DERIVATIVES OF INDOLYLL AS SEROTONERGIC AGENTSField of the InventionThis invention relates to a series of novel heteroaryl-β-hydroxypropylamines which are effective pharmaceutical products for the treatment of conditions related to or affected by the reuptake of serotonin. The compounds are particularly useful for the treatment of depression, anxiety, withdrawal of drugs, eating and sexual disorders, and other conditions for which serotoner reuptake inhibitors are used.
Background of the InventionIn his article "4- (? Ndol? L-3) -1- (benzimidazolonilalkyl) -piperidines, a Novel Group of Potential Antiallergic Compounds".
Arzneim-Forsch, 35 (1), 272-276 (1985), Freter et al. Describes the compounds of the formula:Ref: 12170As anti-allergic agents by virtue of their histamine Hl-blocking actions in addition to the weak properties of mast cell stabilization.
Brief description of the inventionDepression is a psychiatric condition that is thought to be associated with decreased serotoner release. Most antidepressant agents (eg, fluoxetine) potentiate the effects of serotonin by blocking the termination of its activity through reuptake within the nerve terminals. The present invention provides a series of novel indolyl derivatives that inhibit the reuptake of serotonin, the processes for their preparation, the pharmaceutical compositions containing them and their use in therapy for the treatment of disorders of the central nervous system, particularly depression. .
The compounds of the present invention are particularly represented by the general formula (I)(1)wherein: Ri and R2 each independently represent hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, CN, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, CF3 and phenyloxy or benzyloxy, wherein the aromatic ring may be optionally substituted with 1 to 3 groups selected from alkoxy of 1 to 6 carbon atoms (preferably OMe), F, Cl, Br, I, and CF3; R3 and R4 are each independently 1 hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a CH2Ph group in which the phenyl ring may be optionally substituted with 1 to 3 groups selected from alkoxy of 1 to 6 carbon atoms (preferably OMe), F, Cl, Br, I, and CF3;And is selected from CH? or CH and, X is selected from a group represented by nitrogen, CR3 CHR3, CHCH; or a pharmaceutically acceptable salt thereof. A preferred group of compounds of this invention are those in which X is N and Ri and R2, R3, R4, and Y are as defined above. Another preferred group herein comprises the compounds wherein X is CR3, CHR3 or CHCH and Ri, R2, R3, R4 and Y are as defined above. The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic acid such as an inorganic or organic acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic.
Detailed description of the inventionThe compounds of the present invention can be prepared using conventional methods. For example, the treatment ofmdol or benzimidazole derivative (2) with glycidyl tosylate provides the epoxide (3). The reaction of the epoxide with the piperidine or tetrahydropipdin derivatives (4) and (5) provide the respective products (1).
The preparation of the 3- (4-pipepdmil) indoles and substituted 3- (4-tetrahydropyridyl) indoles can be achieved by conventional known methods.
For example, reaction of a mdol optionally substituted with 4-p? Per? Dona provides 3- (4-tetrahydropyridyl) mdol (5). This can be reduced using the standard catalytic hydrogenation methodology to provide a 3- (4-piperidyl) mdol (4). Such methodology is described in C. Gueremy et al., J. Med. Chem, 1980, 23, 1306-1310, J-L. Malleron et al., J. Med. Chem. 1993, 3_6, 1194-1202 and J. Bergman, J. Heterocyclic. Chem. 1970, 1071-1076.
The present invention provides methods for inhibiting the reuptake of serotonin in mammals, preferably in humans. The compounds of the present invention inhibit with very high affinity the binding of paroxetine to the serotonin transporter and consequently, these are useful for the treatment of disorders of thecentral nervous system such as depression, anxiety, including generalized anxiety disorder, sleep disorders, sexual dysfunction, obsessive-compulsive disorders, obesity, bulimia nervosa, chronic fatigue syndrome, pain, particularly neuropathic pain, panic disorder, disorder for post-traumatic stress disorder, late luteal phase dysphoric disorder (also known as premenstrual syndrome), Tourette syndrome, alcohol and cocaine addiction,Par mson, schizophrenia and for the improvement of cognition such as in Alzheimer's disease.
