FI63023B - FOERFARANDE FOER FRAMSTAELLNING AV SMAERTLINDRANDE 4-AMINO-TRANS-DEKAHYDROKINOLINDERIVAT - Google Patents

Description

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Patent- och ragittarstyraltan 'Arattkin ucb «d odi utUkrtfcM published 31.12. Θ2 (32) (33) (31) Pyyd · »/ * cuelk« «i— · * | Μ prIoriMt. 12.75

England-England (GB) 51507/75 (71) Sanofi, ^ 0, avenue George V, 75008 Paris, France-France (FR) (72) Maurice Prost, Brussels, Belgium-Belgium (BE) (7 ^) 0y Borenius & Co Ab (5 * 0 Process for the preparation of analgesic β-amino-β-trans-decahydroquinoline derivatives - For the preparation of β-amino-trans-decahydroquinoline derivatives)

The invention relates to processes for the preparation of 4-amino-trans-decahydroquinoline derivatives and their pharmaceutically acceptable acid addition salts.

The general formula of the compounds according to the invention is 0 0) "* 3 in which R1 represents a branched or straight-chain alkyl or alkoxy group having 1 to 4 carbon atoms, or a phenyl, turyl or pyridyl group, r2 represents a methyl- or a phenyl group or a naphthyl, benzyl or cyclohexyl group optionally substituted by a methoxy radical, and R 3 represents a benzyl, phenethyl, cinnamyl or phenylpropyl group, or a group of the general formula 2,63023

An X-Y

wherein A represents a branched or straight-chain alkylene group having 1 to 4 carbon atoms, Y represents an oxygen or sulfur atom or a carbonyl group, X represents a thienyl radical or optionally a fluorine, chlorine or bromine atom, or a methyl or methoxy group a monosubstituted phenyl group and n is 0 or 1, provided that when n is 0, Y represents a carbonyl group.

Compounds of formula (I) may be prepared by a) boiling under redistillation using a compound of general formula BX-B2 0) p wherein r2 and R3 are as defined above, together with the following general formula

O

OF

With a compound of formula R1-C-Cl (XV), wherein R1 is as defined above, to give the desired compound in the form of its free base. The reaction is conveniently carried out in an inert organic solvent, e.g. dichloroethane, methylene chloride, benzene or toluene, optionally in the presence of a base, e.g. triethylamine, trimethylamine or pyridine.

Alternatively, those compounds of formula (I) wherein R 1 represents a non-alkoxy group may be prepared by refluxing a compound of general formula (III) in combination with a compound of general formula 3 63023 O o

N M

R1-C-O-C-R1 (V) wherein R1 is as defined above. The reaction is conveniently carried out in an inert organic solvent, e.g. dichloroethane, methylene chloride, benzene or toluene, optionally in the presence of an acid, e.g. p-toluenesulphonic acid or sulfuric acid.

The compounds of formula (I) may be converted into the corresponding pharmaceutically acceptable acid addition salts by treatment with a suitable acid and by application of methods known in the art.

Compounds of formula (III) may be prepared by reacting a 4-amino-trans-decahydroquinoline of the general formula HM-R 2 a) in which R 2 is as defined in formula (I) with a halogenated compound of the general formula

Hal-R3 (IX) in which Hal represents a chlorine, bromine or iodine atom and r3 has the same meaning as in formula (I). This reaction is conveniently carried out in a liquid medium which may be an inert organic solvent, e.g. benzene, toluene, xylene, dichloroethane or tetrahydrofucan, or an alcoholic medium, e.g. butanol or aqueous ethanol, or a ketone, e.g. acetone or methyl ethyl ketone in the presence of an acid scavenger. a compound, e.g. an alkali metal carbonate such as potassium carbonate or sodium bicarbonate.

The reaction, which can be accelerated by using a small amount of potassium iodide, is suitably carried out at the reflux temperature of the liquid medium.

Compounds of formula (IX) are known in the art, while compounds of formula (VIII) may be prepared by reacting the known compound 4-oxo-trans-decahydroquinoline with a suitable catalyst, e.g. p-toluenesulphonic acid, trifluoroboronate, zinc chloride or titanium tetrachloride. , suitably in an inert organic solvent, e.g. hexane, benzene or toluene, and at the reflux temperature of the solvent, with an amine of general formula R 2 -NH 2 (X) wherein r 2 is as defined in formula (I), the water formed being removed by azeotropic distillation . The resulting imino derivative is hydrogenated with sodium borohydride in methanol or lithium hydride in tetrahydrofuran. This hydrogenation can be performed over a wide temperature range.

According to the above method, the compounds of formula (VIII) are prepared as a mixture of axial and equatorial isomers. This mixture can be divided into two fractions due to the different solubilities of the hydrochloride of the isomers in an aqueous solution having a pH of 3 or by chromatography. Thus, the compounds of formulas (I) and (III) may be obtained either as a mixture of their axial and equatorial isomers or as their axial or equatorial isomer. Until now, however, it has not been possible to determine whether a fraction that is insoluble in water having a pH of 3 is either an axial or an equatorial isomer, or possibly a mixture of both, and the same applies to the soluble fraction. Therefore, the phrase "Form a" will hereinafter be used to denote a compound of formula (VIII) having an Rf value in the selected thin layer chromatography experiment lower than the Rf value of the corresponding isomeric compound of formula (VIII), hereinafter referred to as "Form b". . The results of this thin layer chromatography test are illustrated in the accompanying drawing, and the details of the test, as well as the details of the test, are as follows: 5 63023 Turner: silica gel 60 F.254 (manufactured by Merck) thickness: 0.25 mm

Development and saturation solvent (in ammonia gas) hexane: 80 ml 2-propanol: 20 ml method: ascending 13 cm samples: 200 yug (chloroform solution) expression: UV, 2540 A, in iodine vapor (1) 4-phenylamino-trans-decahydroquinoline (form a ) (2) 4-phenylamino-trans-decahydroquinoline (form b)

The same expressions "Form a" and "Form b" will be used hereinafter for the corresponding isomers of the compounds of formulas (III) and (I) starting from either "Form a" or "Form b" of the compounds of formula (VIII). Thus, the process described above for the preparation of derivatives of formula (I) using derivatives of formula (VIII) as starting materials is equally applicable to either "form a" or "form b" of derivatives of formula (VIII) using the corresponding formula of formula (I). to prepare the isomer.

