BE854655A - 9-HYDROXYHEXAHYDROBENZO (C) QUINOLEINS AND SYNTHESIS INTERMEDIARIES - Google Patents

Description

       

  PFIZER INC.

  
  <EMI ID = 1.1>

  
derivatives, usable as agents acting on the central nervous system, in particular as analgesics and tranquilizers, as hypotensive agents in mammals and man, as agents for treating glaucoma and as diuretic agents; and this invention also relates to suitable intermediates and processes for the preparation of the aforementioned compounds.

  
Among these active compounds and their intermediates are the compounds of formula:

  

  <EMI ID = 2.1>


  
in which A is chosen from the group comprising:

  

  <EMI ID = 3.1>


  
and ketals and thioketals of compounds in which A has formula III ', where the ketal part has two to four carbon atoms, and pharmaceutically acceptable acid addition salts of compounds in which A has formula I' or II ', where -O-alkylene-O- is an alkylenedioxy group having from two to

  
  <EMI ID = 4.1>

  
  <EMI ID = 5.1>

  
foregoing can also be described as represented in Formulas I, II, III, IV, V, VI and II below.

  
Another possibility of nomenclature for the compounds described herein of formula I to IV is based on the replacement of the

  
  <EMI ID = 6.1>

  
methyl-3- (5-phenyl-2-pentyloxy) phenanthridine.

  
Despite the current availability of a number of analgesic agents, research for new and improved agents continues, highlighting the lack of

  
an agent that can be used to combat high pain with minimal side effects. The most commonly used agent, aspirin, is not of practical value for the control of severe pain and is known to have various undesirable side effects. Other stronger analgesic agents

  
like d-propoxyphene, codeine and morphine, have addictive properties. The need for improved and potent analgesic agents and therefore evident.

  
  <EMI ID = 7.1>

  
11-hydroxy-A -THC, have been described by Wilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), J. Med. Chem. 17,

  
  <EMI ID = 8.1>

  
U.S. Patents Nos 3,507,885 and 3,636,058 issued respectively on April 21, 1970 and January 18, 1972, describe

  
  <EMI ID = 9.1>

  
9 substituents such as oxo, hydrocarbyl, and hydroxy or chloro, hydrocarbylidene groups, and their appropriate intermediates.

  
The U.S. patent N [deg.] 3,649,650 issued March 14, 1972 describes a series of tetrahydro-6,6,9-trialkyl-6Hdibenzo [b, d] pyran derivatives having in position 1 a W-dialkylaminoalkoxy group, active as psychotherapeutic agents .

  
  <EMI ID = 10.1> <EMI ID = 11.1>

  
  <EMI ID = 12.1>

  
or alkylene, as hypotensive, psychotropic, sedative and

  
  <EMI ID = 13.1>

  
  <EMI ID = 14.1>

  
that they have the same utility as the corresponding 9-hydroxyl compounds, are described in German patent application N [deg.] 2,451,932 published on May 7, 1975.

  
  <EMI ID = 15.1>

  
describes a series of 3-alkoxy-dibenzo [b, dJpyranes having anti-arthritic, anti-inflammatory activity and activity on the central nervous system.

  
  <EMI ID = 16.1>

  
replacement of the pentyl group in position 3 of 7,8,9,10-

  
  <EMI ID = 17.1>

  
an alkoxy group (butoxy, pentyloxy, hexyloxy and octyloxy) and have found that it leads to biological inactivity. It is stated that the hexyloxy derivative exhibits a low activity of

  
  <EMI ID = 18.1>

  
activity at doses up to 20 mg / kg.

  
  <EMI ID = 19.1>

  
1200-1206 (1973) describe a comparison of 7,8,9,10-tetrahydro-

  
  <EMI ID = 20.1>

  
  <EMI ID = 21.1>

  
  <EMI ID = 22.1>

  
  <EMI ID = 23.1>

  
  <EMI ID = 24.1>

  
attached through an oxygen atom; and 5 times more

  
  <EMI ID = 25.1> <EMI ID = 26.1>

  
Mechoulam and Edery in "Marijuana" edited by Mecoulam, Academic Press, New York, 1973, page 127, observe that the major structural changes in the tetrahydrocannabinol molecule appear to give significant reductions in analgesic activity.

  
Paton in Annual Review of Pharmacology, 15, 192 (1975) presents generalizations on structure-action relationships among canhabinoid-type derivatives. The presence of the gem-dimethyl group on the pyran ring is crucial for cannabinoid-like activity and the substitution of N at 0 in the pyran ring removes the activity.

  
  <EMI ID = 27.1>

  
1-Hydroxy-tetrahydroquinolines (IV) are effective as agents acting on the central nervous system, in particular as analgesics and tranquilizers, as hypotensive agents, which are not narcotic and which are free of addiction, as agents for the treatment of glaucoma and as diuretic agents. Also included in this invention are various derivatives of said compounds which are useful as dosage forms and as intermediates. The above-mentioned compounds and their derivatives have

  
  <EMI ID = 28.1>

  
precursors of the compounds of formulas II and I.

  

  <EMI ID = 29.1>
 

  
  <EMI ID = 30.1>

  
  <EMI ID = 31.1>

  
R is selected from the group consisting of hydroxy, alkanoyloxy having one to five carbon atoms and hydroxymethyl;

  
R- is chosen from the group comprising hydrogen atoms and benzyl, benzoyl and alkanoyl groups having from one to

  
  <EMI ID = 32.1>

  
  <EMI ID = 33.1>

  
from the group consisting of hydrogen atoms and alkyl groups having from one to four carbon atoms; or else R2 and R- taken with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring chosen from the group comprising the piperidino, pyrrolo, pyrrolidino, morpholino and Nalkylpiperazino groups in which the alkyl group has a with four carbon atoms;

  
  <EMI ID = 34.1>

  
and alkyl groups having 1 to 6 carbon atoms and <EMI ID = 35.1>

  
R5 is chosen from the group comprising hydrogen atoms and methyl and ethyl groups;

  
  <EMI ID = 36.1>

  
  <EMI ID = 37.1>

  
of carbon in the alkoxy group and y is 0 or an integer of

  
  <EMI ID = 38.1>

  
carbon atoms, alkyl having from one to six carbon atoms; <EMI ID = 39.1>

  
  <EMI ID = 40.1>

  
methylene and alkylenedioxy having two to four carbon atoms;

  
  <EMI ID = 41.1>

  
Z is chosen from the group comprising:
(a) alkylene groups having from one to nine carbon atoms <EMI ID = 42.1>

  
  <EMI ID = 43.1>

  
  <EMI ID = 44.1>

  
an integer of 1 to 5 and b is 0 or an integer of 1 to 5; provided that the sum of a and b is not greater than 5; and ketals of compounds of formulas II, IIII and IV in which the ketal part has two

  
with four carbon atoms.

  
Also included in this invention are the pharmaceutically acceptable acid addition salts of compounds of formulas I and II. Examples of these salts are salts of mineral acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; salts of organic acids such as citrate, acetate, sulfosalicylate, tartrate, glycolate, malonate, maleate, fumarate, malate, 2-hydroxy-3-naphthoate, pamoate, salicylate, stearate, phthalate, succinate,

  
  <EMI ID = 45.1>

  
The compounds of formulas I, II and III above exhibit asymmetric centers at positions 6a and / or 10a. There may be additional asymmetric centers in the substituent by

  
  <EMI ID = 46.1>

  
  <EMI ID = 47.1>

  
9 and due to their quantitatively superior biological activity. For the same reason, the trans (6a, 10a) diastereomers of compounds of formula I are generally preferred over

  
  <EMI ID = 48.1>

  
  <EMI ID = 49.1>

  
  <EMI ID = 50.1>

  
biological activity. As regards the compounds of formula IV, asymmetric centers exist at position 9 and in the

  
  <EMI ID = 51.1>

  
given, one will generally be preferred over the other and racemic. because of its greater activity. The preferred enantiomer is determined by the procedures described herein. By

  
  <EMI ID = 52.1>

  
  <EMI ID = 53.1>

  
  <EMI ID = 54.1>

  
  <EMI ID = 55.1> <EMI ID = 56.1>

  
Racemic mixtures, diastereomeric mixtures as well as pure enantiomers and diastereomers is determined by the bioassays described below.

  
In addition, various intermediates useful in the preparation of compounds of formulas I, II, III and IV are also included in this invention. Intermediaries have the formulas

  

  <EMI ID = 57.1>


  
  <EMI ID = 58.1>

  
is lying ;

  
  <EMI ID = 59.1>

  
and formyl groups; and

  
Y1 is chosen from the group comprising hydrogen atoms and groups protecting the hydroxy group, in particular the methyl, ethyl and benzyl groups.

  
Asymmetric centers may exist in intermediates V, VI and VII at position 2 and in the substituent at position 7 (-ZW) and obviously at other positions, for example in the substituent at position 1. Positions 2 and 7 of the formulas V to VII correspond respectively to positions 6 and 3 of the compounds of formulas I, II, III and IV.

  
Due to their greater biological activity compared to that of other compounds described herein, compounds of

  
  <EMI ID = 60.1>

  
previously;

  
  <EMI ID = 61.1>

  
  <EMI ID = 62.1>

  
ethyl;

  
and R4 and R6 each is a hydrogen atom or an alkyl group;

  
Z and W have the meanings given below:

  

  <EMI ID = 63.1>


  
Preferred compounds of formula I are the preferred compounds described above where R represents a hydroxy group and which have the trans configuration. Preferred compounds of formula II are

  
  <EMI ID = 64.1>

  
Particularly preferred are the preferred compounds of formulas I and II in which:

R is a hydroxy group (formula I only);

  
R. is a hydrogen atom or an acetyl group

  
  <EMI ID = 65.1>

  
R. is a methyl or propyl group;

  
  <EMI ID = 66.1>

  
when Z is an alkylene group having 2 to 5 carbon atoms, W is a phenyl or 4-pyridyl group;

  
  <EMI ID = 67.1>

  
is 1, (alk2) n is an alkylene group having from four to nine carbon atoms, W is a hydrogen atom or a phenyl group; and

  
when Z is an alkylene group having from five to nine carbon atoms, W is a hydrogen atom.

  
Further, preferred classes of intermediates of formulas III, IV, V, VI and VII include compounds having said formulas which serve as intermediates to prepare preferred compounds of formulas I and II.

  
  <EMI ID = 68.1> that a hydrogen atom, an alkyl group and a group

  
  <EMI ID = 69.1>

  
of formulas 1 and II in which R is a hydrogen atom or

  
  <EMI ID = 70.1>

  
  <EMI ID = 71.1>

  
appropriately substituted anilines, for example

  
  <EMI ID = 72.1>

  
  <EMI ID = 73.1>

  
which can be removed to regenerate the hydroxyl group. Suitable protecting groups are those which do not interfere with subsequent reactions of said substituted and protected anilines at position 3, and which can be removed under conditions which do not cause undesirable reactions at other sites of said compound (s) obtained from. aniline. The groups

  
  <EMI ID = 74.1>

  
benzyl, substituted benzyl, the substituent of which is, for example, an alkyl group having from 1 to 4 carbon atoms, a halogen atom (Cl, Br, F, I) or alkoxy having from one to four carbon atoms.

  
The exact chemical structure of the protective group is not critical to the invention since its importance lies in its ability to play the role described above.

  
The choice and identification of the appropriate protective group can easily and quickly be made by those skilled in the art. The suitability and effectiveness of a group as a protecting group for the hydroxy group is determined using such a group in the reaction sequence described above. It must therefore be a group which is easily removed to allow the recovery of the hydroxyl groups. The methyl group is preferred as an alkyl protecting group because it is easily removed by treatment with pyridine hydrochloride. The benzyl group which is also a preferred protecting group is removed by catalytic hydrogenolysis or acid hydrolysis.

  
  <EMI ID = 75.1>

  
preferably a benzyl or substituted benzyl group because it can then be removed without harming the Z group.

  
The protected aniline derivative VIII is then converted to a compound of formula IX by known methods, as described herein.

  
An abridged reaction scheme (Scheme A) of the preparation of representative compounds of Formula V is given below, starting from a 3- (protected hydroxy) -5- (Z-W-) aniline of formula VIII

  
  <EMI ID = 76.1>

  
Diagram A

  

  <EMI ID = 77.1>


  
R [deg.] In the preceding diagram represents an alkyl group

  
  <EMI ID = 78.1>

  
the illustration in the overall diagram is shown as a

  
  <EMI ID = 79.1>

  
  <EMI ID = 80.1>

  
methyl or ethyl).

  
The substituent at the 5-position of compounds of formula VIII may be the -Z-W group desired in compounds of formula II or I, or a group easily convertible into this compound.

  
  <EMI ID = 81.1> <EMI ID = 82.1> is 1, n is 0 and W is hydrogen, the substituent in position becomes - (alkl) m-X-H. The -XH group is advantageously protected in the manner described above.

  
The appropriate 5-substituted 3-hydroxy-anilines described above are reacted, preferably in the form of derivatives in which the 3-hydroxy group (and the 5-hydroxy group if present) is protected as mentioned above to obtain

  
  <EMI ID = 83.1>

  
reflux temperature of the solvent under conditions which result in the removal of water as a by-product. Benzene and toluene are effective solvents when the reaction is carried out at reflux temperature because they allow azeotropic removal.

  
  <EMI ID = 84.1>

  
molecules can be used, as well as other solvents

  
  <EMI ID = 85.1>

  
; Preferred protecting groups for reagents 3-

  
  <EMI ID = 86.1> <EMI ID = 87.1> The preferred catalyst is platinum dioxide because it allows the reaction to be conveniently carried out at low pressures, i.e., pressures below 3.5 kg / cm. Other catalysts such as noble metals, for example platinum, palladium, rhodium, supported or not, can be used with hydrogen pressures ranging from atmospheric pressure to higher pressures, for example 140 kg / cm. In addition to these catalysts which are heterogeneous catalysts, this step can be carried out using homogeneous catalysts such as Wilkinson's catalyst, tris- (triphenylphosphine) chlororhodium
(I).

  
Obviously, when the protecting group (s) is a benzyl or substituted benzyl group, catalytic hydrogenation will result in their removal. For this reason, ethyl or methyl groups are preferred as protective groups for 3- and / or 5-hydroxy groups of the reactants of formula VIII.

  
Alternatively, the compounds of formula X can be prepared directly from compounds of formula VIII by reaction of the compounds

  
  <EMI ID = 88.1>

  
acetic. The reaction is conveniently carried out by reacting

  
  <EMI ID = 89.1>

  
  <EMI ID = 90.1>

  
reflux temperature.

  
Or-, we. can directly prepare compounds of formula

  
  <EMI ID = 91.1> <EMI ID = 92.1>

  
  <EMI ID = 93.1>

  
Then the alkyl 3-anilino-3- (R4) -propionate (X) is cyclized to

  
  <EMI ID = 94.1>

  
using a suitable cyclizing agent such as polyphosphoric acid (PPA), hydrogen bromide-acetic acid mixture, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, the phosphoric acid-formic acid mixture, and other cyclizing agents known to those skilled in the art. In a modification of this transformation, the alkyl 3-anilino-3- (R4) -propionate of formula (X) can be transformed into the corresponding acid, for example by saponification of the ester followed by acidification, before cyclization. .

  
The ether protecting groups are groups 3-
(and 5-) hydroxy can be removed at the time of cyclization using hydrobromic acid in acetic acid as the cyclization agent and deblocking agent. 48% aqueous hydrobromic acid is generally used because it provides satisfactory cycling and unblocking. The reaction is carried out at elevated temperatures and preferably at the temperature

  
  <EMI ID = 95.1>

  
Cyclization conditions using polyphosphoric acid or trifluoroacetic acid should be used to avoid cleavage of the ether or thioether bond.

  
Or, the protecting group (s) can be removed after the cyclization reaction. The hydrobromic acid-acetic acid mixture is also a preferred agent for deblocking at this stage of the overall synthesis. The reaction is carried out as described above.

  
Other reagents, such as hydriodic acid, pyridine hydrochloride or hydrobromide, can be used to remove protective ether groups such as methyl and ethyl groups. When the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, in particular on a carbon support. Or we can

  
  <EMI ID = 96.1> <EMI ID = 97.1>

  
satisfactory conditions and allows the use of relatively mild conditions, involves the transformation of compounds of formula X into N-carbalkoxy derivatives in which the N-carbalkoxy group has from two to five carbon atoms, by reaction with alkyl or chloroformate. appropriate benzyl. The N-carbalkoxy or N-carbobenzyloxy derivative of formula X is then cyclized using a polyphosphoric acid to the corresponding N-carbalkoxy or carbobenzyloxy derivative of the compounds of formula V. The N-substituted derivatives of the compounds of formula X can if we want it to be hydrolyzed

  
  <EMI ID = 98.1>

  
3- (R4) -propionic corresponding before cyclization. Polyphosphoric acid generally gives maximum cyclization and is a preferred cyclizing agent.

  
Is treated with the hydrobromic acid-acetic acid mixture, to obtain the compounds of formula V-A, the compounds of formula V in which the hydroxy group (s) are protected and in which the nitrogen atom is substituted by a carbalkoxy group. When the protective group (s) of the hydroxy group are benzyl or substituted benzyl groups, the regeneration of the hydroxy groups is carried out by catalytic hydrogenolysis. A carbalkoxy group, if it is present on the nitrogen atom, is not modified by this reaction. It can, if desired, then be removed by treatment with the mixture of hydrobromic acid-acetic acid or with any of various acids or bases.

  
  <EMI ID = 99.1>

  
trifluoroacetic acid, also eliminates any Ncarbalcoxy group present.

  
When the substituent -Z-W of compounds of formula V is -XH
(X = 0 or S) and that it is desired that this substituent zZ-W represents

  
  <EMI ID = 100.1>

  
  <EMI ID = 101.1>

  
  <EMI ID = 102.1> <EMI ID = 103.1> <EMI ID = 104.1>

  
0 or 1 and W is other than hydrogen, is conveniently carried out at this stage of the reaction sequence, via the Williamson reaction.

  
Various groups, such as those included in the definition of R6 'can be used in place of carbalkoxy or carbobenzyloxy groups in this preferred method to protect nitrogen from protonation.

  
The group R, - if it is not already present in the compounds of formula V-A, V-B or V-C, can be introduced before formation of the derivative containing a hydroxymethylene group (formula VI) by reaction with

  
  <EMI ID = 105.1>

  
  <EMI ID = 106.1>

  
example acetyl, in the products of formulas I or II, these groups are generally introduced at this moment of the reaction sequence (scheme B) after formation of the compounds of formula II in which R6 is a hydrogen atom, for example by acylation with the appropriate acyl halide according to known procedures.

  
The compounds of formula V and obviously of formula V-A, V-B and V-C, are transformed by the following representative scheme (scheme

  
  <EMI ID = 107.1>

  
representation).

  

  <EMI ID = 108.1>


  
The quinolines of formula V are converted to hydroxymethylene derivatives of formula V by reaction with ethyl formate and sodium hydride. This reaction, a formylation reaction, provides the bis-formyl derivative of formula (VI) in excellent yield. Treatment of the bis-formyl derivative with methyl vinyl ketone gives a mixture of the corresponding mono-Nformylated Michael adduct (VII) and the 1,3-bis-formylated Michael adduct. The two products are conveniently separated by chromatography on a silica gel column.

  
The conversion of compounds of formula VII to compounds of formula III is carried out in an aldol condensation of the mono-N-formyl compound of formula VII. The 1,3-bis-formyl Michael adduct, when subjected to aldol condensation, gives a spiran cyclization product (III-A) as the main product. However, VII-A can be converted to VII by eutreatment with one equivalent of potassium carbonate in methanol.

