DE2121831A1 - Chemical compounds such as pyrrole ethers and alcohols for therapeutic use - Google Patents

Description

Chemical compounds such as pyrrole ethers and alcohols for therapeutic use.

The invention relates to chemical compounds for therapeutic use, relating to ethers and alcohols refer to, which are related to pyrrole.

So far one has little ethers and alcohols of a pharmacological one Subject to investigation. Beta-pyrrolyl-ethanol and gamma-pyrrolyl-ethanol have local anesthetic properties and found in (dimethyl-2,5 pyrrolyl) -3 propanol-2. When examining agents for antispasmodic Properties, the (methoxy-ethyl) -1 dimethyl-2,5 pyrrole has proven to be ineffective.

The object of the invention is to find new chemical compounds of the substances mentioned at the beginning that are suitable have therapeutic effects.

_ 2 109849/1974

—2—

A solution was found in chemical compounds according to the formula

CH ₃

- CH ₂ - CH - R ₂ (I)

are constructed, where if R is a phenyl, H ₁ can be H, while R ₂ is OCH ₅ , OC ₃ H ₅ , O (CH ₂ ) ₅ N (CH ₅ ) ₂ , CH ₂ OCH ₅ , 0 (CHg) ₃ OC ₂ H ₅ .. can be

'or when R _{1 is} CH, while then R _{3 is} OCH, or when R _{1 is} OH, while then R _{2 is} CH ₂ N (C ₃ Hp.) ₂ , and when R is methyl and R _{1 is} H. , while then R ₂ equals OC ₃ H ₅ , CH ₂ OCH ₅ , CH ₂ O (CH ₂ ) ₂ OC ₂ H ₅ , 0 (CH ₂ ) _? Is N (CH ₅ ) _g,
or when R _{1 is} OH, while then R _{2 is} CH ₃ NiC ₃ Hr) ₃ .

As can be seen from the following, a particularly useful compound is represented by £ (Mmethylamino-3-propoxy) -2jt "thyl]] k 1-methyl-2-phenyl-5 pyrrole.

You can build up according to the formula I compounds by reaction of the phenacylacetone or the acetonylaoeton with the Produce amino alcohol or the amino ether according to the formula

H ₂ N - CH - R ₂

^R 1
where R ₁ and R _{3 are} as defined above.

- 3 - 109849/1974

Those compounds which correspond to formula I and Ether compounds can also be represented by etherification the corresponding alcohols are obtained.

The two manufacturing methods are described in detail below.

Method A ;

1. The starting point is acetonylacetone.

Mol in an Erlenmeyer flask of 100 ml were mixed for E4N 0.1 + 5 i ° excess gamma diceton and 0.1 mol Aminoäther or aminoalcohol. The reaction is generally exothermic; When it has calmed down, it is placed in a reflux vessel and held there for 15 minutes, the water is then eliminated by distillation under atmospheric pressure and the residue is then distilled under a vacuum of 0.1-0.2 mm Hg.

2. The starting point is phenacylacetone.

A mixture of 0.1 mol is heated in the reflux vessel. Gamma-dicetone and 0.1 mol. + 20 $ excess of amino ether or amino alcohol in a time that varies between 2 and 12 hours (e.g., for the compound in R 972, which will be explained later, 2 hours; for R 961 4 hours; for R 963 7 1/2 Hours; for R 966 12 1/2 hours).

109 * 849/1974

One can easily find these times through the VerscLwinder of the

Determine cetone by infrared or gas phase chromatography or by measuring the amount of water formed.

In the case of phenylacetone and, on the other hand, of acetonylacetone, it is important to use an excess of amine, because this gamma-dicetone often gives an azeotropic one Mixture with the pyrrole depending on the ether formed.

Method B:

In a »reaction vessel of 500 ml with a stirrer is provided, 0.2 mol of pyrrole alcohol is added to 50 ml dissolved in dry toluene. The solution is placed in a reflux vessel and 0.2 mol is added there one after the other Sodium divided into fine lamellas is added. When all of the sodium has reacted (this may take 6 to 8 hours take) the temperature is about 40 °; then halogens of alcohol or dialkülamino alcohol (0.3 mol) added on two or three times and all over again about one

Hour put in a container to let cool, educated Ittayl

The / sodium halogen is air dried, several times with / ether washed. After evaporation of the ethyl ether and then of the toluene in vacuo, the residue is also distilled under a vacuum of 0.1 to 0.2 mm Hg.