The compounds of the invention have been found to have valuable pharmacological properties, as they have been found to have a useful analgesic effect, which is very strong for some compounds. There is also no morphine-like effect associated with this analgesic effect.

Because of these properties, the compounds are particularly valuable in the treatment of pain.

Thus, the compounds of the invention may be used to alleviate pain in a subject in need of such treatment by administering to the subject an effective amount of a suitable compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Analgesics are drugs that relieve pain by acting on the central nervous system to raise the pain threshold, but without disturbing consciousness or altering any other sensitivity properties.

Substances that are primarily used to relieve pain symptoms can be divided into two general groups to facilitate classification: 1) Narcotic analgesics such as opium derivatives Of these, morphine is one of the most important drugs with numerous valuable properties, one of the main effects of which is pain relief.

No other drugs are so commonly used to relieve various types of severe pain. Unfortunately, morphine causes a morbid feeling of well-being and leads to surrender to the drug as a slave as well as difficulty breathing.

Long-term administration of morphine or a related compound develops tolerance to the analgesic effect, with the dose having to be increased periodically to achieve corresponding pain relief. For these reasons, it is generally believed that morphine and its derivatives should not be used against pain in the event that another analgesic is sufficient.

The analgesic compounds according to the invention do not have any morphine-like effects and their use can therefore be recommended in a greater number of cases than the use of morphine derivatives.

2) Non-narcotic analgesics, e.g., salicylate derivatives These are generally less effective than narcotic analgesics, but on the other hand they do not make breathing difficult or cause a preference for the drug or cause this only to a very small extent.

It has been found that the analgesic compounds of the invention are quite advantageous compared to most commonly used non-narcotic analgesics.

7 63023

In addition to the analgesic effect described above, certain compounds of formula (I), i.e. those in which R1 represents a branched or straight-chain alkoxy group, have also been found to have useful pharmacological properties which make them of considerable value in the treatment of cardiovascular disorders. blood pressure.

Thus, these compounds of the invention may also be used to treat pathological disorders of arterial pressure, in particular hypertension, in a subject in need of such treatment by administering to the subject at least one suitable compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

There are numerous types of hypertension, but today there is no known cure for all of these different types of the disease, as personal cases vary widely in terms of their response to different drugs.

m For this reason, there are numerous antihypertensive drugs that can be used to treat different types of hypertension.

Among these, some compounds are known which exert a ganglioplegic effect so as to interrupt sympathetic-voltage impulses and thus cause a tension in the vascular wall tension. Others are characterized by a relatively narrow safety margin between a therapeutic dose and a toxic dose.

Finally, it is known that some anti-stressors cause such a sudden and strong anti-stress effect that it is difficult to control their effect.

The stress-reducing compounds prepared according to the invention do not have these disadvantages.

630 2 3

Pharmacological experiments have been performed to demonstrate the analgesic and anti-stress effect of the compounds of the invention.

1) Pain relieving effect

The following compounds of formula I have been found to be particularly useful as analgesics: 4 - ((N-phenyl-N-acetyl) -amino) -1- (3- (4-fluorobenzoyl) -propyl) -trans-decahydroquinoline (Compound A), 4 - ((N-phenyl-N-propionyl) amino) -1- (3- (4-fluorobenzoyl) propyl) -trans-decahydroquinoline (Compound B) / 4 - ((N-phenyl -N-butyryl) -amino) -1- (3- (4-fluorobenzoyl) -propyl) -trans-decahydroquinoline (Compound C), 4 - ((N-phenyl-N-valeryl) -amino) -1 - (3- (fluorobenzoyl) propyl) -trans-decahydroquinoline (Compound D), 4 - ((N-methoxyphenyl-N-propionyl) amino) -1- (3- (4-fluorobenzoyl) propyl ) -trans-decahydroquinoline (Compound E), 4 - ((N-ethoxycarbonyl-N-phenyl) -amino) -1- (3- (4-fluorobenzoyl) -propyl) -trans-decahydroquinoline (Compound F), ^ 4 - ((N-nicotinoyl-N-phenyl) -amino) -1- (3- (4-fluorobenzoyl) -propyl) -trans-decahydroquinoline (Compound G), 4 - ((N-isonicotinoyl-N-phenyl) ) -amino) -1- (3- (4-fluorobenzoyl) -propyl-trans-decahydroquinoline (Compound H), 4 - ((N-phenyl-N-propionyl) amino) -1- (3- (benzoylpropyl) -trans-decahydroquinoline (Compound I), 4 - ((N-acetyl-N- phenyl) amino) -1- (4- (4-fluorobenzoyl) butyl) trans-decahydroquinoline (Compound K), 4 - ((N-cyclohexyl-N-propionyl) amino) -1- (3- ( 4-Fluorobenzoyl) propyl) -trans-decahydroquinoline (Compound L), 4 - ((N-methoxycarbosyl-N-phenyl) -amino) -1- (3- (4-fluorobenzoyl) -propyl) -trans-decahydroquinoline ( compound M).

The first experiment was performed using the method described by Koster (Fed. Proc. 18, 412, 1959) using 20 mice, 9,63023 that had been without food for 18 hours.

Each group of animals, except the control animals, was administered an intraperitoneal dose of the test compound so that each group received a higher dose than the previous one. Thirty minutes after administration, 0.2 ml of 0.25% acetic acid solution / 10 g body weight was administered intraperitoneally to the animals in each group as well as to the control animals.

Within 20 minutes after acetic acid injection, the number of characteristic twists performed by the animals was recorded. The absence of convulsions corresponds to animals that were under the influence of an analgesic.

The AD50 value was recorded, i.e., the dose of compound that caused pain relief in half of the treated animals.

The test results are shown in the following table:

Table I

Compound_AD5Q mg / kq_Compound_AD50 mg / kg A 38 g 80 B 25 h 100 C 30 i 75 D 25 K 100 E 55 L 100 E_100__M _ <50_

The same experiment was performed with five commonly used analgesics, giving the following results:

Table II

10 63023

Compound_AD50 mg / kg acetylsalicylic acid 150 antipyrine 120 phenacetin 160 glafenine 110 pentazocine 45

The second experiment was performed using the method of Nilsen (Acta Pharmacol, et Toxicol. 18, 10, 1961) using groups of 10 mice.

The animals were connected to an electrical power source with two electrodes inserted into their tails.

