CA1101870A - 1,2,4-triazolidine-3,5-dione derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A compound of formula (I):

(I) wherein;

n is 1 to 5 Y is-CH2 -CH2 or -CH=CH-;
R1 is hydrogen or C02R1 represents an ester group in which the R1 moiety contains from 1-12 carbon atoms R2 is hydrogen, C1-4 alkyl, or phenyl, R3 is hydroxy or protected hydroxy, R4 is hydrogen, C1-9 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, phenyl, phenyl -C1-6 alkyl, naphthyl, naphthyl C1-6 alkyl, any of which phenyl moieties or naph-thyl moieties may be substituted by one or more halogen, trifluoromethyl, C1-6 alkyl, hydroxy, C1-6 alkoxy, phenyl C1-6 alkoxy or nitro groups, R5 is hydrogen, C1-6 alkyl, C5-8 cycloalkyl, phenyl, phenyl-C1-6 alkyl or phenyl C3-6 cycloalkyl, any of which phenyl moieties may be substituted by one or more halogen, tri-fluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups or R2 and R4 taken with the carbon atom to which they are joined represent a C5-8 cycloalkyl group, and salts thereof; has useful pharmacological activity.

Description

L8~
Th;~ application is a divisional of S.N. 293,240 filed December 16, 1977 and is directed to the preparation of certain novel intermediates and the intermed-iates so produc~d ~ereas the parent ap~lication is directed to the preparation of ~ounds of formula (I) and the colrpo~ds so produced.
This invention relates to novel compounds having pharma-cologlcal activity, to a process for -their preparation, to intermediates useful in that process and to pharmaceutical compositions containing them.
Offenlegungsschrift No: 2323193 discloses that pyrazoli- ;
dine derivatives of the formula (I)':

Y
CH2(A)m(CH2)nco2R

`~
;, . \ C~l2-c~l2(~ (c~l2)pcll3 whereln; 0~l is CH-CII or Cr~C, R is H, an alkali metal, an a~line salt, or an ,~ 12C hydrocarbon or chlorohydrocarbon residue, m is O or 1, n is 0-6; p is 0-6, and ~Y and æ are O or H except that Y and~Z
are not both 0, have similar biological properties to the pros-taglandins or are antagonists of prostaglandlns.
French Patent Application No: 2258376 disclos~s that 10-aza prostaglandins of formula (II)":
O
.: . I' 2C~12C~12CH2CH2CE~2C- OR

, R - R' (II)"

:; \Y-~-c-c~l2cH2cH2cH3 R"
wherein~
R=H or lower alkyl, R' and R" -- CH~3or C2H5, R = H or lower alkyl, Y = -CH2-CH2-, or -CH = CH-, ~ = -CO or -C~ OH)-: are ~, useul in the treatment of blood pressure and gastro-intestinal .. ' , ' .
' ' ' : ' ' ' ' .
.

. !

clisorders, .~nd in the prepara-tion for confinement.

Bclyian ~cltent No: ~3359~39 discloses that compounds of the formula (III)":

X . C~12 - Y ~ ~C~2~n Rl ( 2)m ~ R2 (III)"

\ R3 4 wherei.n:
X is CO, protected CO, CROH in which R is hydrogcn or Cl ~lkyl and in which the OH moiety may be protected, Y is CH2CH2or CH=CH, Z is CO or CH2; n is 1 to 8, m is 1, 2 or 3, R1 is hydrogen, CH20H, CH20H in which the O~I moiety is protected, C02W where.irl W is hydrogen or C02W represents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH2; R2 is hydrogen, Cl 4 alkyl, or taken together with R3 and the carbon atom to which it is attached represents a carbonyl group, R3 is hydrogen, hydroxy or protected hydroxy, R4:ls hydroyen or Cl galkyl, and salts thereof, have useful pharmacological activity.
A novel class of compounds also having useful pharmacolo-20gical activity has now been discovered, which compounds are structurally distinct from the pr.ior art referred to above.

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

-`` 3L~Q~

Accordingly the present invention provides a compound of the formula (I): ;
.~: ' ' .
O CH2-Y-(cH2)nco2 1 0 R~
wherein;
n is l to 5 - Y is-CH2-CH2 or -CH-CH-;
Rl is hydrogen or CQ2Rl represents an ester group in which the Rl moiety contains from 1-12 carbon atoms;
R2 is hydrogen, Cl ~ alkyl, or phenyl;
R3 is hydroxy or protected hydroxy;
R~ is hydrogen, Ci g alkyl, C3_~ cycloalkyl, C
cycloalkyl~Cl 6 alkyl, phenyl, phenyl -Cl 6 alkyl, naphthyl, ;~
naphthyl Cl 6 alkyl, any of which phenyl moieties or naph-thyl moieties may be substituted hy one or more halogen, trifluoromethyl, C~ 6 alkyl, hydroxy, Cl 6 alkoxy, phen~l -~ Cl 6 alkoxy or nitro groups; , ~5 is hydrogen,:Cl 6 alkyl, C5 8 cylcoalkyl, phenyl, phenyl-Cl~6 alkyl or phenyl C3 6 cycloalkyl, any o~ which phenyl moieties may be substltuted by one or more halogen, trifluoromethyl, Cl 6 alkyl, Cl 6 alkoxy or nitro groups:
or ~
R2 and R4 taken with the carbon atom to which khey are joined represent a C5 8 cycloalkyl group; and salts thereof. _ .
-:
~ :

~ 4 ~

; ~, . ,, , ' ' A group of compounds within formula (I) include -those wherein:

n i.s l to 5, ;' Y i.s -C:~12-C`TI2 or -CM=CE[-, Rl is hydrogerl o:r C02R~ represents an ester group in which the,Rl moie-ty contains from 1 to 1.2 carbon atoms; ~' R2 is hydrogen, Cl 4 alkyl, or phenyl, R3 is hydroxy or pro-tected hydroxy, : R4 is hydrogen, C~ 9 alkyl, C5 8 cycloalkyl, C5 8 cycloalkyl-Cl_6 alkyl, phenyl, phenyl -Cl 6 alkyl, naphthyl, naphthyl Cl 6 alkyl, any of which phenyl or naphthyl moieties may be substi-tuted by one or more halogen, trifluoromethyl, CL 6alkyl, Cl 6 alkoxy or nitro groups, R5 is hydroqen,Cl 6 alkyl, phenyl or phenyl-Cl 6 alkyl, and ~' 15 salts thereof.
: i . ' "
Suitably n is 2, 3 or 4, preEerably 3.
Similarly Y may be -CH2-CH2-- or -CH=CI-I-, suitably -CH2-CH2-. ~:

Rl is hydrogen or C02Rl represents an ester group in which the Rl moiety contains from l to L2 carbon atoms. Examiples of Ri : 5 ~:
.. .
," , .

: :

7l3 include hydrogerl, rnethyl, ethyl, n- and :so- propyl, n--, sec- ancl tert- butyl, phenyl, benzyl, toLuyl. and the llke, whi.le norlnally hydrogen or Cl 6 al.kyl groups are preferred.
Sui.table examples o~ R2 include hydrogen, methyl, ethyl and phenyl. Preferred examples of R2 include hydrogen.
SLIitab]e protected hydroxy groups R3 ir.alud~ readily hydrolysable derivatives such as acylated hydroxy groups i which the acyl moiety contains 1 to 4 carbon atoms, for example the acetoxy group, and hydroxy groups e~herified by readily removable inert groups such as the benzyl or like groups. Preferably however R3 is hydroxy.
Suitable groups R~ when R4 is an alkyl group include C
alkyl groups. Such C4_9 alkyl groups may be straight chain alkyl (Jroups, such as n-butyl, n-pentyl, n-hexyl and.n~heptyl, 15 or may be alkyl groups branched by one or two rnethyl groups :~ (at the same or different carbon atoms). Thus for exampl.e, R4 may be a group CH2R6, CH(CH3)R6 or C(CH3)2R6 , wherein R6 is a straight chain alkyl group such -that the carbon content.
.
: of the resultant group R~ is 4 to 9.
. 20 In general preferred groups R~ when R4 is an alkyl group include straight chain pentyl, hexyl and heptyl groups.
Other preferred groups R4 include groups CEi(CH3~R and C(CH3)2Rj;
wherein R 6is straight chain butyl, pentyl and hexyl.
~: W~en R4 is or contains a C3_j3 cycloalkyl moiety, the moiety ~.
~;~ 25 may suitably be a C5 ~3 cycloalkyl moiety such as a cyclohexyl moiety. It may be a cyclopropyl moiety. Examples of sultable Cl 6 alkyl moieties when R4 is a cycloalkyl-Cl 6 alkyl group include methyl, ethyl, propyl, butyl and amyl. - ;~

;' `,~ ' , `

~ ,, ,:: ' When R2 and R~ together w:ith the carbon atom to which they are joined represent a C5 8 cycloalkyl group, they suitably represent cyclohexyl.
When R4 is an aryl group as previously defined, suitable groups R4 include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl, phenyl~n-butyl, naphthyl, naphthylmethyl, naphthyl-ethyl, naphthyl n-propyl and naphthyl _-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or difEerent carbon atoms). These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups selected from those substituent groups listed hereinbefore. Examples of suitable substituent groups include fluorine, chlorine and bromine atoms and C~3, methyl, ethyl n~and lso-propyl, methoxy, ethoxy, n- and lso--propoxy and nitro groups. Other examples of such groups include hydroxy and benzyloxy. Preferably the aryl moieties when substituted by such groups will be mono-~or di-substituted.
Suitable examples of R5 include hydrogen; methyl, ethyl, n- and lso-propyl, and n-, sec- and ert-butyl; phenyl; phenyl-methyl, phenylethyl, phenyl-n-propyl and phenyl-_-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). Preferred R5 groups include Cl 6 alkyl.

' ~-`

7~

Other examples of RS include c~clohexyl; and the aEorementioned R5 phenyl containing groups in which the phenyl moieties are substituted as for R4 aryl groups.

R5 may also be a phenyl-C3 6 cycloalkyl group, in which case suitable examples of R5 include phenyl-cyclo-propyl.

.~
The compounds of the formula (I) may form conventional salts when R1 is hydrogen and also when R5 is hydrogen.

Such salts include those with alkali and alkaline earth metals, suitably sodi~l and potassium, and ammonium and s~bstituted a~noni n salt,.

, ., ~

~0 y~' Normally salts of the R5 hydrogen will be with alXali me-tals. One particu]arly suitable sub-group of conpounds ` wi-thin formula (I) is of formula (II):
:

o CH2-Y-(CH2)nl-Co2 OH / `R
whereln:

Y Rl and R5 are as defined in formula (I) n-L is 2 3 or 4;
R12 ls hydrogen me-thyl e-thyl or phenyl R14 is hydrogen or Cl g al]cyl and salts thereof.
Suitably in formula (II) nl is 3.
Suitably Rl is hydrogen or Cl 6alkyl preferably hydrogen.
Suitably R12 is hydrogen methyl or ethyl.
~lile R4 may be hydrogen or a Cl g alkyl group in formula (II) it is normally a C4 9 alkyl group. In such cases suitable and preferred straight chain and branched groups R 4 include those previously described as sui-table and preferred for the group R4 when R4 is a C4 9 alkyl group. Such preferred groups R14include straight chain pentyl hexyl ~lnd heptyl. Other preferred groups R14 include CH(CH3)R16and C(CH3) Rl wherein R16is straight chain butyl pentyl or hexyl.
Often in forrnula (II) R5 will be a C1 6alkyl phenyl or phenyl Cl 6 alkyl group or hydrogen.
Preferably R5 is a Cl 6 alkyl group-:~ ~9_ . . .

