LU80458A1 - NOVEL PHTALAZINE DERIVATIVES, PROCESS FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Description

OC 5ο.113

GRAND DUCHY OF LUXEMBOURG

Patent No ............. go ..... 4 ...... 1 Q

du .... 3.3 — OcfctMDEe ..... 15.7.0 O Minister

Tit.ro issued · from the National Economy and the Middle Classes ___ Industrial Property Service

, 41 LUXEMBOURG

\ jf Wn Patent Application

'‘P

j, I. Request .J ^ .. saeiBt £ ... aite: .... mm..œ ^ .............. (i) ....... ..............

- ~!:;> 2 ~ ï ^ LScn ~ 3Sî2û & æ # .JLlo3 <> - E3 ^^^ ... Jacquss- .da.I3 ^ £ sr., .... agis £ arifc ... ea .. t ^^ ............................................... .....................................

removal - this oc-fcnbre 19.00-BQix.ant.e .-? d5 ^ i; ~ Imit; ........... (3) to ...... 15 .... ......... ..... hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning:. . "i; iouv £ aux..dêri ^ és .... de ..... phtal.2.a.ine.f .............. (4) .. ..... at ... coiapositlon ..... phama.cfâufciQU.e ..... les ..... CDrÆÿncnt ”................. .................................................. ..............

declares, assuming responsibility for this declaration, that the inventor (s) is (are): -VG-llSÎ ..... cU .... v-Ü-UQ · -...... .................................................. ...............-.................................. ....................-..... ........................ ............................................... (5) 2. the delegation of power, dated ............ lf? ..._ s £ jr.Jr ._____............

3. language deseriotion ............ 5eAg; C.SX & S ........................... ..... of the invention in two exerrr! · es; 4 ........... /. / .............. drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on ... 31 ..... 02 ..... ISIS -................ .................................... ~~ ............ ............................................ -..... .................................................. .

claims for the above patent application the priority of one (or more) application (s) of (6) ........................ 3 Λύ- 1! ........................................... filed in (7) ......... mM b-LLLmbbb .. .A .............................. .........................

the 3. ïiC "C 2: 2 :: 22 15.1.7 ........... (ilo * .45.5.7.0 / 21.) ................ .................................................. .................................................. ......... (8) ** on behalf of ................................. ............... ................................... .................................................. ..................................... (9) elect domicile for him / her and, if appointed, for its representative, in Luxembourg ........................................

-35., ..... blue ..... 32221 .................................. .................................................. .......... ........................................ .................................................. ................. (10) requests the grant of a patent for the subject described and represented in the appendices

* 1 O

above, n— with postponement of this issue a. ..- ¾ ................................. months.

U L.JU, i-4 | Λ \ II. Deposit Minutes

The above application for patent to invert, good has been filed with the Ministry of National Economy and Middle Classes, Industrial Property Service in Luxembourg, dated: r '~ ·' ^, · Pr · the Minister to ....... il .............. heures ** / “> Γν \ ^ ε l'Lconc-rn.e Nationale and these Average Classes, fi rc '% \ bw, ·; con [i% -n. ·! / ^ f, .f.s7 ^ ir g; /: I D. 50.113

CLAIM OF PRIORITY

of the patent application / di /% ___. _______.__ „_ _____

In Great Britain

*. * NOVEMBER 3, 1977 \ AJOOJA) Brief Description submitted in support of a request for

PATENT

at

Luxembourg

on behalf of: PFIZER CORPORATION

for: "New phthalazine derivatives, their production process, and pharmaceutical composition containing them".

Λ i t ’*

V

* t · *: Î The present invention relates to therapeutic agents which are novel derivatives of phthalazine and · it relates, in particular, to derivatives of this type which carry a piperidino substituent in position 1.

The compounds of the invention are phosphodiesterase inhibitors and cardiac stimulants of which a popular class selectively elevates the force of contraction of the myocardium without producing noticeable accelerations in heart rate. The compounds of the invention are advantageous to use in the curative or prophylactic treatment of cardiac affections, in particular of cardiac insufficiency.

The invention offers new phthalazine compounds of formula: * 4-

| I

ROα * \ ± --- (I)

Y

(in which 15 R is a lower alkyl group, and Y is linked to the piperidino ring in the 3- or 4- position and represents a group of formula: “X— (CHR ~) -Z m in which 20 R is a atom 'hydrogen or a lower alkyl group, and m is equal to 1 or 2, provided that when m is equal to 2, the symbols R' may be the same or different; X is an oxygen atom or a direct bond , a "condition that when nt is equal to 1, X is a / _

i R

i 2.

direct link; Z is a group corresponding to one of the formulas: -oconr4r5 -OCOR3 5 -N (R2) COR3 -N (R2) SO „R3? ^ 45 -N (R) CONR R, and -N (R2) COOR3 in which '2 10 R is a hydrogen atom or a lower alkyl group; 3 R is a lower alkyl, phenethyl, benzyl, phenyl or 2-, 3- or 4-pyridyl group; and 45 R and R each independently represent hydrogen 3 or a group as defined in R above) and their pharmaceutically acceptable acid addition salts.

The term "lower" denoting an alkyl or alkoxy group means that this group contains up to 6 carbon atoms, preferably up to 4 carbon atoms, and the corresponding groups can be in a straight chain or, where appropriate, in branched chain.

The compounds of the invention having one or more centers of asymmetry exist in the form of one or more pairs of enantiomorphs and these pairs or the individual isomers can be separated by physical operations, for example by fractional crystallization suitable salts.

Ή *,,, A, The invention relates to separate pairs ae as well as their me-30 languages, that is to say racemic mixtures or the isomeric forms d and 1 optically active individual.

The pharmaceutically acceptable acid addition salts of the compounds of the invention include the salts formed from acids which give non-toxic, ac-dition salts containing pharmaceutically acceptable anions - r η * ceutiqua, such as hydrochlorides, hydrochydrates, iodhyorsces, sulphates, bisulphates, phosphates, acid phosphates, acetates, rr.al-éstes, fumarates, lactates, tartrates, citrates, gluccnaces, · 'seccharates and p-tcluèn- asulfonsts.

3.

The cardiac stimulation activity of the compounds of the invention is demonstrated by their effectiveness in one or more of the following tests: (a) increase in the force of contraction in the preparation of the two isolated atria of the guinea pig, executing beats spontaneous; (b) elevated myocardial contractility (dP / dt max. left ventricular) in anesthetized dogs with a left ventricular lead; (c) the elevation of the myocardial contractility in the non-anesthetized dog, with implantation of a transducer in the left ventricle.

In test (a), the inotropic and chrono-tropic responses of the atria vis-à-vis the test compound are measured at various doses and compared to the responses caused by isoprenaline. A comparison of the response curves at dose gives a measure of the selectivity towards the gain in fc-rcs rather than in the frequency of contraction, of the test compound.

In test (b), the positive inotropic action of the test compound, after intravenous administration, is measured in the anesthetized dog. The magnitude and the duration of this action are obtained, and the selectivity towards the gain in strength rather; that in frequency of contraction of the test compound, just as j j determines its peripheral effects, for example the effect exerted i on the blood pressure.

