WO1995001354A1 - Pharmacologically active enantiomers - Google Patents
Pharmacologically active enantiomers Download PDFInfo
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- WO1995001354A1 WO1995001354A1 PCT/EP1994/002061 EP9402061W WO9501354A1 WO 1995001354 A1 WO1995001354 A1 WO 1995001354A1 EP 9402061 W EP9402061 W EP 9402061W WO 9501354 A1 WO9501354 A1 WO 9501354A1
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- Prior art keywords
- compound
- formula
- acid
- alk
- physiologically acceptable
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Definitions
- This invention relates to pharmacologically active
- compositions containing them are provided.
- PCT/EP93/00080 describes a class of novel compounds of the general formula:
- R, R', R" and R"' is an alkyl having from 1 to 3 carbon atoms while the others are hydrogen.
- Alk is an alkyl having from 1 to 3 carbon atoms, and their addition salts with physiologically acceptable acids.
- Suitable acids are hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, lactic acid, succinic acid, acetic acid, tartaric acid, malic acid, citric acid, benzoic acid, 2-naphthalenesulfonic acid, adipic acid and pimelic acid.
- the preferred compound of this invention is the (S) enantiomer of formula (IA) wherein Alk is methyl.
- mice The analgesic activity of the compounds of this invention has been proved in mice by means of the phenylquinone test via subcutaneous route (Pharmacol. Exp. Ther., 125, pp 237-240, 1959). Thirty animals were treated with each product. The experimental results are reported in Table 1.
- Table 1 shows that a higher dose of racemic compound is needed to achieve the same analgesic action. This means that the racemic compound has less analgesic activity compared to the single enantiomers. Table 1 also shows that (S) enantiomer is more active than (R) enantiomer.
- the alphalytic activity was evaluated on an isolated organ (deferent of rat) according to the technique described in "Clinical and Experimental Pharmacology & Physiology", 6, 275-279, (1979).
- the compounds of this invention can be prepared by fractional crystallization of the salts thereof with an optically active acid, and by stereospecif ic synthesis.
- Suitable solvents are lower alcohols and water.
- Alk has the above mentioned meaning
- X" is a leaving group selected from the group comprising
- Compound (II) has the absolute (R) or (S) configuration, in the presence of a suitable organic diluent or a mixture of organic diluents at a temperature of from 40°C to the boiling temperature of the reaction mixture, and, when desired, the thus obtained enantiomer is salified with a physiologically acceptable acid.
- reaction essentially involves the alkalinization of a secondary amino group and may be carried out according to conventional techniques (J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, N.Y., pages 364-365).
- the compound of formula (III) is reacted in the form of an alkaline salt such as, for example, the sodium salt described by US-A-3.381.009.
- Typical meanings of Z are methyl, phenyl, tolyl and
- the reaction is preferably carried out by reacting the sodium salt of the compound of formula (III) with a compound of formula (II) in the presence of a suitable organic diluent or a mixture of organic diluents at a temperature of from 40°C to the boiling temperature of the reaction mixture.
- suitable organic diluents are: aromatic hydrocarbons, aliphatic alcohols, amides and mixtures thereof.
- Examples of preferred aromatic hydrocarbons are benzene, toluene and xylene.
- Examples of aliphatic alcohols are butanol, t-butanol, s-butanol, isobutanol, pentanol and t-pentanol.
- a typical example of a preferred amide is dimethylamide.
- stereospecific synthesis of the compounds of formula (II) can be performed by reacting a compound of formula where Alk has the above mentioned meaning,
- X' is CH 3 -O-SO -O- or halogen
- Y is an alkyl having from 1 to 3 carbon atoms
- reaction between Compound (VIII) and Compound (VII) to yield Compound (VI) is preferably carried out in the presence of an acid acceptor and a suitable solvent.
- Suitable acid acceptors are triethylamine and pyridine.
- Suitable solvents are the aromatic hydrocarbons such as toluene and xylene.
- a typical example of a preferred strong acid is hydrochloric acid.
- the compounds of this invention may be administered as they are but it will be preferred to administer them as pharmaceutical compositions.
- compositions are a further object of this invention and contain a therapeutical amount of at least one enantiomer of formula (IA) or of an addition salt thereof with a
- physiologically acceptable acid together with liquid or solid pharmaceutical carriers.
