CA2026318A1

CA2026318A1 - Use of oxoquinazoline derivatives

Info

Publication number: CA2026318A1
Application number: CA002026318A
Authority: CA
Inventors: Helmut Ensinger; Franz Birke; Ilse Streller; Kurt Schromm
Original assignee: Individual
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1989-01-30
Filing date: 1990-01-27
Publication date: 1990-07-31
Also published as: IL93202A0; DE3902639A1; WO1990008546A1; KR910700050A; IE900317L; AU5026390A

Abstract

Abstract For the treatment of cytotoxic effects, e.g. damage after ischaemia and for cardioprotection, it is proposed to use compounds of formulae (I), (II), (III) and

Description

2 ~ 2 ~ 3 1 8 The invention relates to the use of oxoquinazoline derivatives in the treatment and prevention of damage in which cytotoxic processes are largely implicated.
In cytotoxic processes, xanthinoxidase plays an important part. Xanthinoxidase brings about, inter alia, the increased reaction of xanthine and hypoxanthine to produce uric acid. This results in the formation of oxygen radicals which cause irreversible cell damage.
Furthermore, this enzymatic reaction causes xanthine and hypoxanthine to be removed from the pool of purine moieties, which would be capable of supplying new ATP through the salvage circle. This ATP is essential for re-establishing the homeostasis of damaged cells.
By inhibiting the enzymatic activity of xanthinoxidase it is possible to prevent both the formation of oxygen radicals and the depletion of the purine moieties (for the production of ATP).
The oxoquinazoline derivatives defined hereinafter are characterised in that they have, inter alia, a strong inhibitory effect on xanthinoxidase. The compounds arè therefore suitabl-e for use in diseases in which cyto~rotection has to be achieved.
A major group of diseases in which the oxoquinazoline derivatives mentioned below may be ; successfully used are connected with ischaemia (e.g.
cardiac, cerebral, gastrointestinal, pulmonary, renal ischaemia, ischaemia of the liver, ischaemia of the skeletal musculature). Corresponding diseases include, ' for example, coronary heart disease, angina pectoris, embolism in the circulation of the lungs, acute or chronic kidne~y failure, chronic kidney insufficiency, brain infarct, chronic blood flow disorders in the brain.
It is known that, for example, in the reperfusion ~; of the ischaemic heart (e.g. after an attack of angina pectoris or cardiac infarct) irreversible damage occurs : .
: .

", :,, " : ~ : . - :

-``` 2~3~ 8 to cardiomyocytes in the affected region. The contractile force of the heart is reduced, there is a loss of energy-rich phosphates (ATP, PCr) which is also caused by the rapid metabolism and washout of the nucleotide precursors adenosine, inosine and hypoxanthine.
In the important cardioprotective field of application, the compounds which may be used according to the invention not only demonstrate the desired cardioprotective activity but surprisingly improve the contractility of the heart as well.
When used to treat ischaemia, there is also the prevention of damage which might occur as a result of reduced blood flow in the case of transplants.
However, the cytoprotective activity is not -restricted to the consequences of ischaemia but may be used in general whenever the above-mentioned biochemical process, particularly the effects of xanthinoxidase, have a major influence on the course of the disease.
Examples include Crohn's disease, ulcerative colitis, arthritis, pancreatitis and Lesch-Nyhan syndrome.
Suitable compounds for use according to the invention are the compounds according to German Offenlegungsschrift P 25 57 425 (or French Application No. 76 38 ~35) and European Patent Application O 113 911. -~
The most important groups can be characterised by the following formulae I to IV and the associated definitions~

~ ' - ,.,,~ .' I` .
2~2~3~ ~

I. Compounds of formula Rl (I) wherein Rl to R4 are defined as below: :

Compound Rl Rz R3 R~

(a) COOH H H H

N - N
( b ) ~ H H H
`N -- N

H

H H N CH(CH~)z o ~ (d) COOH- N H H CH(CHZ)z (e)~ CONH~l H H CH(CH3)2 H
' ( f)~' ~ H H H COOH

~ ~ (g) CH~ H H COOH

; (hj CH30 H H COOH

.