In test (c), the positive inotropic action of the test compound is measured after intravenous or oral administration! to an unaesthetized dog in the left ventricle of which [! * a transducer is installed. We obtain the magnitude of 1 * ac-; inotropic action, selectivity toward strength gain rather than contraction frequency and duration of action of the inotropic effect of the test compound.

Among the compounds of the invention, those which correspond to the formula are appreciated: I ï 1

CH-0 / N

3 i --- (II) AT T4.

in which ‘Y has the definition given for formula (I).

X is preferably a direct bond.

The group ”- (CHR) -” is preferably a group '' 5 of formula -CHg-, -CH (CH3) -, -CH2CH2 ~, -CH2CH (CH3) ~ or ~ CH (CH3) CH2 ~ Z represents preferably: (a) a group -OCONHR in which R is a C 1 to C 6 alkyl radical phenyl or 2-, 3- or 4-pyridyl; 1 ^ 3 3 (b) a group -OCOR in which R is a C 10 -C 10 alkyl radical; ^ 2 3 2 x (c) a group -N (R) COR in which R is a hydrogen atom - • 3 ne or an alkyl radical in C ^ to and R is an alkyl radical in C ^, phenyl, phenethyl or 2-, 3- or 4-pyridy-le; 2 3 2 15 (d) a group -N (R) SO „R in which R is a hydrogen atom or a C1-to-alkyl radical and R is a C1-C4 alkyl radical, phenyl, bensyl or 2-, 3- or 4-pyridyl; 2 ^ 5 2 (e) a group -N (R; CONR'R in which R is an atom of hy-

N / A

Drogen or an alkyl radical in C ^, R is a hydrogen atom or an alkyl radical in à and R ~ * is an alkyl radical in C ^ to C4, phenyl or 2-, 3- or 4-pyridyl; or ““ 2 3 2 (f) a group -N (R) C00R in which R is a hydrogen atom or a C1 to C4 alkyl radical and R is a C1 to C4 alkyl radical.

„· The preferred individual compounds correspond to formula (II) in which Y is a group of formula:„ -CH2CH2OCONHC2H5, -CH2CH2NHCOOC2H5, -CH2CH2N (CH3) S02CH3, -CH2N (CH3) CO (CH2) 2CH3, -CH2CH2N (CH3) S02.phenyl, -CH (CH3) CH2N (CH3) S02CH3, 35 -CH2CH2N (CH3) S02- (CH2) 2CH3, -CH2CH2N (CH3) S02C: H5, -CH 2CH2N (CH 3 ^ C0N <CH 3> 2 "-CH2CH 2N (CH 3) SO p. (3-py r idy1e) 5.

or -ch (ch3) ch2n (ch3) so2c2h5.

The invention also relates to the pharmaceutically acceptable bioprecursors of the compounds of formula (I).

The term "pharmaceutically acceptable bioprecursor" requires some explanation. It is well known in pharmaceutical chemistry to remedy some unwanted physical or chemical properties of a drug by transforming it into a chemical derivative which does not have; "10 this undesirable property but which, when administered to an animal or a human being, returns to its initial form.

I For example, if a drug is not well absorbed when it | is administered to the animal or; Orally patient, it may be considered to transform it into a chemical derivative which is well absorbed and which resumes the form of the initial drug in the serum or in the tissues. Likewise, if a drug is ins-i! table in solution, it is possible to prepare a chemical derivative of this drug which is stable and which can be administered in solution but which reorients the form of the initial drug to PQ in the body. The specialist in pharmaceu- tical chemistry | .

; tick is fully aware of the possibilities that are of-! fertility to remedy intrinsic defects in the case of a drug by chemical modifications which are only temporary and which are reversible upon administration to the animal or to the patient.

For the purposes of this specification, the expression "bioprocessor acceptable from the pharmaceutical point of view" of a compound of formula (I) qualifies a compound whose structure is different from that of the compounds of formula (I) but which , by ad-30 ministration to an animal or to a human being, is converted in their organism into a compound of formula (I).

The compounds of the invention can be administered alone, but they are generally administered in admixture with a pharmaceutical carrier which is chosen taking into account the desired route of administration and normal pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, alone or in /

/ U

6.

mixture with excipients, or in the form of elixirs or suspensions containing perfumes or dyes. · They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other dissolved bodies, for example sufficient amounts of salts or glucose to make the solution isotonic.

For administration to humans in the curative or preventive treatment of heart conditions such as congestive insufficiency, the oral dosages of most of the active compounds of the invention should be in the range of 20 mg to 1 g per day, in two to four doses spread over the course of a day, for an adult patient of average weight (70 kg).

The dosages for intravenous administration should be in the range of 1 to 300 mg per single dose, as required for example in the treatment of acute heart failure. Thus, for an adult patient of normal weight, individual forms of tablets or capsules could contain 5 to 250 mg of active compound, in a pharmaceutically acceptable vehicle or carrier.

Consequently, the present invention relates to a composition containing a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt of this compound, in combination with an acceptable diluent or carrier from the pharmaceutical point of view.

The compounds of the invention can be applied to the stimulation of the heart of an animal or of a human being, by administration to the animal or to the patient of a compound of formula 30 (I) or of a salt. of this compound as defined above or of a pharmaceutical composition also as defined above, in an amount sufficient to stimulate the heart of the animal or of the patient.

The compounds of the invention can be prepared by various methods, as indicated below: METHOD A:

Compounds of formula (I) can be prepared by reaction of a suitably substituted phthalasin oe f \ t i 7.

formula :

RO N

I> JL JL x s - f '111'

RO

Q1 · * (in which Q represents an easily eliminated group such as a chloro, bromo, iodo, lower alkoxy or (lower alkyl) -thio radical) with an amine of formula:

H

J - (XV) *! Ί Λ 5 the reaction leading to the elimination of an HQ molecule “. Q ~ is preferably a chloro or bromo radical. The reaction is advantageously carried out in an inert organic solvent such as ethanol with heating, for example at reflux in a temperature range of 75 to 150 ° C, for a period of up to 48 hours. When Q is a chloro, bromo I or iodo radical, the presence of a base such as triethylamine or of an excess of reactant of formula (IV) is advantageous; se. The product can be isolated and purified by conventional operations.

The compounds of the formula (rV) are co-occurring compounds or can be prepared by analogy with known methods, for example by hyorogenation of the corresponding derivatives of pyridine.

I PROCESS B:. The composites of formula (I) in which Z is a group -N (R) C0NHR can be prepared by reaction of a phthalazine of formula: f1 "'' 4 8.

ε ° τγΎ ^

RO

Q. , ""

X- (CHR Î ^ -NHR

5 s with an isocyanate of formula R NCO, in which R represents something other than a hydrogen atom or else, to prepare compounds in which R is a hydrogen atom, with sodium or potassium cyanate in the presence of an acid.

The acid can come from the use of an acid addition salt of the compound of formula (V) as the starting compound.

According to a conventional procedure, the reactants can be reacted at room temperature for a period of up to 24 hours in a suitable solvent such as anhydrous chloroform. The mixture can then be evaporated, leaving an oil which can be triturated for example with a mixture of ether and ethyl acetate, leaving the product in the form of a crystalline solid which can be recrystallized from a suitable solvent. such as ethanol.