- compositions of this invention may be solid, such as tablets, sugar-coated pills, capsules, powders and controlled release forms, or semi-liquid, such as creams and ointments, or liquid, such as solutions, suspensions and emulsions.
- compositions of this invention may contain other suitable pharmaceutical additives, such as preservatives, stabilizers, emulsifiers, salts to regulate osmotic pressure, buffers, colouring and flavouring agents.
- suitable pharmaceutical additives such as preservatives, stabilizers, emulsifiers, salts to regulate osmotic pressure, buffers, colouring and flavouring agents.
- compositions of this invention may also contain other compatible active ingredients, whose contemporaneous administration is
- the effective amount of the enantiomer of formula (IA) to be administered can vary widely depending on various factors such as the particular therapy required, the pharmaceutical composition, the method of administration and the effectiveness of the specific enantiomer of this invention that is used. Nevertheless, the optimal effective amount can be chosen by simple routine procedures.
- the daily posology of the enantiomers of formula (IA) preferably ranges from 0.1 to 10 mg/kg.
- compositions of this invention can be prepared according to conventional techniques known to the pharmaceutical chemist, which comprise admixing, granulating and compressing, when necessary, or variously mixing and dissolving the ingredients, when appropriate to obtain the desired result.
- the solid separated by cooling was collected by filtration and recrystallized from absolute ethyl alcohol until a constant melting point was obtained.
- the corresponding base was obtained by suspension of the salt in water and alkalinization, under stirring, with powdered potassium carbonate.
- reaction mixture was washed with water and extracted with a solution of 1N hydrochloric acid.
- aqueous phase was alkalinized with powdered potassium carbonate and extracted with methylene chloride.
- the thus obtained base was purified by flash chromatography (silica gel, hexane-ethyl acetate 1:1).
- the title product was prepared, starting from the compound prepared in the previous step (a), in a manner similar to that described in the patent application PCT/EP93/00080.
Abstract
(S) or (R) enantiomer of a compound of formula (IA), where Alk is an alkyl having from 1 to 3 carbon atoms, and an acid addition salt thereof with a physiologically acceptable acid.
Description
"Pharmacologically active enantiomers."
* * * * * *
DESCRIPTION
This invention relates to pharmacologically active
enantiomers, their salts with physiologically acceptable acids, a method for their preparation and the pharmaceutical
compositions containing them.
PCT/EP93/00080 describes a class of novel compounds of the general formula:
where only one of R, R', R" and R"' is an alkyl having from 1 to 3 carbon atoms while the others are hydrogen.
The pharmacological data reported in the above mentioned application show that the compounds of formula (I) are endowed with a pharmacological profile similar to that of trazodone (I, R = R' = R" = R"' = H) but also have some advantages such as, for example, a reduced affinity for adrenergic receptors.
It has now surprisingly been found that both (S) and (R) enantiomers of the compounds of formula (I), where R, R', R"' are hydrogen and R" is an alkyl having from 1 to 3 carbon atoms, have an improved analgesic activity compared to their racemates.
This finding is even more surprising since both the
enantiomers have a lower alphalytic activity, and consequently less undesirable effects, compared to the corresponding racemates.
It is therefore a first object of this invention to provide (S) and (R) enantiomers of the compounds of formula:
Examples of suitable acids are hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, lactic acid, succinic acid, acetic acid, tartaric acid, malic acid, citric acid, benzoic acid, 2-naphthalenesulfonic acid, adipic acid and pimelic acid.
Although both (R) and (S) enantiomers are more active than the corresponding racemates, (S) enantiomers are more active than (R) enantiomers. Hence, (S) enantiomers are preferred.
As far as the meanings of Alk are concerned, methyl is preferred.
Thus, the preferred compound of this invention is the (S) enantiomer of formula (IA) wherein Alk is methyl.
The analgesic activity of the compounds of this invention has been proved in mice by means of the phenylquinone test via subcutaneous route (Pharmacol. Exp. Ther., 125, pp 237-240, 1959). Thirty animals were treated with each product. The experimental results are reported in Table 1.