A threshold voltage was then determined, i.e., the minimum voltage at which the animals would wiggle at least once in two during two consecutive electric shocks. The test compound was then administered intraperitoneally. At different time points after administration, four consecutive electric shocks were administered at the specified threshold voltage, and it was found that the animal was protected unless it wiggled after any electric shock.

The dose of AD50 of the compound that suppressed the vetch was recorded.

The results of this experiment are shown in the following table:

Table III

Compound_AD50 mg / kg A 110 B 30 C 70

The same experiment was also performed with three known painkillers in 11,63023, and the following results were obtained:

Table IV

Compound_AD50 mg / kg

Acetylsalicylic acid 1100

Antipyrine 400

Phenacetin 450

Other pharmacological experiments were performed to determine the analgesic effect of the preferred compound of the invention, namely: 4- [4- (N-phenyl-N-propionyl) -amino] -3- (4-fluorobenzoyl) -propyl] -7-trans-decahydroquinoline (Compound B) .

The first experiment was performed by applying the Koster method described above, but using a subcutaneous injection of the test compound.

Compound B was compared with two well-known analgesics, and the following results were obtained:

Table V

Compound_AD50 mg / kg B 2 pethidine 7

Pentazocine 5

The second experiment was performed by applying the Nilsen test described above but administering the test compound by subcutaneous injection.

Compound B was compared with pethidine and pentazocine, two well-known analgesics, and the following results were obtained: 63023 12

Table VI

Compound_AD50 mg / kq B 4

Pethidine 7

Pentazocine 12

The third experiment was performed using the method described by Siegmund et al. (Proc. Soc. Exp. Biol. Med. 95, 729, 1957) using groups of 10 male mice.

A typical syndrome was induced in animals by intraperitoneal injection of 0.25 ml of a 0.02% aqueous solution of 2-phenyl-1,4-benzoquinone (phenylbenzoquinone).

The syndrome in question is characterized by intermittent abdominal cramps, twisting and twisting of the body, and straightening of the hind limbs. The number of movements that occurred over a 30 minute period, starting 15 minutes after phenylbenzoquinone injection, was recorded.

The test compound was injected 30 minutes before phenylbenzoquinone so that each group received a higher dose than the previous group, and the control group received only phenylbenzoquinone.

The AD50 value was recorded, i.e., the dose of compound that reduced at least half the number of twists in half of the animals compared to the number of twists in the control group.

The following results were achieved:

Table VII

13 63023

Compound_AD50 mq / kq B 7

Acetylsalicylic acid 50

Antipyrine 100

Phenacetin 80

Glafenine 325

The fourth experiment was performed using the method of Charlier et al. (Arch. Int. Pharmacodyn. 134, 306, 1961) using groups of 10 rats.

The animals were connected to an electrical power source with two electrodes, one attached to the tail and the other kept in the anus. The pain threshold voltage for each rat was then determined by bringing the current to a voltage of 2 volts and increasing the current by increasing the voltage by one volt at a time until the animal screamed. This comparative experiment was repeated 3 times at 15 minute intervals. The test compound was then administered intraperitoneally, and starting from the threshold voltage determined above, the voltage that caused the animals to wiggle was measured every 10 minutes for 2 hours.

The results were plotted using the scale presented by Winter and Flataker (J. Pharmacol. Exp. Therap. 98, 305, 1950) and the AD50 values obtained are listed in the following table.

Table Vili

Compound_AD50 mq / kq B 30

Acetylsalicylic acid 1300

Antipyrine 500

Phenacetin 750

Pethidine 50 14 63023

Finally, the experiment was performed using the method of d'Amour and Smith (J.Pharm.Exp. Ther. T2, 74 1941) using groups of 10 male rats weighing about 200 g.

A 300 watt heat lamp was focused on the tip of the rat's tail at a distance such that a typical tail flicktail was observed after 4 to 6 seconds of radiation.

The animals, with the exception of the control group, were administered the test compound subcutaneously, and the time elapsed from the onset of the radiation to the first reaction of the animal (reaction time) was recorded as compared with the reaction time of the control animals.

The AD50 values obtained are shown in the following table:

Table IX

Compound_AD50 mg / kg B 2.5

Pethidine 5.5

Pentazocine 3

From the foregoing experiments, it can be concluded that the compounds of the invention have analgesic properties that are much superior to those of known analgesics.

2) Antihypertensive effect

As indicated above, those compounds of formula (I) wherein R 1 represents a branched or straight chain alkoxy group are also useful in the treatment of hypertension.

In this context, the most suitable compound of the invention is: 4 - ((N-phenyl-N-ethoxycarbonyl) amino) -1- (3- (4-fluorobenzoyl) propyl) -trans-decahydroquinoline (Compound F).

A pharmacological experiment was performed to demonstrate the antihypertensive effect of Compound F.

is 63023 This experiment was performed on male rats belonging to a strain specially developed to produce animals with high blood pressure using the method of Okamoto and Aoki (Jap. Circul. J. 22, 282, 1963).

The animals used were approximately 10 weeks of age and had blood pressure in the range of 180 mm Hg.

This experiment was divided into two series. In the first series, the test compound was administered as a single dose intraperitoneally to each animal, and the animal's venous pressure was measured once an hour for six hours after compound administration.

In the second series, the test compound was administered in the same manner every day for eleven consecutive days, and arterial pressure was measured daily during this period.

The amount of compound administered was varied from animal to animal in the first set of experiments.

The following results were achieved:

Table X

Arterial blood- Arterial blood- Type of treatment Dose mg / kg maximum pressure maximum pressure -__ decrease mm Hg reduction time

Single dose 3 27 3 hours 10 44 4 "Daily dose (11 days) 10 29 8 days From these results, it can be concluded that compound P has a potent antihypertensive effect.

3) Acute toxicity

Acute toxicity experiments were performed in rats and mice, and the animals were observed for 12 days after a single administration of the compound.

The following results were achieved:

a) compound B

63023

Animal_Method LD50 (mp / kp)

Mice intra-gastrointestinal 500

Rotat "" 350

Mice intraperitoneally 55

Rotat "" 55

Mice subcutaneously 550

h) Compound F

Animal_Method of administration_LD50 (mp / kg)

Mice gastrointestinal 750

Rotat "" 450

Rats intravenously 15

Mice ... »32 These numerical values are very advantageous when compared to the effective doses at which the effects were achieved as described above. From this comparison, it can be seen that there is a rather wide safety margin between the toxic doses and the therapeutic doses of the preferred compounds of the invention.

