CH635838A5 - Process for preparing nitrogen-containing heterocyclic carbonylpiperazinylquinazolines - Google Patents

Description

The present invention relates to the preparation of new nitrogen-containing heterocyclic carbonylpiperazinylquinazolines which are highly effective antihypertensives and generally have a smaller a-adrenergic blocking effect than 2- [4- (2-furoyl) piperazin-l- yl] --4-amino-6,7-dimethoxyquinazoline, which is a known antihypertensive agent.

In particular, the present invention relates to a process for the preparation of compounds of formula 20

25th

s-r3

0

-c-z

30th

CH30

(ii)

wherein Z is a substituted or unsubstituted oxazole, isoxazole, thiazole, isothiazole or alkylthio substituted 1,3,4-oxadiazole, as well as pharmaceutically usable acid addition salts of the compounds mentioned.

U.S. Patent Nos. 3,511,386, 3,635,979 and 3,663,706 contain various 4-amino-6,7-dimethoxy 2- [4- (heterocyclic - 2-carbonyl) piperazin-l-yl] quinazolines. One of these connections, i.e. 2- [4- (2-Furoyl) -piperazin-l-yl] -4-amino-6,7-di-40 methoxyquinazoline, described in Example LXXII of the aforementioned PS, is a clinically usable antihypertensive and is used in many countries around the world known as Prazosin. It is recognized that the antihypertensive effects of prazosin result from a dual mechanism re-45:

(i) a direct peripheral vasodilation effect on vascular smooth muscle tissue, and

(ii) functional peripheral a-adrenergic receptor blocking,

50 H. Adriaensen, The Practitioner, 214, 268 (1975);

Mroczek et al., Current Therapeutic Research, 16, 769 (1974);

Scriabine et al., Experientia, 24, 1150 (1968); Constantine and co-workers, Hypertension: Mechanisms and 55 Management, edited by Onesti, Kim and Moyer; Green and Stratton, 1973 pp. 429-44 and Zacest, Med. J. of Austral, Special Supplement, 1, 4 (1975).

Although initial clinical trials with prazosin showed an almost complete absence of side effects 60, more recent reports have described severe side effects in the form of postural hypotension in some patients, Bendall and co-workers, Brit. Med., J., 727 (June 28, 1975); Rees, Brit. Med. J., 593 (September 6, 1975); Gabriel and co-workers, The Lancet, 1095 65 (May 10, 1975); and Bloom and co-workers, Current Therapeutic Research, 18, 144 (1975). It is generally believed that this type of side effects result from the a-blocking component of prazosin. did

3rd

635838

In fact, R. Zacest in Med. J. of Austral., Special Supplement, 1, 4 (1975) found that: "If the adrenergic blocking effect is high due to high doses, this can lead to postural hypotension".

U.S. Patents 3,669,968 and 3,769,286 contain trialkoxy quinazolines such as those of the formula:

CHoO

where R can mean a large number of different groups, including furyl and thienyl. The PS mentioned claim some advantages over the corresponding 6,7-dialkoxy compounds as those from the PS mentioned above. Such compounds are said to: "have a more suitable pharmacological profile (ie they are not adrenolytic in dogs) and they show greatly improved solubility characteristics (especially in water) compared to the corresponding 6,7 dialkoxy compounds as they are known so far ». One of the compounds from this PS is known under the name Trimazosin and has the formula:

CHoO

CH3O

Expect 1.5 to 15 mg for prazosin. Trimazosin is therefore 100 times weaker than prazosin at the lower end of the dose range.

U.S. Patent Nos. 3,517,005, 3,594,480 and 3,812,127 describe piperazinylquinazolines with both bronchodilating and anti-hypertensive effects, e.g. a compound of the formula:

R »

10th

ShC-R u where A and B can both be alkoxy, etc., R 'can be hydrogen or alkyl and R "can be hydrogen or a radical such as alkyl, benzoyl, etc.

20 U.S. Patent 3,920,636 describes homopiperazinequinazolines as antihypertensive agents, e.g. the connection

^ 2

25th

0 CHo

^ ■ Jl i

^ -C-O-CHp-C CHo w

Trimazosin is known as an antihypertensive in humans, DeGuia et al., Current Therapeutic Research, 15, 339 (1973); Vlachakis and co-workers, Current Therapeutic Research, 17, 564 (1975). However, it is much less effective than prazosin and the corresponding clinical daily doses are approximately 150 to 500 mg for trimazosin compared.

