News amino-5 oxaline-2, their method of preparation like their therapeutic application.

Novel amino-_aminométhy1 2 and 5 oxazoline-a 2.

The present invention relates to novel amino 2 aminomethyl-5 oxazoline-to-2, a process for their preparation and their therapeutic use.

The products of the present invention have the general formula

with R ^, =same or different unsubstituted alkyl (such than CH ^,

C. ^ mmHg)^or unsubstituted arylalkyl (such as benzyl substituted) or aryl (such as

phenyl); the R ^ and R of £may form with the nitrogen atom to which they are attached form a heterocycle such as piperidine derivatives, a pyrrolidine, a morpholine, tétrahydroisoquinoléïne, or pipér-to-IDINEs or piperazine substituted by R with R=lower alkyl Cl to c4, ally, a benzyl, or pyridyl, phenyl unsubstituted or substituted with one or more substituents such as halogen (e.g. chlorine, fluorine, bromine), trifluoromethyl, methyl, methoxy, hydroxyl.

It is known already amino 2 oxazoline-a 2. Thus 1 * amino 2 phenyl-5 oxazoline 2

has been patented by the company McNeil Laboratories Ltd. Incorporated France in the n° 2448m known to be stimulate the central nervous system and its anorexigenic activity. The amino-a 2 (dichloride 3.4 phénoxyraéthyl) -5 oxazolin~2 was tested by Ampere Hours, Abdullah et al. for its cardiovascular activity and anorexigenic (F344 rats, appl. Hyg ., 1973, 26, 513 - 22; 1973, 25, 344 - 53) .et was patented by the

Dow Chemical in the United States under the no. 3637726 9 April 1970 for its antimicrobial activity.

The products of the present invention are distinguished in one amino 2 oxazoline-to-2 already known by the presence in position 5 of the cycle of a substituted aminomethyl. They have pharmacological properties for their therapeutic use especially cardiovascular, psychotropic, antiinflammatory, antiallergic, antihistamine, anti-h2.

These are prepared by condensation, in a solvent such as methanol, of the derivative monosodé cyanamide on i^O amino 1 epoxy-2.3 propan-n-substituë corresponding

THE R "

/

NR

CH_

THE R,

- Ch-ch-" - F.

vBE1/²

O

NaNHCN

The epoxides are conventionally prepared by reacting the amine HNRjR ^ (wherein ^ and R have the meanings indicated

highest) and epichlorohydrin.

The invention is indicated in the following examples without however do not limLtent its range.

Example 1

Preparation of the amino-a 2 nth, n diéthylaminomëthyl-to-5 oxazoline 2.

Formula I with R ^=R.₂ ≈^C 2^5 *

In a reactor equipped with a stirrer, a refrigerant bulb to bromine introduced one mole of diethylamine. Is introduced, with stirring, dropwise one mole of epichlorohydrin in maintaining the

temperature 25 °c. The stirring is continued for 5 hours

3

ambient temperature. 300 Cm of ether is added to the reactor and then 48 g of soda finely pulverized. Stirring is continued at room temperature overnight. Filtering and centrifuging the ether layer.

It is washed by 50 cm of water. After decanting the organic phase is dried carefully on sulfate of Na. The solvent is removed under reduced pressure and the diethylaminoethyl 1 epoxy-2.3 propane is separated by

distilling. 60% Yield. To EB " ≈ 44 and 48 degrees Celsius. Eb__nC =157 °C.

8,760

Has 12.8 g of the cyanamide derivative monosodé 200cra dissolved in anhydrous methanol is added dropwise with thorough mixing 0.2 mole of diethylaminoethyl 1 epoxy-2.3 propan thus prepared. After 15 hours of stirring at room temperature the methanol is evaporated and the residue

3

resumed by 300 cm of ether. The precipitate is removed by filtration. The

3

ether layer is washed two foisfois.par 2 cm of water and then dried on the Na₂ S0 ^ after settlement. The ether is evaporated under reduced pressure. The oil phase obtained crystallizes after washing with 1' boiling heptane derivatives " the amino-a 2 diéthylaminométhyl-to-5 oxazoline 2 is thus obtained in a yield of 68%. It is purified by recrystallization from 1' to heptane.

