CH628613A5 - Process for the preparation of aminoalkoxyphenylalkyl benzyl ethers - Google Patents

Description

The present invention thus relates to a process for the preparation of benzyloxyalkyl compounds of the formula I.

45

50

R —CH

(I),

-N

\ r3

° - (CH2'n where

X is a hydrogen or halogen atom;

R1 is an alkyl radical with up to 4 carbon atoms; R2 and R3, which are the same or different, each represent an alkyl radical having up to 4 carbon atoms or, together with the nitrogen atom to which they are attached, a heterocyclic ring; and n represents the number 2 or 3,

as well as their pharmacologically acceptable salts with inorganic or organic acids.

Halogen atoms are fluorine, chlorine or bromine.

3rd

628 613

The alkyl radicals R2 and R3 can be straight-chain and represent, for example, an ethyl, n-propyl or n-butyl radical. However, if there is no steric hindrance, they can also be branched and e.g. represent an isopropyl or iso-butyl group. Furthermore, the radicals R2 and R3 together with the amino nitrogen atom can form a heterocyclic ring having 4 to 6 carbon atoms, such as e.g. form a pyrrolidine or piperidine ring. The alkyl radical R1 can be straight-chain or branched and z. B. represent a methyl, ethyl, n-propyl, isopropyl or n-butyl group.

Preferred compounds of the formula I are those in which X is a hydrogen, fluorine or chlorine atom, R1 is a methyl or ethyl group, R2 and R3 are a methyl or ethyl group and n is the number 2 or 3, and the pharmacologically acceptable salts thereof.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that a compound of the formula II

OH

RX-CH

L // W

di)

° - (CII2) n ~ N

/ R '

with a compound of formula III

Ni3

(m),

where Y represents a reactive ester group,

reacted and, if appropriate, subsequently converting the compound obtained into a pharmacologically acceptable salt by reaction with an inorganic or organic acid.

The compounds of formula II used as starting product are advantageously obtained by using an aldehyde of formula IV

CHO

° - (CH2> n-N

/

(IV)

R

R °

with a Grignard compound of formula V

R'-Mg-Hal (V),

wherein shark is a halogen atom, preferably a bromine or

Iodine atom means

implements.

The compounds of formula IV are known. The reaction of the compounds IV is carried out in a solvent customary for Grignard reactions, preferably in a lower aliphatic ether, such as diethyl ether or tetrahydrofuran, at a temperature between 30 and 60 ° C., preferably at about 40 ° C.

The compounds of the formula II obtained after the removal of the solvent after customary cleaning are then generally 30-80 ° C., preferably at about 60 ° C.

with a strongly basic condensing agent, such as. B. sodium hydride or sodium amide using a solvent customary for such reactions, e.g. Benzene, toluene, dimethylformamide, dimethyl sulfoxide or a mixture thereof, preferably reacted with the known compounds of formula III using dimethylformamide.

In the context of this invention, reactive ester groups Y are understood to be groups suitable for nucleophilic exchange. The halides, methane sulfonates, benzenesulfonates or p-toluenesulfonates are particularly suitable.

The free bases of the formula I are converted into their pharmacologically acceptable salts in a manner known per se by neutralization with an inorganic or organic acid which is harmless in the applied dose, e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, naphthalenesulfonic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid or ascorbic acid, preferably in an aqueous, aqueous / alcoholic or alcoholic solution.

The compounds produced according to the invention show, with unusually low toxicity, pronounced and valuable anti-inflammatory properties which are associated with a good analgesic effect. They are therefore particularly suitable for the steroid-free therapy of inflammatory and degenerative diseases of the musculoskeletal system, for pain relief and for anti-inflammation.

30 Due to their valuable activity profile, 1-p-chlorobenzyloxy-1 (o - /? - diethyIaminoäthoxyphenyl) -ethane and l-benzyloxy-l (o- / 3-diethylaminoäthoxyphenyI) -ethane are particularly preferred.

The compounds of the formula I can be administered enterai or parenterally in liquid or solid form. The main injection solution used is water, which contains the additives common to injection solutions, such as stabilizers, solubilizers or buffers.

