LU81835A1 - ALKYLENE-DIAMINES DERIVATIVES AND THEIR PREPARATION - Google Patents

Description

This certificate of addition relates to alkylc · -} nc-diamine derivatives and their preparation.

1.1 J -

In main patent application No. 80.880 have been described compounds of formula (I) 5 CH3 ° \ ^ N-C H- -N-CO-R. / τλ 1 n 2n 1 î1) R.

ch3 <zj!

NH2 I

! in which i

10 R and R „each independently represent one another, an ato 1 2 - I

me -dénydrogen, an alkyl of 1 to 4 carbon atoms, or the radical "benzyl,. .

(n is equal to 2.3 or 4, and j R represents either a cycloalkyl radical of 3 to 6 carbon atoms

• I- (CH2) m I

- a radical-J— where m is 0, 1 or 2; be a radical · | j I- (CH-) m! or a radical -4- j where m is 0, 1 or 2 and p; 20 is 0, 1 or 2- d

<°> p I

The Applicant, after numerous structural studies, realized that formula (I) did not correspond to the structure of these compounds and that there was an inversion between the radicals R ^ and R ^.

The comoosés of the invention in fact give up the formula (I bis) j i! ! !

:: nxi - N N-C H_ -N-CO-R

I n 2n j:! T 1 52 Ri (Ibis> i 'ch3 <> AA <^

; / SEEN

! ‘1 2 J

in which i R and R „each independently of one another, represent an ato-1 2 -“ | me of hydrogen, an alkyl of 1 to 4 carbon atoms, or the benzyl radical, 5 n is equal to 2.3 or 4, and R represents either a cyclcalkyl radical of 3 to 6 carbon atoms; I— (CH-) j is a radical —J— 1 where m is 0, 1 or 2; j is a radical —j-j- [j or —j— jj; j 10 j I- (CH2) m ’is a radical —J— I where m is 0, 1 or 2 and ρ: is 0, 1 or 2.;

"Wp_ _ I

The new compound structure (Ibis) has been confirmed by numerous studies of IR and RMiî spectra.

The structure of the compounds (I) follows from the structure of the intermediate amines (III) which are condensed on the 6,7-dimethoxy which; nazolines (II). ; **. i i

The structure of the amines (III) does not correspond to the formula j 20 (III) 'i R.HN-C EL · -N-CO — R 1 1 n 2n i I! R2 i! but to the formula (III bis)

i R.HN-C K- -N-COR

j 2 n 2n j, i25 ·· R.

If- ·· - 1 I! i! Ξη in particular, the intermediate amines in which R, is H,! :; 1 day; - obtained because reaction of an aminonitrile R-HN-C, _-CN with! ; "2 π-l 2n-2:? · RCOOH acid (or one of its functional derivatives) then reduction j i of the intermediate compound RCGHC H- CH,

"; f 1 Π-χ · iTi — sL

t 1: <1

13. J

! i corresponding to the formula (III bis) j:! 1 R-CO-N-C H_ -KHR. . \ | n 2n 2> I 'H! 115 13

N NMR spectrum and C NMR spectrum confirm the structure

S

5 of the amines (III bis).

In particular in the case where R = H and R = CH- and n = 3 # the amine | intermediate (III bis) to the formula i j ί CH-KN-C-H - N-CO-R! ! 3 3 6 d! H · ί i

IF

j,! | LO is a secondary axnine. j t i I Now in the main patent the intermediate amine was represented! because the formula (III) · I ·. -:! H_N-C-H - N-CO-R î 2 -3 6 j L5 CH3 i

and was a primary amine. * J

However, the 2 NMR spectra confirm the secondary amine structure:! indeed i the NMR spectrum ^ N: the spectrum coupled in nitrogen 15 gives -> q a doublet centered at 90.4 ppm / ^ NH ^ ti N03 corresponding to nitrogen amidicu (ljl5., „= 91.5 Hz) and a sinçulet to | 1.6 ppm / 1 ^ NH4 ’,„ N03. He didn’t go | of couolace with hydrogen this one i i! ; 25 *; ci being very mobile (its speed i h.,. '* iT-i.

i I; g ecnange is greater than J).

Mi i i ‘i!. !

L4 J

* 13 the NMR spectrum ç: the carbon spectrum 13 gives CEL forj · a sizing J = 132.5 HZ -3 '1.3 CH j characteristic of a group CH ^ -HN- L ·' amine (III bis ) is therefore a secondary amine.