It should be noted that the compounds of the invention are normally administered for pharmaceutical use as a pharmaceutical composition containing as active ingredient at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, together with a suitable pharmaceutical carrier and / or diluent.

For pharmaceutical use, the composition is conveniently presented in unit dosage form suitable for the intended use, e.g., as a coated or uncoated tablet or hard or soft gelatin capsule for oral administration, as an injectable solution, or as a suppository for oral administration.

Regardless of the form of the mixture, the pharmaceutical composition will normally contain at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof together with a suitable pharmaceutical diluent or carrier, exemplified by one or more of the following: milk, sugar, starches, talc, talc, i7 63023 magnesium , alginic acid, colloidal silica or spice.

The following examples illustrate the invention:

Example 1 4- [N- (N-Phenyl-N-propionyl) -amino] -7-1- [3- (4-fluorobenzoyl) -N-pyrrole] 7-trans-decahydro-quinoline hydrochloride (Form (a)) Preparation of trans-decahydroquinoline A solution of 76.8 g (0.5 moles) of 4-oxo-trans-decahydroquinoline and 1.0 g of p-toluenesulfonic acid in 350 ml of hexane was refluxed in a 1 liter beaker and 46, 3 g (0.5 moles) of aniline.

Refluxing was continued until the water formed was completely removed using a Dean-Starck system and 140 ml of hexane was distilled off. The solution was then allowed to cool, and 250 ml of henzene was added thereto. The reaction medium was washed first with water, then with dilute aqueous sodium hydroxide solution, and finally again with water. The resulting solution was dried over anhydrous sodium sulfate, filtered and the solvents were removed to give 102.4 g of crude 4-phenylimino-trans-decahydroquinoline (yield 89%).

An amount of 102.4 g of 4-phenylimino-trans-decahydroquinoline thus obtained was dissolved in 190 ml of methanol containing 200 mg of sodium hydroxide in a 1 liter beaker, and the temperature of the solution was maintained at about 20 ° C.

A solution of 20 g of sodium borohydride in 20 ml of methanol, stabilized with 600 mg of sodium hydroxide, was added, after which the temperature of the reaction mixture was maintained at 20-22 ° C for a few hours.

The solution was then finally heated at 40 ° C for 8 hours, after which it was allowed to cool. The solvent was removed and the residue was taken up in 150 ml of hensene and 250 ml of water.

The mixture was decanted and the aqueous phase was extracted with benzene. The organic phase was then extracted with 240 ml of 4N hydrochloric acid. The mixture was decanted and sodium hydroxide was added until pH = 3. Filtered to give an acidic aqueous filtrate and a precipitate, m.p. 63023 which was dried to give 43.8 g of 4-phenylamino-trans-decahydroquinoline hydrochloride (Form a).

Yield 33%, melting point 265-270 ° C.

Isolation of form b

The acidic aqueous filtrate was basified by the addition of sodium hydroxide, and extracted with henzene. The resulting mixture was decanted and the organic phase was washed with water, dried over anhydrous sodium sulfate and filtered. The benzene was removed and the residue was taken up in 35 ml of diethyl ether. The solution thus obtained was cooled to 0-5 ° C, filtered and washed with diethyl ether to give 9.2 g of 4-phenylamino-tranB-decahydroquinoline (form b).

Yield 7%, melting point 118 ... 120 ° C.

Using the same procedure but using the appropriate starting materials, the following compounds were prepared:

Compound Melting point ° C

4- (4-N-phenylphenyl) amino-trans-decahydroquinoline 92-94 4- (4-Methoxyphenyl) -amino-trans-decahydroquinoline 144-145 4-Benzylamino-trans-decahydroquinoline non-crystallized 4- (1-Naphthylamino-trans-decahydroquinoline "4-cyclohexylamino-trans-decahydroquinoline" b) 1- [3- (4-fluorobenzoyl) -propyl 7-4-phenylamino-trans-decahydroquinoline dihydrochloride manufacture (form a)

In a 4-liter beaker, a solution of 230 g (1 mole) of 4-phenylamino-trans-decahydroquinoline (form a) in 920 ml of n-butanol was boiled under reflux in the presence of 100 g of sodium bicarbonate. While continuing the redistillation, a solution of 274 g (1.12 moles) of 4-chloro-1,1-ethylenedioxy-1- (4-fluorophenyl) butane in 200 ml of n-butanol was added, and the redistillation was continued until the formed the water had been completely removed using the Dean-Stark system. The solution was allowed to cool to 50 ° C, and the salts thus precipitated were filtered off.

The solvent was evaporated from the solution under reduced pressure, and the resulting residue was taken up in 2500 ml of 2500 ml of benzene. The solution thus obtained was extracted with a solution of 250 ml of concentrated hydrochloric acid in 1250 ml of water. The resulting mixture was decanted and the hydrogen chloride solution was stirred for 3 hours, after which the solution was basified and extracted with benzene. The resulting organic phase was washed with water, dried over anhydrous sodium sulfate and filtered, and the benzene was removed. The resulting residue was taken up in ethyl acetate, and a 2-propanol solution of gaseous hydrochloric acid was added. The precipitate formed was filtered off, washed with ethyl acetate and dried. The obtained crude product was recrystallized from a mixture of ethyl acetate and methanol to give 303 g of 1- [3- (4-fluorobenzoyl) propyl] -4-phenylamino-trans-decahydroquinoline dihydrochloride (Form a).

Yield 64t8%, melting point 204 ... 206 ° C.

By applying the same procedure but using the appropriate starting compounds, the following compounds were prepared, the melting points of which are indicated after recrystallization from the indicated solvents.