Such additives are e.g. Tartrate and citrate buffers, 40 ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide for viscosity regulation. Solid carriers are, for example, starch, lactose, mannitol, ethyl cellulose, talcum, highly disperse silica 45, higher molecular weight Fatty acids (such as stearic acid) gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (such as polyethylene glycol); preparations suitable for oral administration may contain flavorings and sweeteners if desired.

so The compounds I can be administered enterai or parenterally in a dose of 100 to 300 mg once or several times a day.

The following examples serve to explain the invention in more detail:

55 Example 1

1- (O- / 3-diethylaminoethoxyphenyl) ethanol

In anhydrous diethyl ether, a Gri-gnard solution is prepared from 2.43 (V10 mol) magnesium shavings and 14.2 g (Vio mol) methyl iodide. A solution of 22.1 g (V10 mol) of o-diethylaminoethoxybenzaldehyde in 70 ml of anhydrous ether is added dropwise to this Grignard solution at 60 reflux temperature within one hour.

Then heated to boiling for 1 hour. The 65 adduct is split by dropwise addition of a 20% ammonium chloride solution. The ether phase is separated off, dried over sodium sulfate and filtered. The residue of the phase is distilled in a fine vacuum. Yield of l- (o- / 3-diethylaminoethoxyphenyl) ethanol: 21.1 g (89% of theory) of bp 0.3

628 613

4th

130 to 131 ° C. Characterization as hydrochloride: mp 166 ° C (from isopropanol)

[CI4H24C1N02; Molgew. 273.81]

Calc .: C 61.40 H 8.84 N 5.12 Cl 12.95% Found: C 61.34 H 8.69 N 4.94 Cl 12.50%

Example 2

l-p-chlorobenzyloxy-l- (o- / j-diethylaminoethoxyphenyl) ethane

20 g of l- (o- / 3-diethylaminoethoxyphenyl) ethanol are dissolved in 25 ml of dry dimethylformamide. The solution thus obtained is added dropwise at 60 ° C. to a suspension of 4.2 g of 50% sodium hydride in 40 ml of anhydrous dimethylformamide. A solution of 13.7 g of p-chloro-benzyl chloride in 15 ml of dimethylformamide is then allowed to flow in and the mixture is stirred at 60 ° C. for 1 hour. After filtration, the solvent is drawn off at 20 torr and the residue is distilled under a fine vacuum. Kp0il 174 to 177 ° C. The oil obtained is taken up in isopropanol and precipitated with an isopropanol solution of naphthalene-1,5-disulfonic acid. The crystals are redissolved from ethanol.

22.3 g (52% of theory) of l-p-chlorobenzyloxy-l- (o- / 3-diethylaminoethoxyphenyl) -ethane-naphthalene-l, 5-disulfonate are obtained; Mp 179-181 ° C.

[C26H32C1 NOsS; Molgew. 506.08].

Calc .: C 61.70 H 6.37 N 2.77 Cl 7.01 S 6.34% Found: C 61.84 H 6.25 N 3.03 Cl 6.41 S 6.68%

Example 3

l-Benzyloxy-l- (0- / j-diethylaminoethoxyphenyl) ethanol 15 g of the l- (o- / j-diethylaminoethoxyphenyl) ethanol prepared according to Example 1 are, as described in Example 2, in a suspension of sodium hydride and anhydrous Dimethylformamide reacted with 7.9 g of benzyl chloride. L-Benzyloxy-l- (o- / 3-diethylaminoethoxyphenyl) -ethane is obtained in an oily form (bp 0.05 1 60 to 162 ° C.) as a free base, which in a manner analogous to that described in Example 2 is added to the V2. Naphthalene-1,5-disulfonate is transferred. Yield: 10 g (35% of theory)

After recrystallization from isopropanol, the salt has a melting point of 157 to 158 ° C.

