IE47481B1

IE47481B1 - 1-piperidinophthalazine cardiac stimulants

Info

Publication number: IE47481B1
Application number: IE2166/78A
Authority: IE
Original assignee: Pfizer Ltd
Priority date: 1977-11-03
Filing date: 1978-11-02
Publication date: 1984-04-04
Also published as: ES479992A1; CA1114379A; ES474764A0; YU253678A; DE2847621A1; FR2407927B1; SE7811322L; FR2407927A1; YU211682A; AU4127678A; JPS5498783A; AR217577A1; IT7829369A0; LU80458A1; ES479993A1; ES479991A1; ATA783978A; IE782166L; BE871770A; AU507007B2

Abstract

1-Piperidino-6,7-dialkoxy-phthalazine derivs. of formula (I), their acid addition salts and bioprecursors are new as the separate isomers or their mixtures. In (I), R is lower alkyl; Y is joined to the piperidino ring in position 3 or 4 and =-X-(CHR1)m-Z; R1=H or lower alkyl; m=1 or 2 with the condition that when m=2 then the two R1 groups may be identical or different; X=O or a bond with the condition that when m=1 then X= a direct bond; Z= -OOCNR4R5, -OOCR3, -N(R2)-CO-R3, -N(R2)-SO2-R3, -N(R2)-CO-NR4R5 or -N(R2)-COOR3; R2=H or lower alkyl; R3=lower alkyl, phenethyl, benzyl, phenyl or 2-, 3- or 4-pyridyl and R4, R5 independently=H or an R3 group. Lower group = =6C atoms pref. =4C atoms and are opt. branched. (I) phosphodiesterase inhibitors and cardiac stimulants which selectively increase myocardial contraction force without accelerating cardiac rhythm. They are used therapeutically or prophylactically for the treatment of cardiac insufficiency, in daily oral doses of 20mg-1g as 2-4 unit doses or in the case of acute cardiac insufficiency they are administered intravenously in doses of 1-300mg.

Description

This invention relates to therapeutic agents, which are novel derivatives of phthalazine, and is particularly concerned with such derivatives having a substituted piperidino group in the 1- position.

The compounds of 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. The compounds are useful in the curative or prophylactic treatment of cardiac con10 ditions, in particular heart failure.

According to the invention there is provided novel phthalazine compounds of the formula: wherein , R. is. a lower alkyl group; and 15 ; y is attached to the 3- or 4- position of the piperidino ring and represents a group of the formula: , '‘Λ j : -X-fCHR ) -z m wherein R^ is a hydrogen atom or a lower alkyl group, I i , - 3 and π is 1 or 2, with the proviso tiiat 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: -OCONR R -OCOR3 3 -N(R )COR -n(r2)so2r3 4 5 -N(R )CONR R and -N(R2)COOR3 3 wherein R is hydrogen or lower alkyl; R is lower alkyl, phenethyl, benzyl, phenyl or 2-, 3- or 4- pyridyl; and R and R are each independently hydrogen or a group as defined for R above; and the pharmaceutically acceptable acid addition salts thereof.

The term lower applied to an alkyl or alkoxy group indicates that such a group contains up to 6 carbon atoms, preferably up to 4 carbon atoms, and such groups may be straight or, when appropriate, branched chain.

The compounds of the invention containing one or more asymmetric centres will exist as one or more pairs of enantiomers, and such pairs or individual Isomers may be separable by physical methods, e.g. by fractional crystallisation of suitable salts. 1-----47481 - 4 The invention includes the separated pairs as well as mixtures thereof,!.e.racemic mixtures or as separated d- and 1- opticallyactive isomeric forms.

The pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

The cardiac stimulant activity of the compounds of the invention is shown by their effectiveness in one or more of the following tests: (a) increasing the force of contraction in the isolated, spontaneously beating, guinea pig double atria pre15 paration; (b) increasing myocardial contractility (left ventricular dP/flt max.) in the anaesthetised dog with a left ventricular catheter; (c) increasing myocardial contractility in the conscious dog with an implanted left ventricular transducer.

In test (a) the positive inotropic and chronotropic responses of the atria to the test compound are measured ac several doses and compared with the responses elicited by isoprenaline. The comparison of the dose response curves obtained gives a measure of the force versus rate selectivity of'the test compound. 4748 - 5 In test (b) the positive inotropic action of the test compound following intravenous administration is measured in the anaesthetised dog. The magnitude and duration of 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.

In test (c) the positive inotropic action of the test compound following intravenous or oral administration 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 frequency of contraction, and the duration of action of the inotropic effect of the test compound are all obtained.

The preferred compounds of the invention have the formula: wherein ϊ is as defined for formula (I). Preferably X is a direct link -(CHR1^- is preferably -CH2~, -CHfCf^)-, -CH2CH2-, -ch2ch(ch3)- or -ch(ch3)ch2~. - 6 Z is preferably:5 5 (a) -OCONHR wherein R is C^-C^ alkyl, phenyl or 2-, 3- or 4-pyridyl; 3 (b) -OCOR wherein R is C^-C^ alkyl; 3 2 3 (c) -N(R )COR wherein R is hydrogen or Cj-C^ alkyl and R is C^-C^ alkyl, phenyl, phenethyl or 2-, 3- or 4- pyridyl; 3 2 3 (d) -N(R )SO2R wherein R is hydrogen or Cj-C^ alkyl and R is Cj-C^ alkyl, phenyl, benzyl or 2-, 3- or 4- pyridyl; 4 5 2 4 (e) -N(R )CONR R wherein R is hydrogen or C^-C^ alkyl, R is hydrogen or C^-C^ alkyl, and R$ is alkyl, phenyl or 7.-, 3- or 4- pyridyl; or 3 2 3 (f) -N(R )COOR wherein R is hydrogen or C^-C^ alkyl, and R is Cl-C4 alky1· The preferred individual compounds have the formula (II) wherein Y is: -ch2ch2oconhc2h5 -ch2ch2nhcooc2h5 -ch2ch2n(ch3) so 2ch3 -CH2N (CH3) CO (CH2) 2CH3 -CH2CH2N(CH3)SO2.Phenyl -ch (ch3 ) ch2k (ch3 ) so2ch3 -CH2CH2N(CH3)S02.(CH2)2CH3 -CH2CH2N (CH3) SO2C2H5 -CH2CH2N(CH3) CON(CH3)2 -CH2CH2N(CH3)SO2.(3-pyridyl). or -ch(ch3)ch2n(ch3)so2c2h5· - 7 The invention also includes the pharmaceutically acceptable biopreeursors of the compounds of the formula (I).

