DE2213843A1 - New pyran compounds, processes for their preparation and their possible applications - Google Patents

Description

Note : Jan Marcel Didier

ARON-SAMUEL

1Λ. March 1972

New pyridine compounds. Procedure to their manufacture and their possible uses

The present invention relates to new pyridine derivatives, processes for their preparation and their possible uses, in particular in the therapeutic field.

E. Profit and ¥. Steinte have in J. Prak. Ghem. I ^, p. 58, 1961, derivatives of the N-oxides of pyridine-carboxyl-2-acid described, which should have an antibacterial effectiveness.

The applicant has found new pyridine derivatives that have a have pronounced hypotensive effectiveness.

These new derivatives correspond to the following general formula:

NO _n

—N

(D

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in the

R represents a hydrogen atom or an alkyl radical with 1 - 6 carbon atoms,
R. represents a hydrogen atom or an alkyl radical with 1-6 carbon atoms alone,

the formula

- (CH ₂ ) _n -

R "alone is a radical of the formula

represents

where η is an integer from 0-6 and R ~ is a heterocycle with 3-7 members, which may be an alkyl radical with 1-6 carbon atoms

or a radical of the formula

- B - N

R ₅

wearing,

where B is a linear or branched alkylene radical with 1-6 Carbon atoms is

the total number of carbon atoms of B and R, considered individually, amounts to at least 3,

where R. is a hydrogen atom or an alkyl radical with 1-6 Carbon atoms is and

R- is an alkyl radical with 1-6 carbon atoms,

or R ^ and R ₂ together with the nitrogen atom to which they are bonded form a heterocycle with 3-7 members, which may have an alkyl radical with 1-6 carbon atoms.

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If R _{2 is} a - (CH ₂ ) -R ^ radical, then R ^ is preferably a nitrogen-containing and / or oxygen-containing heterocycle,

When R. and R "together with the nitrogen atom to which they are attached are, form a heterocycle, this heterocycle can be a nitrogen or an oxygen atom as the second hetero atom contain.

Some derivatives of formula i can contain an asymmetric carbon atom. The invention, of course, encompasses this racemic as well as the enantiomorphic forms of these optically active products.

The derivatives of the formula i according to the invention can also occur in the form of their non-toxic additional salts with acids, e.g. in the form of their halohydrates, sulfates, phosphates, methane sulfonates, Maleates, acetates, fumarates, lactates or tartrates, which can be obtained by the action of the derivatives of the formula i on the can produce stoechiometrically equivalent amount of acid that corresponds to the selected salt.

To make the derivatives yourself, you can use a compound the formula

Ii

⁶ (ii)

0
let react

in Rg an alkyl radical on an amine of the following formula is:

H - h '" ¹ 209842/1211

R, EL and R "have the aforementioned meanings, so that the derivative of formula 1 can be achieved.

Compounds of formula 2 are usually used in which R ^ is a methyl radical * The preparation of starting materials of this type is described by E. Profft and ¥. Steinke in J «, Prakt. Chem. 13_, 7i (1961) and by H.W. Krauss and W. Lagenbeck in Ber. 9_2, 159 (1959).

The reaction of the compound of formula 2 on the amine can be carried out without further warm or cold, in the absence of a solvent or in the presence of a polar or non-polar protic or aprotic solvent, which may the reacting, excess amine may be. The most common solvents are ethers and Alcohols, especially alkanols, to be mentioned.

Three examples are given below to illustrate the manufacturing process according to the invention.

Each derivative is provided with a number immediately after the name. All melting points mentioned were determined in the capillary tube with the introduction of the product at a temperature lying around 10 ° C. below the melting point. The heating rate was 2 ° C / min.

example 1

N- £ jethyl-1 pyrrolidinyl-2) methyl / nitro-4 oxide-1 pyridinecarboxamide-2; LA-2510; R = R ₁ = H, n «1, R, = N-ethylpyrrolidinyl-2.

A solution of 23 »5 g of ethyl-1 aminomethyl-2 pyrrolidine in 36O ml of ethyl oxide are 36.3 g of methyl ester- the nitro-oxide-1 Pyridine carboxyl-2-acid added. The suspension is at Heated to reflux for six hours. The reaction mixture is

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- ζ -

cooled and filtered to remove the unreacted ester turn off.