It is understood that the therapeutically effective dose that is going to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include psychosis specific to the state of anxiety and the patient's size, age and response pattern. The novel method of the invention for the treatment of conditions related to or affected by the reuptake of serotonin, comprises the administration to warm-blooded animals, including humans, of an effective amount of at least one compound of this invention or a saltby pharmaceutically acceptable, non-toxic addition thereof. The compounds can be administered orally, rectally, parenterally or topically to the skin and mucous membranes. The usual daily dose is dependent on the specific compound, the treatment method and the condition treated. An effective dose of 0.01 1000 mg / kg can be used for oral application, preferably 0.5-500 mg / kg and an effective amount of 0.1-100 mg / kg can be used for parenteral application, preferably 0.5-50 mg / kg. . The therapeutically effective dose that will be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include the specific disease or disorder and the patient's size, age and response pattern. The present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Solid carriers, or excipients, applicable, may include one or more substances thatthey can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents or an encapsulating material. In the powders, the carrier is a finely divided solid which is in mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions, and compacted in the desired shape and size. The powders and tablets preferably contain up to 99 ° of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrm, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting point waxes, and ion exchange reams. . The liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, or aorganic solvent, a mixture of pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (containing particularly additives as described above, for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols ) and its derivatives, and oils (for example fractionated coconut oil and peanut oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions of sterile liquid form for parenteral administration. Liquid pharmaceutical compositions that are sterile solutions or suspensions can beuse for example by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The oral administration can be either the liquid or solid composition form. Preferably, the pharmaceutical composition is in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage forms may be packaged compositions, for example packaged powders, flasks, ampoules, prefilled syringes or sacks containing liquid. The unit dosage form may be, for example, a capsule or a tablet itself, or this may be the appropriate number of any such compositions in package form. The affinity of the drugs for the serotonin transporter was determined by assessing the ability of the agents to specifically displace the bound 3H-paroxetma, which is ligated from rat cortical membranes. This procedure is a modification of that used by Cheetham and collaborators 1993(Neuropharmacol., 32: 737-743, 1993). The non-specific binding was determined using fluoxetma. Using this assay, the following Ki's were determined for a series of standard serotonin reuptake inhibitors.
Linkage of 3H-paroxetma to Evaluate the Affinity of Drugs for the Serotonin TransporterA protocol similar to that used by Cheetham et al. (Neuropharmacol, 32: 737, 1993) was used to determine the affinity of the compounds for the serotonin transporter. Briefly, the frontal cortical membranes prepared from rats S.D. Male were incubated with 3H-paroxetma (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained either the vehicle, the test compound (one to eight concentrations), or a saturation concentration of fluoxetine (10 μm) to inhibit the specific binding. All reactions are determined by the addition of ice-cooled Tris buffer, followed by rapid filtration using a Tom Tech filtration device to separate bound 3H-paroxetme from free.
The bound radioactivity was quantified using a Wallac 1205 Beta Píate® counter. Non-linear regression analysis was used to determine the ICsc values that were converted to Ki values using the Cheng and Prusoff method (Biochem Pharmacol, 22: 3099, 1973); Kl = IC50 / ((Radioligand conc.) / (1 + KD).
Compound Inhibition of the [3H] - paroxetine linkage, Ki (nM)Clomipramma 0.18 Fluoxetma 4.42 Imipramine 17.6 Zimelidine 76.7The results for a number of examples of the compounds of formula (1) in this experimental test procedure were as follows:Compound Inhibition of the [3H] - paroxetma bond, Kl (nM)Example 8 1.4Example 10 0.01 Example 11 0.04 Example 12 1.7 Example 13 0.4 Example 14 0.03 Example 15 0.3The following specific non-limiting examples are included to illustrate the specific procedures used to prepare compounds of the formula (1). In these examples, all intermediate chemical products are either commercially available or can be prepared by standard procedures found in the literature or are known to those skilled in the art of organic synthesis.
Example 1 l-N-gl? C? D? L-5-fluoro-? NdolEpibromohydrin (1.4 ml, 16.5 mmol) was added to a stirred solution of 5-fluoromol (2.0 g, 15 mmol) and sodium hydride (0.66 g, 16.5 mmol) in 20 ml of dimethyl formamide and the mixture was heatedat 60 ° C under nitrogen atmosphere for 15 hours. 100 ml of water were added and the product was extracted into methylene chloride (3 x 35 ml). The combined organic extracts were washed with 25 ml of water, with 25 ml of brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a viscous yellow oil (2.7 g). This was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title product as a viscous oil (2.5 g, 89% yield).