:
: . . ;

:

From the aforesaid .it will be realised that one pre-ferred group within formula (II) is of formula (III):

~ \N/ (CH2) 6C2Rl ~ :
R 5- N I (I II ) ~N ~< R 2 ~ . I

wherein: :
Rl is as defined in formula (I);
R12 is hydrogen, methyl or ethyl; :~
R 4 is a C~ g alkyl group;
R15 is a Cl 6 alkyl group;
and salts thereof.
Suitahly Rl i.n formula (III) is hydrogen Or Cl 6 alkyl, preerably hydrogen. Suitable~and pre erred group~s R24~ in~clude those listed hereinbe~ore for~R]4 when Rl~ is a C4 9 alky~
group.
Preferred groups Rl5 include meth.yl.
Ano*her particularly sui.table sub-group o compounds ~:
withill formula (I) is of formula (IV):

~ ~ ~ / 2 2 n 2 1 R5 N ¦ / XRl2 (IV) : : OH R 4 wherein:
:~ ~, Rl, and R5 are as defined in formula (I), :
~20 : nl is 2, 3 or 4; .
R12 is hydrogen, m~thylj ethyl or phenyl;

R ~ is a group of formula (V):

: - 10 -v z wherein;
T is a bond, or a Cl 6 alkylene group which may be stralght chain or branchecl by one or two methyl groups at the same or different carbon atoms; and V, W and Z are each hydxogen or fluorine, chlorine or bromine atoms, or CF3, methyl, ethyl, n- or lso_ propyl, methoxy, ethoxy, n or 1so-propoxy or nitro groups; and salts thereof. ;~
In formula (IV) it is preferred that n is 3.
Suitably Rl is hydrogen or Cl_6 alkyl, more preferahly hydrogen.
In formula (V) it is often preferred that T is a group ~(CH2)q - wherein q is 0 to 4. Also V and W will often be hydrogen. -~
Otten in ~ormula (II) R5 will be a Cl 6 alkyl, phenyl or phenyl Cl 6 alkyl group, or hydrogen.
Preferably R5 is a Cl 6 alkyl group, such as methyl.
A further sub-group of compounds within the formula (I~ is o~ formula (VI):

5 - N ~ N CH2 Y (cH2)n~-co2R
b~ ~ (Vl ~ ~

;
. .

;

.
; - 11-`"~
. .

w~erein ~he variable groups are as definecl in forrnula (II) and R44 ls a group of formula (VI:C);

~CH2~r T ~ ~ (V~
~ .
wherein T i5 as defined in foxmula (V) ancl r is 0-3 ; Suitable and preferred variable groups in :Eormula (VI~ are as in formula (II).
, :~
T will often be a group ~(CH2)q wherein q is 0 to 4.
Also suitably r is 1.
One compound of the invention that is particularly ~ 10 prefe~red for its useful activity is compound 32 of Table 6 :~ of the Examples. ~ ,;-The invention also provldes a process for the prepara-.~ . tion of a compound of the formula (I~ which process comprises ;, react.ing a compound of formula (IX):

N-H :~
R_ - N ¦ R2 (IX) R3 R~ :
wherein;
R2, R3, R4 and R5 are as defined in formula (I), with a compound of formula ~X): Z-CH2-Y-(CH2) CO2Rl ~ :
, whereln Z is a group readily removed by nucleophiles, and Y, n and Rl are as defined in formula (I~

" :
. :

:, '^'` ~ ~
.'~ :

., `: .

u .

Z is suitably a haloyenf such as bromine, and the reac-tion suitably carried out in an or~anic solvent such as hexa-methylphosphoramide or the like in the presence of a base such as sodium earbonate or the like. Generally it is preferred that Rl in the compound of formula (X) is other than hydrogen, and so if in this case a Rl hydrocJen compound o~ the formula (I) is desired it is prepared from the thus formed compound of the formula (I) by a conventional de-esterification reaction.
When R3 is a protected hydroxy group in the compound of formula tIX~, then if in this case a compound of the formula (Ij wherein R3 is hydroxy is required it is prepared from the thus `-~
formed R3 protected hydroxy compound by conventional de-; proteetion reactions. For example, when R3 is a benzyloxy group, the benzyl group may readily be removed by hydrogenolysis.
Thus lt can be seen that compounds of the ~ormula (I) wherein R3 is protected hydroxy are usef~ul ~ .

~: .
~0 ~:
~' 8'713 intermediates in -the preparation of the corresponding free hydro~y compounds of the formula (I).
The .invention also provides a preferred process for -the preparation of a compound o the forMula (I), which process comprises re~lctin~ a compound of the formula (XI):

1~ ,CI-I2--Y--(C~I2)nC02Rl )! \j - ~ ,R (XI) wherein, Y, n, ~1~ R4 and R$ are as defined ~ Eormula (I), with a reducing agent to give a corresponding co.mpound of the formula - ~I) wherein R2 is hydrogen and R3 is hydroxy, or with ~ 15 a Cl 4alkyl or phenyl Grignard reagent or Cl_4 alkyl or phenyl metallic complex to give a corresponding compound of the formula (I) wherein, R2 is Cl_4 alkyl or phenyl, and R3 is hydroxy, and then optionally protecting the R3 hydroxy moiety. .
The reduction of the side chain carbonyl in a compound of the formula (XI) may be carried ou-t hy conventional methods for reducing a ketone to an alcohol, for example by sodium horo-hydride reduction.
The Cl 4 alkyl or phenyl Grignard reagent or Cl 4 alkyl or phenyl metallic (suitably Cl 4 alkyl or phenyl lithium) complex reaction may be carried out under conventional conditions for such reactions, ~or example in an inert anhydrous solvent.
'';, ` :

' .- ~

'~ .

;

-rrhe optiollal protection of the R3 hydroxy moiety may be carried out in conventional manner, for examl~le by acyla-tin~, alkylatiny or benzylating the R3hydroxy compound.
After these reactions if so desired the group Rl in tlle thus formed compounds of -the formula (I) may be varied by conventional esterification and/or de-esterification reactions.
Similarly wllen Rl and/or R5 is hydrogen in such compounds of the formula (I), salts of these compounds may be prepared in conventional manner, for example, by reacting the chosen compound of -the formula (I) with the required base. Preferably ~;
strong bases such as so~ium in an alcohol, e.g. ethanol, and similar reagents are used to obtain salts of R5=H compounds.
Th~ preparation of the in-termediates for use in the processes of the invention will now be described.
Compounds of the formula (IX) may be pre-pared by reacting a compound of the formula (XII):

H
N~ R~ (XII) with a red~cing agent to give a corresponding compound of the formula (IX) wherein R2 is hydrogen and R3 is hydroxy;
or by reactir~ a compound of formula (XIII) as hereinafter defined with a cornpound OL formula (XVI) as hereillafter defined.
'''; ' ' ~

~ ~ .

..

- ~ . . , .
. .
'' 8~

Compo~ds of formula (IX) can also be prepared by reacting a compound of formula (Xll) with a Cl 4 alkyl or phenyl Grignard reagent or Cl ~ alkyl or phenyl metallic complex -to give a ccmpound of formula (IX) wherein R2 is Cl 4 alkyl orphenyl and R3 is hydroxy and if required protecting the hydroxy group.
The reduction may be carried out as hereinbefore described with reference to compounds of the formula (XI).

-15a-'.:

.'.~ :.
`:
:: .
, '.
:, ', ' '.'' . ' ' ' ~ ' '' ' ' g..~ .87~3 .. ~

rrhe reaction of a compouncl oE form~lla (XIII) wlth a compound of formula (XVI) ~ay suitably be carried out as describecl on page 18, lines 3 to 8.

Com~ounds of the formula (X) are either known compounds or may be prepared by a process analogous to those used for pre-paring ~nown compounds.
Compounds of the formula (XI) may be prepared by a process which comprises reacting a compound of the formula (XII) as defined with a compound of the formula (X) as de-fined.
Compounds of the formula (XII) may be prepared by reacting a compound of formula (XIII):

-N - H
H (XIII) .

with a strong base and a compound of formula (XIV):

,/"' \ ~R~ ;
(XIV) Compounds of the formula (XIII) are either known compounds or ca~ be prepared in analogous manner to known compounds.
.

', ~, .
, ~

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

~r~ 8 70 .
For example in our hands, one su:itab].e reaction s~heme for the preparation of -these compounds is shown below:

1. Na H2NC02Et ~ N(C02Et)3

2. Cl.C02E-t H ~-I2 !O; l R5NC
/ `~ -H ~-2- KH'H2 - H2N.NI-IC02E-t ~ - N -H 3. HCl,~I20 .;
(XIII) The invention also provides a further preferred process for the preparation of a compound of the formula (I), which process comprises reactin~ a compound of formula ( XV ):
5'1 , CH2-Y- ( CH2 ) nC2Rl ~ R5 - N ~ (XV) ~ -N-H

wherein, Y, n, Rl and R5 are as defined in formula (I), with a compound of formula (XVI):

2S \ / \ ~ / 2 (XVI) ~ 3 4 : -17-~ .
~'; ; , ~ ` ' ' , ' ' . .
. , :
- : .
' : ~
' 7~

wherein D is a group ~eadily rernoved b~ nucleophiles, and R2, R3 and R4 are as defined in formula tI).
This reaction is suitably carried out in an inert organic solvent, such as hexamethylphosphoramide or N,N -di-methylformamicle, at room temperature, in the presence of a base, such as sodium carbonate or sodium hydride, and a source oE alkali me-tal iolls, such as an aLkali metal halide. Sui-table alkali halides include sodium iodide and lithium iodide.

Suitable examples of D include tosylate, bromide or iodide.
Preferably D is a tosylate residue.
The compound of formula (XV) may be prepared ~y react-ing a compound of formula (XVII):
'I\
R - N N (XVII) O ~:
with a compound of formula ~``(CH2)n-~1 C2Rl' and then if -~
necessary reducing the resulting Y is CEI=CH compound to the corresponding Y is CH2CH2 compound.
This reaction is suitably carried Ol1t in an inert oryanic solvent, such as ben2ene, at the reflux temperature, under an inert atmosphere. It should be mentioned that to prepare a compound of the formula (XV) wherein ~ is other than hydrogen, it is generally pre~erred to prepare the correspond~
ing compound of the formula (XV) wherein R1 is hydrogen and -then to convert tha-t compound to the desired compound by conventional methods. For example a Rl is hydrogen--compound may be converted to a Rl is methyl compound by treatment with acetyl chloride in methanol.
The optional reduction can be carried out in con-ventional manner.

. .

.

The compound of formula (XVII) may be prepared by treat-inq a compound of formula ~XIII) as hereinbeEoLe deflned, that is, a compound of formula:
O

R5 _ N/ `N - H (XIII) ~ - H

with an oxidising agent, such as N2O~ or t-butyl hypochloride.
Thls reaction is suitably carried out by suspendin~ the chosen compound of the formula (XIII) in an inert organic solvent, such as dichloromethane, at 0C, and bubbling N204 through this suspenslon, or adding a known volume oE N204 in dichloromethane slowly to the suspension.

The preparation of the compounds of the formula (XIII) has been discussed hereinbefore.
It is believed that compounds of formula (IX3, (XI), (XII) and (XV) are novel compounds, and these compounds are useful intermediates as hereinbefore described. As such, they form an important part of this invention.
Certain of the foregoing novel intermediates can be characterixed by the general formula.

