GB2082569A - Phthalimides - Google Patents
Phthalimides Download PDFInfo
- Publication number
- GB2082569A GB2082569A GB8027240A GB8027240A GB2082569A GB 2082569 A GB2082569 A GB 2082569A GB 8027240 A GB8027240 A GB 8027240A GB 8027240 A GB8027240 A GB 8027240A GB 2082569 A GB2082569 A GB 2082569A
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- Prior art keywords
- beta
- diethylaminoethylphthalimide
- preparation
- compound
- acid
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Indole Compounds (AREA)
Abstract
3- and 4-Amino and butylamino and 3-hydroxy, methoxy, ethoxy, propoxy and butoxy- beta -diethylaminoethylphthalimide and their salts possess local anaesthetic and anti-arrhythmic activity. The preparation of 3 - alkoxyphthalic acids and anhydrides is described.
Description
SPECIFICATION
Beta - diethylaminoethylphthalimides having local anaesthetic and anti-arrythmic activity, and method fortheir preparation
This invention relates to the preparation of beta diethylaminoethylphthalimides, substituted in the positions 3 or4 with the amine or nor butylamine group (formula I) or in the 3-position with the hydroxyl group or lower alkoxy groups (formula IV). The invention also relates to the preparation of 3 - alkoxyphthalic acids (formula II) and of the corresponding 3 - alkoxyphthalic acid an hydrides (formula Ill) which have not been described in the literature heretofore and are employed as the starting compounds for the preparation of the beta - diethylaminoethyl phthalimides substituted in the 3-position by a hydroxyl or a lower alkoxy group (formula IV).
Phthalimides having alkoxy groups in the 4-position had already been disclosed in S.
Kanewskaya and V. B. Brasyunas, Zhur. Obshchei
Khim. 29, 1930-1932 (1959) and C.A., M, 8710 a-e (1960).
A few phthalimides of the general formula (I) and of the general formula (IV) possess both local anaesthetic and anti-arrythmic activity which are positively improved overthose of known products such as novesine and lidocaine.
The general formulae from (I) to (IV) inclusive are reported hereunder for ready reference:
wherein R is a member selected from the group consisting of H and nor-C4Hg;
wherein R is a member selected from the group con sisting of C2Hs, nor.-C3H7 and nor-C4Hg;
wherein R is a member selected from the group con sisting of nor.-C3H7 and nor.-C4Hg;
wherein R is a member selected from the group consisting of H, CH3,C2Hs, nor.C3H7 and nor.C4Hg.
Accordingly the present invention provides 3-or 4 amino - beta - diethylaminoethylphthalimide.
The invention will now be described with reference to the following examples which illustrate a few products according to the invention and their methods of preparation, without any implicit limitation thereto.
EXAMPLE 1.
Preparation of the 3 - amino - beta - diethylaminoethyphthalimide (la)
A mixture of 0.1 mol of 3 - aminophthalic acid and 0.11 mol of N,N - diethylethylenediamine is heated to 170"C for 60 to 90 minutes. The product thus obtained is crystallized from gasoline (petrol) or extracted by an apolar solvent (such as benzene) and the solution is chromatographed on alumina by eluting with the same solvent: 3 - amino - beta - dieth ylaminoethylphthalimide is obtained in yellow crystals melting at 64"C-66"C. The yield is about 50% of theory. The hydrochloride of the product melts at 248"C-251 C.
EXAMPLE 2.
Preparation of the 4 - amino - beta - diethylaminoethylphthalimide (Ib) A yield of about 60% of theory was obtained by operating in a manner similar to the one described in
Example 1 for the 3-amino isomer. The product con sistsofyellowcrystals having a m.p. of 85 C-88 C.
The corresponding hydrochloride melts at 237"C-240"C.
EXAMPLE 3.
Preparation of the 3 - butylamino - beta - diethylaminoethylphthalimide (Ic)
To a hot stirred mixture of (a) 1 mol, glacial acetic acid (4 mols), zinc dust (4 mols) and an excess of benzene, there is added dropwise a solution of 1.1 mol of butanal in an apolar solvent. The mixture is refluxed with stirring for 90 to 120 mins., whereafter it is filtered when still hot and the residue is washed on the filter with acetic acid. The filtrate is evaporated to dryness under vacuum and the oily residue is dissolved in water. The aqueous solution is made alkaline with 10% NaOH, then extracted with a chlorinated solvent. The extracts are dried and evaporated to dryness under vacuum.The oily residue is taken up with benzene and the solution is chromatographed on neutral alumina. 3 butylamino - beta - diethylaminoethylphthalimide (Ic) is obtained as a yellow oil with a yield of about 58% of theory. The hydrochloride is a highly hygroscopic yellow solid which melts at 91 C-94 C in a closed capillary tube.