~ :
"~

L:.

` 2~c~

Compound R1 Rz R3 R4 .
(i) Cl H H COOH

(j) Br H H COOH

(k) -CH=CH-CH=CH- H COOH

(1) C2H50 H H COOH

(m~ CH(CH3) 2 H H COOH

(n) CH(CH3)2 H H COOH

(o) COOH H H CH3 p) CH(CH3)2 H H
N
: -:
H ; :-~

The entire group 4 :~ 3 ~

:~; -' ~:.~:
may also be replaced by the group ;~

j I ~ wherein R1 is COOH
:~ ~ ~ / and R2 is H (q) ~ ' ~
The majority of the compounds which may be used according to the invention specified here and hereinafter are already known, e.g. from DE-A 25 57 425, ~2&~

26 45 110, 28 12 586 and 33 15 471. Otherwise, the compounds, such as compound (c) and compound (~), may be obtained analogously to the methods described therein.

Elementary analysis:

% C - % H % N % S
(c) Calculated: 62.74 4.57 27.45 Found: 62.51 4.30 27.19 Melting point 251C (decomp.) (q) Calculated: 60.81 2.70 9.46 10.82 : `Found: 60.99 2.80 9.26 10.80 II. Compounds of formula R
H~ R (II~

wherein R1 and R2 are defined as follows:

.:~ Compound R~ R

(a) H H
(b) CH(cH3)2 H
; ' (c) ; CH3 H
(d) Cl H
(e) CH30 H
(f) CH(CH3)2O H
(g) ( 2H5 : (h) -CH=CH-CH=CH-.

l ~" , , " ,.", . ..
,,"~ ~

2 ~ Y

III. Compounds of formula O N _ N

R

R2 , ,~, ~
wherein R1 and R2 have the following meanings: ;;

; Compound R1 R2 ;

:~ (a) H H
(b) CH3 H
~: (c) CH(CH3)2 H
`~ (d) H CH3 ::
(e) C2H5 H -~

IV. Compounds of formula : R ~ N

wherein R1 and R2 are defined as follows: ~ ~

: ~ Compound Rl R2 ~-~, ~
:`` (a) H H
(b) CH3 H
(c) CH(CH3)2 H ~:

:

8 2~2~3~

The entire group R ~

R2~/

may also represent ~ ~\S/
~: :
(Compound (d)).

Most of the compounds of groups II to IV are known from European Patent Application 113911, for example. The new compounds III(c), III(d), IV(c) and IV(d) may be obtained analogously.

Elementary analysis:

~ % C % H % N % S
;~ III(c) Calculated: 64.50 4.6g 25.08 ~; Found: 64.11 4.44 25.23 ~; III(d) Calculated: 62.15 3.61 27.89 Found: 61.16 3.42 27.35 IV(c) Calculated: 64.50 4.69 25.08 Found: 64.73 4.31 24.76 IV(d) Calculated: 57.33 2.39 23.89 10.93 Found: 57.74 2.16 23.50 10.62 ~ , The above compounds of formulae I to IV have already been described as pharmaceutical substances. -~
The fields of application specified were: the prevention and treatment of allergic diseases such as asthma, 2 ~

hayfever, conjunctivitis, urticaria, eczema and dermatitis. A muscle-relaxant (bronchodilatory) and vasodilatory activity were also mentioned. However, there is no reference to the new possible applications according to the invention.
The LD50 (mouse) is low. Compounds of formula I
administered orally have an LD50 f more than 3000 mg/kg and intravenously more than 800 mg/kg. For the compounds of formulae II, III and IV which are generally much more effective, the oral LD50 in the mouse is over ;~
300 mg/kg.
For use, the compounds were processed in the usual way with known excipients and/or carriers to form conventional galenic preparations, e.g. tablets, suppositories, granules, suspensions and delayed release ;~ ;
forms, and injectable solutions and infusions.
The daily dosage by oral route is about 100 to 1000 mg; it may be administered in one to three single doses. When injectable solutions or infusions are used, ;~
much lower dosages are generally possible.
Whilst solid preparations are generally used for preventive treatment, in acute~cases the use of injectable solutions is preferred.

