SI8710906A8 - Process for preparation of 1-(hydroxystyrol)-5h-2,3-benzodiazepine derivatives - Google Patents

Description

DERIVATE 1- (HYDROXYSTYROD-5H-2,3-BENZODIAZEPINE

Technical field

The invention is from the field of organic preparative and pharmaceutical chemistry.

Technical problem

The present invention relates to novel 1- (hydroxystyrene) 5H-2,3-benzodiazepines α-derivatives of general formula (I) and a process for their preparation further to pharmaceutical preparations containing the same,

R '

R 0 CH -

where

R represents a hydrogen or halogen atom or a C 1-4 alkoxy group,

R represents a hydrogen atom or C ^^ alkyl, a smaller group, _su ig-fci i označavaju G ^ _ ^ alkyl group or kombinovani označavaju methylene smaller group.

In the above definitions, the term halogen denotes chlorine or bromine, the term C 1-6 alkyl denotes a norraalane or ralvate chain saturated aliphatic hydrocarbyl groups containing one or more carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, etc.).

The state of the art

The compounds of general iormula (1) are novel and possess a new type of positive inotropic (cardiotonic; effect unknown among 5H-2,3 ~ benzodiazepine derivatives described in the literature (U.S. Patent No. 5,775,515 and Belgian Patent Specification Nos. 879, ^ .04 and 902.955). 8

Carrying out a technical problem with performance examples

Preferred representatives of the compounds of general formula (I) are those described in the examples.

Particularly preferred representatives of the compounds according to the invention are the following derivatives:

l- (4-hydroxystyryl) -4-methyl "7,8-dimethoxy-5H-2 ₁ $ benzodiazepine, l- (2-hydroxystyryl) -4-methyl-7,8-dimethoxy ^_" 5H-2,3- benzodiazepine, and 1- (4-hydroxystyryl) -4-methyl-7,8 ~ diethoxy '5H-2,3-benzodiazepine.

The invention further provides a process for the preparation of a compound of general formula (I), characterized by the reaction of 2-beazopyrilium perchlorate of general formula (II) 'CH

II

R OH ρ χ where R, R, E and R have the meanings defined, in the hydrazine hydrate solvent.

Polar or non-polar solvents, preferably water, C1-6 alcohols, dioxane, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, pyridine, or mixtures thereof, are used as solvents.

The reaction is carried out between 0 ° G and the boiling point of the solvent, preferably in the temperature range + 10 ° C to + 12O ° C.

Concentrated, preferably 90 to 100% hydrazine hydrate is used in preferably quadruple excess.

According to a preferred embodiment of the process, the inventive 1 mol of 2-benzopyrilium perchlorate of general formula (II) in aqueous 95 to 100% ethanol with three moles of 90 to 100% hydrazine hydrate at room temperature for several hours is then evaporated. The crystalline residue is treated with warm water to remove by-products and the final product is filtered and purified, if desired, either by recrystallization or by resuspension in warm alcohol.

According to a further preferred embodiment of the method, the inventive compound of general formula (II) is suspended in solvent and the reaction mixture is refluxed one hour after the addition of 3 moles of 90 to 100% hydrazine hydrate. During the reaction, the by-products are gradually deposited. After completion of the reaction, the mixture was evaporated under reduced pressure. The crystalline residue was treated with warm water to remove by-products, the final product was filtered off and purified, if desired, either by recrystallization or by reflux in ethanol.

According to another preferred embodiment of the method, the inventive compound of general formula (II) is added to a mixture of 3 moles to 100% hydrazine hydrate and dimethylformamide at 5 to 10 ° G, and the reaction mixture is left to cool. Upon addition of water, the by-product is precipitated from solution. This crystalline mass was washed with water to remove by-products and, if desired, purified either by recrystallization or by reflux with ethanol.

• The starting compounds of the general formula (II) used in the process are, in part, novel and partially known derivatives.

New compounds can be prepared according to the procedures described in the literature: Khim.Heterocycle. Soedin. 1970 .1503 /C.A. 74.

76295 (1971) /, same. 1975, 568.1458 / C.A.^, 18629 (1975),

80, 70649 (1974).

