IE912979A1 - Imidazoline derivatives - Google Patents
Imidazoline derivativesInfo
- Publication number
- IE912979A1 IE912979A1 IE297991A IE297991A IE912979A1 IE 912979 A1 IE912979 A1 IE 912979A1 IE 297991 A IE297991 A IE 297991A IE 297991 A IE297991 A IE 297991A IE 912979 A1 IE912979 A1 IE 912979A1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- enantiomer
- formula
- salt
- efaroxan
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The substantially pure (-) enantiomers of 2-[2-(2-alkyl-2,3-dihydrobenzofuranyl)]-2-imidazolines of formula (1), wherein R is hydrogen or methyl, their non-toxic salts, processes for their preparation and pharmaceutical compositions thereof. Also described is a method of treating diabetes.
Description
- 1ftIMIDAZOLINE DERIVATIVES
This invention relates to imidazoline derivatives, their salts, process for their preparation and pharmaceutical compositions thereof.
In our European patent specification No 0071368 we describe and claim dihydrobenzofurany1 imidazolines of the formula
2 wherein R is hydrogen or alkyl 0^ gj R is hydrogen, methyl, chloro, bromo or fluoro; R^ is hydrogen, methyl, hydroxy, methoxy, fluoro, chloro or bromo; and their non-toxic salts. The compounds of Formula A contain an asymmetric carbon atom and the invention embraces both the racemic mixtures and the optically active enantiomers. All the compounds exemplified were in the form of the racemates.
The compounds of Formula A possessed c^-adrenoreceptor antagonist activity and by virtue of such activity had potential utility for the treatment of those conditions in patients in which activity at the a^-adrenoreceptors was implicated such as endogenous depression, cardiac failure, diabetes, obesity, migraine etc.
Our subsequent investigations of the compounds of
Formula A led to the identification of 2-[2-(2-ethy1-2,3Ί dihydrobenzofuranyl)]-2-imidazoline (in Formula A R =
- 2 2 3 ethyl, R = R = hydrogen; INN efaroxan). Efaroxan, as the racemate, has been shown to be a particularly potent and selective aj-adrenoreceptor antagonist and based on those properties was identified as a potential antidiabetic drug.
We have now extended our investigations of the compounds of Formula A and have found that efaroxan and the analogous novel isopropyl compound (in Formula A R = 2 3 i-propyl, R = R = hydrogen) are pharmacologically 1 different from the analogous compounds where R is hydrogen, 10 n-propyl or longer chain alkyl. Furthermore we have now resolved efaroxan and its isopropyl analogue into their optically active enantiomers and have found that the (-) enantiomers have a most unexpected pharmacological profile.
According to this invention there is provided the (-) enantiomer of a compound of Formula 1
wherein R is hydrogen or methyl, in substantially pure form, and its non-toxic salts.
By (-) enantiomer of a compound of Formula 1 in 25 substantially pure form we mean that the amount of the ( + ) enantiomer present does not exceed 5$ and preferably does not exceed 2%.
Examples of non-toxic salts are those with inorganic salts such as hydrochloric acid, sulphuric or phosphoric acid; or organic acids such as acetic, propionic, malonic, succinic, fumaric, tartaric or citric acid. A preferred salt is the hydrochloride.
The invention also includes pharmaceutical compositions comprising the (-) enantiomer of a compound of Formula 1 in substantially pure form or a non-toxic salt thereof, together with a pharmaceutically acceptable diluent or carrier .
The literature clearly points to the relationship between antagonism at o^-adrenoreceptors and stimulation of
insulin secretion (Robertson R P and Porte D, Diabetes, 1973, 22,1; Efendic S, Cerasi E and Luft R, Acta Endocrinologies, 1973, 74, 542-547; Linde J and Deckert T,
Horm Fletab Res 1 973, 5, 391 -395). In particular the antidiabetic effects of Flidaglizole (DG 5128) have been attributed to c^-antagonism (Kameda Kui-ya, Shin-etsu Ono, Isao Koyama and Yasushi Abiko, Acta Endocrinologica 1982,
99, 410-415).