The piltrate is concentrated under vacuum. The red oil achieved is taken over by 100 ml of isopropyl oxide »When hot the resolution a full. By cooling at + 10 C The crystalline mass obtained is washed with isopropyl oxide and dried. In this way 39.4 g of the basic product are obtained. Mp = 71-73 ° C,

The chlorohydrate melts at 186-188 ° C. The fumarate melts at 134-135 ⁰ C (crystallized with 2 H ₂ O).

Example 2 .

N- (piperidino-2 ethyl) nitro-4 oxide-1 pyridine carboxamide-2 * LA-2514; H = B ^ = H; n = 2, B ₃ = piperidino.

A solution of 13 g of piperidino-2 ethylamine in 200 ml of ethyl oxide is added to 20 g of methyl ester of nitro-4-oxide-1-pyridine-carboxylic acid. The suspension is heated to reflux. Complete dissolution takes place. After 30 minutes, insolubles are formed. The reflux is maintained for 4 hours. After cooling down, it is filtered. The precipitate is washed with 4 * ky! Qxyd and re-crystallized in 250 ml of methanol. 23 g of the product sought are obtained. * Fp = 134-136 ^P C »

The chlorohydrate melts at 228-230 ⁰ C with simultaneous decomposition,

Example 3

N. «(Dietbyiamino-g ethyl) N-methyl-Ni tro-4 Oxyd-i pyridine carbox-

R: ^ I; R ₁ = methyl; R ₂

A lager of, 2.6 g (diethylaminoethyl) methylianiine in 400 ml of methanol was the \ 0 g of methyl ester of the Ni tr 0-4 Oxyd-1 pyricUri-

carboxyl-2-acid added. The suspension is heated at Bückfluß _m ^. This reflux is maintained for four hours after complete dissolution. After cooling, the JLösung is ¹ × concentrated under vacuum and then taken up by 250 ml Methylenehlorid again ifch purification by passage through an alumina column and concentration the absence of air to obtain an oil which is dissolved in 200 ml of ethanol. By adding the stoechiometric amount of fumaric acid in the hot state and recrystallizing in ethanol, 36 g of fumarate of the desired product are obtained. Mp = 143-144 C (This fumarate contains two basic molecules in one fumaric acid molecule.)

Derivatives of the formula i were prepared in a similar manner, in which R = H,

The other characteristic values relating to the structure are shown in the five first columns of Table I below are summarized.

In the sixth and seventh columns of the table are the Key numbers of these derivatives and their physical properties are listed.

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- 7 - TABLE I

^R l Diethylamine
nopropyl η Β ,, NR ₁ R ₂ ; LA-2511 Melting point H Dibutyl
aminopropyl LA-2512 Raw material
73-5
Chlorohydrate
180 H - LA-2513 Raw material
42-3
Pumarat 148-9 H 3 Hexame thy1en-
imino LA-2517 Raw material
84-5
Pumarat 16O H 0 N-ethyl
Piperidyl-3 LA-25I8 Raw material
9I-2 Me
thyl Dimethy1-
aminoiso
propyl 1 N-Athyl PynD-
lidinyl-2 LA-2519 Raw material
92 H LA-2521 Raw material
'86-7 Me thy 1-4
-Pipera-
zinyl LA-2522 Raw material
144-45 H 1 Pyridyl-3 LA-2523 Base 178
Chlorohydrate
222-223 H 2 Pyridyl-2 LA-2524 Basic substance Ib4 H 2 N-Ethyl Pyr
rol idinyl-2 LA-2526 Basic material 85 H 1 Pyridyl-2 LA-2527 Chlorohydrate
198-2ΟΌ H 2 Pyrrolidinyl LA-2529 Raw material
142-143 U 1 Tetrahydro
furyl-2 LA-2530 Raw material
101 [I. 0 ^ 2-imidazo-
linyl-2 ι
Raw material
212

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The derivatives of Formula I have been found to be effective Means to lower blood pressure are. This pharmacological activity is all the more interesting as its toxicity is low, as the following results of the toxicological investigation show.

Toxicological investigation ;

The degree of toxicity was determined on rodents with the help of Lichtfield and Wilcoxon developed method (j. Pharm. Exp. Ther. 19 ^ 9, £ 6, 99-113). The results of this investigation are summarized in Table II below. In the first column are the key numbers of the derivatives the formula, in the second column the oral administration in mice and in the third column the number of test animals, that have been observed for a week.