  

  <EMI ID = 109.1>


  
In addition to the spiran cyclization product, small amounts of the desired enone are also obtained (formula III)

  
and compound (V).

  
The enone of formula III is converted by Birch reduction to the compound of formula II. The cis and trans isomers are obtained. This reduction is conveniently carried out using lithium as the metal. Sodium or potassium can also be used. The reaction is carried out at a temperature of about -35 [deg.] C to about
-80 [deg.] C. Birch reduction is preferred because it allows stereoselectivity resulting in the formation of the desired trans-ketone of formula II as the main product. Catalytic reduction on a noble metal is preferred when the cis-diastereomers are desired as the main product.

  
  <EMI ID = 110.1>

  
  <EMI ID = 111.1>

  
  <EMI ID = 112.1>

  
unstable. At rest, they undergo oxidation as shown

  
the formation of purple to red colorations. The formation of the colored byproducts occurs even when the hydroxy ketone is subjected to reduction by sodium borohydride. It has been found that the formation of the colored by-products can be prevented by acylation, and in particular acetylation, of the 1-hydroxy (OR.) Group by acetic anhydride in pyridine, and by formation of the addition salts. acid, for example hydrochlorides. Acetylated derivatives are stable on standing and even when subjected to a subsequent reaction.

  
The aforementioned colored by-products are believed to have

  
  <EMI ID = 113.1>

  
hydroxy (OR1) in an oxo group and the introduction of a second oxo group in position 2 or 4. The by-products have by them- <EMI ID = 114.1>

  
Even have activity on the central nervous system, in particular as analgesics and tranquilizers and as hypotensive agents, and are used in the same manner and in the same doses as the compounds of formulas I and II.

  
The reduction of the 9-oxo group of the compounds of formula II, and preferably for the aforementioned reasons of stability of the acetyl derivative of formula II, by reduction with a metal hydride gives compounds of formula 1 in which the hydroxy group in position 1 is present as the acetyl derivative. Sodium borohydride is preferred as a reducing agent in this step because not only does it provide satisfactory yields of product but it keeps the acetoxy group in position 1 and reacts slowly enough with hydroxylated solvents (methanol, ethanol, water) to allow their use as solvents. Typically a temperature of about 0 [deg.] C to about 30 [deg.] C is used.

   Lower temperatures even down to about -70 [deg.] C can be used to improve the selectivity of reduction. Higher temperatures cause the sodium borohydride to react with the hydroxylated solvent and deacetylation. If higher temperatures are desired or if they are necessary for a given reduction, isopropyl alcohol or diethylene glycol dimethyl ether is used as solvents. A preferred reducing agent is sodium tri-s-butyl borohydride.

  
  <EMI ID = 115.1>

  
xy. The reduction in dry tetrahydrofuran is carried out at a temperature below about -50 [deg.] C using equimolar amounts of the 9-oxo compound and a reducing agent.

  
Reducing agents such as lithium borohydride or lithium aluminum double hydride require anhydrous conditions and non-hydroxylated solvents, such as 1,2-dimethoxyethane, tetrahydrofuran, ether, diethyl ether.

  
  <EMI ID = 116.1>

  
Or, and preferably, the compounds of formula III, in particular those in which the hydroxy group is protected by an ester or a benzyl ether, are converted into compounds

  
  <EMI ID = 117.1>

  
Convenient comprises catalytic hydrogenation on palladium, for example palladium-on-carbon or on another noble metal, whether supported or not.

  
The -acetylated derivatives of formula I thus obtained are transformed <EMI ID = 118.1>

  
  <EMI ID = 119.1>

  
obtained in the reduction steps described above. Treatment of ketone compounds of formulas II-IV with the appropriate alkylene glycol or alkylenedithiol having two to four carbon atoms, in the presence of a dehydrating agent such as p-toluenesulfonic acid, or other acid used in

  
  <EMI ID = 120.1>

  
corresponding ketals (Fahrenholtz et al., J. Am. Chem., Soc., 89,
5934 1967).

  
  <EMI ID = 121.1>

  
hydroxymethyl group via the reaction of <EMI ID = 122.1>

  
The reaction is carried out under relatively mild conditions.

  
  <EMI ID = 123.1>

  
9-methylene compound by hydroboration-oxidation then provides

  
  <EMI ID = 124.1> is commercially available and gives satisfactory yields of the desired hydroxymethyl compound. The reaction is generally carried out in the <EMI ID = 125.1>

  
The borane product is not isolated but is directly oxidized

  
  <EMI ID = 126.1>

  
  <EMI ID = 127.1>

  

  <EMI ID = 128.1>
 

  
  <EMI ID = 129.1>

  
scheme B) into corresponding ketals by reaction with an appropriate alkylene glycol (e.g. ethylene glycol) in the presence of approximately equivalent amounts of p-toluenesulfonic acid or another acid commonly used for ketal formation, as previously described in benzene with azeotropic elimination from water. A mixture of two ketals is obtained; II-A the reduced form and IV-A the oxidized form. The formation of IV-A is promoted by adding agents such as air, Pd / C, sulfur or 2,3-dichloro-5,6-dicyanobenzoquinone to the reaction mixture. The exclusion of oxidizing agents from the reaction mixture or the addition of reducing agents to the reaction mixture promotes the formation of compound II-A.

  
Decetalization of compounds of formulas II-A and IV-A by procedures known to those skilled in the art provides compounds of formulas II and IV. These latter compounds are then converted into compounds of formulas I and IV by the procedures of scheme B.

  
Reduced compounds of Formula II-A are oxidized (dehydrogenated) by various oxidants, including iodine, by conventional techniques to form compounds of Formula IV-A.

  
  <EMI ID = 130.1>

  
easily adds organometallic reagents on the azomethine bond. Organolithium reagents, for example

  
  <EMI ID = 131.1>

  
giving adducts of formula III-B. Oxidation of the adduct thus formed with various oxidizing agents, conveniently air, aromatizes the adduct to give the compound of formula IV-B substituted in position 6. Subsequent reaction of the compounds of formula IV-B 6 substituted with

  
  <EMI ID = 132.1>

  
formula I] 7-B.

  
  <EMI ID = 133.1>

  
  <EMI ID = 134.1> <EMI ID = 135.1>

  
react readily with an excess of an organolithium reagent or a Grignard reagent (see Hoops, et al., 'J.- Org. Chem. 33,
2995-6, 1968) by forming the compounds of formula II-B trisubstituted. Hydrolysis of the ketals of formulas II-B and III-C provides the corresponding enones which are converted into compounds of formulas II and I by the procedures described above.

  
  <EMI ID = 136.1>

  
is a benzyl group, the reduction with lithium and ammonia of the enone also cleaves the benzyl group.

  
Another procedure for introducing alkyl groups in position 6, with final production of the compounds of formulas I and II, is that of scheme D.

  
- Diagram D
  <EMI ID = 137.1>
 ...........

  
  <EMI ID = 138.1>

  
IV-C and IV-E from compounds of formulas IV-A and IV-D, by reacting them with sodium or potassium hydroxide at high temperatures, for example at about 200 [deg.] - 300 [ deg.] C. The transformation into quaternary nitrogen derivatives of compound IV-A, by reaction of compound IV-A with methyl or ethyl iodide, benzyl bromide or another aralkyl halide, makes it possible to carry out the reaction with sodium or potassium hydroxide under more moderate conditions. The intermediate addition product formed is easily oxidized by moderate oxidizing agents, including air, to an oxo compound of formula IV-E but which obviously, as a result of the reaction for the formation of quaternary derivatives, bears a substituent (methyl, ethyl , aralkyl) on the nitrogen atom.

  
Another procedure is to treat compound IV-A with a peracid, for example m-chloroperbenzoic acid, peracetic acid, to form the corresponding N-oxide which is then reacted with acetic anhydride in a transposition of the N-oxide to give the compound of formula IV-C (Boekelheide transposition). Other methods known in the art can be used for the conversion of N-oxides to lactams.

  
The compounds of formula IV-C or IV-E are then treated with an excess of a suitable Grignard reagent, for example

  
  <EMI ID = 139.1>

  
dialkylated corresponding II-B.

  
3-Hydroxy-5- (ZW) anilines are prepared from 5- (ZW) resorcinols by the Bucherer reaction, which consists of reacting the appropriate 5- (ZW) resorcinol with ammonium sulfite or bisulfite aqueous. The reaction is carried out in an autoclave at elevated temperatures, for example from about 150 to about
230 [deg.] C. The obtained aniline is isolated by acidifying the cooled reaction mixture and extracting the acidic mixture with, for example, ethyl acetate. The acidic solution is neutralized and extracted with a suitable solvent, for example chloroform, to collect the obtained aniline. Or, the aniline obtained is isolated by extracting the cooled reaction mixture with an appropriate solvent and then carrying out column chromatography of the crude product.

  
If 5- (Z-W) resorcinols are not known, they are prepared from 3,5-dihydroxybenzolque acid. The procedure consists of esterifying 3,5-dihydroxybenzolque acid in which the hydroxy groups are protected (for example in the form of methyl, ethyl or benzyl ether); or to perform

  
  <EMI ID = 140.1>

  
The overall abbreviated sequence is shown below
(diagram E).

  
Diagram E

  

  <EMI ID = 141.1>


  
The starting substance, 3,5-dihydroxybenzoic acid XI, is converted into a compound of formula XII in which Y2 represents an alkoxy group, preferably a methoxy or ethoxy group for reasons of ease of preparation,

  
  <EMI ID = 142.1>

  
hydroxy group, according to methods described in the literature.

  
The diprotected benzoic acid derivative of formula XII is then converted into a compound of formula XIV by known methods. In one procedure, compound XII is hydrolyzed to <EMI ID = 143.1>

  
react with the appropriate alkyl lithium to produce the alkyl -
(disubstituted phenyl) -ketone (Y2 = alkyl). When using methyl lithium, the resulting acetophenone derivative is treated with a Grignard reagent (W-Z'-MgBr). The corresponding alcohol intermediate adduct is hydrolyzed and hydrated.

  
  <EMI ID = 144.1>

  
hydrogen atom. This procedure is particularly useful for compounds in which Z is an alkylene group.

  
The ether groups are released by the following means:
treatment with pyridine hydrochloride (Y. = methyl) or

  
  <EMI ID = 145.1>

  
acid such as trifluoroacetic, hydrochloric, hydrobromic or sulfuric acid. Acid debenzylation is obviously used when the -Z-W group contains sulfur.

  
Another method of converting compounds of formula XII to those of formula XIV comprises reacting a ketone of formula XII (Y2 = alkyl) with the appropriate derivative of bromide.

  
  <EMI ID = 146.1>

  
for example sodium hydride. The reaction is carried out via an alkene which is then hydrogenated catalytically to the corresponding alkane (Z-W) and which is released to obtain the dihydroxy compound XIV. Obviously, when -Z- is

  
  <EMI ID = 147.1>

  
Or, the transformation of compounds of

  
  <EMI ID = 148.1>

  
In this sequence, the benzamide is transformed twice

  
protected (XII, Y2 = NH2) in ketone (XII, Z '= Z minus a CH2 group) by reaction with the appropriate Grignard reagent
(BrMg-Z'-W) then reaction with methyl- or ethylmagnesium halide to form the corresponding alcohol. Dehydration of the alcohol, for example with p-toluenesulfonic acid, provides the corresponding alkene which is then hydrogenated catalytically (Pd / C) to obtain the alkane (XIV). We unlock

  
(the ether groups are converted into a hydroxyl group) as described above.

  
  <EMI ID = 149.1>

  
alkyl group having from one to four carbon atoms or

  
  <EMI ID = 150.1> <EMI ID = 151.1>

  
perform a particular role, that is to say the protection of hydroxy groups, rather than its structure which is important.

  
The choice and identification of appropriate protecting groups

  
  <EMI ID = 152.1>

  
The suitability and effectiveness of a group as a protecting group for the hydroxy group is determined using such a group in the reaction sequence described above. It must therefore be a group that is easily
- eliminated to allow the restoration of the hydroxy groups. The methyl group is preferred as an alkyl protecting group because it is easily removed by treatment with pyridine hydrochloride. The henzyl group; if used as a protecting group, is removed by catalytic hydrogenolysis or acid hydrolysis.

  
  <EMI ID = 153.1>

  
preferably a benzyl or substituted benzyl group because it can then be removed without harming the Z group.

  
Compounds of formula VIII-A can also be prepared from 3-amino-5-hydroxybenzoic acids by the procedure of Scheme F below.

  
Compounds of formula VIII-A in which -Z-W is a

  
  <EMI ID = 154.1>

  
W and n are as defined previously and X 'is 0 or S, are obtained by the following diagram (diagram F):

  

  <EMI ID = 155.1>


  
The first step of the previous sequence (reaction of

  
  <EMI ID = 156.1> <EMI ID = 157.1>

  
thus obtained is reduced to the corresponding saturated alcohol by reaction with lithium aluminum hydride. The presence of a small amount of aluminum chloride sometimes accelerates

  
  <EMI ID = 158.1>

  
benzyl (eg methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium on carbon, then treating the saturated ester thus obtained with lithium aluminum hydride. The transformation of the alcohol into the corresponding tosylate or mesylate followed by the alkylation of the tosylate or mesylate with an alkali metal salt of the reagent

  
  <EMI ID = 159.1>

  
  <EMI ID = 160.1>

  
  <EMI ID = 161.1>

  
methyl group.

  
A variation of the preceding sequence involves the bromination of alcohol rather than its transformation into a tosylate or mesylate.

  
Phosphorus tribromide is a suitable brominating agent.

  
  <EMI ID = 162.1>

  
  <EMI ID = 163.1>

  
Williamson}.

  
The brominated compounds also serve as valuable intermediates making it possible to increase the length of the chain of

  
  <EMI ID = 164.1>

  
  <EMI ID = 165.1>

  
  <EMI ID = 166.1> <EMI ID = 167.1> corresponding compounds where X is -S-. Hydrogen peroxide is a convenient agent for the oxidation of thioethers to sulfoxides. The oxidation of thioethers to corresponding sulfones is conveniently carried out using a peracid such as perbenzoic, perphthalic or m-chloroperbenzoic acid. The latter peracid is particularly useful because the by-product, m-chlorobenzoic acid, is easily removed.

  
Esters of compounds of formula II to IV where R is an alkanoyl group or -CO- (CH2) p-NR2R3 are readily prepared by reacting compounds of formulas II to IV with the acid

  
  <EMI ID = 168.1>

  
presence of a condensing agent such as dicyclohexylcarbodiimide. Alternatively, they are prepared by reacting a compound of formula II - IV with the appropriate alkanoic acid chloride or anhydride, for example acetyl chloride or acetic anhydride, in the presence of a base. like pyridine.

  
The esters of the compounds of formula I in which

  
  <EMI ID = 169.1>

  
the procedures described above. The compounds in which only the 9-hydroxy group is acylated are obtained by moderate hydrolysis of the corresponding 1,9-diacylated derivative, using the greatest ease of hydrolysis of the phenolic acyl group; The compounds of formula I are obtained in which only the 1-hydroxy group is esterified by reduction with borohydride of the corresponding ketone of esterified formula II.

  
  <EMI ID = 170.1>

  
  <EMI ID = 171.1>

  
which the ester groups in position 1 and 9 are different.

  
The presence of a basic group in the -ester part,
(OR of the compounds of this invention allows the formation of salts

  
  <EMI ID = 172.1> <EMI ID = 173.1>

  
free. The free base can then be converted to other acid addition salts by known procedures.

  
It is obviously for those skilled in the art that the addition salts

  
  <EMI ID = 174.1>

  
quinoline. These salts are prepared by standard procedures. The basic ester derivatives can obviously form mono- or di-acid addition salts, due to their basic double function.

  
The analgesic properties of the compounds of this invention are determined by assays using thermal nociceptive stimuli, such as the thrill procedure of the body.

  
tail of a mouse, or chemical nociceptive stimuli, for example by measuring the ability of a compound to suppress convulsions induced by an irritant agent which is phenylbenzoquinone, in mice. These and other tests are described below.

  
Tests Using Thermal Nociceptive Stimuli a) Hot Plate Analgesic Test in Mice

  
The method used is modified from Woolfe and McDonald, J. Pharmacol. Exp. Ther., 80, 300-307 (1944). A determined thermal stimulus is applied to the paws of the mice on an aluminum plate 3.2 mm thick. A 250 watt reflective infrared heat lamp is placed under the lower part of the aluminum plate. A thermal regulator, connected to thermistors on the surface of the plate, programs the heating lamp to maintain a constant temperature of

  
  <EMI ID = 175.1>

  
  <EMI ID = 176.1>

  
  <EMI ID = 177.1>

  
Half an hour and two hours after treatment with the compound,

  
  <EMI ID = 178.1>

  
  <EMI ID = 179.1> <EMI ID = 180.1>

  
  <EMI ID = 181.1>

  
born applied to the tail. Each mouse is placed in a narrow metal cylinder, the tail protruding at one end. This cylinder is placed so that the tail lies flat on a hidden heat lamp. At the start of the test, an aluminum cover is removed from the lamp, allowing the light beam to pass through the slit and focus on the end of the tail. Simultaneously activates a stopwatch. The waiting time for a sudden tail twitch is determined. Untreated mice usually react within 3 to 4 seconds after exposure to the lamp. The end point for protection is 10 seconds. Each mouse is tested for half an hour and

  
2 hours after treatment with morphine and the test compound.

  
  <EMI ID = 182.1>

  
Test using chemical nociceptive stimuli Suppression of seizures induced by pheylbenzoguinone

  
Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine or the test compound. Twenty minutes later (if they are treated subcutaneously) or 50 minutes later (if they are treated orally), each group is treated by intraperitoneal injection of phenylbenzoquinone, an irritant that produces abdominal contractions. Mice are observed for 5 minutes to determine the presence or absence of seizures beginning 5 minutes after injection of the agent.

  
  <EMI ID = 183.1>

  
the drug with regard to blocking seizures.

  
The results of previous tests are recorded as the percentage of maximum possible effect (% MPE). The% MPE of each group is statistically compared to the% MPE of the reference product and of the control before drug. The% MPE is calculated as follows:

  
  <EMI ID = 184.1>

  
  <EMI ID = 185.1>

  
In the tables below, the analgesic activity is

  
  <EMI ID = 186.1>

  
given half of the maximum possible analgesic effect.

  
The compounds of the present invention are analgesics active by oral and parenteral administration and are conveniently administered as a composition. Such compositions comprise a pharmaceutical carrier chosen according to the route <EMI ID = 187.1>

  
example, they can be administered in the form of tablets, pills, powders or granules containing excipients such as starch, lactose, certain types of clay, etc. They can be administered in capsules, in mixtures with the same excipients or equivalent excipients. They can also be administered in the form of suspensions, solutions, emulsions, syrups and elixirs intended for the oral route, which may contain flavoring and coloring agents. For oral administration of the therapeutic agents of this invention, tablets or capsules containing from about 0.01 to about 100 mg are suitable for most applications.

  
The attending physician will determine the correct dose

  
best for the particular patient, and this dose will vary with the age, weight and reaction of the particular patient and the route of administration. However, in general, the initial analgesic dose in adults can range from 0.01 to 500 mg / day, in a single dose or in several separate doses. In most cases, it is not necessary to exceed 100 mg / day. The preferred oral dose range is from about 0.01 to about
300 mg / day; the preferred dose is about 0.10 to about

  
50 mg / day. The preferred parenteral dose is from about 0.01 to about 100 mg / day, the preferred range is from about 0.01 to about 20 mg / day.

  
The analgesic activity of several compounds of this invention and of certain compounds of the prior art was determined using the foregoing procedures.

  
The following abbreviations are used in the tables:
PBQ = convulsion induced by phenylbenzoquinone; TQ tail twitch; PC = hot plate.

