BE828694R - THIENO-BENZOPYRANS AND THIOPYRANO-BENZOPYRANS, INTERMEDIATE PRODUCTS AND PROCESS FOR THEIR OBTAINING - Google Patents

Description

       

   <EMI ID = 1.1>

  
intermediate products and process for their production.

  
 <EMI ID = 2.1>

  
! and thiopyranobonzopyranes corresponding to the following general formula:

  

 <EMI ID = 3.1>


  
in which :

  
 <EMI ID = 4.1> <EMI ID = 5.1> <EMI ID = 6.1>

  
carbamoyl, lower N-alkylcabamyl, lower N, N-dialkylcarbamyl, phosphonyl or a water solubilizing substituent such as dialkylaminoalkyl, hemi-succinate or the like, or a phosphate ester; m being equal to one or two; n being equal to 0 or 1; and m + n being equal to 2 or 3.

  
The present application relates to novel thiopyranobenzopyranes of similar structure, as well as to their reaction intermediates and to their method of preparation and use.

  
The first aspect of the invention resides in the design of a class of chemical compounds which more particularly includes those designated as 8-alkyl (and 8-cycloalkyl-lower alkyl) -10-hydroxy (and 10-0-ethers) -

  
 <EMI ID = 7.1>

  
their appropriate acid addition salts. The second aspect of the invention resides: in the design of a class of chemical compounds which more particularly comprises those designated as 8-alkyl (and 8-cycloalkyl-lower alkyl) -

  
 <EMI ID = 8.1>

  
The compounds of the first class of the present invention show inherent biological activity as can be determined by

  
'usual pharmacological tests used for drugs.

  
 <EMI ID = 9.1>

  
biological activity. The first object of the present invention is therefore to provide new chemical compositions, novel reaction intermediates and processes for preparing said chemical compositions and said intermediates.

  
Another object is to provide chemical compositions exhibiting pharmacological properties and methods for treating pain and hypertension. Other objects of the invention will emerge or follow.

  
evidently from the following description.

  
The invention therefore relates to the different stages and the relation of one or more of these stages to each of the others, the composition of the product having the characteristics, properties and the relation

  
 <EMI ID = 10.1>

  

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 <EMI ID = 12.1>

  
 <EMI ID = 13.1>

  
 <EMI ID = 14.1> <EMI ID = 15.1>

  
 <EMI ID = 16.1> alkyl groups containing 1 to 20 carbon atoms and cycloalkyl groups containing 3 to 8 carbon atoms.

  
The term "lower alkyl" denotes saturated monovalent aliphatic groups, including straight and branched chain groups having

  
from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl,

  
 <EMI ID = 17.1>

  
The term "alkyl" denotes monovalent aliphatic groups

  
 <EMI ID = 18.1>

  
with 20 carbon atoms, such as methyl, n-amyl, n-hexyl, 2-methyl, 2-heptyl,

  
 <EMI ID = 19.1>

  
2-eicosanyl and the like.

  
 <EMI ID = 20.1>

  
lower alkyl, lower alkanoyl, carbamyl, N-lower alkylcarbamyl, N, N-dialky] lower carbamyl or phosphosnyl are obtained by reaction of

  
 <EMI ID = 21.1>

  
basic catalyst, with a lower alkyl halide for

  
 <EMI ID = 22.1>

  
 <EMI ID = 23.1>

  
phosphorus followed by the reaction of the resulting dichlorophosphinate with carbon

  
 <EMI ID = 24.1>

  
smells of a phosphonyl group. Suitable solvents for use in these syntheses are benzene, toluene, xylene and the like. Suitable basic catalysts are alkali metal carbonates, bicarbonates or hydroxides, dimethylaniline, pyridine and the like.

  
When R ,, denotes a dialkylaminoalkyl group, the compounds

  
 <EMI ID = 25.1>

  
alkali metal in a solvent such as ethanol, to obtain the alkali derivative which upon treatment with a dialkylaminoalkyl halide in a solvent such as benzene provides the desired derivatives. The acid addition salts of the dialkylaminoalkyl derivatives can be prepared by reacting the free base with a suitable acid in a suitable organic solvent, in which case the acid salts can be separated directly or obtained by concentration of the solvent.

  
 <EMI ID = 26.1> <EMI ID = 27.1>

  
Vu 9000 0, * 00 04 or the acid salt of the amir.o group, to provide either the free base or the acid addition salt directly. If the free base form is obtained then it is converted to the acid addition salt in the same manner as that

  
 <EMI ID = 28.1>

  
alkyl. It is well known to switch from one acid addition salt to another by regenerating the free base form and acidifying it.