TABLE 1
| Compound IA | ANALGESIC ACTIVITY | | form | Alk | Phenylguinone, ED50 (mg/kg) I | Racemate | CH3 | >12.50 |
| (R) | CH3 | 9.02 | | (S) | CH3 | 7.80 |
Table 1 shows that a higher dose of racemic compound is needed to achieve the same analgesic action. This means that the racemic compound has less analgesic activity compared to the single enantiomers. Table 1 also shows that (S) enantiomer is more active than (R) enantiomer.
Since an interference with the adrenergic system is an index of undesirable effects, both the capability of binding to alpha 1 adrenergic receptors, as IC (Table 2), and the alphalytic activity (Table 3) of the same compounds have been evaluated.
As far as the receptor binding test is concerned, reference is made to "Molecular Pharmacology", 20, 295-301, (1981).
In turn, the alphalytic activity was evaluated on an isolated organ (deferent of rat) according to the technique described in "Clinical and Experimental Pharmacology & Physiology", 6, 275-279, (1979).
The experimental results are reported in Tables 2 and 3.
Table 2
| Compound IA | Affinity for alpha 1 | | Form | Alk | adrenergic receptors (IC50) | | Racemate | CH3 | 471 | | (R) | CH3 | 533 | | (S) | CH3 | 981 |
Table 3
| Compound IA | Alphalytic activity | | Form | Alk | pA2 | | Racemate | CH3 | 7.70 ± 0.7 | | (R) | CH3 | 6.75 ± 0.2 | | (S) | CH3 | 5.40 ± 0.7 |
In Table 2 the affinity for the alpha 1 adrenergic receptors is as much high as low is the value of IC50, whereas, in Table 3, the alphalytic activity is as much high as high is the value of pA . Also the data of Tables 2 and 3 are therefore totally unexpected since they show that both the interference with the adrenergic receptor and the alphalytic activity, and thereby the undesirable effects of both (S) and (R) enantiomers, are lower than those of racemate while the alphalytic activity of (S) enantiomer is lower than that of (R) enantiomer.
Thus, for the enantiomers and the racemate of formula (IA) the greater the analgesic activity the lower the undesired alphalytic activity.
The compounds of this invention can be prepared by fractional crystallization of the salts thereof with an optically active acid, and by stereospecif ic synthesis.
In the first method the salts with tartaric acid proved to be particularly helpful.
It is therefore a second object of this invention to provide a method for the preparation of enantiomers of formula (IA), characterized in that a racemic compound of formula (IA) is salified with (R,R or S,S) tartaric acid, the pair of the thus obtained diastereoisomeric salts is separated by fractional crystallization from a suitable solvent, and, when desired, the thus obtained enantiomer is salified with a physiologically acceptable acid.
Examples of suitable solvents are lower alcohols and water.
The salts of the enantiomers of this invention with (R,R or S,S) tartaric acid are also novel and therefore are a third object of this invention.
It is a further object of this invention to provide a method
for the stereospecif ic synthesis of enantiomers of formula (IA) and their addition salts with physiologically acceptable acids, characterized in that a compound of the formula (III):
Alk has the above mentioned meaning, and
X" is a leaving group selected from the group comprising
chlorine, bromine and -O-SO2-Z where Z is alkyl or aryl, and Compound (II) has the absolute (R) or (S) configuration, in the presence of a suitable organic diluent or a mixture of organic diluents at a temperature of from 40°C to the boiling temperature of the reaction mixture, and, when desired, the thus obtained enantiomer is salified with a physiologically acceptable acid.
The above mentioned reaction essentially involves the alkalinization of a secondary amino group and may be carried out according to conventional techniques (J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, N.Y., pages 364-365).
Preferably, the compound of formula (III) is reacted in the form of an alkaline salt such as, for example, the sodium salt described by US-A-3.381.009.
Typical meanings of Z are methyl, phenyl, tolyl and
p-bromo-phenyl.
The reaction is preferably carried out by reacting the sodium salt of the compound of formula (III) with a compound of formula (II) in the presence of a suitable organic diluent or a mixture of organic diluents at a temperature of from 40°C to the boiling temperature of the reaction mixture. Examples of suitable organic diluents are: aromatic hydrocarbons, aliphatic alcohols, amides and mixtures thereof.