Although the secretion of insulin from pancreatic islets in response to glucose stimulation is the result of a complex sequence of events, changes in potassium permeability are of major importance. Thus increased potassium permeability (potassium channel opening) reduces 25 insulin secretion whereas the converse is true with potassium channel blockade. A potassium channel permeability number of drugs affect and the antidiabetic sulphonylureas function as potassium channel blockers.
In
- 4 contrast the vasodilator diazoxide, which can induce a diabetic state, increases potassium channel permeability and therefore reduces insulin secretion.
The mechanism by which c^-antagonists stimulate insulin secretion has been related to their effects on K+ channels in pancreatic islet cells. Thus the reduction of !< + channel permeability by efaroxan was shown to occur over the same concentration range as its blockade of a^-adrenoreceptors (Sehlin J, Doxey J C and Lindstrom P,
Diabetologia, 1987, 30, 7, 580A No 503). The opposite effect was shown by UK 14304 a selective a^-agonist.
These observations were confirmed in the mouse vas deferens by the work of Zimanyi I, Folly G and Vizi E S (j. Neuroscience Res, 1988, 20, 102-108) who concluded that stimulation of o^-adrenoreceptors (by a^-agonists) leads to enhanced K+ permeability.
These results clearly indicate that there is a direct relationship between -adrenoreceptors and changes in K+ channel permeability in both islet and non-islet tissues.
Chan S L F and Morgan N G, (Eur J Pharmac, 1 990, 1 76,
97-101) recently concluded that the ability of efaroxan to stimulate insulin secretion from isolated rat pancreatic islets could not be attributed to interaction of efaroxan with '’classical a^-adrenoreceptors since the effect was not reproduced by the related c^-antagonist idazoxan at the same concentration. However, very high concentrations of efaroxan were required to achieve the effect and since idazoxan is 3-5 time less potent than efaroxan an active
- 5 concentration level for idazoxan may not have been reached. Chan and Morgan also showed that efaroxan had a greater effect than idazoxan in reversing the inhibitory effects of diazoxide on glucose-induced insulin release, though again very high concentrations of efaroxan were required.
It has now been shown that the a^-adrenoreceptor blocking effects of racemic 3 is between 300 and 5000.
Table 1
ENANTIOMER SEPARATION AT NON-ISLET ALPHA 2-ADRENORECEPTORS
RACEMATE ( + ) (-) (+)/(-) RATIO IN VITRO Rat vas deferens pA2 8.9 8.9 5.2 5,011 * IN VIVO 20 Rat vas deferens DR2 umoles/Kg IV 0.05 0.02 12.7 635** RADIOLIGAND BINDING Rat cerebral cortex K1 nM 1 .3 0.88 3,871 4,398**
* Determined by taking anti-logarithum of pA2(+) - pA2(-) ie 3.7 ** Potency ratio by dividing reciprocal of (+) by reciprocal of (-)
1_ ~ _1_ = 12.7 ie
635
0.02
12.7
0.02
- 6 All three methods indicate a good separation of activity.
Details of the tests are as follows:
. The in vitro prejunctional -adrenoreceptor antagonist potencies (pAj values) were determined in the prostate section of the rat vas deferens using previously described methodology (Doxey et al, Br J Pharmac, 1984, 33, 713).
The a^-adrenoreceptor agonist employed in these studies was p-aminoclonidine.
2. The in vivo prejunctional -adrenoreceptor antagonist 10 potencies were determined in the vas deferens of pithed rats using a previously described method (Welbourn et al, J Med Chem, 1986, 29, 2000). Antagonist potencies were determined as the dose (μ moles/Kg, iv) required to produce a 2-fold shift (DR2) of the dose-response curve to UK-14304 on the twitch response of the vas deferens.
3. The radioligand binding affinities (K1 , nM) were determined from their ability to displace the saturable binding of [3H] idazoxan from ac*renoreceptor sites prepared from rat cerebral cortical membranes (Welbourn et al, J Med Chem, 1986, 29, 2000).
