FI71745B - FOERFARANDE FOER FRAMSTAELLNING AV BETA- (IMI-DAZO- / 2,1-B / -1,3,4-THIADIAZOL-5-YL) -AL-KEN-CARBOXYL-SYROR VILKA AER MELLANPRODUKTER VID FRAMSTAELLNING AV DIURETISKA IMIDAZOTDIA IMIDAZOTDIA - Google Patents

Description

1 71745

Process for the preparation of β- (imidazo [2,1-b] -1,3,4-thiadiazol-5-yl) -alkenecarboxylic acids which are intermediates in the preparation of diuretic imidazothia-diazolecene carboxylic acid amides 5

Divided separated from application No. 811630

The present invention relates to a process for the preparation of novel imidazothia-diazolecene carboxylic acids which are therapeutically useful in the preparation of intermediates, in particular antihypertensive drugs, diuretics and uric acid enhancers.

It has already become known that certain imidazo-15 thiadiazoles have biological effects, in particular antithrombotic and antimicrobial properties (cf. DE-A-2 823 686).

It is further known that certain imidazothiaziazoles and imidazothiazole sulfonamides have brain-20 effects (J. Med. Chem. 1980, 117, I. C. Barnisch et al.).

More particularly, the invention relates to a process for the preparation of β- (imidazo [2,1-b] -1,3,4-thiadiazol-5-yl) alkenecarboxylic acids which are intermediates in the preparation of diuretic imidazothiadiazole alkenecarboxylic acid amides of formula (V) R4

X

CH = C-COOH

N - NS '30 2 (V) wherein R 1 is hydrogen, C 1-4 alkyl, C 1-4 alkenyl, 1- o 2-6 benzyl, phenyl, tolyl, C 1-4 dialkylamino, N-methyl-35-cyclohexylamino, N-methylanilino , morpholino or 271745 pyrrolidino, R is phenyl which may be substituted by one or two C 1-4 alkyl, C 1-4 alkoxy or halogen radicals, thienyl or C 1-4 alkyl, and

4 1 ~ D

R is hydrogen or methyl.

Compounds of formula (V) are prepared by reacting an aldehyde of general formula (VIII)

^ CHO

N - N --------- 10 li 1 (VIII) Λ8Λ. · 'Λί! 1. In R 2, R and R are as defined above, condensed with malonic acid of general formula (IX) HOOC-CH-COOH (IX) R 1 ti 20 wherein R is as defined above, in the presence of an inert organic solvent and optionally condensing. in the presence of.

In the process according to the invention, customary inert organic solvents can be used as diluents.

These preferably include ethers such as diethyl ether, glycol ethers such as glycol dimethyl ether, dioxane, tetrahydrofuran or alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol or sulfoxides such as dimethyl sulfoxide, bases such as pyridine, picine, picine, picine. hydrocarbons such as benzene, toluene, xylene as well as dimethylformamide.

In the preparation of alkenic acids of general formula (V), the corresponding esters are preferably used as saponification bases; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth hydroxide such as barium hydroxide or calcium hydroxide.

3,71745

In the preparation of aldehydes of the general formula (VIII) with malonic acids of the general formula (IX), the following are preferably used as condensing agents: pyridine, substituted pyridine derivatives such as dialkylaminopyridine, quinoline, isoquinolinepipyrrolidine, dialkylamines, dibutylamines, bases.

The compounds prepared using the intermediates of the invention are characterized by surprisingly strong biological effects. In particular, they have clear diuretic and renal sodium-increasing effects and can therefore be used as diuretics, saluretics and antihypertensives.

Animal studies in mice, rats or dogs show that the new compounds, when administered orally at doses below 10 mg / kg, have a clear diuretic and saluretic effect with simultaneous good suitability. The state of the art could not expect these advantageous features.

Surprising and advantageous effects of compounds of formula (I) of formula (I) H R 3