Compound Melting point ° C

1- [3- (4-fluorobenzoyl) propyl] -4- (4-methoxy-179-182 phenyl) amino-trans-decahydroquinoline dihydro (ethyl acetate / chloride (form a) methanol) 1- “3- (4-Fluorobenzoyl) propyl] -4- (4-methyl-188-194 phenyl) amino-trans-decahydroquinoline dihydro (ethyl acetate / chloride (form a) methanol) 1- (3-benzoylpropyl) ) -4-> phenylamino-trans-206-208 decahydroquinoline hydrochloride (form a) (ethanol) 1- [3- (4-methylbenzoyl) propyl] -4-phenylamino-trans-decahydroquinoline hydrochloride ( Form a) 226-227 (ethyl acetate / methanol) 1- [3- (4-chlorobenzoyl) -propyl] -4-phenyl-248-249 amino-trans-decahydroquinoline hydrochloride (Form a) (methanol / ethanol) 1- [3- (4-fluorobenzoyl) propyl] -4-phenyl-227-230 amino-trans-decahydroquinoline dihydrochloride (form b) ethanol 20 63023 1- [3- (4-fluorobenzoyl) ) - propyl-7- (4- (4-methyl-235, 2,338-phenyl) -amino-trayns-decahydroquinoline-dihydro- (ethyl acetate / chloride (form b) methanol) 1- (4-Bromobenzoyl) -propyl-7-4-phenylamino-241-243 Trans-decahydroquinoline hydrochloride (Form a) (ethanol / methanol) 1- [3- (4-methoxybenzoyl) -propyl] -4-phenyl-230. ..232 amino-trans-decahydroquinoline hydrochloride (ethanol) (form a) 1- (4-fluorobenzoylmethyl) -4-phenylamino-255-257 trans-decahydroquinoline hydrochloride (form a) (2-propanol) 1-Benzoylmethyl-4-phenylamino-trans-deca-230 (decomposed) hydroquinoline hydrochloride (form a) (ethanol / methanol) 1- [3- (2-thenoyl) -propyl] -4-phenylamino-167 .. .169 trans-decahydroquinoline dihydrochloride (form a) (ethyl acetate / methanol) 1-phenethyl-4-phenylamino-trans-decahydroquino-258-260 line hydrochloride (form a) (ethanol) 1-cinnamyl-4-phenylamino -trans-decahydro-170-172 quinoline acid oxalate (form a) (2-propanol) 1- (3-phenylpropyl) -4-phenylamino-trans-148-150 decahydroquinoline oxalate (form a) ) (2-propanol) 1- [3- (4-chlorobenzoyl) -propyl] -4- [(4-224-226 methoxyphenyl)] li) -amino 7-trans-decahydroquinoline 1- (ethyl acetate / dihydrochloride (form a) methanol) 1- [4 '(4-fluorobenzoyl) -butyl-7-4-phenyl-182-1884 amino-trans-decahydroquinoline hydrochloride (ethanol) (form a) 1- (2-phenoxyethyl) -4-phenylamino-trans-decahydro-165-167 quinoline (form a) (methanol) 1- [3- (4-fluorophenylthio) -propyl-7-4-phenyl-83-85 amino-trans-decahydroquinoline (form a) (heptane) 1- [3- (4-fluorobenzoyl) -propyl] -7-4-benzyl-255-256 amino-trans -decahydroquinoline-1-hydrochloride (ethyl acetate / (form a) methanol) 21,63023 1- [3- (4-fluorobenzoyl) -propyl] -4-4-cyclo-211..214 hexylamino-trans-decahydroquinoline hydrochloride (form a) methanol) 1 - [(3- (4-fluorobenzoyl) propyl] -4- (1-naphthylamino) trans-decahydroquinoline non-crystallized c) 4 - [(N-phenyl-N-propionyl) amino] -7- Preparation of 1- [3- (4-fluorobenzoyl) propyl] -7-trans-decahydroquinoline hydrochloride

With stirring, 394 g (1 mol) of 1- [3- (4-fluorobenzoyl) propyl] -4-phenylamino-trans-decahydroquinoline (form a) were dissolved in 800 ml of dichloroethane in a 2-liter flask. The resulting solution was cooled to about 20 ° C and a solution of 105 ml of propionyl chloride in 105 ml of dichloroethane was added.

The reaction mixture was then kept at 20 ° C for 1 hour, after which it was heated at 45-50 ° C for 16 hours. The solution was then cooled to 10-15 ° C and the precipitate formed by filtration was 1- [3- (4-fluorobenzoyl) propyl] -4-4-phenylamino-trans-decahydroquinoline dihydrochloride.

Excess propionyl chloride was hydrolyzed with 120 ml of methanol and the solution was evaporated to dryness.

The residue obtained was taken up in 150 ml of acetone, refluxed and the solvent was removed by distillation. This treatment was repeated twice.

at the reflux temperature of the solvent, the residue was dissolved in 150 ml of acetone, and a 2-propanol solution with a small amount of gaseous hydrochloric acid was added. The resulting solution was allowed to crystallize at room temperature, and the formed precipitate was filtered off, washed with acetone and dried to give 318 g of a crude product. Recrystallization from a mixture of ethyl acetate and methanol (2: 1 by volume) gave 263 g of 4 - [(N-phenyl-N-propionyl) -amino] -1- [3- (4-fluorobenzoyl] -7-trans-decahydroquinoline hydrochloride ( Yield: 54%, melting point 158 ... 160 ° C.

By applying the same procedure but using the appropriate starting compounds, the following compounds were prepared, the melting points of which were marked after recrystallization from said solvents.