[C26H33N05S; Molgew. 471.63]

Calc .: C 66.21 H 7.05 N 2.97 S 6.80% Found: C 66.16 H 6.90 N 3.17 S 6.83%

Example 4

l- (o- / 3-Diethylaminoäthoxyphenyl) -propanoI From 2.43 g (710 mol) of magnesium shavings and 15.6 g (710 mol) of ethyl iodide a Gri-gnard solution is prepared in dry diethyl ether and in an analogous manner as in Example 1 described with 22.1 g (V10 mol) of o-diethylaminoethoxy-benzaldehyde. 20 g (80% of theory) of 1- (o- / 3-diethvlaminoethoxyphenyl) propanol of Kp0, i 112 ° C. are obtained.

Characterization as acidic oxalate: mp 105 ° C (from methyl ethyl ketone).

[C17H27N06; Molgew. 341.41]

Calc .: C 59.80 H 7.97 N 4.11%

Found: C 59.67 H 7.69 N 3.99%

Example 5

l-p-chlorobenzyloxy-2- (o- / 3-diethylamino-ethoxyphenyl) -pro-

pan

20 g of l- (o-ß-diethylaminoethoxyphenyl) propanol are dissolved in 25 ml of dry dimethylformamide. The solution thus obtained is added dropwise at 60 ° C. to a suspension of 4.2 g of 50% sodium hydride in 40 ml of anhydrous dimethylformamide. A solution of 13.7 g of p-chlorobenzyl chloride is then allowed to flow in and the mixture is stirred at 60 ° C. for 1 hour. After filtration, the solvent is drawn off at 20 torr and the residue is distilled under a fine vacuum.

1-p-Chlorobenzyloxy-l- (o- / 3-diethylaminoethoxyphenyl) propane is initially obtained as an oily base, which distils at KpQ> 1 190 to 200 ° C. The base is precipitated in ethanol with an ethanolic solution of citric acid and the citrate thus obtained is recrystallized from water. Yield: 9 g; Mp 128-129 ° C.

[C28H28C1N09; Molgew. 568.05]

Calc .: C 59.20 H 6.74 N 2.47 Cl 6.24%

Found: C 59.25 H 6.81 N 2.73 Cl 5.83%

Example 6

l-Benzyloxy-l- (o- / 3-diethylaminoethoxyphenyl) propane

In an analogous manner to that described in Example 5, 8.5 g of 1-benzyloxy- are obtained by reacting 25 g of l- (o- / 3-diethylaminoethoxyphenyl) propanol with 12.7 g of benzyl chloride and then neutralizing with hydrochloric acid. 1 - (o- / j-diethylaminoethoxyphenyl) propane in the form of the hydrochloride; Mp 126 ° C (from isopropanol).

[C22H32C1N02; Molgew. 377.96]

Calc .: C 69.91 H 8.53 N 3.71 Cl 9.38%

Found: C 69.75 H 8.46 N 3.89 Cl 9.15%

Example 7

The 1- (o-dimethylaminopropoxyphenyl) ethanol is prepared analogously to the manner described in Example 1 by reacting a 0.1-molar Grignard solution of methylmagnesiumjo-did with dimethylaminopropoxybenzaldehyde in tetrahydrofuran. 19.5 g of the free base are obtained. Kp01; 122 to 125 ° C.

Example 8

l- (p-chlorobenzyloxy-l- (o-y-dimethylaminopropoxyphenyl) -

äthan

15 g of l- (o-dimethylaminopropoxyphenyl) ethanol are reacted in an analogous manner as described in Example 2 with 11 g of p-chlorobenzyl chloride. The base, which was distilled after filtering and stripping off the solvent at 20 torr in a fine vacuum (Kpo.i 173 to 176 ° C.) (yield 16 g [68.5% of theory]), is precipitated from ethanol using oxalic acid. The oxalate obtained has a melting point of 152 to 153 ° C. C22H28C1N06; Molgew. 437.9]