The term pharmaceutically acceptable bioprecursor 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, fcy the oral route, it may be possible to convert it into a chemical derivative which is well absorbed and which in the serum or tissues is reconverted to the parent drug. Again, if a drug is unstable in solution, it may be possible to prepare a chemical derivative of it which is stable and may be administered in solution, 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 modifications which are only temporary and are reversible upon adminis20 tration to the animal or patient.

For the purpose of this specification the term pharmaceutically acceptable bioprecursor of a compound of the formula (I) means a compound having a structural formula different from the compounds 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). . - 8 The compounds of the invention can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard 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 15 treatment of cardiac conditions such as congestive heart failure, it is expected that oral dosages 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 (70 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 might contain from 5 to 250 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.

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 metliod of stimulating the heart of an animal, including a human being, which comprises administering to the animal a compound of the formula (I) or salt thereof as defined above, or a pharmaceutical composition as defined above, in an amount sufficient to stimulate the heart of the animal.

The compounds of the invention may be prepared by a number of routes: Route A Compounds of the formula (I) may be prepared by reacting an appropriately substituted phthalazine of the formula: bromo-, iodo-, lower alkoxy or (lower alkyl)thio, with an amine H of the formula: I ---(IV) with resultant elimination of is preferably chloro or bromo. - 10 * The reaction is preferably carried out in an inert organic solvent such as ethanol with heating, e.g. under reflux, in a temperature range of 75° to 150°C for up to 48 hours. When Q1 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 conventional methods.

The compounds of the formula (IV) are either known compounds or may be prepared by procedures analogous to the prior art, e.g. by the hydrogenation of the corresponding pyridine derivatives.

Route B Compounds of the formula (I) in which Z is -N(R JCONHR may be prepared by the reaction of a phthalazine of the formulas with an isocyanate R^NCO, R3 being other than hydrogen, or, to prepare compounds in which R^ is H, sodium or potassium cyanate in the presence of acid. _ ιι _ The acid may be supplied by using an acid addition salt of the compound of the formula (V) as the starting material.

In a typical procedure, the reactants may be reacted together at room temperature 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 acetate to leave the product as a crystalline solid which may be recrystallised from a suitable solvent, e.g. ethanol.

Route C Compound.'.; of the formula (I) wherein Z is either -N(RZ)C0R3, -tl(R2)COOR3, -N(R2)SC>2R3, or -N(R2)CONR4R5, R4 and R5 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 3 3 ? 2 2 COOR or acyl halide of the formula R COQ , wherein Q is chloro 2 2 or bromo; (b) a sulfonyl halide of the formula R SO2Q , Q being 4 5 2 chloro or bromo; (c) a carbamyl halide of the formula R R HCOQ 2 wherein R and R are both other than hydrogen and 2 is chloro or bromo; or (d) an anhydride of the formula (R CO)20.

Typically the reactants are allowed 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. - 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, dissolving the oil in ethyl acetate and applying-.it to a column of e.g'. Florisil (Trade Mark) the product being eluted with e.g. 10¾ ether in ethyl acetate.

Route D Compounds of the formula (I) wherein Z is -OCONHR may be prepared by reacting a phthalazine of the formula: with an isocyanate R NCO, R being other than hydrogen, or, to 5 prepare compounds in which R- is hydrogen, sodium or potassium cyanate in the presence of acid.

In a typical procedure, the reactants are heated together in a suitable organic solvent, e.g. dry chloroform, ^at 4(7 - 70°C 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 suitaile column to purify it.

Route Ε 3 Compounds of the formula (I) in which 7. is -N(R )COR , may be prepared by reacting a phthalazine of the formula (V) as previously defined with an ester of N-hydroxy succinimide of the formula: ---(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 techniques, typically by reaction of an acid of the fonnula R COOH with N-hydroxysucoinimide or N-hydroxyphthalimide in the presence of dicyclohexylcarbodiimide.

Route F Compounds of the formula (I) in which Z is a group of the 3 formula -OCOR may be prepared by acylating the corresponding compound in which Z is a hydroxy group (formula /Vl7 Route D) with the appropriate acid anhydride, or acyl chloride or bromidezo£ the 3 3 3 formula (R CO)2O, R COCl or R COBr respectively. _ 14 _ The reaction may be carried out in a conventional manner. For example, the hydroxy-containing starting material may be treated with the appropriate acid anhydride (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, e.g. chloroform. The product may be isolated and purified by conventional methods.

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.

The following Examples illustrate the invention: - 15 EXAMPLE 1 \ CONH (CH2) 3CH3 l-Chloro-6,7-dimethoxyphthalazine (1.12 g), 4—/Tl-methyl-3n-butylureido)methyl7piperidine mono-oxalate (2.0 g) and triethylamine (2.5ml) were heated together under reflux for 100hours in ethanol (100 ml).

After concentration in vacuo, the residue was suspended in water (25 ml), basified to pH 10with 5N sodium hydroxide solution and extracted into chloroform (2 x 25ml). The dried (MgSO^) extracts were taken to dryness in vacuo giving a brown oil which was dissolved in the minimum volume of chloroform and applied to the top of a chloroform/Florisil (Trade Mark) column (bed size 30 x 2.5 cm) 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 takenof which fractions 12-18 were combined and taken to dryness in vacuo.