Other than in its relationship to a^-adrenoreceptor antagonism the suggestion has never been made that inhibition of K+ channel permeabiltiy is a stereospecific phenomenon. Indeed the very high concentration of efaroxan required to inhibit diazoxide's effect on pancreatic islet cells (Chan and Morgan 1990) suggests a non-specific effect.
We have now found unexpectedly that the inhibitory effect of efaroxan on K+ channel permeability (and hence its
- 7 IE 912979
ability to stimulate insulin secretion) resides in a single enantiomer (-), which is not the active a?-antagonist enantiomer. The data as shown in Figs 1 to 3 were determined as follows: Fiqure 1 Groups of isolated rat islets were incubated with 20mM
glucose, ΙμΜ UK 14304 and increasing concentrations of the (+) and (-) enantiomers of efaroxan. After incubation for 60 minutes at 37°C, samples of medium were removed and 10 assayed for insulin. Data are mean values ± SEM for 10-18 observations.
Figure 2
Groups of isolated rat islets were incubated with 20mM glucose, 250μΜ diazoxide and increasing concentrations of 15 the (+) and (-) enantiomers of efaroxan. After incubation for 60 minutes at 37 °C, samples of medium were removed and assayed for insulin. Data are mean values ± SEM for 10 —1Θ observations.
Figure 3 20 Groups of isolated rat islets were incubated with 8mM glucose in the presence of increasing concentrations of the (+) and (-) isomers of efaroxan. (Procedure then similar to that used in Figures 2 and 3),
In Fig 1 insulin secretion stimulated by 20mM glucose 25 is inhibited by the a^-agonist UK14304 (ΙμΜ). This inhibitory effect is reversed in a dose-related manner by ( + ) but not (-) efaroxan. This confirms that the antagonist activity resides in the (+) enantiomer in
- 8 pancreatic islets as well as in non-islet cells. Fig 2 shows that insulin secretion stimulated by 20mM glucose can also be inhibited by diazoxide, a known K+ channel opening agent, and this effect is reversed by (-) but not (+) efaroxan. Thus the K+ channel effect of efaroxan on the pancreatic islets is due to the (-) enantiomer. Fig 3 shows that the (-) enantiomer potentiates insulin secretion at a threshold glucose concentration, an effect which is not shared by the (+) enantiomer. This confirms that the iO dominant insulin secretion effect of efaroxan is controlled by K+ channel permeability changes brought about by the (-) enantiomer .
The -adrenoreceptor antagonist data and the K+ channel data for various racemic compounds of Formula A in 2 3
. which (R =R =hydrogen) are shown in Table 2. The ^-potency is expressed in terms of the potency of the compound relative to idazoxan in the rat vas deferens (in vitro) test. The K+ channel data is in terms of percentage reversal of the reduction of 20mM glucose stimulated insulin secretion by diazoxide (250μΜ) by ΙΟΟμΜ of test substance.
TABLE 2 R1 c^-potency (relative to idazoxan) K + % H 1 .7 0 ethyl 1 .8 1 00 i-propyl 0.06 89 n-propyl 1.9 0 n-pentyl 0.44 2
- 9 Results in Table 2 further emphasise the unexpectedness and unpredictability cf the results with the compounds of this invention - they also stress the point that the K + channel effects are totally independent of any a^-activity 5 that the compounds possess (ie there is in fact no relationship between c^-adrenoreceptors and changes in K + channel permeability within the compounds). Compounds in which R =H, ethyl, n-propyl and n-pentyl (racemates) all possess appreciable antagonist activity; with the exception of the latter they are equipotent being approximately twice as potent as idazoxan. Only efaroxan (R =ethyl) however possesses the K channel inhibitory 1 properties. In contrast the compound where R =i-propyl has markedly reduced c^-antagonist activity yet is approximately equieffective as efaroxan in inhibiting K + channels.
