carbonyl groups is the residue of a dicarboxylic acid,
R
2
is H, acyl and R
3
is H, or
R
2
and R
3
together are a divalent radical R
1
, and salts, in particular pharmaceutically usable salts, of these compounds.
R
1
and R
4
have the following meanings in particular:
a) R
1
and R
4
are, independently of one another, C
1
-C
10
-alkylene, branched or unbranched, which is optionally interrupted by O, S, NR
9
, arylene, heteroarylene, cycloalkylene, heterocycloalkylene and/or optionally substituted by R
10
,
R
9
=alkyl, benzyl, aryl, acyl,
R
10
=R
9
, also halogen, OH, SH, NO
2
, CN;
b) R
1
and R
4
are, independently of one another, C
1
-C
10
-alkylene, branched or unbranched, which comprises one or more isolated and conjugated double bonds and is optionally substituted by R
10
, and/or is optionally interrupted by O, S, NH, NR
9
, arylene, heteroarylene, cycloalkylene, heterocycloalkylene;
c) R
1
and R
4
are, independently of one another, cycloalkylene or heterocycloalkylene with 3-8 ring members or such cycles with, optionally, 1-2 bridges with in each case 1-3 chain members, which comprise C, O, NH, NR
9
, S, and arylene or heteroarylene with 5-7 ring members, which are optionally substituted by R
10
;
d) R
1
and R
4
are, independently of one another, two cycloalkylenes linked by R
11
and optionally interrupted in the ring by O, S, NH, NR
9
and/or optionally substituted by R
10
, O or S;
R
11
alkylene, O, S, S
2
, NR
9
.
R
4
can moreover have the following meanings:
a) R
4
is two arylene or heteroarylene radicals linked by R
12
;
R
12
=alkylene, Fe, O, S, S
2
, NR
9
b) R
4
is porphyrindiyl, optionally substituted one or more times by alkyl, unsaturated one or more times, having central atoms such as, for example, Zn, Ca, Mg and Fe, where a residual charge occurring after the complexation is neutralized by an anion of a pharmaceutically acceptable acid.
Salts of compounds of the formula 1 are, in particular, pharmaceutically acceptable salts and may have been produced by quaternization, either by reacting the product with conventional alkylating agents or by using building blocks which have already been quaternized. Salts of the invention are also those produced by protonation of compounds of the formula 1 by reaction with monobasic to tribasic acids with a maximum charge corresponding to the number of protonatable positions, in most cases the number of implemented nitrogen atoms. Acids which can be used in this connection are inorganic acids such as, for example, hydrohalic acids, sulfuric acid and phosphoric acid, and the amides thereof, or other pharmacologically suitable derivatives. The organic acids may be, for example, carboxylic, sulfo or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid.
Preference is given to the following compounds of the formula 1, in which
R
2
, R
3
, R
6
, R
7
, R
8
are H; R
5
is CH
3
,
R
1
and R
2
are, independently of one another, five- to eight-membered cycloalkyl or heterocycloalkyl, optionally unsaturated one or more times, or are aryl and heteroaryl consisting of one or two rings with a ring size of 5 to 7 members. Said cycles can optionally be substituted by halogen, nitro, amino or alkyl-substituted amino, alkoxy, OH, SH, O and S. The heterocycles mentioned can comprise one or more heteroatoms, in particular N, O or S. It is also possible for R
1
and R
4
to be C
2
-C
8
-alkylene which ca
Glusa Erika
Grabley Susanne
Haertl Albert
Thiericke Ralf
Wyrwa Ralf
Aulakh Charanjit S.
CyBio Screening GmbH
Reed Smith LLP
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