Examples of formulations ~ - .
1. Tablets ll-Oxo~ H-pyrido[2,1-b]-' quinazolin-2-carboxylic acid100 g Colloidal silica 10 g Lactose 118 g Potato starch 60 g Polyvinylpyrrolidone 6 g Sodium cellulose glycolate4 g Nagnesium stearate 2 g : ::::

-2~3~ 8 The ingredients are processed in the usual way to form tablets weighing 300 mg.

2. Capsules Active substance of formula I, II, III or IV . 300 g Corn starch 100 g The ingredients are thoroughly mixed and the mixture is packed into oblong gelatine capsules in batches of 400 mg.
~ ( '~
`: ' , :

,, ~ :

, .

~ ~ 2 ~

Pharmacoloqical and biochemical_investigations 1. Inhibition of xanthinoxidase The inhibitory constant Kl [mol/litre] is used as a measurement of the inhibition of xanthinoxidase. It was determined in the usual way for a representative ::
selection of the substances which can be used according ~ ~ -to the invention.

Compound K1 value [mol/litre] -~

Formula I (a) 8xlo 5 ~ :.
( (b) 4x10-6 :~
(d) 6x10-6 (h) 2x10-5 (j) 4Xlo~6 (k) 5x10-6 (~) 2xlO

Formula II (a) 3xlO 8 (b) 4xlO-9 - .
(c) 2xlO
(d) 2x10-8 (e) lx10-8 :
-, (f) 4xlO 9 ~ ~
(g) lxlO~8 Formula III (a) 5x107 (b) 2x10-7 (c) 2X10-8 .
Formula IV (b) lx10-5 (d) lx10-5 -:
~,. .
: ~

-` 2~ 31! ~
.

2. Demonstration of cardiorotective activity on the isolated vital heart The intracellular concentrations of the high-energy phosphates adenosine triphosphate (ATP) and creatine phosphate (PCr) reflect the energy state of the cells.
From the content of high energy phosphates the muscle cell supplies the energy requirements for the work of contraction and ion homeostasis. For this reason, ATP
and PCr constitute the basal biochemical parameters for the vitality of the cells.
The method of nuclear spin magnetic resonance of natural 31-phosphorus ( 31p NMR) was used to provide a continuous and non-destructive measurement of the high energy phosphates of the isolated heart. All the measurements were taken using an AM 300 spectrometer made by Messrs. Bruker.
On an isolated, retrogressively perfused rat heart (Langendorff heart) the physiological parameters of isovolumetric contractile force, heart rate and coronary flow were recorded continuously. The measurement of heart performance used was the product of the contractile force (amplitude) ànd heart rate (RPP = rate pressure product). The test procedure includes a period of control perfusion (15 minutes without test substance) followed by preliminary perfusion (30 minutes, with test substance in the perfusion), anoxia (30 minutes with N2 bubbled into the medium) and a reperfusion phase (45 minutes).
The table of results demonstrates the change in the measuring parameters of RPP, ATP and PCr during this procedure, comparing control hearts (without the test substance) with test hearts (1 x 10-qM test substance, in this case compound (a) of formula II).
The test substance raised the PCr level significantly during the period of anoxia from 38% to 58% of the initial level. During the reperfusion phase the hearts attained significantly higher ATP and PCr 2 ~ 8 levels in the presence of the test substance. The ~:~
contractility of the heart was also improved (the :
cardioprotective effect of the test substance is not accompanied by a cardiodepressive effect).

tt . ~-: ,.. , ,:
,.,~, : ' t , ~ :

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,~ +' o ~, . .
+l +, ~' ~C ,i a~
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+' +' ~. ~
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o I +~ I ~
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X ~
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H ~ ~ ~i _ ~ o 0 ~ P- : JJ 11 .C ~i 11 ~i ~J R ~
3i l~ i.4 i ` : : :

--- 2 ~ 3 ~
.