CHqO

30 US Pat. No. 3,780,040 describes compounds which have antihypertensive activity such as the compound:

CII3O

35

40 Dutch patent application 72 06, 06 (CA, 78, 72180s) describes a process for the preparation of amino-quinazolines, such as prazosin, by treating the corresponding o-aminobenzonitriles in the presence of phenyl-lithium according to the following mechanism:

45

PhLi

CH3O

wherein R2N can be the group 4- (2-furoyl) -l-piperazinyl.

The present invention relates to the preparation of compounds of the formula

60

65

635838

4th

where Z

R

-N

Sx o

-R-,

R

R2

or represents, wherein X represents either oxygen or sulfur, R1 and R2 are the same or different and are hydrogen, lower alkyl having 1-6 C atoms, lower alkoxy having 1-6 C atoms and lower alkylthio having 1-6 C atoms mean and R3 represents lower alkyl having 1-6 C atoms, and on pharmaceutically usable acid addition salts of the compounds mentioned, which have the antihypertensive activity, comparable to prazosin, but generally have a smaller peripheral a-adrenergic blocking action than that of prazosin. A preferred embodiment of the present invention is the preparation of the compounds of the formula:

S-R

wherein R represents lower alkyl with 1-6 C atoms and pharmaceutically acceptable acid addition salts thereof. These compounds show antihypertensive activity, comparable to prazosin, but show very little or no peripheral a-adrenergic blocking activity like prazosin. These compounds are potent antihypertensives that have little or no side effects as a result of a lack of adrenolytic activity.

The most preferred method of the present invention relates to the preparation of 4-amino-6,7-dime-thyIoxy-2- [4- (5-methylthio-l, 3,4-oxidiazol-2-carbonyl) piperazine -l-yl] -quinazoline of the formula

CHoO

CH3O

and acid addition salts thereof, especially the hydrochloride.

The term "pharmaceutically usable" is used to describe an acid addition salt of a compound of the formula I and refers to those salts of a large number of various relatively non-toxic inorganic or organic acids. The anion does not contribute significantly to the toxicity or the pharmacological effects of the salt. Examples of such salts are those of acetic acid, lactic acid, larulinic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfonic acid, such as methanesulfonic acid such as Benzenesulfonic acid, p-toluenesulfonic acid and related acids. The preparation of the 10 mono acid addition salts can be carried out in a conventional manner by treating a solution or a suspension of the free base in an inert organic solvent with a chemical equivalent of the acid or, if the corresponding diacid addition salt is desired, at least 15 chemical equivalents the acid mentioned. Conventional concentration or crystallization methods are used for isolation.

The process according to the invention for the preparation of compounds of the formula I is characterized in that 20 is a quinazoline derivative of the formula

A

25th

II

J—? N.

wherein the substituent A is NH2 or NR'2, wherein R'2 30 is a conventional amino protecting group, with a reagent of the formula

O

35

40

in which Y represents a carbonyl activating group as normally used in amidation reactions, e.g. Halogen, azido, ethoxy, carbonyloxy, 1-imidazole or the like, and Z is a radical of the formula

R1

45

\ y /

4-R2,

represents in which X represents oxygen or sulfur, R1 and R2 are the same or different and represent hydrogen, lower alkyl having 1-6 C atoms, lower alkoxy having 1-6 60 C atoms or lower alkylthio having 1-6 C atoms and R3 represents lower alkyl having 1-6 C atoms, whereupon any amino protective group R'2 which may be present is removed in a conventional manner and whereupon the product obtained is converted into a non-toxic, pharmaceutically acceptable acid addition salt in a conventional manner as required becomes.

The following reaction scheme illustrates the synthetic route for the preparation of the compounds of formula (I)

according to the inventive method. Scheme

5

635838

0

y-c-z - ^

chqo

CH3O

r \ II

N / XN ^ ^ I-C-Z

(I)

In a preferred embodiment of this method, Z is a group of the formula

N-

-n

0

^ —Sr wherein R represents a lower alkyl group and the reaction is carried out in an inert solvent such as dioxane, chloroform, methylene chloride, glyme or the like at room temperature and / or with heating to reflux temperature.