  

  <EMI ID = 188.1>
 

  

  <EMI ID = 189.1>
 

  

  <EMI ID = 190.1>
 

  

  <EMI ID = 191.1>
 

  
  <EMI ID = 192.1>

  
ability to lower the blood pressure of conscious hypertensive rats and dogs to a statistically significant degree when administered orally to hosts at the above doses.

  
Their tranquilizing activity is demonstrated by oral administration to rats at doses of approximately 0.01 to 50 mg / kg, with subsequent decreases in spontaneous motor activity. The daily dose in mammals is about 0.01 to about 100 mg.

  
The utility of these compounds for the treatment of glaucoma is believed to be due to their ability to reduce intraocular pressure. Their effects on intraocular pressure are determined by tests on dogs. The test drug is instilled into a dog's eye as a solution or is administered systemically over various periods of time, after which the eye is anesthetized by instillation of tetracaline hydrochloride, 0.5 %, 2 drops. A few minutes after this local anesthesia, intraocular pressure measurements are made with a Schiotz mechanical tonometer, and after administration of fluorescein with a Holberg manual application tonometer.

  
The test drug is conveniently used in a solution such as the following: test drug (1 mg), ethanol
(0.05 mL), Tween 80 (polyoxyalkylene derivative of mono-oleate of

  
  <EMI ID = 193.1>

  
19899, U.S.A.) (50 mg) and saline solution (to make 1 ml), or in a more concentrated solution where the ingredients are present in the respective proportions of 10 mg, 0.10 ml, 100 mg and 1 ml. For human use drug concentrations of 0.01 mg / kg to 10 mg / kg are suitable.

  
Their activity as diuretic agents is determined by the

  
  <EMI ID = 194.1>

  
which uses rats as test animals. The dose interval for this use is the same as stated previously

  
  <EMI ID = 195.1>

  
  <EMI ID = 196.1>

  
as previously stated, to obtain the daily / effective dose for a particular utility.

  
The compounds (drugs) described herein can be prepared for administration in solid or liquid form for oral or parenteral administration. Capsules containing drugs according to this invention, that is to say compounds of formula I or II, are prepared by mixing one part by weight of the drug with nine parts of excipient such as starch or lactose and then introducing the mixture into gelatin capsules fitting together so that each capsule contains

  
100 parts of the mixture. Tablets containing compounds of formula I or II are prepared by mixing appropriate mixtures of the drug and conventional ingredients used in the preparation of tablets, such as starch, binders and lubricants, so that each tablet contains 0, 01 to

  
100 mg of drug.

  
Suspensions and solutions of these drugs, in particular

  
  <EMI ID = 197.1>

  
hydroxy group, are usually prepared just before use to avoid drug stability issues

  
  <EMI ID = 198.1>

  
example precipitation) of the drug during its storage. Compositions suitable for such use are generally dry solid compositions which are reconstituted for administration by injection.

  
EXAMPLE 1

  
  <EMI ID = 199.1>

  
87.2 ml (0.670 mole) of ethyl acetoacetate, 535 ml and 3.3 ml of glacial acetic acid, and the water is collected using

  
  <EMI ID = 200.1>

  
  <EMI ID = 201.1>

  
filter and then concentrate it under reduced pressure, which gives

  
  <EMI ID = 202.1>

  
  <EMI ID = 203.1>

  
  <EMI ID = 204.1>

  
  <EMI ID = 205.1> <EMI ID = 206.1>

  
and 250 mg of platinum oxide. The reaction mixture is filtered through a filter aid, 50 ml of benzene is added and

  
  <EMI ID = 207.1>

  
the oil is taken up in chloroform, the solution is washed successively with a saturated solution of sodium bicarbonate

  
(2 x 50 mL) and saturated sodium chloride solution. Then

  
dried over MgSO4, filtered and concentrated under reduced pressure to give the product as an oil
(5.1 g).

  
The repetition of the previous operating mode but using
168.7 g of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate, 320 ml of glacial acetic acid and 2.15 g of platinum oxide gives 160.8 g of product.

  
EXAMPLE 2

  
ethyl dl-3- (3,5-dimethoxyanilino) butyrate

  
To a solution of 370 g (1.45 mol) of 3,5dimethoxyaniline hydrochloride, of 4.5 L of reactive methanol and of 286.3 g

  
(2.64 moles) ethyl acetoacetate in a round-bottomed flask of
12 liters, with 3 nozzles, equipped with a mechanical stirrer and a reflux condenser, 54 g (0.76 mol) of sodium cyanoborohydride are added all at once. Once reflux has resumed (10 min), the mixture is heated on a steam bath for an additional 20 minutes. To the cooled reaction mixture, 5.4 g is added.
(0.07 mol) of additional sodium cyanoborohydride and 28.6 g
(0.26 mol) of ethyl acetoacetate and the mixture is heated under reflux for 30 minutes. This last operation is repeated once more.

  
The reaction mixture is isolated in portions, pouring approximately
500 ml in 1 liter of ice water mixed with 500 ml of methylene chloride, separating the layers and backwashing the aqueous phase with an additional 100 ml of methylene chloride. This process is repeated using 500 ml portions until the entire reaction mixture is worked up.

  
Combine the methylene chloride layers and dry over MgSO4, decolorize with charcoal, filter.

  
and they are evaporated to give a yellow oil.

  
The excess ethyl acetoacetate is distilled off at an oil bath temperature of 130 [deg.] C and a pressure of 1-5 mm, which leaves
376 g (72% yield) of crude ethyl 3- (3,5-dimethoxyanilino) butyrate which is a viscous amber-colored oil which <EMI ID = 208.1>

  
it is used without further purification.

  
The compound has the following spectral characteristics:

  
  <EMI ID = 209.1>

  
4.20 (q, 2H, methylene ester), 3.80-4.00 (m, 2H, -NH and N-CH-CH3), 3.78 (s, 6H, -OCH3), 2 , 40-2.55 (m, 2H, -CH2COOEt), 1.78
(d, 3H, methyl) and 1.29 (t, 3H, methyl).

  
EXAMPLE 3

  
ethyl dl-3- (3,5-dimethoxyanilino) hexanoate

  
Following the procedure of Example 2, the condensation of 3,5-dimethoxyaniline hydrochloride and butyrylacetate

  
  <EMI ID = 210.1>

  
It is converted into the hydrochloride by adding hydrogen chloride to a solution of this compound in methylene chloride; m.p. 127-129.5 [deg.] C. Recrystallization from a 5: 1 mixture of cyclohexane and benzene gives the analytical sample, m.p. 126-128.5 [deg.] C.

  
  <EMI ID = 211.1>

  
  <EMI ID = 212.1>

  
Found: C, 57.89; H, 7.74;

  
N, 4.40% m / e - 295 (m +)

  
  <EMI ID = 213.1>

  
2H, NH2 +), 6.77 (d, J = 2Hz, <3> 2H, H to meta), 6.49, 6.45 (d of d,

  
  <EMI ID = 214.1>

  
about 3.5-4.8 (m, 1H, CH-N), 2.90 (t, 2H, CH2-C = O), about

  
  <EMI ID = 215.1>
-C-CH3).

  
EXAMPLE 4

  
  <EMI ID = 216.1>

  
Method A -

  
71.4 ml (0.75 mol) of ethyl chloroformate are added dropwise over 45 minutes to a mixture of 159.8 g (0.598 mol) of 3- (3,5-dimethoxyanilino) butyrate. , 100 ml of methylene chloride and 5 ml (1.24 mol) of pyridine at 0 [deg.] C under a nitrogen atmosphere. The mixture is stirred for 40 min after addition of ethyl chloroformate and then poured into a mixture of 750 ml of chloroform and 500 ml of ice-water. The chloroform layer is separated, washed successively with 10% hydrochloric acid (3 x 500 ml), saturated sodium bicarbonate solution (1 x 300 ml) and saturated solution. <EMI ID = 217.1>

  
sodium chloride aqueous solution (1 x 400 mL) then dried over MgSO4. It is then decolorized with activated charcoal and concentrated under reduced pressure to an oil (215 g). The product is used as is.

  
Method B

  
Under a positive nitrogen atmosphere, stirred and cooled in an ice bath to 0-5 [deg.] C a mixture of 376 g (1.4 mol) of 3- (3,5-dimethoxyanilino) butyrate. ethyl, 1.4 1 chloride

  
of methylene and 388.8 g (2.81 moles) of anhydrous potassium carbonate. 153 g (1.41 mol) of ethyl chloroformate are added all at once. The mixture is allowed to warm up to room temperature over an hour, another 153 g is added.
(1.41 mol) of ethyl chloroformate and the mixture is heated

  
at reflux on a steam bath for 1 hour. It is then allowed to cool to room temperature and the potassium carbonate is removed by filtration. The red filtrate is washed successively with water (2 x 1000 ml), brine (1 x 500 ml),

  
  <EMI ID = 218.1>

  
reduced pressure to give 439 g of crude product which is used without further purification.

  
  <EMI ID = 219.1>

  
  <EMI ID = 220.1>

  
methylene ester), 3.70 (s, 6H, -OCH3), 2.30-2.60 (m, 2H,
-CH2COOEt), 1.00-1.40 (m, 9H, 3 methyl).

EXAMPLE 5

  
  <EMI ID = 221.1>

  
Method A -

  
Combine and stir at room temperature for a period of

  
  <EMI ID = 222.1>

  
aniline) ethyl butyrate, 595 ml aqueous sodium hydroxide

  
  <EMI ID = 223.1>

  
volume of about 600 ml under reduced pressure, the concentrate was diluted with water to a volume of 1200 ml and extracted with ethyl acetate (3 x 750 ml). The aqueous layer was then acidified with 10% hydrochloric acid to pH 2 and extracted again with ethyl acetate (3 x 750 ml). These latter extracts are combined, washed with brine,

  
  <EMI ID = 224.1>

  
which gives the title product in the form of an oil
(163.5 g, 88.2%).

  
  <EMI ID = 225.1>

  
It is introduced into a round bottom flask with three tubes, 5 liters, equipped with a mechanical stirrer and a condenser.

  
  <EMI ID = 226.1>

  
2 L of 1N sodium hydroxide are added and the mixture is heated under reflux on a steam bath for 3 hours. The reaction mixture is poured into 5 L of ice water and extracted in portions of

  
1 1 with diethyl ether (500 ml per serving). The aqueous layer was cooled by adding about 1 L of ice followed by acidifying with concentrated hydrochloric acid (1.75 mL, 2.1 moles). Extracted in 1 L portions with methylene chloride.

  
(250 ml per serving). The methylene chloride layers are combined and dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness to give a viscous yellow oil. Crystallization from a 1: 2 mixture of ether and cyclohexane afforded 224 g (55.3%) of the crystalline product, m.p. 78-80 [deg.] C. Use this substance without further purification in the next step.

  
  <EMI ID = 227.1>

  
  <EMI ID = 228.1>

  
2H, methylene ester &#65533; 3.78 (s, 6H, -OCH3), 2.40-2.60 (m, 2H,
-CH2COOH), 1.18 (t), 1.28 (d, 6H, methyl), 10.8 (broad s, variable, 1H, COOH).

  
MS (molecular ion) m / e - 311.

  
An analytical sample obtained by recrystallization from

  
  <EMI ID = 229.1>

  
  <EMI ID = 230.1>

  
N, 4.50% Found: C, 58.08; H, 6.65;

  
N, 4.46% EXAMPLE 6

  
  <EMI ID = 231.1>

  
butyric

  
A mixture is dissolved in 500 ml of methylene chloride

  
  <EMI ID = 232.1>

  
(136.6 g, 0.44 mol) and 1-ephedrine (72.5 g, 0.44 mol). Then the methylene chloride is removed under vacuum to obtain the salt

  
  <EMI ID = 233.1> <EMI ID = 234.1>

  
102 g, m.p. 114 [deg.] - 116 [deg.] C. Recrystallization from a 1: 1 mixture of ethyl acetate and hexane affords 71.1 g (34%) of the sodium salt.

  
  <EMI ID = 235.1>

  

  <EMI ID = 236.1>


  
  <EMI ID = 237.1>

  
1000 ml of ethyl acetate and 400 ml of hydrochloric acid

  
  <EMI ID = 248.1>

  
  <EMI ID = 238.1>

  
  <EMI ID = 239.1>.-Dried and concentrated under reduced pressure to an oil.

  
  <EMI ID = 240.1>

  

  <EMI ID = 241.1>


  
  <EMI ID = 242.1>

  

  <EMI ID = 243.1>


  
  <EMI ID = 244.1> <EMI ID = 245.1>

  

  <EMI ID = 246.1>


  
EXAMPLE 7

  
Methyl 3- (3,5-dimethoxyanilino) propionate

  
A mixture of 3.5dimethoxyaniline (114.9 g, 0.75 mol), methyl acrylate is refluxed for 20 hours.
(69.73 g, 0.81 mol) and 2 ml of glacial acetic acid. The reflux is stopped and the reaction mixture is concentrated and then distilled in vacuo, which gives 106.8 g (73.9%) of the title product, bp 174-179 [deg.] C (0.7 mm). ).

  
  <EMI ID = 247.1>

  
3H, COOCH3), 3.41 and 2.59 (two triplets of 2H, -NCH2CH2CO2).

  
EXAMPLE 8

  
  <EMI ID = 249.1>

  
methyl

  
A mixture of 1.0 g is heated at 106-110 [deg.] C overnight.

  
  <EMI ID = 250.1>

  
methyl and 0.1 ml of acetic acid. The cooled residue is dissolved in 100 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution. Then

  
  <EMI ID = 251.1>

  
crude residue which is chromatographed on 130 g of silica gel

  
  <EMI ID = 252.1>

  
  <EMI ID = 253.1>

  
  <EMI ID = 254.1> <EMI ID = 255.1>

  
  <EMI ID = 256.1>

  
ethyl chloroformate then at room temperature for
20 minutes more, and then pour it into a mixture of
75 ml of methylene chloride and 50 ml of ice water. The methylene chloride layer was separated, washed successively with 10% hydrochloric acid (2 x 50 ml), a saturated aqueous solution of sodium bicarbonate (1 x 30 ml) and a saturated aqueous solution of chloride. sodium (1 x 40 mL) and dried over MgSO4. Then it is decolorized with activated charcoal and concentrated under reduced pressure to an oil.

  
(2.72 g). The product is used as is.

  
EXAMPLE 10

  
  <EMI ID = 257.1>

  
methyl ethoxycarbonyl) anilino] propionate, 8.4 ml hydroxide

  
  <EMI ID = 258.1>

  
overnight under nitrogen at room temperature. The reaction mixture is then concentrated under reduced pressure to half volume, diluted with 35 ml of water and extracted with ethyl acetate. The aqueous phase is acidified to pH 2 with 10% hydrochloric acid and extracted with methylene chloride
(3 x 50 ml). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give the product in

  
  <EMI ID = 259.1>

  
EXAMPLE 11

  
  <EMI ID = 260.1>

  
rique then cooled to 0 [deg.] C. It is then taken up in 200 ml of a 1: 1 mixture of methylene chloride and water. The organic layer is separated and the aqueous phase is extracted again with methylene chloride (2 x 100 ml). The combined extracts are washed.

  
  <EMI ID = 261.1>

  
  <EMI ID = 262.1> <EMI ID = 263.1>

  
A mixture of 60 ml of glacial acetic acid, 60 ml of 48% hydrobromic acid is heated at reflux overnight and

  
  <EMI ID = 264.1>

  
4-tetrahydroquinoline then concentrated in vacuo to a dark oil. The oil is dissolved in 50 ml of water and the aqueous solution is neutralized to pH 6-7 with 1N sodium hydroxide.

  
50 ml of a saturated solution of salt in water are added and the mixture is

  
  <EMI ID = 265.1>

  
  <EMI ID = 266.1>

  
under reduced pressure to an oil. The oil is taken up in a 1: 1 mixture of benzene and ethyl acetate and the solution is loaded into a column of silica gel. The column is eluted with a volume of benzene equal to the volume of the column then with
250 ml of a 4: 1 mixture of benzene and ethyl acetate then

  
250 ml of a 2: 1 mixture of benzene and ethyl acetate. 75 ml fractions are collected. Fractions 4 to 9 are combined and evaporated under reduced pressure. The oily residue is crystallized from a 1:10 mixture of ethanol and hexane. 1.86 g is obtained, m.p. 166 [deg.] - 169 [deg.] C.

  
Further recrystallization raises the melting point to
171 [deg.] - 172.5 [deg.] C.

  
  <EMI ID = 267.1>

  
Analysis: Calculated for C9H903N: C, 60.33; H, 5.06; N, 7.82%

  
Found: C, 60.25; H, 4.94; N, 7.55% EXAMPLE 13

  
  <EMI ID = 268.1>

  
quinoline

  
A solution of 4.0 g is added dropwise with stirring.

  
  <EMI ID = 269.1>

  
butyric acid in 2 ml of chloroform containing 5.0 g of polyphosphoric acid

  
  <EMI ID = 270.1>

  
  <EMI ID = 271.1>

  
  <EMI ID = 272.1>

  
  <EMI ID = 273.1>

  
(2 x 100 ml) and the combined organic extracts are washed so

  
  <EMI ID = 274.1>

  
  <EMI ID = 275.1> <EMI ID = 276.1>

  
  <EMI ID = 277.1>

  
Purification is carried out by column chromatography of a benzene solution of 2.5 g of the product, on 95 g of silica gel. The column is eluted with a volume of benzene equal to half the volume of the column, then with a 1: 1 mixture of benzene and ethyl acetate. 40 ml fractions are collected. Fractions 9:18 were combined and evaporated in vacuo to give 1.55 g of the product which was then purified by recrystallization from petroleum ether, 1.33 g, m.p. 92.5-94 [deg.] C.

  
Recrystallization of this product from a hot 1: 1 mixture of ethyl acetate and hexane provides an analytical sample; m.p. 94-95 [deg.] C.

  

  <EMI ID = 278.1>


  
EXAMPLE 14

  
  <EMI ID = 279.1>

  
Method A -

  
A mixture of 240 ml of glacial acetic acid, 240 ml of 48% hydrobromic acid is heated at reflux overnight.

  
  <EMI ID = 280.1>

  
4-oxo-1,2,3,4-tetrahydroquinoline then concentrated in vacuo to a dark oil. The oil is dissolved in 200 ml of water and the aqueous solution is neutralized to pH 6-7 with 1N sodium hydroxide. Add a saturated solution of salt in water
(200 mL) and the resulting mixture was extracted with ethyl acetate (3 x 500 mL). The extracts are combined, dried over MgSO4 and concentrated under reduced pressure to an oil.

  
  <EMI ID = 281.1>

  
of ethyl acetate and the resulting crystals were collected by filtration, 3.8 g, m.p. 158 [deg.] - 165 [deg.] C. Trituration of the crystals in ethyl acetate gave 1.65 g of product, m.p. 165-168 [deg.] C.

  
Additional material separates from mother liquors

  
on standing (2.9 g, mp 168-17C [deg.] C). Column chromatography of the filtrate on silica gel using a 1: 1 mixture of benzene and ether as a solvent gave an additional 4.6 g of product, m.p. 167-169 [deg.] C.

  
Further purification is obtained by recrystallizing

  
the product in ethyl acetate; m.p. 173-174 [deg.] C.