  
Suitable acid addition salts are those derived from acids

  
 <EMI ID = 29.1>

  
phthalic, anthranilic acid, 1-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2-furancarboxylic acid,

  
 <EMI ID = 30.1>

  
3-indoleacetic, quinic acid, sulfamic acid, methanesulfonic acid, isenthionic acid, benzenesulfonic acid, p-toluenesulfonic acid,

  
benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, acid

  
 <EMI ID = 31.1>

  
hydrobromic acid, hydriodic acid, perchloric acid, nitric acid,

  
sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride and the like.

  
Compounds of formula I are prepared by reacting

  
corresponding oxo compound of formula II:

  

 <EMI ID = 32.1>


  
with a lower alkyl magnesium halide according to the following scheme:

  

 <EMI ID = 33.1>


  
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halogen. The Grignard reaction is carried out in an organic solvent, inert under the reaction conditions. Suitable solvents are diethyl ether, dibutyl ether, tetrahydrofuran, anisole, pyridine and the like.

  
After reaction, most of the isolated product is a triol of formula IV. This triol is dissolved in a suitable solvent such as benzene and the whole is refluxed with an acid catalyst such as p-toluenesulfonic acid. The compound of formula III is thus obtained according to the following scheme:

  

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acid catalyst such as HCl dissolved in ethanol. The reaction can be schematized as follows:

  

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The 5-alkyl or 5-cycloalkyl-lower alkyl-resorcinol intermediates of formula VI are advantageously prepared according to generally known methods such as dehydration of a 3,5-dialkoxy lower phenylalkyl or (cycloalkyl-lower alkyl) carbinol, reduction of 3 , 4-lower dialkoxy

  
 <EMI ID = 39.1> <EMI ID = 40.1>

  
can be prepared according to the method of Leonardo and Figueras, J. Amer. Ci :: '! .. Se- ?.

  
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associated psychoneurotic depression symptoms.

  
The anti-depressive activity of the compounds has been demonstrated: in

  
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tion of acquisition, by learning, etc.

  
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It has been shown in particular that the compound of formula VII:

  

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 <EMI ID = 48.1>

  
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administered to a mammal in pain and significantly reduced blood pressure when administered to a mammal with hypertension.

  
The analgesic activity of the compound of formula VII was demonstrated in mice and evaluated using a painful stretching test caused by acetic acid. The test used was a modification <EMI ID = 51.1>

  
5 minutes after the acid injection. Analgesic activity is calculated

  
based on the difference between the test groups and their controls.

  
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painful is summarized in Table 1 below.

  
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Painful stretching test induced by acetic acid in mice (oral).

  

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VII) has been demonstrated in genetically hypertensive rats. However, the compound exhibits weak direct cardiovascular effects in normotensive animals at therapeutic doses.

  
The anti-hypertensive activity of the compound is demonstrated in genetically hypertensive (spontaneously hypertensive) rats of the strain

  
locked up

  
 <EMI ID = 56.1>

  
blood pressure by indirect method. Half an hour before the blood pressure measurement, the rats are placed in a warm room, maintained at a constant temperature of 36 [deg.] C. An occlusive sleeve connected to a programmed sphygmomanometer is placed near the base of the tail of each

  
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speed. The total time required for each inflation-deflation cycle of the cuff is 50 seconds and the interval between successive cycles is <EMI ID = 59.1>

  
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Five interference-free signals obtained during deflation are recorded for each rat. Only rats with systolic blood pressure of

  
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To record the blood pressure of the rats, a Grass Model 7 polygraph was used.

  
The compound of formula VII was tested on four rats, according to

  
 <EMI ID = 63.1>

  
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The results obtained are listed in Table 2.

TABLE 2

  
Blood pressure of rats.

  
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The compound of formula VII was also tested orally at a dose of 10 mg / kg in two rats. The results are listed in Table 3.

  
TABLE 3

  
Blood pressure of rats.

  
(oral dose of 10 mg / kg)
 <EMI ID = 67.1>
  <EMI ID = 68.1>

  
gesic or antihypertensive, in mammals at daily doses

  
from 0.01 - 40 mg / kg body weight, preferably in spaced doses, i.e. 3 to 4 times a day. The compound exhibits analgesic and antihypertensive activities when administered orally and by parentage.

  
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The oral route is the preferred mode of administration.

