AU718075B2 - Intermediates for the preparation of pharmacologically active enantiomers of triazolone compounds - Google Patents
Intermediates for the preparation of pharmacologically active enantiomers of triazolone compounds Download PDFInfo
- Publication number
- AU718075B2 AU718075B2 AU69041/98A AU6904198A AU718075B2 AU 718075 B2 AU718075 B2 AU 718075B2 AU 69041/98 A AU69041/98 A AU 69041/98A AU 6904198 A AU6904198 A AU 6904198A AU 718075 B2 AU718075 B2 AU 718075B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- formula
- alk
- acid
- enantiomers
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Description
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): ANGELINI RICERCHE SPA SOCIETA' CONSORTILE *00 0a invention Title: INTERMEDIATES FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE ENANTIOMERS OF TRIAZOLONE
COMPOUNDS
The following statement is a full description of this invention, including the best method of performing it known to me/us: 1A This invention relates to intermediates for the preparation of pharmacologically active enantiomers of triazolone compounds as described in our copending application 70729/94 (689478), from which the present application is divided.
The present invention provides a method to cyclize a compound of formula -NH-CH -CH -NH 2 2 I (VI) CL YOOC-CH 15 Alk Shaving or configuration, to.yield a compound of formula SALk 0 CL HN\/
(V)
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 is obtained, after a brief heating, by alkalinization of the resultant solution.
The strong acid is preferably hydrochloric acid.
1B The present invention also includes an or (R) intermediate compound of formula (V) Alk 0 CL
HN(V)
where Alk is an alkyl having from 1 to 3 carbon atom.
As indicated in the abovementioned copending application, PCT/EP93/00080 describes a class of novel compounds of the general formula: 2 0
R
R' R" where only one of R, R" and 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 are endowed with a ph-armacologica profile similar to that of trazodone (I, R R' R" H) but also have some advantages such as, for exampLe, a reduced affinity for adrenergic receptors.
2 It has now surprisingly been found that both and (R) enantiomers of the compounds of formula where 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.
The abovementioned copending application provides and (R) enantiomers of the compounds of formula: ALk where Alk is an alkyL having from 1 to 3 carbon atoms, and their addition salts with physiologically acceptable acids.
Examples of suitable acids are hydrogen chloride, hydrogen bromide, phosphoric acid, suLfuric acid, Lactic acid, succinic 25 acid, acetic acid, tartaric acid, maLic acid, citric acid, benzoic acid, 2-naphthaenesufonic acid, adipic acid and pimelic acid.
ALthough both and enantiomers are more active than the corresponding racemates, enantiomers are more active than enantiomers. Hence, enantiomers are preferred.
As far as the meanings of ALk are concerned, methyL is preferred.
2A 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.
TABLE1 IComoound IA ANALGESIC ACTIVITY Form I ALk t PhenY Lgyinon~ED I Racemate CH 3 )12.50 3 I I CH 3 I 9.02 I I I 7.80 I 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 enantiomer is more active than enantiomer.
Since an interference with the adrenergic system is an index of undesirable effects, both the capability of binding to alpha 10 1 adrenergic receptors, as IC50 (Table 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.
S....Table 2 "20 Comoound IA I Affinity for alpha 1 I I Form I Alk I adrenerqic receotors_(IC I Racemate I CH 3 471 I I CH I 533 I I CH 3 981 _TabLe 3 I Comoound IA Alphalytic activity Form I ALk I2 2 Frm A I Racemate ICH I 7.70 0.7 I I CH 3 I 6.75 0.2 I S) ICH 3 5.40 0.7 (S 3 4 In Table 2 the lowest numerical value of the affinity for the alpha 1 adrenergic receptors IC 50 indicates the highest activity, whereas, in Table 3, the highest numerical value of the alphalytic activity pA 2 indicates the highest activity. 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 and enantiomers, are lower than those of racemate while the alphalytic activity of enantiomer is lower than that of enantiomer.
Thus, for the enantiomers and the racemate of formula (IA) the greater the analgesic activity the lower the undesired alphalytic activity.
15 The compounds of this invention can be prepared by fractional crystallization of the salts thereof with an optically active acid, and by stereospecific 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 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, the tartrate salt of the desired enantiomer is optionally converted to the corresponding free base, and the thus obtained free base is optionally 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 H;\Simeona\K~ep\70729 94.doc 15/01/98 5 for the stereospecific synthesis of enantiomers of formuLa (IA) and their addition salts with physioLogicaLLy acceptable acids, characterized in that a compound of the formula (III): N 'N (III)
O----SH
or an aLkaLi metaL salt thereof is reacted with a piperazine 10 compound of formula (II): V 2 (NI 2 3 wherein ALk has the above mentioned meaning, and X" is a Leaving group seLected from the group comprising chLorine, bromine and -O-SO -Z where Z is aLkyL or aryL, 2 and Compound (II) has the absoLute or configuration, in the presence of a suitabLe organic diluent or a mixture of organic diluents at a temperature of from 40 0 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 March, Advanced Organic Chemistry, 3rd ed., J. WiLey Sons, pages 364-365).
