DE2834911C2 - Antihypertensive agent - Google Patents

Description

is,
wherein

η is an integer from 7 to 10 and A is a group of the general formula II

CH ₃ -CH ₂ -CC = CH

I I I

OH a b

(Π)

means in which

a and b are each hydrogen or can form a bond with one another, or a group of the general formula III

CH ₃
-CH ₂ -C = CH-CH ₂ -OR (JS)

means in which

R denotes hydrogen or -COR ', where

R 'is a saturated or unsaturated alkyl group with 1 to 17 carbon atoms, a cyclohexyl group, an unsubstituted phenyl group or a phenyl group which is substituted with a halogen atom or a lower alkoxy group, a (halogen-substituted phenoxy) lower alkyl group or pyridyl group.

The invention relates to an antihypertensive agent containing a pharmaceutical carrier and a polyprenyl compound as an active ingredient.

Various antihypertensive agents have been used to treat hypertension. These medicines however, have various side effects, and therefore occur in the administration of these agents Problems arise, especially when given in large quantities continuously over long periods of time will. For example, diuretic antihypertensive drugs, such as sulfonamide preparations and thiazide preparations, the serious side effects that they have increased blood uric acid levels and a potassium deficiency effect in the blood. Spasmolytic agents such as reserpine preparations and methyldopa preparations, have the side effects of producing dryness in the mouth, obscuring consciousness and unity cause orthostatic negative pressure. Vasodilators, such as apresolin, have the side effects of causing headaches, Cause tachycardia and angina pectoris.

The older DE-OS 27 23 213 already relates to an antihypertensive agent containing a pharmaceutical A carrier and a polyprenyl compound as an active ingredient, the active ingredient being a polyprenyl carboxylic acid compound the general formula

CH ₃

CH ₂ -C = CH-CHi ₁ - ^ - CH ₂ - C = CH-COOR

is,
wherein

R is a hydrogen atom or an alkyl, alkenyl, cycloalkyl or aryl radical and η is an integer from 6 to 11.

The object of the present invention is to provide new antihypertensive agents with improved safety to deliver.

This object is achieved by an antihypertensive agent according to the patent claim.

As saturated or unsaturated alkyl groups with 1 to 17 carbon atoms in general formula I. can be given as examples; Methyl, ethyl, propyl, pentyl, hexyl, heptyl, octyl, nonyl, decariyl, Undecanyl, dodecanyl, tridecanyl, tetradecanyl, pentadecanyl and hexadecanyl groups as well as related unsaturated alkyl groups such as vinyl, propenyl, butenyl, 9-decenyl, 8,11-Hepla.decadieny] - and 8,11,14-heptadecatrienyl groups. The following lower alkoxy groups can be mentioned: methoxy, ethoxy, Propoxy and butoxy groups. The following can be mentioned as lower alkyl groups: methyl, ethyl, propyl and Isopropyl groups. The following pyridyl groups can be mentioned: 2-, 3- and 4-pyridyl groups.

According to the invention, the following compounds are preferably used as active ingredients:

3,7,11,15,19,23,27313539-decamethyl-l, 6,10,14,18,22,26303438-tetracontadecaen-3-ol 3 ^^ 13 ^ 93h

3,7,11,15,19,23,27313539-decamethyl-6,10,14,18,22,26303438-tetracontanonaen-1-yn-3-ol

3,7,11,15,19,23,273 1-octamethyl-2,6,10,14,18,22,2630-dotriacontaoctaen-1-ol 3,7,11,15,19,23,273135-nonamethyl-2,6,10,14,18,22,263034-hexatriacontanonaen-1-ol 3,7,11,15,19,23,27313539-decamethyl-2,6,10,14,18,22,26303438-tetracontadecaen-l-oI 3.7, ll, 15,19,23,27313539,43-undecamethyl-2,6,10,14,18,22,26303438,42-undecaen-1-ol 3,7,11,15,19,23,27,3 l-octamethyl-2,6,10,14,18,22,2630-dotriacontaoctaenyl acetate 3.7, ll, 15.19 ^ 3 ^ 7 ^ 15-nonamethyl-2,6,10,14,18 ^ 2 ^ 6 ^ 0 ^ 4-hexacontanonaenyl-2- (p-chlorophenoxy) -t.-butyrate

3,7,11,15,19,23,27,313539-decamethyl-2,6,10 ₎ 14,18,22,26303438-tetracontadecaenyl-3,4,5-trimethoxybenzoate 3,7,11, 15,19 ^ 3 ^ 7 ^ 1ß5-Nonamethyl-2,6,10, ί4,18 ^ 2 ^ 6 ^ 034-hexatΓiacontanonaenylcyolohexylcaΓboxylat 3,7,11,15,19 ^ 3 ^ 7ßlß5-Nonamethyl-2,6,10,14, 18 ^ 2 ^ 6 _r 30 _r 34-hexatriacontanonaenylpentanoate 3,7,11,15,19,23,27313539-decamethyl-2,6,10,14,18,22,26303438-tetΓacontadecaenylaCTylate