Calc .: C 60.30 H 6.44 N 3.20 Cl 8.10%

Found: C 60.37 H 6.51 N 3.33 Cl 7.68%

Example 9

l- (p-fluoro-benzyloxy) -l- (o- / 3-diethylaminoethoxyphenyl) -

äthan

44 g of the 1- (o- / 3-diethylamino-ethoxyphenyl) ethanol obtained according to Example 1 are dissolved in dry dimethyl sulfoxide and at 60 ° C. in a suspension of sodium hydride with a solution of 26.8 g of p-fluorobenzyl chloride Implemented dimethyl sulfoxide. After working up, 52 g (81% of theory) of l- (p-fluorobenzyloxy) -l- (o- / 3-diethyIami-noäthoxyphenyl) -ethane are obtained as an oily base (bp0, i 175 to 181 ° C) which can be precipitated and characterized from ethanolic solution with naphthalene-l, 5-disulfonic acid as V2-naphthalene-l, 5-disulfonate with mp 169 to 170 ° C.

[C26H32FNOsS; Molgew. 489.7]

Calc .: C 63.76 H 6.58 N 2.86 S 6.54%.

Found: C 63.74 H 6.57 N 3.11 S 6.58%

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

628 613

Comparative pharmacological studies with aminophenazone. Meperidine, phenylbutazone and tilidine 1. Acute toxicity method

Acute toxicity was determined on 5 male mice (NMRI) with a body weight of 19 to 25 g. All test animals were fasted for 16 to 18 hours before the start of the test. Water was available ad libitum. There were 4 animals in each dose group. The sequence of doses was logarithmic. The volume of liquid administered was 1 ml / 100 g with subcutaneous administration and 2 ml / 100 g with intragastric administration.

Table I Acute toxicity in mice

Test substance

Application type

LD50

mg / kg

Example 5

i-g-

1,200

Example 5

s.c.

> 1,000

Example 6

s.c.

1,000

Example 3

i-g-

1,000

Example 2

i-g-

> 2,000

Example 8

i-g-

1,600

Aminophenazone i-g-

475

Aminophenazone s.c.

300

Meperidine i-g

252

Meperidin s.c.

154

Phenylbutazone i-g-

714

Tilidine i-g

437

From Table I it can be seen that the substances produced according to the invention are distinguished by a remarkably low toxicity compared to the comparison substances.

2. Analgesic effect To characterize the analgesic effect of the compounds, generally customary methods such as the phenyl-p-quinone test and the hotplate test were used.

2.1 Phenyl-p-quinone test method

Fasted male mice (NMRI) with a body weight of 19 to 27 g were used. 15 minutes after subcutaneous application of the test substances or 30 minutes after intragastric administration, 0.25 ml / 20 g body weight of a 0.02% solution of phenyl-p-quinone in 5% alcohol was administered intraperitoneally. In the course of a further 20 minutes, it was observed how many of a total of 12 animals in a dose group had the typical pain reactions after phenyl-p-quinone administration.

The results are summarized in Table II:

Table II Phenyl p-quinone test in mice

Test substance dose application animals LDS0

mg / kg type number of animals with positive

Pain-therapeutically effective dose response

control

-

s.c.

12th

12th

-

Meperidine

7.5

s.c.

12

5

20.5

Example 6

100.0

s.c.

12

4th

10.0

control

-

i-g-

12

12th

-

Meperidine

40.0

i-g-

12

4th

6.3

Example 2

200.0

i-g-

12

5

> 10.0

control

-

i-g-

12th

11

-

Tilidine

30.0

i-g-

12th

3rd

14.6

Example 8

300.0

i-g-

12

4th

5.3

control

-

i-g-

12

12th

-

Tilidine

30.0

i-g-

12th

2nd

14.6

Example 9

150.0

i-g-

12

2nd

3.3

Table II shows that all the investigated distance from the therapeutically effective dose to the ten compounds has an analgesic active component with an LD50 value and is therefore alone in relation to those that have a comparative analgesic effect with standard commercial substances Comparative substance meperidine is clear. Example 2 is characterized by a particularly large loan.