5 Chemical considerations relating to the reduction of the intermediate nitrile; RCO-N-C .H. nCN! j n-1 2n-2 j: also made it possible to confirm the structure of the amines (III bis) 1.

1-0 In fact, the catalytic reduction of the intermediate nitrile leads, according to the reduction conditions, to the primary amine (III) and to the secondary amine (III bis) which is formed because cleavage of a tetra- hydropyrimidine intermediate; \! -5 - R-C / i /. i t. j l. . j ·! sometimes isolated during reduction. ! t i j

The following references confirm this reaction: i t • ÎO the French patent 1,415,468 (Arraour and Co.) and the article by Haliiia i

Mikolajewska and Antoni Kotelko (Akad. Med., Lodz). Acta Polon. ! Pharm. 22 (3), 219-24 (1965) (Pol), reproduced in C.A. € 13, 17891-1965]

The Applicant has checked in the particular case of the final comoose

(CH2 ’3-fC ° - O

25 | 1 tH H

• 1 ^ 1J / Vj "3 i!; NH2!; F Ri = H es I; / -. (I bis) i _

I · LO

I that during the reduction of the nitrile LJ — CO-N- (CH ,.) -CN, (intermediate or | i 2 2 I CH3 preparation of the amine condensed with quinazoline) a mixture of the 5 two amines _CO-N- (CH2) j-NH2 (III) CH3 j and

"I — I

l J— CO-N- (CH2) 3-NH-CK3 (III bis): 10 1! i which have been separated by chromatography and the structure of which has been verified j. i i i

; · I

The "Applicant has observed (. That the amine (III) reacts only slowly with L5 quinazoline (II) under the conditions described:.. That the amine (-III bis) reacts quickly with quinazoline (II) .

. and that, over time, the amine (III) becomes ei amine (III bis).

Consequently, the final compounds correspond to the formula (I bis).

Furthermore, the Applicant was able to synthesize the final compounds. Because another orocede yes' also confirms the structure (I bis) Γ; since the compounds obtained by this new process have the same | At this fusion, the same physical characteristics and the same spectra as the compounds obtained by the process described in I! orir.cioal patent.

L.ç. J

This new process consists in reacting a quinazoline (II) \ nh2 -5 with a nitrile R2-NH-Cn-1H2n-2-Ct 'j then in reducing the intermediate nitrile obtained in compound a3 ° wVrcA ^!

T f] sî I

i 10 NH0! Z 1. '. . ! which is reacted with a .RCOX compound to obtain the final compound j (I bis)

ÏÏj 'K2 H

13 d NH- ’2 i î j

The following examples illustrate the preparation of the compounds (I bis) The first example repeats the process of the main patent.

! ii '"!: -The 2nd and. 3rd examples illustrate the new process ae preoaraei! i.' 'ii il 1! 20! i EXAMPLE 1 v N„ - {4-amino-dimethoxv-6,7 çuinazolyl-2) ^ % -méthvl;! ii 1 *:! I j! · IN? -tétrahydrofuroyl-2 propylenedia.nsrne et son me-!!:; j 'nochlorhydrate.

'I.

[·, ·· .ν ", ..... -f)!

f-7 -J

Tetrahydrofuioic acid-2 is prepared according to the method of Kauf -; I man and Adams (J. Am. Chem. Soc. 1923/45/3029). This acid boils down! 84 ° under 0/1 mm Hg.

... - 1

34/8 g (0/3 mole) of tetrahydrofuroic acid-2 and 5 / 30/3 g (0/3 mole) of triethylamine are dissolved in 250 ml of tetrahydrofuran

The solution is cooled to 0-5 ° and 32/4 g (0/3 mole) of ethyl chloroformate are added dropwise while keeping the temperature below 5 °. When the addition is complete / the mixture is stirred for another 1/4 hour and then a solution of j [0 25/2 g (0/3 mole) of 3-methylamino-propionitrile in 100 ml of j tetrahydrofuran is added slowly. The mixture is kept at a temperature below 5 ° for 1 hour, then it is left to stand for: overnight at room temperature. The precipitate formed is filtered, J j the solvent is evaporated from the filtrate and the residue is distilled. The cvano-2 N-methyl-N-tetrahydrofuroyl ethylamine] was thus collected, which boiled at 118-120 ° under a pressure of 0.05 mm Hg.! i

9.1 g of this nitrile are hydrogenated at 40 ° under a pressure of 50-6 atmospheres of y- i i, in solution in 100 ml of ethanol J

S closing 1% ammonia and in the presence of 10 g of rhodium on aluminum. When the absorption of hydrogen is complete, the catalyst is filtered, the solvent is evaporated and the residue is distilled. We collect!

