CA1114379A - Piperidino-phthalazines - Google Patents

Abstract

Abstract The invention relates to new phthalazines of the formula and the pharmaceutically acceptable salts thereof, wherein R is lower alkyl and Y is attached to the 3- or 4- position of the piperidino ring and represents a group of the formula -X-(CHR1)m-Z
wherein R1 is hydrogen or lower alkyl, m is 1 or 2 (when m is 2, each R1 may be the same or different), X is oxygen or a direct link (when m is l, X is a direct link), and Z is selected from -N(R2))COR3 -N(R2)SO2R3 -N(R2)CON4R5 and -N(R2)COOR3 where R2 is hydrogen or alkyl; R3 is alkyl, phenethyl, benzyl, phenyl or pyridyl; R4 and R5 are each hydrogen or a group as defined for R3. Several pro-cesses for preparing same are described. The new compounds are phosphodi-esterase inhibitors and cardiac stimulants.

Description

3~

This invention rela-tes to therapeuti.c agents, which are novel derivatives o~ phthalazina, ancl is ~lrticularly concexned with such derivatives having a substituted piperidino group in :.' I
1 the 1- position~
The compounds oE the invention are phosphodiesterase inhibitors and cardiac stimulants of which a preferred class ` ~ selectively increase the force of myocardial contraction without , producing significant increases in heart rate. ~he compounds are : I useful in the curative or prophylactic treatment of cardiac con~
1 10 ditions, in par-ticular heart failure, .' ~ .
:'. According to the invention there is provided novel , phthalazine compounds of the formula:

,~ . RO ~ ~ 3 ~J , , . :

:~ ~ N ~ . --- (I) -.~ ' ~ , , .

Y
~ wherein R is a lower alkyl group; and : lS Y is attached to the 3- or 4- position of the piperidinoring and represents a group of the formula:
` -X-(CHR )m~Z
wherein R is a hydrogen atom or a lower alkyl group, ':
, ~P~C. 2~9) . . . . .

.~
: ' , ' .

and m is 1 or 2, ~Yith the proviso that when m is 2, each Rl may be the same or different;
X i5 an oxygen atom or a direct :Link, with the pro-viso that when m is 1, X is a direct link; and Z is a group selected from:

- ocoR3 -N(R2)COR
-N~R2)So2R3 -N(R2)CoNR4R5 and -N(R2)CooR3 ;~ wherein R2 is hydrogen or lower alkyl; R3 is lower alkyl, phenethyl, benzyl, phenyl or 2-, 3- or 4- pyridyl; and R4 and R5 -~
are each independently hydrogen or a group as defined for R3 above;
and the pharmaceutically acceptable acid addition salts thereo0 The term "lower" applied to an alkyl or alkoxy group ,,~
indicates that such a group contains up to 6 carbon atomsO
` Preferably such groups contain up to 4 carbon atoms, and such groups may bs straight or, when appropriate, branched chainO
The compounds of the invention containing one or more asymmetric centres will exist as one or more pairs of enantiomers, and such pairs of individual isomers may be separable by physical methods, e.gO by fractional crystallisation of suitable salts.

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. - 3 -:

- ~ -The invention includes the separated pairs as well as mixtures thereof,i.e.rac~mic mixtures or as separat~ d- and 1- optically-active isomeric forms.
The pharmaceutically acceptable acid addition salts of S the compounds of the invention are those f.ormed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydro-iodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.
The cardiac stimulant activity of thé compounds of the invention is shown by their effectiveness in one or more of the following tests: ta) increasing the force of contraction in the isolated, spontaneously beating, guinea pig double atria pre-paration; (b) increasing myocardial contractility ~left ventricular dP/dt max.) in the anaesthetised dog with a left ventricular catheter; (c) increasing myocardial contractility in the conscious dog with an implanted left ventricular transducer.
Xn test (a) the pos tive inotropic and chronotropic ` 20 xesponses of the atria to the test compound are measured a~t several doses and compared with the responses elicited by iso-prenaline. The comparison of the dose xesponse curves obtained j~
~ives a measure of the force versus rate selectivity of'the test cornpound.

tP~C. 269) ` ' ' ~ ' ;, - s -In -test (b) the positive inotropic action of the test compound following intravenous administration is measured in the anaesthetised dog. The magnitude and duratiorl o this action, and the selectivity for increase in force versus frequency of contraction of the test compound are obtained, as are its peripheral effects, e.g.
the effect on the blood pressure. ..
~ n test (c) the positive inotropic action oE the test compound following intravenous or oral adrninistration to a conscious dog with an implanted left ventricular transducer is measured. The magnitude of the inotropic action, the selectivity for increase in force versus fre~uency of contraction, and the duration of action of the i.notropic effect of the test compound are all obtained.
The preferred compounds of the invention have the formula:
. ~ , : CH30 ~ ~ N

CH30 ~ N

:1 wherein Y is as defined for formula (I). Preferably X is a direct link.: j I "-(CHR1~ -" is prèferably ~CH2-, -CH(CH3)-, -CH2CH2-, -C~2cH(cH3)- or CH(CH3)C 2 , ., ' .
.~ (PLC. 269) ' , , . ~

Z is preferably:- ¦
ta) -OCONMR wherein R is C1-C4 alkyl, phenyl or 2-, 3- or 4-pyridyl;

(b) -N(R )COR wilcrein R is hydrogen or CL-C~ alkyl and R is C1-C4 alkyl, phenyl, phenethyl or 2~, 3- or 4- pyridyl;
~ ~c) -N (R )SO2R wherein R is hydrogen or C1-C4 alkyl and R3 is : C1-C4 alkyl, phenyl, benzyl or 2-, 3- or 4- pyridyl;
(d) -N (R ) CONR R wherein R is hydrogen or C1-C4 alkyl, R is hydrogen or C1-C~ alkyl, and R is C1-C4 alkyl, phenyl ox

2-, 3- or 4- pyridyl; or ~e) -N(R )COOR wherein R is hydrogen or C1-C4 alkyl, and R is Cl-C4 alkYl The preferrcd i.ndividual compounds have the for~ula (II) wherein Y is:

`CH2CH2NEfCOOC2H5 -CH2N(CH3)co(cH2)2c 3 ~cEl2cH2N(cH3)so2.phen -CH(cE~3)cH2N(CH3)so2cH3 ~C~2CH2M(CEl3)sO2-(c~I2)2 3 -CH CH N(CH )SO C H
-cH2cEl2N(cH3)coN(cH3)2 -cH2cH2N(cH3)so2-(3-pyridyl)-or -c~(cH3)cH2N(cH3)so2c2H5 (PLC. 269) ' , . . . .
, ~^ .
- . .

