FI64942C - ANALOGIFICATION OF THE THERAPEUTIC FREQUENCY OF THERAPEUTIC 6'-DESOXO-9,10-DIHYDRO-BETA-ERGOCRYPTIN AND SALTER DAERAV - Google Patents

Description

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Wa W (11) utlAgcnincsskrift 04? 4 l ^ T ^ (51) Kv.lk 3 / lnt.CI.3 C 07 D 5 ^ 9/02 ENGLISH - FI N LAN D (21) Pn.flttlhik.mui —P «t« nt * iweknln | 772557 (22) Htk.mlspllv · - AMttknlngfdsg 29-08.77 '(23) Home_GIM | h «« daf 29-08-77 (41) Tullut | ulklMlul - Bllvlt oftuntllj 07-03- 78

National Board of Patents and Registration of the Republic of Finland - Q

Patent and registration authorities' Aiweku utitfd oeh uti. »Krift * n publicand 31-10.03 (32) (33) (31) stuolksu» - B. * Ird priority 06.09 - 76 06.09.76 Switzerland-Switzerland (CH) 11286/76 , II287 / 76 (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Peter Stutz, Vienna, Austria-Austria (AT),

Paul Stadler, Biel-Benken, Switzerland-Schweiz (CH) (7 ^) Oy Kolster Ab (5 ^ +) Analog method for the preparation of therapeutically useful 6'-deoxo-9,10-dihydro-p-ergocryptine and its salts -Analogiförfarande för 6'-desoxo-9,10-dihydro-β-ergocryptine and other salts

The present invention relates to an analogous method for the treatment of coronary artery disease with a 6'-deoxo

9,10-dihydro-γ3-ergocryptine of formula I

ch (ch3) 2 v + bi ^ r1 H. '1 —V ^ CH2' ch2ch (ch3) 2 HN_ 64942 and its acid addition salts.

Some FI patents describe similar ergo peptide derivatives which act on blood vessels (FI patent 49 517), which are used to treat migraine and as a substance that stimulates childbirth (FI patent publication 48 274) or which have a vasodilatory effect (FI patent publication). patent publication 59 254). The novel compounds prepared by the process of the invention differ from the known ergotpeptide derivatives in that they have a methylene group in the 6-position instead of a carbonyl group. In addition, these new compounds have novel pharmacological properties, making them suitable for the treatment of coronary insufficiency.

6-deoxo-9,10-dihydro-β-ergocryptine is an ergopeptide derivative that substantially reduces the determinant of myocardial oxygen consumption and thus reduces the need for myocardial circulation as well as the β-blocker. The compound inhibits the action of noradrenaline and serotonin in the isolated coronary artery without significantly affecting its own ot-st lymphatic effect. Thus, it is expected that the large coronary artery can now be protected from the anticonvulsant effect.

In comparative experiments, it was found that the compounds prepared according to this application are better as antihypertensive compounds than the compounds according to FI patent publication 49 517.

The method according to the invention is characterized in that

a) reducing the 6'-carbonyl group in a compound of formula II

Chich-J ----.

o · * 'ti Tr! B) condensation of the acid addition salt of the compound of formula III CH (CH 2) --- I PH J ^ H i h2nn! / 0VS / VCH CH (CH 2, n_ch 3 2 3 2 i HN- 3 64942 b)

Il III

J-N CH9 O 1 CH2CH (CH3) 2 with a reactive acid derivative of a compound of formula IV,

COOH

vS

Hv H I

UU

j HN - (and the compound of formula I thus obtained is recovered in the form of a base or an acid addition salt.

The process option a) can advantageously be carried out as a one-step process using a reactive borane, e.g. diborane. The process can be carried out for the reduction of diborane by methods known per se under mild conditions. 5 to 15 moles of reactive borane are used per mole of compound of formula II. Tetrahydrofuran, diethyl ether or methylene chloride can be used as solvents. The reduction preferably takes place at temperatures between about -20 ° C and + 20 ° C.