Elemental analysis for: CnHioFNO Calculated: 69.10; H, 5.27; N, 7.33 Found: 69.24; H, 5.67; N, 7.36Eg 2 l-N-gl? C? D? L-4-methox? -mdolEpibromohydride (0.64 ml, 7.5 mmol) was added to a stirred solution of 4-methoxydol (1.0 g, 6.8 mmol) and sodium hydride (0.3 g, 7.8 mmol) inml of dimethylformamide, and the mixture was heated at 60 ° C under a nitrogen atmosphere for two hours. HEthey added 100 ml of water and the product was extracted in 3 portions of 25 ml of methylene chloride. The combined organic extracts were washed with 25 ml of water, with 25 ml of brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a yellow oil 1.5 g. This was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title product as a clear oil (1.27 g, 92% yield).
Elemental analysis for: Ci2H? 3N02 Calculated: 70.92; H, 6.45; N, 6.89 Found: 71.05; H, 6.57; N, 6.96Example 3 1-N-glycidi 1-4-fluoro-indoleEpibromohydpna (0.64 ml, 7.5 mmol) was added to a stirred solution of 4-fluoromol (1.0 g, 7.4 mmol) and sodium hydride (0.32 g, 8.1 mmol) in 20 ml of dimethylformamide, and the mixture was heated to 60 °. C ba or nitrogen atmosphere for 15 hours. 100 ml of water was added and the product was extracted in3 25 ml portions of "Methylene chloride." The combined organic extracts were washed with 25 ml of water, 25 ml of brine and dried over anhydrous sodium sulfate, filtration and concentration in vacuo gave the crude product as an oil. 1.34 g yellow This was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title product as a clear oil (1.27 g, 90% yield).
Elemental analysis for: CnHioFNO Calculated: 69.10; H, 5.27; N, 7.33 Found: 69.24; H, 5.37; N, 7.46Example 4 1-N-gl? C? D? L-mdolEpibromohydpna (0.73 ml, 8.5 mmol) was added to a stirred solution of indole (1.0 g, 8.5 mmol) and sodium hydride (0.34 g, 8.5 mmol) in 20 ml of dimethylformamide, and the mixture was heated to 60 ° C. or nitrogen atmosphere for two hours. 100 ml of water were added and the product was extracted into 3 portions of 25 ml of methylene chloride. TheThe combined organic extracts were washed with 25 ml of water, 25 ml of brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a pale yellow oil 1.45 g. This was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title product as a clear oil (1.37 g, 93% yield).
Elemental analysis for: CnHuNO Calculated: 76.27; H, 6.40; N, 8.09 Found: 76.24; H, 6.37; N, 8.06Example 5 1-N- (S) -gl? C? D? L-4-methox idolThe (2S) - (+) - glycidyl tosylate (1.55 g, 6.8 mmol) was added to a stirred solution of 4-methoxnol (1.0 g, 6.8 mmol), and sodium hydride (0.3 g, 7.5 mmol) and -corona-6 (10 mg) in 20 ml of dimethylformamide, and the mixture was heated at 60 ° C under nitrogen atmosphere for five hours. 100 ml of water were added and the product was extracted into 3 portions of 25 ml of methylene chloride. TheThe combined organic extracts were washed with 25 ml of water, 25 ml of brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a pale yellow oil 1.15 g. This was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title product as a clear oil (0.65 g, 47% yield).
Elemental analysis for: Ci2H? 3N02 Calculated: 70.92; H, 6.45; N, 6.89 Found: 71.11; H, 6.59; N, 6.99Example 6 1-N- (S) -glycidyl-4-f luoroindoleThe (2S) - (+) - glycidyl tosylate (1.7 g, 7.4 mmol) was added to a stirred solution of 4-fluoroindole (1.0 g, 7.4 mmol), and sodium hydride (0.33 g, 8.1 mmol) and -'Cone-6 (10 mg) in 20 ml of dimethylformamide, and the mixture was heated at 60 ° C under nitrogen atmosphere for five hours. 100 ml of water were added and the product was extracted into 3 portions of 25 ml of methylene chloride. TheThe combined organic extracts were washed with 25 ml of water, with 25 ml of brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow oil 1.15 g. This was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title product as a clear oil (0.4 g, 28% yield).