5 - N N-H and salts thereof \, ~-X
~:
~` 20 wherein X is a group of formula -C~12-Y~(CH2) CO2R
- wherein n is I to 5; Y is -CH2-CH2 or -CH=CH-; and R
is hydrogen or CO2Rl represents an ester group in which the R
molety contains from 1-12 carbon atoms;

.

~L~LC73Li~17 or X is a gL`OUp of formula wherein R2 is hydrogen, Cl 4 alkyl or phenyl; R3 is hydroxy or protected hydroxy; or R2 and R3 taken with the carbon atom to which they are joined represent a carbonyl group;
~4 i5 hydrogen, Cl 9 alkyl, C3 8 cycloalkyl, C3_8 cyclo- ;
alkyl, C3 8 cycloalkyl-C1 6 alkyl, or any of which phenyl moieties or naphthyl moieties substituted by one or more halogen atoms or trieluoromethyl, Cl 6 alkyl, hydroxy, Cl 6 alkoxy, phenyl-Cl_6 alkyl, hydroxyr C1 ~ alkoxy, phenyl-Cl 6 alkoxy or nitro groups;
or R2 and R~ taken with the carbon atom~to which they are joined represent a C5 8 cycloal]cyl group and wherein;
R5 is hydrogen, Cl 6 alkyl, C5 ~ cycloalkyl, phenyl, phenyl-Cl 6 alkyl or phenyl C3 6 cycloalkyl, or any of which phenyl moieties substituted by one or more halogen atoms or trifluoromethyl, Cl 6 alkyl, Cl 6 alkoxy or nitro groups; and salts thereof It will be realised by the skilled reader that although the reaction sequences leadiny to the active compounds of the invention hereinbefore described are particularly suitable, a number of variations in the sequences are possible. -It is -~
believed these variations are best illustrated by use of the Eollowing flow dlagram.

~ The reactions represented by arrows in the ~low diagram are carried out as hereinbe~ore described, or in an analogous manner).

- l~a -.

7~3 ,, ~1 , o-~z ^~ \

o = O

Ln X
H

~ I / / I

N

D ~ io :~ Ln ~ Z

~ æ ~~

",, ~
. ~ .

! ` , It will of course be realised that -the compounds oE the formula (I) have an asymmetric cen-tre, and thus are capa~le of e~i~tlnc~ in -two enantiomeric forms. The i.nventi.on extends to each of th~se isomeric forms, and to mixtures -thereof. Tlle different lsomeri~ forms ma~ be resolved by the us~ial methods.
Compounds within the formula ~I) have useful pharmacologi-cal activity. For example compounds within the formuIa (I) have anti-gastric secretion activity e.g. anti-ulcer activity, cardiovascular activity e.g. anti-hypertensive actlvity or anti arrhythmic activity, platelet aggregation inhibition activity, af-fect the respiratory tra~-t e.g. bronchodilator activity, and have anti-fertility and smooth muscle activity.
In general it may be said that compounds within the formula (I)have a range of pharmacological activities similar to those shown by the natural prostaglandins, but that these acti~vities ;
: tend to be rather more selective. .
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
Clearly the formulationofthesaid pharmaceutical composition will depend on the nature of the activity shown by the chosen .
compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular ~ mode of administration.
.

, .,, , . , ~ : ;. .- -7~ ~
The compositions may be in the form of tablets, capsules, powders, granules, lo~enges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral adm:inistration may be in unit dose presentation form, and may contain conventional ex~
cipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable ~etting agents and the like. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrupsj or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents, and ~-the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula tI) and a : 20 sterile vehicle. The compound, depending on the vehicle and :: concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injectlon and filter sterilized before filling in-to a suit-able vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the com- :
pound is suspended in the vehicle instead of being dissolved `.
and sterilization cannot be accoMplished by filtration. The compound can be sterilized by exposure to ethylene oxide before ;.~ suspending in the sterile vehicle. Advantageously, a surfac-tant ~ or wetting agent is included in the composition to facilitate uniform distribution of the compollnd.
When appropriate, the compositlons of thi.s invention may be presented as an aerosol for oral adminls-tration, or as a microfine powder for insufflation.
As is common prac-tice, the compositi.ons will usually be accompanied by written or printed directions for use in the medical treatment concerned.
It will of course be realised -that the precise dosage used in the treatment of anv of the hereinbefore described 10 disorders will depend on the actual compound of the formula (I) ~ ;
used, and also on other factors such as the seriousness of the disorder being treated.
The invention also provides a method of treatment and/or prophylaxis of disorders in huoan beings or animals which comprises the aclministration to the sufferer of an effective amount of a compound of the formula (I).
Normally however the compounds will be used in the therapy of human disorders. ~ , :

~ 30 : , , ' r~ , . : .

Examples 1 to 9 i.llustrate -the prcp~ll.ation of -the active compounds of the invention by -the (XIII)~ XII) (XI)--~(I) route, as illus-trated in the flow di.ayram.
;

~ -24-I
. ~, :;`

Y~

;: ~
., ~ ., .

Ex~nple 1 Preparation of ethyl-N-tricarboxylate ,~

Ref. Org. Syn. Coll. Vol.III, p. 415, C.F.H. Allen and Alan Bell.
Sodium (~4y, 1.93y atom) was cut lnto small pieces and added to a solution of urethane (90y, 1.01 mol~ in dry ether (1.5 1) [the urethane was dried overniyht in vacuo over KOH~.
The mixture was stirred for 2 hours, then boiled at reflux for 3 hours and then cooled in ice-water. Ethyl chloroformate (210gl 1.95 mol) was then added dropwise over 2 hours and the resultant mixture stirred overnight at roorn tempera-ture and then filtered. The residue was washed with ether (2 x 200 ml) ~, and the ether was removed from the iltrate by evaporation in vacuo. The residual oil was distllled b.p. 118-128/6mm. Yield 86g.

:~ " ' ''.
, ' , , ' ; ~, ;' ' ~
. .

'~
.'' ,.: ~, .: . :

. . , . :
. . ..

8~3 F,xc~mple 2 Pr~paration of e-thyl carba~at~
____ _ . _ C.F.H. Allen and Alan Bell. Org. Syn. Coll, Vol. III, p. 404, To ethyl-N-tricarboxylate (86g, 0.37 mol) stirred and cooled in an ice-bath was addecl slowly hydrazine hydrate ~50g, 1,0 mol). After complete addition the mix-ture was heated on a water bath for 0,5 hr and to the reaction mixture ethanol (1()0 ml) was added. This mixture was heated on the wa-ter bath (with stirring) for a further 2 hr and then cooled and filtered. The residue was washed with ethanol and the filtrate evaporated in vacuo to give an oil to which more ethanol was added and the solution was allowed to stand over-night a-t room temperature, The resultant mixture was re-filtered, the ethanol was removed from the filtrate ln vacuo and -the residual oil distilled, b.p. 64-66 / 3 mm Yield 68g, This distillate was re-dis-tilled, b.p, 92-95 / 15 mm, Yield 60g, .

. . .

-~6-' , ~ .

. .
. ' ~, ................. .

. -- --37~ :
Example _ 4-Methyl-l,2,4 triazolidine-3,5-clione (Cs~mpouncl 21 G. Zimmer and W. Deucker. Arch. Pharm., 1961, 294, 370 C. ~. 1961, 55, 22298 Ethyl carbazate (12.0 g, 0.115 mol) in dry benzene ~60ml) was treated dropwise with methyl isocyanate (6.5ml, 6.0g, 0.105 mol) and after complete addltion the mixture was boiled at reflux for 20 min. This solution was allowed to cool and then 4N aqueous potassium hydroxide (50ml) was -;
added and the resul-tant mixture heated at ca. 40C for 20 min.
This solution was then cooled and acidifled with concentrated hydrochloric acid and then evaporated in vacuo to give a white solid. This solid was boiled at reflux in ethanol (300ml) for 2 hr and the resultant mixture filtered while hot.
The filtrate was allowed to cool and refiltered, this filtrate was evaporated to dryness to afford 4-methyl urazole (10.5g), m.p. 222-4 . The compounds in Table 1 were prepared in similar manner.

Table l R5 / ~

`: ~
., ~ ___ .
Compound I~ m.~, 1 Ph 204-6 ~`
2 Me 222~4 . . 3 _ _ _ ~t 184-6 R5 = H (4), available commercially .~ ~

! 27 ' ~

Example 4 4-Methyl-2-(3'-oxo-octyl)-1,2,4-triazol_dine-3,5-dione (Com~ound 7) To a solution of 4~methyl-1,2,4-triazolidine-3,5-dione (5.75 g, 0.05 mol) in dry dimethylforma~lide (40 ml) stirred at under a nitrogen atmosphere was adde~ portionwise sodium hydride (1.575g, 0.055 mol, as an 80% dispersion in mineral oil) and the resultant solution stirred at 75 for 0.5 hr. To this solution was added o t-l-en-3-one (6.57g, 0.055 mol) drop-wise is dimethylformamide (20ml) and the solution heated with stirring for 48 hr at 75. The reackion m~x-ture was then cooled, taken up in ethyl acetate (lOOml) and poured into ice-cold 5N aqueous hydrochloric acid (200ml). The aqueous layer was separated and extracted with ethyl acetate (4 x lOOml).
The cornbined extracts were washed with SN aqueous hydrochloric acid, water and then brine, then dried ~Na2S04), filtered and the solvent removed by evaporation in vacuo, to leave a gum (6.55g). This was chromatographed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:20 wlth chIoroform as eluant, to afford the triazolidine-3,5-dione (4.61g) as a gum, which later solidified (Iri subseque~t preparations the crude material from the reaction mixture could be triturated with hexa~e to induced crystall~sation) r m.p. 76-8 .

. i .

. ' , ~
~0 .:

~.7 The compounds shown in Table 2 were prepared in a sim:ilar manner.
' :

T~ble 2 O

R5~ R :~

. _ I . I Q ~, Compound , R5 R~ ! m.p. C ~ ~
~ :
,: _ I I , I , .
. ' C51l11 ; 91-2 ; 6 , Ph l C5Hll j 109-111 ; 7: Me I C5Hll 76-78 ~ -8 Et C6H13 50-S2 .
I
9 Et I C5Hll GUM

¦ 11 Me ¦ C6H13 75-77 ,:

' .
~ .
..
;:
~ ~ , :~
:~ .
..

~, " ' ' ' ',' ~ :~ . " ' '' ' " : ~ ;
- : . :,- ~ :
.
,: ' ' , ~'xam~le 5 , 1-(6'-Ethoxyca _onyl ~-hex~1)-4-methxl-2--(3"-oxo ~-o~

1,2,4-triazolidine-3,5-dione (CompouIld 14 .. . .. _ .
4-Methyl-2-(3'oxo-n-octyl)-1,2,4~triazolidine-3~5-dione (4.0 g, 0.017 mol) was dissolved in hexamethylphosphoramide (60 ml) and sodium carbonate (5.0 g, 0.04 mol), sodium iodide (0~5 g) and ethyl 6-bromoheptanoate (4.327 g, 0.018 mol) in hexameth~lphosphoramide (20 ml) were added and the mixture stirred at room temperature for one week. The resultant mixture was poured into water (300 ml), ex-tracted wi-th ethyl acetate (5 x lOOml), and the combined extracts washed with water (3 x 200ml), brine (2 x 200ml), then dried, (Na2SO4) and filtered. The ethyl acetate was removed ln vacuo to leave a gum (6.77 y) which was chromatographed on silica gel (Merck, Kiesel~el 60), packing ratio 1:20, using chloroform as eluant to afford 1-~6'-ethoxycarbonyl-rl-hexyl)-4-methylw2 (3'' ~ triazolidine-3,5-dione (3~56g)--as a gum.
O O O
I.r. (cm ): 1770, N-C-; 1680-1750, -C-, -N-C-.
:
NMR ~ 5.82 q, 2H, -C02C~12CH3; 6-15 t, NC~I2; 6.42t,~CH2; 6-90s, O O
Il 11 N-CH3; 7.29 t, CH2-C-, 7.65 t, CC~I2, -CH2CO2Et- ~ ;~
. ~, ':
The compounds listed in Table 3 were prepared in a similar manner.
: : ~
;: .