F=90 °C. Molecular weight 171,

Infrared spectrum: ^ n-L-band!₇ 3360 cm ^ ^ c=n 1680 cm

Proton NMR in L) MSOI) F.>(the R; knockout given the chemical shifts are expressed in ppm relative to strip the PR v - c string internal standard): 5.78 ppm, singlet, 07555

2 proton (the NL ^); 4, 67 - 4, 29 ppm, massive complex, 1 proton abstraction (Η - 5 on ring oxazolin); 3, 78 - 3, 05 ppm, massive complex, 2 proton (H 4 on the cycle of oxazoline); 2, 71 - 2, 31 ppm, massive complex, 6 proton (n-Ch ^);

0.93 ppm, the triplet, 6 proton (Gil - ^).

Example 2

Synthesis of the amiiio-a 2 (n-butyl-n méthylam±nométhyl) -5 oxazoline 2.

Formula I with R, HM=", the R"=C., hr ".

1, 3 2, 4 9

This product is prepared according to the method described in the example 1.

The epoxide intermediate has a boiling point of 44 - 50° under 0,665 millibars.

The final product is purified by recrystallization from hexane.

F=86 °C. Molecular weight 185.

Infrared spectrum 3280 cm VBE1 c=n 1680 cm

NMR spectrum in leDMS0D6: 5.8 ppm, singlet, 2 proton (^ does);

4, 71 - 4, 33 ppm, massive complex, 1-proton (H 5 cycle of oxazoline));

3.78 - 3 ppm, massive complex, 2 proton (H 4 cycle of oxazoline);

2, 62 - 2, 1 ppm, massive complex, 7 proton (- PWC ^ - ^ - n-Gil -);

1.55 - 1.05 ppm, massive complex, 4 proton (C. Ch ^ ^ - HM - C.); 1 - 0, 71 ppm, massive complex, 3 proton (eyelash ^ - C.),

J3 g.

Synthesis of the amino-a 2 pyrrolidinométhy1-to-5 oxazoline 2, formula I with R_{the R}R₂ HM=-₂ - HC₂ - HC₂ IN CU - -

This product is prepared according to the method described in the example 1 with the only difference that the to addition reaction of pyrrolidine and epichlorohydrin is carried out in the presence of ether. The epoxide intermediate has a boiling point of 73 °c under 33.2 millibars.

The amino-a 2 pyrrolidinométhyl-to-5 oxazolLne-a 2 is purified by recrystallization from heptane.

F=123 °C. Molecular weight 169.

Infrared spectrum: ^ the NH₂ C=n 1685 cm ^ ^=3300 cm

NMR spectrum in the DMS0D6: 5.82 FIPD, singlet, 2 proton (NHj);

4, 71 - 4, 29 ppm, massive complex, 1-proton (H 5 cycle of oxazoline);

3, 78 - 3, 02 fIPD, massive complex 2 proton (H 4 cycle of oxazoline);

2, 66 - 2, 31 ppm, massive complex, 6 proton (HM₂ The n -); 1, 87 - 1, 44 FIPD, massive complex, 4 proton (HM₂ THE C -).

Example j4

Synthesis of the amino-a 2 piperidinomethyl-to-5 oxazoline 2. Formula I with^R the^R 2⁼ "^hM₂ "^HM 2^HM 2^{- HC} 2^HM 2 *

This product is prepared according to the method described in the example 1.

The epoxide ' intermediate has a boiling point of 51 °c under 0,665 millibars. The final product is purified by recrystallization from heptane.

F=127 °C. Molecular weight 183.

>ectre 3350 cm ^ ^ infrared ΝΗ, ^ ℮=Ν 1680 cm

in the NMR oectreDMS0D6: 5.8 ppm, singlet, 2 proton (naked ^);

, 77 - 4.35 ppm, massive complex, 1-proton (H 5 cycle of oxazoline);

, 77 - 2.95 ppm, massive complex, 2 proton (H 4 cycle of oxazoline);

, 58 - 2.16 ppm, massive complex, 6 proton (^ - n-Gil); 1, 64 - 1, 2 ppm, massive omplexe, 6 proton (IC ^ - C.).

j5 xemple

Synthesis of the amino-a 2 (pipéridinoraéthylraéthyl and 4) -5 oxazoline 2.

ormule 1 with rj, R.₂ =- Ch-to-CIIg-to-fJH Ch - HC₂ -

gil₃

This product is synthesized according to the method described in the example 1.