Ila N ^ -methyl ^ -tétrahy'drofuroyl propylène-âiamine which boils at j n i 114-116 C under 0.07 mm of Hg .;

The IR spectrum shows the disappearance of the band due to the j 25 -C = N radical. j

A suspension of 3.7 g is then brought to reflux temperature: (0.02 mole) of the preceding amine, 4.8 g (0.02 mole) of 4-amino-2-chloro-6-dimethoxy, 7 quinazoline in 35 ml isoamylic alcohol '

Boiling is maintained for 7 hours, the mixture is left i 30 i overnight, then the precipitate is filtered and washed with | ? ~ * ~ j: ethyl acetate and then ether.

"* I!

j I

j | The filtration mother liquors are evaporated to dryness and the residue i = obtained is triturated in acetone. We will get a precipitate that! i "i

[AJ

’Thanol and ether. There is thus obtained (4-amino-dimethoxy-6,7 quinazolyl-2) hydrochloride N ^ -methyl N2 * -tetrahydro £ uroyl-2 prc-pylene-diamine which melts at 235 ° C (dec.).

EXAMPLE 2 N ^ - (4-amino dimethoxy-ô, 7 quinazolyl-2) N ^ -methyl 5 N2-tetrahydrofuroyl-2 propylenediamine and its hydrochloride. i

The mixture is heated at reflux temperature for 5 hours. of 14.4 g (0.06 mole) of 2-chloro-4 amino-dimethoxy-6,7 quinazoline, * 10 g (0.12 mole) of 3-methylamino propionitrile in 100 ml of al-! . L0 cool isoamylic. The precipitate is filtered off after cooling and washed several times with hot ethanol. ! i

12.1 g of N ^ - (4-amino-dimethoxy-6,7 quinazolyl-2) are thus obtained! N ^ -methyl-2-cyanoethylamine melting around 270 ° C * i *! \ / ·! 15 In a 250 ml autoclave, hydrogenation is carried out at 80 kg of pressure at 70 ° C. in the presence of Raney nickel, 5.65 g (0.0196 mol) of the above nitri-le in 120 ml of 15% ammoniacal ethanol %. !

. I

The catalyst is separated, the solvent is evaporated and the residue is taken up! residue with methylene chloride to separate a slight insoluble matter, then the solution is concentrated to dryness; the amine obtained after evaporation is converted into the hydrochloride in isopropanol with the theoretical amount of hydrochloric ethanol. We recrystallize "! | twice in isopropanol. ;

3 g of N ^ - (4-amino-dimethoxy-6,7-quinazolyl-2) N ^ -methyl 25 ‘orouylenediamine are obtained, melting at around 270 ° C.

J

| A solution of 0.937 g (0.0065 mole) of furoised tetrahydrous acid, 1.37 g (0.0085 mole) of carbonyl-diimidazole in 30 ml is stirred. what TH? for 10 minutes at 20 ° C, then heating to 40 ° C for:)! i! 30 minutes until the end of this decomposition of carbon dioxide.

(--9 J

at reflux for 1 h 30. The solvent is evaporated off and the 2N sodium hydroxide is added to the evaporation residue. We grind it then decant the soda. The residual oil is taken up in chloroform. We wash! the organic layer with 2N sodium hydroxide, dried over ira-5 cesium sulfate and evaporated in vacuo.

The residual amine is converted into the hydrochloride in Isopropanol by adding the theoretical amount of hydrochloric ethanol. 1/84 g of N .- (4-amino dimethoxyi i 6,7 quinazolyl-2) Nj-methyl N2 ”tetrahydrofuroyl-2 propylenediaminej LO, melting at 235 ° C., is obtained. !

* I

The product obtained is identical in TLC to the product of Example 1. j i (

The melting points of the products of Example 1 / of Example 2 and of the mixture of these are the same. j% i EXAMPLE · 3 N, - (4-amino-dimethoxy-6/7 quinazolyl-2). N -methyl |

- "T — 1 - '- 1 I

15 - ^ -cyclopentyl-carbonyl propylenediamine and bran; monohydrochloride.