. ~:
; -- 30 -~`

; ' : ' , ~ ~ '~ :

37~ :

Table 3 !~
.~ .

R5 / ~ ~ "- ( 2 6 2 1 ~

O `\ ~/~ ",' . ~ _ Compound R5 j ~1 I R4 ~ ~
. ._. ~ ~ ~ ~

12 , H I EtC5H11 : 13 I Ph Et C5H11 ~;
14 . Me Et ~ C51I
lS t Et C5H

18 ~i Me ~ Et I C6H13 ¦

Co~æo____12 - ' . ':~
R5=H, R1= Et, R4 C5H11 O O O
I.r. (cm j: 1760, -N-C- ; 1680-1740, -C--, N-C- , -C02Et ~MR (r): 5.95 q, 2H, C02CH2CH3, 6.15-6.8 brm,:4H, (2 ~ N-CH2), ::~
I ~ (CDC13) 7.1-8.0 brm, 6H, -C-2-c-c-2' -CH2c2Et :~ -31- :

.

.

~:

3L87~
.. . . .

Compo_nd 13 ~`
RS= Ph, R~= Et, R~= C5H

r (cml): 1775 N-C-N, 1680-1760, N-C-N, -C-, CO2Et.

: 2.2-2.9m, 5H, C6H5; 5.92q, 6.1-6.7m, CO2CH2OEI
(CDCl ) 8 "

3 (-~-C1l2-)2; 7.32 t, CH2C-; 7,7S t, CCH2, CH2CO2E-t.

Compound 18 RS= Me, Rl= Et~ R~ C6~13 O O , ;~
I.r. (cm ): 1775, -N-C-;-1660-1740, N-C-, -C-, CO2Et, NMR ( r ) : 5.9$q, CO2CH2CH3, 2H; 6.2-6.8m, (2 x NCH2), 4H
(Cc14) ~

0 7.07s, 3H, N-CH3, 7.3-8-0m, 6H, -C_2C02C2H5, CH2C-C_2, 8.1-9.3 brm, 22H.
~nalysis: Found C, 61.50; El, 9.08; N, 10.27~ C21H37N3O5 requlres, C, 61.29; H, 9.06; N; 10.21%.
Mass Spec: Meas. mass 411.2721, Calc. mass 411.2708.

` Compound 15 E~5=Et~ Rl=Et~ R4 C5Hll O o I.r. (cm 1): 1770, -N-Y-; 1680-1750, N-C-, -CO2Et, -~
N m r (60MEIz, CDC13)r: 5.90q, 2H, C02CH2 3 6H, (N-CH2)3; 7-1-7-9 m, 6H, C~-I2CCH2, CEI2CO2Et, 8-0-9-3 brm, ;
0~ 23H, ~ .
, , , , :. . ~ .: .
', ' ' : ' , ~ 7~ ~:

~xamp1e 6 1 (G'-~tlox~ ~ ex ~ ydro~n-octyl)-~-me-thy.l-L,2,4-triazolidlne-3,5-clione (Compound 21) 1-(6'~ethoxycarbonyl-n-hexyl) 2-(3"~oxo~n-octyl)-

4-methyl-1,2,4-triazolidine-3,5-dione (3.56 g) 9 m moli was dissolved ln dry ethanol (60 ml) and sodium borohydride (0.375 g, 10 m mo:L) was added por-tionwise.
After s-tirring a- room -temperature for 18 hr the ethanol was removed in vacuo, the residue dissolved in water (lOOml) and acidified~with 5N aqueous hydrochloric acid. This aqueous mixture was eY~trac~ed with e-thyl acetate (4 x lOOml) and the combined extracts washed with brine (2 x lOOml), then dried (Na2S04), Eiltered and the solvent removed ln vacuo, to leave a gum (3.26g). This gum was chromatograph-ed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:30 using benzene and benzene: ethyl acetate mixtures as eluant, to afford 1-( 6 ~ -ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n= octyl)-4-methyl-1,2,4-triazolidlne-3,5-dlone (0.94g) as a gum.
Mass Spec: Meas. mass 399.2733, calc. mass 399.2733.
O O
; I.r. (cm ): 3500, -OH; 1760, N-~-, 1680-1730, N-C-, C02Et.

~ NMR ( r) : 5.81q, C02CH2CH3, 2H, 6.0-6.1 brm, 5H, (2 x N-C_2),CE;-~H, 3 6.88s, 3H, -N-CH3, 7.30 brs, lH, -0_, 7.65 brt, -CH2C02Et.
. .
The compounds listed in Table 4 were prepared in a similar ~anner.
; -33-. ~ ~ . . . - , - . .

.

Table 4 O ( CH 2 ) 6C2Rl `\ // \6 / 4 _ _ ':
Compound I R5I Rl R4 : ~

19 Hj Et CSH11 : 20 Ph¦ E-t C5Hll : 5 . 21 1 ~e ~Et C5H
~ L 22 1 ~t ~ ~t C5~111 ~______ _.__ Compound l9 Analysis: ~gH3sN3Qs requires C, 59.20, H, 9.15, N, 10.90% ¦
found: C, 59,50, H, 9.39, N, 10.63%
O O
10I.r. (cm ): 3500, -OH; 1760, -N-C-N; 1670-i730, -N~ N, CO2Et.
NMR (CC14)r: 5.86 q, -CO2CH2CH3; 6.1-6.7 brm, 2 x N-CH2, . CH-OH,.CH-OH; 7.71 brt, Ch2CO2Et; 8.0-9.3 brm.

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

,_ :: ~

:; . : ~
, , . :
:
} -:
:" . '' ' .

Compound 20 ~na1ysis: C25H39N3O5 requires C, 65.05; N, 9.l0; H, 8.52~o Found: C, 65.13; N, 9.21; H, 8.71~o O O
I.r. (cm ): 3500, -OH; 1765, N-C-N; 1680-1740, N-C-N, CO2Et NMR (CC14) 't:2.6 brm, C6H5; 5.90 q, -CO2CH2CH3, 6.1~6.9 brnl, (N-CH2), Cl-l-OIl, CH-OH; 7.75 brt, C~12CO2Et, 8.0-9.3 brm.
., :
~ Compound 22 :
R5=Et. Rl=Et, R4 C5111 Ana1ysis: C211l39N3O5 requires C, 60.99; H, 9.51; N, 10~16-o Found: C, 61.18; H, 9.47; N, 10.16 o O
I.r. (cm ~: 3500, -OH, 1760, -N-C-N; 1670-1730 N-C-N, CO2Et NMR (60 MHz, CDC13)r: 5.91 brq, 3H, C~-OH, CO2CH2CH3;
6 10-6.80~brm, 7H, (NCH2)3~, CH-OHj~
7.74 brt, 2H, CH2CO2Et; 8.0-9.3 brm.
Mass Spec. Meas. mass 413.2914, calc. mass 413.2889.~
' ' . ' ~, ' : .'. ' - ';:, ',''' ~ f ' .~. . ' ' ' ~
_35- - ~
' : ~
'~' ~ , , ~ ' ;

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

, :
:

8i7 E~ample 7 2-(3'-~y o~- ~ methy_-1,2,4-tridz (Compound 23) 2-(3'-Oxo-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione ~0.5 c~, 21 m mol) was dissolved in dry methanol (20 ml) and sodlum borohydride (0.087 g, 2.3 m mol) was added portionwise. The reac-tion mix-ture was stirred overnigh-t at .room temperat:ure and then the ethanol. was removed by evaporation ln vacuo. The residual gum was dissolved lQ in water (20ml) and acidified with 5N aqueous hydrochloric acid, then cxtracted with ether (4 x 50ml). ~he combined extracts were washed with brine (3 x 50ml), dried (Na2SO~) and the ether : removed by evaporation ln vacuo to give a white rosidual solid, (0.36g), m.p. 85-88 , of 2-(3'-h~drox~-n--oc-ty].)-4-methy~-].5 l,2,4-trlazolidine-3,~5-dlonc (23).
Foun~, C, 54.77, H, 8.55'-o .
C11H21N303 require.s, C, 54.30; H, 8-7% 0 I.R. (nujol, cm ): 3500, -OH; 167Q-1760, N-C-.
NMR (60 MHz, CDC13)r: 6.22 brq, 3H, N-C~12t CH-OII; 6.90 s, 3~ N-CH3; 8.0-8.8 brm, 11H, (CH2)5, OH; 9.08 brt, 3H, C~l3.

- .

~ 7~

Example 8 1-(6'-Carbox~_-hexyl -( -hyclroxy-n-octyl)-4~meth 1,_,4--triazolidine-3,5-dione :
(Coln~ouncl 24) _ _ _, . :

To a solution of 1-(6'-e-thoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-metnyl-1,2,4-triazolldine-3,5-dione :~ . (0.43 g, 1:.1 m mol) in dry ethanol (20 ml) was added anhydrous potassium carbonate (1.0 g) and the mixture boiled under reflux for 24 hours. The mix-ture was cooled, carefully acidified wlth ice-colcL 5N aqueous . hydrochloric acid and extraeted wi-th ethyl acetate (4 x 100ml).
The combined extracts were washed wi.th brine, dried (Na2SO~), : Filtered and e-thyl acetate removed ln vaeuo to leave a gum (0.409g). This gum was chromatographed on silica gel (Merck, Kieselgel 60) (20g) usin~ chloroform and chloroform-methanol mix-tures (5% gradient) as eluant, to afford .l-~6'-carboxy-n-hexyl)-2-(3"-hydroxy-n-oetyl)-4-metllyl-1,2,4-tri_zolid_ne-3,5-dione (24) as a yum (200 mg).
__ ;. Mass Spec. Meas. ~ass 371.2416, calc. mass 371.2421.

I.r. (cm ): 2400-3600, CO2EI, OH, 1640-1800, CO2H, N-C-.
: 3.32 brs, 2H, CO2H, OH, 6.4 brm, 5H, CH-OH, (N-CE12)2, (CDC13) 6.97s, 3HI N-C_3, 7.70 brt, 2H, CH2CO2H.

-: ., ; ~ . :- -~

: .

: ~ ' W ~ tjj~
Example 9 hex ~ 2-(3"-h~__oxy-3"-m-eth~ n n~
4-rrleth ~-1,2,4- riazolidine-3,5--dione_(Compound ~5) To a soLut:ion of ]-(6'-ethoxycarbonyl-n-hexyl)-(3"-o.Yo-n-nonyl)-4-methyl-1,2,~--triazolidine-3,5-dione (l3) (0 82 g, 0.002 mol) in tetrahydrofuran (20 ml) cooled -to -78 under a ni-trogen atmosphere, .
methyl lithiurn (1.1. ml, 2.2m mol) as a 2M solution in ether was added dropwise. After complete addition the reaction mixture was stirred for a further 1 hr at -78 , allowed to warm to ca. -20 and then quenched with saturated ammonium chloride solution (20ml). This mixture was extracted with ethyl ace-tate (4 x 50ml); the combined ex-tracts washed with hrine (2 x 50ml) dried (Na2SO~) and the solvent removed ln lS vacuo to leave a gum (812mg). This gum was chromatographed ~;
on silica gel (Merck, Kieselgel 60, 20g) using chloroform as ~
.
eluant to afford 1-(6'-ethoxycarbonyl n-hexyl)-~-(3"-h~rcxx-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidlne-3,5-dlone (25) as a yellow gum (252 mg). +
Mass spec. C22H41N3O5 requires M
found: M 427 (100%) Major 412 (M-Me, ca. 10%), 382 (M-OEt,ca30/O) 342 (M-C6H13,ca.50%),324(M-H2O,C~H13, ca. 20%), 322 (M-C~4~ C6H13' 20%~
~ 296 (M-H20, C2H4~ C6~13~ 30%)' 284 (M-CgHlgO , 80%), 226~M-C12H252 :: 1 00/0 ) 128~ (M 18 35 3' o I.r. (cm ): 3500, -OH; 1760j -N-C-; 1670-1740, N-C- , CO2Et .0 r 5.84q, 2H, CO2C_2CH3, 4.05-4.55m, 4H, (N--CH2)2, (CDC13) 6.92s, 3H, N-CH3, 7.32brs1 lH, -OH, 7.70 brt, 2H,C_2CO2Et.

.

37~
- . .

The following Examples i].lustrate the preparat:ion of the active compounds o~ -the invention by the (XI~ XVII) - ~ (XV) -~(I) route, as illustrated in the flow diagra~.

. ~ ~

.
: .

.

.
' ~ : ~39~

:. J

.- ' : ' ' ,, ' ', ', ' ' : , :
.' . ` ' '-~ '': ' ' . ' ' .
.` ~ ` . ' ,' ': ' ' ' ' ~ :

Example 10 Preparation of hept-6-enoic acid ( ~ (CH2)n~l C02R~ where n = 3, Rl- H) Ref: E.A. Brande, R.P. Linstead, and K.R.H.
Wooldridge, JCS , 1956, 3074.

To a solution of sodium (19g, 0~826g atom) in e-thanol (250ml) at room -temperature was added, dropwise, with stir- --' ring diethyl malonate (158g, 1.0 mol) in ethanol (lOOml) and the mix-ture stirred fox a fur-ther 1 hr at room temperature after com~lete addi-tion. ,' To this mixture was added dropwise with s-tirring 5-bromo-pent-l-ene (lOOg, 0.671 mol) in ethanol (50ml) and after addi-tion was complete -the mix-ture was stirred for a fur-ther 12 hr at room temperature. This resuItant mixture was acidified by the addition of acetic acid (15ml) and the e-thanol was removed ;' in vacuo. The residue was mixed with ether (500ml), filtercd - and the filtrate was washed wi-th saturated sodium chloride solu,tion until neutral. The organic phase was then dried (Na2S04) filtered and the e-ther removed ln vacuo. The resul-tant liquid was dis-tilled to afford die-t'hyl-pent-4-e~ylmalonate o O
b.p. 131-6 /14 mm (80g) (ref. b.p. 134/14 mm).
The diethyl-pent-4-enylmalonate (80g, 0.351 mol) was added, to a solution of potassium hydroxide (120g, 2.143 mol) in wa-ter (75ml) containing ethanol (15ml) and the resultant mixture stirred for 12 hr at room -temperature. This mixture was then acld-ified with 5~ sulphuric aci~ (ca.250ml) and concentra,ed sulphuric ,~
acicl (ca.25ml) and the resultant mixture e~tracted with ether :' ' : , " - .
:
:: ~

' (3 x 200ml). The combined extracts wcre washed with water (2 x 200ml) and satura-ted sod:ium chlori.61e solution (2 x 200ml).
The o:cganic phase was dried (Na S0~), fi.ltered and -the ether rcrmoved from the iltra-te in vacuo. The residua:l-oil was decarboxylated at a ba-th -tempera-ture o~ 160 and pressure 20mm Hg ancl the hept-6-enoic acid collected at 120 /20 mm. (38.2g) (ref. b.p. 74 /0.5 mm).

,~..

.: -41-' ' ' :

87~ ~
Example 11 a? Preparation of 1-(6'-methox~carbonyl-n-hex-2~enyl)-4-methyl-1,2,4 - triazolidlne - 3,5-dione ~26) (C~2)6C02~e ~ NH
O ::
(2) Dinitrogen tetroxide was bubbled through a suspension of 4-methyl - 1,2,4 -triazolidine - 3,5 -dione (23.0g, 0.2mol) in dichloromethane (250ml) cooled to O C, un-til a clear, homo-genous deep red solution was obtained. This solution was then dried (Na2S04), Eiltered, and the filtrate evaporated at room temperature in vacuo to yive 4-methyl-1,2,4 - triaæolidine - 3,

5-dione (m.p. 105 decomp). To the 4-methyl-1,2,4-tria~oline-3,5-dione(23.0g, 0.2 mol) dissolved ln benzene ~200ml) was added dropwise hept-6-enoic acid (23.0g, 0.18 mol) in benzene (lOOml) and the resultant solution boiled under reflux in an atmosphere of nitrogen, until a pale yellow solution had been obtained (in - 1 hr). The resultant solution was evapoxated ln vacuo and the residue dissolved in a 10% solution of acetyl chloride in methanol (300ml). This solution was boiled at reflux for 5 hr, stirred at room temperature overnight and then evaporated in ;~
vacuo. The residue (44g) was chromatographed on silica gel (Merck ~ieselgel 60, 900g) using chloroformi methanol as eluant (0-5~ methanol), to afford 1-_6 -methoxycarbonyl-n-hex-2-enyl)-4~methyl - 1,2,4 - -triazolldine - 3,5, -dione (l9.lg~ m.p. 55-7 : , ~ ' .

~2 : - ,,, .,: , :
, - .

8~

found: C, 51.55 , H, 6.56, N 16,59%
CllH17N304 requlres C, 51.76; H, 6.71; N 16.46%
NMR (CDC13) ~: 0.8-1.2 brs, lH, N-H; 4.37m, 2H, CH = CH; 5.97 brd, 2H, ~-CM2- ; 6.40 s, 3H, -CO2CH3, 7.00, S, 3H, N-CH3, `
7.5-8.8 brm, 6H, -(CH2~3.
O O
IR (crn ) : 1760, -N-C, 1670-1740, N-C, C02Me;
- Mass Spec. Meas. mass 255.1243 calc. mass 255.1219.
10 , "
(b) Preparation of 1-~6'-methoxycarbonyl-n-hex~ 4-methyl-1,2,4 - trlazolidine-3,5-dione The 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine -3,5-dione (12.4g, 0.0486 mol) was dissolved in dimethoxyethane (200ml) and 10% palladiurn on charcoal (3g) was added and the resultant mixture was allowe~l to take up hydrogen (ca~ llOOmls). After the reaction was complete the resultant mixture was fil~ered through a kieselguhr bed and the filtrate evaporated in vacuo to afford 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4,- triazo]idine-3,5-dione (12.3g).
m.p. 80-1 .
, : ::
found: C, 51.12, H, 7.71; N 16.38%
C-lHlgN3O4 re~uires C, 51i35; H, 7.44; N, 16~33%.

~-43-'; ,'~ :
~: .
'' ~ , ,. . . . .

. , ~ , , .
:

t7 NMR (CDC13~ ~ : 6.39 s, 6.48 m, 5E1, -C02CE13, CH2- , 6.97s, 3E1, N-CE13.
7.73 m, 2H, -CEI2C02Me, g 07-g A 78 brm. -(CH2~4, 8E~- ~

-1 1 ' .
IR (nujol) cm : 1660-1780, N-C- , C0 Me.

Mass Spec: Meas. mass 257.1377 calc~ mass 257.13i5.

, ~' .

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

-, . : : , :, . .

~ '7~D :

Exam~le 12 ~eL~ ion_of l-(p-tolu nesulp~y To a slurry of zinc (33g, 0.5 mol) in benzerle (50ml) con-taining a small crystal of iodine, boiled at reflux, was added carefully 40ml of a mix-ture of cyclo'nexylmethyl ketone (37g, 0.294 mol), ethyl bromoacetate ~84g, 0.5 mol) and benzene (50ml). After initiation of -the reaction , the rest of the mixture was added a-t such a rate tha-t reflux was main-tained. After complete addition of the ke-tone mixture -the resultant reaction mixture was boiled at reflux for a further l hr. The mixture was then cooled and poured into ice-cold 20% sulphuric acid (200ml) and extracted with ether (4 x 200ml). The combined extracts were washed with water ( 2 x 250ml), saturated sodium hydrogen carbonate solution (2 x 250ml) and saturated sodium chloride solution until neutral.
The extract ~as then dried (Na2S04), fil-tered and the filtrate evapora-ted in vacuo to remove ether to give an oil ~97g).
This residual oil was then distilled to afford ethyl-3 cyclo-hexyl-3-hydroxy-butyrate, (36g) b.p. 90-94/OAO5 mm.
To a slurry of lithium aluminium hydride (6.39g, 0.168 mol) in ether (250ml), in an atmosphere of nitrogen and cooled in an ice-bath was added dropwise ethyl-3-cyclohexy1-3-hydroxy-bu-tyrate (36 g, 0.168 mol) in ether (lO0 ml)~ After complete addition of the ester the resultant mixture was boiled at ~'--:~ :
'.' ' :, . . . . . . . .

, : . :: . .

~ 3'7~

reflux for 1 hr, then cooled in an ice-bathO Excess lithium alulninium hyclride was clestroyed by success:i.ve dropwise adclition of water (7ml), 10% sodium hydroxide solu-tion (7ml) and wa-ter (21ml). The reaction m:ixture was filtered, the filter c~ke washed with ether (2 xlOOml) and the fil-trate ~.
washed with saturated sodium chloride solution (1 x 250 ml) and then dried (Na2SO4). This mixture was fi.ltered and the filtrate evaporated in vacuo to remove ether to give 3~cyclo-hexylbutane-1,3-diol (25g~ as an oil.

, ~

,, - :
, ' ' ~ ' ' ' : ' ~

N~ (C~C13)2~: 5.Sl ,lll, -OH, 6.26 brm, 3H, -OH, CH2-OH, 1 8.0-9.5 brm, 8.92 s, 16H, -(CH2~6 ~ -C_-~ CM
IR (cm ) 3500, -OII.

The 3-cyclohexylbutan-1,3-diol (25g, 0.145 mol) was dissolved in pyridine (130ml) and cooled to O C with stirring.
Toluene sulphonyl chloride (29 g, 0.152 molj was added ~ortion-wise and -the resultant reaction mLxture stirred for 45 minutes at O . The reaction mixture was then stored in a refrigerator for lS hr and then poured into iced-water ~200ml). The~reaction mixture was extracted with ether (3 x 200 ml) and the combined extrac-ts washed with 10% HCL (2 x 200 ml), saturated sodium chloride solution ( 3 x 200 ml) and then dried (Na2504). This mixture was iltered and the filtrate evaporated ln vacuo at room temperature to remove ether *o leave a gum (45g). Thls gum was mixed with petrol (bp 60-80 , 200 ml) gradual~ly cooled to -78 with stirring, and the petrol decanted. Residual petrol was removed by evaporation ln vacuo at room temperature to leave l-(p-toluene sulphonyl)-3-cyclohexybutan-3-ol ~40y) as a gum.

ound: C, 62.36, H, 7.99, S, 9~40%
:
C17H26S04 requires C, 62.56, H, 8.03; 5, 9 30%
IR (cm ): 3600, OH, 1190,11ôO,-S - C ~ - CH3 The ethyl hydroxyesters and corresponding tosylates given in Table 1. were prepared in a similar manner.