Elemental analysis for: CnHioFNO Calculated: 69.10; H, 5.27; N, 7.33 Found: 69.27; H, 5.40; N, 7.43Using 7 l-N-gl? C? D? L-2-met? Lbenc? M? DazolEpibromohydrin (1.0 g, 7.6 mmol) was added to a stirred solution of 2-methobenzene diazole (1.0 g, 7.6 mmol) and sodium hydride (0.3 g, 7.6 mmol) in 20 ml of anhydrous dimethylformamide and the The mixture was heated to 60 ° C under a nitrogen atmosphere for 0.5 hours. 100 ml of water were added and the product was extracted into 3 portions of 25 ml of methylene chloride. The combined organic extracts arewashed with 25 ml of water, with 25 ml of brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a pale yellow oil 1.4 g. This was purified by flash chromatography on silica gel (10% methanol in methylene chloride) to give the title product as a clear oil (0.64 g, 45% yield).
Elemental analysis for: CnH12N.O Calculated: 70.19; H, 6.43; N, 14.88 Found: 70.24; H, 6.47; N, 14.98Example 8 1- (5-fluoro-? Ndol-l-? L) -3- [4- (lH-? Ndol-3-? L) -3,6-d? H? Dro-2H-p? R ? dm-l-? l] -propan-2-olA methanol solution of lN-gl? C? D? L-5-fluoromol (0.52 g, 3.0 mmol) from Example 1 and 3- (4-tetrahydropyridinyl) mdol (0.59 g, 3.0 mmol) was heated to reflux under an atmosphere of nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (ethyl acetate)to provide the title compound as a light yellow solid (0.91 g, 78% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required salt as a yellow solid. The product was recrystallized from ethanol.p.f 206-207 ° C Elemental analysis for: C .4H24FN3O »0.5C4H404 Calculated: C, 69.78; H, 5.86; N, 9.39 Found: C, 69.46; H, 5.71; N, 9.21Example 9 1- (5-fluoro-? Ndol-l-? L) -3- [4- (lH-? Ndol-3? L) -p? Per? Dm-l-? L] -propan- 2-olA methanolic solution of lN-gl? C? D? L-5-fluoromodol (0.52 g, 3.0 mmol) from Example 1 and 3- (4-piperidyl) indole (0.6 g, 3.0 mmol) was heated to reflux or atmosphere of nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (ethyl acetate) to give the title compound as aoil (0.599 g, 50% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required salt as a white solid. The product was recrystallized twice from ethanol.p.f 215-216 ° C Elemental analysis for: C2 H25FN3O »0.5C4H4O4« 0.8CH2C1 Calculated: C, 68.65; H, 6.22; N, 9.21 Found: C, 68.44; H, 6.36; N, 9.14EXAMPLE 10 1- (4-fluoro-mdol-1-yl) -3- [4- (lH-? Ndol-3? L) -3,6-d? H? Dro-2H-p? R? d? nl-? l] -propan-2-olA methanolic solution of lN-gl? C? D? L-4-fluoromdol (0.52 g, 3.0 mmol) from Example 1 and 3- (4-tetrahydro??? D? N? L)? Ndol (0.59 g. , 3.0 mmol) was heated to reflux under nitrogen atmosphere for 15 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (ethyl acetate) to give the title compound as a pale yellow solid (0.61 g, 53% yield). The treatment with a solutionEthanolic 0.25 M of || P * fumaric acid (0.5 equivalents) gave the. { The product required as a yellow solid. The product was recrystallized from ethanol.mp 136-137 ° C Elemental analysis for: C24H24 3O »0.5C H4O4» 0.12H, O »0.3EtOH Calculated: C, 68.93; H, 6.10; N, 9.07 Found: C, 68.58; H, 6.17; N, 8.82Example 11 l- [4- (lH-? Ndol-3-? L) -3,6-d? H? Dro-2H-p? R? D? Nl-? L] -3- (4-methoxy? -mdol-l-il) -propan-2-olA methanolic solution of lN-gl? C? D? L-4-methoxnol (0.6 g, 3.0 mmol) from example 2 and 3- (4-tetrahydropyridyl) mdol (0.59 g, 3.0 mmol) was heated to reflux under an atmosphere of nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (ethyl acetate) to give the title compound as a yellow solid (0.73 g, 60% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5equivalents) gave the required product as a yellow solid. The product was recrystallized from ethanol.mp 140-143 ° C Elemental analysis for: C25H27N3O2 »0.5C H4? 