109849/1974

In the following table I are the test numbers of the compounds of the formula I, as well as the manufacturing processes used, the yield, the boiling or melting

point in C and the breaking index contain:

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109849/1974

The pharmacodynamic effects of the ± ix pyrrole alcohols and ethers in Table I are shown on the living organism and in the

Laboratory examined with the usual techniques. A. Experiments on the living organism

1. Highly toxic behavior.

It has been examined on parts of ten male mice weighing 18 to 22 g. The fatal dose of $ 50 for each administration (intraperitoneally and orally) is according to the method of KlHBER and BEHRENS and according to the graphical method logs probit
has been calculated.

2. Effect on the central nervous system. a - effect on the postural reflexes

The rotating bar technique was used to study equilibrium reflexes in the mouse.

The so-called "pulling thread test" was used to investigate the possibility of recovery of the mouse, whereby this was hung with the hind paws on a horizontally stretched metal thread.

b - Enhancement of anesthesia with hexobarbital.

A barbituric compound, hexobarbital, is administered intraperitoneally in a sleep-promoting dose of 75 mg / kg to the Maua.

1 09849/197 4

The previous administration of a substance containing a Causes anesthesia, transmits its effect on the central nervous system over the course of time.

c - antispasmodic effect.

The! the pentetrazole or the dash nin

examined by prior administration of agents to be studied.

d - analgesic effect.

An analgesic effect is examined in the mouse using two techniques:

the Eddy method (heated plate); - the EMELE method (phenylbenzoquinone).

3. Effects on the cardiovascular system.

This effect is measured in a cat according to the arterial pressure of the head artery or by means of a mercury manometer na ^ h IUDYfIG examined.

The variations in the rhythm and amplitude of the breathing movements are examined with a drum from MAHEY, those with the vein by inserting a flexible catheter

is connected. -

109849/197 4.,

The vasomotor effects of certain products that are found to be relaxing are examined in a dog. The blood flow of a femoral artery is determined with an electromagnetic flow meter. The flow differences, the differences in pressure in the head artery and the amplitude of the breathing rhythm are registered simultaneously by a multiple writer.

4. Effect on the autonomic nervous system.

The experiments are carried out on a cat.

Administration of a product can cause reactions

change tension with different means: adrenaline,

Norepinephrine, acetylholine and histamine.

5. Other antihistamine effects.

after she is examined at the cat and sway-mi ^ ele of

HALPEM technology on a guinea pig. It consists "in the fier against the effects of a lethal dose of histamine in the form of the aerosol by injecting one too to protect the studying product.

B. Experiments in the laboratory .

Experiments in the laboratory on isolated intestinal fragments serves to clarify the spasmolytic effect of a substance see below.

- 9 109849/1974

This spasmolytic effect is found on the ileum of the guinea pig which is subject to a stiffening effect of the histamine or the serotonine or of nicotine and on the duodenum of someone who had the effects of the Ae etJSyl chains or barium chloride is subject.

The experiments which were carried out with the compounds of Table I gave the results set out below guided.

The compounds are not very toxic, they are higher than 500 mg / kg in the case of intraperitoneal administration at the mouse.

It has also been established:

- in the central nervous system:

a gain in barbituric anesthesia of $ 180 at 50 mgAg »I.P. for the connection E 978 and $ 120 for the compound R 966 at 200 mg / kg, I.P. at the mouse in both cases;

b a protective effect of $ 20 for the animals that the kraapf

triggering effect of pentetrazole with the compounds R 967 and 968 with 200 mg / kg are subjected;

- in the heart vessels:

some undervoltage, but short-lived for the connections R 967, 976 and 1006 and overvoltages for R 963, 966 and 972 and a medium increase, but permanent

10-9949- / 197 4

for femoral artery flow in the dog for compounds H 967 and 978. Finally, the effects on the smooth muscles were found to be very constant in this series, as can be seen from the following Table II.