The resultant oil, which solidified on cooling, 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-l-/4-^(1-methyl3-n-butylureido)methylJpiperidino/phthalazinemonohydrate (0.37 g) were collected by filtration, softening at 100°C, and melting at 114—127°C. -15aAnalysis %:Found: C, 60.6; H, 8.1; N, 15.9 Calculated for C22H33N5°3-H2O: C, 61.0; H, 8.1; N, 16.2 EXAMPLES 2-33 The following compounds were prepared similarly to Example 1, starting from l-chloro-6,7-dimethoxyphthalazine and the appropriately substituted piperidine. - 16 " - 1¾ - I Analysis % (Theoretical in brackets) C Η N r- in CD CD ^3· CO CO r* r- sj* sj· in in 53.2 6.2 10.6 (53.9 7.1 10.9) O CM sr sr a—t rd CO CO CO CO si* ω in sr in in 53.6 5.7 11.3 (54.1 6.1 11.0) Form Isolated and m.p. (°C) Oxalate mono- hydrate, 188 - 190° I *o •Η Φ O ia +» «η d w ti M +> τι ι ti >1 Η Λ bti σ» $ Free base, 181 - 182° Hydro chloride monohydrate, 210 - 212° in >1 frj β ti Λ CM O ω cn * E U ^CM E U CM E a 1 8 o u n E □ 55 CM E U rn E U E υ 1 cn E Sn o w * E SCM E U CM E ϋ 1 £ ti X E CM O w m 8 Ha E U 1 Example No. CM CM m CM sf CM in CM o 01 *d > tK kO id CO tX» w p 0) X ϋ rt k Λ 3 Μ1 ro vM N-K CM Nd Ν—I nH kp in Td vH n-ι O Ν—1 tH « •H V) >1 rd s rt rt •H rd (0 U Ή •P a 6.4 6.8 6.6 7.0 <4* CO C· Γ O Cl k£> kO Φ Xi u kO co r- co in Cl Cl in in d o in m m ro k0 kO ro ro in in Form Isolated and m.p. ( C) Oxalate sesquihydrate, 83 - 87° a Ό *0 •H <1> «ή· k -Ρ ο 0 Π3 tH «—ι k Λ V 1 υ ν 0 Λ CM k Ο O' r0 G τ-< N 0 a s Free base, j i83° : 0 * co 5 £ 0 NO •G T-l *d 47 Cl ro a u B u r^o B ZC4 a a 1 in a CM u Cl O a ro a u Xm a υ CM a u 1 ro a 8 z Cl a υ Cl a o 1 ro a 8 u u? υ S nT u a u 1 Example o kD CM c· CM co CM o Cl s. ι cn ω w in KO [ in φ Ζ CM CM MP CO o o o o <4 vH τ-Ι Ή rH rH ν ω χ 0 (0 k <# 43 ϋ) C mp o o CM O σ\ ω -.4 ·Η 3$ W r- r- r** r- KO KO in in Ϊ*1 r-j cd υ G -Η < JJ φ k 8 m ω co T-l CO CM o Εκ U r* γ- co co CO CM σ> σ> m tn in in in in MT MP Ό **» Φ U +J0 *. o (0 —* *0 (UO Φ0 »» o fl) o JJ Γ- JJ CO Φ KO ο · w in - (0 CO f0 Mf Jj r-l ω Οι 0 k W Η Ή (0 Η »Λ , Ρ Ό f0 i—1 1 ε <0 >i I X 1 <0 β rH JD 0 X MP Η Ό oj in r- O in ο 6 k mp X rJf* co Jf< CM t4 Εμ <0 Pm Ο Ή v< «-1 T—i tn ed CM in u ED CM CM co o U co ED W ED EG U Z □ CM CO O O o ED u U ω X u co co co Z ' ED ED fi CM U U * U ED u co z ro Z CM EDs« ED s ED O U υ u CM CM ED ED ED ED U U U 1 U 1 O O 1 ω a ~ o CM co θ ο 2 ζ co co ro CO ω • 47481 _ 24 _ EXAMPLE 34 Preparation of 6,7-dimethoxy-l-/4-^2- Q-Zi-pyrldyV-l-methylureidol ethyl·^ piperidino7phthalazine CH2CH2NCONH.(3-pyridyl) Me 6,7-Dimethoxy-l -/4-£2-N-methylaminoethylJpiperidino7phthalazine (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 (NagCO^) and evaporated to dryness in vacuo to give an oil. The oil was triturated with a mixture of ether and ethyl acetate (30 ml, 9:1) to produce a crystalline solid which was recrystallised from ethanol to give pure 6,7-dimethoxy1-/4-^2- (3-/3-pyridyl7-l-niethylureido) ethyljjpiperidino/ phthalazine j hydrate (0.45 g), m.p. 200 - 204°C.

Analysis ϊ:~ Found: C, 63.2; H, 6.7; N, 18.1 C24H30N6O3’ZU2° C> 63·3' H' 6‘8f H' 18·5· EXAMPLES 35 TO 37 The following compounds were prepared similarly to the previous Example, starting from 6,7-dimethoxy-l-/4-(2-N-methylamino ethyl or N-methylaminomethyl)piperidino7 phthalazine and the appropriate isocyanate.

Analysis % (Theoretical in brackets) CHN 52.6 6.7 12.0 | (52.8 6.7 12.3) 56.3 5.8 11.7 (56.3 6.5 12.2) 62.9 6.5 19.2 (63.3 6.5 19.3) Form Isolated and m.p. (°C) l’s Oxalate hydrate, 88 - 95° i ο. •rt ω Ό ’Φ fl) 0 4J ·Ρ 1 ίύ <ι «-< Ο Λ °<Μ Φ ιη Μ CN nJ Λ I ο ο A) ιη k CN h K u CN CN a U a g u ro a u is CN a a CN δ 1 tn a CD U ! δ δ CN ? r*{ & Ό •ri co a s u n 6 δ Example No- 35 ω ro 37 f EXAMPLE 38 Preparation of 6,7-dimethoxy-l-/4-^2-(1,3,3-tr piperidino/ phthalazine CH3\ NCOCl CH3° rn / CH„CH-HCOM A Zl \ OH z 32I \ CH3 CH3 phthalazine (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 (Na2CO3> and evaporated to dryness in vacuo. The oily residue was retaken in the minimum quantity of ethyl acetate and was then applied to the top of a column of Florisil1' (Trade Mark) (bed size 35 cm x 1.5 cm). Elution was commenced with 10¾ ether in ethyl acetate and ten fractions, each of 50 ml, were collected. Fractions 3 to 9 were combined and evaporated to dryness in vacuo to give an oil which solidified on trituration with ether containing 10¾ ethyl acetate.