Compound Melting point ° C

4 - [(N-phenyl-N-acetyl) -amino-7-1- [3- (4-fluoro-168-170 benzoyl) -propyl] 7-trans-decahydroquinoline (ethyl acetate / hydrochloride) (Form a) methanol) 4 - ["(N-phenyl-N-butyryl) -amino] -7-1- [3- (4-174.175 fluorobenzoyl) -propyl] 7-trans-decahydroquino- (ethyl acetate / line) hydrochloride (form a) methanol) 4 - [- (N-phenyl-N-valeryl) amino] -7-1- [3- (4-158-160 fluorobenzoyl) propyl] trans-decahydroquino- (ethyl acetate) line hydrochloride (form a) methanol) 4 - [(N-phenyl-N-propionyl) amino] -7-1- [3- (4-161-162 fluorobenzoyl) propyl] 7-trans-decahydroquino- ( ethyl acetate / line oxalate (form b) acetone) 4 - ['(N-4-methylphenyl-N-propionyl) -amino] -7-20-2020 .203 / 3- (4-fluorobenzoyl) -propyl 7- Trans-decahydro- (ethyl acetate / quinoline hydrochloride (form a) methanol) 4- [N- (N-4-methoxyphenyl-N-propionyl) -amino] -7-1193-1953- (3- (4-fluorobenzoyl)) -propyl_7-trans-decahydro- (ethyl acetate / quinoline hydrochloride (form a) methanol i) 4 - [(N-phenyl-N-acetyl) -amino] -7- (3-benzoyl-227-2288 propyl) -trans-decahydroquinoline hydrochloride (ethyl acetate / (form a) methanol) “(N-Phenyl-N-propionyl) -amino] -7-1- (3-benzo-128-130-yl-propyl) -trans-decahydroquinoline hydrochloride (ethyl acetate / di (form a) methanol) 4- [ (N-Phenyl-N-acetyl) -amino] -7-1- [3- (4-methyl-185-1886 benzoyl) -propyl] 7-trans-decahydroquinoline hydrochloride (ethyl acetate (form a)) methanol) 4 - [(N-phenyl-N-propionyl) amino] -7-1- [3- (4,214-215 methylbenzoyl) -propyl] 7-trans-decahydroquino- (ethyl acetate / line hydrochloride (form and methanol 23 6 3 0 2 3 4 - [(N-phenyl-N-acetyl) -amino] -7- [3- (4-chloro-193-194 benzoyl) -propyl] -trans-decahydroquinoline- (ethyl acetate / hydrochloride (form a) methanol) 4 - [- (N-phenyl-N-propionyl) -amino] -7-1- [3- (4-130-131 chlorobenzoyl) -propyl] -trans-decahydroquino- (ethyl acetate / line hydrochloride (form a) methanol) 4 - / - (N-acetyl-N-phenyl li) -amino_7-1 - ["3- (4-fluoro-188-190 benzoyl) -propyl 7-trans-decahydroquinoline 1- (ethyl acetate / hydrochloride (form b) methanol) 4 - /" (N-benzoyl- N-phenyl) -amino_7-1- [3- (4-fluoro-139-141 benzoyl) -propyl] -7-trans-decahydroquinoline (ethyl acetate / hydrochloride (form a) hexane) 4 - / (N-nicotionyl) -N-phenyl) -amino_7-1- [3- (4- (211-2133) fluorobenzoyl) -propyl] 7-trans-decahydroquino- (methylethylcholine-dihydrochloride (form a) ni / hexane) (N-Isonicotionyl-N-phenyl) -amino-7-1- [3- (4-213-215 fluorobenzoyl) -propyl] -7-trans-decahydroquino- (methylethylcholine-dihydrochloride (Form a)) Hexane) 4 - [(N-2-furoyl-N-phenyl) -amino] -7-1- [3- (4-fluoro-230-231 benzoyl) -propyl] 7-trans-decahydroquinoline (ethyl acetate / hydrochloride) (Form a) Methanol) 4 - [(N-acetyl-N-phenyl) -amino] -7-1- [3- (4-bromo-219-221-benzoyl) -propyl] 7-trans-decahydroquinoline (ethyl acetate) / hydrochloride (form a) methanol) 4 - [- (N-phenyl-N-propi onyl) -amino_7-1- [3- (4-bromo-143-145 benzoyl) -propyl] 7-trans-decahydroquinoline (ethyl acetate / hydrochloride (form a) methanol 4 - [(N-acetyl-N -phenyl) -amino_7-1- [3- (4-methoxy-184-186 benzoyl) -propyl 7-trans-decahydroquinoline- (ethyl acetate / hydrochloride (form a) methanol) 4 - / - (N-phenyl) -N-propionyl) -amino-7-1- [3- (4-methoxy-214-216 benzoyl) -propyl] 7-trans-decahydroquinoline- (ethyl acetate / hydrochloride (form a) methanol) 24,6302 3 4- ~ (N-acetyl-N-enyl) -amino_7-1- (4-fluoro-236 benzoylmethyl) -trans-decahydroquinoline (acetone) hydrochloride (form a) 4 - [(N-phenyl-N- propionyl-amino-Zl- (4-fluoro-225 ... 227 benzoylmethyl) -trans-decahydroquinoline- (ethyl acetate / hydrochloride (form a) methanol) 4- [1- (N-acetyl-N-enyl) - amino_7-1-benzoyl-233-235 methyl-trans-decahydroquinoline hydrochloride (ethyl acetate / (form a) methanol) 4 - [(N-phenyl-N-propionyl) -amino] -7'-benzoyl-229 methyl trans-decahydroquinolin n-hydrochloride (ethyl acetate / (form a) methanol) 4 - [((N-acetyl-N-enyl)) amino] -7 ", 1" -? "- 3" (4-theno-205..207-yl) - propyl 7-trans-decahydroquinoline hydro- (ethyl acetate / chloride (form a) methanol) 4 - [(N-phenyl-N-propionyl) -amino] -7-1- [3- (2-11-113-tenoyl) ) -propyl_7-trans-decahydroquinoline- (acetone hydrochloride (form a) 4 - [(N-acetyl-N-4-methoxyphenyl) -amino] -7-1193-1954 "3- (4-chlorobenzoyl) -propyl 7-trans-decahydro- (ethyl acetate / quinoline hydrochloride (form a) methanol) 4 - [(N-4-methoxyphenyl-N-propionyl) -amino] -7-1-213-215-1-3- ( 4-Chlorobenzoyl) -propyl] -7-trans-decahydro- (acetone) quinoline hydrochloride (Form a) 4 - [(N-Acetyl-N-phenyl) -amino] -7-1- [4- (4-fluoro-212). .214 benzoyl) -butyl 7-trans-decahydroquinoline- (acetone) hydrochloride (form a) 4 -C (N-phenyl-N-propionyl) -amino_7-1- [4- (4-fluoro-162 ... 164 benzoyl) -butyl 7-trans-decahydroquinoline hydro- (ethyl acetate) chloride (form a) 4- [(N-acetyl-N-phenyl) -amino_7-1-benzyl-180-182 trans-decahydroquinoline hydrochloride (form a) (ethyl acetate) 25 6 3 0 2 3 4 - [(N-phenyl-N-propionyl) -amino] -7'-benzyl - 198 .. .200 trans-decahydroquinoline hydrochloride (form a) (ethyl acetate / methanol) 4 - [(N-acetyl-N-phenyl) -amino_7-1-feaethyl-232-234 trans-decahydroquinoline hydrochloride (form a) (ethyl acetate / methanol) 4 - [- (N-phenyl-N-propionyl) -amino] -7-1'-phenethyl-231-233 trans-decahydroquinoline hydrochloride (form a) (ethyl acetate / methanol) 4- (N-acetyl-N-phenyl) -amino] -7- (3-phenyl-196..198 propyl) -trans-decahydroquinoline hydrochloride (ethyl acetate / (form a) methanol) 4 - (- N- phenyl-N-propionyl) amino-7 ', 1' (3-phenyl-210 to 212 propyl) -trans-decahydroquinoline hydrochloride (ethyl acetate / (form a) methanol) 4 - [(N-acetyl-N-phenyl) ) -amino_7-1-cyananyl-136. .138 trans-decahydroquinoline (form a) (heptane) 4- [** (N-benzyl-N-propionyl) -amino] -7-1- [3- - 147 ... 149 fluorobenzoyl over) -nropyl 7-trans-decahydroquino- (ethyl acetate / line hydrochloride (form a) diethyl ether) 4 - [(N-1-naphthyl-N-propionyl) -amino] -7- (3- 122-124 (fluorobenzoyl) -propyl 7-trans-decahydroquino- (ethyl acetate / line hydrochloride (form h) methanol) 4 - [(N-cyclohexyl-N-propionyl) -amino] -7-1- [3- 154-156 (4-fluorobenzoyl) »* .propyl 7-trans-decahydroquino- (ethyl acetate / line hydrochloride (form a) methanol) 4 - [(N-cyclohexyl-N-propionyl) -amino] -7-1- 3 '- 178-180 (4-fluorobenzoyl) -nropyl 7-trans-decahydroquino- (ethyl acetate / linoleic acid oxalate (form b) methanol) 4 - [(N-phenyl-N-acetyl) - amino_7-1 - ["3- (4-fluoro-158-160 benzoyl) -propyl 7-trans-decahydroquinoline- (ethyl acetate / hydrochloride (form a) methanol) 26 63023 4 - [(N-phenyl- N-propionyl) -amino-1- (2-phenoxy-159-1161 ethyl) -trans-decahydroquinoline hydrochloride (ethyl acetate / (form a) methanol) 4 - [(N-phenyl-N-propionyl) ) -amino_7 “1" Z "* 3- (4- 120 ... 12 2 Fluorophenylthio) propyl 7-traps decahydrochloro- (ethyl acetate / line hydrochloride (form a) methanol) 4 - [(N-acetyl-N-phenyl) amino-7-1- " 3- (4-Fluoro-150.-152 phenylthio) -propyl 7-trans-decahydroquinoline (ethyl acetate / hydrochloride (form a) methanol)

