WO1992020678A1 - New berbane derivatives, pharmaceutical compositions containing these compounds and process for the preparation of same - Google Patents
New berbane derivatives, pharmaceutical compositions containing these compounds and process for the preparation of same Download PDFInfo
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- WO1992020678A1 WO1992020678A1 PCT/HU1991/000020 HU9100020W WO9220678A1 WO 1992020678 A1 WO1992020678 A1 WO 1992020678A1 HU 9100020 W HU9100020 W HU 9100020W WO 9220678 A1 WO9220678 A1 WO 9220678A1
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- formula
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
Definitions
- the invention relates to new berbane derivatives, to pharmaceutical compositions containing these compounds and a process for the preparation of same.
- the berbane analogues of the biologically active alcaloides of the Rauwolfia plant family exhibit in many cases much better pharmacological activity than the indol analogues.
- the ⁇ 2 -receptor blocking activity of the berbane analogues see e.g.
- the aim of our invention is to provide new compounds which are more selective than the known ⁇ 2 adrenoceptor antagonists and so may advantageously be used in the therapy.
- R 1 and R 2 together form a methylene dioxy group
- R 3 stands for a straight or branched alkyl having
- the new 13,14-didehydroberbane derivatives of formula (I) - wherein R 1 , R 2 and R 3 are the same as mentioned above - may be prepared by eliminating water from a racemic or optically active 14-hydroxy derivative of formula (II)
- R 1 , R 2 and R 3 are the same as mentioned above.
- the new compounds according to the invention exhibit ⁇ 2 -adrenoceptor antagonistic activity and so they may be used in the pharmaceutical compositions according to the invention as active ingredient
- compositions according to the invention may be prepared by any known method, e.g. by admixing the compounds of formula (I) or salts thereof optionally with known additives (e.g. diluents, solvents, lubricants, fillers, etc.) and converting the mixture obtained into a form suitable for administration, e.g. for parenteral, oral or rectal administration.
- additives e.g. diluents, solvents, lubricants, fillers, etc.
- pharmaceutical compositions e.g. tablets, pills, solutions, suspensions, powders, sprays may be prepared.
- Methyl-7,8-(methylene-dioxy)-13,14-didehydro- alloberbane-13-carboxylate (compound la) is one of the preferred compounds of the formula (I) and shows a very effective ⁇ 2 -adrenoceptor antagonistic activity in comparison with yohimbine. Moreover this compound does not possess any ⁇ -1 adrenoceptor blocking
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to new berbane derivatives, to the pharmaceutical compositions containing these compounds and to the preparation of same. In formula (I) R?1 and R2¿ together form a methylene dioxy group and R3 represents an alkyl group having 1-6 carbon atoms.
Description
New berbane derivatives, pharmaceutical
compositions containing these compounndss
and process for the preparation of same The invention relates to new berbane derivatives, to pharmaceutical compositions containing these compounds and a process for the preparation of same.
The berbane analogues of the biologically active alcaloides of the Rauwolfia plant family exhibit in many cases much better pharmacological activity than the indol analogues. The α2-receptor blocking activity of the berbane analogues (see e.g.
Vizi, E.S., Tόth, I., Somogyi, G.T., Szabό, L.,
Harsing, L.G. and Szantay, Cs.: J. of Med. Chem. 30,
1355 (1987)., EP No. 202 950) is particularly
interesting.
The aim of our invention is to provide new compounds which are more selective than the known α2 adrenoceptor antagonists and so may advantageously be used in the therapy.
It has been found that the racemic and optically active new 13,14-didehydroberbane derivatives of formula (I)
R1 and R2 together form a methylene dioxy group,
and
R3 stands for a straight or branched alkyl having
1-6 carbon atoms - obtained in the course of our experiments, meet this requirement.
According to the process of the invention the new 13,14-didehydroberbane derivatives of formula (I) - wherein R1, R2 and R3 are the same as mentioned above - may be prepared by eliminating water from a racemic or optically active 14-hydroxy derivative of formula (II)
- wherein R1, R2 and R3 are the same as mentioned above.
The elimination of the water may be carried out e.g. by the known Vilsmeier reaction (see L.Szabό,
I. Tόth, L. Tóke, Cs.Szántay; Liebigs Ann. Chem. 1977, 642), wherein thionyl chloride is used as eliminating agent in the presence of dimethyl formamide. The bases obtained are converted into salts by reacting them with physiologically acceptable acids (e.g. hydrochloric acid, sulfuric acid, citric acid, tartaric acid), as these compounds are more suitable for biological use.
The starting compounds of formula (II) are
disclosed in EP No. 202 950 and may be prepared
according to the methods described therein and in the references cited therein.
The new compounds according to the invention exhibit α2-adrenoceptor antagonistic activity and so they may be used in the pharmaceutical compositions according to the invention as active ingredient
optionally in combination with other known active compounds.
The pharmaceutical compositions according to the invention may be prepared by any known method, e.g. by admixing the compounds of formula (I) or salts thereof optionally with known additives (e.g. diluents, solvents, lubricants, fillers, etc.) and converting the mixture obtained into a form suitable for administration, e.g. for parenteral, oral or rectal administration. As pharmaceutical compositions e.g. tablets, pills, solutions, suspensions, powders, sprays may be prepared.
Methyl-7,8-(methylene-dioxy)-13,14-didehydro- alloberbane-13-carboxylate (compound la) is one of the preferred compounds of the formula (I) and shows a very effective α2-adrenoceptor antagonistic activity in comparison with yohimbine. Moreover this compound does not possess any α-1 adrenoceptor blocking
activity.