' epoxide intermediate has a boiling point of 55 °c under, 665 millibars. The final product is recrystallized in heptane.

¹ =130 °C. Molecular weight 197.

^ ^ Ii infrared Ipectre nor 3260 cm * 1690 cm

in the NMR ipectreDMS0D6: 5.82 ppm, singlet, 2 proton (Niy " μ, 78 - 4.33 ppm, massive complex, 1 proton abstraction (R 5 cycle of oxazoline);

(, 78 - 3 ppm, massive complex, 2 proton (H 4 cycle of oxazoline);

5 - 0, 9 ppm, massive complex, 11 proton (LC ^ - n + h of the piperidine ring);

3.87 ppm, dipole, 3 proton (ch-^).

j6 ïxemple

Synthesis of the amino-a 2 (ethyl-2 piperidinomethyl) -5 oxazoline 2 formula I with R ^, R.₉ =

C₀ Ii_{the R}

This product is synthesized according to the method described in the example 1. The epoxide intermediate has a boiling point of 83 °c under 0,665 millibars. The final product is recrystallized in heptane.

F=114 °C. Molecular weight 211.

Infrared spectrum 3350 cm ^ c=n 1680 cm

NMR spectrum in the DMS0D6: 5.82 ppm, singlet, 2 proton (nor ^);

4, 75 - 4, 33 ppm, massive complex, 1-proton (H 5 cycle of oxazoline);

3, 86 - 3, 05 ppm, massive complex, 2 proton (H 4 cycle of oxazoline);

3 - 2, 05 ppm, massive complex, 5 proton (the Cu ^ - + n-ch-n); 1, 77 - 1, 11 ppm, massive complex, 8 proton (LC ^ - C.); 0.8 ppm, the triplet, 3 proton (ch-^),

7 Exemple_

Synthesis of the amino-a 2 morpholinomethyl-to-5 oxazoline 2. Formula I with R_{the X} the R₂ HM=-₂ - hC₂ the O-CH2 -₂ gil -₂ -

This product is synthesized according to the method described in the example 1. The epoxide intermediate has a boiling point of 67 °c under 0,665 millibars. The final product is purified by recrystallization from SKC₄ .

F=152 °C. Molecular weight 185.

The NH ^ ^ ii infrared spectrum 3340 cm VBE1 ^ C=n 1680 cm

NMR spectrum in the DMS0D6 5.84 ppm, singlet, 2 proton (the NH₂ ), 4, 82 - 4, 38 ppm, massive complex, 1-proton (H 5 cycle of oxazoline);

3.77 - 3 ppm, massive complex, 2 proton (H 4 cycle of oxazoline);

3.55 ppm, the triplet, 4 proton (IC - ^ the O); 2, 58 - 2, 29 ppm, massive complex, 6 proton (HM₇ THE N -).

Example 8

Synthesis of the araino-a 2 (n-methyl-n-phénylaminométhyl) - oxazoline 2 - 5.

Formula I with R=OH, ., r=c, H_.

Ithe I 2 to GOL

This product is synthesized according to the method described in the example 1 except that the throughout the reaction between the n-methylaniline and 1' epichlorohydrin, the reaction mixture is heated with 5q °C. The epoxide intermediate has a boiling point of 105 °c under 0,665 millibars.

The final product is in the form of a oil indistillable. Molecular weight 205.■

Infrared spectrum 3340 cm * ^) θ=Ν 1680 cm

NMR spectrum in the DMS0D6: 7, 4 - 6, 4 ppm, massive complex, 5 proton (H of the aromatic ring.) ; 5.65 ppm, massive complex, 2 proton;

4.89 *=4, 44 ppm based, 4 - 3, 05 ppm, massive complex, 4 proton (ch-^,); 3 ppm, the triplet, 3 proton (ch-^).

Example the j?

Synthè se.de the amino-a 2 (n-benzyl-n méthylarainométhyl) -5 oxazoline 2.