  
  <EMI ID = 282.1>

  
  <EMI ID = 283.1>

  
  <EMI ID = 284.1>

  
Method B -

  
Heated in an oil bath at 110 [deg.] C for 2 hours a

  
  <EMI ID = 285.1>

  
ethoxycarbonyl) anilino] butyric acid, 500 ml of 48% hydrobromic acid and 300 ml of glacial acetic acid. Then the temperature of the oil bath is raised to 145 [deg.] C and heating is continued for a further 2 hours. During this last heating period, an azeotropic mixture distills (boiling point

  
  <EMI ID = 286.1>

  
dark red cool to room temperature. Pour the mixture onto water and ice (3 liters) and ether

  
(2 liters), the layers are separated and the aqueous solution washed with ether (2 x 1000 ml). The ethereal layers are combined and washed successively with water (2 x 1000 mL), brine (1 x 500 mL), saturated NaHCO 3 solution (4 x 250 mL) and brine (1 x 500 mL). ) then they are dried (MgSO.). Decoloration with charcoal and evaporation of the ether gives a yellow foam which is recrystallized from about 300 ml of methylene chloride to give 31.3 g (50.4%) of 5.7-

  
  <EMI ID = 287.1>

  
can isolate more product from mother liquor by silica gel chromatography.

  
  <EMI ID = 288.1>

  
  <EMI ID = 289.1>

  
  <EMI ID = 290.1>

  
  <EMI ID = 291.1>

  
Found: C, 62.01; H, 5.85; N, 7.02%

  
  <EMI ID = 292.1>

  
Column graphing using silica gel and a 5: 1 mixture of benzene and ether as eluent.

  
m / e - 309 (ni)

  
  <EMI ID = 293.1>

  
  <EMI ID = 294.1> <EMI ID = 295.1>

  
methylene).

  
  <EMI ID = 296.1>

  
  <EMI ID = 297.1>

  
3,4-tetrahydroquinoline, m.p. 167-168 [deg.] C.

  
  <EMI ID = 298.1>

  
  <EMI ID = 299.1>

  
  <EMI ID = 300.1>

  
  <EMI ID = 301.1>

  
  <EMI ID = 302.1>

  
hydroquinoline; m.p. 166 [deg.] - 168 [deg.] C.

  
  <EMI ID = 303.1>

  
  <EMI ID = 304.1>

  
  <EMI ID = 305.1>

  
Found: C, 61.82; H, 5.83; N, 7.22% EXAMPLE 15

  
  <EMI ID = 306.1>

  
A mixture of 230 g is heated at reflux for 6 hours.
(1.5 moles) of 3,5-dimethoxyaniline, 150 (1.5 moles) of methyl crotonate and 90 g (1.5 moles) of glacial acetic acid. An additional 90 g of glacial acetic acid is added and the mixture is heated at reflux overnight. 1000 ml of a 48% solution of hydrobromic acid and 850 ml of glacial acetic acid are added to the reaction mixture which is refluxed for 4 1/2 hours. The title product is isolated and purified according to the procedure of Example 12. 36 g, m.p. 166-170 [deg.] C.

  
EXAMPLE 16

  
  <EMI ID = 307.1>

  
A mixture of 4.6 g is heated at 185-200 [deg.] C for 45 minutes.
(0.03 mole) of 3,5-dimethoxyaniline, 2.54 g (0.03 mole) of protonic acid and 3.0 g (1.26 mole) of pyridine hydrochloride. The cooled reaction mixture is suspended in 500 ml. <EMI ID = 308.1>

  
resulting for 10 minutes. We separate the organic layer, we

  
  <EMI ID = 309.1>

  
yellow.

  
A mixture of 110 ml of glacial acetic acid, of
110 ml of 48% hydrobromic acid and yellow oil for

  
1 hour then concentrated in vacuo to a dark oil. The oil is dissolved in water and the solution is neutralized

  
  <EMI ID = 310.1>

  
saturated salt solution in water and the resulting mixture was extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated under reduced pressure to a dark oil (2.8 g). Silica gel column chromatography of the crude residue using a 4: 1 mixture of benzene and ether as eluent gave an additional 510 mg of product, m.p. 168-170 [deg.] C.

  
Further purification is obtained by recrystallizing the product from ethyl acetate, m.p. 173-174 [deg.] C.

  
  <EMI ID = 311.1>

  
Found: C, 62.00; H, 5.83; N, 7.14% m / e - 193 (m +), 178 (m + -methyl, base peak).

  
Similarly, 3,3-dimethylacrylic acid and 3,5-dimethoxyaniline give, after purification by chromatography on silica gel (1: 1 mixture of benzene and ether as eluent), 5,7- dihydroxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydroquinoline in the form of a yellow oil.

  
Analysis (SM)

  
Parent peak (m +)

  
  <EMI ID = 312.1>

  
Found: 207.0895

  
  <EMI ID = 313.1>

  
  <EMI ID = 314.1>

  
Found: 192.0655

  
Likewise, styrylacetic acid and 3,5-dimethoxyaniline

  
  <EMI ID = 315.1>

  
3,4-Tetrahydroquinoline as an oil after purification using a 3: 1 mixture of benzene and ether as eluent.

  
m / e = 269 (m +) and 178 (m + -benzyl, base peak)

  
NMR (CDCl3) S (ppm): 8.76 (s, 1H, 5-OH), 7.18-7.6 (m, 5H,

  
  <EMI ID = 316.1> <EMI ID = 317.1>

  
quinoline

  
325 mg (52 mmol) of potassium hydroxide pellets are added to a solution of 1.0 g (52 mmol) of d, 1-5,7-dihydroxy-

  
  <EMI ID = 318.1>

  
160 mg of additional potassium hydroxide followed by 500 mg of

  
  <EMI ID = 319.1>

  
the addition of potassium hydroxide and d, l-2-bromoheptane, each time using 80 ml of potassium hydroxide and 250 mg of d, l-2-bromoheptane. The reaction mixture is stirred for a further 10 minutes and then cooled. 50 ml of chloroform and 25 ml of aqueous sodium hydroxide are added

  
  <EMI ID = 320.1>

  
layers. The chloroform extraction was repeated, the extracts combined, dried over MgSO4, and concentrated under reduced pressure to a dark oil. The oil is chromatographed on
120 g of silica gel using benzene as solvent. Fractions of 30 ml each are collected. We combine the fractions
12-18 and concentrated under reduced pressure to a clear yellow oil (850 mg) which crystallizes on standing. The desired product is filtered off and recrystallized from

  
  <EMI ID = 321.1>

  
The previous procedure is repeated on a scale

  
20 times larger, but using a 9: 1 mixture of benzene and ethyl acetate as a chromatographic solvent. Fractions of 750 ml each are collected. Combining fractions 2-6 provides 32 g of an oil which partially crystallizes from hexane on standing and cooling to give 18.2 g.

  
  <EMI ID = 322.1> <EMI ID = 323.1>

  
and 5.7 (d, 2H, J = 2Hz, aromatics), 4.6 (br s, 1H, -NH), 4.1-4.6 (m, 1H, -0-CH-), 3, 3 (t, 2H, J = 7Hz, -CH2-), 2.6 (t, 2H, J = 7Hz, -CH2-), 2.0-0.7 (m, protons remaining).

  
EXAMPLE 18

  
  <EMI ID = 324.1>

  
tetrahydroquinoline

  
Cooled in an ice-water bath a mixture of

  
16.4 g (5 mmoles) of 5-phenyl-2- (R, S) -pentanol, 28 ml (200 mmoles) of triethylamine and 80 ml of tetrahydrofuran under a nitrogen atmosphere. 8.5 ml (110 mmol) of

  
methanesulfonyl chloride in 20 ml of dry tetrahydrofuran

  
at a rate such that the temperature remains essentially constant. The mixture is allowed to warm to room temperature and then filtered to remove triethylamine hydrochloride. The filter cake was washed with dry tetrahydrofuran and the combined washing liquid and filtrate evaporated under reduced pressure to obtain the product as an oil. The oil is dissolved in 100 ml of chloroform and the solution is washed with water (2 x 100 ml) then with brine.

  
saturated (1 x 20 ml). Evaporation of the solvent gives 21.7 g

  
  <EMI ID = 325.1>

  
in the next step without further purification.

  
Heated to 80-82 [deg.] C in an oil bath for 1 3/4 h

  
  <EMI ID = 326.1>

  
then poured into 300 ml of ice and water. The aqueous solution was extracted with ethyl acetate (2 x 50 ml) and the combined extracts washed successively with water (3 x 50 ml).

  
  <EMI ID = 327.1>

  
  <EMI ID = 328.1>

  
  <EMI ID = 329.1>

  
pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, 612 ml of N, Ndimethylformamide, 174.8 g (1.265 mole) of potassium carbonate

  
  <EMI ID = 330.1>

  
The reaction mixture was cooled and poured onto 4 L of ice-water and the aqueous solution extracted into ethyl acetate (2 x 4 L). The combined extract was washed with water (4 x 2 L) brine (1 x 2 L) and dried over MgSO 4. Evaporation gave 196 g of the title product. It is used without further purification.

  
  <EMI ID = 331.1>

  
aromatics), 5.80 (d, J = 3 <3> Hz, 1H, H mixed), 5.58 (d, J = 3 Hz, 1H, H in meta), 1.25 (d, 6H, CH3-CH-N and CH3-CH-O- ), 1.41-4.81 (m,
11H, protons remaining).

  
EXAMPLE 19

  
  <EMI ID = 332.1>

  
quinoline

  
Repeating the procedure of Example 18 but in

  
  <EMI ID = 333.1>

  
74% yield.

  
m / e - 325 (m +)

  
  <EMI ID = 334.1>

  
Found: C, 73.69; H, 7.15; N, 4.08%

  
  <EMI ID = 335.1>

  
7.3 (s, 5H, aromatics), 5.8 (d, 1H, aromatic, J = 2Hz), 5.6

  
(d, 1H, aromatic, J = 2Hz), 4.7-4.1 (m, 2H, NH and 0-CH), 3.5 (t, 2H, CH2 'J = 7Hz), 3.1- 2.1 (m, 4H, 2-CH2-), 2.1-1.5 (m, 4H, 2-CH2),; 1.3 (d, 3H, -CH-CH3 'J = 6Hz).

  
  <EMI ID = 336.1>

  
2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline with 35.2 g (0.154 mole)

  
  <EMI ID = 337.1>

  
  <EMI ID = 338.1>

  
in a 1: 2 mixture of ethyl acetate and hexane gives the sample.

  
  <EMI ID = 339.1> <EMI ID = 340.1>

  
  <EMI ID = 341.1>

  
  <EMI ID = 342.1>

  
1H, H to meta), 4.36 (br s, 1H, NH), 3.33-4.08 (m, 3H, -O-CH2,
-CH-N), 2.29-2.83 (m, 4H, -CH2-C = O, C6H5-CH2), 1.51-1.92 (m, 4H,
- [CH2] 2) '1, <2> 3 (d, 3H, CH3-).

  
Likewise, alkylation of d-5,7-dihydroxy-4-oxo1,2,3,4-tetrahydroquinoline with d-2-octyl methanesulfonate affords d-5-hydroxy-2-methyl- 7- (2- (R) -octyloxy) -4-oxo-1,2,3,4tetrahydroquinoline, mp 64 [deg.] - 68 [deg.] C.

  
  <EMI ID = 343.1>

  
  <EMI ID = 344.1>

  
oxo-1,2,3,4-tetrahydroquinolé &#65533; ne in 1140 g (14.6 moles) of ethyl formate to 72 g of sodium hydride (3.0 moles), obtained by washing 140 g of '' a 50% solution of sodium hydride with

  
3 times 500 ml of hexane, stirring well. After about 1 1/2 hours when 2/3 of the ethyl formate solution has been added, the addition is stopped to allow the significant foam to reabsorb

  
that formed. 600 ml of diethyl ether are added and the mixture is stirred for 15 minutes before adding the remainder of

  
ethyl formate solution. When the addition is complete, 600 ml of diethyl ether are added, the reaction mixture is stirred for a further 10 minutes and then poured into 2 L of ice water. Acidify to pH 1 with 10% HCl and separate the phase which is extracted with ethyl acetate (2 x 2 L). The combined organic solutions were washed successively with water (2 x 2 L), brine (1 x 1 L) and dried over MgSO4. The concentration gives 231 g of a reddish brown oil which is used without further

  
  <EMI ID = 345.1>

  
  <EMI ID = 346.1>

  
  <EMI ID = 347.1> <EMI ID = 348.1>

  
propyl-4-oxo-1,2,3,4-tetrahydroquinoline. It is used in the following examples as is.

  
EXAMPLE 21

  
  <EMI ID = 349.1>

  
To 18.2 g (0.38 mol) of sodium hydride obtained by washing with pentane a 50% dispersion of sodium hydride in mineral oil, is added dropwise, over 1/2 hour, a solution of 11.1 g (0.038 mol) of d, l-5-hydroxy-2-methyl-7- (2-

  
  <EMI ID = 350.1>

  
(1.48 mol) of ethyl formate. An exothermic reaction occurs with vigorous evolution of hydrogen and formation of a yellow precipitate. The reaction mixture was cooled, 150 ml of ether was added, then the resulting mixture was heated to reflux and stirred for 3 hours. Then cooled to 0 [deg.] C

  
  <EMI ID = 351.1>

  
The ethereal layer is separated and the aqueous phase is extracted with ether (2 x 150 ml). The ethereal extracts are combined, washed successively with saturated sodium bicarbonate solution (2 x 100 mL) and brine (1 x 150 mL) and then dried over MgSO4. Concentration of the dried extract provides an orange foam (10.8 g). An additional 2.3 g is obtained by acidifying the sodium bicarbonate washing solutions with concentrated hydrochloric acid and then extracting the acidic solution with ether (2 x 100 ml). Concentration of the combined ethereal extracts, after drying, gives 2.3 g of product (in total 13.1 g). The product is used as is.

  
  <EMI ID = 352.1>

  
c), 8.8-11.9 (m, 1H, variable, = COH), 8.73 (s, 1H, N-CHO), 7.41
(s, 1H, = CH), 6.32 (s, 2H, aromatics), 5.52 (q, 1H, -CH-N), 4.18-

  
  <EMI ID = 353.1>

  
  <EMI ID = 354.1>

  
broad, 1H, ArOH), 8.8-11.6 (variable, 1H, = COH), 8.64 (s, 1H, -CHO), <EMI ID = 355.1>

  
6.17 (two doublets of 1H, J = 2Hz, meta), 5.42 (broad q, 1H,

  
  <EMI ID = 356.1>

  
(m, 4H, - (CH2) 2-) '1.29 (overlapping doublets, 6H, CH3-C-N and CH3-C-O).

  
  <EMI ID = 357.1>

  
7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, which is an oil.

  
  <EMI ID = 358.1>

  
  <EMI ID = 359.1>

  
  <EMI ID = 360.1>

  
ques), 4.5 (br s, 2H, -CH2-), 4.2-4.8 (m, -O-CH2-), 2.0-0.7
(remaining protons).

  
  <EMI ID = 361.1>

  
d, 11-formyl-5-hydroxy-3hydroxymethylene-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline. oxo-1,2,3,4-tetrahydroquinoline. .

  
  <EMI ID = 362.1>

  
  <EMI ID = 363.1>

  
8.5 (s, 1H, CHO), 7.2 (m, 6H, aromatics and = CH-), 6.2 (m, 2H, aromatics), 4.5 (s, 2H, -CH2-), 4.4 (m, 1H, -CH-CH3), 2.6 (bt, 2H, -CH2-), 1.7 (m, 5H, protons remaining), 1.3 (d, 3H, -CH- CH3, J = 6Hz).

  
  <EMI ID = 364.1>

  
quinoline, m.p. 132 [deg.] - 135 [deg.] C (in hexane). Recrystallization from hot methanol gives the analytical sample, m.p. 131 [deg.] -
132 [deg.] C.

  
  <EMI ID = 365.1>

  
Found: C, 69.25; H, 5.88; N, 3.88%

  
  <EMI ID = 366.1>

  
  <EMI ID = 367.1>

  
  <EMI ID = 368.1>

  
  <EMI ID = 369.1>

  
  <EMI ID = 370.1>

  
2.02 (m, 4H, - CH2 2-), 1.27 (d, 3H, CH3).

  
  <EMI ID = 371.1>

  
ne (229 g, approximately 0.58 mol) in 880 ml of methanol under a nitrogen atmosphere, 27.2 ml of triethylamine are added with stirring. Then 97.0 ml of methyl vinyl ketone was added and the mixture was stirred overnight at room temperature.

  
The reaction is complete at this point and includes mixing

  
  <EMI ID = 372.1>

  
methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4tetrahydroquinoline. The following steps are necessary to convert the diformyl compound to the desired title compound.

  
The reaction mixture is diluted with 6 l of ether and then washed successively with 10% aqueous sodium carbonate.

  
(4 x 1700 mL), brine (1 x 2 L) then dried over MgSO4. Concentration of the solution provides 238 g of a reddish brown oil. The oil is dissolved in 1920 ml of methanol and the solution is cooled to 0 [deg.] C. 21.2 g of potassium carbonate are added,

  
the mixture is stirred for 3 hours at 0 [deg.] C and then treated with
18.7 g of acetic acid. The methanol was removed under reduced pressure and the resulting oil was stirred with 2 L of water and 2 L of ethyl acetate for 10 minutes. The aqueous phase is separated, extracted with ethyl acetate (1 x 2 L) and the combined ethyl acetate solutions washed with water (2 x 2 L), brine. (1 x 2 L) and dried over MgSO4 'Concentration under reduced pressure and chromatography of the concentrate on silica gel (1.8 kg) gave 159 g of the title product.

  
  <EMI ID = 373.1>

  
  <EMI ID = 374.1>

  
1H, -CHO), 7.22 (s, 5H, aromatics), 6.22 (broad s, 2H, H in meta), 2.12, 2.07 (s, 3H, -CH3-CO-), 1.31 (d, 3H, -CH3-CO-), and 1.575.23 (m, 13H, protons remaining).

  
The similar treatment of 35 g (0.09 mol) of d, l-1-formyl-

  
  <EMI ID = 375.1>

  
1,2,3,4-tetrahydroquinoline gives 22.7 g (60%) of d, ll-formyl5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline, mp 101-103 [deg.] C. The analytical sample is obtained by recrystallization from methanol, m.p. 104-105 [deg.] C.

  
  <EMI ID = 376.1>

  
broad, 1H, -CHO), 7, <2> 9 (s, <3> 5H, C6H5), 6.25 (br s, 2H, H in

  
  <EMI ID = 377.1>

  
  <EMI ID = 378.1>

  
CH3).

  
  <EMI ID = 379.1>

  
  <EMI ID = 380.1>

  
oxobutyl) -1,2,3,4-tetrahydroquinoline which is used as is.

  
EXAMPLE 23

  
  <EMI ID = 381.1>

  
butyl) -1,2,3,4-tetrahydroquinoline and d, ll, 3-diformyl-5-hydroxy2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2 , 3,4-tetrahydroquinoline

  
Has a solution of 13.1 g (37.7 mmol) of d, l-5-hydroxy-3-

  
  <EMI ID = 382.1>

  
hydroquinoline in 56 ml of methanol and 5.52 mg (68 mmol) of methyl vinyl ketone, 1.3 ml (9.3 mmol) of triethylamine are added. The mixture is stirred for 18 hours under a nitrogen atmosphere at room temperature and then diluted with 550 ml of ether. The solution was washed with 10% aqueous sodium bicarbonate solution (4 x 60 mL), then with brine (1 x 100 mL) and dried over MgSO4. Removal of ether by evaporation gave a dark oil (16 g). The oil is dissolved in a minimum volume of benzene and the solution is loaded onto a column of
500 g of silica gel. The column is then eluted with a volume of benzene equal to the volume of the column.

   A mixture of 15% ether benzene is then used as elution solvent and 100 ml fractions are collected when the first colored band begins to elute from the column. Fractions 5 to 13 are combined and

  
  <EMI ID = 383.1>

  
diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) 1,2-3,4-tetrahydroquinoline in the form of a yellow oil (8.7 g ).