In particular, Y chlorine, Z is a group of the formula n n

Example 3

4-Amino-6,7-dimethoxy-2- [4- (5-isopropylthio-l, 3,4-oxadiazol-2-carbonyl) piperazin-l-yl] -quinazoline hydrochloride

20 The compound mentioned was prepared from 1.54 g (7.5 mmol) of 5-isopropylthio-1, 3.4 oxadiazole-2-carbonyl chloride and 2.1 g (7.5 mmol) of 4-amino-6,7-dimethoxy -2- (l-piperazinyl) -quinazo-lin prepared as described in Example 1. The product showed a mp of 260-263 ° C with decomposition.

25 Analysis for: C20H25N7O4S. HCl Calc .: C 48.43 H 5.28 N 19.77 Found: C 48.05 H 5.20 N 19.61

30th

ch0 3

and the reaction is carried out in dioxane.

example 1

4-Amino-6,7-dimethoxy-2- [4- (5-methylthio-l, 3,4-oxadiazole - 2-carbonyl) piperazin-l-yl] quinazoline hydrochloride

A solution of 0.601 g (3.36 mmol) of 5-methylthio-l, 3,4-oxadiazole-2-carbonyl chloride in 10 ml of dioxane was added to a solution of 0.972 g (3.36 mmol) of 4-amino-6, 7-di-methoxy-2- (l-piperazinyl) -quinazoline in 100 ml of dioxane. The mixture obtained was stirred at room temperature for 65 h and then heated to reflux temperature for 30 min. After filtering off, 1.56 g of the desired compound were obtained and recrystallization from methanol gave a product of mp. 280 to 285 ° C. with decomposition.

Analysis for: C18H21N704S. HCl calc .: C 46.20 H 4.74 Cl 7.58 N 20.96 S 6.85 found: C 46.34 H 4.89 Cl 7.59 N 20.38 S 6.58

Example 4

4-Amino-6,7-dimethoxy-2- [4- (5-n-propylthio-l, 3,4-oxa-diazol-2-carbonyl) piperazin-l-yl] quinazoline hydrochloride

The compound mentioned was prepared from 1.68 g (8.16 mmol) of 5-n-propylthio-l, 3,4-oxadiazole-2-carbonyl chloride and 2.36 g of 35 (8.16 mmol) of 4-amino-6, 7-dimethoxy-2- (l-piperazinyl) -quinazoline prepared as described in Example 1. The product showed a mp. Of 230-245 ° C with decomposition.

Analysis for: C20H25N7O4S. HCl

40

45

calculated: found:

C 48.43 C 48.11

H H

5.25 5.35

19.77 19.65

Example 5

4-Amino-6,7-dimethoxy-2- [4- (5-n-butylthio-l, 3,4-oxadiazole - 2-carbonyl) piperazin-l-yl] quinazoline hydrochloride

Example 2

4-Amino-6,7-dimethoxy-2- [4- (5-ethylthio-l, 3,4 ~ oxadiazole - 2-carbonyl) piperazin-l-yl] -quinazoline hydrochloride

This compound was made from 0.79 g (4.1 mmol) of 5-ethyl-thio-1,3,4 oxadiazole-2-carbonylchloride and 1.19 g (4.1 mmol) of 4-amino-6,7-dimethoxy -2- (l-piperazinyl) -quinazoline prepared as described in Example 1. The product had a mp of 246-248.5 ° C.

Analysis for: C19H23N704S. HCl calc .: C 47.34 H 5.02 N 20.34 S 6.65 found: C 47.37 H 4.76 N 20.15 S 6.71 (corr. For 4.11% H20)

The compound mentioned was prepared from 5-n-butylthio-l, 3,4-oxadiazole-2-carbonyl chloride and 4-amino-6,7dimethoxy-2 - (l-piperazinyl) -quinazoline as described in Example 1-50 posed.