Formula I with R, HM=" C._C.H_, R."=HM, ..

o I-Z-Y ό

This product is synthesized according to the method described in the example 1. The final product is recrystallized in heptane.

F=98 °C. Molecular weight 219,

Infrared spectrum 3490 cm^1680 cm

NMR spectrum in CDCl ^: 7.22 ANC, singlet, proton (H-aromatic)•5. ;

4.84 nPP, singlet, 2 proton (the NH,,); 4, 82 - 4, 48 ppm, massive complex, 1-proton (H 5 cycle oxazolin * ^ 3, 8 - 3 Η, 18 ppm, massive complex, 2 proton (H 4 cycle oxazolin) ; 3, 53 ppb, singlet, 2 proton (HM,, benzyl); 2, 82 - 2, 17 ppm, massive complex, 2 proton (ch-^ in 5 on ring oxazolin); 2.29 ppm, singlet " 3 proton (NCH ^).

0 G.

Synthesis of the amino-a 2 (methyl-4 pipërazinyl) methyl-5 oxazoline 2.

vBE1 R.

Formula I with R, an NR "=CH,,-n-n--,

12, 3

3

To a solution of 0.25 mole.de N-methylpiperazine in 200 cm of ether, is added dropwise to. drop 0.25 moles (23.13 grams) of epichlorohydrin.

The reaction mixture is maintained at a temperature below 35 °c during the addition; it is then heated in a water bath for two hours at the boiling temperature of the ether, 10 grams (0.25 moles) of soda are added finely pulverized. The precipitate is removed by filtration.

3

The ether layer is washed twice by two cm of water and then dried on the Na₂ S0 ^. The solvent is removed and the raéthylpipérazinyl-to-1 epoxy-2.3 propane is separated by distillation.

Boiling point under 1.33 mb=100°>C..

The purity of this product is controlled infrared by disappearance of the strip the NH of the starting amine and appearance of a stripe c 0-c 930 cm

Has 0.1 moles (15.6 grams) of n-methyl piperazinyl-1 epoxy-2.3 propan dissolved

3

in 150 cm of methanol is added 0.1 moles (6.4 grams) of the derivative of the raonosodé

3

cyanamlde in solution in 100 cm of methanol. After 15 hours

stirring at ambient temperature the methanol is evaporated and the residue

3

crN material 200 again in ethyl ether. The precipitate is removed by

3 filtering. The ether layer is washed quickly with 5 cm of water and then dried on the Na ^ ^ OS. The ether is evaporated under reduced pressure.' the amino-a 2 n-methyl pipôrazinylméthyl-to-5 oxazolLne-a 2 is collected as oil that takes into mass and is then recrystallized in CCL is ^.

F.=130° c. yielding 61%. Molecular weight 198. Microanalysis: 9.09 g as calculated %, 54.54% Hr, n-28.28%; found H, 13%, hr 54.41%, n'28.19%.

IR spectrum: bands Preservation Library of_? 3300 and VBE1 3180 cm

strip

C=n 1680 cm

Proton NMR in CDCl ^

2.1 - 3.0 ppm, 13 proton,

3.1 - 4.1 ppm, 2 proton, massive complex, the CLL ^ oxazoline; 4, 4 - 5, 0 ppm, 1 proton abstraction, massive complex, the CHO; 5.4 ppm, 2 proton, broad peak, the NH ^, exchangeable with

Example^11

massive complex

, ÏJîLcH " + ci1₃ to 2.3 ppm

Synthesis of the araino-to-2 (phenyl-4 piperazinyl) methyl-5 oxazoline 2.

vBE1 R.

Formula I with R_{the R}NR_=.C..H..-N-N--.

1, 2 6, 5/VBE1 _

This product is prepared according to the method described in the example 10.

The epoxide intermediate is obtained in crystalline form. F.=89° C.;

(recrystallization solvent of heptane).

The final product is purified, by recrystallization from 1' to heptane.

F.=174° c. yielding 51%. Molecular weight 260. Microanalysis ii calculated 3, 7.69 the X, X-64.62 hr, n-21.54%; found C. 7.60%, 64.40% hr, n-X-21.34.