  
The column is then eluted with a mixture of 15% ether and benzene. Combine fractions 19 to 37 and concentrate them <EMI ID = 384.1>

  
as an oil (4.6 g). Additional monoformylated product is obtained as follows:

  
1 g of the diformylated product is stirred with 200 mg of potassium carbonate in 25 ml of methanol for 2 hours at 0 [deg.] C. The solvent is then evaporated off in vacuo and the residue is suspended in ether and filtered. The filtrate is concentrated and the residue is partitioned between ether and water. We separate the organic layer, we. the aqueous phase is acidified with 10% hydrochloric acid and extracted with ether. The combined ethereal extracts are washed successively with saturated sodium bicarbonate solution and saline solution and then

  
  <EMI ID = 385.1>

  
obtain additional monoformylated product.

  
The monoformylated derivative has the following NMR spectrum:

  
  <EMI ID = 386.1>

  
8.87 (S, 1H, N-CHO), 6.12 S, 2H, Aromatics), 4.78-5.50 (M, 1H, N-CH), 4.11-4, 72 (M, 1H, -O-CH), 2.21 (S, 3H, CH3-CC (= O), 0.633.12 (M, 22H, other hydrogens).

  
Likewise, the following compounds are prepared from the appropriate reagents:

  
  <EMI ID = 387.1>

  
1,2,3,4-tetrahydroquinoline, which is an oil,

  
  <EMI ID = 388.1>

  
(S, 1H, N-CHO), 6.1 (S, 2H, aromatics), 4.1-4.6 (m, 1H, -O-CH),

  
  <EMI ID = 389.1>

  
  <EMI ID = 390.1>

  
A solution of 174 g (0.398 mol) of d, l-1-formyl- is stirred and refluxed overnight under a nitrogen atmosphere.

  
  <EMI ID = 391.1> 2N and 5.9 liters of methanol. To the cooled solution is added
708 g of acetic acid drop by drop with stirring over 15 minutes.

  
The resulting solution is concentrated in a rotary evaporator.
(under vacuum, water pump) to a semi-solid which is filtered and washed first with water to remove potassium acetate and then with ethyl acetate to 'that the black tar is removed. 68 g (44%) of yellow solids are obtained, m.p.
188-190 [deg.] C. Recrystallization from hot ethyl acetate affords pure product, m.p. 194-195 [deg.] C.

  
  <EMI ID = 392.1>

  
  <EMI ID = 393.1>

  
Found: C, 76.43; H, 7.48; N, 3.58%

  
  <EMI ID = 394.1>

  
0.3 ml of CD3S (0) CD3) (ppm): 7.21 (s, 5H; aromatics), 5.80 (s, 2H, H in meta), 1.20 (d, 6H, CH3-CHO and CH -CH-N).

  
From the mother liquors *, a small amount of the corresponding axial methyl derivative is obtained by evaporation. It is purified by chromatography on a column of silica gel in

  
  <EMI ID = 395.1>

  
Evaporation of the eluate and recrystallization of the residue from a 1: 1 mixture of ether and hexane afforded an analytically pure substance, m.p. 225 [deg.] - 228 [deg.] C.

  
Rf sound by thin layer chromatography on silica gel

  
  <EMI ID = 396.1>

  
  <EMI ID = 397.1>

  
  <EMI ID = 398.1>

  
  <EMI ID = 399.1>

  
  <EMI ID = 400.1>

  
  <EMI ID = 401.1> <EMI ID = 402.1>

  
one, m.p. 222-224 [deg.] C. The analytical sample is obtained by recrystallization from methanol, m.p. 224 [deg.] - 225 [deg.] C.

  
  <EMI ID = 403.1>

  
Found: C, 76.03; H, 7.08; N, 3.68%

  
  <EMI ID = 404.1>

  
  <EMI ID = 405.1>

  
  <EMI ID = 406.1>

  
Evaporation of the mother liquor gives 2.8 g (mp 185-195 [deg.] C) of product which NMR shows to be a mixture of the derivative.

  
  <EMI ID = 407.1>

  
one.

  
  <EMI ID = 408.1>

  
  <EMI ID = 409.1>

  
  <EMI ID = 410.1>

  
5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4tetrahydroquinoline in 150 ml of methanol per 150 ml of a hydroxide solution of 2N methanolic potassium. This mixture is stirred for one hour at room temperature and then heated to reflux under a nitrogen atmosphere for 20 hours. The dark red mixture is allowed to cool to room temperature, neutralized with acetic acid and concentrated under pressure to about 100 ml. The concentrate is diluted with 400 ml of water and the red-brown solid is filtered off, washed with water and dried (about 6 g). It is triturated first in ether then in methanol, filtered and dried.
(1.96 g); m.p. 223-229 [deg.] C. Recrystallization from hot methanol affords crystals melting at 235-237 [deg.] C.

  
  <EMI ID = 411.1>

  
Found: C, 73.22; H, 8.30; N, 4.11% Additional material was collected by evaporating all mother liquors and extracting with chloroform the aqueous solution from which the red-brown crude product was obtained and then evaporating the extract. We purify the residues

  
  <EMI ID = 412.1>

  
  <EMI ID = 413.1>

  
  <EMI ID = 414.1>

  
chloroform).

  
  <EMI ID = 415.1>

  
Analysis: Calculated for C24H2703N: C, 76.36; H, 7.21; N, 3.71%

  
Found: C, 76.38; H, 7.21; N, 3.85%

  
  <EMI ID = 416.1>

  
quinolin-9 (8H) -one; m.p. 208 [deg.] - 209 [deg.] C.

  
  <EMI ID = 417.1>

  
Analysis: Calculated for C20H2703N: C, 72.92; H, 8.26; N, 4.25%

  
Found: C, 72.92; H, 8.31; N, 4.42%

  
  <EMI ID = 418.1>

  
Analysis: Calculated for C27H3303N: C, 77.29; H, 7.93; N, 3.34%

  
Found: C, 76.97; H, 7.98; N, 3.41%

  
  <EMI ID = 419.1>

  
  <EMI ID = 420.1>

  
  <EMI ID = 421.1>

  
Found: C, 76.32; H, 7.36; N, 3.33%

  
  <EMI ID = 422.1>

  
methylbenzo [c] quinolin-9 (8H) -one; m.p. 172 [deg.] - 174 [deg.] C.

  
  <EMI ID = 423.1>

  
  <EMI ID = 424.1>

  
  <EMI ID = 425.1>

  
Found: C, 76.40; H, 7.39; N, 3.51% EXAMPLE 26

  
  <EMI ID = 426.1>

  
We add drop by drop through an ampoule

  
  <EMI ID = 427.1>

  
20 ml of tetrahydrofuran, to a rapidly stirred solution of

  
  <EMI ID = 428.1>

  
through potassium hydroxide pellets}. We rinse the bulb

  
  <EMI ID = 429.1>

  
  <EMI ID = 430.1>

  
  <EMI ID = 431.1>

  
to remove the blue color. The excess ammonia is allowed to evaporate and the residue is taken up in 100 ml of water and 50 ml of ethyl acetate. The ethyl acetate layer was separated and the aqueous phase extracted with ethyl acetate (2 x 50 ml).

  
  <EMI ID = 432.1>

  
MgSO4 and concentrated under reduced pressure to a brown semisolid (1.35 g). Trituration of the semi-solid in a 1: 1 mixture of pentane and ether gives a light brown solid (0.884 g); m.p. 130-138 [deg.] C.

  
  <EMI ID = 433.1>

  
of lithium, 140 ml of liquid ammonia and 45 ml of tetrahydrofuran. The residue (2.1 g) remaining after evaporation of the ammonia is dissolved in benzene and introduced onto a chromatographic column (3.8 x 61 cm) containing 250 g of silica gel.

  
The column is eluted with a volume of degassed benzene equal to the volume of the column and then with 1700 ml of a 9: 1 mixture of degassed benzene and ether. Continuous elution (1100 ml) gives a brilliant red eluate which is concentrated to 580 mg of a brilliant purple solid under reduced pressure which is triturated in a 1: 1 mixture of benzene.

  
  <EMI ID = 434.1>

  
store under nitrogen and in the dark. Isolated solids are

  
  <EMI ID = 435.1>

  
m / e - 345 (m +)

  
  <EMI ID = 436.1>

  
CDC13

  
broad, OH), 5.67, 5.71, 5.85, 5.93 (d, J = 2Hz, 2H in total, aromatic hydrogens of the cis / trans mixture), 0.90 (t, 3H, CH- terminal), 1.12-4.43 (m, H remaining).

  
EXAMPLE 27

  
  <EMI ID = 437.1>

  
acetic under a nitrogen atmosphere. The mixture is stirred for an hour and a half at room temperature and then poured onto

  
50 ml of ice. The gum is extracted with ether (3 x 50 ml)

  
which separates and the combined extracts are washed first with water

  
(4 x 50 ml) then with brine (1 x 60 ml). The extract is dried over MgSO4 and then evaporated under reduced pressure to

  
red oil (250 mg),

  
The oil was dissolved in a minimum of hot ether and loaded onto a column of 45 g of silica gel, packed and eluted with a 3: 1 mixture of pentane and ether. The column was eluted with 200 µl of a 3: 1 mixture of pentane and ether. Elution is continued and

  
the 10 ml fractions are collected. The fractions 22-32 are combined

  
and concentrated to a foam (113.5 mg) which crystallizes

  
  <EMI ID = 438.1> <EMI ID = 439.1>

  
a foam (89.7 mg) which is recrystallized from petroleum ether in the form of white crystals; mp 78-82 [deg.] C.

  
The products are the isomeric monoacetyl components.

  
EXAMPLE 28

  
  <EMI ID = 440.1>

  
benzo [c] quinoline-9 (8H) -one

  
The procedure of Example 26 is repeated but using double the amounts of reagents. The product (2.22 g) is then directly acylated according to the procedure of Example 34, which gives 2.35 g of the acetylated product. This product is triturated in a 3: 1 mixture of pentane and ether until a yellow-brown solid (905 mg) is obtained which, when recrystallized from ethanol, gives 404 mg of light yellow-brown crystals; mp 112-113.5 [deg.] C.

  
The mother liquors are combined and concentrated from which each of the above solids has been separated. The residue is dissolved in a minimum of a 1: 1: 1 mixture of benzene, ether, and methylene chloride and placed in a 275 g column of silica gel (packed and eluted with a mixture of 3: 1 petroleum ether and ether). The column is first eluted with 2 L of a 3: 1 mixture of petroleum ether and ether, then with 1.5 L of a 2: 1 mixture of petroleum ether and ether, then with 2 L of a 1: 1 mixture of petroleum ether and ether. Fractions 2-11 (50 ml each) of the eluate from the solvent system are combined.

  
  <EMI ID = 441.1>

  
(496 mg). Crystallization from petroleum ether gave white crystals, mp 100-113 [deg.] C (410 mg). Recrystallization in

  
  <EMI ID = 442.1>

  
9 (8H) -one, melting at 111-112 [deg.] C.

  
  <EMI ID = 443.1>

  
Analysis calculated for C 23 H 34 N: C, 71.29; H, 8.58; N, 3.61%

  
  <EMI ID = 444.1>

  
  <EMI ID = 445.1>

  
and concentrated to give 273 mg and 208 mg, respectively, of the acetylated product. Crystallization of the residue from fractions 19-27 from petroleum ether gives 119 mg of white crystals, mp 84-88 [deg.] C. Recrystallization from a 1:10 mixture of ethyl acetate and

  
  <EMI ID = 446.1>

  
  <EMI ID = 447.1>

  
  <EMI ID = 448.1>

  
found: C, 71.05; H, 8.48 N, 3.56% Likewise, the following compounds are prepared from the appropriate reagents:

  
  <EMI ID = 449.1>

  
m / e - 435 m)

  
Analysis calculated for C27H3304N: C, 74.45; H, 7.64; N, 3.22%

  
found; C, 74.43; H, 7.73; N, 3.28%

  
  <EMI ID = 450.1>

  
79-80 [deg.] C.

  
m / e - 463 (m)

  
  <EMI ID = 451.1>

  
in the form of the hydrochloride.

  
  <EMI ID = 452.1>

  
  <EMI ID = 453.1>

  
in the form of hydrochloride.

  

  <EMI ID = 454.1>


  
m / e - 435 (m) N, 2.97%

  
  <EMI ID = 455.1>

  
  <EMI ID = 456.1>

  
found: C, 69.24; H, 7.30, /

  
  <EMI ID = 457.1>

  
in the form of the hydrochloride.

  

  <EMI ID = 458.1>


  
  <EMI ID = 459.1>

  
hydrochloride form.

  

  <EMI ID = 460.1>
 

  
  <EMI ID = 461.1>

  
92 [deg.] - 96 [deg.] C as the hydrochloride.

  

  <EMI ID = 462.1>


  
  <EMI ID = 463.1>

  
1150 ml of ammonia are directly condensed under atmosphere

  
  <EMI ID = 464.1> <EMI ID = 465.1>

  
with water and the combined organic phases are washed successively with water (four times 1 liter) in a saturated solution

  
sodium bicarbonate (1x1 L), saline (1 x 1 L);

  
dried over MgSO4 and concentrated to a light brown oil (about 27 g). The residue is chromatographed on 1.8 g of

  
silica gel, using benzene5 / ethyl acetate as elution solvent. One liter fractions are collected.

  
After elution of the non-polar impurities, the

  
Fractions 16-20 and evaporated to a residue which crystallizes from a mixture of ether and petroleum ether, to give 5.6 g
(23.4%) of the trans isomer of the title product. The fractions 21-27 are combined and 7.6 g (yield 31.8%) of a

  
mixture of trans and cis isomers, and the fractions 28-32 are combined

  
which gives 2.5 g (10.4%) of the cis isomer of the product mentioned in

  
title.

  
The trans isomer has the following characteristics:

  
  <EMI ID = 466.1>

  
  <EMI ID = 467.1>

  
  <EMI ID = 468.1>

  
  <EMI ID = 469.1>

  
  <EMI ID = 470.1>

  
The cis isomer has the following characteristics:

  
  <EMI ID = 471.1>

  
  <EMI ID = 472.1>

  
  <EMI ID = 473.1> <EMI ID = 474.1>

  
a 1: 5 mixture of ethyl acetate and persian.

  
  <EMI ID = 475.1>

  
found: C, 74.00; H, 7.47; N, 3.22%

  
  <EMI ID = 476.1>

  
Further purification of the last columns by additional chromatography on a silica gel column using a 1: 1 mixture of cyclohexane and ether as eluent,

  
  <EMI ID = 477.1>

  
95-96 [deg.] C, after recrystallization from a 1: 5 mixture of ethyl acetate and hexane.

  
  <EMI ID = 478.1>

  
analysis calculated for C26H3104N C, 74.08; H, 7.41; N, 3.32%

  
found: C, 73.95; H, 7.51; N, 3.31%

  
EXAMPLE 31

  
  <EMI ID = 479.1>

  
quinoline-9 (8H) -one

  
A solution of 9.0 g of d, l-5,6,6a is added dropwise,

  
  <EMI ID = 480.1>

  
in 100 ml of tetrahydrofuran, to a rapidly stirred solution of 0.1 g of lithium in 750 ml of liquid ammonia. Additional 0.1 g of lithium is added in portions during the addition,

  
  <EMI ID = 481.1>

  
  <EMI ID = 482.1>

  
of ammonium chloride. Allow excess ammonia to evaporate

  
and the residue is taken up in a mixture of water and ethyl acetate. The organic layer is separated and the aqueous phase is extracted two

  
  <EMI ID = 483.1>

  
combined extracts, with brine, dried over MgSO and evaporated to give 8.45 g of the crude product as a solid

  
  <EMI ID = 484.1> <EMI ID = 485.1>

  
  <EMI ID = 486.1>

  
dark color which is chromatographed on a column of 450 g of silica gel. The column is eluted successively with a 1: 1 mixture of ether and hexane, a 2: 1 mixture of ether and hexane, and

  
ether. The fractions of 18 ml each are collected. Fractions 176-224 were combined and concentrated to an oil which crystallized from hexane to give 3.24 g (32%) of the trans isomer of the title compound as light yellow crystals, mp 65.5 [deg.] - 68 [deg.] C.

  
  <EMI ID = 487.1>

  
  <EMI ID = 488.1>

  
Fractions 246-290 were combined and concentrated to give 0.55 g (5%) of the crude cis isomer of the title compound as an oil. It is then purified by column chromatography as described above, to obtain the pure cis isomer in the form of an oil.

  
  <EMI ID = 489.1>

  
  <EMI ID = 490.1>

  
  <EMI ID = 491.1>

  
  <EMI ID = 492.1>

  
found: C, 70.90H, 8.54; N, 3.79% Fractions 225-245 were combined and evaporated to give 2.69 g (26%) of a mixture of the cis and trans isomers which was separated by the procedure described above.

  
The following compounds are prepared in a similar manner from

  
  <EMI ID = 493.1>

  
  <EMI ID = 494.1>

  
  <EMI ID = 495.1>

  
found: C, 74.16; H, 7.59; N, 3.20%

  
  <EMI ID = 496.1>

  
  <EMI ID = 497.1>

  
  <EMI ID = 498.1> * * 9 iaie 0ç-

  
  <EMI ID = 499.1>

  
The isomeric products are converted to their hydrochlorides as described in the general salt formation procedure. The characteristics of the salts are given below:
  <EMI ID = 500.1>
(a) thin layer chromatography in benzene: ether 1: 1
(b) calcd for C27H3304N.CH1: C, 68.71; H, 7.26; N, 2.96

  
EXAMPLE 32

  
  <EMI ID = 501.1>

  
benzo [c] quinoline-9 (8H) -one in 10 ml of ethanol at 0 [deg.] C, one adds
40 mg of sodium borohydride. After half an hour, the reaction mixture is poured into a mixture of 50 ml of 5% acetic acid and 75 ml of ice-cold ether. After separation of the ethereal layer, the aqueous phase is extracted again with

  
ether (2 x 50 mL). The combined ethereal extracts are washed successively with water (2 x 50 ml), saturated sodium bicarbonate.

  
(1 x 50 mL), brine (1 x 75 mL), dried over MgSO4,

  
filtered and concentrated under reduced pressure, which gives
156 mg of a white foam containing a mixture of alcohol

  
axial (small quantity) and equatorial alcohol (prepon-

  
  <EMI ID = 502.1>

  
  <EMI ID = 503.1>

  
IR (CHCl3 to 5.72, (carbonyl ester)

  
  <EMI ID = 504.1>

  
at 2.28 ppm for the methyl acetate.

  
The main and minor isomers are separated as follows: 180 mg of the alcohols of d, l-trans-5,6,6a, 3- are introduced. <EMI ID = 505.1>

  
of silica and elution is carried out with a solvent mixture of 3 parts of benzene and 1 part of ether. 15 ml fractions are collected. Fractions 6-8 are combined, concentrated under reduced pressure, which

  
  <EMI ID = 506.1>

  
Other compounds prepared from suitable reagents according to the foregoing procedure include the following:

  
  <EMI ID = 507.1>

  
m / e - 437 (m)

  
  <EMI ID = 508.1>

  
Conversion to the hydrochloride gives a solid, mp 188-190 [deg.] C. Recrystallization from a 25: 1: 100 mixture of acetone, methanol and ether provides an analytical sample of the 9 & -alcohol, mp 193-194 [deg.] C.

  

  <EMI ID = 509.1>


  
The transformation into methane sulfonate (with methanesulfonic acid in dichloromethane) gives a solid which is recrystallized from ethyl acetate, obtaining white crystals, mp 110-114 [deg.] C.

  

  <EMI ID = 510.1>


  
  <EMI ID = 511.1>

  
m / e - 437 (m +)

  
  <EMI ID = 512.1>

  
  <EMI ID = 513.1>

  
(dec.) as hydrochloride.

  
nv
  <EMI ID = 514.1>
  <EMI ID = 515.1>

  
found: C, 68.24; H, 7.68; N, 3.00%

  
  <EMI ID = 516.1>

  
125 [deg.] C (dec.) As the hydrochloride.