EXAMPLE 4.
Preparation of the 4 - butylamino - beta - dieth ylaminoethylphthalirnide (Id) This compound is obtained with a yield of 50% of
theory approximately in the form of a yellow oil
starting from (Ib, Example 2.) and operating in a
manner akin to that disclosed above for the 3
butylamino isomeride (Ic, Example 3). The hydroch
loride is a highly hydroscopic yellow solid having a
melting point of 130t-1 33CC in a closed capillary tube.
EXAMPLE 5.
Preparation of the 3 - ethowyphthalic acid (ill) To a solution of 10 millimol of 3 - hydrowyphthalic
acid (or acid anhydridef in about 16 mls of a 10% soln. of NaOH, there are added 50 millimols of an ethyl halide. The reaction mixture is refluxed for 24 hours. Upon cooling, the mixture is extracted with choloroform and then made acidic with conc.HCI.
The as-formed precipitate is collected and crystallized from water and 3-ethoxyphthalic acid is obtained in the form of pale yellow crystals having a melting point of 177"C-180"C, the yield being about 65% of theory. The 3-ethoxyphthalic acid anhydride has already been described in the literature: Michio
Takido, Chem. Pharm. Bull., 6,397-400 (1958) and C.A.
53, 3168f(1959).
EXAMPLE 6.
Preparation ofthe 3-nor. propoxyphthalic acid (lid) and its acid anhydride (slid) 3-nor. propoxyphthalic acid (lId) is prepared with same procedure described for 3-ethoxyphthalic acid.
Upon crystallization from water, 3-nor. propoxyphthalic acid, a pale yellow crystalline product having a melting point of 187CC-190 C is obtained with a yield of 64% of theory 3-nor.propoxyphthalic acid anhydride (lid) is obtained by sublimation of the 3-nor.propoxyphthalic acid at 1600C-1800C under an absolute pressure of 0.3 to 0.2 mm of Hg: it is a pale yellow crystalline product having a melting point of 121 C-124 C.
EXAMPLE 7.
Preparation of the 3-nor.butoxyphthalic acid Flue) and its acid anhydride Tulle).
3-nor.butoxyphthalic acid (lle) is prepared with the same procedure as disclosed for the 3-ethoxyphthalic acid.
Upon crystallization from benzene, the 3-nor.butoxyphthalic acid, a pale yellow crystalline
product having a melting point of 145 C-148 C, is obtained with a yield of about 33% of theory.
The 3-nor.butoxyphthalic acid anhydride is
obtained by sublimation of the 3-nor.butoxyphthalic
acid of 160 C-180 C under an absolute pressure of 0.3-0.2 mm of mercury and is a pale yellow crystal
line product having a melting point of 129 C-130 C.
EXAMPLE 8.
Prenaration of the 3 - hydroxy - beta - dieth ylaminoethylphthaiimide (IVa)
One mol of 3-hydroxyphtha(ic acid anhydride, and
from 2 to 2.1 mols of N,N-diethylethylenediamine
are heated to 10"C-170"C for 60 to 90 mins. Upon
cooling, the product is dissolved in diluted HCI and
the solution is neutralized with an alkali.
The as formed precipitate is collected and purified by crystalization from benzene The as obtained yeilow product (IVa) melts at 134 C-136GC. The yield is about 40% of theory. The corresponding hydrochloride melts at 1 83'C-1 85 C.
Preparation of the 3 - alkoxy - beta - dieth ylaminoethylphthallmides UVb, IVc, IVd, IVe).
EXAMPLE 9.
Preparation of the 3 - methoxy - beta - diethylaminoethylphthalimide (IVb).
One mol of 3-methoxyphthalic acid an hydride (or of the corresponding acid) and 1.1 moi of N,Ndiethylethylenediamine are heated to 170 C for 60 to 90 mins. The reaction product can be crystallized from gasoline (petrol) or extracted with benzene when hot, and the solution is chromarographed on alumina, eluting with benzene. The pale yellow product thus obtained melts at 58"C-60"C.