N these compounds of the general formula (I) of the invention possess valuable positive inotropic (cardiotonic) effects which have been confirmed in vivo by experiments carried out according to the following procedures. The known compounds isoproterenol (B-isopropylnoradrenaline hydrochloride) and amrinone (5-amino-5,4'-dipyridyl6 (1H) -one) serve as reference compounds.

Methods

A) Tensimetric method in open-breasted anesthetized cats

Male and female cats were anesthetized with a 1: 5 mixture of chlorazurethane and artificial respiration was performed via a windpipe with a Howard 665 A respirator. ^χ οΐ3β of the opening of the chest bag, the tensimeter is sewn to the epicardium of the left ventricle according to the Walton and Brodie method /J.Pharmacol.Eyp. ^x her.90, 26 (1947) and measured mycardial contractile. force (MCE). The arterial blood pressure was continuously monitored by an electrometer via a catheter inserted into the femoral artery and connected to a Statham P 25 Bb transducer. The heart rate is continuously recorded with the help of a pulse tachometer. Test compounds were injected intravenously through a vein. Fifteen minutes before each experiment, the reactivity of the rat's heart was correlated with intravenous administration. 0.2 / ug / kg isoproterenol. In these experiments, isoproterenol is not used as a common reference compound. Partially used to control sensitivity! of the tested system and. partly to test the strength of the compounds tested. The relative potency of the test compounds is expressed by comparing the effect induced in HCP by 5 mg / kg iv of the test compound with that of 0.2 ^ ug / kg iv isoproterenol in the same cat, thiobium values are good indicators of the positive inotropic effect of the compound as individual sensitivity

Al an animal that can be ruled out this way. The results are shown in Table 1.

Table 1

single dose Relative power compared to isoproteranol duration ' effect min. HR min ?! * A Hgmm ij · cf. br ·, • i.v. mg / kg 1 5 2.04 50 ♦ 40 -35 \ .2 5 1.56 14 ♦ 35 -33 4 5 0.25 2 ♦ 5 ♦ 23 6 5 1.14 8 ♦ 55 -26.6 7 5 4.00 80 ♦ 70 -50 Aarinon 5 1.50 > 60 +40 -28.3 Isoprote- renol 0.2 South / kg 1 4.76 .5 44.5 -33.05

HR: Change in heart rate

P ^: change in systemic arrest blood pressure

B) Anesthesia examination with open chest breasts

Myocardial power (MCE) was measured according to the procedure described in A) and coronary flow changes were monitored using an electromagnetic flowmeter.

The compound of Example 1 was administered iv at doses of 0.25, 0.5, and 1.0 mg / kg and the results are given in Table 2. The increasing MOF effect was dose dependent, both in amount and in length of action. while the coronary flow was only slightly increased. l-iCE and coronary effects of 2mg / kg iv, the amrinone used as the reference substance is achieved by the compound according to the invention already at an immediately low dose such as 1 mg / kg. The specific advantage of the compound is inventive in that the changes induced in systolic and diastolic blood pressure do not exceed 10%. Favorably fact pronalska compounds in itchaemična of heart diseases is an additional advantage jedinjenja.Miokardična ischaemia is izazvana pressing silaznog part of the left coronary artery, ^"with increased power MCE compounds from Example 1 men be Merena zag flow reperfusion (business prekidnog pritiskivanja).

G) Testing on conscious cats with a tube inserted

The experiment was performed according to the method of Babloczky and Mader (Measurement of Systemic and Pulrnonary Pressure in Conscious Animals, lecture at the Congress of the International ^{in the} Pharmacologists' Nation, Budapest, 1980) or a modification thereof. The aorta and pulmonary arrest are chronically catheterized to measure arterial pressure. In the modification, the right ventricle is also catheterized to determine the dp / dt value, ie MCE. The compound of Example 1 was administered orally (po) at doses of 1 and 2mg / kg. These doses do not cause significant changes in the systolic or diastolic blood pressure of the animals or in the heart rate. The increasing MCE effect is obtained over a period of 15 to 30 minutes, and remains at this considerable level for a further 60 to 90 minutes. The peak of the MCE increase goes from 20 to 25%.

