DD225131A1 - PROCESS FOR PREPARING 2-SUBSTITUTED 3,4-DIHYDROCHINAZOLIN-4-ONE - Google Patents

Abstract

The invention relates to a method of producing 2-substituted-3,4-dihydroquinazolinone-4-one by desamming the corresponding 3-amino compounds. SUCH CHINAZOLINONE ARE CNS EFFECTIVE COMPOUNDS. A METHOD OF DETERMINING ANTIHYPERTENSIVELY EFFECTIVE PHARMACY UNDER THEM IS TO DETERMINE THE INHIBITION OF ANGIOTENSIN I CONVERTING ENZYME THROUGH THE SUBSTANCES TO BE TESTED. FIELD OF APPLICATION OF THE INVENTION IS THE PHARMACEUTICAL INDUSTRY.

Description

Process for the preparation of 2-substituted he 3,4-dihydroquinazolin-4-one

Field of application of the invention

The invention relates to a process for the preparation of 2-substituted 3,4-dihydroquinazolin-4-ones and to a method for determining relationships between the structure of 2-, substituted "quinazolones" and their biological, dissociation · Such quinazolones are known as ZHS-active substances and have found application as anaetics and antihypertensives »

Areas of application of the invention are the active ingredient research and the pharmaceutical industry ·

Characteristic of the known technical solutions

The 2-substituted quinazolines are known in large numbers (Johne, S ", Progress in Drug Research, Vol · 26, 1982, 259,341) also their use as antihypertensive agents and as compounds having antimicrobial properties is also _e 3,4-dihydroquinazolin-4 -one substituted in the 2-position and derivatives derived therefrom have already been described and presented as substances with antiallergic, antihypertensive and antiinflammatory properties (Johne, Se a «aQ ·) · 2-amino-3,4-dihydroquinazolin-4 one have been prepared in various ways, such as from the corresponding 2-halogen compounds (Pesson, M. and D. Sicher, "C" R, Hebrew. Seances Acad * Sei, 260 (1965), 603), 2-Sulfo2y-4 (3H) quinazolinones (Manolov, 3 *, Compt "Send Acad" Bulgare Sei, S (1965), 243; C, A. 62, (1965), 4291) or from the corresponding 2-alkylthioene bonds

(Gupta, CM; AP Bhaduri and Έ.M. Khanna, Indian J. Gliem, 8 (1970), 1055; Gupta and co-workers, J. med. Chem. VJ_ (1968), 392).

2-anilino-4 (3H) quinazolinones have also been described as compounds which are said to be useful as fungicides against late blight and as antianaphylactics and anti-rheumatics (DD-WO 62 062 and 137 713, Dymek, W. and Lucka-Sebstel, Diss. Pharm. Pharmacol., 20, 43 (1968) and ibid., 21, 195 (1965), Grout, RJ and MW Partrigde, J. Chem. Soc. (London) 1960, 3540, Tayler, SC and RY Ravindranathan, J. Org. Chem. 27, 2622 (1962);

U.S. Patent 4,079,057).

Relationships between the structure of 2-substituted · quinazolinones and their biological activity have not been described. When angioterisin I-converting enzyme (ACE) / SO 3 · 4 · 15 · 1 / pure purine, ζ. B. ACS isolable from porcine lung (molecular weight: 270,000, SDS-polyacrylamide gel electrophoresis, electrophoresis uniform, activity: cleavage of 80,000 nHol of Hip-His-Leu per 1 mg of Snzyme protein (Iowry, 0H, UJ. Rosebrough, AL. P'arr and R.J. Randall, 1951, J. Biol., 193, 265-275), at 37 ^° C per minute) _; The inhibition of ACS by 2-substituted quinazolinones can be determined.

Object of the invention

It is the object of the invention to provide · biologically active heterocycles of the 2-substituted-3,4-dihydroquinazolin-4-one type which act as antihypertensives as well as antihistamines and show connections between the structure of 2-substituted quinazolines and their biological activity.