4» 0.17H20 Calculated: C, 70.10; H, 6.39; N, 9.08 Found: C, 69.70; H, 6.27; N, 8.93Example 12 l-? Ndol-l-? L-3- [4- (lH-mdol-3? L) -3,6-d? H? Dro-2H-p? R? Dm-l-? L ] -propan-2-olA methanolic solution of 1-N-gl? C? D? Lmdol (0.52 g, 3.0 mmol) from Example 4 and 3- (4-tetrahydropipdimethyl) indole (0.59 g, 3.0 mmol) was heated to reflux under a nitrogen atmosphere. 24 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (ethyl acetate) to give the title compound as a yellow solid (0.53 g, 47% yield). The treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as aSolid yellow. The product was recrystallized from ethanol.p.f 209-210 ° C Elemental analysis for: C-4H-5N3O «0.5C4H4O4 Calculated: C, 72.71; H, 6.34; N, 9.78 Found: C, 72.72; H, 6.49; N, 9.62For example 13 l- [4- (lH-mdol-3? L) -3,6-d? H? Dro-2H-p? Pd? Nl-? L] -3- (2-met? L- benzo? m? dazol-l-? l) -propan-2-olA methanol solution of lN-gl? C? D? L-2-methylbenzimidazole (0.64 g, 3.4 mmol) from Example 7 and 3- (4-tetrah? Drop? Pd? N? L) indole (0.67 g, 3.4 mmol. ) was heated to reflux under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (10% methanol in ethyl acetate) to give the title compound as a pale yellow solid (0.11 g, 9% strength). performance) . The treatment with a 0.25 M ethanol solution of fumapco acid (0.5 equivalents) gave the required product as aSolid yellow. The product was recrystallized from ethanol.p.f 206-208 ° C Elemental analysis for: Calculated: C, 66.22; H, 6.63; N, 11.88 Found: C, 66.29; H, 6.20; N, 11.73Example 14 (2S) -l- [4- (lH-mdol-3? L) -3,6-d? H? Dro-2H-p? R? Dm-1-? L] -3- (4 -metox? -mdol-l-? l) -propan-2-olA methanolic solution of 1-N- (S) -glycidyl-4-methoxydol (0.65 g, 3.2 mmol) from example 5 and 3- (4-tetrah? Drop? Pdm? L) indole (0.63 g, 3.2 mmol) was heated to reflux under nitrogen atmosphere for 24 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (10% hexane in ethyl acetate) to give the title compound as a pale yellow solid (0.6 g, 47% strength). performance) . The treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as aSolid yellow. The product was recrystallized from ethanol.mp 155-158 ° C Elemental analysis for: C25H2, N30.0.5C H40 .1H20 Calculated: C, 67.91; H, 6.54; N, 8.80 Found: C, 67.81; H, 6.31; N, 8.50Example 15 (2S) -1- (4-fluoro-mdol-1-yl) -3- [4- (lH-? Ndol-3? L) -3,6-d? H? Dro-2H- p? r? dm-l-? l] -propan-2-olA methanolic solution of IN- (S) -fluoromodol (0.396 g, 2.3 mmol) from Example 6 and 3- (4-tetrahydro? Drop? Pd? N? L)? Ndol (0.46 g, 2.3 mmol) was heated to reflux under nitrogen atmosphere for 24 hours. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (10% hexane in ethyl acetate) to give the title compound as a pale yellow solid (0.44 g, 48% strength). performance) . The treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as aSolid yellow. The product was recrystallized from ethanol.p.f 135-136 ° C Elemental analysis for: C24H24FN3O «0.5C" H4O4 »0.5H2O» 0.32EtOH Calculated: C, 67.90; H, 6.19; N, 8.92 Found: C, 68.08; H, 6.10; N, 8.76It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.