The following in vitro experiments were performed to verify direct inotropic effects:

D) The compound of Example 1 elicits a dose-dependent positive inotropic effect in an electrically simulated, isolated rabbit ventricular papillary muscle. Low doses like 10 ^- ¾ already cause a considerable response, while a dose of 5 10 ^- ¾ causes a 200% increase.

E) The compound of Example 1 causes a dose-dependent MCF increase in the electrically stimulated isolated left atrial rabbit preparation, a modest increase of 15% of heart rate was found in the unstimulated right atrium preparation.

According to the data of Tables 1 and 2, the compounds of Examples 1 to 7 of the invention were shown to be the most potent. They reach or even exceed the activity of the reference amrinone compound.

According to biochemical studies, they show a positive inotropic effect by inhibiting the phosphodiesterase enzyme.

Not Cj • * «*.

A A

OJ ©

rrt «

0Γ .a © srt • Η

Ό p

rt άθ, Ρ • rt rt ©

rt ο

>

P ο

cti a

• rt

M

Pi

B • rt

S rt • rt co ©

P ro

9 'id rt ©

i

-rt •• H rt

S ©

• rt rrt «S rt ©

B • rt rt

P.

cd • ro rt ©

Ό rt • rt • rt ©

It ©

• O rt ©

• rt

P • rt

Pi ω

H rt ©

rt>

© §

co ©

>

© ©

a o

rt

P

A irt «Γ rt cn

5 ^>

S> P • rt © P B • rt © P rt M © • rt P ©

to rt ©

to rt • rt

A ©

TO n · a (N cr>

rrt

PH tn a • ♦ a a »rt A

H CN A rrt

A cn • · n ·

A

-H-l

CO »rt N * co

A A »« σι h o rt · • · n · σι A

A CO 8 "σι n ·" "

A A

A

PH

IA A • ·

From rrt I rrt rrt ^ nrrt ««

PH n a * · a m -H-l oo a. · M n · rrt • H-l

CN A a m -H-l a o

CN Ν 'i — I • rt rt rt ©

§ rt o

Λ4 * ~ r- O

TT rH + -H

SS n a

A A rH

-H-l

AN A A cn o A rrt PH a cn • *

About a

A A

A N *

A

PH

U * O O • · co cn CN

A A • «I

A a

CN

-H-l

Λί

Oh

P a N · · ·

A A A rrt PH a cn • · ·

A A A rrt r »a σ> n · rrt rrt ©

το r-i rt <y © • ro rt g

'4 1 © rt «o P * rrt co. · A A

A

X (You

A A

A

PH

A rrt • · A N · a n ·

A rrt

A 00 o a • · rrt A A

N · N · • · σι a A rrt σι a A »rt

N · rrt σ, n · • ·

A O N · rrt

X

A N · • · σ \

Ul <N | 00 • · · · 'CN

А А.

I ©

TO rrt rt ©

TO rt • rt Ό ©

Ά ffi rt ©

a p

rt p

σι A

A O A rrt

AN · rrt Ol • · a σι N · rrt

CO O A «rt

I

A | O ί rH • H rt rt o

rt .O

Ni rM

Oh

P

CO A * ·

A A A rrt -H-l

And what about?

I

CN N * O cn and n · co ιή

CN

-H-1 cn »h cn Γη

CN- CN • ·

CM kO

H

HM io in * ·

00 '00 CN σι in • ·

CN IO

Th cn m • · m and CN

-HM

CO CN * · co cn cn

-HM

H O • · cn co

Th rH CN «· cn cn? H

CO N * and cn cn • · m cn m <h -HM

S

P ω

ω β

cu

CO., LTD

H ω

cO n

H IO

Γ- ID and h HM

X io n * cn oo and rH and o • · «M rH and rH

LO in «

o

Cu,

About s:

cn rH and σι oo co

O <H c

o c

• H o

(N o

and · O O

Oh

V a,

In cu

According to a further feature of the present invention, new pharmaceutical compositions are provided which contain at least one compound of the general formula as the active ingredient. (I) together with one or more pharmaceutical carriers, diluents and / or additives. Pharmacopoeial preparations may also contain other biologically active substances, in particular other cardiotonic agents.