"15 PROCESS C:

We can prepare compounds of formula (I) in ~? where? 3 which 2 represents a group -N (R) C0R, -N (R) C00R, ~ N (R2) S02R3 or ~ N (R2) C0NR4R5, (R4 and R5 representing something other than hydrogen in the latter case ) by reaction of a laid corn-20 of formula (V) as defined above with, as appropriate: (a) a haloformate of formula Q COOR or an acyl halide of formula R COQ, the symbol Q representing a chloro or brorno rcaecal; (b) a sulfonyl halide of formula 3 2? , R SO ^ Q, the symbol Q representing a chloro or orc radical; (4) carbarnyl halide of formula R "R MCOQ, s s ms ms z- to s -i.

the R 'and R each representing something other than agony 1:.

9.

hydrogen and being a chloro or bromo radical; QU (d) a 3 anhydride of formula (R C0) 20.

Usually, the reactants are allowed to stand in the presence of each other at room temperature for a period of up to 24 hours in an inert organic solvent such as chloroform, in the presence of a base such as triethylamine.

The product can be isolated and purified by conventional operations, for example by washing with an aqueous base solution, drying and then evaporation of the organic phase to obtain an oil which is dissolved in acetate. ethyl and the solution of which is loaded on a column for example of "Florisil" (registered trademark), the product being eluted for example with 10% ether in ethyl acetate.

j 15 PROCESS P:

The compounds of formula (I) in which Z is a group A —C0NHR group can be prepared by reaction of a phtala- !! zine of formula: jl j; | i

I N

/ N \ - (VI) k> l! \,

: „X- (CHR) -OH

! m 5 5 with an isocyanate R NCO, the symbol R representing something other than a hydrogen atom, or else, to obtain compounds in which R is a hydrogen atom, the phtala-zine is reacted (VI ) with sodium or potassium cyanate in the presence of an acid.

According to a normal procedure, the reactants are heated together in a suitable organic solvent such as anhydrous chloroform, at a temperature of 40 to 70 ° C.

/ t ".

10.

for 5-10 hours. The solution can then be evaporated under vacuum, leaving an oil which can be triturated for example with ether to leave a residue which can be chromatographed on a suitable column for its purification.

PROCESS E:

The compounds of formula (I) in which Z is a 2 3 rf group -N (R) C0R can be prepared by reaction of a phthalazine of formula (V) as defined above with an ester of N-hydroxysuccinimide of formula: r3coo 0 I 0 Y7 The corresponding ester of N-hydroxyphthalimide can also be used.

In a normal procedure, the reactants can be stirred together in a suitable solvent, for example anhydrous chloroform, for 2 to 6 hours at room temperature.

The product can be isolated and purified by conventional operations.

The starting esters can be prepared by conventional techniques, for example by reacting an acid of formula R 3 COOH with N-hydroxysuccxnimide or N-hydroxyphra-limid in the presence of dicyclohexylcarbodiirnide.

PROCEDURE F:

The compounds of formula (I) in which Z is a group of formula -OCOR can be prepared by acylation of the corresponding compound in which Z is a hydroxy group (formula [VI], method D) with the corresponding acid anhydride or the corresponding acyl chloride or bromide, of formula

O O Q

respective (R ^ CO ^ O, R cOCl or R COBr. The reaction can be carried out in a conventional manner. For example, the starting compound containing a hydroxy group can be treated with the anhydrace • "* 11 .

corresponding acid (e.g. acetic anhydride) in the presence of a suitable base (e.g. triethylamine) at room temperature for up to 24 hours and in the presence of a suitable organic solvent such as chloroform . The product can be isolated and purified by conventional operations.

Acid addition salts of the compounds of formula (I) can be prepared from the crude or pure free base obtained as produced by the conventional technique "of reacting the free base with the acid in a inert solvent, for example by mixing alcoholic solutions of each and collecting the resulting precipitate by filtration, The product can then be purified by recrystallization.

The starting phthalazines used in the above methods can be prepared by analogy with the pro | transferred from the prior art. Likewise, piperidines and others | starting compounds which are used are known compounds or can be prepared by conventional methods. The production of many starting compounds is illustrated in "preparations" 1 to 13.

:! The invention is illustrated by the following examples: Ί \ J EXAMPLE 1. -

; I

:. £ QO ‘! -Nrrï

. ch3o ^ Y "™ CA0H N

ci 3 ch3o y XCOUH (CH) CH,

i P

I '/ * 2 CH2N ^ 6 \ CGK3 (CK2) .a

: / U

/.

12.

The whole is heated under reflux for 100 hours in 100 ml of ethanol 1> 12 9 of 1-chloro-6,7-dimethoxyphtala-zine, 2.0 g of 4 - [(1-methyl-3- n-butylureido) ~ methylj-piperidine e *: 2j5 of triethylamme.

5 After concentration in vacuo, the residue is suspended in 25 of water, the suspension is made alkaline at a pH equal to 10, by addition of a 5N sodium hydroxide solution and extracted in two times 25 ml of chloroform.

The dehydrated extracts on magnesium sulfate are evaporated to dryness under vacuum, leaving a brown oil which is dissolved in the minimum volume of chloroform and the solution is loaded at the top of a column of "Florisil" ( registered trademark) (3C * 2.5 cm) which is eluted with chloroform containing increasing qualities of methanol (up to 15 50%). After having r-cueüli 500 ml of solvent, 18 fractions of 50 r * are collected? fractions 12 to 18 are collected and evaporated to dryness: '° us vide.

The resulting oil, which solidifies on cooling, is dissolved in the minimum volume of ethyl acetate 20 and the solution is kept in a refrigerator for 18 hours for the purpose of stalling. 0.37 g of cries are collected by filtration! Λχ of 6,7-dimethoxy-1- [4- (l-methyl-3-n-butyl neido) -methylj-piperidino] monohydrate ~ pure phthalazine, softening at IC. SC and melting at 114-127 ° C.

25 Analysis: iLuJi calculated for ^ 22 ^ 33-- '3 * ^ 2 ^ 61.0 8.1 16.2 found 60.6 8.1 15.9.

EXAMPLES 2-33 -

The following horns were prepared in the same manner as in Example 1 from 1-chloro-6,7-dimethoxy-phthalazine and suitably substituted peridine.

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i% .1 io tl CN o OOO oi »Λ / EXAMPLE 34. - Preparation of 6,7-dimethoxy-l-r4-f2- (3-Γ3- pyridyll-l-methyluréido) -éthylj-pioéridino'1- phthalazine 18.

acjÎ \ CH30 1 1 \ = - »I | οπ3οΛ ^ γ

ΓΊ A

V y CH2CK2NhCH3 ch2ch2kcokiî. (3-pyridyle)

Me

1 g of 6,7-dimethoxy-1- [4- £ 2-N ~ 5-methylami-noethylj-pipenidinoj-phthalazine is stirred in 10 ml of anhydrous chloroform and the mixture is heated with 0.6 g of isocyanate of 3 -pyridyle. After allowing the mixture to stand for approximately 16 hours, it is washed with water, it is dried over sodium carbonate and it is evaporated to dryness under vacuum to obtain an oil. This oil is triturated with a mixture of ether and ethyl acetate (30 ml, 9: 1 ratio) to obtain a crystalline substance which is recrystallized from ethanol, thus obtaining 0.45 g of 6,7-dimethoxy-l- [4- | 2- (3- [3 -pyri dy 1] -1-mé thy luréido) -é thylj - piper idino] -pht al azine 15 1/4-hydrate pure melting at 200-204 ° C.