TABLE II.

No. LA-2510 DL 50 (mg / kg) Number of attempts LA-25Ü animals LA-2512 1200 80 LA-2513 17OO 60 LA-2514 1400 45 LA-2515 1100 45 LA-2517 2000 45 LA-25I8 I3OO 45 LA-2519 I5OO 30th LA-2521 ■> i500 30th LA-2522 120.0 30th LA-2523 1100 40 LA-2524 1800 40 LA-2526 > 2000 40 LA-2527 > 2000 40 LA-2529 > 1500 40 LA-2530 1000 60 500 50 > 1000 40

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Pharmacological examination ;

The following is about the results of the pharmacological Experiments reported that the effectiveness of the derivatives of formula I and in particular their suitability for lowering blood pressure in the sleeping animal and especially in the animal with normal blood pressure or in which a state of excitement is generated was to point out.

With the sleeping animal ; Experiments were carried out on k dogs, 12 rabbits, 15 guinea pigs and 21 rats, in which the blood pressure was measured with the aid of a mercury manometer attached to the head and artery. At the same time, the movements of the peripheral vessels were recorded with the help of the Schuhfried's rheograph (Die Diabetis, Volume 16, No. 4, Oct.-Dec. 68, 269-274, Sterne), the heart with the help of the electrocardiograph, the kidneys and examined the spleen with the help of an oncograph and the bowel movements by inserting a balloonet into the intestinal duct

The pressure drop is slow and gradual over a longer period of time and according to the dose given themselves.

It usually starts at a dose of 5 mg / kg - at the same time with a general vasodilatation.

The derivatives of the formula I multiply the lowering of blood pressure caused by the excitation of the vagus and by the inhibitors β as well as the effect of adrenaline "

Table III below gives an overview of the blood pressure lowering effectiveness of the Derivatives of formula I that are injected intravenously into sleeping rats.

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TABLE III

Key number Dose mg / kg Depreciated blood
pressure LA-2510 5
20th - 20 %
- 50 % LA-2511 5
20th - 10 %
- hO% LA-2512 20th - 10 % LA-2513 20th - 8th % LA-251 ^ 5
20th - 15 %
- 50 % LA-2515 20th - 20 %

Not only the intensity but also the duration of the effect are proportional to the dose. This duration is a few minutes at low doses, and it is between 30 and 120 min. for heavy doses.

Vascular dilatation can also be seen at the edge of the kidney and spleen.

When the animal is awake ; experiments were carried out on 8 dogs. These dogs were administered orally 10 mg / kg of derivatives of the formula I, and a decrease in blood pressure was observed after 1/2 hour, which lasted for several hours. .

Repeated administration of derivatives of the formula I for several days increased this effect.

The test results are summarized in Table IV.

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TABLE IV

Oral administration to awake blood pressure lowering effects

Dogs

key
number Doses mg / kg Reducing the
Blood pressure in % Duration in
hours LA-2510 5
10 '35 1o
40 % 6 h
12 h LA-2511 10 35 % 6.5 h LA-2514 10 20 % 3.5 h LA-2515 10 25 % 8 h LA-25I8 10 17 % 4.5 h LA-2519 10 12 % 4 h LA-2521 10 10 % 4 h LA-2522 5
10 12 io
24 % 4.5 h
6.5 h LA-2523 10 13 % 4.5 h LA-2524 10 16 % 5 h LA-2526 10 η% 5.5 h LA-2527 10 13 % . 4 h LA-2529 10 12 % 3.5 h LA-2530 15th 15 % 6 h

For comparison purposes, 10 mg / kg of a known derivative of pyridinecarboxyl-2-acid, the N- (Diethyl Aminoäthyl-2) Nitro-4 Oxyd-1 Pyridinkarboxamid-2, administered. There was no change in blood pressure.

In the artificially overexcited animal ; with the aid of the technique of Selye, Goldblatt H. and A. (J. Exper. Med. 1934, Vol. 59, 347), hats were placed in a state of extreme excitation. The blood pressure was equal to that of Ben. Civil G. and A. (Arch. Int. Pharm. 1964, Vol. 149, 52?).

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The experiments were carried out on 64 rats, and the blood pressure was measured on the tail of the animal using a photoelectric VerJöirens measured.