3,7,11,15,19 ^ 23 ^ 731 ^ 5-nonamethyl-2,6,10,14,18 ^ 2 ^ 6 ^ 0 ^ 4-hexatriacontanonaenyl p -chlorobenzoate 3 _> 7, ll, 15.19 , 23 ^ 7 _r 3U539,43-Undecamethyl-2,6,10,14,18 ^ 2 ^ 6 ^ 0 _r 34 _r 38,42-tetΓatetracontaundecaenyl- 3S acetate

benzoate

3,7,11,15,19,23,273135-Nonamethy! -2,6,10,14,18,22,263034-hexatriacontanonaenyl nicotinate 3,7,11,15,19,23,273135-nonamethyl-2,6,10,14,18,22,263034-hexatriacontanonaenyl propionate 3,7,11,15,19 ^ 3 ^ 73135-nonamethyl-2,6,10,14,18,22 ^ 63034-hexatriacontanonaenyl stearate 3,7,11,15,19 ^ 3 ^ 73135-nonamethyl-2,6,10,14,18 ^ 2 ^ 63034-hexatriacontanonaenyl linolate

The invention is explained in more detail with reference to the drawings.

Fig. 1 shows the antihypertensive effect of the compound according to the invention 3,7,11,15,19,23,27313539-decamethyl-1,6, I0,14,18,22,26303438-tetracontadecaen-3-ol (hereinafter referred to as Compound A) when administered to spontaneous hypertensive rats.

Fig. 2 shows the antihypertensive effect of the compound according to the invention 3,7,11,15,19,23,2731-octamethyl-2,6,10,14,18,22,2630-dotriacontaoctaen-1-ol (Compound B) when administered to high pressure spontaneous rats (hereinafter referred to as SHR). so

Fi g. 3 shows the antihypertensive effect of the compound according to the invention 3,7,11,15,19,23,27,3135-nonamethyl-2,6,10,14,18,22,263034-hexatriacontanonaen-1-ol (Compound C) when administered to SHR.

Fig. 4 shows the antihypertensive effect of the compound according to the invention 3,7,11,15,19,23.27313539-decamethyl-2,6,10,14,18,22,26303438-tetracontadecaen-l-ol (Compound D) when administered to SHR

The following are pharmacological effects and toxicity (acute toxicity) of the present invention Compounds determined by animal experiments.

Pharmacological tests

Hypotensive effects on spontaneous Okamoto & Aoki hypertensive rats (hereinafter referred to as SHR)

[Method]

The antihypertensive effects of the test compounds at Okamoto & Aoki SHR were measured. SHR animals with chronic hypertension who were 40 weeks old were used as test animals. The maximum Blood pressure was about 265 mm Hg. The blood pressure was measured by means of a continuous blood pressure measurement

Shimazu type direction (Model SCS-301, manufactured by Shimazu Seisakusho K.K., Japan) was measured. Of the systolic blood pressure was measured without drawing blood on the tail artery.

The test compounds were suspended in acacia gum. The test animals were divided into two groups accordingly the administered amount of the test compound (50 mg / kg). Similarly, it became a control group tested who had only been given an aqueous acacia gum solution. Each group passed from four test animals. The test compounds were applied continuously to the SHR animals once a day for 3 days administered.

The blood pressure was measured before the administration and then after 6 h, 24 h (at the time of the second administration), Measured 48 h (at the time of the third administration) and 72 h. The change in blood pressure in the ίο The passage of time was examined.

[Test connections]

3,7,11,15,19,23,27,3U9-decamethyl-1,6,10,14,18 ^ 2 ^ 6 ^ 0,34 ^ 8-tetracontadecaen-3-ol (hereinafter referred to as Compound A denotes);

3,7,11,15,19,23,27,31-octamethyldotriacontan-1-ol (hereinafter referred to as Compound B);

3,7,11,15,19,23,27,31,35-nonamethyl-hexatriacontan-1-ol (hereinafter referred to as Compound C); and

3,7,11,15,19,23,27,31,35,39-decamethyltetracontan-1-ol (hereinafter referred to as Compound D).