The yield is about 40% of theory. The corresponding hydrochloride melts at 179"C-181"C.
EXAMPLE 10.
Preparation of the 3 - ethoxy - beta - dieth ylaminoethylphthallmide (IVc) It is prepared with the same procedure as described for the 3 - methoxy - beta - diethylaminoethylphthaiimide. Upon crystallization from petroleum ether, the expected compound is obtained as a white crystalline product having a melting point of 70"C-72"C, with a yield of 66% of theory. The corresponding hydrochloride is a white crystalline product having a melting point of 172"C-175"C.
EXAMPLE 11.
Preparation of the 3 - nor. propoxy - beta - dieth ylaminoethylphthallmide (lVd) This compound is prepared with the same procedure as adopted for preparing the 3 - methoxy - beta - diethylaminoethylphthalimide (Example 10, IVb).
By extraction, with petroleum ether, of the reaction mixture, the expected compound is obtained as a pale yellow oil, with a yield of 81% of theory. The corresponding hydrochloride is a white crystalline product having a melting point of 1 52 C-1 56 C.
EXAMPLE 12.
Preparation of the 3 - norbutoxy - beta - dieth ylaminoethylphthalimide (IVe)
This compound is prepared with the same procedure as described for preparing the 3 - methoxy beta - diethylaminoethylphthalimide (IVb) in Example 10. hereof. Upon extraction of the reaction mixture with petroleum ether, the expected compound is obtained as a pale yellow oil, with a yield of 90% of theory. The corresponding hydrochloride is a pale yellow crystalline product which has a melting pgint of 1 36 C-1 40 C.
All of the above described products have been analysed for C, H and N and have shown values comprised within + 0.3% with respect to the calculated value. Their IR and NMR spectra demonstrate unequivocally the structures which have been indicated.
PIL-'\ RMA COL 0 GICA L TESTS FOR LOCAL ANAS THETiC A CTION As a demonstration of the efficacy of one product according to the invention, that is ADF7, the following Table shows the results of comparison tests between the product in question, novesine and lodocaine.
LOCAL ANAESTHETICACTION IN CORNEAL REFLEX TEST IN RABBITS
Dosage micrograms Substances in in the BASAL Peak Time hydrochloride conjuctival/ (Stim. (mins. after Activity Duration ED84- ED50 - ED16 (4) form sac (1) min.) treatment) STIM. + ES/min. % (3) mins. microgramslconjunctiva Its (2) NOVESINE 20 14,63 15 48,85 + 8,81 - 40,08 30 40 11,12 15 71,56t9,16 - 9,16 68,00 60 70 12,16 15 88,44 + 492 - 86,84 60 64,00 -25,50 -10,00 200 12,31 10 100,00 -100,00 > 130 400 9,20 5 100,00 -100,00 > 130 LIDOCAINE 400 7,78 30 29,77 t 5,39 - 23,84 50 500 8,37 10 41,00 t 5,94 - 35,61 65 1500 9,50 10 63,00 6,15 - 59,66 120 2700-900,00-295 2000 11,56 10 79,00 9,54 - 76,08 120 3000 11,87 5 88,83 5,35 - 87,32 > 130 ADF7 15,62 14,12 20 33,50 483- 22,55 45 31,25 14,62 15 57,83 + 6,87 - 50,40 65 68,50-30,00-12,7 62,50 11,29 10 84,50 6,008 - 85,51 100 125,00 18,49 5 100,00 -100,00 > 130 (1) Method derived from the paper by J. Boberg-Ans, Acta Ophthalmologica, 34, 149, (1956).
(2) The tabulations are the average values of the STIM.min. counted at peak time and of those counted at the immediateiy preceding and the immediately following control times.
(3) (Stim./min. - Basal) = % activity 100 - Basal (4) Determined according to Litchfield J., and Wilcoxon, F., J. Pharmacol., 95,99 (1949).
The accompanying drawings are graphs which better illustrate the anaesthetic action and the antiarrythmic action of the compound according to the invention which is particularly considered here.
More particularly, in the drawings:
Fig. is a graph showing the local anaesthetic activity in the corneai reflex test in rabbits.
Fig. 2 is a graph similar to that of Fig. 1.
In Figures 1 and 2, the abscissae are the control times in minutes, and the ordinates are the stimulations per minute.