The method option b) can be carried out according to methods known per se for the preparation of similar cyclic peptide ergo alkaloids.

A suitable acid addition salt of a compound of formula III is 2,5-naphthalenedisulfonic acid salt.

As the functional, reactive derivatives of the compound of the formula IV, for example, acid chloride, acid azide or an acid azide mixed with sulfuric acid or trifluoroacetic acid can be used. Preferably, the adduct of a compound of formula IV is used with dimethylformamide or acetamide and thionyl chloride, phosgene or oxyl chloride. Preferably, the reaction is carried out in the presence of triethylamine or pyridine. Suitable solvents are, for example, chloroform, methylene chloride, dimethylformamide or acetonitrile.

The reaction can take place at temperatures between -30 ° C and + 20 ° C.

The starting compounds are known or can be prepared from known compounds by methods known per se. Thus, a compound of formula III can be prepared from an aminocyclol of formula V.

CH (CH,) - _, i, ° h Lh j C2H5OOC '

- N V

0> <tr ch2ch (ch3) 2 in a manner known per se.

For example, the corresponding acid can be formed first, which is then converted via the acid chloride to the corresponding acid amide, which in turn is converted to the amine.

A compound of formula V may be prepared by reacting a compound of formula VI

CH (CH3) 2

C2H5OOC --- y - 0CH2 C6H5 VI

C0C1

to react with a compound of formula VII

li 5 64942 • The hydrogenation of already H CH2CH (CH3) 2 and the resulting product is carried out as above.

A compound of formula VII may be prepared by reacting a compound of formula Vili, Λ | ° HN1 VI11 CH2CH (CH3) 2 to react with lithium aluminum hydride.

Acid addition salts are obtained from the base of the formula I in known ways and vice versa. Suitable salts also include the hydrochloride and methanesulfonate.

The compound of the formula I, as the free base or as physiologically tolerable acid addition salts, has interesting pharmacological properties.

The compounds of the invention can achieve good results when used to treat coronary artery disease and when used as antihypertensive agents. They can be formulated, for example, as solutions or tablets, which can be prepared in a manner known per se, using common excipients and carriers.

In an experiment comparing a novel compound (Compound 1) prepared by the method of the invention, which is 61-deoxo-9,10-dihydro- / O-ergocryptine, with a compound known from FI patent publication 49 517 (Compound 2), which is 2'-isopropyl -5'-n-propyl-9,10-dihydroergopeptin (Example 1), the following results were obtained:

A cat with an open abdominal cavity was administered 0.12 mg / kg of Compound 1 intraperitoneally, followed by a 13% reduction in blood pressure of 6,64942 and an 11% reduction in blood pressure when Compound 1 was administered intravenously at 0.03 mg / kg. In contrast, compound 2 caused a dose-dependent increase in blood pressure when administered intravenously to a spinal anesthetized cat. Compound 2 had virtually as strong an antihypertensive effect as the known dihydro-ergotamine (1.2 + 0.2 ml dihydroergotamine in the range of 0.005-0.02 mg / kg).

The following examples illustrate the invention. Temperature values are given in degrees Celsius and are uncorrected.