[Results]

Clear antihypertensive effects as shown in Figures 1 to 4 were seen in the groups of test animals (Okamoto & Aoki SHR) found giving 50 mg / kg of compound A, B, C or D orally for 3 days continuously had been administered. So was z. B. a clear antihypertensive effect in a group of Test animals were found to be given 50 mg / kg of Compound A orally continuously for 3 days as shown in FIG. The rats in the control group (initial blood pressure 265 mg) showed practically no change in blood pressure after the 3-day trial period (blood pressure after the trial 269 mm Hg). In the group administered with Compound A, the blood pressure became 264 mm Hg before testing to 228 mm Hg 6 hours after the first administration and to 234 mm Hg 24 hours after the first administration (i.e. at the time of the second administration) decreased. It was therefore a continuous, antihypertensive effect noted.

In the group of rats administered with Compound B, the blood pressure was determined from 256 ± 5 mm Hg in the initial stage of the test to 230 ± 7 mm Hg 6 h after the first administration and 234 ± 8 mm Hg decreased 24 hours after the first administration (i.e. at the time of the second administration), while in the control group the blood pressure of 259 ± 4 mm Hg in the initial stage of the test decreased 3-day trial period changed only insignificantly to 258 ± 4 mm Hg.

From this it can be seen that compounds A, B, C and D are significant, continuous antihypertensive Have effects.

Toxicity tests

SD rats (male and female animals weighing about 200 g) were used as test animals. 500 mg / kg of the test compounds were administered orally in the same manner as the pharmacological ones described above Tests administered. No deaths or side effects were observed.

From the above results of pharmacological tests and toxicity tests, it can be seen that the compounds of the general formula I according to the invention for the prophylaxis and treatment of renal hypertension, endocrine hypertension, cardiovascular hypertension, nervous hypertension or essential hypertension are very effective. The amounts of compounds of the general formula I that are administered, and the methods of administration are selected appropriately They depend on the disease states which are to be medicated starting, Tm general, the compounds in the case of the oral Administration to adults in amounts of 10 to 200 mg, preferably 50 to 100 mg, administered per day. The compounds of formula I according to the invention can be converted into pharmaceuticals using conventional techniques Preparations are converted.

These formulations are prepared using an optional pharmaceutical carrier or an excipient is used and they are administered in a conventional manner

It is preferred that the pharmaceutical preparation be administered in a form suitable for absorption is suitable in the stomach and intestines As oral administration forms containing a unit dose, Examples include tablets and capsules. These tablets and capsules can contain binders, such as syrup, acacia gum, gelatin, sorbitol, tragacanth gum and polyvinylpyrrolidone, extenders such as lactose, Sugar, corn starch, calcium phosphate, sorbitol and glycine, disintegrators such as potato starch, and pharmaceutical include acceptable humectants such as sodium lauryl sulfate, as commonly used. The tablets can be coated by known methods. Liquid preparations for oral use Administration can be aqueous and oily suspensions, solutions, syrups or elixirs. Furthermore can they are also dry products which are soaked in water or other suitable vehicle before administration to be dissolved again. These liquid preparations can contain additives, as are customary be used in this field, such as suspending agents such as sorbitol, syrups, methyl cellulose, Glucose / sugar syrups, gelatine, hydroxyethyl cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose

lulose, aluminum stearate gels and hydrogenated edible fats, emulsifiers such as lecithin, sorbitol monooleate and Acacia, non-aqueous vehicles such as almond oil, fractionated coconut oil, oily esters, propylene glycol and Ethyl alcohol, and antiseptics such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and sorbic acid.

Injectable preparations are, for example, ampoules which contain a unit dose or a vial of a unit amount for multiple administration together with an antiseptic eye Additive. The preparation can be a suspension, a solution or an emulsion in an oily or be aqueous carrier. It can also contain a surfactant or a stabilizer.

The active ingredients of the agent according to the invention include both known compounds and new compounds a. The following compounds, for example, can be named as new compounds: which can be produced by the processes described below:

Synthesis example 1

^^^ S ^ Sl

0.24 g of metallic magnesium tape was added to 20 ml of dry tetrahydrofuran. Vinyl chloride gas was then introduced until the magnesium tape dissolved. A solution of 5 g of decaprenyl acetone in 20 ml of dry tetrahydrofuran was added dropwise to the solution. When the addition was complete, the mixture was left to stand overnight, 5 ml of saturated aqueous ammonium chloride solution were added dropwise, and then 50 ml of η-hexane and a further 30 ml of water were added. The organic solvent layer thus deposited was washed with water and concentrated. The concentrate was dissolved in 30 ml of acetone and the solution was cooled ^{to 0 ° C.} The thus precipitated crystalline compound having a melting point of 38 to 40.0 ⁰ C was taken as the final product. Yield 5.0g.