Analysis: C, _% H,% calculated for '' 24 ^ 30 ^ 6 ^ 3.l / 4HpO 63.3 6.8 18.5 found 63.2 6.7 18.1.

EXAMPLES 35 to -'7. - ". ......— —--— # 20 The following compounds were prepared as in the previous examples, from 6,7-dimethoxy ~ l- [4- (2-i: -methylaminoéi '-yl - or N-methylaminomethyl) -periQino] -phtala-zine and 1 * .socyanate corresponding.

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- \ _____ 0 EXAMPLE 38. - Preparation of 6,7-dimethoxy-l ~ r4- ^ 2- (l, 3,3- trimethylureido) -ethylJ-piperidino1-phthalazine 20.

CH3

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0.7 g of 6,7-dimethoxy-1- [4 ~ ^ 2-N-methylamx-noethyl ^ -piperidinoj-phthalazine is stirred in a mixture of 25 ml of anhydrous chloroform and 2 ml of triethylamine while adding slowly drop by drop 0.23 g of N, N ~ dimethyl carbamoyl chloride. The mixture is then left to stand for approximately 16 hours, then 20 ml of water are added thereto. The chloroform phase is separated, dried over sodium carbonate and evaporated to dryness under vacuum. The residual oil is taken up in the minimum amount of ethyl acetate and the solution is loaded at the top of a column of "Florisil" (registered trademark) (35 x 1.5 cm). The elution is started with 10% ether in ethyl acetate and ten fractions of 50 ml each are collected. Fractions 3 to 9 are combined and evaporated to dryness under vacuum to obtain an oil which solidifies by trituration with ether containing 10% ethyl acetate. By recrystallization from ethyl acetate, 0.2 g of pure 6,7-dimethoxy-1- [4- ^ 2- (1,3,3-trimethylureido) -20 ethylj-piperidinoj-phthalazine is obtained, melting at 140 ~ 141 ° C.

Analysis: H, j £ N_, J ”calculated for 62, S 7.8 17.4 found 62.6 7.8 17.2.

Λ * / 21.

EXAMPLES 39 to 42.-

The following compounds were prepared in the same way as in the previous example, starting from 6,7-dimethoxy- 1- [4- (2-N-methylaminoethyl- or N-methylaminomethyl) -piperidino] -5 phthalazine and sulfonyl chloride, acid chloride or corresponding carbamoyl chloride.

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r-i χ en o r-i cm - p ro -c v vr <3 c * s îü j EXAMPLE 43. - Preparation of 6.7-dimethoxy-l-r3- (N-ethylcar- i · bamoyloxymethyl) -piperidinol-phthalazine 23.

] | I + CH3CH2NCO-), I I

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s nN · / V

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i H 2.

i j1 0.69 g of ethyl isocyanate is slowly added to i the stirred solution obtained by dissolving Qi7Sgde 6 * 7-diînéthc- 5;: yi- [3- (hydrôkyîtié.uhyl) -pipérièiào] -phta. in the 10in dechioro-fovrnatuihydre at 5fiCs then heating at S0 ° C for 7 hours. A: thin layer chromatography shows that the reaction is not finished, so we continue to add isocya-! ethyl nate (0.5 ml) and stirred at room temperature for 18 hours. The solution is then concentrated! vacuum packed by giving an oil which is ground with 30 ml | "Of ether, and the residue is separated by decantation. 1 is dissolved in the minimum volume of chloroform and the solution is stored at the top of a chromatographic column of! 15 silica powder, garnished with chloroform (40 x 2 cm), that; then eluted with chloroform containing increasing amounts of methanol (up to 5%). The 100 ml fractions are collected and checked by chromatography on a neck! ehe thin. The appropriate fractions are collected and con- | 20 centered in vacuo giving the product in the form of an oil (0.45 g).

This oil is suspended in 25 ml of ethyl acetate and the suspension is added with a quan ci this

i have

/ J _ 24.

sufficient ethanol for complete dissolution, then a solution of oxalic acid in ethyl acetate is added until the mixture is acidic (pH 3-4). The precipitate is collected by filtration and crystallized from isopropyl alcohol, giving 0.30 g of 6,7-dimetho-xy-1- [3- (N-ethylcarbamoyloxymethyl) -piperidino] -phthalazine monooxalate -hydrous melting at 132-134 ° C.

Analysis: C,% H,% N,% calculated for ^^ gH26 ^ 404 * C2H2 ° 4 '10 1 / 4H 0 53.8 6.1 11.9 found 53.4 5.9 11.9.

EXAMPLES 44 to 47. -

The following compounds were prepared as in the previous example from 6,7-dimethoxy-1- [4 ~ (2-hydroxy-15 ethyl- or 2 ~ hydroxyethoxy) -piperidino] -phthalazine and the corresponding isocyanate . These starting phthalazines correspond respectively to Examples 5 and 25 of British patent application No. 26 202/78, filed on June 1, 1978.

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Î! 4 J 1 ........ ~ 1 “1" '' 'y, EXAMPLE 48. - Preparation of 6,7-dimethoxy-l- [4- $ 2- (N-nico-tinoyl- N-rethylamino) -éthylJ-pipéridino ~] ~ phtal3- zine 26.

2.3 g of N-hydroxysuccinimide and 4.1 g of Ν, Ν-dicyclohexylcarbcdiimide are added to a suspension with stirring 5 of 2.3 g of nicotinic acid in 350 ml of anhydrous chloroform at 30 ° C. After 5 minutes, the suspension has practically dissolved and is then gradually replaced by a white crystalline precipitate. The mixture is stirred for another hour and then filtered. An aliquot of the filtrate (60 ml) is treated by adding a solution of 1 g of 6,7-dimetho-xy-1- [4— | ^ 2-N-methylamino4thylj; -piperidino] -phthalazine in 20 ml of anhydrous chloroform and the solution is stirred at room temperature for 2.5 hours, then 50 ml of water are added. The chloroform phase is separated, washed with 20 ml of water, dried over magnesium sulfate and evaporated in vacuo to give an oil containing a small amount of solid matter. The oil-solid mixture is stirred with 15 ml of chloroform, filtered and the filtrate is evaporated in vacuo to give an oil. The oil is dissolved in 20 30 ml of isopropanol, the solution is treated with an isopropanolic solution of oxalic acid (until the pH is equal to 2) and the precipitated solid is collected by filtration. By recrystallization from isopropanol, 290 mg of 6,7-dimethoxy-l- [4-d2 ~ (N-nicotinoyl-N-me-25 thylamino) -ethylj -pipericinoj-phthalazine rnonohydrate fondant 110-115 ° C.

Analysis: C,% H,% N,% calculated for C24H29N5 ° 3 * C2H2 ° 4 * H2 ° 57.4 6.1 12.9 30 found 56.9 5.8 12.7.