3. Cardioprotective effect on isolated rat he_rt (Langendorff heart) Investiaations on the isolated Langendorff heart Nethod Isolated rat heartj, retrogressive perfusion through the aorta. Electrical stimulation (300 pulses per minute, duration of pulse 1 msec). Measurement of the pressure developed in the left ventricle using a liquid-filled latex balloon. After 20 minutes equilibration, a state of oxygen depletion is created with a 100-fold reduced flow by constricting the perfusion flow for 60 minutes, the return to normal flow brings about a sharp increase in the base voltage, under control conditions the activity of the heart is reestablished irregularly after 6 to 7 minutes and after 15 to 18 minutes there is a rapid transition to regular contractions. Compounds with a cardioprotective activity shorten the time taken for regular contractions to be established. Infusion of the test substance (dissolved in perfusion medium with no gas introduced therein) during the period Of 2 depletion into the perfusion system close to the heart.
~ With the compounds according to the invention, e.g.
compound (a) of formula II, a protective effect is achieved even with concentrations of less than 30 mg/ml.

1~1.~,: : I , . I

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Claims

1. Cytoprotective agent, characterised in that it contains a compound, optionally in salt form, of the following formula (I) wherein the substituents R1, R2, R3 and R4 in this order represent (a) COOH/H/H/H, (b) Tetrazol-5-yl/H/H/H, (c) Tetrazol-5-yl/H/H/i-propyl, (d) COOH/H/H/i-propyl, (e) Tetrazol-5-yl-NHCO/H/H/i-propyl, (f) H/H/H/COOH, (g) CH3/H/H/COOH, (h) CH3O/H/H/COOH, (i) Cl/H/H/COOH, (j) Br/H/H/COOH, (k) R1+R2 equals -CH=CH-CH=CH-/H/COOH, (l) C2H5O/H/H/COOH, (m) OCN(CH3)2/H/H/COOH, (n) CH(CH3)2/H/H/COOH, (o) COOH/H/H/CH3, (p) CH(CH3)2/H/H/Tetrazol-5-yl or (q) the entire group represents or (II) wherein the substituents R1/R2 represent (a) H/H
(b) CH(CH3)2/H, (c) CH3/H , (d) Cl/H, (e) CH3O/H
(f) CH(CH3)2O/H, (g) C2H5/H or (h) together represent -CH=CH-CH=CH- or (III) wherein the substituents R1/R2 represent (a) H/H, (b) CH3/H, (c) CH(CH3)2/H or (d) H/CH3 (e) C2H5/H
or (IV) wherein the substituents R1/R2 represent (a) H/H
(b) CH3/H or (c) CH(CH3)2/H, together with conventional excipients and/or carriers.

2. Agent for preventing organ damage after ischaemia and for cardioprotection, characterised in that it contains a compound of formula I, II, III or IV
according to claim 1 together with conventional excipients and/or carriers.

3. Use of compounds of formulae I, II, III or IV
according to claim 1 for the preparation of pharmaceutical compositions for cytoprotection.

4. Use of compounds of formulae I, II, III or IV
according to claim 1 in the treatment and prevention of diseases in which cytotoxic effects are implicated to a critical extent, particularly those wherein xanthinoxidase plays a major part.

5. Use of compounds of formulae I, II, III or IV
according to claim 1, for the preparation of pharmaceutical compositions for the prevention of damage after ischaemia and for cardioprotection.

6. Use of compounds of formulae I, II, III or IV
according to claim 1 in the prevention of damage after ischaemia and for cardioprotection.