Recrystallisation from ethyl acetate gave pure 6, 7-dimethoxy-l/4-^2-(1,3,3-trimethylureido) ethyl^piperidino/ phthalazine (0.2 g) m.p. 140 - 141°C.

Analysis ί:- Found: C, 62.6; II, 7.8; N, 17.2C21H31N5°3 C, 62.8; H, 7.8; N, 17.4 EXAMPLES 39 TO 42 The following Examples were prepared similarly to the previous Example, starting from 6,7-dimethoxy-l-/3-(2-N-methylamino10 ethyl or N-methylaminomethyl)piperidino/ phthalazine and the appropriate sulfonyl chloride, acid chloride or carbamoyl chloride.

I in ίο d tn C- yj o in 2 d d d d 1 1 d d rH ν—1 rH «—1 r-1 «—1 r—1 P ω X u a m dP Λ M G •η ή a co co cn ο* cn d sp m ω in in > r* in in W Φ ίή r4 r4 fl nj υ G -rl < -P Q) M S X5 o O' cn ό sp Oi C— co η υ O' Oi O Oi Oi Oi m si· CO 10 in sp in in ω o Τ! τ; rd o « 0 u *H »—ι 0 -PO Μ «Η U) o 0 0Λ fl o Φ in a) u d skO r( r-1 --P bin w sp •p QJ r-4 Φ qj to S ή Λ QJ tf pm fd 4-> I P -P <-1 tn Oi O -P om Λ .-1 nJ β rd H · o nJ ω 1 nJ Μ I r-1 M 1 G mmg (II 0) g nd fl Ό B Ό Ό Φ tj-p α sp o s^o £ u Ό Sh Sh -P nJ m sp xi o o xi 0 0 χί x: TJ ft ή JP TH vH Ui fl ♦H 0 G TH JP JP Q JP W nJ s & i-4 r4 G >1 o Ό G ft 43 •rl o cn Γ ft M 43 E cn & ft U d E f \ / d U cn 2 O d *—* O ΪΜ to s d 0 cn o O cn S3 u ω E O · υ cn rn s E E 2 d U □ d E E a 2 2, a d d d d E E E E U 1 U 1 U 1 U I QJ ft · O' o «< d ε o cn SP SP SP ιΰ 2 w _ 30 _ EXAMPLE 43 Preparation of 6,7-dimethoxy-l-/3-(N-etliylcarbamoyloxymethyl) piperidino/ phthalazine Ethyl isocyanate (0.69 g) was added slowly to the stirred solution of 6,7~dimethoxy-l-/3-(hydroxymethyl)piperidino7 phthalazine (0.76 g) in dry chloroform (10 ml) at 5°C, 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 give an oil which was triturated with ether (30 ml) and decanted. The residue was dissolved 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 quantities of methanol (up to 5%). - 31 100 ml Fractions were collected and monitored by thin layer cliromatography. Appropriate fractions were combined and concentrated in vacuo to give the product as an oil, (0.45 g).

This oil was suspended in ethyl acetate (25 ml) and 5 enough ethanol was added to give a complete solution, then a solution of oxalic acid in ethyl acetate was added until the mixture was acidic (pH 3-4). The precipitate was collected by filtration and crystallised from isopropyl alcohol to yield 6,7dimethoxy-1-/3-(N-ethylcarbamoyloxymethyl)piperidino/ phthalazine : mono-oxalate : | hydrate (0.30 g), m.p. 132 - 134°C.

Analysis %:Found: C, 53.4; H, 5.9; N, 11.9 Calculated for ε19Η26Ν4Ο4:ε2Η2Ο4:ΙΗ2θ! C' 53'8; H' 6*lf N' 11,9 EXAMPLES 44 TO 47 The following compounds were prepared similarly to the previous Example, starting from 6,7-dimethoxy-l-/4-(2-hydroxyethyl or 2-hydroxyethoxy)piperidino7 phthalazine and the appropriate isocyanate. These starting phthalazines are the subject of Examples 5 and 25 respectively of our co-pending British Patent Application No. 26202/78 filed 1st June, 1978.

EXAMPLE 48 Preparation of 6,7-Dimethoxy-l-/4-£2- (N-nicotinoyl-N-methylamino) ethylj -piperidino/ phthalazine To a stirred suspension of nicotinic acid (2.3 g) in dry chloroform (350 ml) at 30°C, were added N-hydroxysuccinimide (2.3 g) and Ν,Ν-dicyelohexylcarbodiimide (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-dimethoxyl-/4-^2-N-methylaminoethylJpiperidino7 phthalazine (1 g) in dry chloroform (20 ml) and the solution was stirred at ambient temperature for 2¾ hours, after which water (50 ml) was added. The chloroform layer was separated, washed with water (20 ml), dried (MgSO^) 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 isopropanol solution of oxalic acid (to pH 2) and the precipitated solid was recovered by filtration. Recrystallisation from isopropanol gave pure 6,7-dimethoxy-l-/4-£2-(N-nicotinoyl-N-methylamino) -piperidino7 phthalazine oxalate monohydrate (290 mg), m.p 110 - 115°C. - 34 Analysis %:Found: C, 56.9; H, 5.8; N, 12.7 C24n29N5O3'C',H2O4‘H2O re9uires: c< 57N' 12.9.

EXAMPLE 49 Preparation of 1-/4-(2-acetoxyethyl)piperidino/-6,7~dimethoxyphthaiazine Acetic anhydride (0.4 ml) was added slowly to a stirred solution of 6,7-dim ethoxy-1-/4-(2-hydroxyethyl)piperidino/ phthalazine (0.63 g) and triethylamine (1.1 ml) in dry chloroform (10 ml) at 5°C, followed by stirring at room temperature for 16 hours. The solution was then shaken with water (15 ml) and separated. The chloroform phase was dried (MgSO^), and concentrated in vacuo to give a sticky brown oil. This was diluted with a small amount 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 quantities of methanol (up to 10%). " 35 Of the twelve 80 ml fractions collected, numbers 4- 7 were shown by t.l.c. to contain the desired product and were combined and taken to dryness in vacuo. The resultant oil was acidified (pH 3 - 4) with a solution of oxalic acid in ethyl acetate to precipi5 tate the oxalate salt, which was then crystallised from ethanol to yield l-ji-(2-acetoxy3ethyl)piperidinc}-6,7-dimethoxyphthalazine oxalate, m.p. 175 - 177°C.

Analysis Found: C, 56.4; H, 6.3; N, 9.7 Calculated for C, 56.1; H, 6.1; N, 9.4.

The following Preparations illustrate the preparation of certain of the starting materials:47481 - 36 Preparation 1 Preparation of 4-(2-acetamidoetliyl) piperidine 4- (2-Acetamidoethyl)pyridine (33 g) in ethanol (250 ml) was acidified to pH 4 with hydrochloric acid and hydrogenated at 60 p.s.i./60°C over a platinum oxide catalyst for 18 hours, after which time the uptake of hydrogen was complete. The catalyst 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-(2acetamidoethyl)piperidine (18 g) as a white solid, m.p. 60°C.

The oxalate salt was also prepared, m.p. 125 - 129°C. Analysis l··.15 Found: C, 50.9; Η, 7.7; N, 10.4 Calculated for C9H18N2O:C2H2O4! C, 50.8; Η, 7.8; N, 10.8. -- 37 Preparation 2 Calculated for ΟιθΙΙ^ΙΛ^.Ηα..jH^O: M~ 4- (2-Acotoxy-ii-propyl) piperidine hydrochloride - hydrate, m.p. 188 - 191°C, was prepared similarly to the above Preparation, starting from dl-4~(2-hydroxy-n-propyl)pyridine, but using acetic acid as solvent. Acetylation occurred during the hydrogenation.

Analysis ¢:Found: C, 52.8; H, 9.1; N, 6.3 C, 53.1; H, 9.1; K, 6.2. 1. ίο preparation 3 (A) 4- (3-ii-Butyl-l -methylureidomethyl) pyridine 4-(N-Methylaminomethyl)pyridine (3.6 g) in dry chloroform (70 ml) was stirred and cooled in an ice bath whilst n-butylisocyanate (9.9 g) was added slowly, dropwise. The mixture was then allowed to stand at ambient temperature overnight after which methanol (15 ml) was added and stirring continued for a further minutes. 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-l-methylureidomethyl) pyridine sesqui-oxalate (7.2 g), m.p. 86 - 90°C.

Analysis ¢:Found: C, 50.4; H, 6.6; N, 11.9 C^H gH O.lMCjB^) requires: C, 50.6; H, 6.2; N, 11.8. ~ 38 ~ Also synthesised by a similar method were: 4- (1,3-Dimethylureidomethyl)£>yridiiie (crude base, unpurified) 4-(2-/3-Ethylureido7ethyl)pyridine ( ) 4-(l-Methyl-3-n-propylureidomethyl)pyridine (crude base, unpurified) 4-(2-/3-Ethyl~l-methylureido/ethyl)pyridine ( ) and dl-4- (l-/3-ethyi-l-methylureido/ethyl) pyridin^ ) (B) The above pyridines were then hydrogenated to the corresponding piperidines similarly to Preparation 1, Preparation 4 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 40°C during the addition, after which the orange solution was left to stand at room temperature overnight. Water (50 ml) was then added, the chloroform phase was separated, and the agueous phase extracted with chloroform (100 ml). The two chloroform'solutions 20 were combined, dried (MgEO^) and taken to dryness in vacuo to give a yellow oil which solidified immediately.

This solid was crystallised from ethanol to yield white crystals of 4-(2-methanesulphonamidoethyl)pyridine (1.4 g) .

A small sample was recrystallised from ethanol, m.p. 114 - 116°C. Analysis Found: C, 47.9; H, 6.0; N, 14.0 Calculated for CgH^NgC^S: C, 48.0; H, 6.0; N, 14.0 (B) Preparation of 4-(2-methanesulphonamidoethyl)piperidine hyd rogenation n )— ch2ch2nh.so2ch3 > HN •ch2ch2nh.so2ch3 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 pressure of 50 p.s.i. over a platinum oxide catalyst until hydrogen uptake ceased. The catalyst was then removed by filtration and the filtrate was taken to dryness in vacuo to give a white solid which was dissolved in the minimum volume of hot ethanol, filtered quickly, and left at room temperature overnight. The resultant white crystals were collected by filtration and dried to yield 4-(2-methanesulphonamidoethyl)piperidine hydrochloride (8.3 g), m.p. 165 - 167°C.

Analysis Found: C, 39.6; H, 7.8; N, 11.7 Calculated for c8H18N202SiHCl! C, 39.6; H, 7.9; N, 11.5. - 40 Also synthesised in a similar fashion to Part (A) were: (4~(2-/N-isoPropyl~methanesulphonamido7cthyl)pyridine oxalate, ( ( m.p. 129 - 131 . Found: C, 46.7·, H, 6.2; N, 8.0.

( ( CUH18N2O2S,C2H2°4 c- 47-°l H< θ-b Ν, δ·4%· 4-(2-/N-Methyl-methanesulphonamido7ethyl)pyridine - crude oil, 4-(2-/N-Methyl-benzenesulphonamido7ethyl)pvridine - crude oil, (4-(2-Benzenesulphonamidoethyl)pyridine, m.p. 109 - 110°, ( ( Found: C, 59,5; H, 5.4; N, 10.6. Cj3Hj4N2°2S re The above were then hydrogenated similarly to Part (E) to give the corresponding piperidines. _ 41 _ Preparation 5 (Λ) 4-(N-Methyl-butyramidomethyl)pyridine n-Butyryl chloride (2.8 ml) in dry methylene chloride (20 ml) was added slowly to a stirred, cooled mixture of 4-(N5 methylaminomethyl)pyridine (3 g) and triethylamine (5 ml) in dry methylene chloride (30 ml). The mixture was then stirred at room temperature for 2¾ hours, after which water (30 ml) was added.

The organic phase was separated, washed with dilute aqueous sodium hydroxide (5%, 30 ml), dried (NajCO^) and evaporated to dryness .in vacuo. The resultant dark brown oil (3.8 g) was chromatographed - on a Florisil (Trade Mark)(15 g) column, using chloroform as eluant. Appropriate fractions were identified 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 1(B) to the corresponding piperidine.

Also prepared similarly to the above were: 4-/N-Methyl-benzamidomethyl/pyridine, and 4-/l,3,3-Tritnethylureidomethyl/pyridine (crude oil), which were then hydrogenated as Preparation 1(B) to the corresponding piperidines. - 42 Preparation 6 4-(l-/N-Methylacetamido7prop-2-yl)pyridine 4-(l-N-Methylamino-prop-2-yl)pyridlne (4.5 g) in acetic acid (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 40°C) to remove 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 chloroform (3 x 60 ml) and the bulked extracts were dried (NajCO^) and evaporated to dryness in vacuo to give a near-colourless oil (6.8 g) The oil was distilled to give pure dl-4-(l-/N-methyl-acetamido/prop-2yl)pyridine (3 g), b.p. 138 - 140°/0.4 m.m. Hg. (as a colourless oil).

Analysis Found: C, 65.8j H, 8.5; N, 14.2 εΐ1Η16Ν20,,ίΗ2Ο re(3"ites: C, 65.7; H, 8.5; N, 13.9%.

The following compounds were synthesised by a similar method: 4-(2-/N-Methylacetamido/ethyl)pyridine oxalate, m.p. 120 - 124°, 4-(2-Acetaraidoethyl)pyridine, b.p. 158 - 160°/0.6 m.m., 4-( AcetamidomethyUpyridine, m.p. 83 - 88°, 4-(N-Methylacetamidomethyl)pyridine - crude oil, and dl- 4-(l-/N-methylacetamido/ethyl)pyridine - crude oil.

The above were then hydrogenated similarly to Preparation to give the corresponding piperidines. - 43 Preparation 7 4-(2-/N-Ethoxycarbonyl-N-methylamino/ethyl)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 (MgSO^) and evaporated in vacuo to give 4-(2-/N-ethoxycarbonyl-N-methylamino/ethyl)pyridine as an oil (20 g), Also prepared similarly to the above was: *»· ' ' —··' ' · 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-l-(3-hydroxymethylpiperidino)phthalazine l-Chloro-6,7-dimethoxy phthalazine (2.25 g), 3-hydroxymethylpiperidine (1.72 g) and triethylamine (1.3 ml) in isoamyl alcohol (60 ml) were heated at 95°C for 42 hours. 7 4 81 - 44 The cooled reaction mixture was then filtered and the filtrate was taken to dryness in vacuo. The residue was dissolved in water (100 ml), 5N sodium hydroxide solution was added to give a pH of 11 and the basic mixture was then extracted with chloro5 form (2 x 100 ml). The chloroform extracts were combined, dried (MgSO^) and concentrated in vacuo to give a brown oil, which was triturated with ether (50 ml) and filtered. The resultant solid was crystallised twice from acetonitrile, yielding 6,7'dirnettoxy1-(3-hydroxymethylpiperidino)phthalazine (1.83 g), m.p. 162 - 165°C.

Analysis Found: C, 63.7; H, 6.9; N, 13.7 Calculated for C16H21N3O3: C, 63.4; H, 7.0; N, 13.9.

Preparation 9 4-(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 for 20 hours. The mixture was cooled, basified to pH 12 - 13 (20% NaOH) and extracted with chloroform (3 x 200 ml). The bulked extracts were washed with water (100 ml), dried (MgSO^) and evaporated in vacuo to give a green oil. The oil was distilled and the fraction boiling at 84 - 90°C/l m.m. was collected (16.5 g) and identified (by spectroscopy) as 4-(2-lsopropylamlnoethyl)pyridine. n.m.r. 4*7481 - 45 Also synthesised by a similar route were: 4-(2-Aminoethyl)pyridine, 4-(2-Methylaminoethyl)pyridine, and dl-4-(1-Methylamino)prop-2-yl)pyridine.

Preparation 10 6,7-Dimethoxy-l-/4-^2-N-methylaminoethyi^--piperidino/ phthalazine 6.7- Dimethoxy-l-/4-(2-N-methylacetamidoethyl)-piperidino/ 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 wnder reflux for 70 hours. The ethanol was removed by evaporation in vacuo and the aqueous phase was diluted with water (10 ml) and extracted with chloroform. The extract was dried (Ηα,,ΟΟ^) and evaporated in vacuo to give an oil, v;hich on trituration,with hexane gave 6,7-dimethoxy-l-/4-(2-N-methylaminoethyl)piperidino/15 phthalazine as a pale yellow solid (1.5 g), A small sample was characterised as the. dioxalate monohydrate, m.p. 159-162°C.

Analysis ¢:- Found: C, 49.8; H, 5.7; N, 10.3; Calculated for C18H26N4°2· Zc2H2°4-H2O: C' 50‘0; H' 6·1’ N' 10·6· 6.7- Dimethoxy-l-/4-(N-methylaminomethyl)piperidino/ phthalazine was prepared similarly to the above, starting with 6,7dimethoxy-1 -/4- (N-methylacetamidomethyl)piperidino/ phthalazine (prepared as in Example 3). A small sample of the product was characterised as the dioxalate, softening at 140°C, with decomposition at 180°C. Analysis ¢:- Found: C, 50.1; H, 5.7; N, 11.5 Calculated for CJ?H24N4O2.2C2H204: C, 50.8; H, 5.7; N, 11.3. 7 4 81 - 46 Preparation 11 A. Preparation of 6,7-Dimethoxyphthalazine-l-one CiLO Xa CH,0 COOH CH-.0 H„N.NH_:H_O J Z_Z Z_v EtOH ' ίο 4,5-Dimethoxyphthalaldehydicacid (10 g) and hydrazine hydrate (2.4 ml) in etharnl (150 ml) were heated under reflux for 20 hours during which time a white crystalline solid formed. The mixture was cooled in an ice bath, filtered and the resulting product dried to give crude 6,7-dimethoxyphthalazin-l-one (7 g).