  
  <EMI ID = 517.1>

  
  <EMI ID = 518.1>

  
  <EMI ID = 519.1>

  
found: C, 68.41; H, 7.54; N, 2.95%. Similarly, the compounds given in the table below are prepared from the appropriate reagents.

  

  <EMI ID = 520.1>
 

  
  <EMI ID = 521.1>

  
7.57 g (0.20 mole) of sodium borohydride are added to 200 ml of methanol, under a nitrogen atmosphere and the mixture is cooled in a bath of acetone and carbon dioxide snow to approximately -75 [deg.] C. The mixture is stirred for about 20 minutes to dissolve most if not all of the sodium borohydride. We cool to about
-50 [deg.] C a solution of 8.71 g (0.02 mol) of d, l-trans-5,6,6a &#65533; -7.10, <EMI ID = 522.1>

  
add drop by drop for 5-10 minutes to sodium borohydride solution. The reaction mixture is stirred at about 70 [deg.] C for
30 minutes then poured into a mixture of water (1000 ml) containing 45 g (0.81 mol) of ammonium chloride, 250 ml of ice

  
  <EMI ID = 523.1>

  
extract the aqueous layer with ethyl acetate (3 x 200 mL). The combined extracts are washed with water (1 x 100 ml) and dried over

  
  <EMI ID = 524.1>

  
drop by drop in 15 minutes a solution of ethyl acetate (15ml) /

  
  <EMI ID = 525.1>

  
hydrochloride of the title product precipitates. We stir the mixture

  
  <EMI ID = 526.1>

  
  <EMI ID = 527.1>

  
with decomposition.

  
  <EMI ID = 528.1>

  
following procedure.

  
It is hydrogenated at room temperature in a

  
  <EMI ID = 529.1>

  
  <EMI ID = 530.1>

  
  <EMI ID = 531.1>

  
a saturated solution of hydrogen chloride ethyl acetate to precipitate the hydrochloride of the product mentioned in

  
  <EMI ID = 532.1> <EMI ID = 533.1>

  
  <EMI ID = 534.1>

  
quinoline-9 (8H) -one in 45 ml of pyridine at room temperature, 45 ml of acetic anhydride are added. The resulting solution is stirred for 3.5 hours and then poured onto
250 ml of ice-water and the mixture is extracted with isopropyl ether (2 x 250 ml). The extracts are washed with water (3 x 200 ml)

  
  <EMI ID = 535.1>

  
reduced to a yellow-brown oil which solidifies when the sides of the bottle containing them are scratched. Trituration of the solid with n-heptane gives 2.0 g of the 1-acetoxy derivative (yield 40%). It is purified by recrystallization from a mixture

  
Hot 1: 4 of chloroform and n-hexane to give the pure ester mp 136-140 [deg.] C ..

  
m / e - 433 (the +

  
  <EMI ID = 536.1>

  
  <EMI ID = 537.1>

  
  <EMI ID = 538.1>

  
  <EMI ID = 539.1>

  
1.21 (d, J = 7Hz, 6H, CH3-C-N, CH3-C-O), 1.49-4.51 (m, 14H, protons remaining).

  
EXAMPLE 34

  
  <EMI ID = 540.1>

  
  <EMI ID = 541.1>

  
Potassium butylborohydride (2.296 mmol) dropwise in 5: minutes, The reaction mixture is stirred for 30 minutes

  
  <EMI ID = 542.1>

  
  <EMI ID = 543.1>

  
  <EMI ID = 544.1>

  
  <EMI ID = 545.1>

  
  <EMI ID = 546.1> ...............

  
a 3: 1 mixture of benzene and ether as eluent. After elution of the less polar impurities, the title compound is isolated as a clear oil (700 mg). The oil is dissolved in 35 ml

  
of ether and treated with ether saturated with gaseous HCl to obtain the hydrochloride of the title compound (448 mg), mp
115-124 [deg.] C after recrystallization from a mixture of ether and chloroform.

  
MS (molecular ion)

  
IR (KBr) 5.58 (> C = 0 of the ester)

  
  <EMI ID = 547.1>

  
N, 2.96%

  
found: C, 68.52; H, 7.91;

N, 2.73%

  
The following compounds are prepared in the same manner from the appropriate reagents:

  

  <EMI ID = 548.1>


  
hydrochloride. Analysis:

  
  <EMI ID = 549.1>

  
N, 2.96%

  
found C, 68.48; H, 7.57;

  
N, 2.93%

  
  <EMI ID = 550.1>

  
  <EMI ID = 551.1>

  
  <EMI ID = 552.1>

  
an excess of acetic anhydride and pyridine overnight

  
at room temperature. The mixture is poured onto ice water, the aqueous mixture is extracted with ether (3 x 100 ml),

  
and the combined extracts were washed with water, brine then dried over MgSO4 and evaporated. The residue was subjected to column chromatography (40 g of silica gel, benzene: ether 9: 1 as elution solvent) to give 680 mg of d; 1-trans-

  
  <EMI ID = 553.1>

  
of hexane and ethyl acetate, mp 86-87 [deg.] C.

  
  <EMI ID = 554.1>

  
  <EMI ID = 555.1>

  
  <EMI ID = 556.1>

  
  <EMI ID = 557.1>

  
0.8-5.0 (multiplets, protons remaining);

  
  <EMI ID = 558.1>

  
found: C, 69.51; H, 8.54; N, 3.14%

  
  <EMI ID = 559.1>

  
after recrystallization from a 1: 1 mixture of ethyl acetate and hexane.

  
  <EMI ID = 560.1>

  
Analysis calculated for C28H3505N: C, 72.23; H, 7.58; N, 3.01%

  
found: C, 72.17; H, 7.61; N, 3.08%

  
EXAMPLE 36

  
  <EMI ID = 561.1>

  
  <EMI ID = 562.1>

  
  <EMI ID = 563.1>

  
  <EMI ID = 564.1>

  
  <EMI ID = 565.1>

  
sodium bicarbonate, 1 time 40 ml of brine, dried over Mg SO. and it is concentrated under reduced pressure, which gives

  
  <EMI ID = 566.1>

  
amorphous solid, mp 80-100 [deg.] C with decomposition.

  
  <EMI ID = 567.1>

  
The NMR spectrum (CDCl .., 60 MHz,) does not show absorption

  
  <EMI ID = 568.1>

  
no absorption for a carbonyl in the ester.

  
In the same way, the following compound is prepared starting from

  
  <EMI ID = 569.1>

  
  <EMI ID = 570.1>

  
  <EMI ID = 571.1>

  
The transformation into the hydrochloride gives a powder, mp 151-

  
  <EMI ID = 572.1>

  
  <EMI ID = 573.1>

  
  <EMI ID = 574.1>

  
9 (8H) -one to the corresponding 1-hydroxy compound, mp 157-160 [deg.] C.

  
  <EMI ID = 575.1>

  
  <EMI ID = 576.1>

  
found: C, 73.16; H, 9.14; N, 3.85%

  
EXAMPLE 37

  
  <EMI ID = 577.1>

  
421 mg of benzoyl chloride in 5 ml of chloroform are added. After 2 hours, the reaction mixture is poured onto ice and extracted twice with ether. The combined ethereal extracts are washed with water and bicarbonate solution.

  
  <EMI ID = 578.1>

  
after concentration and crystallization from a mixture of ether and

  
  <EMI ID = 579.1>

  
  <EMI ID = 580.1>

  
  <EMI ID = 581.1>

  
  <EMI ID = 582.1>

  
an equivalent amount of acetyl chloride in place of chloru-

  
  <EMI ID = 583.1>

  
following compound:

  
  <EMI ID = 584.1>

  
m / e - 433 (m +)

  
EXAMPLE 38

  
  <EMI ID = 585.1>

  
(8H) -one in 3 ml of acetonitrile, cooled to 15 [deg.] C, 0.5 ml of 37% aqueous formaldehyde is added then 100 mg of sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH until the reaction is complete, as evidenced by the absence of starting materials in thin layer chromatography. The product is isolated as follows.

  
Ice-water and ether are added to the reaction mixture, the ether layer is separated / the aqueous phase is extracted once more with ether. The ethereal layers are combined, dried and evaporated to give d, l-trans-5,6,6a &#65533;,

  
  <EMI ID = 586.1>

  
  <EMI ID = 587.1>

  
  <EMI ID = 588.1>

  
In the same way, the following compounds are prepared from the appropriate reagents:

  
  <EMI ID = 589.1>

  
  <EMI ID = 590.1>

  
In addition, the following compounds are prepared in the same way:

  

  <EMI ID = 591.1>
 

  

  <EMI ID = 592.1>


  
in hydrochloride form

  
Analysis

  
  <EMI ID = 593.1>

  
found: C, 68.72; H, 7.18; N, 2.74% <2> Analysis

  
Calculated for: C28H3504N: C, 74.80; H, 7.85; N, 3.12% Found: C, 74.66; H, 8.05; N, 2.66% Analysis

  
Calculated for: C27H3304N: C, 74.45; H, 7.64; N, 3.22% Found: C, 73.89; H, 7.51; N, 3.04%

  
EXAMPLE 39

  
  <EMI ID = 594.1>

  
  <EMI ID = 595.1>

  
To a solution of 100 mg of lithium aluminum hydride in 5 ml of dry tetrahydrofuran (cooled in an ice-water bath) is added dropwise a solution of 90 mg of

  
  <EMI ID = 596.1>

  
tetrahydrofuran. After the addition is complete, the reaction mixture is heated under reflux for one hour and then allowed to cool to room temperature. Equivalent amounts of water are added followed by 3N potassium hydroxide, the resulting precipitate is filtered off and the filtrate is concentrated in vacuo, this

  
which gives the desired N-ethyl derivative as an oil.

  
m / e - 375 (m +) <EMI ID = 597.1>

  
  <EMI ID = 598.1>

  
  <EMI ID = 599.1>

  
of acetonitrile at room temperature, then 0.262 g of sodium cyanoborohydride. The reaction mixture is stirred for one hour, during which time the pH is maintained at neutral by addition of acetic acid as needed. 0.262 g is added

  
  <EMI ID = 600.1>

  
reaction which is then acidified to pH 3, which is stirred for 2 hours and which is concentrated under reduced pressure to an oil. The oil is diluted with 50 ml of water, then the pH is adjusted

  
to 9-10 using an aqueous solution of sodium hydroxide

  
and the alkaline mixture is extracted with ether (sometimes 200 ml). The combined ethereal extracts are washed with brine,

  
dried over Na2SO4 and concentrated under reduced pressure to a clear oil. Then the oil is dissolved in a 50% mixture of ether and hexane and introduced onto a column of silica gel. The column is eluted first with 50% etherhexane and then with 60%, 70% and 75% ether-hexane mixtures. The eluate is checked by thin layer chromatography (ether / hexane 10: 1). The first product collected is d, 1-trans-5,6,6a, 7,10,10a-hexahydro-1-acetoxy-5-methyl-3- (5-phenyl-2-pentyloxy) benzo [c] quinoline -9- (8H) -one (0.125 g).

  
  <EMI ID = 601.1>

  
  <EMI ID = 602.1>

  
N, 3.22% Found: C, 74.06; H, 7.77;

N, 3.31%

  
The second product is the 9 "-hydroxy diastereoisomer of the title compound (25 mg).

  
m / e - 437 (m)

  
  <EMI ID = 603.1>

  
N, 3.20%

  
found C, 73.96; H, 8.34;

N, 3.00%.

  
The third product is the 9 -hydroxy diastereomer of the title compound (0.7 g) <EMI ID = 604.1>

  
m / e - 387 (m +)

  
  <EMI ID = 605.1>

  
  <EMI ID = 606.1>

  
  <EMI ID = 607.1>

  
  <EMI ID = 608.1>

  
  <EMI ID = 609.1>

  
  <EMI ID = 610.1>

  
  <EMI ID = 611.1>

  
  <EMI ID = 612.1>

  
  <EMI ID = 613.1>

  
then with brine (1 x 10 ml) and dried over MgSO4.

  
Concentration of the chlorofomic solution under vacuum gives

  
a yellow oil which solidifies on standing. Trituration of the solid with hexane gives a white crystalline solid which is collected by filtration and dried (400 mg), mp 128-129 [deg.] C.

Concentration of the hexane filtrate gives 121 mg of oil.

  
EXAMPLE 42

  
  <EMI ID = 614.1>

  
Slowly add 38 mg (1.0 mmol) of sodium borohydride

  
  <EMI ID = 615.1>

  
of absolute ethanol, at 5-10 [deg.] C under a nitrogen atmosphere. The reaction mixture is stirred for one hour and acidified with 10% hydrochloric acid. Ethanol is removed by concentration under reduced pressure. 10 ml of water are added to the resulting solution which is then extracted with ethyl acetate (2 times
50 ml). The extracts are combined, washed with brine and then dried (MgSO 4). Concentration in vacuo affords the title compound as an amorphous solid (213 mg)

  
which is used without further purification.

  
. EXAMPLE 43 <EMI ID = 616.1> <EMI ID = 617.1>

  
  <EMI ID = 618.1>

  
stirring 1 ml of acetic anhydride and the reaction mixture is stirred for 30 minutes at 0 [deg.] C. It is then poured into 20 ml of water

  
  <EMI ID = 619.1>

  
The extracts are combined, washed with brine, dried

  
  <EMI ID = 620.1>

  
The oil was purged with nitrogen and chromatographed on silica gel (40 g) using a 9: 1 mixture of benzene and ether as eluent. Fractions of 10 ml each were collected. Fractions 2:10 were pooled and concentrated to an oil (109 mg).

  
  <EMI ID = 621.1>

  
  <EMI ID = 622.1>

  
found: C, 74.33; H, 8.89; N, 2.23%

  
  <EMI ID = 623.1>

  
6.05 (d, 1H, aromatic), 5.90 (d, 1H, aromatic), 4.90 (broad s, 1H) 4.30 (broad s, 1H), 3.10 (d, 2H, N -CH2), 2.90 (d, 2H, N-CH2), 2.70 (broad s, 2H), 2.40 and 2.15 (s, 6H, 2-CH3-COO-), 1.85 (s wide,

  
  <EMI ID = 624.1>

  
  <EMI ID = 625.1>

  
protons remaining).

  
EXAMPLE 44

  
  <EMI ID = 626.1>

  
742 mg (2.12 mmol) of triphenylmethylphosphonium bromide are added to a solution of 0.95 g (2.0 mmol) of sodium hydride in 50 ml of dimethylsulfoxide at 50 [deg.] C. Then the reaction mixture is heated at 70 [deg.] C for 3 hours, after which it is added

  
  <EMI ID = 627.1>

  
9 (8H) -one in 50 ml of dimethylsulfoxide. The reaction mixture is cooled to 70 ° C. overnight and cooled and poured into a mixture of ice and water containing 12.5 g of sodium carbonate. The aqueous mixture is extracted with benzene,

  
  <EMI ID = 628.1>

  
the gross product. It is purified by chromatography on a column of silica gel in a 1: 1 mixture of hexane and benzene.

  
  <EMI ID = 629.1>

  
  <EMI ID = 630.1>

  
in tetrahydrofuran (borane-tetrahydrofuran complex) (6 ml). After addition, the reaction mixture is kept at room temperature for 30 minutes and then treated with water to decompose excess hydride.

  
The reaction mixture is then warmed to 50.degree. C. in a water bath and 3 ml of 3N sodium hydroxide are added and then 3 ml of 30% hydrogen peroxide are added dropwise. After addition, the reaction mixture is kept at room temperature for one hour, 1.5 g of potassium carbonate are added, and the mixture is separated.

  
  <EMI ID = 631.1>

  
tetrahydrofuran (3 times 10 ml), the extracts are combined, they are

  
  <EMI ID = 632.1>

  
performs the purification by chromagraphy on a silica gel column using an ether / hexane mixture.

  
EXAMPLE 46

  
  <EMI ID = 633.1>

  
heptyloxy) benzo [c] quinoline-9 (8H) -one, 0.43 ml (7.70 mmol) of ethylene glycol and 0.28 g (1.46 mmol) of p-toluenesulfonic acid monohydrate in 25 ml of benzene. The water obtained as a by-product is removed azeotropically. The dark suspensions thus obtained are taken up in a mixture of ether and a solution.

  
  <EMI ID = 634.1>

  
it is washed with an aqueous solution of sodium bicarbonate.

  
  <EMI ID = 635.1>

  
  <EMI ID = 636.1>

  
  <EMI ID = 637.1>

  
  <EMI ID = 638.1>

  
  <EMI ID = 639.1> <EMI ID = 640.1>

  
............ 8.).

  
  <EMI ID = 641.1>

  
  <EMI ID = 642.1>

  
(s, 4H, ethylene ketal) and absorption for the remaining protons.

  
Fractions 42-65 are combined and concentrated to give 146 mg of a yellow solid. Trituration of the solid in a 1: 1 mixture of ether and pentane gives 85 mg of 7,10-dihydro-

  
  <EMI ID = 643.1>

  
mp 171-173 [deg.] C.

  
  <EMI ID = 644.1>

  
  <EMI ID = 645.1>

  
6.6 and 7.0 (broad d, 2H, aromatics,), 4.1 (broad s, 4H, ethylene ketal), 3.9 (broad s, 2H, C-10 methylene), 3.1 (t, 2H,

  
  <EMI ID = 646.1>

  
absorptions for the remaining protons.

  
Analysis calculated for C22H2904N: C, 71, <1> <3>; H, 7.87; N, 3.77%

  
found: C, 71.19; H, 7.67; N, 3.61% In the same way, d, l-5,6-6a, 7,10,10a-hexa-

  
  <EMI ID = 647.1>

  
  <EMI ID = 648.1>

  
  <EMI ID = 649.1>

  
  <EMI ID = 650.1>

  
1H, aromatics), 5.7 (br s, 1H, phenolic), 4.0 (/, 4H, ethylene ketal), 3.9 (s larqe, 2H, D-10-CH2-), 3.1 (t wide,

  
  <EMI ID = 651.1>

  
  <EMI ID = 652.1>

  
EXAMPLE 47

  
  <EMI ID = 653.1>

  
Equimolar amounts of m-chloroperben-

  
  <EMI ID = 654.1>

  
form and acetic acid (2: 1) and the reaction mixture is stirred

  
  <EMI ID = 655.1>

  
the organic phase is washed with water, dried over MgSO4 and evaporated to dryness to obtain the title product.

  
  <EMI ID = 656.1>

  
The procedure of Example 47 is repeated but using 2 equivalents of m-chloroperbenzoic acid of oxidizing agent per mole of thio-ether reagent, to obtain the title compound.

  
EXAMPLE 49

  
  <EMI ID = 657.1>

  
(2-heptyloxy) benzo &#65533; c &#65533; quinoline-9 (8H) -one

  
  <EMI ID = 658.1>

  
one in 25 ml of dry methylene, 0.315 g (1.5 mmol) is added

  
4-morpholinobutyric acid hydrochloride and the mixture is stirred at room temperature under a nitrogen atmosphere. We add

  
  <EMI ID = 659.1>

  
methylene chloride (12.5 ml, 1.5 mmol) and the mixture was stirred for 24 hours. It is then filtered and evaporated to obtain the title compound which is purified by chromatography on a column of silica gel.

  
EXAMPLE 50

  
  <EMI ID = 660.1>

  
methylene, 0.524 g (2.53 mmol) of 4-N-piperidylbutyric acid hydrochloride and 0.573 g (2.78 mmol) of dicyclo are added.