Elemental analysis as C ₅₅ H ₉₀ O:

Theoretical (%): C 86.19 H 11.82
Found (%): C 86.13 H 11.80

MAS spectrum: M ⁺ 766

IR spectrum (cm " ¹ ): 3390 (OH), 2950, 1640, 1450, 1380, 1130, 900 NMR spectrum (CDCl ₃ , ppm):

UO s 3 H -CH ₃

1.60 s 30H -CH ₃

1.65 s 3 H -CH ₃

2.00-2.2 U m 41H -CH ₂ OH

5.00-6.00 m 13 H = CH = CH ₂

Synthesis example 2

0.23 g of sodium metal was added to 150 ml of liquid ammonia from -5o C ^0. Dry acetylene gas was then passed in until the reaction phase had changed its color from purple to white. A solution of 3.4 g of decaprenyl acetone in 100 ml of dry ethyl ether was then added dropwise. After completion of the addition, the reaction mixture was kept for 15 hours at a temperature of -10 ⁰ C to -15 ° C. When the reaction had ended, ammonia was distilled off. 10 ml of saturated aqueous ammonium chloride solution, 200 ml of ethyl ether and 100 ml of water were added successively to the residue. The deposited organic solvent layer was taken out, washed with water and concentrated. iJas concentrate was purified by column chromatography through 80 g of silica gel in a n-hexane / ethyl ether solvent mixture as an elution solvent, thereby obtaining the final product as a yellowish, white solid (bp. 35.5 to 36.5 ⁰ C). Yield 2.5g.

Elemental analysis as C ₅₅ H ₈₈ O:

Theoretical (%): C 86.32 H 11.59

Found (%): C 86.27 H 11.63

MAS spectrum: M ⁺ 764

IR spectrum (cm " ¹ ): 3400 (OH), 2950, 2120, 1640, 1450, 1378, 1128, 1030, 900 NMR spectrum (CDCl ₃ , ppm):

I.

1.30 s 3 H-O-C-CH ₃

1.60 s 30H -CH ₃

sr ^{! Λ} - - - ■ ■ ■ ■ -

1.62 S. 3 H -CH ₃ 2.02-2.08 m 41 H -CH ₂ OH 2.48 S. 1 H -C = CH

5.04-5.17 m 10 H CH-

ίο Synthesis example 3

3.7, ll, 15.19 ^ 3.27 ^ 1-octamethyl-2,6,10,14,18,22 ^ 6 ^ 0-dotriacontaoctaenyl acetate

4.0 g of octaprenol was dissolved in 20 ml of acetic anhydride. 2.0 g of anhydrous sodium acetate was added to the solution at room temperature. The mixture was then ^{stirred at 100 °} C. for 1 h in order to complete the reaction. The reaction product was poured into water to decompose excess acetic anhydride. After extraction with η-hexane, the extract was washed with water and concentrated.

The concentrate was purified by chromatography with 55 g of silica gel in a n-hexane / benzene mixed solvent as an eluting solvent to give a white, waxy product. Yield 3.6g.

Elemental analysis as C ₄₂ H ₆₈ O ₂ :

Theoretical (%): C 83.38 H 11.33
η Found (%): C 83.37 H 11.34

'MAS spectrum: M ⁺ 604

IR spectrum (cm " ¹ ): 2940, 1745, 1670, 1450, 1385, 1370, 1235, 1030

Nuclear Magnetic Resonance Spectrum (CDCl ₁ , ppm):

I I

, "1.56,1.67 s 27 H -C = C-CH ₃

• ii I ι

j! 2.00 m 28 H -C = C-CH ₂

2.03 s 3 H -C -CH ₃

5.07-5.32 m 8 H -C = CH-

Synthesis example 4

3,7,11,15,19,23,27,3135-nonamethyl-2,6,10,14,18 ^ 2.26 ^ 034-hexacontanonaenyl-2- (p -chlorophenoxy) -t -butylate

so 6.0 g of solanesol was dissolved in 30 ml of pyridine. The solution was added dropwise with a 15% solution 4.4 g of 2- (p-chlorophenoxy) -tert.-butyric acid chloride in pyridine were added in the course of 30 minutes. After finished In addition, the mixture was stirred at room temperature for 2 hours to allow the reaction to go to completion bring. The reaction product was diluted with η-hexane, washed with water and concentrated. That Concentrate was crystallized from acetone at -5 ° C to give the final product as a white solid (m.p.

29.5-30 ⁰ C) were obtained. Yield 6.5g.

Elemental analysis as C ₅₅ H ₈₃ ClO ₃ :

Theoretical (%): C 79.81 H 10.11 Cl 4.28
Found (%): C 79.83 H 10.12 Cl 4.25
60

MAS spectrum: M ⁺ 826, 828

IR spectrum (cm " ¹ ): 2950, 1740, 1495, 1450, 1390, 1245, 1180, 825

Nuclear Magnetic Resonance Spectrum (CDCi ₃ , ppm):

1.56 S. 6H O = II
= C-C-CH ₃
I. 1.60, 1.68 S. 30H \
/
\ C = C-CH ₃ 2.02 m 32 H. \ C = C-CH ₂ - 4.64 d 2H C = C-CH ₂ -O 5.08-5.26 m 9H C = CH-

10

6.92 m 4 H <f> - H

Synthesis example 5

25th

3,4,5-trimethoxybenzoate

8.0 g of decaprenol was dissolved in 50 ml of pyridine and a 15% solution of 4.8 g of 3,4,5-trimethoxybenzoyl chloride in pyridine was added dropwise to the solution at room temperature over 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 2 hours to bring the reaction to completion. Then the reaction product was diluted with η-hexane, washed with water and concentrated. The concentrate was purified by column chromatography with 70 g of silica gel in a n-hexane / benzene solvent mixture as the eluting solvent! purified, thereby obtaining the final product as a white solid (mp. 32.3 to 32.8 ⁰ C). Yield 5.0g.

Elemental analysis as C ₆₀ H ₉₂ O ₅ :

Theoretical (%): C 80.66 H 10.38
Found (%): C 80.63 H 10.37

ij MAS spectrum: M ⁺ 892

IR spectrum (cnT ^! ): 2930, 1715, 1595, 1505, 1455, 1385, 1225, 1010, 765 NMR spectrum (CDCl ₃ , ppm):

j 1.58,1,67,1.76 s 30 H -C = C-CH ₃

2.00 m 36 H —C = C-CH ₂ -

3.84 s 9 H -OCH _{3 Jo}

4.78 d 2 K -C = C-CH ₂ -O

5.06-5.41 m 1OH-C = CH

/. -Κ 7.24 s 2 H

Synthesis example 6

3.7, ll, 15,19i3 ^ 7 ^ 15-nonamethyl-2,6,10,14,18,22,26 ^ 0 ^ 4-hexacontanonaenylcyclohexylcarboxyIate

10 g of solanesol was dissolved in 50 ml of pyridine, and the solution was added dropwise with a 15% Solution of 4.6 g of cyclohexylcarboxylic acid chloride in pyridine in the course of 30 min In addition, the mixture was stirred at room temperature for 2 hours to bring the reaction to completion. Then the reaction product was diluted with η-hexane, washed with water and concentrated. That The concentrate was purified by chromatography on 80 g of silica gel in a n-hexane / benzene mixed solvent

Purified as an eluting solvent, leaving the end product as a white solid {m.p. 34.0-35.0 ⁰ C) was obtained. Yield 6.2g.

Elemental analysis as CjOH ₈₄ O ₂ :
Theoretical (%): C 84.26 H 11.42

Found (%): C 84.28 H 11.43

MAS spectrum: M ⁺ 740

IR spectrum (cm " ¹ ): 2930, 1735, 1670, 1455, 1385, 1175, 1135
Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm):

1OH

-H

1.60, 1.70, 1.85-2.05

30H
IH

-C = C-CH ₃
C = O

<»X

2.02-2.06

4.54

5.08-5.30

m 32 H -C = C-CH ₂

2 H -C = C-CH ₂ —O -

_m 9 H -C = CH

30th

Synthesis example 7

3.7, ll, 15.19;! 3 ^ 7 ^ U5-nonamethyl-2,6,10,14,18 ^ 2 ^ 6 ^ 034-hexatriacontanonaenylpentanoate

10 g of solanesol was dissolved in 50 ml of pyridine, and 6.5 g of valeric anhydride was added dropwise to the solution at room temperature over 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 5 hours to bring the reaction to completion. The reaction product was poured into water to hydrolyze excess valeric anhydride. After extraction with η-hexane, the extract was washed with water and concentrated. The concentrate was purified by chromatography on 100 g of silica gel in n-hexane / benzene solvent mixture as an elution solvent, thereby obtaining the final product as a white solid (mp. 34.0 to 35.0 ⁰ C). Yield 8.8g.

Elemental analysis as C ₅₀ H ₈₂ O ₂ :

Theoretical (%): C 83.97 H 11.56
Found (%): C 83.95 H 11.57

MAS spectrum: M ⁺ 752

IR spectrum (cm "'): 2945, 1735, 1670, 1450, 1385, 1175

Nuclear Magnetic Resonance Spectrum (CDCl ,, ppm):

50

55

60

65

0.88 1.24-1.50

1.58, 1.68

1.98-2.04 2.27

4.52 5.05-5.28

t 3H -CH ₃ m 4H -CH ₂ -
I 1 S. 30H 1 1
-C = C-CH ₃
ι ι m 32 H. II
-C = C-CH ₂ t 2H -C-CH ₂ -
H Il
O
t ι d 2H II
-C = C-CH ₂ -O
I. m 9H -C = CH

Synthesis example 8

3,7,11,15,

8.0 g decapreno! were dissolved in 50 ml of pyridine. A 15% solution of 2.1 g of acrylic acid chloride in PyrUin was added to the solution at room temperature over the course of 30 minutes. When the addition is complete, the mixture is stirred at room temperature for 2 hours to bring the reaction to completion. The reaction product was diluted with η-hexane, washed with water and concentrated. The concentrate was purified by chromatography on 80 g of silica gel in a n-hexane / benzene solvent mixture as the eluting solvent to give a white solid (mp. 32.0 to 32.8 ⁰ C) was obtained. Yield 5.8g.

Elemental Analysis as C ₅₃ H ₈₄ O ₂ : Theoretical (%): C 84.51 H 11.24 Found (%): C 84.49 H 11.25

MAS spectrum: M ⁺ 752

IR spectrum (cm " ¹ ): 2940, 1730, 1670, 1450, 1410, 1390, 1190, 810 NMR spectrum (CDCl ₃ , ppm):

I I 20

1.60,1,68,1.72 s 30H -C = C-CH ₃

2.02 m 36 H -C = C-CH ₂ -

I I *

4.65 d 2 H -C = C-CH ₂ -O-

5.08-5.32 m 1 OH -C = CH

j 30

5.68-6.44 m 3 H -CH = CH ₂

Synthesis Example 9 ₃₅

3,7,11,15,19,23,27 ^ U5 _{Nonamethyl-2,6,10,14,18)} 22.26 ^ 0 _r 34 hexacontanonaenyl-p-chloΓbenzoat

8.0 g of solanesol was dissolved in 30 ml of pyridine. To the solution was added a 15% solution of 45 g of p-chlorobenzoyl chloride in pyridine dropwise at room temperature over 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 2 hours to bring the reaction to completion. The reaction product was diluted with η-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g of silica gel in a n-hexane / benzene mixed solvent as the eluting solvent to give the final product as a white solid (m.p. 30 5-31 5 ⁰ C) was obtained. Yield 6.0g.

Elemental analysis as C ₅₂ Hj ₇ ClO ₂ : Theoretical (%): C 81.15 H 10.09 Cl 4.61 Found (%): C 81.13 HlO ₁ IO Cl 4.59

MAS spectrum: M ⁺ 768, 770

IR spectrum (cm " ¹ ): 2930, 1725, 1670, 1600, 1495, 1450, 1385, 1275, 1095, 850, 760 NMR spectrum (CDCl ₃ , ppm):

1.56,1,65,1.74 s 30H -C = C-CH ₃

1.98-2.07 m 32 H.

4.76 d 2 H ^! '

5.05-5.39 m 9 H.

7.31-7.89 m 4 H <f ^ WH

Synthesis example 10

S 3JSg Undecaprenol were dissolved in 15 ml of acetic anhydride and the solution was charged with 2.0 g of anhydrous sodium acetate at room temperature was added The mixture was stirred for 1 h at 100 ⁰ C in order to bring the reaction to VervoUständigung. After cooling, the reaction product was poured into water to hydrolyze excess acetic anhydride. After extraction with η-hexane, the extract was washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in a

, thereby obtaining the final product as a white solid (mp. 36.0 to 37.0 ⁰ C) ίο n-hexane / benzene solvent mixture as the eluting solvent. Yield 3.5g.

Elemental analysis as C ₅₇ H ₉₂ O ₂ :

Theoretical (%): C 84.59 H 11.46 15 Found (%): C 84.61 H 11.46

MAS spectrum: M ⁺ 808

TR spectrum (cm " ¹ ): 2940, 174d, 1670,1450,1390, U70,1235,1030

Nuclear Magnetic Resonance Spectrum (CDCi ₃ , ppm):

II
1.58.1.68 s 36 H -C = C-CH ₃

2.00 m 4OH -C = C-CH ₂ -

25 _o

2.02 s 3 H -C -CH ₃

4 ₅ 3 _d 2 H -C = C-CH ₂ -O

5.08-5.30 m 11 H -C = CH-

Synthesis Example 11

9,43-undecamethyl-2,6,10 ,,
tetraconta undecaenyl benzoate

3.5 g of undecaprenol was dissolved in 30 ml of pyridine, and a solution of 1 3 g of benzoyl chloride in pyridine was added dropwise over 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 1 hour to bring the reaction to completion. The reaction product was diluted with η-hexane, washed with water and concentrated. The concentrate was chromatographed

graphie purified with 50 g of silica gel in a n-hexane / benzene solvent mixture as the eluting solvent, whereby a white, waxy end product was obtained. Yield 3.6g.

Elemental analysis as C ₆₂ H ₉₄ O ₂ :

Theoretical (%): C 85.45 H 10.87 so Found (%): C 85.43 H 10.86

MAS spectrum: M ⁺ 870

IR spectrum (cnT ¹ ): 2940, 1800, 1725, 1670, 1605, 1455, 1385, 1275, 1105, 710

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm):

1,56,1,64,1.73 s 36 H.

1.96-2.06 m 40 H.

4.76 d 2 H.

... 5.04-5.20 m 11 H.

7.40-7.96 m 2 H.

-C = C-CH ₂ -O-

Synthesis example 12
3.7, ll, 15.19 ^ 3 ^ 7,31,35-nonamethyl-2,6,10,14,18,22 ^ 6,30,34-hexatriaconianonaenyl nicotinate

10 g of solanesol was dissolved in 50 ml of pyridine, and the solution was mixed with a solution of 4.5 g of nicotine-5 acid chloride in pyridine was added dropwise over 30 minutes. After the addition was complete, the The mixture was stirred at room temperature for 2 hours to bring the reaction to completion. The reaction product was diluted with η-hexane, washed with water and concentrated. The concentrate was by chromatography with 80 g of silica gel in a D-hexane / ether solvent mixture as the eluting solvent purified, whereby a white-yellow, waxy end product was obtained. Yield 6.5g. 10

Elemental analysis as Cs] H ₇₇ NO ₂ :

Theoretical (%): C 83.21 H 10.54 N 1.90 Found (%): C 83.18 H 10.55 N 1.92

MAS spectrum: M ⁺ 735

IR spectrum (cm " ¹ ): 2930, 1740, 1595, 1450, 1385 NMR spectrum (CDCl ₃ , ppm):

I I

1.57.1.68 s 30H -C = C-CH ₃

I I

1.99-2.04 m 32 H -C = C-CH ₂ -

I!

4.73 d 2 H -C = C-CH ₂ -O-

! I.

5.05-5.25 m 9 H -C = CH

H 30

N- /

7.5-9.5 m 4 H H- / QV-

HH ⁵

Synthesis Example 13

40 3 _> 7, ll, 15 ₎ 19,23,27,31,35-nonamethyl-2,6,10 ₎ 14,18,22,26,30,34-hexatΓiacontanonaenyl propionate

6.3 g of solanesol and 1.6 g of propionic anhydride were dissolved in pyridine and the solution was at

* Stirred at 80 ° C. After completion of the reaction, the reaction product was poured into water to remove excess

hi Nh d Ek

To hydrolyze propionic anhydride. After extraction with η-hexane, the extract was washed with water see, and the hexane layer was distilled under reduced pressure. The oily substance left behind was purified by column chromatography with 50 g of silica gel to give the final product as a white solid (M.p. 33-35 ° C) was obtained. Yield 6.5g (93.4%).

Elemental analysis as GtSH ₇₈ O ₂ : 50

Theoretical (%): C 83.96 H 11.37 Found (%): C 83.91 H 11.40

MAS spectrum: M ⁺ 686

IR spectrum (cm " ¹ ): 2945, 1735, 1670, 1450, 1385, 1175 55

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm):

65 Il
O

11th

1.10 t 3H -CH ₃
IJ 1.58, 1.68 S. 3OH -C = C-CH ₃
ι t 1.98-2.04 m 32 H. II
-C = C-CH ₂ - 2.30 q 2H -—C - CH ₂ -

I I

4.52 d 2 H -C = C-CH ₂ -O-

5.0-5.08 m 9 H -C = CH

Synthesis example 14
3,7,11,15,19,23,27,3 U5-nonamethyl-2,6 ₎ 10,14,18,22,26 _r 30 ^ 4-hexatriacontanonaenyl stearate

16 g Solanesol, 7.5 g stearic acid and 10 g polyphosphoric acid ethyl ester were dissolved in 40 ml chloroform, and the solution was refluxed with stirring for 4 hours. When the reaction was complete, it became The reaction product is poured into water and about 10 g of sodium hydrogen carbonate are added to form the polyphosphoric acid ester to decompose. After extraction with ether, the ether layer was washed with water and washed with distilled under reduced pressure. The residual oily substance was determined by column chromatography Purified with 100 g of silica gel to give 12.5 g (54.8%) of a white solid (m.p. 36-37 ° C).

Elemental analysis as C ₆₃ H ₁₀₈ O ₂ :
Theoretical (%): C 84.31 H 12.13

Found (%): C 84.27 H 12.11

MAS spectrum: M ⁺ 896

IR spectrum (cm ^-1 ): 2945, 1735, 1670, 1450, 1385, 1175
Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm):

0.88 t 3 H -CH ₃

1.25 m 32 H —CH ₂ -

II
1.58.1.68 s 30H -C = C-CH ₃

Synthesis Example 15

3,7,11,15,19,23,27 ^ l _r 35-nonamethyl-2,6,10,14,18 ^ 2 ^ 6 ^ 034-hexatriacontanonaenyl linolate

16 g of solanesol, 7.5 g of linoleic acid and 10 g of ethyl polyphosphorate were dissolved in 40 ml of chloroform, and the solution was refluxed with stirring for 4 hours. After the reaction had ended, the reaction product was poured into water, and 10 g of sodium hydrogen carbonate were added to decompose the ethyl polyphosphate. After extraction with ether, the ether layer was washed with water and distilled under reduced pressure. The remaining oily substance was purified by column chromatography with 100 g of silica gel, whereby 19 g (80.6%) of a colorless oily product were obtained.
55

Elemental analysis as C ₆₃ H ₁₀₄ O ₂ :

Theoretical (%): C 84.69 H 11.73
Found (%): C 84.59 H 11.72

MAS spectrum: M ⁺ 892

IR spectrum (cnT ¹ ): 2945, 1735, 1670, 1450, 1385
Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm):

1.98-2.04 m 32 H. - C ^==: C - CH ₂ - 2.20 m 2H -C-CH ₂ -
Il Il
O 4.52 d 2H -C = C-CH ₂ -O-
II 5.0-5.08 m 9H i I
-C = CH

0.88 t 3H -CH ₃ UO m 16 H. - CH ₂ -
II 1,58,1,68 S. 3OH II
- C = C-CH ₃

1.98-2.04 m 36 H -C = C-CH ₂ -

2.23 m 2 H -C-CH ₂ -

_{m 2} H -A-CH ₁ -A =

I I

4.52 d 2 H -C = C-CH ₂ -O-

5.0-5.08 m 9 H -C = CH

5.28 m 4 H H H

y y

- C = C-

In the following examples examples of preparations are given, which as the invention Active ingredient 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,22,26,30,34-hexatriacontan-1-ol (hereinafter referred to as Active ingredient abbreviated).

example 1
(Capsules)

Active ingredient 5 g

Microcrystalline cellulose 80 g

Corn starch 20 g

Lactose 22 g

Polyvinylpyrrolidone 3 g

A total of 130 g

The individual ingredients were granulated in a conventional manner, and the resulting granules was filled into 1000 hard gelatin capsules. Each capsule contained 5 mg of active ingredient.

The active ingredient was dissolved in acetone and the solution was adsorbed onto microcrystalline cellulose. The cellulose was then dried and mixed with corn starch. The mixture was made to conventional Way deformed into a powder. Thus, it became a powdery product of 1/20 concentration obtain. SO

(Tablets)

55

Example 2 (Powder) Active ingredient
Microcrystalline cellulose
Cornstarch 50 g
400 g
550 g All in all 1000 g

Active ingredient 5g Cornstarch 10 g Lactose 20g Calcium carboxymethyl cellulose 10 g Microcrystalline cellulose 40 g Polyvinyl pyrrolidone 5g Talk 10 g

60

A total of 100 g

The active ingredient was dissolved in acetone and the solution was adsorbed onto microcrystalline cellulose. 65 | The cellulose was dried and mixed with corn starch, lactone and calcium carboxymethyl cellulose. The mixture was mixed with an aqueous polyvinylpyrrolidone solution as a binder and adjusted to conventional Way granulated. The resulting granules were mixed with talc as a lubricant and made into tablet

13th

ten, each weighing 100 mg and containing 5 mg of active ingredient, deformed.

Example 4 (injectable preparations)

Active ingredient 10 g Nikkol HCO-60 (product of Nikko Chemical Co.) 37 g sesame oil 2g Sodium chloride 9g Propylene glycol 40 g Phosphate buffer (0.1 M, pH 6.0) 100 ml Distilled water rest All in all 1000 ml

A mixture of the active ingredient, Nikkol HCO-60, sesame oil and half the amount of propylene glycol was made up

heated to about 80 ^° C. in order to obtain a solution. The solution was made with the phosphate buffer and distilled

Water in which sodium chloride and propylene glycol had been dissolved and which was preheated to about 8O ⁰ C

20 denier was mixed to give 1,000 ml of an aqueous solution. The aqueous solution was in

Entered 2 ml ampoules. The ampoules were sealed and sterilized by heating.

Each ampoule contained 20 mg of the active ingredient.

For this purpose 4 sheets of drawings

25th

Claims (1)

Claim: Antihypertensive agent containing a pharmaceutical carrier and a polyprenyl compound as an active ingredient, characterized in that the active ingredient is a polyprenyl alcohol or that ester of the general Formula I. CH ₃ H - ^ - CH ₂ -C = CH-CH ₂