- 11 - -

109849/1974

Table II V. Effect on the smooth muscles

ί · - ■
No. dose Inhibitor dose
effect Jo 5x10 ~ 6 ' * nhib. nicotine -1 1- Duodenum dose Owner 12th ' \ Owner
V / i rk. '> 0 1 R 963 10 "" ⁵ 37 41 dose 2x10 ~ 5 43 0 0 0 > R 585 2.5x1O * "5 66 5.75x10-5 1.5x10-6 2.5x1O-5 19th 29 Bariiimchlorür 51 50 - »R 961 up to 2.5x10 ~ ⁵ 0 5x10-6 40 ΙΟ- ⁶ to 2.5x1O ~ ⁵ O 16 ^ Dose up to 2.5x10 "5 ο 43 N) I " Crooked co R 967 up to 5x1O ~ ⁵ 0 10-5 43 5x10-5 2x10 " ⁵ ■ 50 up to 2XiO ^-5 up to 5x1O "5 55 A. £ R 968 2x10 "* ⁵ 36 30th 2.5x10-5 Acetylcholih to ΙΟ " ⁵ 0 2.5x10 "5 up to 5x1O "5 24 <° R 976 ΙΟ " ⁶ 60 1.5x10-5 ^ nh'ib.
V, ^r irk./i 5x10-6 0 10-5 0 - * R 978 5x10-7 75 62 3x10-6 41 4x10-6 0 ΙΟ " ⁶ 0 Histamine serotonin S R1006 1.6x10-5 42 Jis 5x10 "" - 44 1.5x10-7 50, 5x1O "5 10 " ⁵ * "R 966 until 10-5 0 5x10-6 0 2.5x10-5 55 up to 2x1O "5 2x10 " ⁵ R 972 until 10-5 0 * x10 "6 0 10-5 64 5x1O "5 up to 2x10-5 R 973 4x10-6 30th 0 1.5x10-6 57 to ΙΟ " ⁵ to 10 ~ 5 up to 2x10 "* 45 48 45 30th 60 ■ o

- 12 The effect of the connection R 978 is particularly remarkable.

This connection, which also enables, the barbituric anesthesia to be carried out in the mouse and to increase in a permanent manner the flow of the femoral artery in the dog, can be used therapeutically for ailments that are antxhistamic as well as antispasmodic and require anti-serotonin treatment.

The compound can be found in a pharmacy as a means for parenteral administration (intravenous or intramuscular) or for oral administration in pressed form or in the form of suppositories.

- 13 109849/1974

Claims (10)

PATENT CLAIMS: exist, where if one R is a phenyl, R .. can be H, while R ₂ is OCH ,, OC ₂ H ₅ , O (CH ₂ ), N (CH ₃ ) ₂ , CH ₂ OCH ^, O (CH ₂ ), OC ₂ H ₅ , or when R _{1 is} CH ₃ while then R _{2 is} OCH-, or when R ^ is OH while then Rp is CH _n F (C ₂ H ₅ ) ₂ , and if R is methyl and R .. is H, while then R ₂ is OG ₂ H ₅ , CH ₂ OCH ₃ , CH ₂ O (CH ₂ ) ₂ OC ₂ H ₅ , ο (CH ^ NiCH ^, or when R _{1 is} OH, while Rp then represents CHpN (CpH ₅ ) ρ. 2. Compounds according to claim 1, characterized in that they are Γ (dimethylamino-3 Propoxy) -2 ethyl ~ | - Contain 1-methyl-2-phenyl-5 pyrrole. 3. Compounds according to claim 1, characterized in that that they are (methoxy-2-ethyl) -1, (methoxy-3 propyl) -1 and (methoxy-2 propyl) -1 ifethyl-2-phenyl-5 Pyrroles included. -H-109849 / 197A 4. Compounds according to claim 1, characterized in that that they (methoxy-3 propyl-1 "(Dimethyl amino-3 Q ethoxy-2 ethoxy) -3 propyl -1, propoxy) -2 ethyl "! -1 dirnethyl-2,5" ~ pyrroles contain 5. Process for the preparation of the compounds according to one of the preceding claims, characterized in that that the reaction of the phenacylacetone or the acetonylacetone with the amino alcohol or the amino ether according to the formula HTST ΠΤΤ T) pJM - L / il - xtp runs, where R, and Rp according to claim 1 are determined. 6. A process for the preparation of compounds according to the formula (I) mentioned in claim 1, characterized It is indicated that the corresponding alcohols are atherified in the ether compounds. 7 Medicines characterized by that it contains one of the compounds mentioned in claim 1. 8. Medicines, which are antihistamine and antispajfmolitic and has antiserotonitic effects, produced according to one of the preceding processes, characterized in that it the compounds according to claim 2 contains. 109849/1974 9 · Medicines that are antihistamine and antispasmodic and exerts antiserotonitic effects, produced according to one of the preceding processes, characterized in that it contains the compounds according to claim 3. 10. Drugs, which are antihistaminic and antispasmodic and exerts antiserotonitic effects, produced according to one of the preceding processes, characterized in that it contains the compounds according to claim 4. 109549/1974