EXAMPLE 49. Preparation of 1— [4- (2-acetoxyethyl) -ploérldi-no] -6,7-dirpethoxyphthalazine 27.

N CH-0 • I 1 1 Π l ck o ”+ îlC2 ° -> | CH 0 r "^ V V o ch2ch2oh en œ2oc ^ 1 .. XcH3 r i i 0.4 ml of acetic anhydride is added slowly to

A stirred solution of 0.63 g of 6,7-dimethoxy ~ 1- [4- (2 ~ hydroxyethyl) —piperidino] —phthalazm and 1.1 ml of triethylamine— in 10 ml of anhydrous chloroform at 5 ° C, then stirred at room temperature for 15 hours. Gn then shakes the solution with 15 ml of water and the phases are separated.

The chloroform phase is dried over magnesium sulfate and concentrated in vacuo to give a brown, sticky oil. It is diluted with a small amount of chloroform ij 10 and the solution is loaded at the top of a chromatographic column formed from chloroform and powdered silica (40 x 2 cm), which is then eluted with chloroform containing increasing amounts of methanol (up to 10%). The following are collected: "twelve 80 ml fractions are collected, the fractions of which numbers 4 to 7 contain, according to thin layer chromatography, the desired product; they are combined and their mixture is evaporated: to dryness under vacuum. The oil resulting is acidified (pH 3-4) by j addition of a solution of oxalic acid in ethyl acetate: j to precipitate the oxalate which is then crystallized in j of ethanol giving l 'oxalate ce 1— [4- (2-acetoxyethyl) —pi— peridino] -6,7-dimethcxyphtalaEine melting at 175-177 ° C.

Analysis: C,% H.% H,% calculated for qH25N3 ^ A * 02 ^ 0 ^ 55.1 6.1 9.4 Λ found 55.4 6.3 9.7.

4 28.

The following preparations illustrate the production of some of the starting compounds.

PREPARAT! ON 1. - Preparation of 4- (2-acetamidoethvl) -pioe- ridine \ = J 2l 3 V_7 2 £ 5 A solution of 33 g of 4- (2-acetamido-. EthyD-pyridine is acidified in 250 ml of ethanol at a pH equal to 4 by addition of hydrochloric acid and hydrogenation is carried out at 60 ° C under pressure of 4.2 bars by passing over a platinum oxide catalyst for 18 hours, the absorption of hydrogen-10 is not complete, the catalyst is then removed by filtration and the filtrate is treated by adding a solution of potassium hydroxide in methanol (1.1 molar equivalent) and a new filtration is carried out. The solvents are removed by vacuum distillation and a clear oil remains which gives 18 g of 4- (2-acetamidoethyl) piperidine in the form of a white solid melting at 60 ° C.

We also prepare 1 Oxalate melting at 125 ~ 129 ° C. Analysis:. €, _% H, _% N,% 20 calculated for C9H18N20: C? H2 ° 4 50.8 7.8 10.8 found 50.9 7.7 10.4.

PREPARAT-ùP 2. -

Dl ~ 4- hydrochloride (2 ~ acetoxy ~ n-propyl) -pip ridine 1 i-hydrate, melting at 188-191 ° C, is obtained in the same manner · ..? in the above Preparation from dl-4- (2-hydroxy -'-yropyl) —pyridine, but using acetic acid as the solvent. Acetylation takes place during the hydrogenation.

! 29.

i i

Analysis: C *% H,% N,% calculation for CqoHl9N ° 2.HCl. 1/4 ^ 0 53.1 9.1 6.2 found 52.8 9.1 6.3.

PREPARATION 3. - 5 (A) 4- (3 ~ n-butyl-1-methylureidomethyl) -pyridine

3.6 g of 4- (N-methylaminomethyl) -pyridine are stirred in 70 ml of anhydrous chloroform and the solution is cooled in an ice bath while slowly adding 9.9 g of n-butyl isocyanate dropwise. The mixture is then allowed to stand at room temperature for about 16 hours, then 15 ml of methanol is added and stirring is continued for 30 minutes. The solvents are removed by evaporation to dryness under vacuum and the residue is redissolved in 50 ml of ethyl acetate.

The oxalate is precipitated by treating the solution with a slight excess of oxalic acid in ethyl acetate. By re-crystallization from Isopropanol, pure 4- (3-n-butyl-1-methylureidomethyl) -pyridine sesquioxalate (7.2 g), melting at 86 ° -90 ° C., is obtained.

| Analysis: C.% H,% N,% I 20 calculated for C ^ 2 ^ 1Q ^ 3 ^ * ^ I 50.6 6.2 11.8 | found 50.4 6.6 11.9.

i | By a similar process, the synthesis of the following compounds is also carried out:! 25 - 4- (1,3-dimethylureidomethyl) -pyrIdine (crude base, unpurified 1 - bound) j - 4 ~ (2 ~ [3-ethylureido] ~ ethyl) -pyridine (crude base, unpurified) - 4 - (l ~ msthyl-3 ~ n ~ propylureidomethyl) ~ pyridine (crude base, unpurified), 30 - 4- (2- [3-ethyl-l-methyluréido] —échyD-pyridine (crude base, unpurified), and - dl-4- (l- [3-ethyl-l ~ methyluréido] -athyl) -pyridine (crude base,; unpurified).

(B) The above pyridines are then hydrogenated to 35 corresponding piperidines, according to the procedure of Preparation 1.

K.

, φ 30.

PREPARATION 4. - Preparation of 4- (2-methanesulfamldô- - ethy1) -pyridine ê \ ch3so2ci // ^ _) -CH2Cri2KH2 --- * J— CH2CH2NH.SQ2CH3

3.5 g of methane sulfonyl chloride are slowly added to 3.6 g of 4- (2-aminoethyl) -pyridine and 3.0 g of triethylamine in 40 ml of chloroform. The temperature is kept below 40 ° C during the addition, then the orange-colored solution is left to stand at room temperature for about 16 hours. 50 ml of water are then added, the chloroform phase is separated and the aqueous phase 10 is extracted with 100 ml of chloroform. The two chloroform solutions are combined, they are dried over magnesium sulfate and they are evaporated to dryness under vacuum to obtain a yellow oil which solidifies immediately. This solid substance gives white crystals (1.4 g) of 4- (2-methanesulfamidoethyl) -pyridine by crystallization from ethanol.

A small sample recrystallized from ethanol., Mp at 114-116 ° C.

Analysis: C. JÔ H.% N,% * calculated for cgHq2N2 ° 2S 48.0 6.0 14.0 20 found 47.9 6.0 14.0.

(B) Preparation of 4- (2-methanesulfamideethyl) -nicerldine ixwnMjtf. / / - <. hydroaeriütiorr / - f \ ........ '/ \ J— CH2CH2I7H.S02CH3 Ht ^ H2NE * S02CH3 L · ~ V ~ 31.