628 613

6

2.2 Hot plate test method

Test animals were fasted male mice (NMRI) with a body weight of 20 to 26 g. The animals were placed on a copper plate kept constant at 55 ° C. and the time until the forefeet licked was measured. After three initial measurements, the test substances were administered. The application volume was 1 ml / 100 g for subcutaneous and 2 ml / 100 g for intragastric body weight

Gift. The measurements after substance application were carried out after 30, 60, 90 and 120 minutes. 10 animals were used per dose.

The mean values of the respective reaction times of the preliminary measurements 5 were formed and the mean values obtained for the reaction times after substance administration were calculated as a percentage thereof.

The results are summarized in Table III:

Table III heating plate test on mice

Test substance, dose, application, output, change in reaction in% after min mg / kg type value in% 30 60 90 120

control

-

-G-

100

+

1

+ 2

+23

+35

ACE

200

-G-

100

+

19th

4- 5

+ 11

+23

Example 2

100

-G-

100

+

92

+48

+82

+82

control

-G-

100

+

27th

+ 14

+26

+51

Meperidine

40

•G-

100

+

81

+49

+71

+72

Example 3

150

•G-

100

+ 123

+94

+79

+89

In the hot plate test, example 3 is in a dosage of 150 mg / kg i. G. with approximately the same ratio of the LD50 value to the therapeutic dose used, significantly more analgesic than 40 mg / kg i.g. Meperidine. Example 2 shows i.g. after a dose of 100 mg / kg. a good effect. The standard substance acetylsalicylic acid (ASA) used for comparison, however, is in a dose of 200 mg / kg i.g. ineffective.

3. Anti-inflammatory effect Rat paw edema was used to investigate the anti-inflammatory effect. Formalin and egg white served as phlogistics.

method

The experimental animals were male rats (strain SIV 50), fasted for 16 hours, with a body weight of 120 to 160 g. After determining the initial value of the paw volume of the right hind limb, the test substances were administered subcutaneously or intragastricly. 10 animals were used per dose. The application volume was 1 ml / 100 g with subcutaneous administration and 2 ml / 100 g with intragastric administration. The paw volume was determined by means of mercury displacement.

45 minutes after the administration of the test substances, 0.1 ml of chicken egg white or 0.1 ml of a 3% formalin solution was injected subplantarally into the right hind paw as phlogistic agent. Two further measurements of the paw volume of the right hind limb followed 60 and 120 minutes after the protein or formalin injection. The average increase in paw volume of the treated and control animals 60 and 120 minutes after the injection of the phlogistics was calculated as a percentage of the mean value of the initial measurements. The mean value from the percentage increase in the paw volume of the control group after 60 and 120 minutes was set equal to 100% and the corresponding values for the treated groups were calculated in% thereof. The difference between these values and 100% of the control group gives the relative inhibition of the paw edema by the test substance.

35

Table IV

Anti-inflammatory effect on rat paw edema

Test substance Dose Application phlogistic Average relative mg / kg type Swelling by value

60 min 120 min%

%%

control

-

s.c.

Protein

60

59

100

Aminophenazone

100

s.c.

Protein

45

43

73

Example 5

100

s.c.

Protein

38

37

63

control

-

s.c.

Protein

83

69

100

Aminophenazone

100

s.c.

Protein

57

52

72

Example 5

150

s.c.

Protein

33

33

43

control

-

i-g-

Protein

69

67

100

Aminophenazone

150

i-g-

Protein

47

44

68

Example 5

100

i-g-

Protein

47

41

64

control

_

s.c.

Protein

60

59

100

Aminophenazone

100

s.c.

Protein

45

43

73

Example 6

100

s.c.