Example 6

4-amino-6,7-dimethoxy-2- [4- (isoxazol-5-carbonyl) piperazin-l-yl] -quinazoline hydrochloride

55

A solution of 1.33 g (0.01 mol) of isoxazole-5-carbonyl chloride in dioxane became a solution of 2.94 g (0.01 mol) of 4-amino 6,7-dimethoxy-2- (l -piperazinyl) -quinazoline in dioxane at 30 ° C. The mixture was heated to reflux temperature for 60 minutes and then stirred at room temperature for 16 hours. Filtration gave 4.02 g (94% yield) of the above compound. After recrystallization from aqueous methanol, a product of mp 270 ° C. with decomposition was obtained. 65 Analysis for: C18H20N6O4. HCl calc .: C 51.37 H 5.03 Cl 8.42 N 19.97 found: C 50.86 H 4.65 Cl 8.52 N 19.81 (corr. For 4.30% H20)

635838

6

Example 7

4-amino-6,7-dimethoxy-2- [4- (isoxazol-3-carbonyl) piperazin-1-yl] -quinazoline hydrochloride

A solution of 0.753 g (0.0057 mol) of isoxazole-3-car bonyl chloride in 20 ml of dioxane was added to a solution of 1.66 g (0.0057 mol) of 4-amino-6,7-dimethoxy-2- ( l-piperazi-nyl) -quinazoline in 60 ml of dioxane. The mixture was stirred at reflux temperature for 30 min and then at room temperature for 64 h. Filtration gave the desired compound after recrystallization from methanol in 1.81 g (75% yield). The product showed a melting point of 268 to 273 ° C with decomposition.

Analysis for: C18H20N6O4. HCl calc .: C 51.37 H 5.03 Cl 8.42 N 19.97 found: C 50.04 H 4.86 Cl 8.66 N 19.57 (corr. For 3.11% H20)

Example 8

4-amino-6,7-dimethoxy-2- [4- (isoxazol-4-carbonyl) piperazin-l-yl] -quinazoline hydrochloride

A solution of 1.06 g (8.08 mmol) of isoxazole-4-carbonyl chloride in 8 ml of dioxane became a solution of 2.34 g (8.08 mmol) of 4-amino-6,7-dimethoxy-2 - (l-piperazinyl) quinazoline in 200 ml of dioxane. The mixture was stirred at room temperature for 20 h and after filtration the desired compound was obtained, which after recrystallization from methanol had an mp of 255-260 ° C. with decomposition.

Analysis for: C18H20N6O4. HCl calc .: C 51.37 H 5.03 Cl 8.42 N 19.97 found: C 51.37 H 4.95 Cl 8.34 N 19.95 (corr. For 1.63% H20)

Example 9

4-amino-6,7-dimethoxy-2- [4- (5-methylisoxazol-3-carbonyl) piperazin-l-yl] quinazoline hydrochloride

A solution of 0.41 g (2.83 mmol) of 5-methylisoxazole - 3-carbonyl chloride in dioxane was added to a solution of 0.82 g (2.83 mmol) of 4-amino 6,7-dimethoxy-2- ( l-piperazi-nyl) -quinazoline added in dioxane. The mixture was processed as described in the previous example and gave the desired compound of mp. 271-273 ° C with decomposition.

Analysis for: C ^ H ^ NgC ^. HCl H20

calc .: C 50.38 H 5.56 N 18.56 H20 3.92 found: C 50.58 H 5.40 N 18.86 H20 3.72

Example 10

4-amino-6,7-dimethoxy-2- [4- (3-methylisoxazole-4-carbonyl) piperazin-1-ylJ-quinazoline hydrochloride

A solution of 1.01 g (6.9 mmol) of 3-methylisoxazole - 4-carbonyl chloride in dioxane and 2.00 g (6.9 mmol) of 4-amino-6,7-dimethoxy-2- (l -piperazinyl) -quinazoline in dioxane was stirred at reflux temperature for 15 h and then worked up as described in Example 6. After recrystallization from methanol, the desired compound showed an mp of 300-301 ° C. with decomposition. Analysis for: C19H22N604. HCl calc .: C 52.47 H 5.33 N 19.33 found: C 52.62 H 5.31 N 19.12 (corr. For 1.13% H20).

Example 11

4-amino-6,7-dimethoxy-2- [4- (3-methylisoxazole-5-carbonyl) piperazin-l-yl] -quinazoline hydrochloride

A solution of 0.73 g (5.02 mmol) of 3-methylisoxazole - 5-carbonyl chloride in dioxane became a solution of 1.45 g (5.02 mmol) of 4-amino-6,7-dimethoxy-2- (l-piperazinyl) quinazoline added in dioxane. The mixture was heated briefly and then stirred at 20 ° C. for 2.5 h. After working up as described in Example 6, the desired compound with a melting point of 263-264 ° C. with decomposition was obtained.