8.4 g of 4- (2 ~ methanesulfamidoethyl) - I pyridine are acidified in 85 ml of ethanol by addition of 2N hydrochloric acid until the pH is 2 and hydrogenation is carried out at ambient temperature and under pressure of | 5 3.5 bar per passage over a platinum oxide catalyst until the absorption of hydrogen has ceased. The catalyst is then removed by filtration and the filtrate is evaporated to dryness under vacuum, leaving a white solid substance, which is dissolved in the minimum volume of hot ethanol; the solution is quickly filtered and kept at room temperature for about 16 hours. The resulting white crystals are collected by filtration and dried to give 8.3 g of 4- (2-methanesulfamidoethyl) -piperidine hydrochloride, melting at 165-167 ° C.

s i 15 Analysis: C,% H,% N,% | calculated for C8H18N202S: HC1 39.6 7.9 11.5] found 39.6 7.8 11.7 d Following the procedure in part (A), we also synthesize the following compounds: 20 - 4- (2- [N-isopropylmethanesulfamidoj-ethyl) -pyridine oxalate

i'm melting at 129-131 ° C

Analysis: C,% H,% N.% j calculated for C ^^ H ^ gN202S.C2H20Æ î 47.0 6.1 8.4 j 25 found 46.7 6.2 8.0.

j - 4- (2- [N-methylmethanesulfamido] -ethyl) -pyridine - crude oil - 4- (2- [N ~ methylbenzenesulfamido] -ethyl) ~ pyridine - crude oil i I - 4- (2-benzenesulfamidoethyl) - pyridine, melting point 109—

I 110 ° C

ί 30 Analysis: C,% H,% N,% j calculated for 59.5 5.4 10.7! found 58.5 5.4 10.6! l, - dl-4- (3- [N-methylmethanesulfamido] -prop-2-yl) -py- oxalate

; curtain, melting point 155 ~ 158 ° C

35 - 4- (2- [N - methyl ~ n-propanesulfamidoj-ethyl) -pyridine, crude oil - 4- (2- [N-methylphenylinethanesulfamidoj-ethyl) -pyridine, melting point 109-110 ° 32.

Analysis: C,% H,% N,% calculated for 62.1 6.3 9.7 found 62.0 6.3 9.7 - 4- (N-methylmethanesulfamidomethyl) -pyridine, crude 5 - 4- (2 - [N -methylethanesulfamido] -ethy $ -pyridine, crude oil - dl-4- (l- [N-methylethanesulfamido] -prop-2-yl) hydrochloride -pyridine, crude oil and

- 4- (N-methylbenzenesulfamidomethyl) -pyridine, melting point 101-102 ° C

10 analysis: C,% H,% N,% calculated for 59.5 5.4 10.7 found 59.9 5.4 11.1.

The above compounds are then hydrogenated as in part (B) to form the corresponding piperidines.

PREPARATION 5. - (A) 4_- C N-meth y Ibu tvramld ométhvl) -pyridine

2.8 ml of n-buty-ryle chloride in 20 ml of anhydrous methylene chloride are slowly added to a cooled mixture with stirring of 3 g of 4- (N-methylaminomethyl) -pyridine and 5 ml of triethylamines in 30 ml of anhydrous methylene chloride. The mixture is then stirred at room temperature for 2.5 hours, then 30 ml of water are added. The organic phase is separated, washed with 30 ml of dilute aqueous sodium hydroxide solution at 5 ί, it is dehydrated over sodium carbonate and evaporated to dryness under vacuum. The resulting dark brown oil (3.8 g) is chromatographed on a 15 g column of "Florisil" (registered trademark) using chloroform as eluent. Suitable fractions are identified by thin layer chromatography , combined and evaporated in vacuo giving 3.2 g of pure 4- (N-methylbutyramidomethyl) -pyridine in the form of an oil.

(B) The oil is then hydrogenated as in (B) in Preparation 1 to give the corresponding piperidine.

By proceeding as indicated above, the following compounds were also prepared: / ^ 33.

_ 4- [N-methylbenzamidomethyl] -pyridine and 4- [1,3,3-trimethyl-ureidomethyl] -pyridine (crude oil), which are then hydrogenated as indicated in (B) in Preparation 1 to form the corresponding piperidines.

5 PREPARATION 6. - 4- (l- [N-methylacetamido] -prop ~ 2-yl) -pyridine 4.5 g of 4- (lN-methylamino-prop-2-yl) -j pyridine are treated in 15 ml . of acetic acid by carefully adding 10 ml of acetic anhydride, then the mixture is allowed to stand at room temperature for about 16 hours.

20 ml of methanol are then added to destroy the excess acetic anhydride, then evaporated in vacuo at 40 ° C. to remove the methanol and methyl acetate. The residue is diluted with water and the solution is treated by adding solid anhydrous sodium carbonate in portions until the pH is alkaline (10-12). The oily suspension is extracted with three times 60 ml of chloroform and the combined extracts are dehydrated on sodium carbonate and evaporated to dryness under vacuum | yielding 6.8 g of an approximately colorless oil. The oil gives j by distillation 3 g of dl-4- (l ~ [N-methylacetamido] -prop-2-yl)! 20 pure pyridine boiling at 138 ~ 140 ° C / 0.4 mm of mercury (colorless oil i).

]; Analysis: C,% H,% N.% calculated for C ^ H ^ gNgO / l / ^ l ^ O 65.7 8.5 13.9 - found 65.8 8.5 14.2.

25 your synthesis of the following compounds was carried out * by a similar process:] - 4- (2- [N ~ methylacetamido] -ethyl) -pyridine oxalate, melting at 120-124 ° - 4- (2-acetamidoethyl) - pyridine, boiling at 158-160 ° C, 0.6 mrn

30 - 4— (acetamidomethyl) —pyridine, melting at 83—88 ° C

: - 4- (N-methylacetamidcmethyl) -pyridine, crude oil, and - dl-4- (l- [N-methylacetamido] -ethyl) -pyridine, crude oil.

• The above compounds are then hydrogenated as in preparation 1, forming the corresponding piperidines! 3 5 canoes.

. / U

34.

PREPARATION 7. - 4- (2-ΓN-ethoxycarbonyl-N-methylaminol-ethyl) - pyridine

11.2 g of ethyl chloroformate are added dropwise to a cooled mixture, with stirring, of 13.6 g of 4- (2-N-methylaminoethyl) -pyridine and 25 g of triethylamine in 400 ml of anhydrous chloroform. The mixture is stirred at room temperature for about 16 hours, then 100 ml of water is added. The organic phase is separated, it is dried over magnesium sulphate and evaporated under vacuum to ob ~ 10 hold 20 g of 4- (2- [N-ethoxycarbonyl-N-methylamino] -ethyl) -py-ridine in the form of an oil.

Following the above procedure, the following are also prepared: - 4- (2- [N-ethoxycarbonylamino] -ethyl) -pyridine.

The above products are then hydrogenated as in Preparation 1 to form the corresponding piperidines.

PREPARATION S. - Preparation of 6,7-dimethoxy-I- (3-hydroxy- mefhyloiperidino? -Phthalasin "sYT> G -’Xju

O

ch2oh 2o cr. chaulé® at 95 ° C - for 42 hours 2.25 g of 1- chloro-6,7-dir.ethoxi phcal asine, 1,72 g of 2-hydroxymethylpipe-ridine and 1.3 rl this triethylamine in 60 ml of iscarnyl alcohol. The cooled reaction mixture is then filtered and the filtrate is dried in vacuo. The residue is dissolved in 100 ml of water, as a sodium hydroxide solution 5u to adjust the pH to ^ then the base mixture is extracted: u- ·.

✓ “35.

with twice 100 ml of chloroform. The chloroform extracts are combined, they are dried over magnesium sulphate j and they are concentrated under vacuum to obtain a brown oil which is triturated with 50 ml of ether and then filtered. The resulting solid is crystallized twice from; 11acetonitrile, which gives 1.83 g of 6,7-dimethoxy-1- (3-hydroxymethylpiperidinoj-phthalasine, melting at 162-165 ° C.

Analysis: C,% H,% N.% calculated for ^ ΐ6Η21Ν3 ° 3 63.4 7.0 13.9 ’10 found 63.7 6.9 13.7.

PREPARATION 9. - 4- (2-isoorooylaminoethvl) -pyridine

While cooling, 21 g of 4-vinylpyridine, 24 g of isopropylamine, 40 g of concentrated hydrochloric acid and 100 ml of water are mixed, then the mixture is boiled at reflux for 20 hours. It is cooled, it is alkalized to a pH of 12-13 (20% sodium hydroxide) and it is extracted with three times: 200 ml of chloroform. The combined extracts are washed with 100 ml of water, dried over magnesium sulfate and evaporated in vacuo to give a green oil. The oil is distilled and the fraction boiling at S4-90 ° C / 1 mm is collected (16.5 g) and identified by nuclear magnetic resonance spectroscopy: this is the 4— ( 2 — isopropylamxnoethyl) -pyri dine.

! By a similar procedure, the following compounds are also synthesized:, - 4- (2-aminoethyl) -pyridine, I - 4- (2 ~ methylaminoethyl) -pyridine, and I - - dl ~ 4- (l-methylamino) -prop ~ 2-ylpyrïdine.

PREPARATION 10. - 6 ^ A ^ thcxv ^ J4j ^ f 2-M-m athv 1 amlnogtfivl? - 30 jpipé ridlno] -ohtalasine

2.0 g of 6,7-dimethoxy-1- [4- (2-N -; vethylacetamiooethyl) -piperidino] -phta-lasine (prepared as in Example 4) is heated under reflux for 70 hours. ml this is mixed with 1: 1 of ethanol and 5N sodium hydroxide solution. The ethanol is removed by evaporation in vacuo and the aqueous phase is diluted with 10 ml of water, then it is extracted with chloroforra.

/ 36.

The extract is dried over sodium carbonate and evaporated in vacuo to give an oil which, by trituration in hexane, gives 1.5 g of 6,7-dimethoxy-1- [4- (2-N-methylamino-ethyl) ~ piperidino] -phthalazine in the form of a pale yellow so-5 substance. A small sample characterized as dioxalate monohydrate, melts at 159-162 ° C.

Analysis: C,% H,% N,% calculated for 2 6 ^ 4P24 '^ 2® 50.0 6.1 10.6 10 found 49.8 5.7 10.3.

6,7-Dimethoxy-1- [4- (N-methylaminomethyl) -piperi-dinoj-phthalasine is prepared by following the procedure described above, starting from 6,7-dimethoxy-1- [ 4- (N-methylacetamidomethyl) -piperidinoj-phthalazine (prepared as indicated in Example 3). A small sample of the product was characterized as dioxalate, softening at 140 ° C and decomposing at 180 ° C.

Analysis: C.% H.% N,% calculated for ci7H24N4 ° 2 * 2C2H2 ° 4 50.8 5.7 11.3 20 found 50.1 5.7 11.5.

PREPARATION 11. - (A) Preparation of 6,7-dlmethoxyohtalazine-l-one

CH Os / CHO CH O

3 I if H2N-KK2: H2 ° __V fl I

^ A. Et0H JL · nh C ^ O ^^ / COCH CK30 ^ 0

10 g of 4,5-dimethoxyphthalaldehyde acid and 2.4 ml of hydrasine hydrate in 150 ml of ethanol are heated at reflux for 20 hours and after the heating period, a white crystalline solid is formed. The mixture is cooled in an ice bath, filtered and the resulting product; . 37.

i I # is dried to give 7 g of crude 6,7-dimethoxyphthalazine-one. A sample crystallized in water gives colorless needles melting at 254-256 ° C.

Analysis: C,% H,% N,% 5 calculated for c ^ o ^ 10N2 ° 3 58.3 4.9 13.6 J found 58.4 4.8 13.9.

(B) Preparation of 1-chloro-6,7-dimethoxyphthalazine üL; j0ffî οη3οΛ ^ χ ^ * ch3oA ^ Y n 0 cl I 20.6 g of 6,7-dimethoxyphtala- is refluxed; zine-l-one with 200 ml of phosphoryl chloride for 6 hours | 10 res, then the mixture is allowed to cool to ambient temperature and the excess phosphoryl chloride is removed under reduced pressure. The resulting brown solid is suspended I in 150 ml of acetone and the suspension is poured i onto 200 ml of cold concentrated ammonium hydroxide (5 ° C). The crude product is filtered, washed with 200 ml of water, then 200 ml of petroleum ether. The solid yellow-yellow solid is dried; (20 g), dissolved in the minimum volume of chloroform and preci-! pitted with excess petroleum ether, then she was again. collected by filtration, washed again with 100 ml of petroleum ether and dried to give 13 g of l-chlorc-6,7-dimethoxyphfca-i lazine melting at 195-197 ° C while decomposing.

Analvase: é H, _% N,% calculated for C1QH9C1N202 53.5 4.0 12.5 found 53.3 4.2 12.7.

PREPARATION 12. - (A) Preparation of l-benzyl-4- (2.2-diethcxyethoxv) - piperidine / U, (38.

_-v OCH „CH

\ / \ / \ \ = - f OCH, CH,

11.5 g of 1-benzyl-4-hydroxypiperidine are dissolved in 25 ml of anhydrous dimethylformamide (DMF) and the solution is added dropwise to a suspension with stirring of sodium hydride (2.8 g of dispersion at 50% in oil) in 25 ml of anhydrous DMF, operating under an atmosphere of anhydrous nitrogen, then the mixture is stirred at room temperature for 3 hours. The suspension is cooled in an ice-water bath while adding dropwise 13.0 g of 2-bromacetaldehyde diethylacetal in 25 ml of anhydrous dimethylformamide, then stirred at room temperature for 24 hours. The above operation is repeated to add another 2.8 g of sodium hydride and 13.0 g of acetal. 50 ml of isopropyl alcohol are added and the mixture is stirred for half an hour, then it is filtered through "Hyflo" (registered trademark). The fil-15 trat is concentrated under vacuum, it is suspended in 100 ml of water and the suspension is made alkaline at a pH equal to 11 by addition of 5N sodium hydroxide. After extraction with twice 100 ml of chloroform, the combined extracts are evaporated to dryness under vacuum to obtain an orange-colored oil which is distilled = under vacuum, which gives 14.1 g of l-benzyl. ~ 4 ~ (2,2 ~ diethoxy-ethoxy) -piperidine boiling at 152 ° C under a vacuum of 0.1 mm.