- , ~
~' : . . ", ,,. , ' .. . . . .

1~ # ~

The invention also includes the pharmaceutically acceptable bioprecursors of the compounds of the formula (I).
The term "pharmaceutically accep-table bloprecursor"
requires some explanation. It is, of course, common practice in pharmaceutical chemistry to overcome some undesirable physical or chemical property of a drug by converting the drug into a chemical derivative which does not suffer from that undesirable property, but which, upon administration to an animal or human being, is converted back to the parent drug. For example, if a drug is not well absorbed when given to the animal or patient, by the oral route, it may be possible to convert it into a chemical derivative which is well absorbed and which in the sèrum or tissues is reconver-ted to the parent drug. ~gain, if a drug is unstablè in solution, it may be possible to prepare a chemical derivative of it which is stable and may be administered in solu-tion, but which is reconverted in the body to give the parent drug.
The pharmaceutical chemist is well aware of the possibility of ~;; overcoming intrinsic deficiencies in a drug by chemical modifi-: . .
cations which are only temporary and are reversible upon adminis-tration to the animal or patient.
For the purpose of this specification the term "pharma-ceutically acceptable ~ioprecursor" of a compound of the formula (I) means a compound having a structural formula different from the comEounds of the formula (I) but which nonetheless, upon administration to an animal or human being, is converted in the patient's body to a compound of the formula (I).

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The compounds of the inventi.on can be administered alone but will generally be administered in admixture wi.th a pharmaceuti.cal carrier selected witll regard to the intended route of administration and s-tandard pharmaceutical practice. For example they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules : either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
They may 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 solutes, for example, enough salts or glucose to make the solution isotonic.
For administration to man in the curative or prophylactic treatment of cardiac conditions such as congestive heart failure, it is expected that oral d~sages of the most active compounds of the invention will be in the range from 20 mg to 1 g daily, taken in 2 to 4 divided doses per day, for an average adult patient t70 kg). Dosages for intravenous administration would be expected to be within the range 1 to 300 mg per single dose as required, for example in the treatment.of acute heart failure. Thus for a typical adult patient, individual tablets or capsules mi.ght contain from 5 to 250 mg of active compoundl in a suitable pharmaceutically acceptable vehicle or carri.erO

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, _ 9 l Thus the present invention provides a pharmaceutical composition comprising a compound of the formula (I) as defined above or pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier.
The invention also provides a method of stimulating the heart of an animal, including a human being, which comprises ad~inistering to the animal a compound of the formula (I) or ' salt thereof as defined above, or a pharmaceutical composition as i defined above, in an amount sufficient to stimulate the heart of1 10 the animal.
The compounds of the invention may be prepared by a number of routes:
Route A
Cornpounds of the formula (I) may be prepared by reacting~
an appropriately substituted phthalazine of the formula:

. R0 ~ ~ N

; RO ~ N --- (III) :~ Ql , wherein Q1 represents a facile leaving group such as ch~oro-, bromo-, iodo-, lower alkoxy or (lower alkyl)thio, with an amine : of the formula: I
~ N ~
20 ~ - (IV) with resultant elimination of HQ1. Q1 is preferably chloro or ; bromo.
~ (PLC. 269) : '.,~, . .

, ' ' ' ' '' The reaction is preferably carried out in an inert organic solvent such as ethanol with heating, e.g. under reElux, in a temperat~e range of 75 to 150C for up to 48 hours. When Q
is chloro-, bromo- or iodo-, the presence of a base such as triethylamine or of excess reagent of the formula (IV) is advantageous. The product may be isolated and purified by con-ventional methods.
The compounds of the formula (IV) are either known I compounds or may be prepared by procedures analogous to the prior art, e.g. by the hydrogenation of the corresponding pyridine ¦ derivatives.
I Route B
I
Compounds of the formula (I) in which Z is -N(R )CONE~
may be prepared by the reaction of a phthalazine of the formula:

RO ~ N

RO ~ ~
~ - (V) X-(CHR ) -N~IR ~

~¦ with an isocyanate R NCO, R being other than hydrogen, or, to prepare com~ounds in which R5 is H, sodium or potassium cyanate in the presence of acid.

''1 ' ' , :' !
(PI,C. 259) ~, . 1 , .:` :. , . : ,, . , , ` ~,. . .

;, , ~ . ' I :
- , ., :
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.' ~ .:

The acid may be supplied by using an acid addition salt of the compound of the formula (V) as the s-tarting material.
In a typical procedure, the reactants may be reacted together at ; room t~nperature for up to 24 hours in a suitable solvent, e.g. dry chloroform. The mixture may then be evaporated to leave an oil which may be triturated with e.g. a mixture of ether and ethyl ace-tate to leave the product as a crystalline solid which may be recrystallised from a s~itable solvent, e.g. ethanol.
Route C
Compounds of the formula (I) wherein Z is either -'N~R )COR , -N(R )COOR , -N(R )SO2R , or N(R )CONR R , R and R
both being other than hydrogen in -the latter case, may be prepared by reacting a compound of the formula ~V) as previously defined with, as appropriate, either: (a) a haloformate of the formula Q2CoOR3 or acyl halide of the formula R3CoQ2, wherein Q2 is chloro ; or bromo; (b) a sulfonyl halide of the formula R3So2Q2, Q being chloro or bromo; (c) a carbamyl halide of the formula R R NCOQ2 wherein R and R5 are both other than hydrogen and Q is chloro or bromo; or (d) an anhydride of the formula (R3Co)2o.
Typically the reactants are allow~ to stand together at room temperature for a period of up to 24 hours in an inert organic solvent, e.g. chloroform, in the presence of a base such as triethylamine.

' ~: - - ' .:
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(PLC..269) .
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- 12 _ The product may be isolated and purified by conventional methods, e.g. by washing with aqueous base, drying and evaporating the organic layer to leave an oil, dissolvir1g -the oil in ethyl acetate and applyi~g~i~ to a column of e.g. "~lorisil" (Txade Mark), the produc-t being eluted with e.g. 10~ ether in ethyl acetate.
Route D
Compounds of the formula (I) wherein Z is -OCONHR
may be prepared by reacting a phthalazine o~ the formula:

RO ~ N

RO ~ N
N ~ (VI) l ~\ ' .
,, I . X- (C~3Rl)m-CH

with an isocyanate R NCOJ R being other than hydrogen, or, to prepare compounds in which R is hydrogen, sodium or potassium ll cyanate in the presence of acid.
:
In a typical procedure, the reactants are heated together 1l in a suitable organic solvent, e.g. dry chloroform, at 4~ - 70C
1 15 for 5 - 10 hours. The solution may then be evaporated in vacuo to leave an oil which may be triturated with e.g~ ether to leave a residue which may be chromatographed on a suitable column to purify it.
. ~ I .

(PLC. 269) ~', I .

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:
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:~ . . ~ . . . . . .
:~ - : ' ' .

Route E
Compounds of the formula tI) in which Z is -N(R )COR , may be prepared by reacting a phthalazine o the formula (V) as previously defined with an ester of N-hydroxy succinimide of the formula: R3Ca~
O O
N ~
~ VII).

The corresponding ester of N-hydroxyphthalimide may also be used.
In a typical procedure, the reactants may be stirred together in a suitable solvent. e.g. by dry chloroform, for 2 - 6 hours at room temperature.
The product may be isolated and purified by conventional methods.
The starting esters may be prepared by conventional techni~ues, typically by reaction of an acid of the formula R3CoOH
with N-hydroxysuccinimide or N-hydroxyphthalimide in the presence ; of dicyclohexylcarbodiimide.

,~ , : ' .
: .

~J~

Acid addition salts of the compounds of formula (I) may be prepared from the crude or pure free base product by the ~` 10 conventional technique of reacting the free base with the acid in an inert solvent, e.g. by mixing alcoholic solutions of each and collecting the resulting precipitate by filtration. The product may then be recrystallised to purity.
The phthalazine starting materials used in the preceding routes may be prepared by procedures analogous to those of the prior art. Similarly the piperidine and other starting materials used are either known compounds or may be prepared by conventional methods. The preparation of many starting materials is illustrated in Preparations 1 to 13.
ZO The following Examples illustrate the invention:

~, : . ' , ',; ' ' ' :'.
(~LCs 269) . ' .

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:~ . . . , :
.
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E~MPI.F. 1 'I 11 3 \~ ~ N~: (CO~H)2 (C H ) N ~ ~ N

CH30 ~ ~ H~JN ~ 3 Cll30 /~
2)3 3 ~ N~

CH
C112N ~ 3 2)3 3 -Chloro-6r7-dimethoxyphthala~ine (1.12 g), 4-/(1-methyl-3-n-butylureido)methyl7piperidine mono-oxalate (2.0 g) and triethylamine (2.5ml) were heated together under reflux for 100hours in ethanol (100 5 ml).
AEter concenkration ln vacuo, the residue was suspended in water ~25 ml), basified to pH 10 wi-th 5N sodium hydroxide solution and extracted into chloroform (2 x 25 ml). The dried (MgS04) extracts were taken to dry-ness in vacuo giving a brown oil which was dissolved in the minimum volume 1-0 of c:hloroform and applied to the top of a chloroform¦"Flor1sil" (q'rade Mark) column (bed size30x 2.5cm) which was eluted with chloroform containing - increasing quantities of methanol (up to 50%). After 500 ml of solvent had :. . .
been collected 18 x 60 ml fractions were taken of which fractions 12-18 were combined and taken to dryness in vacuo.
15 The resultant oil, which solidified on coolins, was dissolved in the minimum volume of ethyl acetate and left in a refrigerator for 18 ~- hours to crystallise. Crystals of pure 6,7 dimethoxy-1-/4-{1-methyl-` 3-n-butylureido)methyl~piperidino7phthalazineDlonohydrate (0.37 g) were collected by filtration, softening at 100 C, and melting at 114-127 C.

~PLCo 269) . . ' .
~ .. - ` . :
::~, - ' , ' : ,1 1 -15a -Ana.lysis ~:-.l Found: C, 60. 6; H, 8.1; N, 15.9 CalCUlat~d ~or C22H33N53 2 C, 61.0; H, 8.1; N, 16.2.

The followin~ compounds were prepared similarly to Example 1, starting from 1-chloro-6,7-dimet:hoxyphthalazine and the .
. ' appropriately substituted piperidine.

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Z ~ ~ ~ N ., ~ _~ ~
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:.
(PLC. 26g) - ~.S ' _1'.. . ! , ', - 1 9 -~

Z ~.__ __ ............. __ - :~, _ ~ ~ ~ ~ o o ~ ' .Y ~
. ~P~ ~_ .
a~ ~ ~0~ r~r~ o~

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a w 8 ~ o ~ ~ ~ . ~ _ ~
z ~ æN m . ~ 1~ W W
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,, .' ~ ' ~ ' ' ' ¦ F.XAMPLr: 34 i Preparation of 6,7-dime-thoxy-i-/4- ~-(3-/3-pyridyl7~1-methylureido~
ethyl~pipel-idino7phthalazine CH30 ~ N OC ~ 3 ~ N

N

CH2CH2NHCH3 CH2CH2NCONH.(3-pyridy]) Me 6,7-Dimethoxy-1-/4-{2-N-methylaminoethyl~piperidino7-phthalazine (1 g) in dry chloroform (10 ml) was stirred and heated with 3-pyridyl isocyanate (0.6 g). After allowing the mixture to stand overnight the mixture was washed with water, dried (Na2CO3) ~! and evaporated to dryness in vacuo to give an oil. The oil was ;¦ 10 triturated with a mixture o~ ether and ethyl acetate (30 ml, 9 to produce a crystalline solid . which was recrystallised from ethanol to give pure 6,7-dimethoxy-1-/4-~ -(3-/3-pyridyl7-1-methylureido)ethyl~piperidino7 phthalazine hydrate (0.45 g), m.p. 200 - 204C.

(PLC. 269) ., ~ ' ."

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.

, ~ 25 -i I Analysis '~.-_ _ _ _ _ _ Found: C, 63.2; H, 6.7; N, 18.1 C2 H N O ,1EI O xequires: C, 63.3; El, 6.8; N, 18.5.
, .
EXAMPLES 35 'ro 37 The following compounds were prepared similarly to the previous Example, starting from 6,7~dimethoxy-1-/4-(2-N-methylamino-'' ethyl or N-methylaminomethyl)piperidino7 phthalazine and the appropriate isocyanate.

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br 3,:-, ~ :~

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_ 27 -EX~MPIE 38 Preparation of 6,7-dime-thoxy 1~ 2-(1,3,3-trime-thylureido)et piperidino7 phthalaæine -CH
CH30 ~ ~ ~ N ~ NCOCl CH30~1 ~ N

CH30 ~ N ~ 3 ~N

~ ~ CH2CH2NHCH3 ' CH2cH2lNcoN
;~ CH3 CH3 6~7-Dimethoxy-l-/4-~2-N-methylaminoethyl~piperidino7 phthala7ine (0.7 g) in a mixture of dry chloroform (25 ml) and triethylamine (2 ml), was stirred Whilst N,N-dimethyl-carbamoyl chloride (0.23 g) was added slowly, dropwise. The mixture was ; then allowed to stand overnight after whiCh water (20 ml) was added. The chloroform layer was separated, dried (Na2C03) and evaporated to dryness in vacuo. The oily residue was retaken in the minimum quantity of ethyl acetate and was than applled to the top o~ a column of "Florisil" (Trade Mark)(bed size 35 cm x 1.5 cm), Elution was commenced With 10~ ether in ethyl acetate and ten fractions~ each of 50 ml, were collected. Fractions 3 to 9 were com~ined and evaporated to dryness in vacuo to give an oil which solidified on trituration with ether containing 10% ethyl acetate.
.
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- 2~ _ Recrystallisatiorl Ero~l ethyl acetate gave pure 6,7 dime-thoxy-1-/4-~2-(1,3,3 trimethylureiclo)ethyl~piperidino7 phthalazine (0.2 g) m.p. 140 - 14lC.
Analysis %:-Found: C, 62.6; H, 7.8; N, 17.2 21E131N53 rec~ires: C, 62.8; H, 7.8; N, 17.4.

The following Examples were prepared similarly to the previous Example, starting from 6,7-dimethoxy-1-/4-(2-N-methylamino-ethyl or N-methylaminomethyl)piperidino7 phthalaæine and the appropriate sulfonyl chloride, acid chloride or carbamoyl chloride.
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CH30 , ~ CH3CH2NCO ~ ~ ~ N

C~20~ Ch20C~

~ 5 Ethyl isocyanate (0.69 g) was added slowly to the stirred - solution of 6,7-dimethoxy-1-/3-(hydroxymethyl)piperidino7 phthalaæine (0.76 g) in dry chloroform (10 ml) at 5C, then heated at 60~C for 7 hours. Thin layer chromatography showed that the reaction had not gone to completion so more ethyl isocyanate (0.5 ml) was added and stirring was continued at room temperature for 18 hours. The .. ~ ~
solution was then concentrated in vacuo to qive an oil which was triturated with ether (30 ml) and decanted. The residue was dis-solved in the minimum volume of chloroform and applied to the top of a chromatography column, made up of chloroform and powdered silica (bed size 40 x 2 cm), which was then eluted with chloroform containing increasing ~uantities of methanol (up to 5~).

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1 on ml Fractions were col.lected and monitored hy thin layer chro--matography. ~ppropriat.e frac-tions were combined and concentrated n vacuo to give the produc-t as an oil, (0.45 g).
This oil was suspended in ethyl acetate (25 ml) and enough ethanol was added to give a complete solution, then a solution of oxalic acid in ethyl aceta-te was added until the mixture was acidic (pH 3-4). The precipitate was collected by fi.ltration and crystallised from isopropyl alcohol to yield 6,7-.
: dimethoxy~ 3-(N-ethylcarbamoyloxyme-thyl)piperidino7 phtL~lazine :

mono-oxalate : 4 hydrate (0.30 g), m.p. 132 - 134 C.

Analysis %:-: Found: C, 53.4; H, 5.9; N, 11.9 ca~.culated ~or C19~126N~4 C2H24 4 2 l'he following compounds were prepared similarly to the previous Example, starting from 6,7-dimethoxy-1-/4-(2-hydroxyethyl . or 2-hydroxyethoxy)piperidino7 phthalazine and the appropriate iso-.` cyanate. These starting phthalazines are the subject of Examples 5 and 25 respectively of our co-pending British Patent Application . 20 No. 26202/78 filed 1st June, 1978.
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EXAMPL~_~8 Prepara~ion oE 6,7-Dimethoxy~ 2-~2-(N-nicotinoyl-N-methylamino) ethyl~-piperidino7 phthala2ine To a stirred suspension of nico-tinic acid (2.3 g) in dry chloroEorm (350 ml) at 30C, were added N-hydroxysuccinimide (2.3 g) and N,N-dicyclohexylcarbodiimide (4.1 g). After five minutes the suspension had substantially dissolved and was then gradually replaced by a white crystalline precipitate. The mixture was stirred for a further 1 hour and was then filtered~ An aliquot of the filtrate (60 ml) was treated with a solution of 6,7-dimethoxy-/4-~2-N-methylaminoethyl~piperidino7 phthala~ine (1 g) in dry chloroform (20 ml) and the solution was stirred at ambient tempera-; ture for 2~ hours, after which water (50 ml) was added. The chloro-form layer was separated, washed with water (20 ml), dried (MgSO4) and evaporated in vacuo to give an oil containing a small amount _ _ ~ of solid. The oil-solid mixture was stirred with chloroform (15 ml) ;~ filtered and the filtrate was evaporated in vacuo to give an oil.
The oil was dissolved in isopropanol (30 ml), treated with an iso-propanol solution of oxalic acid (to pH 2) and the precipitated solid was recovered by filtration. Recrystallisation from iso- -propanol gave pure 6,7-dimethoxy-1-/4-~2-(N-nicotinoyl-N-methylamino) ethyl~-piperidino7 phthala~ine oxalate monohydrate (290 mg), m.p.
110 - 115C.
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Analysis %:-Found: C, 56.9, H, 5.8; N, 12.7 24 29Ns3 C2H20~ ll2o requires C, 57.4; H, 6.1; N, 12.9 The following preparations illustrate the prepara~ion o:E
certain o:E the starting ~aterials:-.

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Preparation of 4-(2-~cetclmidoethyl)piperidine . _ _ ~ 11 hydro~ ~ N
N r 2 2 il 3 ~ HN ~ H2CH2NCjCN3 :-' \~/ O

4-(2-Ace-tamidoethyl)pyridine t33 g) in ethanol (250 ml) was acidified to pH 4 with hydrochloric acld and hydrogenated at ~; 60 p.s.i./60C over a platinum oxide catalyst for 18 hours, after which time the uptake of hydrogen was complete. The catalys-t was then removed by filtration and the filtrate was treated with a solution of potassium hydroxide flakes in methanol (1.1 molar equivalents) and refiltered. The solvents were distilled off in vacuo, leaving a clear oil, which on standing gave 4-(2-acetamidoethyl)piperidine (18 g) as a white solid, m.p. 60C.
The oxalate salt was also prepared, m.p. 125 - 129 C.
Analysis %:-15 Found: C, 50.9j H, 7.7; N, 10.4 Calculated for C9H18N2 C2H24 C, 50.8; H, 7.8; N, 10.8.

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Preparation 2 ~ Q-4-(2-Acetoxy~ propyl)pipcridine hydrochloride 4 hydrate, m.p. 188 - 1~J1 C, was prepared similarly to the above Preparation, starting from dl-4-(2 hydroxy-n-propyl)pyridine, but using acetic

5 acid as solvent. Acetylation occurred during the hydrogenation.
nalysis ~:-.
Found: C, 52.8; H, 9.1; N, 6.3 Calculated for C10H19N2-HC1-4H2 C, 53.1; H, 9.1; N, 6.2.

. Preparation 3 (A) 4-(3-n-Butyl-1-methylureidomethyl)pyridine ~-(N-Methylaminomethyl)pyridine (3.6 g) in dry chloroform ~70 ml) was stirred and cooled in an ice bath whilst n-butyliso-cyanate (9.9 g) was added slowly, dropwise. The mixture was then allowed to stand at ambient temperature overnight after ~hich . .
methanol (15 ml) was added and stirring continued for a further 30 minutesO The solvents were removed by evaporation to dryness in vacuo and the residue was redissolved in ethyl acetate (50 ml).
The oxalate salt was precipitated by treating the solution with a slight excess of oxalic acid in ethyl acetate. Recrystallisation from isopropanol gave pure 4-(3-n-butyl-1-methylureidomethyl) pyridine sesqui-oxalate (7.2 g), m.p. 86 - 90 C.
' Analysis ~:-Found: C, 50.~; H, 6.6; N, 11.9 12 1gN3 l~(C2H2O4) requires C, 50.6; ~, 6.2; N, 11.8.
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and dl-4~(1-/3-ethy~-1-methylureido7ethyl)pyrid~e( (B) The above pyridines were then hydrogenated to the corres-ponding piperidines similarly to Preparation 1.
` 10 Preparation 4 (A) Preparation of_4-(2-methanesulphonamidoethyl)pyridine ... _ .. _ . .. . .. . _ _ _ " '~ CE1'3S02Cl ~
C~32CEI2NH2 ~ N ~ CH2CH2NH-SO2CH3 Methanesulphonyl chloride (3.5 g) was added slowly to 4-(2-aminoethyl)pyridine (3.6 g) and triethylamine (3.0 g) in chloroform (40 ml). The temperature was maintained below 40C
during the addition, after which the orange solution was l~ft to stand at room temperature overnight. Water (50 ml) was then added, the chloroform phase was separated, and the aqueous phase extracted with chlo~oform (lO0 ml). The two chloroform solutions were combined, dried (MgSO4) and taken to dryness in VACUO to give a yellow oil which solidified immediately.

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3~ :-This solid was crystallised from ethanol to yield whi-te crys-tals of 4-~2-methclnesulpllonclmidoethyl)pyridine (1.4 g).
A ~small sample was recrystallised :Erom ethanolt m.p.
lla. - 116 C.
S Analysis ~:-_ Found: C, 47.9; El, 6.0; N, 14.0 Calculated Eor C8Hl~N2O2S: C,48.0; H,6.0; N, 14Ø

(B) Preparation of 4-(2-methanesulphonamidoethyl) piperidine ~ hydrogenatio~

N~ CH2cH2NH.so2cH3 EIN ~CH2CH2NH.SO2C~3 ; ` ' ' 4-(2-methanesulphonamidoethyl)pyridine (8.4 g) in ethanol (85 ml) was acidified to pH 2 with 2N HCl and hydrogenated at - room temperature and a pressu~e of 50 p.s.i. over a platinum oxide catalyst until hydrogen uptake ceased. The catalyst was then removed by ~iltration and the filtrate was taken to dryness in vacuo 15 to give a white solid which was dissolved in the minimum volume of hot ethanol, filtered quickly, and left at room temperature over-night. The resultant white crystals were collected by Eiltration and dried to yielc~ 4-(2-methanesulphonamidoethyl)piperidine hydrochloride (8.3 g), m.p. 165 - 167C.
20 ~:~
Found: , ~ C, 39.6; H,7.8; Nt11.7 Calculatedfor C8H18N2O2S:HCl: C, 39~6j H, 7.9; N, 11.5 (PLC. 269) "- ! - ~ ~, ' . A , '. ' .
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Also synthesised in a si.milar ~a9}1io~ -to Part (A) were:
(4-(2-/N-i Propyl-methanesulphollamido7ethyl)pyriCIine o~a]ate, :: ( o ( m.p. 129 - 131 ~ Found: C, 46.7; H, 6.2; N, 8Ø
( CllH18N202S.C2H2O~ requires: C, 47.0; H, 6.1; N, E.4%.
4-(2-/N-Methyl-metharlesulpllonamido7ethyl)pyridine - crude oil, 4-(2-/N-Methyl-ben~enesulphonamido7ethyl)pyridine ~ crude oil, (4-(2-Benzenesulphonamidoethyl)pyridine, m.p. 109 - 110, ( Found: C, 59.5; H, 5.4; N, 10.6. C13H14N2O2S requires:
C, 59.5; M, 5.4; N, 10.7%.
(dl-4-(3-/N-Methyl-methanesulphonamido7prop-2-yl)pyridine oxalate, ( mOp. 155 - 158r j 4-(2-/N-Methyl-n-propanesulphonamido7ethyl)pyridine - crude oil, (4-(2-/N-Methyl-phenylmethanesulphonamido7ethyl pyridine, m.p. 109-110, ( Found: Cr 62.0; Hr 6.3; Nr 9.7. C15H18N2O2S re~uires:
;-~ 15 ( Cr 62.1; H, 6.3; N, 9.7%.
4-(N-Methyl-methanesulphonamidomethyl)pyridine - crude, 4-(2-/N-methyl-ethanesulphonamido7ethyl)pyridine - cxude oil, (dl-4-(1-/N-methyl-ethanesulph~amido7prop-2-yl)pyridine hydrochloride -( crude oil, and (4-(N-Methyl-ben~enesulphonamidomethyl)pyridine, m~p. 101 102, Found: C, 59.9; H, 5u4; N, 11.1. C13H14N202S xequires:
( C, 59.5; H, 5.4~ N, 10.7%~
The above were then hydrogenated similarly to Part (B) ; 25 to give the corresponding piperidines.
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~) 4-(N-Methyl-butyramidomethyl)pyridine n-Butyryl chloride (2.8 ml) in dry methylerle chloride (20 ml) was added slowly to a stirred, cooled mixture of 4-(N-methylaminomethyl)pyridine (3 g) and triethylamine (5 ml) in dry methylene chloride (30 ml). The mixture was then stirred at room temperature for 2~ hours, after which water (30 ml) was added.
The organic phase was separated, washed with dilute aqueous sodium ;~
hydroxide (5~, 30 ml), dried (Na~CO3) and evaporated to dryness in acuo. The resultant dark brown oil (3.8 g) was chromatographed on a "~lorisil" (Trade Mark)(15 g) column, using chloroform as eluant. Appropriate fractions were identifled by t.l.c., bulked and evaporated in vacuo to give pure 4-(N-methyl-butyramidomethyl) pyridine as an oil (3.2 g).
(B) The oil was then hydrogenated similarly to Preparation , l(B) to the corresponding piperidine.
Al~o prepared similarly to the above were:
4-/N-Methyl-benzamidomethyl7pyridine, and 4-/1,3,3-TrLmethylureido-methyl7pyridine (crude oil), which were then hydrogenated as Preparation 1(~) to the corresponding piperidines.
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' Prep~ration 6 4-(1~/N-Methylacet~ido7prop-2-yl)pyridine 4-(1~N-Methylamino-prop-2-yl)pyridine (4.5 g) in acetic ~cid (15 ml) was treated cautiously with acetic anhydride (10 ml) followed by allowing the mixture to stand at ambient temperature overnight. Methanol (20 ml) was then added to destroy excess acetic ¦ anhydride, followed by evaporation in vacuo (at 40C) to remove I methanol and methyl acetate. The residue was diluted with water and treated portionwise with solid sodium carbonate (anhydrous) until alkaline (pH 10 - 12~. The oily suspension was extracted with chloro-form (3 x 60 ml) and the bulked extracts were dried (Na2CO3) and evaporated to dryness in vacuo to give a near-colourless oil (6.8 g) The oil was distilled to give puredl~4-(1 /N-methyl-acetamido7prop-2-yl~pyridine (3 g), b.p. 138 - 140/0.4 m.m. Hg. (as a colourless oil).
Analysis ~
Found: ~ C, 65.8; H, 8.5; N, 1~.2 CllH16N20.~H20 requires: C, 65.7; H, 8.5; N, 13.9~.
The following compounds were synthesised by a similar method:
4-(2-/N-Methylacetamido7ethyl)pyridine oxalate, m.p. 120 - 124, ~; 20 4-(2-~cetamidoethyl)pyridine, b.p. 158 - 160/0.6 m.m., .~
4-~ Acetamidomethyl)pyridine, m.p. 83 - 88 , 4-(N-Methylacetamidomethyl)pyridine - crude oil, and `
dl-4-(l-/N-methylacetamido7ethyl)pyridine - crude oil.
~ 25 The above were then hydrogenated similarly to Preparation -~ 1 to give the correspondin~ piperidines.
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- Pr_parat on 7 4-(2-/N-Ethoxycarbonyl-N-methylamino7ethyl)pyridine Ethyl chloroformate (11.2 g) was added dropwise to a cooled, stirred mixture of 4-(2-N-methylaminoethyl)pyridine (13.6 g) and triethylamine (25 g) in dry chloroform (400 ml). The mixture was stirred at room temperature overnight and then water (100 ml) was added. The organic layer was separated, dried (MgS04) and evaporated in vacuo to give 4-(2-/N-etho~ycarbonyl-N-methyl~
amino7ethyl)pyridine as an oil (20 g).
Also prepared similarly to the ahove _as:
4-(2-/N-ethoxycarbonylamino7ethyl)pyridine.
The above products were then hydrogenated similarly to Preparation 1 to produce the corresponding piperidines.

Preparation 8 Preparation of 6,7-dimethoxy-1-(3-hydroxymethylpiperidino)phthalazine : . . _ H

CH30 ~ ~ ~> ~ ¦ . i.
CH30 ~ CH3 ~ ~ N

ClCH20H N ~

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1-chloro-6,7-dimethoxy phthalazine (2.25 g), 3-hydroxy-methylpiparidine (1.72 g) and triethylamine (1.3 ml) in isoamyl alcohol (60 ml) were heated at 95C for ~2 hours.
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Analysis %:-Found: C, 63.7j ~, 6.9j N~ 13.7 Calculated for C16H21N3O3: C, 6304; H, 7.0; N, 13.9.

Preparation 9 ~-(2-isopropylaminoethyl)pyridine 4-Vinylpyridine (21 g), isopropylamine ~24 g) concentrated hydrochloric acid (40 g) and water (100 ml) were mixed together with cooling, and then boiled under reflux or 20 hours. The mixture was cooled, basified to pH 12 - 13 ~20% NaOH) and extracted with I chloroform ~3 x 200 ml). The bulked extracts were washed with ¦ 20 water tl00 ml), dried (MgSO4) and evaporated in vacuo to give a green oil. ~he oil was distilled and the fraction boiling at 84 - 90C/l m.m. was rollected (16.S g) and identified (by n.m.r.
spectroscopy) as 4-(2-isopropylaminoethyl~pyridine.

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4-t2-Aminoethyl)pyridinel 4-~2-Methylaminoethyl)pyridine~ and ~, dl-4-(1-Methylamino)prop-2-yl)pyridine.
Preparation 10 . .. _

6,7-Dimethoxy-1-/4-~2-N-methylaminoethyl~-piperidino7 ph-thalaziine 6,7-Dimethoxy-1-/'4-(2-N-methylacetamidoethyl)-piperidino7 phthalazine (2.0 g)(prepared as in Example 4) in a mixture of :
ethanol and 5N sodium hydroxide solution (1:1, 20 ml) was heated 10 under reflux for 70 hours. The ethanol was removed by evaporation ~' .
. in vacuo and the aqueous phase was diluted with watex (10 ml) andextracted with chloroform. The extract was dried ~Na2CO3) and ; evaporated in vacuo to give an oil, which on trituration,with hexane gave 6,7-dimethoxy-1-/4-(2-N-methylaminoethyl)piperidino7- ;
phthalazineas a pale yellow solid (1.5 g), A small sample was characterised as the dioxalate monohydrate, m.p. 159-162 CO
Analysis ~:- Found: C, 49.8; H, 5.7; N, 10.3; Calculated for 18 2b 42' 2C2H2o4.~l2o: C, 50.0j H, ~.1; N, 10 6 :: 6,7-Dimethoxy-1-~'4-(N-methylamirlomethyl)piperidino7 2~ phthalazinewas prepared similarly to the above, starting with 6,7-: _ dimethoxy-1-/4- (N-methylacetamidomethyl)piperidino7 phthalazine (prepared as in Example 3). A small sample of the product was characterised as the dioxalate, softening at 140 C, with decompo-`~ sition at 1?30 C. Analysis % - Found: C, 50.1; H, 5.7; N, 11.5 ~alculated for C17~24N4O22C2H2 4 ~ (PLC.,269) ,i : I

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s Preparation 11 A. Preparation of 6, -Dimethoxyphthalazine-1-one CH30 ~ ~ 2 2 ~ ~ ~ I
l EtOH l ~ l NH
C}130 ~ COOH OEl O ~ ~ ~ ~

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4,5-Dimethoxyphthalaldehydicacid (10 g) and hydrazine hydrate (2.4 ml) in ethanol (150 ml) were heated under reflux for 20 hours during which time a white crystalline solid formed. The ~ixture was cooled in an ice bath, filtered and the resulting product dried to give crude 6,7-dimethoxyphthalaæin-1-one (7 g).

A sample was crystallised from water yielding colourless needles, 10m.p. 254 - 256.

Analysis %:- ~

Found: C, 58.4, H, 4.8; N, 13.9 Calculated for C1oH1oN203: C~ 58.3, ~, 4.9; N, 13.6.

B. Preparation of l-Chloro-6~7-dimethoxyphthalazine 3 ~ I POC13 ~3 ~ N
~ I

3 ~ 3 ~ ~ N
Cl 6,7-Dimethoxyphthalazin-1-one (2~.6 g~ was heated under ~-reflux with phosphoryl chloride (200 ml) for 6 hours then cooled to room tempexature and the excess phosphoryl chloride removed under reduced pressure.

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- ,4~ -The resul~nt brown solid was suspended in ace-tone ~150 ml) and poured onto cold (5) concentrated ammonium hydroxide t200 ml).
The cnlde produc~ was filteredt washed with water (200 ml) then petroleum e-ther (200 ml). The pale yellow soiid was dried (20 g), ; 5 dissolved in the minimum volume oE chloroform and precipitated with excess petroleum ether, after which it was recovered by , filtration, washed again ~ith petroleum ether (100 ml) and dried ~I to give 1-chloro-6,7-dimethoxyphthalazine (13 g), m.p. 195 - 197 with decomposition.
Analysis %:-~j Found: C, 53.3; H, 4.2; N, 12.7 Calculated for C1oEIgClN2O2 C, 53.5; H, 4.0; N, 12.5.

Preparation12 _ __ _ _ _ (A) Preparation of l-Benzyl-4-(2l2-diethoxyëthoxy)piperidine ~¦ ~ CH2cH3 ~ r ~ I 2 3 ! 15 ~ 2 ~ OEI + BrCH2CH ~ ~ El ~ OCH2CH

¦ O~l,~CH3 ~ 2~ 3 1-Benzyl-4-hydroxy piperidine ~11.5 g) dissolved in dry dimethylformamide (DMF)~25 ml) was added dropwise to a stirred suspension of sodium hydride (2.8 g of 50% dispersion in oil in dry DMF (25 ml)), under dry nitrogen, and then stirred at room temperature for 3 hours.

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~,`, ` , ~1 The suspension was cooled in an ice/water bath whilst 2-bromo-acetaldehyde diethylacetal (13.0 g) in dry dimethylformamide (25 ml) was added drop~ise, followed by stirring at room temperature for 24 hours. The above process was repeated to add more sodium hydride t2.8 g)andtheacetal(13.0 g). 1so-Propyl alcohol (50 ml) was added, and the mixture was stirred for 1, hour, followed by filtration through '~yflo' (Trade Mark). The filtrate was concen-trated ln vacuo, suspended in water (100 ml) and basified to pH 11 with 5N sodium hydroxide. After extraction with chloroform (2 x 100 ml) the cornbined extracts were taken to dryness in vacuo to give an orange oil which was distilled in vacuo to give 1-benzyl-4-(2,2-diethoxyethoxy)piperidine (14.1 g), b.p. 152C @ 0.1 mm.
~B) Preparation of 1-benzyl-~-/2-(N-methylacetamido)ethoxy7piperidine 1-Benzyl-4-(2,2-diethoxyethoxy)piperidine (50 g) and 2N
hydrochloric acid (130 ml) were stirred together at room temperature for 18 hours. The mixture was basified to pH 9 with 5N sodium hydroxide, extracted into chloroform (2 x 150 ml), dried (MgSO4) and taken to dryness in vacu~. The oil was dissolved in ethanol (150 ml~ and mixed with sodium acetate trihydrate (8.9 g), wa-ter ( 83 ml), glacial acetic acid ~28 ml) and 33~ w/w ethanolic methyl-amine solution (15.5 g). The stirred solution was cooled to 0C
in an ice/salt bath and the temperature was maintained at 0 ~ 2 C
wh1lst sodium borohydride (6.6 g) was added portionwise and then ior the following ~ hour.

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The mixture was stirred at room temperature for ~0 hours, adjusted to p~l 7 with a lit-tle SN sodium hydroxide, concentrated in vacuo, diluted with water (150 ml) and extrac-ted wLth ether (2 x 225 ml).
The aqueous phase was ~asified to pH 10 with SN sodi~ hydroxide, extracted into chloroform (2 x 180 ml), dried (MgSO4) and taken to dryness in vacuo.
; The crude oil (12.5 g) in d~y chloroform ~80 ml) and ~ triethylamine (10.4 ml) was stirred and cooled in an ice/water ; bath durin~ the slow addition of acetic anhydride (6.1 g). The mixture was stirred a~ room temperature for 2 hours, shaken with water (50 ml) and separated. The chloroform phase was dried (MgS04), taken to dryness ln acuo, leauing a brown gum which was dissolved in ethyl acetate and converted to the oxalate salt by addition of oxalic acid in ethyl acetate solution to p~-3.
~ 15 The ethyl acetate was removed by decantation and the residual gum ; was dissolved in hot iso-propyl alcohol, allowed to cool to roomtemperature and diluted with an equal volume of ether to deposit a brown gum. The gum was isolated by decantation of the solvents and dried to give crude l-benæyl-4-/2-(N-metllylacetamido)ethoxy7 piperidine oxalate (10 g).
A second crop of the same material was obtained from the iso-propylalcohol/ether solution. Recrystallisation of this rom methyl cyanide gave pure crystals of 1-benzyl-4-/2-(N-methyl-acetamido)ethoxy7piperidine mono-oxalate monohydrate, m.p. 142 -147C.
':~
(PLC. 269) ~ .
:' ' ' ' :' ' ' ' ' ''';~ ' ~ :