~ j ~, ~ -47-~ ' ,' .- .. ,. . :
., .

::

I cn o Ln Ln o ~-I r~
.~ 2 r~ ¦ r~
~_~ U~ O Llt Oo Ln Lt~ ~n ~ E~ O-t O~t~h ( r oo rt O r~l r I r J r I r~i O i r ~ r-l r-l r-~
,S~ r-l ~ (''1 l ~c E~ ___~ .~
a) I . ~' ~ ~ O o o O O O O ~
1--l I c Ln C~l O O O Lt~ L~') , T rt r~ ~) (~ ~`t r~ ~t C~ I

_. = rn--O . ~ ~_~ : ~ ~
r-l ~ O _~ :
Llt r~ ~ ~ ~ ~ ~ ~`I
r~ ~ : ~P~n1-- ~ o , r~ ~ L~tr-- CO
_, ~`J . . . . . ,-~
_ rn Ch ~ C~ ci~
D~ \ ~ Ltl a) ' r~ ~ ~ I~co~r ~ o ~h E~ ~ ~r~
O ~ r~ . . . . . o O ~1 ~ cn~nrxt a~ Ch r-~ :
U~ O ___ __ O _ .
E~ ,~
r~ r~ cncn~t cn rt~rl r~n : :~ Ln ~~D Ln O~Lt O : ~ .
X L~ ~ ~ r~~D~D r~ a> ~ r-L~ h : ~ r-r~ Llt r-l ~ ~ I rltr~r-l O ~
a~ ~ rn r ~ H ~ r~ Lh r~
~ ~ r~ ~ ~ ~ ~
1-l r~ r--Ir-- ~D H11~ ~D r--l ~_ r~ r ~
r~ V ~ L~t cn ~r ~D Ln ~D ~ O ~ ~n Lr) r~ l ~~ r~ :
r~ ~Lt~~DL~t ~
~ Ln _ __ ~
~l ~ r~
Ln bt . L~
a) r~l ~ r--i O ~I L~t O O ~ ~
h ~ t ) ~ O . \ O ~ - ,:
- O (~t ~ ~ ~ O O ~ O r~
~1 ~ / O ' 1:0 ~ r~ ~D ~ ri ~1 U~ / ~ ~t ~ r ~ Llt IL)r-l \ ^ . ~ j ~ I 1 ~3 1 -L~ O \ c ~ _ ,q ~(~Io ~ o r~ O
~ r~ r~J c~ r~a~r~iOC~ c~ r~ Ln ~rt o--U --tr; -- _ _ -P; .
~ X ~1 rtrt~t r~t ~t r~t r~
U~r~ E-l ~
~ rn ~ r~
r~ : ~ :
~) r~

h r~ .

.; ~ : . ~
.

,: \ ~

71~

___ ~
o o o u~ !
~ r~ a~ r~ !
r-l ~1 r-l r I h r--I r~ I Q
u) o o o ~n o ~-1 oo r~ r.~ oo rra O r--I H r-l r~l ~1 r-~ I r-l r-l r-l r~
~ --__ ~
~ :' ~; O O O O O
~:qU~ O U~O Ll'l ~_1 O U~ 'l Ir~ r~ rf ~ r~l r~

. _~____ _ I I I I $
~~ '~ ~ (~) NC~ . r-l ~i r J ___ __________ ____. O

_-~ ~
~r~ ~: ~n t`J C) _. O ~ ~ ~
rc~ E-~ ~I,~ ~ I I ¦
_ u,~ ~r~o r~ ~0 F~' ~ r~rs~ ~_1 rl O U~ Lrir--I - rl U H ~ ~ U~ r-l pE~
~ ~rx~ O O
_____ ~U ~; ,~ ~ 1 r-l I¢ ~ N O O f ~ td Q rx~ r~ 'd O ~ h O ~ O toJ) D I I I ~O ~ ~ :

r ~ ~ Q h ____ __ ______ __ r~ rcl ~

In L( )>.~ r I ~H vq O O r-l 4 ~ ~r~
~ o o E~ ~ ';J~ ~ C4 ~H
~ r~ O:~ ~ r~l ~rl O r-l r~l ~ O ~J O ~1 . ~ ~13 ~ 0 ~r-~
~ ~ I ~
Q r~ ~ o ,~ r.~ r~3 ~' N _ _ ~_ / ~ r~
Pi i II I
~ r~ r~ r~l r i~ N ~ }~ ~ ~ ~
~ C~ (J
_._ ~:
.~ ~;~ 1'' ~
. . a~. a) I ~
.. __~ O X ~ 4 , ~ 49 ~
;~..

:
..

8~

Example 13 (a) Preparatlon_of 1-(6'-methoxycarbon~ 2-; t3"-hydroxy-3"-me-th~ n-non~ 4-me-thyl-],2,4-triazolidine-3,5--dione. (29) (by procedur _ y~ / (CH2) 6C02Me ~:

o)~--N ,~ ~ 6 13 OH
To a solution of l-(6'-methoxycarbonyl-n-hexyl)-4-Methyl~
1,2,4-triazolidine - 3,5-dione(26)(6.428g, 0.025 mol) in hexa~
~ methylphosphOramide (40ml~ was added sodium carbonate (3.18g, ; 0.03 mol), sodium iodide (lg, 0.007 mol) ancl l-(p-toluenesul- ;~ ' phonyl)-3-methyl-nonan-3-ol (8.204y, 0.025 mol) in hexameth~l-phosphoramide (30ml) and the resul-tant mixture stirred at room temperature for 70~hr. The reaction mixture was then poured into water (200rnl), acidified with 10~ hydrochloric acid and extracted with ethyl acetate (3 x 2Q0 ml3~. The ccmbilled extracts -~
were washed with water (3 x 250 ml) saturated sodium chlorlde solution (3 x 250 ml) and then drled (Na25O4). This mixture was filtered and the filtrate evaporated in vacuo to remove ~ ;~
ethyl acetate to leave a gurn (9 54g). Thi~ gurn was chromato-graphed on silica gel (Merck Kieselgel 60) ~500g) usinq chloro- ;
form:I;nethanol as eluant (0~2~ methanol) to afford 1-(6'-methox~
-carbonyl-n-hexyl)-2-(3"-hydrox~-3"_methyl-n-nonyl)-4-meth~
2-4-triazolidine-3,5--dione(2`9) ~(2.95 g) as a gum. -~;~
found: C, 60.51j~H 9.72; N, 10.05 . ~ ~
~; C21H39N3O5 requires C, 60.99; H, 9.51; N l0.16 NMR (CDC13~ 6.35s,~ 6.36m, 7H, -CO2CH3, (N-CH2)2 ; 6.96s, 3H, N CEI3;
7.46-7.84, 3H, CH2-CO2Me; - OH ~
' ~ ~' '' ~ 50 ~
~' :. ~

8 . 01-8 . 90 m, 3 O 81s, 9 11 m, 26H, ~CE-I 2~o ~ CE~ 3 C ' 2C - 3 IR (cm ): 3500, -OE-I; 1770 -N-C; :L680-1.740 -N-C-, C0 2Me .

~, .
MassSpec:found M 413.2829. Calc. M 413.2769.

" :

,' ~

,~ :' .

:' ' ~'' :

~ '~

(b) Pre~aratio~ o~ ~- 6'-methoxycarbon~L- hexyl)~2-(3"-hyclroxy-3"-cyclopro~yl-~ 1-1,2,4-_ _ triazolidille-3,5,dione ~ ~ ~ 2) J (CH ) CO CH
CI-I3_N N
~3 OH

(6) To a solutlon of 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl- ;~
1,2,4-triazolidirle -3,5-dione (2.0~, o.no78 mol~ in N,N-dimethyl-formamide (20ml) stirred at room temperature was added portlon-wise sodium hydride (0.26 ~, 0.0087 mol) as an 80% dispersion in mineral oil and the mixture stirred for 0.5 hr at room tempera-ture. To this solution was added anhydrous llthiumiodide (2.3 ~, 0.017 mol) and the resultant mixture stlrred for a further 0.5 hr at room temperature. To this resultant solution i was added l-(p-toluene sulphonyl)-3-cyclopropylbutan-3-ol (2.22~, 0.007~ mol) in N,N-dimethyLformamide (20ml) and the reac-tion mixture was stirred for ~4 hr at 50. The reaction mixture was then poured into water (200ml), acidified with 10% hydroc}lloric acid and extracted with ethyl acetate ~3 x 250 ml).. The combined extracts were washed with water (3 x 250 ml) and saturated sodium chloride solution (2 x 250ml) and then dried (Na2S04), filtered and the filtrate evaporated in vacuo to remove ethyl acetate -to afford a ~um (3.51a).
'' ' ' . ' ' ' ; ~
- -..

T}lis gum was chromatographed on silica cJel. (Merck Kieselc3eL 60, 200g) usin~ chloroform:methanol as eluant (methanol 0-2rJ) to afford 1-(6'-methox~carbonyl-n-hexyl)-2-(3"-hydroxy-3"-c~_ o~ pyl-n-but~1)-4-meth~-1,2,4-triazolidine-3,5-dione (35) c~s a gum (558 mg).
The l,2,4-trisubs-tituted-1,2,4-tria~oli~ine-3,5-diones yiven in Table 6 were prepared in a similar manner using either procedure (1) or (2); except (i) the acids (wherein R~-H) which were prepaxed by the procedure illustra-ted in ~:
~:~ 10 Example 14, and (ii) the unsaturated olefinic analogues (wherein Y is CH=CH) which were prepared by the procedure `~
illustrated in Example 15.
: The characterising data for these compounds is given in a separate section.

.
~.; ` ' ... . .

: ~ 53 - :

. .

;, :
i: ~
: , ~ . ~' ::,,: ' , : ~ : : : : - , : ~ ,..... ,, . ~;: , ~ :

7t~
Table 6 1,2,4-trisubstituted-1,2,4-triazolidine-3,5-dione~3 R5 J~ ,CIi2~Y-(cll2) --/R >~ R

No ~ R~ R2 R3 R5 y n Procedu-re _ __. _ 29 CH3 C113 Oil C6il13 Cil3 C~12- C1~2 3 1 30 Ctl3 CH3 Olt CGH5 C~13 Cil2- CH2 3 1 31 CH3 Ctl3 OHC6H5 ~H13 C113 C1~2- C~-12 3 1 32 Cil3 CH3 OHC4H9CH- CH3 Ci-12- Cil2 3 1 33 CH3 CH3 Oll Cil3 CH2- CH2 3 1 34 Cil3 Cl-13 OH~Me Ctl3 Ctl2- Cilz 3 1 3 5 C H 3 CH 3 Otl A Ctl 3Ci ~ 2 - Ctl 2 3 2 ~:

36 .Cil3 CH3 OHC9tll9 C113 CH2- CH2 3 1 37 C l3 Ctl3 OHMeO--<~ CH3 Ci-12 ~ CH2 3 38 CH 3 CH 3 Otl (~)"`~)~ CH 3 CH = Cl l 3 1 39 CH3 CH3 OHF~(~) CH3 C~12- ci~2 3 1 CH 3 Ctl 3 OH CH 3 CH 3 CH 2 ~ C H 2 3 1 41 H CH3 OHC6tll3 . CH3 CH2- Cl-12 3 - ~:

42 H CH 3 OHC6H 5 CH 3 CH 2 - CH 2 3 ~

43 CH3 CH3 OHC6 13 CH3 CH = CH _ :

- i --5 4--~' ~. .