  
  <EMI ID = 661.1>

  
6 hours then cooled for 12 hours and filtered. Evaporation of the filtrate and trituration of the residue with ether gives 1.3 g of solid which is the monohydrochloride.

  
  <EMI ID = 662.1>

  
Preparative thin layer chromatography of part of this solid on silica gel 0.5 irai thick and elution with 10% methanol in methylene dichloride provides the free base, the dichloride. , 1-trans-5,6,6a &#65533;, 7,8,9,10,10a &#65533; -octahy-

  
  <EMI ID = 663.1>

  
  <EMI ID = 664.1>

  
  <EMI ID = 665.1>

  
(aromatic s, 2H) and 7.16 (s, 5H).

  
Treatment of this free base with an excess of hydrogen chloride in ether provides the dihydrochloride in the form of a hygroscopic powder.

  
EXAMPLE 51

  
  <EMI ID = 666.1>

  
one

  
To a 25 [deg.] C solution of 550 mg (1.41 mmol) of d, l-5,6,6a, 7-

  
  <EMI ID = 667.1>

  
  <EMI ID = 668.1>

  
291 mg (1.41 mmol) of 4-N-piperidybutyric acid hydrochloride and 319 mg (1.55 mmol) of dicyclohexylcarbodiimide. This reaction mixture was stirred for 18 hours then cooled to 0 ° C. and filtered. Evaporation of the filtrate and trituration of the residue with ether gives 800 mg of the hydrochloride of d, l-.

  
  <EMI ID = 669.1>

  
phenyl-2-pentyloxy) benzo [c] quinoline-9 (8H) -one as a

  
  <EMI ID = 670.1>

  

  <EMI ID = 671.1>


  
In the same way, the hydrochloride of d, l-

  
  <EMI ID = 672.1>

  
IR (KBr): 3.00, 3.75, 5.67 (ester), 6.15 and 6.30.

  
EXAMPLE 52

  
  <EMI ID = 673.1>

  
ice temperature of 44 mg (2.0 mmol) of methyl lithium in
25 ml of ether. The 5-lithio6-methylated derivative thus obtained is dissolved in dry ether and treated with dry oxygen to obtain <EMI ID = 674.1>

  
solvent.

EXAMPLE 53

General formation of hydrochlorides

  
An excess of hydrogen chloride is passed through a

  
  <EMI ID = 675.1>

  
and separating the resulting precipitate which is recrystallized from a suitable solvent, for example a 1:10 mixture of methanol and ether.

  
In this way, the following salt is prepared:

  
  <EMI ID = 676.1>

  
  <EMI ID = 677.1>

  
  <EMI ID = 678.1>

PREPARATION A

  
2-Bromo-5-phenylpentane

  
To phosphorus pentabromide, prepared by adding 9.0 g of bromine in 10 ml of methylene chloride to 15.0 g of phosphorus tribromide in 15 ml of methylene chloride at 0 [deg.] C, is added
812 g of 5-phenyl-2-pentanol in methylene chloride at

  
  <EMI ID = 679.1>

  
let it warm to room temperature. 50 ml of water are added, the mixture is stirred for one hour and the methylene chloride layer is separated. The extraction is repeated and the combined extracts are washed with water, saturated sodium bicarbonate solution and brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g of the title product as a light yellow oil.

  
  <EMI ID = 680.1>

  
lene), 2.3-3.0 (broad T, 2, methylene benzyl), 3.7-4.2 (M, l, methine), 6.9-7.4 (M, 5, aromatic).

PREPARATION B

  
2- (3,5-Dimethoxyphenyl) -5-phenylpentane

  
A solution of 51.7 g of 1-bromopropylbenzene in 234 ml of ether is added dropwise over two hours to a reflux mixture of 7.32 g of magnesium in 78 ml of ether. The reaction mixture is heated under reflux for an additional 30 minutes, then a solution of 50 g of 3,5-dimethoxyacetophenone in 78 ml of ether is added dropwise and the mixture is heated under reflux for a period of time. <EMI ID = 681.1>

  
extract the aqueous phase with ether (3 times 200 ml). We

  
the combined ethereal extracts are dried over magnesium sulphate and concentrated in vacuo to give 81 g of an oil. We hydrogen
40 g of the oil in a mixture containing 300 ml of ethanol,

  
2 ml of concentrated hydrochloric acid and 5 g of 5% palladium on charcoal. The catalyst is filtered off and the ethanol is removed in vacuo.

  
The residue is distilled in vacuo to give 28 g. of 2- (3,5dimethoxyphenyl) &#65533; 5-phenylpentane, eg 0.125 mm, 154-159 [deg.] C.

  
  <EMI ID = 682.1>

  
  <EMI ID = 683.1>

  
6.2-6.7 (M, 3 aromatics), 7.2 (S, S, aromatics).

PREPARATION C

  
  <EMI ID = 684.1>

  
and 94 g of pyridine hydrochloride under nitrogen. The reaction mixture is cooled, dissolved in 200 ml of 6N hydrochloric acid. and diluted with water to 600 ml. The aqueous solution was extracted with 4 times 100 ml of ethyl acetate, the ethyl acetate extracts were dried over sodium sulfate and concentrated in vacuo, to give 24 g of crude product. The product is purified by chromatography on silica gel, which gives

  
  <EMI ID = 685.1>

  
oil. ', - "_ &#65533; - [.

  
  <EMI ID = 686.1>

  
  <EMI ID = 687.1>

  
aromatics) 6.65 (br S, 2, hydroxyl), 7-7.4 (M, 5, aromatics).

  
Following the procedures of Preparations B and C are Indicated below by substituting the 1-

  
  <EMI ID = 688.1>

  
  <EMI ID = 689.1>

  
  <EMI ID = 690.1>

  
  <EMI ID = 691.1>

  
2.15-2.7 (M, 3, methylene benzyl, methinyl), 6.3 (S, 3, aroma-

  
  <EMI ID = 692.1>

PREPARATION D

  
1- (3,5-Dihydroxyphenyl) -2-methyl-4-phenylbutane

  
29 ml of a 2.2M solution of nbutyllithium are added dropwise to 31.5 g of 3,5-dimethoxybenzyl triphenylphosphonium bromide in 200 ml of tetrahydrofuran, with stirring, and the mixture is stirred for half a year. hour the resulting dark red solution. 9.4 g of benzylacetone are added dropwise and the reaction mixture is stirred for 12 hours. Then we adjust the pH to 7

  
by addition of acetic acid and the mixture is concentrated under reduced pressure. The residue is extracted with methylene chloride

  
  <EMI ID = 693.1>

  
Crude 2-methyl-4-phenyl-1-butene in the form of an oil. It is purified by chromatography of 400 g on silica gel and by elution with benzene. 10 g are obtained in the form of an oil.

  
  <EMI ID = 694.1>

  
6.15-6.6 (M, 3), 1.1-7.5 (M, 6).

  
9.4 g of 1- (3,5-dimethoxy) are dissolved in 250 ml of ethanol.

  
  <EMI ID = 695.1>

  
catalytically at 3.15 kg / cm in the presence of 1 g of 10% palladium on charcoal and 1 ml of concentrated hydrochloric acid. 9.4 g of 1- (3,5-dimethoxyphenyl-2-methyl-4-phenylbutane are obtained in the form of an oil.

  
  <EMI ID = 696.1>

  
  <EMI ID = 697.1>

  
It is demethylated according to the procedure of preparation C

  
  <EMI ID = 698.1>

  
nium by heating to reflux a mixture of 12 g of 3.5-

  
  <EMI ID = 699.1>

  
of acetonitrile for one hour. Then we cool the mixture

  
  <EMI ID = 700.1> <EMI ID = 701.1>

  
ether and replaced with 50 ml of dry benzene and the mixture was heated under reflux for 48 hours. It is then decomposed by cautious treatment with dilute sulfuric acid and heated on a steam bath for one hour. The mixture was then extracted with ether, the extract was dried over MgSO4 and concentrated to an oil. Vacuum oil distillation

  
  <EMI ID = 702.1>

  
pe 168 [deg.] C / 0.2 mm, 2.32 g (60%).

  
58 g of the pentanone thus obtained are dissolved in 400 ml of ether and treated with 10 g of sodium borohydride at room temperature. The reaction mixture is stirred for 12 hours then cooled and neutralized with 6N hydrochloric acid. Ethanol is removed under reduced pressure and

  
  <EMI ID = 703.1>

  
  <EMI ID = 704.1>

  
  <EMI ID = 705.1>

  
16 g of pentanol are taken up in 100 ml of ether and it is

  
reacted with 2.5 g of powdered potassium in 200 ml of ether. An equimolar amount of carbon disulfide relative to potassium is added and the mixture is stirred for half an hour. Then 9.0 g of methyl iodide was added and the reaction mixture was stirred for 6 hours. The resulting suspension is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 150 ml of ether, 25 g of Raney nickel are added and the mixture is heated under reflux for 18 hours. Evaporation of the alcohol and distillation of the residue gives 2-methyl-2 (3,5-

  
  <EMI ID = 706.1>

  
The pentene derivative is catalytically hydrogenated according to the procedure of Preparation D and the

  
  <EMI ID = 707.1>

  
the procedure of preparation C to obtain the product.

PREPARATION F

  
Over an hour and a half, 531 ml of a 2M solution of methyl-lithim (1.06 mol) under nitrogen atmosphere are added to a rapidly stirred solution of 175 g (0.531 mol) of 3,5- acid.

  
  <EMI ID = 708.1>

  
  <EMI ID = 709.1>

  
  <EMI ID = 710.1>

  
  <EMI ID = 711.1>

  
the aqueous layer and extracted with ether (3 x 250 mL).

  
The organic phases are combined, washed with saturated sodium chloride solution (4 times 300 ml), dried over sodium sulfate and concentrated in vacuo, which gives an oil which slowly crystallizes from ether. isopropyl. The crude product is recrystallized from ether-hexane to give
104.7 g (59%) of product, mp 59-61 [deg.] C.

PREPARATION G

  
  <EMI ID = 712.1>

  
A mixture of 43.2 g (0.13 mol) of 3,5-dibenzyloxyacetophenone is heated under a nitrogen atmosphere at 170 [deg.] C for 4 hours.

  
and 90.5 g (0.26 mol) of carbethoxymethylenetriphenylphosphorane. The clear melt is cooled to room temperature,

  
it is triturated with ether, and the precipitate of triphenylphosphine oxide is removed by filtration. The filtrate is concentrated in vacuo to an oily residue which is chromatographed on
1500 g of silica gel, eluting with solutions of benzene and hexane, the benzene concentration of which increases, starting from 40:60 and ending with 100% benzene. Concentration of the appropriate fractions gives an oily residue which is crystallized from hexane. 40.2 g (77%) are obtained, mp 73-75 [deg.] C.

  
Analysis calculated for C26H2604 ° C, 77.58; H, 6.51%

  
found: C, 77.72; H, 6.60%

  
  <EMI ID = 713.1>

  
obtains 61.8 g, 86%, bp 146-162 [deg.] C at 0.3 mm.

PREPARATION H

  
  <EMI ID = 714.1>

  
A solution of 24.1 g (60 mmol) of ethyl 3- (3,5dibenzyloxyphenyl) crotonate in 250 ml of ether is added to a mixture of 3.42 g (90 mmol) of lithium hydride and d aluminum and 250 ml of ether. Aluminum chloride 0.18 g (1.35 mmol) is added and the mixture is heated at reflux for 2 hours and then cooled. Then 3.4 ml of water, 3.4 ml of 6N sodium hydroxide are added successively to the reaction mixture and

  
10 ml of water. The inorganic salts which precipitate are filtered off and the filtrate is then concentrated in vacuo, which gives the desired alcohol under

  
  <EMI ID = 715.1>

  
  <EMI ID = 716.1>

  
  <EMI ID = 717.1>

  
Analysis calculated for C24H2603 ° C, 79.53; H, 7.23%

  
found: C, 79.37; H, 7.11%

  
  <EMI ID = 718.1>

  
ethyl crotonate (60.4 g) in 3- (3,5-dimëthoxyphenyl) butanol

  
(48.0 g, 90%).

  
PREPARATION 1

  
3- (3,5-Dibenzyloxyphenyl) butyl tosylate

  
11.1 g (58.1 mmol) of tosyl chloride is added to a solution of 20.7 g (57 mmol) of 3- (3,5-dibenzyloxyphenyl) -1butanol in 90 ml of pyridine at -45 [deg .]VS. The reaction mixture is maintained at -35 [deg.] C for 18 hours then diluted with 1500 ml of cold 2N hydrochloric acid and extracted with ether.

  
(5 times 250 ml). The combined extracts are washed with saturated sodium chloride solution (4 times 250 ml) and then dried over Na2SO4. Concentration of the dried extract provides the product as an oil. It is crystallized by treatment with a mixture of ether and hexane. 24.63 g (84%) are obtained.

  
  <EMI ID = 719.1>

  
found: C, 72.05; H, 6.29%

PREPARATION J

  
  <EMI ID = 720.1>

  
A solution of 4.56 g (48.6 mmol) of phenol is added in
40 ml of dimethylformamide, under a nitrogen atmosphere, to a suspension of 2.32 g of sodium hydride (48.6 mmoles of a product with

  
50% previously washed with pentane) in 70 ml of dimethylformamide

  
  <EMI ID = 721.1>

  
after which a solution of 23.93 g (46.3 mmol) of 3- (3,5-dibenzyloxyphenyl) butyl tosylate in 80 ml of dimethylformamide is added. The reaction mixture is stirred at 80 [deg.] C for half an hour and then cooled to room temperature.

  
it is diluted with 500 ml of cold water and extracted with ether (4 times 400 ml). The combined extracts are washed successively with cold 2N hydrochloric acid (2 times 300 ml) and a saturated solution of sodium chloride (3 times 300 ml) and then dried over Na 2 SO 4. Removal of the solvent under reduced pressure affords the product as an oil. The oily residue is dissolved in benzene and filtered through silica gel (100 g). Concentration of the filtrate under reduced pressure gave product as an oil, 14.86 g (73%).

  
Rf = 0.7 (silica gel, benzene)

  
  <EMI ID = 722.1>

  
Analysis calculated for C30H3003 'C, 82.16; H, 6.89%

  
found: C, 82.07; H, 6.84%

PREPARATION K

  
  <EMI ID = 723.1>

  
Hydrogenated for 2 hours under 4.2 kg / cm of hydrogen

  
in the presence of 1.5 g of 10% palladium on charcoal

  
a solution of 14.7 g (133.5 mmoles) of 3- (3,5-dibenzyloxyphenyl) -, 1-phenoxybutane in a mixture of 110 ml of ethyl acetate,

  
110 ml of ethanol and 0.7 ml of concentrated hydrochloric acid. Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on 100 g of silica gel, eluting with a mixture of benzene.

  
and ethyl acetate comprising 0-10% ethyl acetate.

  
The fractions of the medium are combined and concentrated to obtain the title product: 7.8 g (80%) in the form of an oil.

  
  <EMI ID = 724.1>

  
  <EMI ID = 725.1>

  
  <EMI ID = 726.1>

  
found: C, 74.13; H, 7.00%

PREPARATION L

  
  <EMI ID = 727.1>

  
A solution of 5.7 ml (0.06 mole) of phosphorus tribromide in 30 ml of ether is added to a solution of 30.0 g (0.143 mole)

  
  <EMI ID = 728.1>

  
temperature of -5 [deg.] C to -10 [deg.] C, and the reaction mixture is stirred

  
at this temperature for 2 and a half hours. Then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured onto 200 g of ice, and the resulting mixture is extracted with ether (3 times 50 ml).

  
The combined extracts are washed with a 5% solution of sodium hydroxide (3 times 50 ml), a saturated solution of sodium chloride.
(1 x 50 mL) and dried over Na2SO4. Elimination of ether

  
and vacuum distillation of the residue provides the title product; 25 g (55%), pe 125-132 [deg.] C at 0.4 mm.

PREPARATION M

  
4- (3,5-Dihydroxyphenyl) -1- (4-pyridyl) pentane

  
  <EMI ID = 729.1>

  
  <EMI ID = 730.1>

  
dimethylsulfoxide to 3.79 g (35.4 mmol) of 4-pyridinecarboxaldehyde in 40 ml of tetrahydrofuran. The resulting mixture is then added dropwise to a suspension of 1.87 g (39 mmol) of 50% sodium hydrochloride in 20 ml of tetrahydrofuran under a nitrogen atmosphere at 0-5 [deg.] C. When the addition is complete, the mixture is stirred for one hour at 0 [deg.] - 5 [deg.] C and then concentrated under reduced pressure. The concentrate is diluted with 200 ml of water

  
  <EMI ID = 731.1>

  
with benzene (4 times 50 ml). Then it is made basic and extracted with ethyl acetate (3 times 50 ml). Evaporation of the combined extracts after drying (MgSO4) gives 4- (3,5-

  
  <EMI ID = 732.1>

  
of an oil.

  
The catalytic hydrogenation of the pentene derivative thus obtained according to the procedure of Preparation D provides 4- (3,5-

  
  <EMI ID = 733.1>

  
mp 131-133 [deg.] C.

  
The pentane derivative thus obtained is demethylated by heating

  
a mixture of 7.15 g (25 mmol) of the compound and 105 g of pyridine hydrochloride under a nitrogen atmosphere at 210 [deg.] C for 8

  
hours. The hot mixture is poured into 40 ml of water and the resulting solution is alkanilized with 6N sodium hydroxide.

  
Water and pyridine are removed by vacuum distillation. We

  
50 ml of ethanol are added to the residue and the mineral salts are filtered off

  
that rush. The filtrate is concentrated in vacuo and the residue is chromatographed under 150 g of silica gel using as eluting agent 4 liters of 5% ethanol in benzene, one liter of 10% ethanol in benzene. 1 L of 13% ethanol in benzene and 5 L of 16% ethanol in benzene. The product is isolated in the form of a glassy solid by concentration of the appropriate fractions of the eluate. 5.0 g (78%) are obtained.

  
3- (3,5-Dimethoxyphenyl) butyltriphenylphosphonium bromide is prepared by heating under reflux a mixture of 1-bromo-3- (3,5-

  
  <EMI ID = 734.1>

  
(20.5 g, 78.5 mmol) in 60 ml xylene for 18 hours. The reaction mixture is then cooled to room temperature and filtered. The filter cake was washed with ether and dried in a desiccator under vacuum to give 36.4 g (86%).

  
  <EMI ID = 735.1>

PREPARATION N ..............

  
  <EMI ID = 736.1>

  
To a solution of 69.4 mmoles of dimthylsulfoxonium methylide in 65 ml of dimethylsulfoxide at room temperature,

  
  <EMI ID = 737.1>

  
The reaction mixture was stirred for one hour at 25 [deg.] C, for half an hour at 50 [deg.] C, then cooled. The mixture is diluted with 50 ml of water and added to a mixture of 200 ml of ice water, 250 ml of ether and 25 ml of low boiling petroleum ether. The organic extract is washed twice with water.
(250 mL, dried over MgSO4 and evaporated to an oil. Fractional distillation of the oil provided 8.0 g (75%)

  
  <EMI ID = 738.1>

  
  <EMI ID = 739.1>

  
  <EMI ID = 740.1>

  
  <EMI ID = 741.1>

  
RMP (CDC13) (60 MHz): &#65533; 1.70 (S, CH3-), 2.76 (d, J = 6Hz,

  
  <EMI ID = 742.1>

  
2 Hz, ArH) and 6.58 (d, J = 2 Hz, ArH).

  
Analysis calculated for C11H1403: C, 68.02; H, 7.27%

  
  <EMI ID = 743.1>

  
  <EMI ID = 744.1>

  
2- (3,5-Dimethoxyphenyl) -2-hydroxypropyl and 2-phenylethylcoxide

  
A mixture of 30 ml is heated at 110 [deg.] C for 30 minutes.