Table 1
Comparison of the α-2 and α-1 adrenoceptor antagonistic activity of yohimbine and
compound Ia
Compound pA2 α-2 pA2 α-2 Selectivity adrenoadrenopA2 α-1/pA2 α-2 ceptor+ ceptor++
Yohimbine 6.3+ 0.2 (3) K 5.9 (2) 2.4
Compound Ia 8.3+ 0.2 (6) K 4 (3) 22387
+ rat's vasa deferens stimulated with electricity,
xylazine antagonist;
++ rat's vasa deferens, phenylephrine agonist (see Vizi, E.S. et al.: J. Pharmacol. Exp. Ther., 1986, 238, 701-706, Vizi, E.S. et al.. J. Med. Chem., 1987, in press).
Mean + S.E.M.: in brackets the number of the
experiments is given; K: competitive The invention is illustrated in detail by the following Examples.
Example 1
Methyl-7,8-(methylene-dioxy)-13,14-didehydro-alloberbane-13-carboxylate (compound Ia), corresponding to compound of formula (I), wherein
R1, R2=OCH2O,
R3 =COOCH3
C1-H, C12-H, C17-H=α
To the solution of 2 g (5.56 mmoles) of methyl- 7,8-(methylene-dioxy)-14-hydroxy-alloberbane-13- carboxylate prepared with 20 ml of dimethyl formamide at 0°C 4 ml of thionyl chloride are added dissolved in 20 ml of DMF and allowed to stay at room temperature for 2 days. The mixture is thereafter poured onto
100 ml of ice-water, made alkaline with cone. NH4OH (to pH=9), the precipitate is filtered, dried and recrystallized from ether or methanol.
Yield: 1.8 g (94.8 %); m. p . (of the HCl salt) 187-189 °C
(MeOH) .
Analysis for C20H23NO4 (341.39):
Calculated: C 70.36 H 6.79 N 4.10
Found: C 70.31 H 6.78 N 4.05
MS m/Z%: 341 /79/, 340 /100/, 326 /79/, 310 /7/ , 300 /2.5
282 /12/, 254 /0.8/, 252 / 1/ , 240 /4/, 226 /7/ ,
216 /17/, 214 /20/, 202 /8/, 189 /83/, 176 /9/,
175 /21/, 174 /22/
NMR /CDCI3/: 7.00 /1H,m,C14-H/, 6.74, 6.53 /2H,s,C6-H,
C9-H/, 5.86 /2H,s,OCH2O/, 3.77 /3H,s, COOCH3/ IR /KBr/: 1720 /COOCH3/, 1650 cm-1 /c=c/.
Example 2
Hydrochloride salt of compound Ia
1 g (2.93 mmoles) of base Ia is admixed with
5 ml of methanol and acified with 30% mixture of
HCl/MeOH to pH=3, thereafter the precipitated
crystalline material is dried and washed with a
1:1 mixture of MeOH/ether.
Yield: 1.05 g (95 %); m.p. 187-189°C (MeOH).
Claims
1. Process for the preparation of recemic or optically active compounds of formula (1)
R1 and R2 together form a methylene dioxy group and
R3 stands for a straight or branched alkyl having
1-6 carbon atoms - characetrized by eliminating water from racemic or optically active compound of formula (II)
- wherein
R1, R2 and R3 are the same as mentioned above - optionally resolving the compound of formula (I) thus obtained or converting a compound of the formula (I) into salts or converting the salts into free base.
2. Process as claimed in Claim 1 characterized by using thionylchloride in the presence of dimethyl formamide for water elimination.
3. Racemic or optically active compounds of formula (I) and salts thereof wherein R1, R2 and R3 are the same as mentioned in Claim 1.
4. Methyl-7,8-(methylene-dioxy)-13,14-didehydro-alloberbane-13-carboxylate.
5. Methyl-7,8-(methylene-dioxy)-13,14-didehydro-alloberbane-13-carboxylate-hydrochloride.
6. Process for the preparation of pharmaceutical composition characetrized by admixing one or more compounds of formula (I) or salts thereof - wherein R1, R2, R3 are the same as mentioned in
Claim 1 - with one or more pharmaceutically acceptable additives and converting the mixture obtained into pharmaceutical composition suitable for
administration.
7. Pharmaceutical composition characterized by containing one or more compounds of formula (I), or salts thereof, wherein R1, R2 and R3 are the same as mentioned in Claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/HU1991/000020 WO1992020678A1 (en) | 1991-05-22 | 1991-05-22 | New berbane derivatives, pharmaceutical compositions containing these compounds and process for the preparation of same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/HU1991/000020 WO1992020678A1 (en) | 1991-05-22 | 1991-05-22 | New berbane derivatives, pharmaceutical compositions containing these compounds and process for the preparation of same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992020678A1 true WO1992020678A1 (en) | 1992-11-26 |
Family
ID=10980924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1991/000020 WO1992020678A1 (en) | 1991-05-22 | 1991-05-22 | New berbane derivatives, pharmaceutical compositions containing these compounds and process for the preparation of same |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1992020678A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0202950A2 (en) * | 1985-05-24 | 1986-11-26 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Berban derivatives and their preparation and pharmaceutical formulation |
-
1991
- 1991-05-22 WO PCT/HU1991/000020 patent/WO1992020678A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0202950A2 (en) * | 1985-05-24 | 1986-11-26 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Berban derivatives and their preparation and pharmaceutical formulation |
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