25 N ----- N-t-C = C-CONrV

! I j: f (I) 30 wherein Y is a sulfur or oxygen atom is hydrogen, alkyl, trifluoromethyl, alkenyl, phenyl, tolyl, dialkylamino, N-phenyl-N-methylamino, N-cyclohexyl-N-methyl - amino, piperidino, pyrrolidinyl, morpholino, hydroxyalkyl, carboxyl, alkoxycarbonyl or alkylthio-20 3 alkyl, R is phenyl which may be substituted by halogen, alkyl or alkoxy, thienyl, or alkyl, R is hydrogen, alkyl, alkoxy, acetyl, cyano, or 4 fluorine, R is hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 2-4 alkenyl, C 1-4 alkoxy-C 1-4 alkyl, trifluoromethyl- C 1-6 alkyl, morpholino-C 1-4 alkyl, di-C 1-4 alkylamino, phenyl, benzyl, piperidyl or hexahydro-1H-azepin-1-yl and R f. is hydrogen, C 1-4 alkyl, -3- * -4-4 C 2-4 alkenyl or C 1-4 hydroxyalkyl, or R and R together with the nitrogen atom to which they are attached form a piperidinone which may be substituted Alkyl, hydroxyalkyl or alkoxycarbonyl, morpholinone, morpholinoalkyl piperazinyl which may be substituted in the 4-position by phenyl or methyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, pyrrolidinyl, which may be substituted by alkyl, pyrazolyl, 2-methylindolinyl, dialkylamino, N-hydroxyalkyl-N-alkylamino, dihydroxyalkylamino, N-methyl-N-propylamino, dialkenylamino, N-methyl-N-trifluoroethylamino , wherein the alkenyl, alkoxy and alkenyl moieties mean lower alkyl, lower alkoxy and lower alkenyl and the alkyl moieties may additionally be straight-chain or branched, can be expressed according to the following test methods: A) Antihypertensive effect in rats reported in the Goldblatt high pressure rat according to Breuniger, H,: Method of unrestricted Messung des Blutdruckes an Kleintieren, Arzneimittelforsch 6, 222-225 (1965).

B. Diuretic effect in rats / kg orally in tylose suspension using a throat tube. Animals are placed in si-35 exchange cages and urine and electrolyte secretion were determined for 6 hours (NA + and K + assay: IL-flame photometer).

5 71745 C) Diuretic effect in dogs The bladder of fasted, awake English hare dogs is catheterized and urine and electrolyte excretion are determined for 180 minutes (every 30 minutes for fractions).

During this time, the animals receive a continuous intravenous infusion of electrolyte solution and the test substance at the beginning of the experiment in 1 ml / kg tylose suspension (0.5%) taken orally.

Urine is analyzed for Na +, K +, chlorine, bicarbonate and pH.

D) Diuretic effect in mice Fasting male SPF mice weighing 20-25 g (n = 6 x 3 animals / cage) receive 100 ml / kg of tylosin suspension (0.5%) as controls or 100 mg / kg of test substance in tylosin suspension taken orally. .

+, +

Urinary, Na and K or uric acid secretion is determined for 2 and 4 hours in metabolic cages.

E) Phenol red retention test in rats To demonstrate uric acid urination, the effect of the compounds of the invention on phenol red blood counts is shown in awake unfed male rats (SPF-Wistar, weight 180-250 g). According to Method 25 of Kreppel E. (Med. Exp. 1 (1959), 285-289), 8 animals each received 75 mg / l of phenol red in 5 ml / kg saline intraperitoneally after administration of 10 mg / kg 30 minutes earlier. tylose suspension (0.5%) as a reference or 100 mg / kg of test substance in a tylose suspension.

Plasma is taken at a retro-orbital venous puncture at 30, 60 and 120 minutes after phenol red administration or 60, 90 and 150 minutes after administration, NaOH is added and the extinction is determined with a 546 nm photometer (Eppendorf).

35 Effective uric acid urination exists when extinction values are significantly higher than in the control group.

6 71745

The compounds of formula (I) are useful as medicaments. When used orally or parenterally, they have the effect of increasing the excretion of water and salt and can therefore be used to treat conditions of edema and hypertension and to flush out toxic substances. In addition, the compounds can be used in acute arrest of renal function. In particular, they also have a beneficial uric acid effect.

The compounds (I) can be formulated in a known manner into conventional preparations such as tablets, capsules, beads, pills, granules, syrups, emulsions, suspensions and solutions using inert non-toxic pharmaceutically acceptable carriers or diluents. In this case, the therapeutically active compound must in each case be present in the total mixture in a concentration of about 0.5 to 90% by weight, i.e. in amounts sufficient to achieve a given dosage range.

Examples for the preparation of alkene-20 acids of general formula (V).

Example 1

^ CH = CH-COOH,

N - N -------- ·!; ! 1 '25 HCl Θ 30 90 g of 2-methyl-6-phenylimidazo [2,1-b7-1,3,4-thiadiazole-5-carbaldehyde are boiled with 60 g of malonic acid and 3 ml of piperidine in 95 ml of pyridine. For 10 hours at reflux. Cool to 5 ° C, stir for 2 hours at this temperature and filter under suction. The residue is washed with water and dried. Yield 7 71745 92 g (84% of theory) of β- (2-methyl-6-phenylimidazo [2,1-b] -1,3,4-thiadiazol-5-yl-propenoic acid with a melting point of 278-280 ° are obtained. C (decomposes).

In an analogous manner, the examples of the following Table 5 were prepared by reacting equivalent amounts of reaction components in each case.

3 71 745 i> 3

QJ W

4J QJ

0 -H ^ -O XJ r- r— in r— * “

C ^ ow ^ 00 Ό CN Γη ^ ^ ^ CO

j3 <j> $ CO tj U _ o o

° 7 N W 5 tN

> iii 7 7 7 γ ^ ά * r r? ? £ 2 ^ 70 ° 1- o w ^ «NtNrs. S £ £] £ £ I I I I ^ fe ti ^ ^ aQQg a a a a g 3 S.