The results obtained with derivatives 2510, 2511 and 2515 and the orally in doses of 10 and 25 mg / kg for the first and 20 mg / kg for the second and the third columns are shown in the last three columns of Table V below. In the second Column shows the pressures observed on control rats at the times stated in the first column.

This table shows that the blood pressure decreases gradually with a minimum after 4-6 hours. After 12-24 The old blood pressure will be reached again for hours.

A dose of 10 mg / kg per animal is sufficient to achieve a result that is significant in every respect.

TABLE V

Time
in hours Control
animals 2510
IO mg / kg 6.5 25IO
25 mg / kg 4.4 20th 2511
mg / kg 2515
20 mg / kg 6.0 O 174 s 174 + 4.5 169 + 5.0 172 + 5.6 I74 + 9.7 1 173 η 163 + 5.0 161 + 4.9 165 + 5.6 159 + 10.2 2 174 η 157 + 5.9 147 + 5.2 156 i ⁶ » ⁷ 160 + 11.0 6th 177 η 160 + 6.0 139 + 8.5 I62 + 4.6 168 + 4.1 8th 174 ι 168 + 4.6 150+ 4.5 166 + 5.9 175 + 7.8 24 173 y 175 + 174 + 179 + 6.4 176 + t 6.5 t 3.1 t ^ »9 t 4.8 t 5.4 ; 4.6

The effectiveness of the derivatives of formula I was ayjeh compared to other types of experimental excitation were also highlighted.

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Experiments were carried out on rats which were brought into a state of extreme excitement by contracting the left renal artery and cutting out the right kidney (H. Goldblatt - J. Lynch - E * P. Hanzal - WW Summerwille, J. Exp. Med. 1934, collective volume 59 » ^s · 347) ·" In these experiments the LA-2510 (10 and 50 mg / kg orally), the LA-2511 (20 mg / kg per animal) and the LA-2515 (2, 5 and 20 mg / kg per animal) The pressure was measured externally, without blood, after 1, 2, 6, 8 and 24 hours.

The LA-2510 has proven to be the most effective derivative: a significant decrease in cardiac pressure was achieved after 1 hour and a decrease in both pressures after 2 hours. The duration of action was 2 hours at a low dose and at strong dose 6 hours.

hh.H LA ~ 2> 11 shows a significant effect after one hour · * «ί fJen cardiac pressure. The LA-2515 is at 5 or 20 atf _r / test "oh" ijner or after two hours effective.

Hh i A αν «η *! The same test model was administered daily for two years Vof; h »; n» Jas l, A-25fO (10 and 50 mg / kg) and the LA-2511 (30 mn, / kg} j *: Tißr. - Significant effects were observed during the entire duration of the treatment, and these effects subsided upon treatment.

Eh wurriij still another type of experimental overexcitation firprobt.

In the dog, the branching off of the carotid artery is surgically trained and then immersed in phenol. By the intervention will affect all of the sensory nerves in this animal converge at this point, turned off. Immediately a stable and very high level of overexcitation occurs (between 27 and 30). The effects of some derivatives of Formula 1 administered orally were determined on these animals. _ £ ._

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The results are summarized in the following table:

key
number Dose mg / kg I.
Maximum sink
of blood pressure in % Duration in
hours LA-2510
LA-2511 to to to
Ul ul ul - 30
- 22
- 12 5 h 30
4 h
3 h

The effects can also be felt in the venous tissue, and one effect of these products, which results in a constriction the veins expresses is both by electromagnetic measurement of the amount of blood in the whole animal as well as in one Nutrient solution to determine isolated parts of veins.

Using (Seser's test results, the chronic toxicity determined in the rat. Groups of OK males and 10 females were given oral doses for three months administered:

LA-25IO: 10, 75 and 300 mg / kg / day.
LA-2511: 20, 100 and 300 mg / kg / day.

There were no detrimental influences on the growth, the disease state, the mortality, the number of Blood cells, the number of leukocytes, the substances in the urine, the azotaemia, the glycaemia, the sodium and potassium content in the Blood observed.

The histological examination of the various organs did not reveal any damage.

It was therefore possible to begin the therapeutic experiments with these two compounds in humans.