The pharmaceutical preparations may be made in solid (such as tablets, coated tablets, capsules, etc.) or in liquid form (such as solutions, suspensions, emulsions, etc.). ^{A, and} axes can be commonly used in pharmacy (e.g., starch, magnesium stearate, magnesium carbonate, talc, stearin, gelatin, lactose, cellulose, calcium carbonate, polyvinyl pyrrolidone, water, polyalkylene glycol, etc.). The preparations may also contain suitable additives (eg suspensions, emulsifiers, stabilizers and buffers, etc.) and other therapeutically valuable agents.

The preparations may be present in the form of preparations for oral or parenteral administration.

Pharmaceutical preparations may be prepared by methods commonly used in the pharmaceutical industry.

The daily dose of the new compounds according to the invention is about 10 to 420 mg, the therapeutic dose depends on the body weight, age and general health conditions of the patient.

The compounds of the invention were identified by elemental analyzes by IC and NMR spectroscopy as well as by mass spectroscopy. Olefin protons were found to be bound exclusively or mainly in the trans position.

The invention is illustrated in detail by non-limiting examples.

Example 1

1- (4-Hydroxystaryl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine

4.5g (10.6mM) 1- (4-hydroxystyryl) -R5-methyl-6,7 ~ dimethoxy2-benzopyrilium perchlorate (mp, 298 to 3OO ° C, dec.) Was suspended in 90 ml of 99.5% ethanol , 1.6 ml (31 * 8 mM) of 100% hydrazine hydrate was added and the solution was stirred for two hours at room temperature. The evaporation half-life under reduced pressure was suspended in 100 ml of water, filtered, washed with 3x5ml water, the crude product resuspended in warm water, filtered, washed with 3x5ml water and dried at 80 to 100 ° C. The yield is 2,656? mp 205 to 207 ° C (decomposed). This crude product was purified by refluxing in 12ml ethanol and then drying, yielding

2,376 (66.4%), m.p. 209 fi 211 ° G (decomposed).

The compounds of general formula (I) obtained according to the procedure in Example 1 are given in Table 3 ·

15.

rt rd (D rO rt

Ed

rt

K rt hD rt

H

N rt ri

H

T3

- 14.

Example 9

1- (4-hydroxystyryl) -4-methyl-7,8-methylenedioxy-5H-2,3benzodiazepine

A mixture of 5g (12.3mM) 1- (4-hydroxystyryl) -3 ~ methyl-6,7-methylenedioxy-3-benzopyrilium perchlorate (mp 306 to 308 ° 0), 100 ml of 99.5% ethanol or 85 ml (36 , 9mM) 100 $ hydrazine hydrate was refluxed for one hour. The by-product begins to precipitate in the first minutes of the reaction, "The mixture was evaporated under reduced pressure, the partially crystalline residue was suspended in 100 ml of water, the crystals were filtered, washed with 3x10 ml of water, the crude product was resuspended in 300 ml of warm water, mixed is 3θ minutes, warm filtered, washed with 2x20ml warm water and dried at 80 to 100 ° G. The yield is 2.18g, m.p. 243-248 ° C (dec). For further purification, this product was refluxed in 10ml of 99.5% ethanol, filtered with walking liquors, washed with 3x2ml ethanol and dried. The yield is 2.08g ($ 52.8), m.p. 246 to 248 ° C (dec.).

Yield 10

1- (3-Methoxy-4-hydroxystyryl) -4-methyl-7,8-methylenedmoxy-5H-2,3-benzadiazepine

Mixture. 12.5ml dimethylformamide and 2, 1ml (42mM) $ 100 hydrazine hydrate was cooled to 5 to 6 ° G with ice water, then 6.14g (14mM) 1- (3-methoxy-4 ~ hydroxystyryl) 3-methyl was added -6,7-methylenedioxyl-2-benzopyrilium perchlorate (mp 300 ° C carbonis.) Stirring for 15 minutes. The solution was stirred for a further 15 minutes, then 12.5 ml of distilled water was added and cooling of the by-product began. The crystalline mass was left for 12 hours at 5 ° 0, profiled, washed with 3x20ml distilled water and dried at 80-100 ° C. The yield is 4.81g, m.p. 210 to 213 ° C. For further purification, this product was refluxed with 24ml

99.5 / ethanol, cooled and filtered, washed with 3x20ml ethanol and dried. The rhinos is 4.59g (95.7 /), m.p. 214 do

216 ° C (diff.

The procedure described in the example lo was used to obtain the following compounds:

Example 11 1- (3-Niethoxy-4-hydroxystyryl) -4-methyl-7,8-dimethoxy5H-2,3-henzodiazepine

Yield 87.2 / m.p. 192 to 193 ° C (ethanol).

Example 12 1- (3-Methoxy-4-hydroxystyrene) '- 4-methyl-7,8-diethoxy-5H

-2,3-benzodiazepine

Prinso 78.2 / m.p. 190 to 191 ° C diff. Tetanol).

Example 13

Taking tablets

Composition for 1000 tablets g

The compound described in Example 1 10 lactose 185 Microcrystalline cellulose 25 Talk 5 Cornstarch 73 Magnesium stearate 2

Total: 300g

The above ingredients were mixed, homogenized and compressed into tablets containing 10 mg of active ingredient.

Example 14

Preparation of solution for injection

Prepare two liters of solution

The compound described in Example 1 2g

Sodium chloride 20g

Water for injection purposes 2000ml

The solution was placed in ampoules containing 2ml solution

-Announcement of the best, APPLICANT TO THE KNOWLEDGE, METHOD OF ECONOMIC USE

FINDING

In the applicant's experience, the present invention can best be realized in the industry, if it is done as follows:

1- (4-Iidx ^, oxo-styryl) -4-methyl-7, d- (lime stream 3i-5H-2,5-benzodiazepine

4.5g (10.6mM) 1- (4-hydroxystyryl) -r5-methyl-6,7-dimethoxy2-benzopyrilium perchlorate (mp 298 to 500 ° C, dec.) Was suspended in 90 ml 99.5 % ethanol, 1.6 ml (51.8 mM) of 100% hydrazine hydrate was added and the solution was stirred for two hours at room temperature. Boise evaporation under reduced pressure, the residue was suspended in 100 ml of water, filtered, washed with 5x5ml water, the crude product resuspended in warm water, filtered with 3x5ml water and dried at 80-100 ° G. The yield is 2.65g, m.p. 205 DEG-207 DEG C. (dec.). This crude product was purified by refluxing in 12 ml of ethanol and then drying. The yield is 2.57g (66.4%), m.p. 209 <0 211 ° C (decomposed).

Claims (2)

Patent claims 1 p χ where R, R, R and R ² have the meaning defined for formula (I) in a hydrazine hydrate solvent. EGIG Gyogyszergyar - ^ udapest, Hungary 9/20/2005 Abstract of invention The present invention relates to novel derivatives., 1- (hydroxystyryl) 5H-2,3-benzodiazepines of general formula (I) and to a process for their preparation, bottles refer to pharmaceutical preparations containing the same. R ⁴ CH R OH where R represents a hydrogen or halogen atom or a C1-4 alkoxy group, represents a hydrogen atom or a C1-4 alkyl group, 1. A process for the preparation of 1- (hydroxystyryl) -5H2,3-benzodiazepines represented by the general formula (I) wherein R represents a halogen hydrogen atom, or an alkoxy group, r1 represents a hydrogen atom or an alkyl group, 2 3 R and r are identical and denote an alkyl group, or combined represent a methylene group comprising the reaction of 2-benzopyri perchlorate of general formula (II) 2.3. R 1 R are identical and denote a C 1-6 alkyl group, or combined denote methylene. Compounds. generalflurane (I) possess valuable positive inotropic (cardiotonic) power and are capable of enlarging the myocardial contraction spike (3rca work in cardiac failure) so that ₄ 0e can be used in the treatment of chronic heart defects and coronary diseases.