IR spectrum: strips of NH_? 3330 and 3180 cm strip c=n 1670 cm

1Mn proton CDCl ^

2, 3 - 4, 1 ppm, 12 proton, massive complex, ch-^ 6; 4, 5 - 5, 0 ppm, 3 proton, nassif complex, the CHO + exchangeable with d ^ O-; 6, 7 - 7, 5 ppm, 5:>letlet us rotons, massive complex, aromatic protons.

Example 12

Synthesis of 1 'amino-to-2 (benzyl 4 piperidinyl) methyl-5 oxazoline 2.

Formula I with R ^ an NR_? HCG=^ ^ HC (

This product is synthesized according to the method described in the example 10.

3on yield ' and of obtaining 46 is %, It is purified by recrystallization ians 1' to heptane.

F. 114° C molecular weight=273. IR spectrum: strips of NH₀ 3320 and

-1 _i D' ¹

3160 cm, c ≈ n-1635 cm strip.

Proton NMR in CDCl ^

1, 1 - 4, 1 ppm, 15 proton, massive complex, 7 + ^ c-ch-piperidine;

4, 4 - 5, 0 ppm, 1 proton abstraction, massive complex, the CHO; 5.1 ppm, 2 proton, broad peak, the NH ^, exchangeable with ^ 0, 0; 6.9 - 7.4 ppm, 5 proton, massive complex, aromatic protons.

Example 13 ___

Synthesis of the amino-a 2 (benzyl 4 piperazinyl) methyl-5 oxazoline 2.

vBE1 R.

Formula I with R, NR in₀ =C., HR_C. HM " - - N-N-.

12652 vBE1 J.

This product is synthesized according to the method described in the example 10.

Its efficiency of obtaining is 48%. It is purified by recrystallization from 1' to heptane.

F. 96° C molecular weight=274. Microanalysis calculated 8.03% C., 65.69% hr, n-20.44%; found C. 8.06%, TFs 64.93%, n-20.34%.

IR spectrum: ^ ^ 3310 and strips the NL VBE1 3160 cm c=n 1680 cm strip

Proton NMR in CDCl ^

/ VBE1

2.2 - 3.0 ppm, 10 proton, massive complex, -] ^ - ^ n-LC; 3, 1 - 4, 1 ppm, 4 proton, massive complex, ^ ^ c-ch-benzyl + oxazoline; 4, 4 - 5, 0 ppm, 3 proton, massive complex, CHO-exchangeable with the NH + ^ d £0;

7.2 - 7.4 ppm, 8 proton, massive complex, aromatic protons.

Example 14

Synthesis of the amino-a 2 (allyl 4 piperazinyl) methyl-5 oxazoline 2.

/ - V.

Formula I with R, RH==ch-ch c1l-n-n--.

1 z. j-L \ α

This product is synthesized according to the method described in the example 10.

The epoxide intermediate has a boiling point of 67° c in 1 mb. The final product obtained in a yield of 43% is purified by recrystallization from heptane.

F. 99° C molecular weight=224. Microanalysis: calculated C. 8.93%,

Hr 58.93%, 25% n-; found C. 8.93%, 58.01% hr, n-24.99 %.

IR spectrum: 3200 and 3160 cm strip c=n 1690 cm strips

Proton NMR in CDC1.

2, 2 - 4, 1 ppm, 14 proton, massive complex, HM - ^ - ^

hM₂ hM +₂ ' oxazoline; 4, 4 - 6, 3 ppm, 6 proton, massive complex, HC₂ ≈ - + + CHO-HM

THE NH

₂ to 4.9 ppm exchangeable with 0₂ 0.

The pharmacology of products of the present invention are exposed hereinafter.

Toxicity has been determined in the mouse for various routes of administration. Table n°l gives the percentages of based on the administered dose.

* Percentage mortality at doses of *** oral 300 mg/kg body weight intraperitoneally '* - 200 mg/kg * 200 mg/kg * 100 mg/kg.

The product of the example 1 present after administration by ' IV in mouse a LD 50 of 128 (116 - 142 mg/kg.).