Subsequent studies with the ( + ) and (-) enantiomers of the isopropyl analogue of efaroxan gave further unexpected results which emphasize the unique action of the (-) isomer of efaroxan on the K+ channel. Thus in a series of 20 experiments carried out in an identical fashion to those on the efaroxan enantiomers and as shown in Figs 4 to 6, a similar and not unexpected difference in a2_adrenorecePt°r potency of the two isopropyl enantiomers was determined (Fig 4). The (+) enantiomer was shown to substantially reverse 25 the inhibition of insulin secretion brought about by the a^agonist UK 14304 whereas the (-) enantiomer was relatively ineffective (Fig 4). This is fully in agreement with other studies which have confirmed that the a2ar|tagonist activity
- 10 of the isopropyl analogue resides in the (+) enantiomer.
Surprisingly however, and in contrast to the situation with the efaroxan enantiomers, both the (+) and (-) enantiomers of the ispropyl analogue were capable of 5 reversing the inhibition of insulin secretion brought about by the K+ channel activator diazoxide (Fig 5). As mentioned earlier with respect to efaroxan this activity was stereospecifically confined to the (-) enantiomer of efaroxan (Fig 2). Furthermore, both of the isopropyl 10 enantiomers of the isopropyl were able to directly stimulate insulin secretion (Fig 6) an activity which was largely confined in the case of efaroxan to the (-) enantiomer (Fig 3) .
It has always been recognised that the ability of 1-5 efaroxan to stimulate insulin secretion through an o^-adrenoreceptor mechanism could be compromised by its actions at non-islet (^-adrenoreceptors.
direct effect on islet a^-adrenoreceptors.
In particular effects on sympathetic neurones would tend to increase circulating catecholamines and this could counteract any Furthermore , increased plasma catecholamines would also increase blood pressure in a group of patients which is prone to hypertensive disease. These limitations are not apparent in the (-) enantiomer of either efaroxan or of its isopropyl 25 analogue which influence insulin secretion directly by an action on potassium channels and which have a very low affinity for «2ac*renoreceP^ors ·
The invention also includes the use of the (-)
- 11 enantiomer of a compound of Formula 1 or a non-toxic salt thereof as a potassium channel blocking agent in the treatment of diabetes. The invention further includes a method of treating diabetes which comprises administering to 5 humans an effective potassium channel blocking amount of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof.
The invention further includes the use of the (-) enantiomer of a compound of Formula 1 or a non-toxic salt thereof in the preparation of a pharmaceutical composition as a potassium blocking agent in the treatment of diabetes without producing any significant effect of an (^-adrenoreceptor.
The (-) enantiomer of efaroxan may be prepared from efaroxan (in base form) by standard methods for preparing optically active enantiomers from racemic mixtures. Thus efaroxan is treated in solution with a (-) optically active acid such as (-)-dibenzoyl-L-tartaric acid, the resultant (-) salt is separated and recrystallized until optical purity is obtained and the (-) enantiomer of efaroxan is obtained following addition of a base such as potassium carbonate. The (-) enantiomer of the compound of Formula 1 in which R is methyl may be prepared in like manner from the racemate prepared by the base catalysed alkylation of dihydrobenzofuran-2-carboxylic acid with 2-iodopropane with the resultant 2-substituted acid being converted to the
2-imidazoline using standard methods.
The examples illustrate the preparation of the (-) and
- 12 (+) enantiomers of efaroxan and of the (-) and (+) enantiomers of its isopropyl analogue. The optical rotations were measured on a Perkin Elmer 141 polarimeter.
EXAMPLE 1 5 Efaroxan (-) Enantiomer
The free base of efaroxan (S.Og) was dissolved in hot acetone (180ml) and added to a solution of (-)-dibenzoyl-Ltartaric acid (l0.44g) in hot acetone (180ml). The cloudy solution was allowed to cool to room temperature and the resulting white solid was filtered off, washed with diethyl ether and dried to give (-) efaroxan dibenzoyl tartrate salt yield 14.1g, optical rotation [α]^=-82.07°(c=1.00 methanol).