Protein

33

36

58

7

Table IV (continued)

628 613

Test substance Dose Application phlogistic Average relative mg / kg type Swelling by value

60 min 120 min '"c

control

-

•G-

Protein

90

90

100

Aminophenazone

150

•G-

Protein

73

79

84

Example 3

50

•G-

Protein

52

54

54

control

-

■ g-

Protein

47

60

100

Aminophenazone

150

•G-

Protein

46

40

80

Example 3

100

•G-

Protein

34

27th

57

control

-

•G-

•G-

Formalin

44

44

100

Aminophenazone

150

Formalin

31

31

70

Example 3

150

•G-

Formalin

29

30th

68

control

•G-

Protein

90

90

100

Aminophenazone

150

•G-

Protein

73

79

84

Example 2

100

•G-

Protein

47

44

47

control

-

•G-

Protein

47

60

100

Aminophenazone

150

•G-

Protein

46

40

80

Example 2

200

■ g-

Protein

27th

21st

44

control

-

•G-

Protein

69

61

100

Aminophenazone

150

Protein

71

57

98

Example 9

100

a

Protein

27th

26

42

control

-

•G-

Protein

75

55

100

Aminophenazone

150

•G-

Protein

68

52

92

Example 9

150

•G-

Protein

62

44

83

control

-

•G-

Formalin

43

46

100

Aminophenazone

150

■ g-

Formalin

31

33

71

Example 9

100

•G-

Formalin

27th

23

56

control

-

•G-

Formalin

53

54

100

Aminophenazone

150

•G-

Formalin

39

43

77

Example 9

150

•G-

Formalin

36

36

67

Table IV shows a remarkable and superior antiphlogistic activity for all compounds examined.

Particularly favorable conditions result from the investigation of the compound of Example 2, which is not only clearly superior to the aminophenazone in its effect in Eivveis edema. but is also characterized by a very low toxicity (Table 1).

The compounds I prepared according to the invention thus represent valuable medicaments with excellent anti-inflammatory and at the same time good analgesic action. Because of their surprisingly low toxicity and the associated wide therapeutic range, they represent considerable technical progress.

Claims (10)

628 613 2nd PATENT CLAIMS 1. Process for the preparation of benzyloxyalkyl compounds of the formula I tion product, as can be obtained by reacting an aldehyde of the formula IV (I), R 0- (CH2) n-N / R wherein X is a hydrogen or halogen atom; R1 is an alkyl radical with up to 4 carbon atoms; R2 and R3, which are the same or different, each represent an alkyl radical having up to 4 carbon atoms or, together with the nitrogen atom to which they are attached, a heterocyclic ring; and n is the number 2 or 3, and their pharmacologically acceptable salts with inorganic or organic acids, characterized in that an amino compound of the formula II (II) R ° - <oh2vnc, R with a benzyl compound of formula III 30th 35 40 (III) wherein Y represents a reactive ester group, and optionally converting the compound obtained with an inorganic or organic acid into a pharmacologically acceptable salt. 2. The method according to claim 1, characterized in that one carries out the reaction at a temperature of 30 to 80 ° C. 3. Process according to claims 1 and 2, characterized in that one carries out the reaction at a temperature of about 60 ° C. 4. Process according to claims 1 to 3, characterized in that one carries out the reaction in the presence of a strongly basic condensing agent. 5. Process according to claims 1 to 4, characterized in that one carries out the reaction in the presence of a solvent. 6. Process according to claims 1 to 5, characterized in that the compound of formula I obtained is converted with an organic or inorganic acid by neutralization into a pharmacologically acceptable salt. 7. Application of the method according to claim 1 to an amino compound of the formula II in the form of the crude reac 60 65 -CHO (IV) Rc '0- (CH „) —NCT -, c n with a Grignard compound of the formula R1 • Mg • shark, in which shark represents a halogen atom. 8. Application according to claim 7, characterized in that one carries out the reaction with the Grignard compound at a temperature of 30 to 60 ° C. 9. Application according to claims 7 and 8, characterized in that one carries out the reaction with the Grignard compound at a temperature of about 40 ° C. 10. Use according to claims 7 to 9, characterized in that one carries out the reaction in a solvent. 25th From DE-OS 1 518 453 o-aminoalkoxy-substituted dibenzyl ethers are known which have, among other things, an analgesic and anti-inflammatory activity. These compounds contain two optionally substituted nuclear benzyl radicals connected via an oxygen or sulfur atom. It has now been found that, surprisingly, the pharmacological properties of certain compounds of this class of compounds can be further improved if the methylene group of one benzyl radical is substituted with a lower alkyl group.