Analysis for: C19H22N604. HCl calc .: C 52.47 H 5.33 Cl 8.15 N 19.33 found: C 51.82 H 5.04 Cl 8.36 N 19.46 (corr. For 4.82% H20).

Example 12

4-Amino-6,7-dimethoxy-2- [4- (oxazole-4-carbonyl) piperazine - 1 -yl] -quinazoline-kyrochloride

A solution of 0.73 g (5.53 mmol) of oxazole-4-carbonyl chloride in dioxane was converted into a solution of 1.60 g (5.53 mmol) of 4-amino-6,7-dimethoxy-2- ( l-piperazinyl) -quinazoline added in dioxane. The mixture was heated to reflux temperature for 0.5 h and then stirred at 20 ° C. for 64 h. The desired compound with an mp of 291-294 ° C. with decomposition after recrystallization from aqueous ethanol was obtained by filtration. Analysis for: ClaH20N6O4. HCl. H20

calc .: C 49.26 H 5.28 Cl 8.08 N 19.15 found: C 48.92 H 4.83 Cl 8.33 N 18.94

Example 13

4-amino-6,7-dimethoxy-2- [4- (2-methyloxazol-4-carbonyl) piperazin-l-yl] quinazoline hydrochloride

A solution of 1.01 g (6.9 mmol) of 2-methyloxazole - 4-carbonyl chloride in dioxane became a solution of 2.00 g (6.9 mmol) of 4-amino-6,7-dimethoxy-2- (l-piperazinyl) quinazoline added in dioxane. The mixture was heated to reflux temperature for 2 hours, after which the desired compound was obtained by filtration in a melting point of 278-280 ° C. with decomposition after recrystallization from methanol.

Analysis for: C10H22N6O4. HCl calc .: C 52.47 H 5.33 N 19.33 found: C 52.08 H 5.43 N 18.89 (corr. For moisture).

Example 14

4-amino-6,7-dimethoxy-2- [4- (4-methyloxazol-5-carbonyl) piperazin-l-yl] quinazoline hydrochloride

This compound was prepared from 0.85 g of 4-methyloxazole-5-carbonyl chloride and 1.68 g of 4-amino-6,7-di-methoxy-2- (1-piperazinyl) quinazoline using the same procedure as in Example 6 described. The product showed a mp of 183.5-288 ° C with decomposition.

Analysis for: C19H22N604. HCl calc .: C 52.48 H 5.33 Cl 8.15 N 19.33 found: C 52.19 H 4.94 Cl 8.13 N 19.05 (corr. For 1.59% H20).

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

635838

Example 15

4-amino-6,7-dimethoxy-2- [4- (isothiazol-4-carbonyl) piperazin-l-yl] -quinazoline hydrochloride

This compound was prepared from 1.01 g of isothiazole-4-carbonyl chloride and 1.99 g of 4-amino-6,7-dimethoxy-2- (1-piper-azinyl) -quinazoline as described above. The product showed a mp of 286-287 ° C with decomposition.

Analize for: Ci8H20N6O3S. HCl calc .: C 49.48 H 4.84 Cl 8.11 N 19.23 S 7.34 found: C 49.20 H 4.81 Cl 8.19 N 19.27 S 7.23 (corr. for 0.93% H20).

Example 16

4-A mino-6,7-dimethoxy-2- [4- (thiazol-2-carbonyl) piperazin-l-yl] quinazoline hydrochloride

This compound was made from 0.79 g of thiazole-2. carbo-nyl chloride and 1.54 g of 4-amino-6,7-dimethoxy-2- (l-piper-azinyl) -quinazoline prepared as described above. The product showed a mp of 273-276 ° C with decomposition. Analysis for: ClaH20N6O3S. HCl calc .: C 49.48 H 4.84 N 19.23 found: C 48.68 H 4.62 N 18.87 (corr. For 4.19% H20).

Example 17

4-amino ~ 6,7-dimethoxy-2- [4- (thiazole-4-carbonyl) piperazin-1-yl] -quinazoline hydrochloride

This compound was prepared from 1.02 g of thiazole-4-carbonlyl chloride and 2.00 g of 4-amino-6.7 dimethoxy-2- (l-piperazinyl) quinazoline as described above. The product showed a mp of 274-277 ° C with decomposition. Analysis for: C18H20N6O3S. HCl calc .: C 49.48 H 4.84 N 19.24 found: C 49.11 H 4.69 N 19.31 (corr. For 4.47% H20).