Explanation of the essence of the invention

It is an object of the invention to develop a process according to which 2-substituted 3,4-dihydroquinazolin-4-ones can be prepared and to show a method according to which relationships between the structure of 2-substituted quinazolines and their biological activity are determined to let. The object has been achieved by reacting 2-substituted-3-amino-3,4-dihydroquinazolin-4-ones of the formula II,

HUO,

in the E ¹ EH aryl with aryl - CgH ₅ , CgH, Hal (halogen = Cl, Br) and H = H, halogen, with nitrous acid too

the 2-substatuted 3,4-dihydroquinazolin-4-ones of. IOR

, -j ο * '- · ^: · ^:

mel I, in which E and E have the meaning given in formula II. The method for determining the relationship between the structure of quinazolinones and their biological effect is to determine the inhibition of angiotensin I converting enzyme (ACE) by quinazolinones. '

In the case of the method developed according to the invention, quinazolinones develop a biological effect in the sense of inhibiting ACE / E.C.3.4.15 · 1 /, depending on their substitution. Thus, such yer

i75

compounds for use as antihypertensive drugs ».

The relationship between the structure of substituted quinazolinones and the extent of the biological effect (ACE inhibition) is shown in Table 1.

1. Quinazolinones which contain substituents 2 in position 2, which have a +! Effect on the quinazolone base due to a free electron pair, cause marked ACE inhibition (cf., 5 and β compared to 15).

2 'This ACl inhibitory effect is favored by a further enhancement of this + M effect, which follows from its structural features (+ I / + M effect) (compare 1 and 2 with 5 and 6),

3 "In contrast, quinazolinones whose substituents in position 2 do not possess a free electron pair and thus do not undergo additional amplification of the mesomerism in the ghinazolinone parent have lower or no ACE inhibitory effects (compare 15 with 1 to 6).

In cases in which the quinazolinone substitution in position 2 is part of a fused-on heterocyclic ring system (z * B.uriazole), the biological ACE-inhibiting activity is retained if continuous mesomerism is not restricted (cf., for example, 38, 39 and 40).

5 · Pur the Pail mentioned in point 4 is the ACE inhibitor. This action can be compensated by preferably met all binding end substituents in the fused thiazole ring (ζ · β _β thiocarbonyl), which probably inactivates primarily enzymatic Zn, (see, for example, US Pat. 24 to 34 with 35 to 3?) O

β "The extent of the ACE-inhibiting activity of the substituted quinazolinones in position 2 is still subject to substitution.

in position 3 and on the adjacent aromatic compounds or the structural features of these substituents. Larger hydrophobic residues than substituents in position 3 on the quinazolinone lead to the enhancement of ACE inhibition (see sections 1 to 4, 13, 14, 35 to 37). Also substitution of the aromatic ring in the quinazolinone with hydrophobic substituents leads to the promotion of the ACE hemi-action (compare 10 with 7 to 9, 16 to 13 with 19 and 20, 33 and 34).

7. The fact that the ACE inhibition by the substituted quinazolinones is not only a relatively nonspecific blocking of the Zn essential for the enzyme action, is expressed by the fact that four representative compounds ("4, 6, 22, 37) are relative good ÄCE-H emmwirkü'hg leucine aminopeptidase, for their effectiveness also Zn is essential, in concentrations of 200, UM practically not inhibit.

If desired, suitable 2-substituted 3,4-dihydroquinazolin-4-ones can be mixed with pharmaceutical carriers and converted into their pharmaceutical administration form. ·:

The invention will be explained in more detail with reference to embodiments.

24 8.84-01 33737

Embodiment 1 e Example 1:

2- (p-Bromophenylamino) -3- (4-dihydroquinazolin-4-one) 0.05 mole of 2- (p-bromophenylamino) -3-amino-3,4-dihydroquinazolin-4-one are dissolved in 250 ml Hydrochloric acid dissolved or suspended. The mixture is cooled to 0 to -5 ⁰ C. To this is added dropwise 7.0 g of HaHO ₂ , dissolved in 100 ml of water. It is constantly being stirred. The precipitate formed in the reaction is filtered off with suction after 3 hours, washed with water and dried on a clay plate

Yield: 80% d. Th. Schinb. 285 to 290 ⁰ C (n-butanol)

C ₁₄ H ₁₀ BrI ₃ O (316.2). I about 13.29. N gef. 13.26.