The salt (13.8g) was recrystallized from methanol/ diethyl ether to give a white solid: yield 4.2g, optical rotation [a]D=-125.20(c=1.03, methanol); 4.0g of the salt was recrystallized a second time from methanol/diethy1 ether to give a sample whose rotation failed to increase on further crystillization; yield 3.2g; optical rotation [a]q=-128.10(c=1.03, methanol).
0.3g of the purified salt was stirred at room temperature with a solution of t^CO^^g in 10ml b^O) and the resulting solution was extracted with dichloromethane. The organic layer was dried and evaporated to give the (-) enantiomer of efaroxan as a white solid; yield 0.09g, optical rotation [ α]θ = -53.8°(c = 1.01 , methanol), m.pt. HCl salt 258-261°C.
EXAMPLE 2
Efaroxan (+) Enantiomer
-13The free base of efaroxan (5.0g) was dissolved in hot acetone (180ml) and added to a solution of (+)-dibenzoyl-D-
tartaric acid (8.7g) in hot acetone (180ml). The cloudy solution was allowed to cool to room temperature and the 5 resulting white solid was filtered off, washed with diethyl
ether and dried to give ( + ) efaroxan dibenzoyltartrate salt yield 8.4g, optical rotation [a]^=+90·940(c=1.01 methanol).
The salt (8.2g) was recrystallized from methanol/ diethyl ether to give an off-white solid: yield 4.3g, optical rotation [o]q=+116.9°(c=1.05, methanol); 4.0g of the salt was recrystallized a second time from methanol/ diethyl ether to give a sample whose rotation failed to increase on further crystallization: yield 1.1g; optical
rotation [a]^=+118.70(c=1.03, methanol). stirred at room 0.3g of the purified salt were temperature with a solution of K^CQ^i^g in 10ml «□) and z the resulting solution was extracted with dichloromethane. The organic layer was dried and evaporated to give the ( + )
enantiomer of efaroxan as a white solid; yield 0.09g, 20 optical rotation [a]^=+52.8°(c=1.00, methanol).
EXAMPLE 3 (-)-2-[2-(2-Isopropyl-2>3-dihydrobenzofuranyl)]-2imidazoline
The free base of 2-[2-(2-isopropyl-2,3-dihydrobenzo25 furanyl)]-2-imidazoline (4g) was dissolved in hot acetone (110ml) and added with stirring to a solution of (-)dibenzoyl-L-tartaric acid (6.54g) in hot acetone (85ml).
The stirred solution was allowed to cool, stirred for 2
- 14 hours at room temperature, and the resulting white solid was removed by filtration and dried to give (-)-2-[2-(2-isopropyl-2, 3-dihydrobenzofurany1)]-2-imidazoline dibenzoyltartrate salt: yield 4.97g; optical rotation =
-106.6°(c = 1.00, methanol).
The salt (4.Sg) was recrystallised from methanol/ diethyl ether to give a white solid: yield 3.4g; optical rotation = -116.1° (c = 1,methanol). 3.25g of the salt was recrystallised a second time from methanol/diethy1 ether to give a sample whose rotation failed to increase on further crystallisation: yield 2.32g; optical rotation [
1.95g of the purified salt was partitioned between dichloromethane and 10$ aqueous sodium carbonate solution, and the organic layer was washed with further 10$ sodium carbonate solution. The organic layer was washed with water, dried and evaporated to give (-)-2-[2-(2-isopropyl-2,
3-dihydrobenzofuranyl)]-2-imidazoline as a white solid: yield 0.75g; optical rotation [= -29.4° (c = 1, methanol), m p HCl salt 277° (dec).
EXAMPLE 4 (+)-2-[2-(2-Isopropyl-2,3-dihydrobenzofuranyl)]-2imidazoline
The mother liquors from the crystallisations of Example
3 (1 χ acetone, 2 x methanol/diethy1 ether) were combined and the solvents removed in vacuo). The residue was partitioned between dichloromethane and 5$ aqueous sodium carbonate solution, and the aqueous layer extracted with
- 15 further dichloromethane. The organic phases were combined and washed successively with further sodium carbonate solution, water and saturated sodium chloride solution.