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

Analysis isFound: C, 58.4; H, 4.8; N, 13.9 Calculated for cjqhiqN2°3: C, 58.3; H, 4.9; N, 13.6.

E. Preparation of l-Chloro-6,7-dimethoxyphthalazine ch3° 6,7-Dimethoxyphthalazin-l-one (20.6 g) was heated under reflux with phosphoryl chloride (200 ml) for 6 hours then cooled to room temperature and the excess phosphoryl chloride removed under reduced pressure.

The resultant brown solid was suspended in acetone (150 ml) and poured onto cold (5°) concentrated ammonium hydroxide (200 ml).

The crude product was filtered, washed with water (200 ml) then petroleum ether (200 ml). The pale yellow solid was dried (20 g), dissolved in the minimum volume of chloroform and precipitated with excess petroleum ether, after which it was recovered by filtration, washed again with petroleum ether (100 ml) and dried to give l-chloro-6,7-dimethoxyphthalazine (13 g), m.p. 195 - 197° with decomposition.

Analysis Found: C, 53.3; H, 4.2; N, 12.7 Calculated for CigHgCl^Oj: C, 53.5; H, 4.0; N, 12.5.

Preparation 12 (A) Preparation of l-Benzyl-4-(2,2-diethoxyethoxy)piperidine OH + BrCH CH I · OCH2CH3 OCH2CH och9ch3 l-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. - 48 The suspension was cooled in an ice/water bath whilst 2-bromoacetaldehyde diethylacetal (13.0 g) in dry dimethylformamide (25 ml) was added dropwise, followed by stirring at room temperature for 24 hours. The above process was repeated to add more sodium hydride (2.8 g) and theacetal( 13.0 g). iso-Propyl alcohol (50 ml) was added, and the mixture was stirred for hour, followed by filtration through 'Hyflo' (Trade Mark). The filtrate was concentrated in vacuo, suspended in water (100 ml) and basified to pH 11 with 5N sodium hydroxide. After extraction with chloroform (2 x 100 ml) the combined extracts were taken to dryness in vacuo to give an orange oil which was distilled in vacuo to give 1-benzyl4-(2,2-diethoxyethoxy)piperidine (14.1 g), b.p. 152°C @ 0.1 mm.

(B) Preparation of l-benzyl-4-/2-(N-methylacetamido)ethoxy/piperidine l-Ber,zyl-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 (MgSO^) and taken to dryness in vacuo. The oil was dissolved in ethanol (150 ml) and mixed with sodium acetate trihydrate (8.9 g), water ( 83 ml), glacial acetic acid (28 ml) and 33% w/w ethanolic methylamine solution (15.5 g). The stirred solution was cooled to 0°C in an ice/salt bath and the temperature was maintained at 0 + 2°C whilst sodium borohydride (6.6 g) was added portionwise and then for the following hour.

The mixture was stirred at room temperature for 40 hours, adjusted to pH 7 with a little 5n sodium hydroxide, concentrated in vacuo, diluted with water (150 ml) and extracted with ether (2 x 225 ml).

The aqueous phase was basified to pH 10 with 5n sodium hydroxide, extracted into chloroform (2 x 180 ml), dried (MgSO^) and taken to dryness in vacuo The crude oil (12.5 g) in dry chloroform (80 ml) and triethylamine (10.4 ml) was stirred and cooled in an ice/water bath during the slow addition of acetic anhydride (6.1 g). The mixture was stirred at room temperature for 2 hours, shaken with water (50 ml) and separated. The chloroform phase was dried (MgSO^), taken to dryness in vacuo, leaving 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 pH '3.

The ethyl acetate was removed by decantation and the residual gum was dissolved in hot iso-propyl alcohol, allowed to cool to room temperature and diluted with an equal volume of ether to deposit a brown gum. The gum vzas isolated by decantation of the solvents and dried to give crude l-benzyl-4-/2-(N-methylacetamido)ethoxy/ piperidine oxalate (10 g).

A second crop of the same material was obtained from the iso-propylalcohol/ether solution. Reerystallisation of this from methyl cyanide gave pure crystals of 1-benzyl-4-/2-(N-methylacetamido)ethoxy7piperidine: mono-oxalate· monohydrate, m.p. 142 147°C. ι • - 50 I Analysis %:Found: C, 57.1; H, 7.0; N, 6.8 Calculated for C, 57.3; H, 7.6; N, 7.0.

The product was hydrogenated as previously described to remove the benzyl group.

Preparation 13 4-/2-(N-methylsulfonamido)ethoxy7piperidine was prepared similarly to the above, but using methanesulfonyl chloride in place of acetic anhydride in step (B).

Claims

1. WHAT WE CLAIM IS:1. A compound of the formula: 5 + 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- (CHR 1 ) -Z m wherein R^ is a hydrogen atom or a lower alkyl group, and m is 1 or 2, with the proviso that when ro is 2, each R^ 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: 4 5 -0C0NR R -0C0R 3 -n(r 2 )cor 3 -n(r 2 )so 2 r 3 2. 4 S -N(R )CONR K 2 3 and -N(R )COOR 2 3 wherein R is hydrogen or lower alkyl; R is lower alkyl, phenethyl, benzyl, phenyl or 2-, 3- or 4- pyridyl; 4 5 and R and R are each independently hydrogen or a group as defined for R above; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 which has the structure: wherein Y is as defined in claim 1.