Example 2:

2- (p-Bromophenylamino) -6-bromo-3 ^ 4-dihydroquinazolin-4-one As Example 1, only 2- (p-bromophenylamino) -3-amino-6-bromo

3,4-dihydroquinazolin-4-one as the starting material.

Yield: 95 % of theory

Schmb. 337 to 340 ^° C (n-butanol).

C ₁₄ H ₉ Br ₂ H ₃ O (394.9). IT about .10.64. H gef. 10.55.

Example 3:

2- (p-Chlorophenylamino) -3 _< 4-dihydroquinazolin-4-one

As Example 1, only 2- (chlorophenylamino) -3-amino-3,4-dihydro-

quinazolin-4-one as the starting material.

Yield: 93 % d. Th.

Schmb. 282 to 287 ⁰ C (n-butanol).

C ₁₄ H ₁₀ ClI ₃ O (271.7) H ber. 15.46. Έ closed 15.73.

Example 4:

Determination of Inhibition of Angiotensin I Converting Snzyme

(ACB) ; ;

The determination of the inhibition of ACE by substituted quinazolinones was carried out using a pig's lung isolated ACE (molecular weight: 270,000, electrophoretically uniform, activity: cleavage of 80,000 nmoles of Hip-His-Leu

per 1 mg of enzyme protein (Lowry) at 37 ^° C. oro minute).

The procedure was as follows:

Assays consisting of 240 / al 0.11 M potassium phosphate buffer (pH 8.3), which is 0.33 M SaCl, and AGE activity of 0.2 nHol Hip-His-Leu cleavage / min. are added, with 5 / ul inhibitor solution (solvent, dimethylformamide) and preincubated for 30 min. At 37 ⁰ C. With the addition of 10 μl of Hip-His-Leu aqueous solution (0.025 M), a 30-minute enzymatic reaction is started. Reaction is terminated with 1.45 ml of 0.28 IT UaOH. The liberated His-Leu is with 100 , υΐ methanolic o-phthalaldehyde solution (reaction time 10 min.) In a fluorescent complex transferred. After addition of 300 / μl of 2 U HCl, the fluorescence is measured in the spear at 365 nm after 45 min. The standard is a substrate-free sample containing 10 μl of a 0.5166 H aqueous His-Leu solution.

The inhibitory activity is expressed by the inhibitor concentration, which causes an enzyme inhibition of 50 % under constant working conditions (test procedures, enzyme activity)

Example 5 · Determination; the inhibition, the LAP activity

The determination of the inhibition of LAP activity was carried out using a commercially available LAP preparation (Serva). The procedure was as follows:

Test mixtures consisting of 100, μl 0.2 M Tris-HCl buffer (pH 8.0), 100 μl of water, 10 μl of inhibitor solution (solvent: dimethylformamide), 50 μl of Snzyme solution (15 μM LAP in 50, μl of Tris buffer (0.2 M, pH 8.0) and 15 μl / μl aqueous 0.125 M leucine amide solution are incubated at 37 ° C for 150 min, then 300 μl of the test mixture are added to the inner container of micro diffusion chambers (according to COMAY) in which There are already 300 μl of saturated potassium carbonate solution, and the outer chamber of the diffusion cell contains 1.5 ml of 0.16 M boric acid.

After 3 hours * the determination of ammonia by means of hinhydin staining in the usual way is carried out in 500 μl of the outer chamber. The evaluation of an inhibitory activity is carried out as in the pail of the ACE inhibition (iC-Q values). Because of the expected interactions between the inhibitors used and the Mn ⁺⁴ "- and Mg ^ ions usually added during IAP determinations - were hereby made aware of additional heavy metals.

L'abel le 1 : ACE-inhibitory activity of quinazolinone derivatives

Substituents former structure No. R. H ₀ R ~ Ar

r. ^H 1 ^H 2 H 1 SH. H H 2 SH H H 3 SH H H 4 SH H

IC 50 " -Value -b M 80 X 10 -6 M 45 X 10 -6 M 7 X 10 -6 M 4.7 X 10

C ₆ H ₄ OCH ₃ (P) (

^C 6 ^H 4 ^OC 5 ^H 11 ^(P)