The solution was dried and evaporated to afford a residue 5 enriched in (+)-2-[2-(2-isopropy1-2,3-dihydrobenzofurany1) ] 2- imidazoline (2.95g).
A portion of this material (2.85g) was dissolved in hot acetone (60ml) and added to a stirred solution of ( + )dibenzoyl-D-tartaric acid (4.65g) in hot acetone (60ml),
The stirred solution was allowed to cool, stirred for 3 hours at room temperature, and the resulting white solid was removed by filtration and dried to give (+)-2-(2-(2isopropyl-2,3-dihydrobenzofuranyl)]-2-imidazoline dibenzoyltartrate salt: yield 4.82g; optical rotation (a]D = +112.8° (c = 1, methanol).
The salt (4.6g) was recrystallised from methanol/ diethyl ether to give a white solid: yield 3.32g; optical 3.1g of the salt was recrystallised a second time from methanol/diethy1 20 ether to give a sample whose rotation failed to increase on further crystallisation: yield 2.75g; optical rotation [a]g = +121.4° (c = 1, methanol).
1.5g of the purified salt was partitioned between dichloromethane and 10$ aqueous sodium carbonate solution, and the organic layer was washed with further sodium carbonate solution. The organic layer was washed with water, dried and evaporated to give (+)-2-(2-(2-isopropyl-2,
3- dihydrobenzofuranyl)]-2-imidazoline as a white solid:
rotation [ a ] g = +120.8° (c = 1, methanol).
- 16 yield 0.57g; optical rotation [ a ] D = +29.7° (c = 1, methanol), m p HCl salt 274° (dec).
The pharmaceutical compositions may be in a form suitable for oral or parenteral administration. Such oral compositions may be in the form of capsules, tablets, granules or liquid preparations such as elixirs, syrups or suspension.
Tablets contain a compound of Formula 1 as hereinbefore defined or a non-toxic salt thereof in admixture with excipients which are suitable for the manufacture of tablets. These excipients may be inert diluents such as calcium phosphate, microcrystalline cellulose, lactose, sucrose or dextrose; granulating and disintegrating agents such as starch; binding agents such as starch, gelatine, polyvinyl-pyrrolidone or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
Compositions in the form of capsules may contain the compound or a non-toxic salt thereof mixed with an inert solid diluent such as calcium phosphate, lactose or Kaolin in a hard gelatine capsule.
Compositions for parenteral administration may be in the form of sterile injectable preparations such as solutions or suspensions in for example water, saline or 1 ,3-butane diol.
For the purpose of convenience and accuracy of dosing the compositions are advantageously employed in a unit dosage form. For oral administration the unit dosage form contains from 1 to 500mg, preferably 1 to 250mg of the
- 17 compound of Formula 1 or a non-toxic salt thereof
Claims (15)
1. The (-) enantiomer of a compound of Formula 1 wherein R is hydrogen or methyl, in substantially pure form, and its non-toxic salts.
2. (-)-2-[2-(2-Ethyl-2,3-dihydrobenzofuranyl)]-2imidazoline in substantially pure form and its non-toxic salts.
3. A pharmaceutical composition comprising a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof, together with a pharmaceutically acceptable diluent or carrier.
4. A pharmaceutical composition as claimed in Claim 3 for oral administration in unit dosage form wherein each unit contains from 1 to 500mg of the compound or a non-toxic salt thereof . 5. The use of a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof as a potassium channel blocking agent in the treatment of diabetes.
5. The use of a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof in the preparation *of a pharmaceutical composition as a potassium channel blocking - 19 agent in the treatment of diabetes without producing any significant effect at an -adrenoreceptor.
6. 7. A method of treating diabetes which comprises administering to humans an effective potassium channel blocking amount of a compound as claimed in Claim 1 or Claim 2 or a non-toxic salt thereof.
7. 8. A process for the preparation of the (-) enantiomer of a compound of Formula 1 of Claim 1 wherein R is hydrogen or methyl in which process a compound of Formula 1 in the form of the racemate is treated in solution with a (-) optically active acid, the resultant (-) salt is separated and recrystallised until optical purity is obtained and thereafter the (-) enantiomer of the compound of Formula 1 is obtained following addition of a base.
8. 9. A process as claimed in Claim 8 wherein the (-) optically active acid is (-)-dibenzoyl-L-tartaric acid. - 20
9. 10. An (-) enantiomer of a compound of Formula 1 given and defined in Claim 1 or a non-toxic salt thereof, substantially as hereinbefore described and exemplified.
10. 11. A process for the preparation of an (-) enantiomer of a compound of Formula 1 given and defined in Claim 1 or a non-toxic salt thereof, substantially as hereinbefore described and exemplified .
11. 12. An (-) enantiomer of a compound of Formula 1 given and defined in Claim 1 or a non-toxic salt thereof, whenever prepared by a process claimed in Claim 8 or 11 .
12. 13. A pharmaceutical composition according to Claim 3, substantially as hereinbefore described.
13. 14. Use according to Claim 5, substantially as hereinbefore described.
14.
15. Use according to Claim 6, substantially as hereinbefore described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909020128A GB9020128D0 (en) | 1990-09-14 | 1990-09-14 | Imidazoline derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
IE912979A1 true IE912979A1 (en) | 1992-02-25 |
Family
ID=10682213
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE297991A IE912979A1 (en) | 1990-09-14 | 1991-08-22 | Imidazoline derivatives |
Country Status (6)
Country | Link |
---|---|
AU (1) | AU8531891A (en) |
GB (1) | GB9020128D0 (en) |
IE (1) | IE912979A1 (en) |
IL (1) | IL99469A0 (en) |
PT (1) | PT98970A (en) |
WO (1) | WO1992005171A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9127050D0 (en) * | 1991-12-20 | 1992-02-19 | Orion Yhtymae Oy | Substituted imidazole derivatives and their preparation and use |
US5399587A (en) * | 1993-12-13 | 1995-03-21 | Merck & Co., Inc. | Biologically active compounds |
FR2733983B1 (en) * | 1995-05-10 | 1997-08-01 | Pf Medicament | PROCESS FOR THE PREPARATION OF AN OPTICALLY PURE BENZOFURANE CARBOXYLIC ACID DERIVATIVE AND THE USE THEREOF FOR THE PREPARATION OF EFAROXAN |
FR2784989B1 (en) * | 1998-09-10 | 2002-09-27 | Fabre Pierre Sante | 2-ETHYL-2,3-DIHYDROBENZOFURANE-CARBOXYLIC ACID ESTER DERIVATIVE, PREPARATION METHOD AND USE FOR THE PREPARATION OF EFAROXAN DERIVATIVES |
US6410562B1 (en) | 1998-12-18 | 2002-06-25 | Eli Lilly And Company | Hypoglycemic imidazoline compounds |
SE9902267D0 (en) * | 1999-06-16 | 1999-06-16 | Astra Ab | New compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ201219A (en) * | 1981-07-28 | 1984-10-19 | Reckitt & Colmann Prod Ltd | Dihydrobenzofuranyl-2-imidazolines and pharmaceutical compositions |
-
1990
- 1990-09-14 GB GB909020128A patent/GB9020128D0/en active Pending
-
1991
- 1991-08-22 IE IE297991A patent/IE912979A1/en unknown
- 1991-09-10 WO PCT/GB1991/001542 patent/WO1992005171A1/en not_active Application Discontinuation
- 1991-09-10 AU AU85318/91A patent/AU8531891A/en not_active Withdrawn
- 1991-09-12 IL IL99469A patent/IL99469A0/en unknown
- 1991-09-13 PT PT98970A patent/PT98970A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
AU8531891A (en) | 1992-04-15 |
IL99469A0 (en) | 1992-08-18 |
PT98970A (en) | 1992-07-31 |
GB9020128D0 (en) | 1990-10-24 |
WO1992005171A1 (en) | 1992-04-02 |
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