Example 18

4-A mino-6,7-dimethoxy-2- [4- (2-methylthiazole-4-carbonyl) piperazin-1-yl] -quinazoline hydrochloride

This compound was prepared from 0.49 g of 2-methylthiazole-4-carbonyl chloride and 0.87 g of 4 amino-6,7-dimethoxy-2- (1-piperazinyD-quinazoline as described above. The product showed an mp of 260-263 ° C with decomposition.

Analysis for: C19H22N603S. HCl calc .: C 50.60 H 5.14 N 18.64 found: C 58.88 H 4.96 N 19.67 (corr. For 2.88% H20).

Example 19

4-amino-6,7-dimethoxy-2- [4- (thiazole-5-carbonyl) piperazine - 1-ylJ-quinazoline hydrochloride

This compound was prepared from 0.77 g of thiazo-5-carbonyl chloride and 1.51 g of 4-amino-6,7-dimethoxy-2- (l-piperazinyl) quinazoline as described above. The product had a melting point of 280-281 ° C. with decomposition. Analysis for: C18H20N6O3S. HCl calc .: C 49.48 H 4.84 Cl 8.11 N 19.23 S 7.34 found: C 49.22 H 5.19, Cl 8.31 N 19.49 S 6.79 (corr for 2.63% H20).

Example 20

4-Amino-6,7-dimethoxy-2- [4- (2-methylthiazole-5-carbonyl) piperazin-1-yl] -quinazoline hydrochloride

This compound was prepared from 0.42 g of 2-methylthiazole-5-carbonyl chloride and 0.75 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline as described above. The product showed a mp of 294-297 ° C with decomposition.

Analysis for: C19H22N603S. HCl calc .: C 50.60 H 5.14 N 18.64 found: C 50.60 H 4.95 N 18.50 (corr. For 1.96% H20).

Example 21

4-amino-6,7-dimethoxy-2- [4- (4-methylthiazol-5-carbonyl) piperazin-l-yl] quinazoline hydrochloride

This compound was prepared from 1.1 g of 4-methylthiazole-5-carbonyl chloride and 2.0 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline as described above. The product showed a mp of 293-295 ° C with decomposition.

Analysis for: CwH22N603S. HCl calc .: C 50.60 H 5.14 N 18.64 found: C 50.47 H 4.72 N 18.43 (corr. For 4.72% H20).

Various comparative tests with prazosin were carried out to determine the effectiveness of the compounds according to the invention as antihypertensive agents.

Table 1 below shows the comparison of the product from Example 1 with prazosin. As can be seen in Table 1, the product of Example 1 (hereinafter referred to as BL-5111) is of comparable antihypertensive activity to prazosin, but has little or no peripheral a-adrenergic blocking activity to prazosin. This compound therefore represents a significant and unexpected advance in the search for new, effective antihypertensive agents that have little or no side effects due to the lack of a-adrenergic blocking effect.

For Table 1, the antihypertensive activity was determined by oral administration in spontaneously hypertensive rats, and the in vitro and in vivo a-adrenergic receptor blocking activity was determined by tests, the description of which follows in Table 1. The in vitro test measured the inhibitory activity of BL-5111 against nor-epinephrine-induced contractions in rat seminal vesicles and the in vivo tests measured the inhibitory activity of BL-5111 against norepinephrine-induced pressure responses in anesthetized dogs. The in vivo tests were carried out with intravenous administration, each compound to be tested being administered to 4 dogs in 2 different doses.

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

635838

8th

TABLE 1

nh2

ch3o

Connection R

Antihypertensive effect

% Blood ED50 dose pressure-mm Hg mg / kg change mg / kg a-adrenergic receptor blocking effect efficacy in vitro in vivo IV LD50 ratio efficacy in mice ratio ratio mg / kg

Prazosin

BL-5111

0 II

.c.