5 S-CJL ₇ Br II CH _Q (CH _Q ) _o (m, p) 7.5 x 10 " ⁵ M

3 7 6 3 3. 2. ^ ₆

6 SO ₄ H ₉ Br HC ₆ H ₃ (CH ₃ ) ₂ (in, p) 4.5 x 10

H H 6 4 ° H H W H H ^C 10 ^H 7 br br C ₆ H ₅ br H

7 NH-NH ₂

8 NH-NH ₂

9 NH-NH ₂

10 NH-NH ₂

11 NH-NH ₀

12 NH-NH ₂ Br HC ₆ H ₃ (CH ₃ ) ₂ (o, rn)

32 X 10 -b M 35 X 10 -6 M > 100 X 10 -6 M 19 X 10 -6 M 55 X 10 -6 M 50 X 10 -6 M

13 NH-NH-CO-NH-C ₆ H ₅ HHC HjCiCp ₆₎ 9 x 10

14 NH-NH-CO-NH-C ₆ H ₅ HHC ₆ H ₄ Br (P) 7.5 x 10 ~ ° M

15 SO ₂ -C ₂ H ₅ HHC ₆ H ₄ Cl (P) 200 χ 10 " ⁶ ^

I νθ -P I U O τ ~ ω M O ο H ιη tn ο ιη ιη H

C ~ \

OJ

ftf

! 4 -P CQ

Φ A ο

νο 1

so

O O

ιη ιη VO O M O ιη νο W ο O νθ VO O O

ffi

? 4

γ-Ι O

ΟΊ

m χ

CVJ

ο ο ο

O OO OO ν \ /

O O π Il &

O O ii Il I

OO

νο I

νο I

X ιη

ιη

VO O

VO

CVJ

ιη

Ά / -ν

V- ^ P)

τ- ν- /

τ-CT ¹

in <t

ο o

1 i

ιη ιη

νο οο ο ο

ΓΛ

ο I

CMJ CM

νο

I ι O CQ O O ι 1 χ a % % ι

CVJ

substituents

cheiru structure I No R ₁ ^R 2 R ₃ ^IG 50 -Value -6 M 24 CH ₃ C ₁₀ H ₇ H > 100 χ 10 ~ 6 M O 25 II C ₁₀ II ₇ H > 100 χ 10 -6 M 26 COOC ₂ H ₅ C ₁₀ H ₇ H > 100 χ 10 -6 M ) - 27 C ₃ H ₇ C ₁₀ II ₇ H > 100 χ 10 -6 M 28 CHO C ₆ H ^ OCH ₃ Cp) br > 100 χ 10 -6 M 29 C ₆ H ₄ OCH ₃ Cp) br > 100 χ 10 -6 M 30 C ₃ H ₇ C ₆ H ₄ ClCp) br '130 χ 10 -6 M 31 G ¹ H ₃ C ₆ H ₄ CH ₃ Co) H > 100 χ 10 -6 M 32 CH ₃ C ₆ H ₃ CCH ₃ ) ₂ Cp , ra) Br 90 χ 10 -6 M 33 C ₁₀ H ₇ H > 100 χ 10 -6 M 34 C.II, OCiU Cp) Br 67 χ 10

anyway, structure

No.-

R

,-Value

J-

 0

C ₆ H ₄ Gl (P) C ₆ H ₄ Br (P)

SH

^G 6 ^H 5

Br Br

Br Br Br

100 χ 10

C ₆ H ₄ Br (P) C ₆ H ₄ Br (P)

br

35 x 10 * " ⁶ μ 6 χ 10 ~ ⁶ M

38 x 10 ~ ⁶ sts

5 x 10 " ⁶ sts

63 x 10 ~ ⁶ sts

Claims (3)

Injury 1 · Process for the preparation of 2-substituted 3,4-dihydroquinazolin-4-ones, characterized in that 2-substituted 3-amino-3,4-dihydroquinazolin-4-ones are deaminated * 2 · Method according to item 1, characterized in that 2-substituted 3-amino-3> 4-dihydroquinazolin-4-ones of the mel II) '. in which R = H ^- H-aryl with aryl = CgH ₅ , CgH.Hal (halogen = Cl, 3r) and E = H, halogen, with nitrous acid see below the .2-substituted 3,4-dihydroquinazolin-4- ones Λ η - -. - -. · ..; ν, -. ·. ...... Pormel I in which R and R have the meaning given in formula II