Table 6 continued , _ _ __ _ _ _ No: R1 R2 R3 R4 R5 y n Proced~re _ il-- __ _ _ __ ..
44 H Cil3 Ol-iC6H13 Cil3CH= CH 3 _ CH3 Cil3 OHC61-113 Cil2- Cil2 3 1 46 C113 Cil3 OilC6ill3 PhCii2~ C~12 3 1 47 Cil3 Cl-13 OHC6ill3 CH3~ ~Cil2- Cil2 3 1 48 H CH3 OHC6H13 CH3 ~Cli2- C112 3 49 CH 3 CH 3 OH _ PhCH2CH= CH 3 , . : . . ' .

,:
' , . ' ' ' ~.

~ 55- :
',': ' "',~ , Example 14 ~lf~187~

Preparat.~on of 1~(6'-carbox~~n-hex~1 ? - 2- ( 3"-h~dro~y-3"-methyl-n-non~ 4-methyl-1,2,4-trlazoli.dine 3,5-dione (41) tCH2)6C02a ~ ~, \ / ~ 6 13 To a solutlon of 1-(61-methoxycarbonyl-n-hexyl)-2(3"- ;
-hydroxy-3"-methyl-n-nonyl)-~-methyl-1,2,4-triazolidine-3,5-dione (5) (2.423g, 0.006 mol) in methanol ~lOOml) was added a 10~ aqueous solution of sodium carbonate (30m1) and the mixture boiled at reflux for 18 hr. The reaction mixture was cooled and evaporated in vacuo. The resiclue was dls.solved in water (lOOml) and extracted wlth ether (3 x lOOml). The ~ :
aqueous phase was then acidified with 10% hydrochl.oric acid and re-extracted with ethyl acetate (3 x 200ml). The com~ined extracts were washed with saturated sodium chloride solution .; :
(2 x 200ml) dried (Na2SO,~)I filtered and the filtrate evapora~
ted in vacuo to remove ethyl acetate to afford 1-(6'-car~oxy-n- ~ :
-hex~l)-2-(3"-hxdroxy-3"-me ~ 1)-4-methyl-1,2,4-tria-zolidlne-3,5-dione (41) .lS a gum (2.404g).

~:

~,:

,: .
; ~ '`

., . ~

~ 37~t :

Examp e :LS

repara-tion of 1-(6'-methoxycarbonyl-n-hex~ 2-enyl)-2-(3''-hydroxy-3''-methYl-n-nonyl)-4-methyl-ll2~4 -triazolidine-3,5-_1one ~43) was carried out as in Procedure (1) o~
Example 13 using 1-(6~-methoxycarbonyl-n hex-2-enyl)-4-methyl-1,2,4- triazolidine-3,5-dione instead of 1-(6l-methoxy-carbonyl-n-hexyl~-4-methyl-1,2,4-triazolldine-3,5 --ione.

~ .

: ' .

,., - ' ' ~ ~

, ~,. :

.

.
... .
, CHARACTERISING DATA_FOR COMPOIJNDS GTVEN IN TABLE6 '.
' :' .

Compound 30 NMR (CDC13) ~ : 2.45-2.82 brm, 5H, -C6H5, 6.295l 6.30-6.77 brm, , 02CH3, ~N-cH2t2~ 70015, N-CH3, 3H,

7.25s, lH, -OEI (exchanged with D20), 7.51-8.09 m, 8.41 s, 8.69 brs, 15H.
3500, -OII ; l660~1770, N-~- , C02Me, N-C-, :
Mass Spec. found M+ 405.2258 Calc~ C21~l3IN305 405-22S2 Compound 31 - ~;
'' ~ ,'' Analys~s:
found: C, 62.Sl, ~I, 8.23 , N, 9.96%
C22H33N305 requires C, 62.99; H, 7.93 N, 10.02%
. ' :
NMR(cDcl3) r 2.75 s, 5I~, -C6H5, 6.32m, 6.36s, 7H, (N-CH2 )2' C02CH3, 6.96s, 3H, -N-CH3, 7-23s~ 2H, C6HsC_2 -, 7~.54s, 7.70t, ~ ~ 3H, -OH, CH2C02Me, 8.09-9.08m, 8.81s,-(CH2~5, -~ CH3 C-OH, 13H-,; :

" ,~

.,,~

, , : . ~ :: ,, ~ . :
:. , : .~ . . .
.: . - . . . .
:
: : ~ : . : .: , -L8`~
~t n IR(cm )~ 3500, -OH, 1765,-N-C~, 1680-1745, N C , CO2 3 MASS Spec: found M 419r2429 Calc. C22H33N3OS: 419.2420 _ __ C~mpound ,~ _ NMR (CDC13) ~: 6.32m, 6.34 s, 7H, (n-CH2~ , CO2CH3;
6.95s, N-CH3, 3H; 7.75m, 3II,-OH, CH2C02Me, 8~1-9.4rn, 8.88s, 26H, -(CH2~8 , C_-CH3, C -~C-OH, C_3-CH2.
IR~cml) : 3500, OH, 1765, -N-Cj 1740, CO2Me, 1685-1710, N-C

Mass S~ec. found M CalC. C21H39N35 413~2959 413O2~389.

Compound 33 NMR (CDC13) ~: 6.31s, 6.37m, 7H, CO2Me, -(N-CH2~2, 6~93s, 3H, N-CH3; 7.67m~3H, -O_, CH2CO2Me 7.98-9.30m' 8.86s, 24H~ -(cH2~l0l CH-CH2, CH3-C-OH.

,:
, ,...... ..

:

- IR (cm1 ) : 3500, -OE~ , 1760, N-~-, 1680-1740, N- , C O2 Me , Mass Spec, found M 411.2690 Ca1c . M C21EI37N35 411.2647 Compound 34 Analysis found, C 63.34 , H, 7.71 ; N 10.0:8 %
C22H33N3O5 requires C, 62.99, E~, 7.93, N, 10.02%

NMR (CDC13) `S: 2.60--2~93r1l~ 4H, C6_4, 6.33 s, 3H, -CO2CEI~;
6.58 brt, 4II, (-NCE12) 2 ~ 7 04s, 3H, -N-CH3, 7.66s, 7.50-8.68 brm, 8.45s, 19H, C6EI5-CEI3, -OH, ( -CH2- ) 6 ~ CE~3- 1l C
.'!'~ IR (cml): 3550, -OH, 1680-1770, N C, CO2CH3, N- -ass SPec. found M~ 419.2446 Ca1cd- M C212H932N42oS
Com~ound 35 .~

, . ' ~ ' NMR (CDC13) ~! 6.00-6077 brm, 6.35s, 7H, (l~r-C_2)2/ -C02CEI3, 6.96s, 3~, N-CEI3, 7.69 brt, 3H, -OH, C_2CO2Me r ` 8-0-9-37 brmi 8.82s, 14H, (CEI2) 5, CEI3, CEI~, 9 ~ 4_ 9 8 brm ~ 4H, ( CoH 2) 2 ll f IR (cm ): 3500, -OH, 1760, -N-C, 1720, -CO2Me: 1690,-N-C
Mass Spec: found Mass 369.2246 Calc. mass 369.2247.
, .

~ ~ -60-. , , ~ ~ .

7~
.

Compouncl 36 AnaLysis: Found: C, 62.90; H, 9.74; N~ 9.26%~
C241145N3O5 reclu1res: C, 63.27; il, 9.95; N, 9~22X~

NMR (60 Mllz, CDC13)~ : 6.0-6.45 m, 6.35 s, (N-Ct!2)2, -CO~CH3;
6.95 s, 3H, N-C~13;
7.5-7.85 m, 3H, C~12CO2C~13, Otl;

8.0-8.8 brm, 29H, 9.1 brt, 3H, -Ctl3.

I.r. (cm ): 3550, -OH; O O
1680-1780, N-C, -CO2Me, N-C-~.

Compound 37 Analysis: ~ouncl: C, 60.49; H, 7.92; N, 9~52%~C22H33NlO6 requires: C, 60-67; H~ 7-64;

NMR (60 MHz, CDC13) ~: 2.6-3.25 rn, 4H, -C6H4;
6.2 s, 3H, -OCH3; 6.35 s, 3H, CO2CH3; ~`
6.4-5.8 m, 4tl, (N-CH2)2;
7.05 s, 3H, N-CH3; 7.45 brs, 1H, -OH;
7.6-8 2 brm, CH2-C(OH), C~12CO2Me;
1 8.2-8.9 brm, 8.46 s, 11H, (CH2)4, Ctl3-C-OH-I.r. (cm ): 3500, -OH; O O
1660-1780, N-C, CO2Me, N-C.
~,:. :

:.i .. : , . . :
,, :: :
'' ~ 7~

Com~ _38 NMR (fi0 Milz, CDC13) r: 2.0-2.62 m, 7H, -C1oH7; 4.62 brq, 2H, -CH=CH; 5.93-6.13 brm, 2H, -CH2-CH-Cli; 6.34 s, 6.23-6.60 brm, 6H, CO2CH3, N-C112, -OH; 7.18 s, 3H, -NCH3; 7.62-8.50 brm, 8.34 s, 11H.
O , O
I.r. (cm ): 3500, -OH, 1660-1-80, N-C, CO2CH3, N-C.

' " ' ' ~.:
`: :
~' ., ~

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

.

~ o Compound 39 NMR (CDC13, 60 Mllz) r: 2.47-3.15 M, 4H, C6H4;
6 36 s, 6 36-6 74 brm, 6.90 brs, 7,04 s, llH, -C02CIl3, -(NC1~2)2, ~ N-C~13;
7.55-8.15 brm, 8.30 8.90 brm, 8.50 s, 15H, (CH2)6, -CH3.
O O
Il 11 I.r. (cm ): 3500, -OH; 1660-1780, N-C-, C02Me, N-C-;
1602, aromatic Mass Spec. Meas. mass, 423.2198; calc. mass, M , 423.2170.

Compound 40 NMR 9C~C13, 60 MH~)r: 6.12-6.58 brm, 6.30 s, 7H, (N-CH2)2, -C02C113;
6.91 s, 3H, -N-CH3;
7 50-8.90 brm, 8.70 s, 19H.
1l I r (cm 1): 3500, -OH; 1760, N-C;
o 1680-1740, N-C, C02Me Mass Spec. Meas. mass, 343.2047; calc. mass, M , 343 2107 -- :
' Compound 41 Analysis: ~ound: C, 59.61; H, 9.57; N, 10.38%.
C20H3705N3 requires: C, 60.13; H, 9.33; N, 10.52%.

NMR (60 Mllz, DMS0)~ : 6.2-6.7 brm, 411, (N-CH2~2;7.09 s, 3~, N-C~I3;
7.81 brt, 2H, Cl-l2C02~l;
8.2-9.4 brm, 9.93 s, 9.12 brt, 26H, ~CH2jl0, I .r . (cm ): 2500-3500, 011, 1770, N-C-1660-1760, N-C-, C= 0 O

Mass Spec. Meas. mass 399.2688; calc. mass 399.2734.
, ' Compound 42 Analy~_s: Found: C, 60.93; H, 7.62; N, 10.72V/o.
C20H2gN305 requireS: C~ 61-36; H~ 7-47; ~ ~;

NMR (60 Milz, CDC13~ 1 2.5-2.85 brm, 5H, -C6H5; 3.72 brg, 2H, C02H, OH;
6.15-6.85 brm, 4H, (N-CH2)2; 7.05 s, 3~1, N-CH3;
7.50-8.15 brm, 8.44 s, 8.72 brs, 15H.
11 ~ O O ....
i I.r. (cm ): 2500-3500, -OH; 1660-1780~ N-C, C ~ N-C .