(B) Preparation of i-bensvl-4-r2- (M-methylacetamido) - ethoxy] · - dipér i di ne

The mixture is stirred at room temperature for 13 hours. 50 g of 1-benzyl-4 ~ (2,2-diethoxyethoxy) -piperidine and 130 ml of 2N hydrochloric acid. The mixture is basified to a pH equal to 9 by the addition of 5N sodium hydroxide, it is extracted into twice 150 ml of chloroform, it is dried over tallow with this magnesium, then it is evaporated in a vacuum bag. -O dissolve in 150 ml of ethanol and mix the solution with 1 - * 39.

i * 8.9 g of sodium acetate trihydrate, 83 ml of water, 28 ml of acetic acid crystallization and 15.5 g of ethanolic methylamine solution at 33% w / w. The stirred solution is cooled to 0 ° C in an ice and salt bath and the temperature is maintained at 0 - 2 ° C while 6.6 g of sodium borohydride is added in portions during the next half hour. The mixture is stirred at ambient temperature for 40 hours, its pH is adjusted to 7 by adding a little 5N sodium hydroxide, it is concentrated under vacuum. 10 diluted with 150 ml of water and extracted with twice 225 ml of ether.

; The aqueous phase is basified to pH 10 by addition of 5N sodium hydroxide, extracted into two times 180 ml of chloroform, dried over magnesium sulphate and evaporated to dryness under vacuum.

The crude oil (12.5 g) in 80 ml of anhydrous chloroform and 10.4 ml of triethylamine is stirred and cooled in an ice-water bath during the slow addition of 6.1 g of acetic anhydride. The mixture is stirred at room temperature for 2 hours, stirred dry with 50 ml of water, then the phases are separated. The chloroform phase is dried over magnesium sulphate, evaporated to dryness under vacuum, leaving a brown gum which is dissolved in ethyl acetate and transformed into oxalate by addition of a solution of oxalic acid in the ethyl acetate at a pH of 25 to 3. The ethyl acetate is removed by decantation and the residual gem is dissolved in isopropanol! hot ; the solution is allowed to cool to room temperature and diluted with an equal volume of ether to form a deposit of brown gum. The gum is isolated by decantation of the solvents and it is dried to give 10 g of crude L-ben3yl-4 ~ [2— (N — methylace— tamido) -ethoxyj-piperidine oxalate.

A second crop of the same substance is obtained from the solution in 1 ’isoproiaanol and ether. By recrystallizing this substance from methyl cyanide, pure crystals of moncoxalate monohydrate of 1-benzy1-4- [2- (N-methylacetamido) -ethoxy] -piperidine are obtained, melting at 142 ° -147 ° C.

/ U

Λ ‘* 40.

Analysis: C,% H,% N,% calculated for ci7H2gNo0.3: C2H204: H2 ° 57.3 7.6 7.0 found 57.1 7.0 6.8.

The product is hydrogenated as described above to remove the benzyl group.

PREPARATION 13. -

Prepare 4- [2- (N-methylsulfamido-ethoxyj-pipé-as above "* but using methane chloride ~ · 10 sulfonyl instead of acetic anhydride in step B.

AT

Claims (5)

1 L i il j 1. Analogical process for the preparation of phthalazines of formula: 5 * N j s p. ex. Y in which R is a lower alkyl group, and Y is linked to the piperidino ring in position 3 or 4 and represents a group of formula: -X- (CHR1) -Z m in which R ^ is a hydrogen atom or a lower alkyl group, while in is equal to 1 or 2, provided that qi when m is equal to 2, the symbols R1 may be the same or different X is an atony of oxygen or a direct bond, provided that, when m is equal to 1, X is a direct bond; and Z is a group corresponding to one of the formulas: * -OCONR4R5 -0C0R3 -N (R2) COR3 ~ n (r2) so2r3 \ ~ n (r2) conr4r5 i and -N (R2) COOR3 j, 2, -5 or R is a hydrogen atom or a lower alkyl group, R is a lower alkyl group, a phenethyl group, a group; _ benzyl, a phenyl group, a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group; | / 4 f and R ^ and R "* each independently of one another represent a hydrogen atom or a group corresponding to the definition of R above, * as well as salts d addition of pharmaceutically acceptable acid to these phthalazines, characterized in that it consists in reacting a phthalazine of formula: RO f R ° .— (111) * Q1 in which R has the meaning defined above, while Q * is an easily eliminated group such as a chlorine atom, a bromine atom, an iodine atom, a lower alkoxy group or a (lower alkyl) -thio group, with an amine of formula: ii, wherein Y has the meaning defined above, this reaction being optionally followed by the transformation of the product of formula (i) into a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 2. Analogical process for the preparation of phtala- * zines of formula (i) defined in claim 1 and in which - - Z is a group -N (R) COR, a group -N (R) COOR, a group -N (R ^) SO „R ^ or a group -N (R ^) CONR ^ R ^, and having the meanings defined for formula (i), while and R3 have the meanings defined for formula (i), but do not represent a hydrogen atom, characterized in that it consists in reacting a compound of formula: * * RO --- »/ χ I iï I (v) RO X / O ,,, · ~ X ~ (CHR) m “NHR in which R,, R ^, X and m have the meanings defined for formula (i), with, under appropriate conditions, (a) an isocyanate of formula R ^ NCO, R ~ * having the meaning defined for formula (l), but does not represent a hydrogen atom, (b) a haloformate of formula Q ^ COOR ^ or R ^ COQ ^ where Q is a chlorine atom or a bromine atom, is a chlorine atom, a bromine atom or a group of formula: 1 O 0 l, 0 \ XJ ! ; ïï 1 while R ^ has the meaning defined for formula (I), I (c) a sulfonyl halide of formula R SO ^ Û in which IR ^ and have the meanings defined above, (d) a token - a carbamyl nide of formula R ^ R ^ NCOQ in which R ^, R and Q have the meanings defined above in this process or (e) an anhydride of formula (R ^ CO ^ O in which has the significant J defined above, this reaction being optionally followed by the transformation of product of formula (I) into a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 3 · analog process for the preparation of a compound of formula (i) defined in claim 1 and in which c <3 is a group -OCONHR or a group -OCOR, characterized in that it consists in reacting a phthalazine of formula î RO NI i R ° —n (vi) - X-ÎCHR1) ra-0H in which R, R1, X and m have the meanings defined for formula (l) j with, according to the appropriate conditions, (a ) an isocyanate of formula R ^ NCO, R ~ * having the meaning defined for formula (l), but does not represent a hydrogen atom, or sodium cyanate or potassium cyanate in the presence of an acid, or (b) an acid anhydride, an acyl chloride or an acyl bromide corresponding respectively to the formulas (R ^ C0) 90, R ^ COCl and 3 1 Δ R COBr in which R ° has the defined meaning for formula (1), this reaction being optionally followed by a transformation of the product of formula (î) into a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 4. Method according to any one of claims 1 to 3j characterized in that R is a methoxy group and the group - (CHR1) m ~ is a group -CH2 ~. -CH (CH3> -, -CH2CH2-, -CH2CH (CH3> - or -CH (CH_) CH. O 5. Method sui% snt any one of claims 1 to 4j characterized in that \ is a direct bond. : νΛΑ klXl) t