S 'D

'U ~ 3 f J § 1 = = = = =! S ^ 1-1 w a; ^ 06 ~ „-T> - = 2: = s = C = = ^ ^ r U - as

"CM

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V

3 g 3 '^ 2 cNro ^ rm vo c- co σ »o t- W fi ^ 71 745 9 s'" 3 s 5 S s S o

QJ

CO -D

u ^ • Ϊ? ? s »Ά S s S p s

^ «N (N (M K

"2 I S ^ fed Ctj Cij

o SS a 6 S g S

x φ X

| .53 *

10 5 O t * -H

Ό 9 3 3 3 M ^ 3 S '««: 4- »O ® Λί X rr 3 Oi = = r-t · ** w s: 3 (0

B

CJ m UH [ij ^ - w $ · ^ tT1 Π ^ * σ oo S 5 • s • H o, ® ^ ή (N ro rr m WC Ή iH i — I, —1 i— | 10 71745 <# > I LO Γ »Λ _

β | 2 ”^ § s S S

C g <D

2 o m Ό <D -h W -U + J

o ^

Λ o i l 7 7 S

^ ~ ^ ~ 'S § 3 - I S § I 1 I 11 ό c m' -'aa

o c dJ

^ 4 * H Φ * H

v jj 'H ^ 5 S-sf § = =, = -H 2 <d

(OF

“TT

OK ΓΕ T- «- λ; ^ s ® x x _ 2 χ x x a

> H

3 <n E-t -1 ° ui m m cm 3- K E »r in m tn m« o ° <? <j ° <? S-y-S ¥ o = o 'u o - «if ^ 9-- Y ¥? -5? ? ¥? -Ο

ε σ «o HtN

• ho HrHrH γΗ (Ν <Ν (Ν

W C

71 745 11 -u tr]

0 <W 4J

- * - / CD (/) I -. _ CVJO) ^ cri Ό 0 (/) ^ Γ '' un

Ό O -M

to -U 4J

u 0 • in a, rr £ <n to '7 ^.

* s s 1 1 § 5 Ο Λ Λ Λί 4-1 111 "e c jp w 8 ς $ § [§ fa" £ 3¾ h Q Q Q Ö 2 o o £ 3 M 3 T) Ί) c - ^ 4 .H a u q.

3 j μ = = = 3 ft) DS a- - κ ® XE e., NT1 -P jo, - u-,> = o- 5 ° 9 - “Π *"> = j ^ 4. Υ _ ro ^ ro m "Π T *

Sx? V.-S ^ '“cd V., / T' yn --P JO rn

? aT ^? 9 V

ε Ή O PO · * Τ If) VD! - ~ 00

MMfM (N (N (N (N CM

M l4 12 71 745

The compound of Table Example 8 is obtained by boiling 15 g of o-methyl-3- (2-methyl-6-phenylimidazo [2,1b] -1,3,4-thiadiazol-5-yl-propenoic acid ethyl ester in 2.8 g of potassium hydroxide. , 200 ml of ethanol and 20 ml of water at reflux for 5 hours, cooled and evaporated to dryness in vacuo, the residue is dissolved in 300 ml of water and filtered, the filtrate is acidified with concentrated hydrochloric acid, the precipitate is filtered off with suction and recrystallized from dimethylformamide. 10-methyl-β- (2-methyl-6-phenylimidazo [2,1-b] -1,3,4-thiadiazol-5-yl-propenoic acid, m.p. 298-300 ° C (yield: 79.5% of theory) ).

Claims (4)

71745 Claim Process for the preparation of * - (imidazo [2,1b] -1,3,4-thiazol-5-yl) -alkenecarboxylic acids / which are intermediates in the preparation of diuretic imidazothiaziazole alkenecarboxylic acid amides of formula (V) R 4 10 / _____ = C-COOH i? ? | 10 (V) 15 wherein R 1 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, benzyl, phenyl, tolyl, C 1-4 dialkylamino, N-methylcyclohexylamino, N-methylanilino, morpholino or pyrrole. -2 lidino, R is phenyl which may be substituted by one or two C 1-6 alkyl, C 1-4 alkoxy or halogen radicals, thienyl or C 1-6 alkyl, and R 4 is hydrogen or methyl, characterized in that the aldehyde of general formula (VIII) 25 N_ N______ CHO 5. I R1 - .. 3 Λ 2, VIII> R ö NR 30 1 2 wherein R and R have the same meaning as above, are condensed with malonic acid of general formula (IX) HOOC-CH-COOH (IX) • 4 35 R 4 14 71 745 wherein R is as defined above, in the presence of an inert organic solvent and optionally in the presence of a condensing agent. il