■ N

o n-

- = - ^ o- ^ SCH:

10th

-42

2.1

1.0

1.0

1.0 36.1

3rd

-29

1

-14

10th

-41

2.3

0.91

0

0.04 45.7

3rd

-26

1

-19

Experiment with isolated rat seed vesicles

Dangan et al., Int. J. Neuropharmacol., 4: 219 (1965) showed that the seminal vesicles of rats are tissue that show response to compounds that activate "receptors, but practically no response to compounds that activate β-receptors. Lietch et al., Brit. J. PharmacoL, 9: 236 (1954) used isolated rat seminal vesicle tissue in a comparative experiment for α-receptor blocking agents and the test we used represents a modification of this experiment.

Male Long Evans rats weighing approximately 300 g were killed by a hard blow to the head. The seminal vesicles were removed and placed in a bowl containing modified Tyrode solution. The seminal vesicles were freed from their contents by gently squeezing with tweezers, a silk thread was attached to both ends of the vesicle and the same in a 20 ml muscle chamber containing modified oxygenated Tyrode solution (g / liter: NaCl 8, KCl 0.2, CaCl 0.26, NaHCO, 1, Na2HP04 0.0575, glucose 0.5 and MgCl, 0.02) was brought. The bath fluid was kept at 37 ° C. and the contractions were registered isometrically using a force displacement transducer and recorded using a Beckmann RP dynograph. Noreprinephrine (NE) was added to the muscle chamber in volumes between 0.1 and 0.4 ml using a 1 ml syringe. NE and the test compounds were dissolved in deionized water.

NE dose response curves were determined in the absence and 30 in the presence of test compounds. Ne was kept in contact with the tissue until a maximum contraction was reached, after which the tissue was washed with a perfusion solution for 15-30 seconds, after which it was returned to its original state before a new dose of NE was administered. Larger portions of NE were subsequently injected into the bath solution until a complete dose response was achieved.

The seminal vesicles used to determine the control NE dose response were discarded and new preparations were prepared to test the test compounds. The test compound was added directly to the perfusion solution (10 nanograms / ml) and the tissue was kept in contact with the bath solution for at least 10 minutes before the NE dose response was determined 45.

The ED50 values for NE were determined using a regression analysis as described by Finney, Probit. Analysis, 2nd edition, Cambridge (1964). A minimum of 4 tissue samples and at least 4 doses were used to determine the regression lines. The ED50 value is defined as the concentration of NE that causes a contraction that is 50% of the maximum contraction.

The ratio of the a-adrenergic blocking effect of BL-5111 to prazosin was calculated as follows:

Percentage change from NE = ED50 NE + test - EDS0 NE alone

X 10

60 ED50 NE alone

The value obtained for BL-5111 was then calculated as a ratio to the value obtained for precision.

% ale change for NE - BL-5111

65 activity ratio

% change for NE - prazosin The results obtained for NE, prazosin and BL-5111 are given in Table 2 below.

9 635838

TABLE 2

Effect of prazosin and BL-5111 on the NE response in isolated rat seminal vesicles

treatment

number

NE-ED50 with 95%

% uale

Activity

Tissue

Trust area

Change ratio

rehearse

([ig / ml)

related to

the on

control

Prazosin

Control 32 0.89 (0.84-0.94)

Prazosin,

10 nano / ml 8 6.93 (5.30-6.81) 578 1.0 BL-5111

10 nan / ml 7 0.93 (0.80-1.08) 4.5 0.008

These data clearly show that a concentration of 10 nanograms / ml in the case of prazosin caused almost a 6-fold decrease in the sensitivity of isolated rat seminal vesicles to the stimulating effect of NE, while BL-5111 showed practically no effect in this direction. It was concluded that BL-5111 has less than 1% of the a-adrenergic blocking effect of prazosin.

Test with anesthetized dogs for a-adrenergic blocking effect

Nash, CB, Pharmacological Research Communications, 4: 423, (1969) and Maxwell, RA, Drill's Pharmacology in Medicine, (1971) p. 683 showed that in anesthetized dogs, a-adrenergic blocking agents antagonize the blood pressure-increasing effect of intravenously administered norepinephrine . Therefore, the reaction of blood pressure to norepinephrine (NE) in anesthetized dogs was used as a comparison test to determine the a-adrenergic receptor blocking effect of various substances.