-6 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 0 C to 10 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, 15 t-butanol, s-butanol, isobutanol, pentanol and t-pentanol. A typical example of a preferred amide is dimethylformamide.
In turn, the stereospecific synthesis of the compounds of formula (II) can be performed by reacting a compound of formula Alk 20 .X'-CH-COOY
(VIII)
where ALk has the above mentioned meaning, X' is CH -S0 2 or halogen, and Y is an alkyL having from 1 to 3 carbon atoms, having the absolute or configuration, with the compound of formula
CL
-NH-CH -CH -NH (VII) 2 2 2 7 to yield a compound of formula S-NH-CH CH -NH CL YOOC-CH
(VI)
ALk where Y and ALk have the above described meaning, having absolute configuration when the Compound VIII has configuration and viceversa.
10 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 S 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 ALk 0 CL
(V)
having the same absolute configuration as Compound (VI).
The cycLization of Compound (VI) to Compound 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 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 8- Compound by alkalinization of the resuLtant soLution.
A typical example of a preferred strong acid is hydrochloric acid.
Compound 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.
S 10 Both during the cycLization step (VI V) and during aLL r 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 The possibibLe racemization, if any, is very smaLL.
For practical purposes the compounds of this invention may be S* 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, q 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 S. 10 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 15 (IA) preferably ranges from 0.1 to 10 mg/kg.
The pharmaceutical compositions of this invention can be *o oprepared according to conventional techniques known to the pharmaceutical chemist, which comprise admixing, granulating and compressing, when necessary, or variously mixing and 20 dissolving the ingredients, when appropriate to obtain the desired result.
The foLLowing examples are intended to illustrate this invention, EXAMPLE 1 A mixture of 12.5 g (0.032 moLes) of racemate R R' H; R" CH as a base, and 4.8 g (0.032 moles) of naturally occuring 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 10 and recrystaLLized from absolute ethyL alcohol untiL a constant melting point was obtained.
20 m.p. 151-152 0 C, aLphal 2 0 13.2 0.3 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 20 63-65 0 C (hexane), CaLphal 32.0 0.3 in absolute
D
ethyl aLcohoL).
10 HydrochLoride, m.p. 122-124 0 C (from ethyL aLcohoL, hygroscopic); SuLfate, m.p. 204-205 0
C;
MaLeate, m.p. 142-143 0
C.
base was recovered from the fiLtered soLution, from which 15 the saLt had been previousLy separated, and was dissoLved in absoLute ethyL aLcohoL.
An equimoLar amount of tartaric acid was then added to this soLution. The saLt was separated by cooLing.
This saLt has the same meLting point (151-152 0 C) as the (S) 20 20 saLt, CaLphal -13.2 0.3.
20 The corresponding base meLts at 63-65 0 C; EaLphal -32.0 0.3 in ethyL aLcohoL).
HydrochLoride, m.p. 122-124 0 C (hygroscopic).
EXAMPLE 2 a) (R)-1-(3-chLoroohen)-3methY ierazin-2-one (formuLa V, ALk CH A soLution of 18.4 g (0.108 moLes) of N-(3-chLorophenyl)ethanediamine 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 11 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 S -was dissolved in 10 parts (by weight) of 2N HCL and the resultant soLution was boiLed until the starting material ~disappeared (TLC).
L 20 The desired product, Ialpha D 50.0 was separated by
D
alkalinization with an alkaline carbonate (sodium or qpotassium).
b) (R)-2-E3-E4-(3-cloLro en (2tlrlirme Spro2yLj:1 24:triazoLr 4,3-a- pyridine -3(2H)-one (formula IA, ALk CH The title product was prepared, starting from the compound prepared in the previous step in a manner similar to.that described in the patent application PCT/EP93/00080.
Base, Ealpha3 -31.8 in ethyl alcoho).
D
Hydrochloride, m.p. 122-124 0 C (aLso in admixture with a sample prepared according to Example 1).
The (R)-1-(3-chLorophenyL)-3-methyLpiperazine intermediate 20 has a rotatory power [alphal +15.0 in ethyl alcohol).
D
EXAMPLE 3 3-4-(3-ch LoropheyL) thyl -i r L o 1 24 tri azo L4 3-aiip dine-3(2H)-one (formula IA, Alk CH The title product was prepared in a manner similar to that 12 described in Examp~e 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 0 C, [aLphal 2 32.0 0.3 in ethyL aLcohoL).