Example 2 4 - [- (N-Phenyl-N-propionyl) -amino] -7-1- [3- (4-fluorobenzoyl) -propyl] -7-trans-decahydroquinoline hydrochloride (Form a) 3.94 g (0.085 mol) ) 1 - [(4-Fluorobenzoyl) propyl] -4-4-phenylamino-trans-decahydroquinoline hydrochloride (Form a) prepared as described in Example 1 was dissolved in 20 ml of dimethylformamide, and 5 , 5 ml of propionyl chloride.

The mixture was heated at 60-80 ° C for 40 hours, and 5 ml of methanol was added.

The reaction mixture was distilled at 80 ° C under reduced pressure until 12 ml of the solution was distilled off, and the residue was poured into dilute sodium hydroxide solution. The reaction mixture was extracted with diethyl ether, and the organic phase was washed with water and treated with activated carbon. The solvent was removed and the residue was dissolved in 150 ml of acetone at the reflux temperature of the solvent. A solution of 2-propanol in a small amount of gaseous hydrochloric acid was added, and the resulting solution was allowed to crystallize at room temperature. The resulting precipitate was filtered off, washed with acetone and dried to give 318 g of crude product.

Recrystallization from a mixture of ethyl acetate and methanol (2: 1 by volume) gave 263 g of 4- [4- (N-phenyl-N-propionyl) -amino] -7-1- [4- (4-fluorobenzoyl) -propyl] -7- (£££ αS-decahydroquinoline). “Hy ^ r ° - chloride (form a).

Yield 65.1%, melting point 158-160 ° C.

27 6302 3

Example 3 4 - [”(N-Phenyl-N-propionyl) -amino] -7-1- [3- (4-fluorobenzoyl) -propyl] 7-trans-decahydroquinoline hydrochloride (Form a)

A solution of 6 g (0.015 mol) of 1- [3- (4-fluorobenzoyl) -propyl] -4-4-phenylamino-trans-decahydroquinoline (form a) prepared according to Example 1 in 45 ml of propionic anhydride and a small amount of p-toluenesulfonic acid, heated at 100 ° C for 20 hours. After cooling the reaction mixture, methanol was added, and the procedure described in Example 1 (c) was applied to give 4.5 g of 4 - [(R-phenyl-N-propionyl) amino] -1-1 - [3- (4-fluorobenzoyl) -]. propyl 7-trans-decahydroquinoline hydrochloride (form a).

Yield 61.6%, melting point 158-160 ° C.

Example 4 4 - [* (N-Phenyl-N-propionyl) -amino] -7-1- [3- (4-fluorobenzoyl) -propyl] 7-trans-decahydroquinoline methanesulfonate (Form a)

A benzene solution containing 98 g (0.22 moles) of 4 - [(N-phenyl-N-propionyl) amino] -7-1- [3- (4-fluorobenzovyl) propyl] 7-trans- decahydroquinoline (form a) was acidified by the addition of 30 g of a 65% aqueous solution of methanesulfonic acid in 2-propanol until a pH of 3.5-4 was reached.

The acidic solution was evaporated to dryness and the residue was taken up in 600 ml of toluene. 100 ml of toluene were removed by azeotropic distillation, followed by crystallization and filtration to give 104 g of 4 - [(N-phenyl-N-proponyl) amino] -7-1 - [(3- (4-fluorobenzoyl) propyl). -trans-decahydroquinoline methanesulfonate (form a).

Yield 88%, melting point 132-134 ° C.

Example 5 (N-Ethoxycarbonyl-N-phenyl) -amino-7- [4- (3- (4-fluorobenzoyl) -propyl] -trans-decahydroquinoline hydrochloride (Form a) 55 g (0.14 moles of the 1-trans-decahydroquinoline hydrochloride) prepared according to Example 1. Β-3- (4-fluorobenzoyl) -propyl-7-4-phenylamino-trans-decahydroquinol was dissolved in 200 ml of dichloroethane, 16 g of ethyl chloroformate were added dropwise with stirring, and the reaction mixture was heated at 50-60 ° C for 16 hours. then the reaction mixture was allowed to cool to 20 ° C, and a 2-propanol solution of gaseous hydrochloric acid was added.