3. A compound as claimed in claim 1 or 2 wherein -(CHR^)^is -CII 2 -, -CH(CH 3 )-, -CH 2 Ch 2 -, -CH 2 CH(CH 3 )- or

4. A compound as claimed in any one of the preceding claims wherein Z is: . - < 5. 5 (a) -OCONHR wherein R is C^-C^ alkyl, phenyl or 2-, 3- or 4-pyridyl; 3 3 (fa) -OCOR wherein R is Cj-Cg alkyl; 2 3 2 3 (c) -N(R )COR wherein R is hydrogen or Cj-C^ alkyl and R is Cj-Cj alkyl, phenyl, phenethyl or 2-, 3- or 4- pyridyl; 2 3 2 3 (d) -N(R')SO 2 R wherein R is hydrogen or C^-C^ alkyl and R is Cj-C^ alkyl, phenyl, benzyl or 2-, 3- or 4- pyridyl; 2 4 5 2 4 (e) -N(R )CONR R wherein R is hydrogen or C^-c^ alkyl, R is hydrogen or Cj-C^ alkyl, and R 5 is Cj-Cj alkyl, phenyl or 2-, 3- or 4- pyridyl; or 2 3 2 3 (f) -N(R )COOR wherein R is hydrogen or Cj-C^ alkyl, and R is Cj-C 4 alkyl.

5. A compound as claimed in any one of the preceding claims wherein X is a direct link.

6. -5 3 A compound as claimed in claim 2 wherein Y is -C11 2 CU 2 OCONI1C 2 H 5 , -Cn 2 CfI 2 NHCOaC 2 H 5 , -CH ? CH 2 N (CH 3 ) SO 2 CH 3 , -CHgN(CH 3 ) CO(CH 2 ) 2 CH 3 , -CH 2 CH 2 N(CH 3 )SO 2 .Phenyl, -CH(CHj)CH 2 H(CH 3 )SO 2 CH 3/ -CH 2 CH 2 N(CH 3 )SO 2 . (CH 2 ) 2 CH 3 , -CH 2 CH 2 N(CH 3 )SO 2 C 2 H 5 , -CH 2 CH 2 N(CH 3 )CON(CH 3 ) 2 -CH 2 CH 2 N(CH 3 )SO 2 . (3-pyridyl) or -CH(CH 3 ) Ciyi (CH 3 > SO^H .

7. A process for preparing a compound of the formula (I) as claimed in claim 1, which comprises reacting a phthalazine of the formula: ίο in claim 1, with an amine of the formula: ---(IV)

8. A process for preparing a compound of the formula (I) as 2 5 claimed in claim 1 wherein Z is -N(R JCONHR , which comprises reacting a phthalazine of the formula: 1 2 X—(CHR ) -NHR m ---(V) ίο -54 1 2 wherein R, R , R , X and m are as defined in claim 1, with 5 5 an isocyanate of the formula R NCO, R being as defined in claim 5 1 other than hydrogen, or, to prepare compounds in which R is H, sodium or potassium cyanate in the presence of acid.

9. A process for preparing a compound of the formula (I) as 2 3 2 3 2 3 claimed in claim 1 wherein Z is -N(R )COR , -N(R )COOR , -N(R )SO 2 R 2 4 5 4 5 or -N(R )CONR R , R and R being other than hydrogen, which comprises reacting a compound of the formula (V) as defined in claim 8 with, as appropriate, either (a) a haloformate of the 2 3 3 2 2 formula Q COOR or acyl halide of the formula R COQ , Q being • 3 chloro or bromo, and R being as defined in claim 1, (b) a sulfonyl 3 2 2 3 halide of the formula R SO 2 Q , Q' being chloro or bromo and R being as defined in claim 1, (c) a carbamyl halide of the formula 4 5 2 4 5 R R NCOQ , R and R being as defined in claim 1 other-than hydrogen 3 3 (R CO)„0, R being as defined in claim 1. 15 and β being chloro or bromo, or (d) an anhydride of the formula >2°

10. A process for preparing a compound of the formula (I) as claimed in claim 1 wherein Z is -OCONHR^, which comprises reacting a phthalazine of the formula: ---(VI) X-(CHR ) -OH m ..- 4 7481 -55 wherein R, r\ X and m are as defined in claim 1, with an 5 5 isocyanate of the formula R NCO wherein R is as defined in claim 1 other than hydrogen, or, to prepare compounds in which R 3 is hydrogen, sodium or potassium cyanate in the presence of acid.

11. A process for preparing a ccmpound of the formula (I) as 2 3 claimed in claim 1 wherein Z is -N(R )C0R , which comprises reacting an ester of N-hydroxysuccinimide or N-hydroxyphthalimide of the formula: R 3 COO or R 3 C00 (VII) wherein R is as defined in claim 1, with a compound of the fonnula (V) as defined in claim 8.

12. A process for preparing a compound of the formula (I) as claimed in claim 1 wherein Z is -OCOR 3 , which comprises acylating the corresponding compound of the formula (I) in which Z is -OH with an acid anhydride, aryl chloride or acyl bromide of the formula 3 3 3 3 (R CO) 2 0, R COCI or R COBr, R being as defined in claim 1.

13. A process as claimed in claim 7 substantially as hereinbefore described in any one of Examples 1 to 33.

14. . A process as claimed in claim 8 substantially as hereinbefore described in any one of Examples 34 to 37.

15. A process as claimed in claim 9 substantially as hereinbefore described in any one of Examples 38 to 42.

16. A process as claimed in claim 10 substantially as hereinbefore described in any one of Examples 43 to 47.

17. A process as claimed in claim ll substantially as hereinbefore described in Example 48.

18. A process as claimed in claim 12 substantially as hereinbefore described in Example 49.

19. A compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof which has been prepared by a process as claimed in any one of claims 7 to 18.

20. A pharmaceutical composition which comprises a compound of the formula (X) as claimed in any one of claims 1 to 6 and 19, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

21. A pharmaceutically acceptable bioprecursor of-a compound of the formula (I) as claimed in claim 1.