Examples of preferred aromatic hydrocarbons are benzene, toluene and xylene. Examples of aliphatic alcohols are butanol, t-butanol, s-butanol, isobutanol, pentanol and t-pentanol. A typical example of a preferred amide is dimethylamide.
In turn, the stereospecific synthesis of the compounds of formula (II) can be performed by reacting a compound of formula
where Alk has the above mentioned meaning,
X' is CH3-O-SO -O- or halogen, and
Y is an alkyl having from 1 to 3 carbon atoms,
having the absolute (S) or (R) configuration,
with the compound of formula
to yield a compound of formula
having (R) absolute configuration when the Compound VIII has
(S) configuration and viceversa.
The reaction between Compound (VIII) and Compound (VII) to yield Compound (VI) is preferably carried out in the presence of an acid acceptor and a suitable solvent.
Examples of suitable acid acceptors are triethylamine and pyridine.
Examples of suitable solvents are the aromatic hydrocarbons such as toluene and xylene.
Compound (VI) is then cyclized to yield a compound of formula
having the same absolute configuration as Compound (VI).
The cyclization of Compound (VI) to Compound (V) could not be performed with the technique described in PCT/EP93/00080 in connection with the corresponding racemic compounds since said technique caused complete racemization. After a number of unsuccessful attempts which led either to racemization or to recovery of unaltered Compound (VI), it was unexpectedly found that the desired cyclization could be very easily performed by dissolution of Compound (VI) in an aqueous solution of a strong acid and separation, after a brief heating, of the desired
Compound (V) by alkalinization of the resultant solution.
A typical example of a preferred strong acid is hydrochloric acid.
Compound (V) thus obtained is then reduced in a manner similar to that described for the reaction Scheme 3 in the above mentioned patent application PCT/EP93/00080.
The prepararation is then prosecuted in a manner similar to that described in the above mentioned patent application in relation to the reaction Scheme 2.
Both during the cyclization step (VI ╌> V) and during all the subsequent steps there is no inversion of the configuration and the thus obtained final compound of formula (IA) has the same absolute configuration as Compound (V). The possibible racemization, if any, is very small.
For practical purposes the compounds of this invention may be administered as they are but it will be preferred to administer them as pharmaceutical compositions.
These compositions are a further object of this invention and contain a therapeutical amount of at least one enantiomer of formula (IA) or of an addition salt thereof with a
physiologically acceptable acid, together with liquid or solid pharmaceutical carriers.
The pharmaceutical compositions of this invention may be solid, such as tablets, sugar-coated pills, capsules, powders and controlled release forms, or semi-liquid, such as creams and ointments, or liquid, such as solutions, suspensions and emulsions.
In addition to conventional carriers, the compositions of this invention may contain other suitable pharmaceutical additives, such as preservatives, stabilizers, emulsifiers,
salts to regulate osmotic pressure, buffers, colouring and flavouring agents.
If required for a particular therapy, the compositions of this invention may also contain other compatible active ingredients, whose contemporaneous administration is
therapeutically useful.
For therapeutical purposes the effective amount of the enantiomer of formula (IA) to be administered can vary widely depending on various factors such as the particular therapy required, the pharmaceutical composition, the method of administration and the effectiveness of the specific enantiomer of this invention that is used. Nevertheless, the optimal effective amount can be chosen by simple routine procedures. In general, the daily posology of the enantiomers of formula (IA) preferably ranges from 0.1 to 10 mg/kg.
The pharmaceutical compositions of this invention can be prepared according to conventional techniques known to the pharmaceutical chemist, which comprise admixing, granulating and compressing, when necessary, or variously mixing and dissolving the ingredients, when appropriate to obtain the desired result.
The following examples are intended to illustrate this invention without, however, limiting it in any way.
EXAMPLE 1
A mixture of 12.5 g (0.032 moles) of racemate (I, R = R' = R"' = H; R" = CH ), as a base, and 4.8 g (0.032 moles) of naturally occuring (R,R) tartaric acid in 125 ml of absolute ethyl alcohol, was briefly heated at almost boiling temperature until dissolution was complete.
The solid separated by cooling was collected by filtration
and recrystallized from absolute ethyl alcohol until a constant melting point was obtained.
tn.p. 151-152°C, [alpha]D 20 = + 13.2 ± 0.3 (1% in water).