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2/1211

In healthy, non-overexcited people, a single dose of 400 mg results in a slow, step-by-step lowering of the maximum and minimum pressures, which is around 20 % and begins after 1/2 to 1 hour and lasts for around 4 hours.

The overexcited person was given either a single dose of 400 mg or the same dose two or three times given on the day.

Of course, people react differently to the drug; However, there is always a significant decrease in both the systolic and the diastolic Determine pressure. This decreasing pressure occurs after 1/2 hour to an hour, and with repeated administration of the cans held this state throughout the day at.

A special feature must be pointed out in this treatment become: there is no orthostatic damping; with some It could be corrected to people for whom it was present. ,

Favorable influences have been observed in people with varicose veins or circulatory disorders.

No side effect or discomfort was noted, and the beneficial effect could be achieved by administering new ones Doses are sustained.

In the opinion of the sick as well as the doctors who LA-2510 and LA-2511 have tried, it is particularly effective and well-tolerated means for lowering blood pressure.

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209 8A 11 1211

The large gap between the therapeutic and the toxic dose takes this into account.

The invention also has a therapeutic composition the subject, which in particular has a blood pressure lowering effectiveness, which is characterized by that they are a derivative of the aforementioned formula I and a pharmaceutically acceptable salt thereof as the active ingredient Derivative contains.

The medicament according to the invention can be used parenterally, rectally or orally, in particular in the form of emulsions, suspensions, Juices or sterile solutions containing water.

It can also be in the form of tablets, dragees, capsules or as a gel in doses between 50-1000 mg at 2-8 units each Can be taken 24 hours. Furthermore, the Apply medication in ampoules, each ampoule containing between 50 and 500 mg of active ingredient. The suppositories usually contain 20 - 500 mg of active ingredient. Between 20 and 2000 mg of this form of the drug can be consumed daily administered.

The solvent or pharmaceutical carrier can be, for example, a solid such as lactose, sebum, etc., or a sterile one Liquid, such as water or a sterile oil, or one or more sweeteners, flavoring, emulsifying, stabilizing, dispersing, thickening or lubricating agents.

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Claims (10)

EXPECTATIONS 1. Compounds of the formula NO, —N In the R is a hydrogen atom or an alkyl radical with 1-6 Represents carbon atoms,
Usually a hydrogen atom or an alkyl radical with i - 6 Represents carbon atoms alone, Rp alone a radical of the formula represents where η is an integer from 0-6 and R- is a heterocycle with 3-7 members is, possibly, an alkyl radical with 1-6 Carbon atoms or a radical of the formula - B - N R, Rr wearing, where B is a linear or branched alkylene radical with 1-6 Carbon atoms is the total number of carbon atoms of B and R ^, considered individually, amounts to at least 3, ■ - 18 - 209842 / 1.2 1 1 where R. is a hydrogen atom or an alkyl radical with 1-6 Carbon atoms is and - is an alkyl radical with 1-6 carbon atoms, or R ^ and R ₂ together with the nitrogen atom to which they are bonded form a heterocycle with 3-7 members, which may have an alkyl radical with 1-6 carbon atoms and its non-toxic additional salts. 2. Compounds according to claim 1, characterized in that R- is a nitrogen-containing heterocycle « 3. Compounds according to claim 1, characterized in that R- is an oxygen-containing heterocycle. k. The N- / Xethyl-i pyrrolidinyl-2) methyl7 nitro-4 oxide-1 pyridinecarboxamide-2 and its non-toxic additional salts. 5. The N- (diethylamino-3 propyl) nitro-4 oxide-1 pyridinecarboxamide-2 and its non-toxic additional salts. 6. Process for the preparation of the compounds according to claim i, characterized in that one is allowed to react Compound of formula in which R ^ is an alkyl radical on an amine of the following formula is: H-N No 209842/1211 R, R. and R "have the meanings given in claim 1. 7. The method according to claim 6, characterized in that R ^ is a methyl radical. 8. Therapeutic composition, which in particular has a blood pressure lowering effect and is characterized by that it is a compound of the formula I as defined in any one of claims 1-5, or one of the contains non-toxic additional salts. 9. Therapeutic composition according to claim 8, characterized in that it is in a form suitable for parenteral, rectal or oral administration. 10. Therapeutic composition according to claim 9 »characterized in that it occurs in certain doses, which contain between 50 and 1000 mg of active ingredient. 209842/1211