The ^ antil antihistaminic activity was determined in vitro on right atrium of spontaneously flap model. Thus the products of examples 1, 2, 6, 13 to inhibit 50% more than the concentration of

100 microg/ml of the chronotropic effect microg/ml. 5 induced by histamine, without having a intrinsic chronotropic effect. The product of example 14 has this activity to the 5.0 microg/ml of concentration.

The positive inotropic activity was determined in vitro on electrically stimulated guinea pig left atrium. The product of the example 1 100 microg/ml is driven to 100% increase of the contractile force of the atrium.

The antiallergic activity was determined in rats in testing the skin passive anaphylaxis. The animals sensitized by intradermal injection of allergen receive immediately after administration of the product to be tested ' by intravenous injection of ovalbumin and place Evans. The products of examples 3 and 4 to 10 mg/kg respectively thereupon drive 53 and 60% inhibition of the spot. evans blue. The product of L|example 11 driven 60.% inhibition when administered to 100 mg/kg body weight orally.

The diuretic activity was determined in rats subjected to a state iydric and enjoyed by the ratio of sodium excreted ctiez treated animals sodium excreted in control animals. The products of 3 and 7 ïxemples multiply the sodium excretion by 4.2 and respectively provided with a dose of 20 mg s9/kg orally bone.

hypocholestérolemiante activity was determined in mice subjected to a diet high in cholesterol and cholic acid during 7 days. After oral product of the example 6 at the dose of " 00 mg/kg and the 6° 7° day, noting a decrease of cholesterol level of 21%.. the such a drop. cholesterolemia is accompanied by a decrease in 20 7, lDL-density lipoprotein fraction, the HPL/cholesterol ratio being equal to 1.01.

Psychotropic antidepressant activities are highlighted in the following tests. The products of examples 11 and 12 administered to the oral dose of 100 RAGs/kg to potentiate the toxicity of yohimbine.

The product of example 11 to 50 mg/kg body weight administered orally inhibits the ptotic induced by reserpine.

The anti-inflammatory activity has been shown in testing to chezchez.le carrageenan edema rats. The product of example 11 delivered orally at the dose of 100 mg/kg of driven expiration of 4 hours 35% inhibition of edema to the carrageenan. With the dose of 200 mg/kg body weight administered per this product is very little nonulcerogenic.

The antiHj antihistaminic activity was determined in vitro on

model of ileum. The products of examples 11 and. 13 inhibit more than 80 7, contractions in the ileum of model induced by histamine when used respectively to concentrations of 25 and 100 tuicrog/platform of the vehicle.

In vitro the product of example 11 driven to the concentration of 25 tnicrog/ml., 80% inhibition of serotonin-induced contraction of ileum on model.

Antiulcerigene activity is demonstrated in testing stress ulcer. The product of example 11 administered to the dosed 25 mg/kg orally ' 88 driven bone 7, inhibiting rat stress ulcer.

In the spontaneously hypertensive rat model, the product of the example 13 administered at the dose of 100 mg/kg orally causes a drop in the pressure of 14 and systolic•respectively 15% to the deadline two and four hours. The product of example 14 administered at the dose of 100 nanograms/the LCG under the same conditions causes a reduction of 21% of the systolic pressure after expiration of six hours.

In view of their pharmacological activities toxicLté joined to a relatively low the products forming the subject of the present invention may be used in human or animal.

Vlnsi, associated with suitable excipients, they can be used in the treatment of depressive conditions, inflammatory conditions and edematous, the the asthma attack or any allergic condition, hypertension îrtérielle, hypersecretions of gastric, ulcers gastroduodenaux, costs EUR. positive inotropic activity ratings for usage in treating acute or chronic heart failure. Their properties allow liuretic very useful in treatment of edema and retentions hydrosodés. Their properties allow them to hypolipidemic îmployer in cholesterolemia and hypertriglyceridemias resistant regime.

They will be administered for example orally in the form of Iragées, tablet, syrup, bulbs, rectally as of juppositoires, intramuscularly or intravenously or orally in the form of salves lopic gel applications. The dosages administered will vary îelon the indication and the subject of 1 to 100 mg/2 to 6 j as taps for the channel irale, thence 100 mg/1 or 2 j as taps for rectal route, of 0.5 to>0 mg injection for parenteral routes. They can also Industry employed e.g. in the form of inhalable nébulisats.