The corresponding base was obtained by suspension of the salt in water and alkalinization, under stirring, with powdered potassium carbonate.
The residue of the extraction with dichloromethane melts at
63-65°C (hexane), [alpha]D 20 = + 32.0 + 0.3 (1% in absolute ethyl alcohol).
Hydrochloride, m.p. 122-124°C (from ethyl alcohol,
hygroscopic);
Sulfate, m.p. 204-205°C;
Maleate, m.p. 142-143°C.
(R) base was recovered from the filtered solution, from which the (S) (R,R) salt had been previously separated, and was dissolved in absolute ethyl alcohol.
An equimolar amount of (S,S) tartaric acid was then added to this solution. The (R) (S,S) salt was separated by cooling.
This salt has the same melting point (151-152°C) as the (S) (R,R) salt, [alpha]D 20 = -13.2 ± 0.3.
The corresponding base melts at 63-65°C; [alpha]D 20 = -32.0 ± 0.3 (1% in ethyl alcohol).
Hydrochloride, m.p. 122-124°C (hygroscopic).
EXAMPLE 2
a) (R)-1-(3-chlorophenyl)-3-methyl-piperazin-2-one
(formula V, Alk = CH )
A solution of 18.4 g (0.108 moles) of N-(3-chlorophenyl)-ethanediamine (J. Med. Chem., 9, 858-860 (1966)), 19.3 ml (0.119 moles) of (S)-methanesulfonyl-lactic acid ethyl ester and 22.8 ml (0.163 moles) of triethylamine in 200 ml of toluene
was boiled and refluxed overnight.
The reaction mixture was washed with water and extracted with a solution of 1N hydrochloric acid. The aqueous phase was alkalinized with powdered potassium carbonate and extracted with methylene chloride.
The thus obtained base was purified by flash chromatography (silica gel, hexane-ethyl acetate 1:1).
The oily residue obtained after evaporation of the solvent was dissolved in 10 parts (by weight) of 2N HCl and the resultant solution was boiled until the starting material disappeared (TLC) .
The desired product, [alpha]D 20 = + 50.0 was separated by alkalinization with an alkaline carbonate (sodium or
potassium).
b) (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]- propyl]-1,2,4-triazol[4,3-a]-piridin-3(2H)-one
(formula IA, Alk = CH )
The title product was prepared, starting from the compound prepared in the previous step (a), in a manner similar to that described in the patent application PCT/EP93/00080.
Base, [alpha]D 20 = -31.8 (1% in ethyl alcohol).
Hydrochloride, m.p. 122-124°C (also in admixture with a sample prepared according to Example 1).
The (R)-1-(3-chlorophenyl)-3-methylpiperazine intermediate (formula IV, Alk = CH3) has a rotatory power [alpha]D 20 =
+15.0 (1% in ethyl alcohol).
EXAMPLE 3
(R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]-propyl]- 1,2,4-triazol[4,3-a]-piridin-3(2H)-one (formula IA, Alk = CH ) The title product was prepared in a manner similar to that
described in Example 2 above except for the substitution of (S)-methanesulfonyl-lactic acid ethyl ester with an equimolar amount of (R)-2-bromo-propionic acid ethyl ester.
Base, m.p. 63-65°C, [alpha]D 20 = + 32.0 ± 0.3 (1% in ethyl alcohol).
Claims
1. An (S) or (R) enantiomer of a compound of formula:
2. (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]-propyl]-1,2,4-triazol[4,3-a3-piridin-3(2H)-one and the acid addition salts thereof with physiologically acceptable acids.
3. (S)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]-propyl]-1 4-triazol[4,3-a3-piridin-3(2H)-one and the acid addition salts thereofwith physiologically acceptable acids.
4. A method for preparing an enantiomer of formula (IA)
where Alk is an alkyl having from 1 to 3 carbon atoms, or an acid addition salt thereof with a physiologically acceptable acid,
characterized in that
(a) a racemic compound of formula (IA) is salified with (R,R or S,S) tartaric acid, (b) the pair of the thus obtained diastereoisomeric salts is separated by fractional crystallization from a suitable solvent, and, when desired,
(c) the thus obtained enantiomer is salified with a
physiologically acceptable acid.