The experiments were carried out with Mongrel dogs anesthetized by sodium pentobarbital (30 mg / kg, i.v.). The left femoral artery was cannulated to measure aortic blood pressure and a femoral vein was cannulated to administer the test compounds. A norepinephrine dose response curve was obtained by administering increasing doses of norepinephrine (0.01-1 ng / kg). The test compound (prazosin, BL-5111) was then administered intravenously in an amount of 3 mg / kg. Approx. Another dose response curve for norepinephrine (0.01-10 [ig / kg) was recorded 30 min later. The dose of norepinephrine (with a 95% confidence interval) that caused a blood pressure increase of 50 mm Hg was obtained from the dose-response curve analysis before and after administration of prazosin or BL-5111. The ratio of the a-adrenergic blocking effect of BL-5111 with respect to that of prazosin was obtained as follows:

TABLE 3

20th

Effect of prazosin and BL-5111 on the blood pressure response to intravenous norepinephrine

Treatment N NE ED50 mm Hg activity ver

25 for 95% ratio relatively trustworthy to prazosin

control

20th

0.23

(0.19-0.28)

-

Prazosin 3 mg / kg

4th

6.90

(4.80-10.7)

1.00

BL-5111

4th

0.47

(0.40-0.55)

0.036

35 Table 4 lists the comparative test results for the products from Examples 6-21 and Prazosin. As can be seen from this table, the products from Examples 6-21 show a comparable antihypertensive activity as prazosin, but they generally have a smaller 40 peripheral a-adrenergic blocking activity than prazosin. These compounds are therefore a significant and unexpected advance in the search for new effective antihypertensive drugs.

Effectiveness ratio

ED50 mm Hg _ ED50 mm Hg BL-5111 NE

60

ED50 mm Hg _ ED50 mm Hg Prazosin NE

The results obtained with norepinephrine, prazosin and BL-5111 are summarized in Table 3. The results show that BL-5111 was about 30 times less active than prazosin, when an a-adrenergic block at 3 mg / kg iv. took place.

635838

example

Prazosi:

(Refere

6

7

8th

9

10th

11

12

13

14

15

16

17th

18th

19th

20th

21st

v

10th

TABLE 4

Antihypertensive effects of a-adrenergic receptor blocking

effect

dose

% ual in vitro in vivo

mg / kg

Blood pressure

Activity activity

change ratio ratio

10th

-42

1.0 1.0

3rd

-29

1

-14

10th

-35

0.11 0.18

3rd

-26

1

-15

10th

-32

3rd

-26

1

-12

10th

-35

0.92

3rd

-23

1

-13

10th

-41

0 0.24

3rd

-18

1

-14

10th

-33

0.30 0.18

3rd

-29

1

-17

10th

-37

0.25

3rd

-21

1

-18

10th

-45

0.6 1.22

3rd

-29

1

-15

10th

-35

0.17

3rd

-31

1

-13

10th

-41

0.19

3rd

-26

1

-14

10th

-25

3rd

-23

1

-14

10th

-33

3rd

-27

1

-14

10th

-32

0.12

3rd

-24

1

-20

10th

-28

0.02

3rd

-28

1

-19

10th

-33

0.10

3rd

-22

1

-12

10th

-37

0.19 0.09

3rd

-25

1

-20

10th

-28

0.35

3rd

-22

1

-4

Claims (5)

635838 PATENT CLAIMS 1. Process for the preparation of compounds of the formula ML where Z R I -n ■ Kc R or -R £ • A means in which X represents either oxygen or sulfur, R1 and R2 are identical or different and are hydrogen, lower alkyl having 1-6 C atoms, lower alkoxy having 1-6 C atoms or lower alkylthio having 1-6 C atoms and R3 represents lower alkyl with 1-6 C atoms; or of non-toxic pharmaceutically usable acid addition salts of the compounds mentioned, characterized in that a quinazoline derivative of the formula a CH3O wherein the substituent A is -NH2 or NR'2, wherein R'2 represents an amino protecting group, with a reagent of the formula O Y —C —Z is implemented in which Y is a carbonyl-activating group, whereupon any amino protective group R'2 which may be present is removed and the product is optionally converted into a non-toxic, pharmaceutically usable acid addition salt. 2. The method according to claim 1, characterized in that in the formula II A represents -NH2. 3. The method of claim 2, wherein Z s-r- represents. 4. The method of claim 3, wherein R3 is methyl. 5. The method according to claims 2, 3 or 4, wherein said method is carried out in the presence of an inert solvent such as dioxane, chloroform, methylene chloride or Gly-me. (I) 10th