  
Solid pharmaceutical carriers, such as calcium carbonate, starch, sugar, talc and the like, can be used to form powders. The powders can be used as such or can be in the form of tablets or capsules. Suitable lubricants such as magnesium stearate, binders such as gelatin and disintegrating agents such as sodium carbonate in combination with citric acid can be used to form the tablets. Care should be taken to choose the solid suppcrts and other ingredients so as to avoid a reaction of the active principle with the excipients. Forms of administration such as tablets

  
and capsules may contain any predetermined suitable amount of the

  
compound of formula VII and may be administered one or more to the

  
times at regular intervals. Such forms should in general contain a minimum concentration of 0.1% by weight of active principle, more particularly from 1 to 75 mg of principle, the dose of 1 to 20 mg being desirable.

  
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89.0 g of mannitol, 4.0 g of Carbopol-934 (binder described in US Pat. No. 2,909,462), 16.5 g of the compound of formula VII and 2.5 g of stearic acid. The product obtained is mixed by passing through a n [deg.] 20 sieve and formed into ingots in the usual manner. The ingots are passed through a n [deg.] 20 sieve and pressed into tablets using a punch.

  
and a 6.4 mm die. The given composition allows to make 1000 tablets. Each tablet contains 16.5 mg of the compound.

  
The compound can also be "engineered" to be administered in liquid form and be used for intramuscular injections.

  
The compound can further be prepared to be administered orally in aqueous, alcoholic, glycolic or oil solutions or in oil emulsions.

  
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classic nales.

  
The following examples illustrate the invention without, however, limiting it.

Example 1

  
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Cooled in an ice-salt bath, a solution of 14.2 g (0.06 mol) of 5- (methyl-2-octyl) resorcinol and: of 11.1 g (0.063 mol) of 3-oxo-2 , 3,

  
 <EMI ID = 75.1>

  
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Rotary evaporator. The residue is dissolved in ether, washed with a solution.

  
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Example 2

  
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and ether. When all the magnesium has reacted, it is refluxed for a short

  
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(0.02 mole) of pyrone (prepared in Example 1) in benzene and the reaction mixture is maintained at 45 [deg.] C for 24 hours. The reaction mixture is then decomposed with a saturated solution of ammonium chloride; the organic phase is separated and the aqueous phase is extracted twice with ether. The organic phases are combined, washed with water, dried and evaporated to give a gummy residue. The IR and NMR spectra lead to the conclusion that 5- (3-methyl-

  
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benzene solution of the above triol and refluxed for 1 hour and <EMI ID = 85.1> of sodium bicarbonate, dried over sodium sulfate and evaporated. This gives a greenish-brown residue.

  
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1.- As new industrial products, benzopyrans report-

  
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is an alkyl group having 1 to 20 carbon atoms or a (cycloalkyl) group

  
 <EMI ID = 92.1> of acid in which the alkanoyl group or the alkyl group or each of the alkyl groups has from 1 to 6 carbon atoms.

  
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3. "Process for preparing a benzopyran having the given formula


    

Claims (1)

<EMI ID = 94.1> terized in that it consists in treating a benzopyran of the following general formula: <EMI ID = 95.1> <EMI ID = 96.1> <EMI ID = 97.1> in claim 1 and X denotes a halogen atom, in an organic solvent inert under the reaction conditions. 4.- Method according to claim 3, characterized in that <EMI ID = 98.1> methyl. <EMI ID = 99.1> the method according to claims 3 and 4. <EMI ID = 100.1> sic and blood pressure reducers, the compounds according to claim 1. 7. A pharmaceutical composition containing the benzopyran according to claim 2, dispersed in a pharmaceutical carrier. <EMI ID = 101.1> ment of pain in a mammal suffering from hypertension and / or undergoing <EMI ID = 102.1> a therapeutically effective amount of the benzopyran according to claim 2. 9.- Method according to claim 7, characterized in that <EMI ID = 103.1> 10.- As a reaction intermediate, benzopyran of formula; : <EMI ID = 104.1> <EMI ID = 105.1> <EMI ID = 106.1> 12.- Process for the preparation of a benzopyran having the general formula <EMI ID = 107.1> an ester of general formula: <EMI ID = 108.1> in which the -COOAlkyl groups and = 0 are linked to adjacent carbon atoms, with a resorcinol of general formula: <EMI ID = 109.1> <EMI ID = 110.1> acid lyser. <EMI ID = 111.1> <EMI ID = 112.1> <EMI ID = 113.1> characterized in that said acid catalyst is hydrochloric acid. 16.- As reaction intermediate, a benzopyran obtained by the process according to claims 12-15.