'*020
Claims (3)
1. A method to cyclize a compound of formula -NH-CH -CH -NH 2 2I (VI) CL YOOC-CH Alk where Y and alk, the same or different, are an.alkyl having from 1 to 3 carbon atoms, having or configuration, to.yield a compound of formula ALk 0 CL 25 having the same absolute configuration as Compound (VI), characterized in that ithe cyclization reaction is performed in the presence of an aqueous solution of a strong acid and that the desired Compound is obtained, after a brief heating, by alkalinization of the resultant solution.
2. A method according to claim 4, characterized in that the strong acid is hydrochloric acid. 14
3. An or intermediate compound of formula (V) AUk 0 CL (V) see* S 0 where Alk is an alkyl having from 1 to 3 carbon atom. Dated this 27th day of may 1998 ANGELINI RICERCHE SPA SOCIETA' CONSORTILE By their Patent Attorneys GRIFFITH HACK Fellows institute of Patent Attorneys of Australia
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT93MI001418A IT1268414B1 (en) | 1993-07-01 | 1993-07-01 | PHARMACOLOGICALLY ACTIVE ENANTIOMERS |
ITMI93A1418 | 1993-07-01 | ||
AU70729/94A AU689478B2 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers of triazolone compounds |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU70729/94A Division AU689478B2 (en) | 1993-07-01 | 1994-06-21 | Pharmacologically active enantiomers of triazolone compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
AU6904198A AU6904198A (en) | 1998-07-16 |
AU718075B2 true AU718075B2 (en) | 2000-04-06 |
Family
ID=25636391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU69041/98A Ceased AU718075B2 (en) | 1993-07-01 | 1998-05-27 | Intermediates for the preparation of pharmacologically active enantiomers of triazolone compounds |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU718075B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3350493A (en) * | 1992-01-17 | 1993-08-03 | Angelini Ricerche S.P.A. Societa Consortile | Alkyl derivatives of trazodone with cns activity |
-
1998
- 1998-05-27 AU AU69041/98A patent/AU718075B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3350493A (en) * | 1992-01-17 | 1993-08-03 | Angelini Ricerche S.P.A. Societa Consortile | Alkyl derivatives of trazodone with cns activity |
Also Published As
Publication number | Publication date |
---|---|
AU6904198A (en) | 1998-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE3700408A1 (en) | Indole derivatives, pharmaceutical preparations containing them and processes for their preparation | |
JPH0261465B2 (en) | ||
US4870095A (en) | 1H-pyrazole-1-alkanamides, antiarrhythmic compositions and use | |
US4797496A (en) | Process for the preparation of pyrrolidone derivatives | |
US5973150A (en) | Pharmacologically active enantiomers | |
AU718075B2 (en) | Intermediates for the preparation of pharmacologically active enantiomers of triazolone compounds | |
FI64145C (en) | FREQUENCY REFRIGERATION FOR 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES | |
IE64438B1 (en) | N, N'-bis(alkoxyalkyl)-pyridine-2, 4-dicarboxylic acid diamides preparation and their use | |
KR19990081970A (en) | 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine used as a drug acting on the central nervous system | |
EP0136736B1 (en) | 1-(4'-alkylthiophenyl)-2-amino-1,3-propanediol n-substituted derivatives | |
FI79297C (en) | Process for the preparation of pharmacologically active benzamide derivatives | |
FR2643373A1 (en) | NOVEL BISARYLALKENES DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
US3988371A (en) | Meta-[2-(benzylamino)-ethyl] benzoic acid amides | |
CH681300A5 (en) | ||
EP0001585A1 (en) | Piperazino-pyrrolobenzodiazepines, methods for their preparation and pharmaceutical compositions containing them | |
EP0079740B1 (en) | Anthraniloyloxyalkanoates | |
CZ292867B6 (en) | Cyclization process of aniline derivatives | |
KR800000901B1 (en) | Process for the preparation of phenyl alkylamines derivatives | |
EP2419431A1 (en) | Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof | |
FR2699533A1 (en) | N-2-piperazinyl 4-amino:benzamide derivs. having antiemetic and antipsychotic activity | |
DD297971A5 (en) | PROCESS FOR THE PREPARATION OF CHINAZOLINE DERIVATIVES | |
IE20000060A1 (en) | Novel Process for Producing AMPA Antagonist Compounds | |
EP2396334A1 (en) | N-[(2-azabicyclo[2.1.1]hex-1-yl]-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof | |
ZA200403560B (en) | Preparation of pharmaceutical salts of 4((Z)-(4-bromophenyl)(ethoxyimino)methyl)-1'-((2,4-dimethyl-1-oxido-3-pyridinyl)(carbonyl)-4'-methyl-1-4'bipiperidine as CCR5-antagonists for the treatment of AIDS and related HIV infections. | |
DE3542363A1 (en) | 1,4-Dihydropyridine derivatives, their preparation and pharmaceutical preparations containing them |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FGA | Letters patent sealed or granted (standard patent) |