28 6 3023

Stirring was continued for 2-3 minutes, the mixture was evaporated to dryness and the residue was taken up in acetone. The reaction mixture was cooled to 0 ° C for 16 hours, and excess 1- [3- (4-fluorobenzoyl) -propyl] -4'-phenylamino-trans-decahydroquinoline was removed by filtration. The filtrate was evaporated to dryness and the residue was taken up in ethyl acetate.

The organic solution was cooled at 0 ° C for 16 hours to crystallize 4- [N- (N-ethoxycarbonyl-N-phenyl) -amino] -7- [3- (4-fluorobenzoyl) -propyl] -trans-decahydroquinoline hydrochloride ( form a), which was separated by filtration and recrystallized from a mixture of ethyl acetate and methanol.

Yield 31%, melting point 134-136 ° C.

By applying the same procedure but using the appropriate starting materials, the following compounds were prepared.

Compound Melting point ° C

4 - [(N-methoxycarbonyl-N-phenyl) amino] -1- [3- (4,194-196 fluorobenzoyl) propyl] -7-trans-decahydroquinoline (ethyl acetate) hydrochloride (form a) (N-sec-butoxycarbonyl-N-phenyl) -amino] -7-187-180 / 3- (4-fluorobenzoyl) -propyl-7-trans-decahydro- (ethyl acetate) quinoline hydrochloride (form a) 4- N- (Nn-butoxycarbonyl-N-phenyl) -amino] -7-118-183 / 3- (4-fluorobenzoyl) -propyl 7-1-trans-deca- (ethyl acetate) hydroquinoline hydrochloride (Form a) 4 - / (N-ethoxycarbonyl-N-phenyl) -amino-7-1-phenethyl-191-193 trans-decahydrocolinoline hydrochloride (form a) (ethyl acetate / methanol)

Claims (6)

29 6 3023 A process for the preparation of analgesic 4-amino-trans-decahydroquinoline derivatives of the general formula O R 1 -H-R 2 CO 6 and their pharmaceutically acceptable acid addition salts, wherein R 1 represents a branched or straight-chain alkyl or alkoxy group having 1. ..4 a carbon atom, or a phenyl, furyl or pyridyl group, R2 represents a phenyl group or a naphthyl, benzyl or cyclohexyl group optionally substituted by a methyl or methoxy radical, and r3 represents a benzyl, phenethyl, cinnamyl or a phenylpropyl group, or a group of the general formula An-YX (ID wherein A represents a branched or straight-chain alkylene group having 1 to 4 carbon atoms, Y represents an oxygen or sulfur atom or a carbonyl group, X represents a thienyl radical, or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom, or a methyl or methoxy group, and n is 0 or 1, provided that when n is 0, Y means a carbonyl group, characterized in that a) a compound of the general formula 303030 HH-B2 y \ yA is boiled using redistillation. (III) kA wherein r2 and R3 are as defined above, together with a compound of the following general formula O «· R1-C-Cl (IV) wherein R1 is as defined above to give the desired compound in the form of its free base, or b) boiling under redistillation using a compound of the general formula HH.B2 fYi. 1 (III) xAr in which R2 and R3 are as defined above, together with a compound of general formula OO nn R1-COC-R1 (V) in which R1 is as defined above, to give the desired compound of formula I in which R 1 is other than alkoxy, in the form of its free base, after which the free base thus obtained is, if desired, reacted with a suitable acid to form a pharmaceutically acceptable acid addition salt. 3i 63023 Process for the preparation of 4 - ((N-phenyl-N-acetyl) amino) -1- (3- (4-fluorobenzoyl) propyl) trans-decahydroquinoline according to Claim 1, characterized in that the starting materials used are a compound of the formula III and a compound of the formula IV or V in which R1 is methyl, r2 is enyl and R3 is 3- (4-fluorobenzoyl) -propyl, Process for the preparation of 4 - ((N-phenyl-N-propionyl) amino) -1- (3- (4-fluorobenzoyl) propyl) trans-decahydroquinoline according to Claim 1, characterized in that the starting materials a compound of formula III and a compound of formula IV or V are used wherein R 1 is ethyl, r 2 is phenyl and R 3 is 3- (4-fluorobenzoyl) propyl. Process for the preparation of 4 - ((N-phenyl-N-carbethoxy) amino) -1- (3- (4-fluorobenzoyl) propyl) trans-decahydroquinoline according to Claim 1, characterized in that the starting materials a compound of formula III and a compound of formula IV or V are used wherein R 1 is ethoxy, R 2 is phenyl and R 3 is 3- (4-fluorobenzoyl) propyl. 32 63023 A compound for the preparation of a smart linear 4-amino-trans-decahydroquinoline derivative having the formula 0 R1-4-H-R2 C0 and a pharmaceutically acceptable alkyl ester, wherein the formula R1 is an alkyl group or an alkyl group. 1 to 4 cholatomers, phenyl, furyl or pyridyl, r2 is optionally substituted with methyl or methoxy, phenyl, naphthyl, benzyl or cyclohexyl, and R3 is benzyl or benzyl. , phenethyl-, cinnamyl- or a phenyl group, or a group, all of the compounds of formula Αη-ϊ-Χ (II) i vilken formula A of the alkyl group and the alkyl group of the form of 1 to 4 chapters, Y of the group or a hydrogen atom or a carbonyl group, X is a substituent on a thienyl radical or an optionally monosubstituted phenyl radical and a fatty substituent on fluorine, chlorine or bromide, or methyl, methoxy or acetyl group, and 0 or 1, under the group, n * 0 beteck nar Y en carbonylgrupp, kännetecknat därav, att man a) under tillämpande av äterlopp kokar en förening med den allmänna formuleln 63023 HU-112 m R1-C-Cl (IV) in the formula R1 is selected from the group consisting of one or more of the compounds of formula HJJ-R2 or one of the formulas R2 and r3 is a form of the form of the form of the form of the form of the form 0 0 • N Rl-COC-Rl (V) 1 of the form of the form of the form of the form of the form of the form of the form of the form of the form of the form of the form of the form The alkoxy is in the form of a base which is free from the base of the reaction and reacted with a lamp to form a pharmaceutically acceptable sugar form.