Mass Spec. Meas. mass M 391.Z116; calc. mass 391.2107.

,~ ~

.

~ 7~

Compound 43 _ NMP~ (60 MHz, CDCL3)~: 3.92-4.92 m, 211, CH~Cil; 5.84 d, 211, J=Siiz, Cil2-Cll-Cil-;
6.26 rm, 6.30 s, 5H, -N-Cil2, -C02CiZ3;
6.9L s, 31-l, N-CH3; 7.55-8.82 m, 8.76 s, 9.06 m, 25H.
O
I.r. (cm ): 3600, OH; 1770, N-C;
; 1770-1750, N-C, C02Me.

Mass Spec. Meas. mass (for M -C6H13), 326.1700;
Calc. mass, 326.1716. No M+.

Compo~lnd 44 NMR (CDC13, 60 MHz)~-: 4.20-4.60 brrn, 2tl, Cil=Cil; 4.90 brs, 2il, -C02il, -OH;
5.85 brd, 2H, N-CH2; 6 10~6.45 m, 211, N-Ci-12;
, , CH3; 7-50-9.20 bFm, 8.77 5, 9.08 brt.

I.r. (cm ): 2600-3500, -OH; 1760, N-C;
O O ::
1660-1750, N-C, C-0.

Mass Spec. Meas. mass, 397.2573; calc. mass, 397.2577.

' :
: , :

.
. . . .
.

~ 7~ ~ ~

Compound 45 NMR (CDC13,60 Mll~ 5 5-5,7 brt, 1H, Ctl-N;
6.1-6.65 brt, 41-l, (-NC~2)2;
6-35 s, 3H, C02CH3; 7 55-7.85 m, 311, Ctl2C02CH3, OH;
7 85-9 0 m~ 33~ (C~12)4, C5tl10-Ctl-N, (Clt2)6, _3;

9.1 m l 3~1, Cll2CH3 Il :
I.r. (cm ): 3500, 011; 1660-1780, (N-C)2, C02Ctl3.

Mass spec. Meas mass, M, 481.3539; calc. mass, M, 4B1.3516.

Compo~lnd 46 NMR(CDC13, 60 Mtl~)r : 2.55-2 65 m, 5H, C6H5;
6.05-6.5 brt, 4tl, (-NCH2)2; ~;
6 33 s, 3tl, C02CH3; 7.55-7.a5 olt~l 3H~ --2 2 3' --7.85-9.0 m, 23H, -(CH2~4~ ? CH2 C 5--10;

~; 9.1 m, 3H, CH2CH3 -,: ' ' O
I.r. (cm ): 3500, OH; 1680-1780, ~N-C)2, C02Ctl3.

Mass spec . Meas . mass , M , 475,3027; calc . mass , M~, 475 3008.
.

: : : ' . .

'~

:: ;, , .' :
~' ~` ' ' , Compouncl 47 ~: Found: C, 65.96; tl, 8.56; N, 8.26%.
C271143N3O5 requlres: C, 66.23; H, 8.85; N, 8.58%.

NMR (C~C13, 60 MHz) r: 2.6-2.9 m, 4tl, C6H4; 6 0-6.45 brt, 4tl, ~(NCH2)2;
6.35 s, 3tl, CO2CH3; 7.5-7 8 m, 3H, Ctl2CO2CH3, OH;
7.6 s, 3tl, C6tl4C1-13; Otl 7,8-9.0 m, 23H, -(CH2)4-~ Cll2-1C-C5tl10;
9.1 m, 3H, cH2c~13. CH3 o I.r. (cm ): 3500, OH; 1680-1780, (N-C)2, C02C113;

Mass Spec. Meas. mass, M, 489.3237; calc, rnass, M~, 489.3203.

Compound 48 NMR (CDC13, 60 MHz)~: 2.6-2.9 m, 4H, C6~; 4.1 s, lH, CO2H;
6.05 6.4 , , --2 2 7-65 s, 3tl~ c6tl4c~l3;
7.65 7.8, 3 ~ --2 2 3 ' ~OH
7 8-9.0 rn, 23H, - (CH2)4, CH2-C-C5Hlo;

9.1 m, 3H, CH2C113. 3 O
I .r . (cm ): 3400, Otl, C02H; 1680- 1780, (N--C) 2 ~ CO2H .

Mass Spec. Meas. mass, M, 475.3046; calc. mass, M, 475.3046, .~' .

, ~ ' .

. .
: ' ; ' ound 49 NMR (CDC13, 60 MHz,~ 2.68 brs, 5H, -C6H5;
4.02-5.04 brm, 211, CH=CH; 5.34 brs, 2H, CH2Ph;
5.62-6.05 brm, 2H, N-CH2-;
6.18-6.44 brm, 6.35 s, 51-1? N-CH2, ~C02CH3;
7.50-9,30 brm, 8.82 s, 25H.
O O
I.r. (cm ): 3550, -0~1; 1660-1770, Il-C-, C02Me, N-C- .

Mass Spec. Meas. mass, 487.3071; calc. mass, M, 487.304$.

.

..
' ~ ~

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

:
- .
:: .

:: .
:: . : ~ .

-, :: . . . , . .~ . :
: :: ;
.
: . :, 87~ ~

Pl-lARMACOl.OGICAL DATA

Bronchodil~tion Activity The cornpounds were examined for their abil.ity to inhibit 5-hydroxy- .
trypcamine or histamine induced bronchoconstriction in the anaesthetised artificially respired guinea-pig (Konzett-Rossler preparation).

The ED50 values (~gtkg, i.v.) for inhibition of bronchocon:striction for a variety of the tria~olidine-3,5-diones are given in Table 7.

Table 7 ~ .
Compound ~g/k~5 i.v.
29 2.6 31 37 :: .
32 0.74 : 43 1-9 24 ~.O

Anti-p.latelet Aggregation Activity 1-(6'-ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-phenyl-.
1,2,4-triazolidine-3,5-dione (il) inhibited col.lagen induced aggregation in h~lman platelet rich plasma.

"- . ' .

, . . ~ . .

Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of formula and salts thereof wherein X is a group of formula -CH2-Y-(CH2)nCO2R1 wherein n is 1 to 5; Y is -CH2-CH2 or -CH=CH-; and R1 is hydrogen or C02R1 represents an ester group in which the R1 moiety contains from 1-12 carbon atoms;
or X is a group of formula wherein R2 is hydrogen, C1-4 alkyl or phenyl; R3 is hydroxy or protected hydroxy; or R2 and R3 taken with the carbon atom to which they are joined represent a carbonyl group;
R4 is hydrogen, C1-9 alkyl, C3-8 cycloakyl, C3-8 cycloakyl, C3-8 cycloakyl-C1-6 alkyl, or any of which phenyl moieties or naphthyl moieties substitued by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, hydroxy, C1-6 alkoxy, phenyl-C1-6 alkyl, hydroxy, C1-6 alkoxy, phenyl-C1-6 alkoxy or nitro groups;
or R2 and R4 taken with the carbon atom to which they are joined represent a C5-8 cycloalkyl group;
and wherein;

R5 is hydrogen, C1-6 alkyl, C5-8 cycloalkyl, phenyl, phenyl-C1-6 aIkyl or phenyl C3-6 cycloalkyl, or any of which phenyl moieties substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
which comprises (i) when X is -CH2-Y-(CH2)nC02R, as defined, reacting a compound of formula (XV11) (XV11) wherein R5 is as defined with a compound of formula wherein n and R1 are as defined and, if required, converting R1 in the resulting compound from hydrogen to an ester group as defined, and reducing said resulting compound where Y is -CH=CH- to the corresponding ccmpound wherein Y is -CH2-CH2-and recovering the required compound;

(ii) when X is a group of formula wherein R4 is as defined reacting a compound of formula (X111) (X111) wherein R5 is as defined with a strong base and a compound of formula (X1V) wherein R4 is as defined (X1V) and recovering said compound;

(iii) when X is a group of formula reacting a compound of formula (X11) (X11) wherein R4 and R5 are as defined with a reducing agent and recovering the required compound;
(iv) when X is a group of formula wherein R4 is as defined, R2 is C1-4 alkyl or phenyl and R3 is hydroxy or protected hydroxy, reacting a compound of formula (X11) wherein R4 and R5 are as defined (X11) with a C1-4 alkyl or phenyl Grignard reagent or C1-4 alkyl or phenyl metallic complex and recovering the required compound and if required protecting the hydroxy group;

(v) when X is a group of formula wherein R2, R3 and R4 are defined, reacting a compound of formula (X111) wherein R5 is as defined with a compound of formula (XV1) (XV1) wherein R2, R3 and R4 are as defined and D is a group readily removed by nucleophiles and recovering the required compound;
and where required after process steps (i), (ii), (iii), (iv) or (v) converting the recovered compound to a salt thereof.

2. A compound of formula and salts thereof wherein X is a group of formula -CH2-Y-(CH2)nCO2R1 wherein n is 1 to 5; Y is -CH2-CH2 or -CH=CH-; and R1 is hydrogen or CO2R1 represents an ester group in which the R1 moiety contains from 1-12 carbon atoms;
or X is a group of formula wherein R2 is hydrogen, C1-4 alkyl or phenyl; R3 is hydroxy or protected hydroxy; or R2 and R3 taken with the carbon atom to which they are joined represent a carbonyl group;
R4 is hydrogen, C1-9 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, or any of which phenyl moieties or naphthyl moietie may be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, hydroxy, C1-6 alkoxy, phenyl-C1-6 alkoxy or nitro groups;
or R2 and R4 taken with the carbon atom to which they are joined represent a C5-8 cycloalkyl group;
and wherein:
R5 is hydrogen, C1-6 alkyl, C5-8 cycloalkyl, phenyl, phenyl-C1-6 alkyl or phenyl C3-6 cycloalkyl, or any of which phenyl moieties substitut by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
when prepared by the process of claim 1 or an obvious chemical equivalent.

3. A process for the preparation of the compound 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione which comprises reacting 4-methyl-1,2,4-triazoline-3,5-dione in an inert organic solvent with hept-6-enoic acid, recovering product 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine-3,5-dione and reducing said product with hydrogen in the presence of Pd on charcoal catalyst and a solvent and recovering the required compound.

4. 1-(6'-Methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione when prepared by the process of claim 3 or an obvious chemical equivalent.

5. A process for the preparation of the compound 4-methyl-2-(3'-oxo-nonyl)-1, 2,4-triazolidine-3,5-dione which comprises reacting 4-methyl-1,2,4-triazolidine-3,5-dione with non-1-en-3-one in a solvent in the presence of sodium hydride andrecovering the required compound.

6. 4-Methyl-2-(3'-oxo-nonyl)-1,2,4-triazolidine-3,5-dione when prepared by the process of claim 5 or an obvious chemical equivalent.

7. A process for the preparation of the compound 2-(3'-hydroxy n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione which comprises reacting 2-(3'-oxo-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione in a solvent with sodium borohydride and recovering the required compound.

8. 2-(3'-Hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione when prepared by the process of claim 7 or an obvious chemical equivalent.