Example 1: 6'-Deoxo-9,10-dihydro-β-ergocryptine (Method a) 1.15 g of 9,10-dihydro-β-ergocryptine (2 mmol) are suspended in 25 ml of dry tetrahydrofuran (THF). and a freshly prepared solution of 20 mmol of BH 2 in 35 ml of dry THF (e.g. NaBH 4 and boron trifluoride etherate) is added dropwise with stirring at 0 ° C. After stirring for 4 hours at 0 ° C, the reaction mixture is cooled vigorously and 9 ml of 6N hydrochloric acid are carefully stirred into the reaction mixture. It is then stirred for a further 30 minutes at + 60 [deg.] C., after cooling, made alkaline with 30% sodium hydroxide and the reaction mixture is extracted thoroughly with methylene chloride. The methylene chloride extract is chromatographed on 100 g of "aliquots" having an activity of 2-3, after which the title compound is crystallized from methylene chloride / ether-free base, m.p. 159-160 °; C 18 H 24 -4 ° (c = 0 * 5 in dimethylformamide). Example 2: 6'-Deoxo-9,10-dihydro-β-ergocryptine (Method b) 10.8 g (40 mmol) of 9,10-dihydrolysergic acid are suspended in 100 ml of dry dimethylformamide (DMF) and the suspension is cooled to -10 ° C. Over 5 minutes, 4.72 g (40 mmol) of thionyl chloride are added dropwise and the reaction mixture is stirred for a further 30 minutes at -5-0 ° C. After adding 40 ml of dry pyridine at -15 ° C with vigorous stirring, 12.68 g (20 mmol) of 2-amino-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy are added. -perhydrooxazole / '3,2-α] pyrrole / 2,1-c] pyrazine-2,5-naphthalene disulfonic acid, stirred vigorously for 2 hours and allowed to rise slowly from -10 ° to 0 °. For further work-up, the mixture 7 64942 is made alkaline with 2N sodium hydroxide solution and then extracted thoroughly with methylene chloride. The methylene chloride extract is chromatographed on 100 g of "aliquots" having an activity of 2-3, the title compound is eluted with methylene chloride / ether and crystallized as the free base, m.p. 159-160 °; = -4 ° (c = 0.5 in dimethylformamide.

The starting material used was 2-amino-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydro-oxazole [3,2-a] pyrrole [2,1-c] pyrazine-2,5- Naphthalenedisulfonic acid is obtained as follows: a) (2S, 7aS) -2-sec-butyl-perhydro-8-oxo-pyrroleZ2> 1-c7pyrazine

Under a nitrogen atmosphere, 36.4 g (960 mmol) of lithium aluminum hydride are suspended in 1.3 liters of dry tetrahydrofuran and a solution of 115.5 g of L-Ile-L-Pro-lactam in 1.4 liters of dry tetrahydrofuran is added dropwise over 45 minutes. . After stirring for 18 hours at -10 °, the mixture is carefully diluted with 350 ml of acetic acid ester and 350 ml of water. The reaction mash is filtered, whereupon the reaction product still present is repeatedly extracted from the filter cake with boiling methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give the title compound.

b) (2R, 5S, 10aS, 10bS) -2-carbethoxy-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydro-oxazoleZ'3,2-a7pyrrole-Q., 1- c7-pyrazine To 40.55 g of (2S, 7aS) -2-sec-butyl-perhydro-8-oxo-pyrrolo [2,1-c] pyrazine in 160 ml of dry dioxane is added 74.4 g of S (+) - isopropyl-benzyloxy -malonic acid ethyl ester chloride and 34.9 g of N-ethyldiisopropylamine and stirred for 1 hour at + 70 °. After dilution with 1 L of ether, the mixture is shaken twice with saturated sodium bicarbonate solution and dried over sodium sulfate. After evaporation of the solvent, crude (2S, 7aS) - (2'S-21-benzyloxy-2'-isopropyl-O-ethylmalononyl-2-sec-butyl-perhydro-8-oxo-pyrrole / 2,1-c7pyrazine is obtained, which is dissolved 1.5 l of ethanol and hydrogenated at 60 [deg.] C. after the addition of 60 g of palladium-on-carbon (10% Pd), which after 14 hours absorbs 6.5 l of hydrogen, after filtration and evaporation of the filtrate to give the title compound.