, : ~

Anal s o~:-E`ound: C, 57.1; H, 7.0; N, 6.8 Calculat~d f~r ~17H26N20~ C2 2 ~ 2 The product was hydrogena-ted as prev;iously described to remove the benzyl group.
Preparationl3 4-/2-(N-methylsulfonamido)ethoxy7piperidine was prepared similarly to the above, but using methanesulfonyl chloride in place :
of acetic anhydride in step (B). ~

,~

(PLC. 269~
. . .
, ,

Claims (7)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing phthalazines of the formula:
---(I) wherein R is a lower alkyl group; and Y is attached to the 3- or 4- position of the piperidino ring and represents a group of the formula:
-X-(CHR1)m-Z
wherein R1 is a hydrogen atom or a lower alkyl group, and m is 1 or 2, with the proviso that when m is 2, each R1 may be the same or different; X is an oxygen atom or a direct link, with the proviso that when m is 1, X is a direct link; and Z is a group selected from:

-N(R2)COR3 -N(R2)SO2R3 -N(R2)CONR4R5 and -N(R2)COOR3 wherein R2 is hydrogen or lower alkyl; R3 is lower alkyl, phenethyl, benzyl, phenyl or 2-, 3- or 4- pyridyl; and R4 and R5 are each independently hydrogen or a group as defined for R3 above; and the pharmaceutically acceptable acid addition salts thereof, which comprises:
(i) reacting a phthalazine of the formula:

---(III) wherein Q1 represents a facile leaving group and R is as defined above, with an amine of the formula:

--- (IV) wherein Y is as defined above; or (ii) to prepare compounds of formula (I) wherein Z is -N(R2) CONHR5, reacting a phthalazine of the formula:
---(V) wherein R, R1, R2, X and m are as defined above, with an isocyanate of the formula R5NCO, R5 being as defined above other than hydrogen, or, to prepare compounds of formula (I) in which R5 is H, with sodium or potassium cyanate in the presence of acid; or (iii) to prepare compounds of formula(I) wherein Z is -N(R2)COR3, -N(R2)COOR3, -N(R2)SO2R3 or -N(R2)CONR4R5, R4 and R5 being other than hydrogen, reacting a compound of the formula (V) as defined above with, respectively, either (a) a haloformate of the formula Q2COOR3 or acyl halide of the formula R3COQ2, Q2 being chloro or bromo, and R3 being as defined above, or (b) a sulfonyl halide of the formula R3SO2Q2, Q2 being chloro or bromo and R3 being as defined above, or (c) a carbamyl halide of the formula R4R5NCOQ2, R4 and R5 being as defined above other than hydrogen and Q2 being chloro or bromo, or (d) an anhydride of the formula (R3CO)2O, R3 being as defined above; or (iv) to prepare compounds of formula (I) wherein Z is -OCONHR5, reacting a phthalazine of the formula:

---(VI) wherein R, R1, X and m are as defined above, with an isocyanate of the formula R5NCO wherein R5 is as defined above other than hydrogen, or, to prepare compounds of formula (I) in which R5 is hydrogen, with sodium or potassium cyanate in the presence of acid; or (v) to prepare compounds of formula (I) wherein Z is -N(R2)COR3, reacting an ester of N-hydroxysuccinimide or N-hydroxyphthalimide of the formula:

or respectively, ---(VII) wherein R3 is as defined above, with a compound of the formula (V) as defined above;

and where required converting any compound of formula (I) so pro-duced into a pharmaceutically acceptable acid addition salt thereof, or any acid addition salt of a compound of formula (I) so produced into the corresponding free base.

2. A process according to claim 1 wherein R is methyl; and -(CHR1)m- is -CH2-, -CH(CH3)-, -CH2CH2-, -CH2CH(CH3)- or -CH(CH3)CH2-.

3. A process according to claim 1 wherein X is a direct link.

4. A process according to claim 2 wherein X is a direct link.

5. A process according to claim 1 or 2 wherein Z is (a) -OCONHR5 wherein R5 is C1-C4 alkyl, phenyl or 2-, 3- or 4-pyri-dyl;
(b) -N(R2)COR3 wherein R2 is hydrogen or C1-C4 alkyl and R3 is C1-C4 alkyl, phenyl, phenethyl or 2-, 3- or 4-pyridyl;
(c) -N(R2)SO2R3 wherein R2 is hydrogen or C1-C4 alkyl and R3 is C1-C4 alkyl, phenyl, benzyl or 2-, 3- or 4-pyridyl;
(d) -N(R2)CONR4R5 wherein R2 is hydrogen or C1-C4 alkyl, R4 is hydrogen or C1-C4 alkyl, and R5 is C1-C4 alkyl, phenyl or 2-, 3-or 4-pyridyl; or (e) -N(R2)COOR3 wherein R2 is hydrogen or C1-C4 alkyl, and R3 is C1-C4 alkyl.

6. A process according to claim 3 or 4 wherein Z is:
(a) -OCONHR5 wherein R5 is C1-C4 alkyl, phenyl or 2-, 3- or 4-pyridyl;

(b) -N(R2)COR3 wherein R2 is hydrogen or C1-C4 alkyl and R3 is C1-C4 alkyl, phenyl, phenethyl or 2-, 3- or 4-pyridyl;
(c) -N(R2)SO2R3 wherein R2 is hydrogen or C1-C4 alkyl and R3 is C1-C4 alkyl, phenyl, benzyl or 2-, 3- or 4-pyridyl;
(d) -N(R2)CONR4R5 wherein R2 is hydrogen or C1-C4 alkyl, R4 is hydrogen or C1-C4 alkyl, and R5 is C1-C4 alkyl, phenyl or 2-, 3-or 4 pyridyl; or (e) -N(R2)COOR3 wherein R2 is hydrogen or C1-C4 alkyl, and R3 is C1-C4 alkyl.

7. Compounds of formula (I) defined in claim 1 and their pharmaceutically acceptable salts, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.