Fig. 3 is a comparative graph which illustrates the anti-arrythmic activity of the compound according to the invention as used for the tests, in comparison with other known anti-arrthymic drugs.
Figs. 4, 5, 6 and 7 are ECG plots made on rats to show the action of different dosages of the compound of the invention used here For the tests, in comparison with an untreated test animal.
The plot of Fig. 1 relates to the local anaesthetic activity (corneal reflex test in rabbits): the solidline-and-white dot line corresponds to 31.25 micrograms/0.1 milconjuctival sac. of the compound according to this invention. The dotted-line-blackdot line corresponds to a dosage of novesine of 20.00 micrograms/0.1 milconjuctival sac.
tn a similar manner, the plot of Fig. 2 corresponds, with the same symbols of Fig. 1, to 62.50 microg rams/0.1 ml/conjuctival sac., and novesine 70.00 micrograms/0.1 ml/conjuctival sac, respectively.
PHARMACOLOGICAL TESTS FOR
ANTI-ARRYTHMICACTION
The compound according to the invention, taken as a mere example here, that is, ADF 7, has been tested for its anti-arrythmic activity in rats at several dosage ratings. The anti-arrythmic action of the compound in question becomes apparent at a dosage of 1 milligram per kilogram body weight and the dosage can attain 10 milligrams per Kg. b.w. without any detrimental effects on the heart: these effects, however, become apparent with higher dosages. At lower dosages no protective activity towards the heart has been detected.
As a matter of fact, by comparing the activity of the compound according to this invention as taken here for exemplary purpose, with the activity of known drugs, the anti-arrythmic activity of which is known, and measuring the efficiency of the exemplary compound of this invention on Guinea pigs in which arrythmia had been induced with aconitin, the protection factor of the drug on the heart can be estimated.
in the plot depicted in Fig. 3, the following are the meanings of the reference numerals reported on the horizontal axis: 1) Control - 32.8 micrograms of aconitin 2) Compound of the invention 1 mg/kg. b.w.: to induce arrythmia, 41.8 micrograms/kg b.w. of aconitin are required.
3) Compound of the invention 2 mg/kg b.w.: to induce arrythmia 49.8 microgramslkg b.w. of aconitin are required.
4) Compound of the invention 5 mglkg b.w.: to induce arrythmia 62.5 microgramslkg b.w. of aconitin are required.
5) Compound of the invention 10 mg/kg b.w.: to induce arrythmia 93.1 microgramslkg b.w. are required.
6) Xylocain 20 mglkg b.w.: to induce arrythmia 59.5 microgramslkg b.w. are required.
7) Procainamide 20 mg/kg b.w.: to induce arrythmia 58.7 micrograms/kg. b.w. are required.
However, if the ECG-plots are examined, it can be seen that the compound according to the invention, taken as exemplary compound here, causes an anomalous activity yet at a dosage of 5 milligrams (mg) per kg b.w., and originates a block
As a matter of fact, a partial block can be observed, and, on seven rats which have been checked, the following situation has been ascertained: -3 rats show no alterations.
-2 rats show an alteration which disappears within the first three minutes.
- 1 rat shows an alteration which has a tendency towards fading away. but which remains in the first three minutes, and - 1 rat shows a constant alteration.
It is to be noted, however, that the greater is the alteration, the greater is also the protection.
In figs 4, 5,6 and 7 of the accompanying drawings, the ECG-plots are reported under various conditions, namely:
Fig. 4 shows the ECG plot for an untreated control rat.
Fig. 5 shows the ECG plot of a rat treated with 1 mg/kg b.w. of the exemplary compound of this invention.
Fig. 6 shows the ECG plot for a rat having been treated with 3 mg/kg b.w. of the exemplary compound of the invention aforesaid.
Fig. 7 shows the ECG plot for a rat which had been treated with 10 mg/kg b.w. of the exemplary compound in question.
In the plot of Fig. 7, as outlined above, the block induced by the drug can be spotted and this block can be seen also in a few controls at the dosage of 5 mglkg b.w.
More particularly, the ECG plots can be interpreted as follows:
Figure 4: A = control; B = after injection of
physiological liquor; C = arrythmia appears (aconi
tin: 32.8 microgramslkg b.w.) D = fibrillation appears Figure 5: A = control; B = after injection of the
compound of the invention at the dosage of 1 mg/kg
b.w.; C = arrythmia appears; aconitin 41.8 microg
rams/kg b.w.; D = fibrillation appears.