5. A method according to claim 4, characterized in that the solvent used in step (b) is a lower alcohol or water.
6. (R)-2-[3-14-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]-propyl]-1,2,4-triazol[4,3-a]-piridin-3(2H)-one (S,S) tartrate.
7. (S)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl]-propyl]-1,2,4-triazol[4,3-a]-piridin-3(2H)-one (R,R) tartrate.
8. A method for preparing an enantiomer of formula (IA)
where Alk is an alkyl having from 1 to 3 carbon atoms, or an acid addition salt thereof with a physiologically acceptable acid,
characterized in that
a compound of the formula (III):
or an alkali metal salt thereof,
is reacted with a piperazine compound of formula (II) 
wherei n
Alk has the above mentioned meaning, and
X" is a leaving group selected from the group comprising chlorine, bromine and -0-SO -Z where Z is alkyl or aryl, and Compound (II) has absolute (R) or (S) configuration, in the presence of a suitable organic diluent or a mixture of organic diluents at a temperature of from 40°C to the boiling temperature of the reaction mixture, and, when desired, the thus obtained enantiomer is salified with a physiologically acceptable acid.
9. A method according to claim 8, characterized in that Z is methyl, phenyl, tolyl and p-bromo-phenyl.
10. A method according to claim 8 or 9, characterized in that the suitable organic diluent is an aromatic hydrocarbon, an aliphatic alcohol or an amide.
11. A method according to one or more of the claims from 8 to 10, characterized in that the aromatic hydrocarbon is benzene, toluene or xylene.
12. A method according to one or more of the claims from 8 to 11, characterized in that the aliphatic alcohol is butanol, t-butanol, s-butanol, isobutanol, pentanol and t-pentanol.
13. A method according to one or more of the claims from 8 to 10, characterized in that the amide is dimethylamide.
14. A method to cyclize a compound of formula
where Y and Alk, the same or different, are an alkyl having from 1 to 3 carbon atoms, having (R) or (S) configuration,
to yield a compound of formula 
having the same absolute configuration as Compound (VI), characterized in that
the cyclization reaction is performed in the presence of an aqueous solution of a strong acid and that the desired Compound (V) is obtained, after a brief heating, by alkalinization of the resultant solution.
15. A method according to claim 14, characterized in that the strong acid is hydrochloric acid.
16. An (S) or (R) intermediate compound of formula (V) 
where Alk is an alkyl having from 1 to 3 carbon atom.
Priority Applications (22)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019950705994A KR100306018B1 (en) | 1993-07-01 | 1994-06-21 | Enantiomers with pharmacological activity |
| RU96104371A RU2128180C1 (en) | 1993-07-01 | 1994-06-21 | (S) or (R) ENANTIOMERS, METHOD OF PREPARING THEREOF, AND INTERMEDIATE PRODUCT |
| SK1664-95A SK281060B6 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers, method for their preparation and intermediates of this method |
| CA002166470A CA2166470C (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers |
| BR9406996A BR9406996A (en) | 1993-07-01 | 1994-06-21 | Enanciomer process to prepare the same process to cyclize a compound and intermediate compound |
| UA96010331A UA53607C2 (en) | 1993-07-01 | 1994-06-21 | Physiologically active enantiomers, method and intermediate for their synthesis |
| HU9503876A HU221631B1 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active 1,2,4-triazo [4,3a] piridin enantiomers, process for producing them and piperazine-intermediates |
| GEAP19943025A GEP19991791B (en) | 1993-07-01 | 1994-06-21 | Pharmacologically Active Enantiomers and Process for its Production |
| PL94312419A PL181831B1 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers |
| US08/564,276 US5741907A (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers |
| SI9430110T SI0707587T1 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers |
| EP94919660A EP0707587B1 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers |
| DE69405999T DE69405999T2 (en) | 1993-07-01 | 1994-06-21 | PHARMACEUTICAL EFFECTIVE ENANTIOMERS |
| AU70729/94A AU689478B2 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers of triazolone compounds |
| JP07503250A JP3096065B2 (en) | 1993-07-01 | 1994-06-21 | Pharmaceutically active enantiomer |
| RO95-02315A RO116899B1 (en) | 1993-07-01 | 1994-06-21 | 1,2,4-triazol[4,3-a]-pyridinone derivatives and process for preparing the same |
| FI956334A FI111943B (en) | 1993-07-01 | 1995-12-29 | Analogous process for the preparation of a therapeutically useful enantiomeric compound which is (S) - or (R) -2- [3 [4- (3-chlorophenyl) -1- (2-alkyl) -piperazinyl) propyl] -1,2 , 4-triazolo [4,3-a] pyridin-3- (2H) -one, and intermediates |
| NO955345A NO305957B1 (en) | 1993-07-01 | 1995-12-29 | Pharmacologically active enantiomers |
| LVP-96-17A LV11546B (en) | 1993-07-01 | 1996-01-26 | Pharmacologically active enantiomers |
| BG100331A BG61815B1 (en) | 1993-07-01 | 1996-02-01 | Pharmacological active enantiomers |
| GR970403452T GR3025806T3 (en) | 1993-07-01 | 1997-12-30 | Pharmacologically active enantiomers |
| US09/076,845 US5973150A (en) | 1993-07-01 | 1998-05-13 | Pharmacologically active enantiomers |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI93A001418 | 1993-07-01 | ||
| IT93MI001418A IT1268414B1 (en) | 1993-07-01 | 1993-07-01 | PHARMACOLOGICALLY ACTIVE ENANTIOMERS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995001354A1 true WO1995001354A1 (en) | 1995-01-12 |
Family
ID=11366510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1994/002061 WO1995001354A1 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers |
Country Status (30)
| Country | Link |
|---|---|
| US (3) | US5741907A (en) |
| EP (1) | EP0707587B1 (en) |
| JP (1) | JP3096065B2 (en) |
| KR (1) | KR100306018B1 (en) |
| CN (3) | CN1046281C (en) |
| AT (1) | ATE158796T1 (en) |
| AU (1) | AU689478B2 (en) |
| BG (1) | BG61815B1 (en) |
| BR (1) | BR9406996A (en) |
| CA (1) | CA2166470C (en) |
| CZ (1) | CZ289526B6 (en) |
| DE (1) | DE69405999T2 (en) |
| DK (1) | DK0707587T3 (en) |
| ES (1) | ES2111309T3 (en) |
| FI (1) | FI111943B (en) |
| GE (1) | GEP19991791B (en) |
| GR (1) | GR3025806T3 (en) |
| HK (2) | HK1018777A1 (en) |
| HU (1) | HU221631B1 (en) |
| IT (1) | IT1268414B1 (en) |
| LV (1) | LV11546B (en) |
| NO (1) | NO305957B1 (en) |
| NZ (1) | NZ268014A (en) |
| PL (1) | PL181831B1 (en) |
| RO (2) | RO116899B1 (en) |
| RU (1) | RU2128180C1 (en) |
| SK (1) | SK281060B6 (en) |
| UA (1) | UA53607C2 (en) |
| WO (1) | WO1995001354A1 (en) |
| ZA (1) | ZA944570B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1268414B1 (en) * | 1993-07-01 | 1997-02-27 | Angelini Francesco Ist Ricerca | PHARMACOLOGICALLY ACTIVE ENANTIOMERS |
| JP2009018992A (en) * | 2007-07-10 | 2009-01-29 | Sumitomo Chemical Co Ltd | Manufacturing method of optically active mirtazapine |
| RU2706700C1 (en) | 2019-09-24 | 2019-11-20 | Общество с ограниченной ответственностью "Научно-производственная компания "СКиФФ" | Pharmaceutical composition for correcting behavior of cats and dogs in stress situations |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993014091A1 (en) * | 1992-01-17 | 1993-07-22 | Istituto Ricerca Francesco Angelini S.P.A. | Alkyl derivatives of trazodone with cns activity |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3365453A (en) * | 1963-10-28 | 1968-01-23 | Sterling Drug Inc | 1-phenyl-4-lower-alkyl-2-piperazinones |
| IT1066857B (en) * | 1965-12-15 | 1985-03-12 | Acraf | DERIVATIVES OF S IPIAZOLE 4.3 A PYRIDIN AND PROCESSES FOR THEIR PREPARATION |
| US5303837A (en) * | 1991-03-05 | 1994-04-19 | Portola Packaging, Inc. | One-piece fitment and plug with tamper-evident band |
| US5543563A (en) * | 1992-01-17 | 1996-08-06 | Istituto Ricerca Francesco Angelini S.P.A. | Alkyl derivatives of trazodone with CNS activity |
| IT1268414B1 (en) * | 1993-07-01 | 1997-02-27 | Angelini Francesco Ist Ricerca | PHARMACOLOGICALLY ACTIVE ENANTIOMERS |
| US5399765A (en) * | 1994-05-23 | 1995-03-21 | Sepracor, Inc. | Enantioselective preparation of optically pure albuterol |
-
1993
- 1993-07-01 IT IT93MI001418A patent/IT1268414B1/en active IP Right Grant
-
1994
- 1994-06-21 RO RO95-02315A patent/RO116899B1/en unknown
- 1994-06-21 WO PCT/EP1994/002061 patent/WO1995001354A1/en active IP Right Grant
- 1994-06-21 CN CN94193226A patent/CN1046281C/en not_active Expired - Fee Related
- 1994-06-21 CA CA002166470A patent/CA2166470C/en not_active Expired - Fee Related
- 1994-06-21 DE DE69405999T patent/DE69405999T2/en not_active Expired - Fee Related
- 1994-06-21 RU RU96104371A patent/RU2128180C1/en not_active IP Right Cessation
- 1994-06-21 AU AU70729/94A patent/AU689478B2/en not_active Ceased
- 1994-06-21 AT AT94919660T patent/ATE158796T1/en not_active IP Right Cessation
- 1994-06-21 ES ES94919660T patent/ES2111309T3/en not_active Expired - Lifetime
- 1994-06-21 SK SK1664-95A patent/SK281060B6/en not_active IP Right Cessation
- 1994-06-21 DK DK94919660.4T patent/DK0707587T3/en active
- 1994-06-21 PL PL94312419A patent/PL181831B1/en not_active IP Right Cessation
- 1994-06-21 HU HU9503876A patent/HU221631B1/en not_active IP Right Cessation
- 1994-06-21 BR BR9406996A patent/BR9406996A/en not_active Application Discontinuation
- 1994-06-21 JP JP07503250A patent/JP3096065B2/en not_active Expired - Fee Related
- 1994-06-21 RO ROA200100015A patent/RO121031B1/en unknown
- 1994-06-21 US US08/564,276 patent/US5741907A/en not_active Expired - Fee Related
- 1994-06-21 NZ NZ268014A patent/NZ268014A/en not_active IP Right Cessation
- 1994-06-21 CZ CZ19953485A patent/CZ289526B6/en not_active IP Right Cessation
- 1994-06-21 KR KR1019950705994A patent/KR100306018B1/en not_active IP Right Cessation
- 1994-06-21 EP EP94919660A patent/EP0707587B1/en not_active Expired - Lifetime
- 1994-06-21 UA UA96010331A patent/UA53607C2/en unknown
- 1994-06-21 GE GEAP19943025A patent/GEP19991791B/en unknown
- 1994-06-24 ZA ZA944570A patent/ZA944570B/en unknown
-
1995
- 1995-12-29 NO NO955345A patent/NO305957B1/en unknown
- 1995-12-29 FI FI956334A patent/FI111943B/en active
-
1996
- 1996-01-26 LV LVP-96-17A patent/LV11546B/en unknown
- 1996-02-01 BG BG100331A patent/BG61815B1/en unknown
-
1997
- 1997-12-22 US US08/995,988 patent/US5817815A/en not_active Expired - Fee Related
- 1997-12-30 GR GR970403452T patent/GR3025806T3/en unknown
-
1998
- 1998-05-13 US US09/076,845 patent/US5973150A/en not_active Expired - Fee Related
- 1998-07-29 CN CNB98116661XA patent/CN1136201C/en not_active Expired - Fee Related
- 1998-07-29 CN CNB981166601A patent/CN1136200C/en not_active Expired - Fee Related
-
1999
- 1999-09-02 HK HK99103792A patent/HK1018777A1/en not_active IP Right Cessation
- 1999-09-02 HK HK99103799A patent/HK1018781A1/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993014091A1 (en) * | 1992-01-17 | 1993-07-22 | Istituto Ricerca Francesco Angelini S.P.A. | Alkyl derivatives of trazodone with cns activity |
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