  
(251 mmol) of dry 2-phenylethanol and 690 mg (30 mmol) of metallic sodium. The resulting 1M solution is cooled to 60 [deg.] C

  
sodium 2-phenylethoxide, 2 g (10.3 mmol) are added

  
  <EMI ID = 745.1>

  
reaction 15 hours at 60 [deg.] C. The reaction mixture is cooled

  
and added to a mixture of ether and water. The ethereal extract is dried over magnesium sulfate and evaporated. We chase excess

  
of 2-phenylethanol by vacuum distillation (pe approximately -65 [deg.] C,

  
0.1 mm), which leaves a residue of 3.5 g. The residue is purified by column chromatography on silica gel 60 from Merck.
(330 g) and eluted in fractions of 15 ml with a mixture of 60% ether in pentane. Fractions 52-88 provide 2.9 g

  
(89%) 2- (3,5-Dimethoxyphenyl-2-hydroxypropyl 2-phenylethyl oxide).

  
  <EMI ID = 746.1>

  
  <EMI ID = 747.1> <EMI ID = 748.1> 3.80 (S, OCH3) 6 6.38 (t, J = 2Hz, ArH), 6.61 (d, J = 2Hz, ArH) and 7.23 (S, PhH).

  
  <EMI ID = 749.1>

  
found: C, 71.92; H, 7.63%

PREPARATION P

  
  <EMI ID = 750.1>

  
  <EMI ID = 751.1>

  
hydroxypropyl and 2-phenylethyl (550 mg, 1.74 mmol),

  
477 ml (5.22 mmol) of phosphorus oxychloride are added dropwise in 2 ml of pyridine. This reaction mixture is left

  
  <EMI ID = 752.1>

  
  <EMI ID = 753.1>

  
150 ml of ether and 100 ml of 5% sodium carbonate. The organic phase is separated and washed with sodium carbonate

  
  <EMI ID = 754.1>

  
evaporated to an oil. The oil is dissolved in 15 ml

  
  <EMI ID = 755.1>

  
  <EMI ID = 756.1>

  
gaseous. When the hydrogen intake stops (26.5 ml, 20 minutes),

  
  <EMI ID = 757.1> <EMI ID = 758.1>

  
aqueous phase, dried over magnesium sulfate and evaporated to an oil. The oil is purified by preparative thin layer chromatography on silica gel plates, eluted 6 times with a mixture of 30% ether in pentane, to give

  
  <EMI ID = 759.1>

  
2-phenylethyl.

  
  <EMI ID = 760.1>

  
  <EMI ID = 761.1>

  
  <EMI ID = 762.1>

  
(t, J = 7Hz, -CH2Ph), 2.80 (H-C-Me), 3.4-3.8 (-CH2OCH2-), 6.08
(t, J = 2Hz, ArH), 6.21 (d, J = 2Hz, ArH) and 7.16 (S, PhH).

PREPARATION R

  
  <EMI ID = 763.1>

  
Under a nitrogen atmosphere, a mixture of 50.0 g (0.15 mol) of 3.5- is added dropwise over a three-quarter hour.

  
  <EMI ID = 764.1>

  
of 7.18 g (0.15 mol) of 3-phenoxypropyltriphenylphospho- bromide

  
  <EMI ID = 765.1>

  
  <EMI ID = 766.1>

  
pentane) in 75 ml of tetrahydrofuran, maintained at 0.5 [deg.] C.

  
  <EMI ID = 767.1>

  
reaction mixture warm to room temperature, then stirred carefully in 2000 ml of ice-water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (5 times 400 ml ). The combined organic phases are washed

  
  <EMI ID = 768.1>

  
it is dried over sodium sulfate and concentrated in vacuo, which gives an oil which is triturated with ether to make

  
  <EMI ID = 769.1> <EMI ID = 770.1>

  
160 ml of absolute ethanol, 160 ml of ethyl acetate and

  
0.2 ml of concentrated hydrochloric acid. Removal of the catalyst by filtration and concentration of the filtrate in vacuo provides
30.8 g (100%) of the product as a viscous oil.

  
Analysis calculated for C17H2003; C, 74.97, H, 7.40%

  
  <EMI ID = 771.1>

PREPARATION S

  
3-Hydroxy-5-pentylaniline

  
1.8 g (0.01 mole) of olivetol, 2.65 g (0.05 M) of ammonium chloride, 5.2 g (0.05 mole) of sodium bisulfite are combined

  
and 12.5 ml of ammonium hydroxide and heated in a steel bomb at 230 [deg.] C for half an hour. The bomb is then cooled and the contents dissolved in 350 ml of ethyl acetate. We add
300 ml of 10% hydrochloric acid, the mixture is stirred and then the organic layer is separated. The extraction is repeated two more times. The aqueous acidic solution is neutralized with 6N sodium hydroxide and extracted with chloroform.

  
(3 times 300 ml). The combined chloroform extracts are dried and concentrated. The residue is taken up in ethyl acetate,

  
it is decolorized with charcoal and concentrated. The addition of hexane to the residue causes it to crystallize: 270 mg; mp 88-91 [deg.] C. When recrystallized from a hot 1: 1 mixture of ethyl acetate and hexane, it melts at 95-96 [deg.] C.

  
  <EMI ID = 772.1>

  
  <EMI ID = 773.1>

PREPARATION T

  
  <EMI ID = 774.1>

  
A solution of 2.4 g (9.5 mmol) of d, l-3-hydroxy-5- (5-phenyl-2-pentyl) aniline in 24 ml is stirred at room temperature for 45 minutes. of pyridine and 24 ml of acetic anhydride. The reaction mixture is poured into 200 ml of water and 200 ml of acid.

  
  <EMI ID = 775.1>

  
organic- and washed successively with water (4 times 100 ni),

  
  <EMI ID = 776.1>

  
  <EMI ID = 777.1> <EMI ID = 778.1>

  
  <EMI ID = 779.1>

  
  <EMI ID = 780.1>

  
an oil which crystallizes from hexane to give 1.5 g of

  
  <EMI ID = 781.1>

  
  <EMI ID = 782.1>

  
  <EMI ID = 783.1>

  
7.12, 6.58 and 6.45 (broad s, variable 1H, ArOH), 2.19-2.78
(m, 3H, Ar-CH, and Ar-CH2), 2.05 (s, 3H, CH3-C (= 0) -), 1.3-

  
  <EMI ID = 784.1>

PREPARATION U

  
  <EMI ID = 785.1>

  
furan, 193 mg (4.03 mmol) of sodium hydride are added to

  
50%. After 30 minutes of stirring, 1.38 g (8.06 mmol) of alpha-bromotoluene is added and stirring is continued for 16 hours. Then the reaction mixture is filtered, 1 ml of acetic acid is added to the filtrate which is then concentrated and chromatographed (silica gel, benzene / ether 2: 1 as eluent)

  
  <EMI ID = 786.1>

  
aniline in the form of an oil.

  
m / e - 387 (m +)

  
  <EMI ID = 787.1>

  
7.20, 6.84, 6.59 (broad s3, 5H, 6H, 1H, 1H, aromatics), 5.0 (s, 2H, -O-CH2Ar), 2.21-2.98 (m, 3H, Ar-CH and Ar-CH2), 2.07

  
  <EMI ID = 788.1>

  
CH3 - &#65533; '- Ar) &#65533;.

  
Refluxed on a steam bath for 4 days a

  
  <EMI ID = 789.1>

  
aniline, 14 ml of 20% potassium hydroxide, 14 ml of methanol and 10 ml of 2-propanol. After cooling, water and ethyl acetate are added and the mixture is stirred for

  
10 minutes. The organic phase is separated and the aqueous phase is extracted again with ethyl acetate. We bring together solutions

  
  <EMI ID = 790.1>

  
and chromatographed on 35 g of silica gel using ^ -

  
  <EMI ID = 791.1> <EMI ID = 792.1>

  
  <EMI ID = 793.1>

  
7.13 (br s, 5H, aromatics), 6.01-6.33 (m, 3H, aromatics), 4.95 (s, 2H, ArCH20), 3.48 (br s, 2H, variable, NH2 ), 2,172.88 (m, 3H, Ar-CH and Ar-CH2), 1.32-1.76 (m, 4H, (CH2) 2) '

  
1.14 (d, 3H, -C-CH3).

PREPARATION V

  
  <EMI ID = 794.1>

  
To a stirred solution of 482 g (2.94 moles) of 5-phenyl-2pentanol in 2250 ml of tetrahydrofuran at 0 [deg.] C is added 300 ml.

  
of methanesulfonyl chloride, at a rate such that the internal temperature does not rise above 10 [deg.] C (total addition time 4.5 hours). After the addition is complete, the reaction mixture is allowed to warm to room temperature, and stirring is continued for an additional hour. The reaction mixture is filtered and the supernatant liquor is concentrated to a light yellow oil (2800 g) which is dissolved in 2 liters.

  
chloroform and washed with water (4 times 1 liter) brine (1 time 1 liter), which is treated with 50 g of charcoal,

  
that we dry on MgS04, that we filter on diatomaceous earth,

  
and concentrated to a light orange oil (687 g, 95% yield). This material can be used without further purification.

  
  <EMI ID = 795.1>

  
  <EMI ID = 796.1>

  
  <EMI ID = 797.1>

  
O-CH-CH3).

  
Likewise, the following mesylates are prepared from the appropriate alcohols:

  
4-phenylbutanol mesylate, yellow oil

  
  <EMI ID = 798.1>

  
  <EMI ID = 799.1>

  
  <EMI ID = 800.1>

  
  <EMI ID = 801.1>

  
1-2-octanol mesylate, colorless oil

  
  <EMI ID = 802.1>

  
  <EMI ID = 803.1>

  
S, CH3), 1.40 (d, 3H, CH3-CH), 0.87 (t, 3H, CH3-ch) '1.0-2.0 (m,

  
  <EMI ID = 804.1>

  
D-2-octanol mesylate

  

  <EMI ID = 805.1>


  
  <EMI ID = 806.1>


    

Claims (1)

1. Compound of formula <EMI ID = 807.1> where A is <EMI ID = 808.1> and ketals and thioketals of compounds in which A is III '<EMI ID = 809.1> pharmaceutically acceptable acid tion of compounds in which A is I 'or II'; where R is a hydroxy, alkanoyloxy group having 1 to 5 carbon atoms or hydroxymethyl; <EMI ID = 810.1> from 2 to 4 carbon atoms; R 'is a hydroxy, alkanoyloxy group having from 1 to 5 carbon atoms, hydroxymethyl, oxo, methylene or alkylenedioxy having from two to four carbon atoms; R is a hydrogen atom or a benzyl or benzoyl group, <EMI ID = 811.1> where p is zero or an integer of 1 to 4; R., and R., taken separately <EMI ID = 812.1> are the same or different and have hydrogen atoms or <EMI ID = 813.1> and R- taken separately with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, said ring being a piperidino, pyrrolo, pyrrolidino, morpholino or N-alkypiperazino group in which the alkyl group has from 1 to 4 carbon atoms; R. is a hydrogen atom or an alkyl group having <EMI ID = 814.1> <EMI ID = 815.1> <EMI ID = 816.1> ethyl; -O-alkylene-O- is an alkylenedioxy group having two to four carbon atoms; <EMI ID = 817.1> carbalkoxy in which the alkoxy group has 1 to 4 carbon atoms, <EMI ID = 818.1> alkanoyl having from 2 to 5 carbon atoms, alkyl having from 1 to <EMI ID = 819.1> <EMI ID = 820.1> <EMI ID = 821.1> Z is an alkylene group having 1 to 9 carbon atoms; <EMI ID = 822.1> different and are alkylene groups having 1 to 9 carbon atoms, provided that the sum of the carbon atoms in (alkl) + (alk2) is not greater than 9; each of n and n is 0 or 1; and <EMI ID = 823.1> <EMI ID = 824.1> <EMI ID = 825.1> <EMI ID = 826.1> <EMI ID = 827.1> <EMI ID = 828.1> <EMI ID = 829.1> <EMI ID = 830.1> <EMI ID = 831.1> benzyl, methyl or ethyl. 2. Compound according to claim 1, characterized in that <EMI ID = 832.1> <EMI ID = 833.1> <EMI ID = 834.1> hydrogen atom or an alkyl group. 3. Compound according to claim 2, characterized in that. <EMI ID = 835.1> <EMI ID = 836.1> a hydrogen atom or a phenyl group. 4. Compound according to claim 3, characterized in that <EMI ID = 837.1> 5. compound according to claim 4, characterized in that <EMI ID = 838.1> acetyl, and. R is a hydroxy group. 6. Compound according to claim 5, characterized in that <EMI ID = 839.1> <EMI ID = 840.1> 8: A compound according to claim 7, characterized in that <EMI ID = 841.1> <EMI ID = 842.1> 9. A compound according to claim 7, characterized in that <EMI ID = 843.1> <EMI ID = 844.1> <EMI ID = 845.1> <EMI ID = 846.1> methyl. <EMI ID = 847.1> <EMI ID = 848.1> <EMI ID = 849.1> of hydrogen. 13. Trans diastereoisomer (6a, 10a) of a compound according to claim 12, characterized in that R is a group <EMI ID = 850.1> 14. Trans diastereoisomer (6a, 10a) of a compound according to claim 12, characterized in that R is an acetoxy group, <EMI ID = 851.1> 15. A compound according to claim 12, characterized in that <EMI ID = 852.1> hydroxy or acetoxy group; Z is an alkylene group; and W is a hydrogen atom or a phenyl group. 16. A compound according to claim 15, characterized in that <EMI ID = 853.1> and W is a hydrogen atom. 17. A compound according to claim 16, characterized in that <EMI ID = 854.1> methyl. 18. A compound according to claim 17, characterized in that <EMI ID = 855.1> <EMI ID = 856.1> 19. A compound according to claim 15, characterized in that <EMI ID = 857.1> is a phenyl group. <EMI ID = 858.1> <EMI ID = 859.1> <EMI ID = 860.1> <EMI ID = 861.1> <EMI ID = 862.1> <EMI ID = 863.1> <EMI ID = 864.1> <EMI ID = 865.1> <EMI ID = 866.1> W is a phenyl group or a hydrogen atom. 23. A compound according to claim 22, characterized in that <EMI ID = 867.1> <EMI ID = 868.1> <EMI ID = 869.1> 24. A compound according to claim 23, characterized in that <EMI ID = 870.1> 25. A trans (6a, 10a) diastereomer of a compound according to claim 24. 26. A cis (6a, loa) diastereomer of a compound according to claim 24. 27. A compound according to claim 22, characterized in that <EMI ID = 871.1> 28. A compound according to claim 27, characterized in that <EMI ID = 872.1> <EMI ID = 873.1> 29. A compound according to claim 1, characterized in that <EMI ID = 874.1> <EMI ID = 875.1> hydrogen or a methyl group; Z is an alkylene group; and W is a hydrogen atom or a phenyl group. 30. A compound according to claim 1, characterized in that <EMI ID = 876.1> <EMI ID = 877.1> <EMI ID = 878.1> phenyl group. 31. A compound according to claim 30, characterized in that Z is -O- (alk2) n. 32. A component according to claim 31, characterized in that <EMI ID = 879.1> 33. A compound according to claim 31, characterized in that <EMI ID = 880.1> 34. A ketal of a compound according to claim 30, characterized <EMI ID = 881.1> 35. A compound according to claim 1, characterized in that <EMI ID = 882.1> 04 water. * Th phenyl group. 36. A compound according to claim 35, characterized in that R 'is an ethylenedioxy group; Z is a group <EMI ID = 883.1> of hydrogen. 37. A compound according to claim 36, characterized in that <EMI ID = 884.1> 38. A component according to claim 35, characterized in that <EMI ID = 885.1> W are each a hydrogen atom. 39. A compound according to claim 38, characterized in that <EMI ID = 886.1> 40. Pharmaceutical composition, characterized in that it contains a pharmaceutical carrier and a compound of formula XX, in which A is I ', II', or IV 'or one of its addition salts <EMI ID = 887.1> <EMI ID = 888.1> cation 1. 41. Pharmaceutical composition according to claim 40, characterized in that said composition is in unit dosage form and contains, as active ingredient, from 0.01 to 50 mg of said compound of formula XX or one of its addition salts. pharmaceutically acceptable acid. 42. Pharmaceutical composition according to claim 41, characterized in that the therapeutic agent is the trans (6a, 10a) diastereoisomer of a compound of formula XX where A is I '. 43. Pharmaceutical composition according to claim 42, characterized in that R is a hydroxy or acetoxy group; <EMI ID = 889.1> hydrogen atom or a methyl group; and R and R 6 are each a hydrogen atom or an alkyl group. 44. A pharmaceutical composition according to claim 43, <EMI ID = 890.1> <EMI ID = 891.1> or a phenyl group. <EMI ID = 892.1> <EMI ID = 893.1> <EMI ID = 894.1> <EMI ID = 895.1> <EMI ID = 896.1> <EMI ID = 897.1> <EMI ID = 898.1> 47. pharmaceutical composition according to claim 43, characterized in that R is a hydroxy group; each of <EMI ID = 899.1> <EMI ID = 900.1> 48. Pharmaceutical composition according to claim 41, characterized in that the therapeutic agent is a compound of formula XX in which A is II ', R. is an acetyl group; R4 is a methyl group; R5 and R, - are each an atom <EMI ID = 901.1> a phenyl group. 49. A pharmaceutical composition according to claim 48, <EMI ID = 902.1> <EMI ID = 903.1> <EMI ID = 904.1> each a hydrogen atom. 50. A method of producing an analgesic, hypotensive or diuretic effect or treatment of glaucoma in a mammal, characterized in that the mammals are administered an effective amount of a compound of formula XX wherein A is I ', II 'or IV' or one of its pharmaceutically addition salts <EMI ID = 905.1> W are as defined in claim 1. 51. A method of producing analgesia in a mammal according to claim 50, characterized in that the mammal is administered an amount making it possible to produce analgesia of said compound of formula XX or of one of its addition salts. pharmaceutically acceptable acid. 52. The method of claim 51, characterized in that A is I '. <EMI ID = 906.1> the compound is a trans (6a, 10a) diastereomer in which R is a hydroxy or alkanoyloxy group; R is an acetyl group or a hydrogen atom; R5 is a hydrogen atom or a methyl group; R. and R6 are each a hydrogen atom or an alkyl group; and W is a hydrogen atom or a phenyl group. 54. The method of claim 53, characterized in that <EMI ID = 907.1> an acetyl group. 55. Method according to claim 54, characterized in that <EMI ID = 908.1> 56. The method of claim 55, characterized in that <EMI ID = 909.1> 57. The method of claim 55, characterized in that <EMI ID = 910.1> of hydrogen. 58. The method of claim 55, characterized in that <EMI ID = 911.1> <EMI ID = 912.1> 59. The method of claim 55, characterized in that <EMI ID = 913.1> <EMI ID = 914.1> 60. The method of claim 54, characterized in that <EMI ID = 915.1> <EMI ID = 916.1> 61. The method of claim 54, characterized in that <EMI ID = 917.1> <EMI ID = 918.1> <EMI ID = 919.1> <EMI ID = 920.1> Z is an alkylene group. 63. The method of claim 62, characterized in that <EMI ID = 921.1> 64. The method of claim 51, characterized in that A is II '. 65. The method of claim 64, characterized in that <EMI ID = 922.1> <EMI ID = 923.1> <EMI ID = 924.1> hydrogen or a phenyl group. 66. The method of claim 65, characterized in that <EMI ID = 925.1> <EMI ID = 926.1> 67. The method of claim 66, characterized in that the compound is the cis diastereoisomer (6a, 10a). 68. The method of claim 66, characterized in that the compound is the trans diastereoisomer (6a, 10a).