S In a 100 ml Erlenmeyer flask, stirred 1/6 g (0/014 mole) of cyclopentane-carboxylic acid, 2.2 g (0.014 mole) of carbonyldiimida- j _ i zole dissolved in 30 ml of THF . The mixture is heated to 40 ° C! t 120 until the end of carbon dioxide evolution. 2.9 g (0.01 mole) of N - (4-amino-dimethoxy-6,7 quinszo- | 1 i lyl-2) Nj ^ -methylpropylenediamine are then added at once, and the solution is heated to the reflux temperature for 3 hours. ; lj i | The solvent is evaporated off and the residue is taken up with 2N sodium hydroxide.

The residual oil obtained after decantation is taken up in chloroform. The organic layer is washed twice with 30 ml of marigold ‘i 2S and dried over macnesium sulfate.

Mi j i! ! ; i; The residual amine is converted into the hydrochloride in iscj J j j: propanol in the usual manner. This gives the chlcrhycrat; ! ; 30i: N - (4-amino-6,7-dimethoxy-2-quinazolyl) N ^ -methyl N ^ -cyclcpenfy:

This compound is identical to the product previously obtained by the method described in Example 1, when the radical R is the cyclopentyl radical instead of the cetrahydrofuryl radical.

/The ; | he ! * i f! i

y - I

: i i

J

he ! i! i i i * i i!: i | ! ! ! : i: t · i) i I 11 j i i In the following table are represented the compounds of the inventioi (I bis) prepared in the same way.

'!

j - TABLE

\! 1. . ~ d

Compound n r2 R F (° C) 5 1 3 H CH3 Μ 235 2 3 H CH3 248 3 3 CH- CH- 182 »4 3 H CH3 125-8 5 5 3 H CH3 | ^ J 228-32! 6 3 H CH ^ 270 IJ ^ i 7 3 H CH- î "j 182 3 8 3 H CH .. II 145 9 3 H CH, - / \ if 268 3 V ^ 0! J _ 10i 10 3 H CH- CH- I 272

M 6 D 2 -k J

! s i * I J. 2 -

The compounds of the invention are useful in the cardiovascular field as antihypertensives.

Their properties are those which have been described in the main patent. j ή v i i! î; i / j * t

-: I

j i 'i j i i r <l i ’! !! \ i i ï - i; * * i i! ‘1! !

Claims (6)

1. Amides of alkylenediamines corresponding to the general formula (Ibis) j J .. * J-. “.W-γίγ ^ ΐΓ CH-jCT I nh2 in which, R ^ and R2 each represent, independently of one another, a hydrogen atom, an alkyl of 1 to 4 carbon atoms, or the LO benzyl radical, in is equal to 2, 3 or 4, and! j! R represents either a cycloalkyl radical of 3 to 6 carbon atoms 1 ‘! I, - (CH2) i] is a radical. — L J. where m is 0, 1 or 2; j 1 / - i 15 is a radical —U · il I or —l— Il I 7 I- <ch5) I is a radical — L 1 where m is .O / 1 or 2 and p is 0, 1 or 2; ! . (">, J, as well as their addition salts with pharmaceutically acce acids:: J. 20 tables. Ï 2. Compounds according to claim 1, for which n is equal to 3 13. Compounds according to claim 2, for which represents a hydrogen atom or the methyl radical, R0 is the metrq le or benzyl radical. dd 1 i 'It i25! 4. Comoosés according to claim 3, oour lescuels R represents I J i j? j M a tetrahydrofuryl, cyclopentyl, cyclopropyl or cihy-j radical! | : drobenzofuryle or benzofuryle. I J * 5. N „- (4-amino-dirnethoxy-6,7 auinazolyl-2) N, -methyl N _- (tetra-hycrofuroyl-2) propylenediamine and its salts, in particular its monohydrochloride. 6. Medicinal product, characterized in that it contains, as active ingredient, one of the compounds specified in any one of claims 1 to 5. i 7. Process for the preparation of derivatives according to claim 1, j process characterized in that a quinazoline (II) j is reacted. CH3 ° \ ^ v / VX! i XÏJ NH2 "with a nitrile VBN-Cn-1H2n-2-CN 'to reduce the intermediate nitrile obtained in comoose -" 1 i 15. I Ίτ 11 T! cHjCK y NH2, which is reacted with an RCOX compound to obtain the final compound (I bis) Λ „N-C Hn -N-CO-R | CH-, O înL / i n 2n | 'XX? 2 *'; CH ο j: I NH I? ^ i. l !! UàXJ. Hj I j. w 'w v. i; ,