8 64942 c) (2R, 5S, IQaS, 10bS) 2-carboxy-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydro-oxazole-1,2-a-pyrrole-2, 1-c / pyrazine 35.9 g (2R, 5S, 10aS, 10bS) 2-carbethoxy-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydro-oxazole / 3,2-a7pyrrole 1,2-C7-pyrazine is dissolved in 245 ml of methanol and 245 ml of 2N sodium hydroxide and stirred for 3 hours at room temperature. For further work-up, the pH is adjusted to 4.5 at 0 [deg.] C. with 2N hydrochloric acid and extracted repeatedly with ethyl acetate. After drying the organic extract and evaporating the solvent at a temperature below + 30 ° C, the title compound is obtained.

d) (2R, 5S, IQaS, 10bS) 2-amino-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydro-oxazole / S, 2-α7-pyrrole-Cl, 1 - c7Pyrazine-2,5-naphthalenedisulfonic acid To a stirred mixture of 4.33 ml of dry dimethylformamide and 30 ml of dry acetonitrile cooled to -15 ° is added dropwise over 10 minutes a solution of 3.84 ml of oxalyl chloride in 15 ml of dry acetonitrile. and stir for another 10 minutes. After dilution with 45 ml of dry ether, 10.87 g of (2R, 5S, 10aS, 10bS) 2-carboboxy-2-isopropyl-3-oxo-5-sec-butyl-10b-hydroxy-perhydrol-oxazole are rapidly added. 3,2-b / pyrrole-Cl, 1-olpyrazine-1/2 H 2 O to give a clear solution containing the acid chloride and stirred for a further 10 minutes at -10 °. A layer of a solution of 20 g of sodium azide in 100 ml of water diluted with 300 ml of methylene chloride is then carefully added to the solution and the 2-phase mixture is shaken vigorously for 4 minutes. Add 150 ml of ice-cold saturated sodium carbonate solution, separate the organic phase and dry well over sodium sulfate. After evaporation of the solvent below 30 [deg.] C., a solution of 7.78 g of 2,5-naphthalenedisulphonic acid in 200 ml of dimethoxyethane and 20 ml of acetonitrile is stirred and slowly evaporated in vacuo. After dilution with dry ether, the acid azide separates as a salt to a light brown powder. 6.35 g of the dried powder are heated for 1 hour at 80 ° with 120 ml of dimethoxyethane containing 0.166 ml of water to give a brownish semi-crystalline powder during continuous scaling which, after cooling, filtration and drying at room temperature under vacuum, can be used directly for condensation. .

Il

Claims (2)

9 64942 Claim An analogous method to 6'-deoxo-9,10-dihydro-β-ergocryptine of formula I, J_N CH-, which is useful in the treatment of coronary artery disease and is effective in lowering blood pressure. ... '1. N-CH, Hf ^ -CH ^ CH (CH2) _ w HN_-i and its acid addition salts (characterized in that) a) a 6'-carbonyl group in a compound of formula II ch ( ch3) 2 _ »H | 0H I sA ° —n> 6 ^ ° 11 „I 2 I" 'CHOCH (CH,) I N-CH- 2 32 3 HN --- 10 64942 b) condensing the acid addition salt of the compound of formula III ch (ch3) 2 _ _ OH ^ H Η2Ν '^ 0 ^ νΝΧ IIL III O & -N CH2 H ^ "" CH2CH (CH3) 2 with a reactive derivative of an acid of formula IV, COOH H. H'N-CH3 CO11HN_I and the compound of formula I thus obtained is recovered in the form of the free base or of an acid addition salt .. 6 64942 Analogs for the preparation of a coronary anhydrous and anhydrous end of 6'-deoxo-9,10-dihydro-β-ergocryptin in CH ), ---- 0 J * H 11H H ^ M "^ 1 O '' -« v / CH2 1 Jk I! H CH2CH (CH3) 2 HN- and the addition moiety, preferably a) reducing 6'-carbonyl groups and en for form II II ch (ch3) 2 ------ Il H f ^ o PHJ <- *. r- r 'O “oJ-- HH [ch2ch (ch3) 2 kA J HN-1