Figure 6: A = control; B = after injection of the
compound of the invention at the dosage of 3 mglkg
b.w.; C = arrythmia appears: aconitin 49.8 microg
rams/kg b.w.
Figure 7: A = control; B = after injection of the
compound of the invention at the dosage of 10
mg/kg b.w.; C = arrythmia appears: aconitin 93.1 microgramslkg b.w.; D = fibrillation appears.
The method which has been followed for determining the above reported data is disclosed by B.
Vargaftig and J. L. Coignet in "A Critical Evaluation of three Methods for the study of adrenergic Betablocking and anti-arrythmic agents", European
Journal of Pharmacology, 6,49-55 (1969).
While this invention has been shown and described in connection with a few exemplary embodiments thereof, be it understood that modifications and changes may be introduced therein without departing from the spirit and scope of the same invention, as defined in and by the claims appended hereto.-
Claims (14)
1. 3 - amino - beta - diethylaminoethylphthalimide.
2. 4 - amino - beta - diethylaminoethylphthalimide.
3. 3- butylamino - beta - diethylaminoethylphthalimide.
4. 4 - butylamino - beta - diethylaminoethylphthalimide.
5. 3 - hydroxy - beta - diethylaminoethylphthalimide.
6. 3- methoxy - beta - diethylaminoethylphthalimide.
7. 3- ethoxy - beta - diethylaminoethylphthalimide.
8. 3- not.propoxy - beta - diethylaminoethylphthalimide.
9. 3- nor.butoxy - beta - diethylaminoethylphthalimide.
10. Method for the preparation of the compounds claimed in any of claims 1 and 2, comprising the step of reacting the corresponding aminosubstituted phthalic acid with N,Ndiethylethylenediamine under reflux conditions and isolating the reaction product by extraction or crystallization.
11. Method for the preparation of the compounds claimed in any one of Claims 3 and 4, comprising the step of reacting a compound as claimed in claims 1 and 2 with butanal under reflux conditions and isolating the reaction product by extraction with a chlorinated solvent.
12. Method for the preparation of the compounds claimed in any one of claims 5 to 9, comprising the step of reacting the corresponding hydroxy or alkoxy-substituted phthalic acid an hydride with
N,N-diethylethylene diamine under reflux conditions and collecting the reaction product thus obtained.
13. A beta - diethylaminoethylphthalimide having local anaesthetic and anti-arrythmic activity substantially as described herein with reference to the
Examples.
14. A method for the preparation of a beta diethylaminoethylphthal imide having local anaesthetic and anti-arrythmic activity substantially as described herein with reference to the Examples.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8027240A GB2082569A (en) | 1980-08-21 | 1980-08-21 | Phthalimides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8027240A GB2082569A (en) | 1980-08-21 | 1980-08-21 | Phthalimides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2082569A true GB2082569A (en) | 1982-03-10 |
Family
ID=10515593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8027240A Withdrawn GB2082569A (en) | 1980-08-21 | 1980-08-21 | Phthalimides |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2082569A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0703232A3 (en) * | 1994-08-11 | 1996-10-09 | Hoechst Roussel Pharma | 2,3-Dihydro-1H-isoindole derivates, a process for their preparation and their use as serotonin reuptake inhibitors |
-
1980
- 1980-08-21 GB GB8027240A patent/GB2082569A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0703232A3 (en) * | 1994-08-11 | 1996-10-09 | Hoechst Roussel Pharma | 2,3-Dihydro-1H-isoindole derivates, a process for their preparation and their use as serotonin reuptake inhibitors |
| US5869685A (en) * | 1994-08-11 | 1999-02-09 | Hoechst Marion Roussel Inc. | 2,3-dihydro-1H-isoindole derivatives |
| US5869502A (en) * | 1994-08-11 | 1999-02-09 | Hoechst Marion Roussel Inc. | 2, 3-dihydro-1H-isoindole derivatives and their use as serotonin reuptake inhibitors |
| US5874458A (en) * | 1994-08-11 | 1999-02-23 | Hoechst Marion Roussel Inc. | 2,3-dihydro-1H-isoindole derivatives and their use as serotonin reuptake inhibitors |
| US5874583A (en) * | 1994-08-11 | 1999-02-23 | Hoechst Marion Roussel Inc. | 2,3-dihydro-1H-isoindole derivatives |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |