CA1040647A - Intermediates for novel 3-amino-prop-1-enes - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel intermediates and their process of preparation are provided which are useful in the preparation of substituted 3-amino-prop-1-enes which have a trypanocidal effect and can be used in the treatment of infections caused by Trypanoaoma cruzi, for example, Chagas' disease, the intermediates have the formula (V)

Description

104~47 Thi~ invention relates to novel intermediates useful in the preparation of novel substituted 3-amlno-prop-1-enes This application is a division of Canadian Patent 1,009,255, issued April 26, 1977.
There are described in the parent Canadian Patent 1,009,255, novel substituted 3-amino-prop-1-enes which have been found to have a trypanocidal effect; in particular, they have been found to kill rypanosoma cruzi when administered to mice infected with this organism.

Infections by Trypanosoma cruzi, are fairly common in South America causing Chagas' disease in humans, which disease has heretofore proved to be extremely difficult to treat effectively.
The substituted 3-amino-prop-1-enes described in the aforementioned Canadian patent application have the formula (I):

\ C = CH - CH2 - N
R2 / \ R4 (I) where Rl and R2 are the same or different and can each represent a halo-substituted or unsubstituted biphenylyl group, fluorenyl group, or halo- or nitro substituted or unsubstituted phenyl groupj with the proviso that both of Rl and R2 cannot rep~esent a halo-substituted biphenylyl group or a halo- or nitro sub-stituted or unsubstituted phenyl group, and that when one of Rl and R2 represents a halo-substituted biphenylyl group the other I represents a halo- or nitro substituted or unsubstituted phenyl group; and R3 and R4 are the same or different and can each represent a hydrogen atom, an alkyl group having from 1 to 4 : carbon atoms or a benzyl group; the salts thereof, especially ~ 30 the pharmaceutically acceptable salts thereof are also described.
q~

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

~040~
As mentioned above one or both of the R3 al~d R4 substituents may represent benzyl groups.
Examples of halo suitable substituents are fluorine, chlorine, bromine and iodine.
Compounds in which Rl represents a substituted 4~
biphenylyl group and R2 represents a substituted phenyl group `
have been found to be highly active. Such compounds exhibit geometrical isomerism and it should be noted that the cis isomer, i.e. the isomer of formula (II) ~' .

\ C = C (II) --

2 /
R H

where Rl, R2, R3 and R4 are as defined above, generally shows a higher activity, in some cases a much higher activity, than the corresponding trans isomer of formula (III) R H
C = C (III) R2 / \ CH2NR R

which, in some cases, may have only a low activity against Trypanosoma cruzi infections, This property also applies to other compounds of the invention where the possiblity of cis (the larger Rl/R2 group being on the same side of the double bond as the CH2NR R group) and trans (the larger Rl/R group being on the opposite side) exists. For example, compounds of formula (IV) .~

.
- : .. :
.

i0~0647 R C( ~ C /~ Cd21~R R

C = C (IV) R10~ 1)/ \ H

where R3 and R4 are as defined above, R10 is a hydrogen or halogen atom or nitro group, Rll is a hydrogen or halogen atom, and wherein R10 and Rll may be the same or different have been ~-found to be of notably high activity.
Compounds in which R and R are identical do not exhibit geometrical isomerism. In this class of compounds those in which Rl and R2 both represent biphenylyl, preferably 4-biphenylyl, groups ar~ particularly of note. Two such compounds are 1, 1 - di(4-biphenylyl)-3-dimethylamino-prop-1-ene, and 1,l~di(4-biphenylyl)-3-methylamino-prop-1-ene.
In the above classes of compounds where Rl and R2 are both biphenyl groups R3 and R4 may represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, with the proviso that both R3 and R4 should not represent hydrogen.
There is some evidence that as the size of the alkyl group in R and/or R is increased, the activity of the com- -pounds tend to diminish. Accordingly, compounds where R3 and R4 represent hydrogen atoms and/or methyl groups are provided in a preferred embodiment of the invention.

, .
:

.

,, -~04~)647 Several methods for preparing the compounds of formula (I) are described in the aforementioned Canadian patent application, but one has been found advantageous. This method comprises :~

reacting a compound of formula (V) :

Rl '',:' C - CHM (V~ -~

Q G

where Rl and R2 are as defined above, as specified hereunder:
(a) when Q and G taken together represent a single bond, (i) when M represents a nitrile group; a :
group of formula CYNR R where Y is an oxygen or sulphur atom, a group of formula CH2A where A represents the group -NC, -NR3CoR9 or -NR COOR
where R represents an alkyl group having .
from 1 to 4 carbon atoms and where R9 represents a hydrogen atom or an alkyl , group having from 1 to 3 carbon atoms;
selectively reducing the compound of ' 20 formwla (V) so that the double bond in the RlR2C = C moiety remains unreduced, .`. . :~

,~ .
.

`

~040647 (ii) when M represents a group of formula CH2Z, where Z represents a leaving group, readily displaceable by an amino group, for example, a bromo or tosyloxy group, reacting the compound of fonmula (V) with an amine of formula HNR R4, (iii) when M represents a group of formula CH2NR3R4, where one or both of R3 and R4 represent hydrogen atoms, mono or dialkyla-ting the NR R group, or (iv) when M represents a group of formula C~ NR B where B is a protecting group for . - amino, for example, an acyl group, remov-; ing the protecting group, (b) or when Q represents a hydroxyl group, G re-presents a hydrogen atom and M represents a ~ -group of formula CH2NR R eliminating a mole- . :
cule of GQ from a molecule of formula (V) The intermediates of formula (V) are novel and con-stitute an aspect of the invention.
` Thus according to the invention there is provided ~
a compound of formula (V) ~ ~ -Rl C CHM (V) R ~ 1 G
wherein Rl and R2 are the same or different and can each represent a halo substituted or unsub~tituted hiphenylyl, halo- sub~tituted or unsubstituted phenyl group, with the proviso that both of Rl and R cannot represent a halo-substituted biphenylyl group or a halo- substituted or unsubstituted phenyl group and that when :- 5 - :

- , ~ , ..

10406~7 one of Rl and R2 represents a halo-sub~tituted biphenylyl group the other represents a halo- substituted or unsubstituted phenyl ..
group and either (a) Q and G taken together represent a single bond, when M represents: (i) a nitrile group, a group of formula CONR R , a group of formula CH2A where A represents a nitrile group or a group -NR COR9 where R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and where R3 and R are the same or different and can each represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, (ii) a group of formula CH2Z where Z represents -:
a leaving group readily displaceable by an amino group, for example, tosyloxy or bromo or (b) Q represents a hydroxyl group, G represents a hydrogen atom and M represents a group of formula CH2NR R , where R and R are defined in (a)(i). : ;

According to another aspect of the invention there is -provided a method of preparing a compound of formula (V) R

C C~M (V) /t wherein Rl and R2 are the same or different and can each represent a halo-substituted or unsubstituted biphenylyl, halo- substitute~ or un~ub~tituted phenyl group, with the proviso that both of Rl and R2 cannot represent a halo-sub-stituted biphenylyl group or a halo- substituted or unsub- -stituted phenyl group, and that when one of Rl and R2 repre~ents a halo-substituted biphenylyl group the other represents a halo- substitu~ed or unsubstituted phenyl group, , ~ ~ - 6 -io40647 and either (a) Q and G taken together represent a ~ingle bond, when M represents: (i) a nitrile group, a group of formula CONR R ; a group of formula CH2A where A represents a nitrile group or a group -~R3CoR9, where R9 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and where R3 and R4 are the same or different and can each represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; (ii) a group of formula CH2Z where Z represents a leaving group readily displaceable by an amino group, for 10 example, tosyloxy or bromo, or (b) Q represents a hydroxyl group, G represents a hydrogen atom and M represents a group of formula CH2NR R , where R and R are defined in (a) (i), which comprises: A) when Q and G taken together represent a single bond, and M is a group of formula CH2Z where Z is a ~-tosyloxy group, reacting an alcohol of formula Rl C = CH . CH20H
/
R
with p-toluene sulphonyl chloride, or B) when Q and G taken together represent a single bond, and M is a group of formula : -CH2Br, reactingia prop-l-ene of formula (XXX) ., Rl .. \ . . .
~ ~H.CH3 (XICX) ` ' ;

~ _ 7 _ .~ ~
'' ' , ~ , :
. .

1046)647 with bromo succinimide and azobisisobutyronitrile; or C) when Q is a hydroxyl group, G is a hydrogen atom and M i~ a group of formula CH2NR R where R and R are as defined in a)(i) above, and Rl and R2 are the same, reacting an organometallic reagent of formula R T wherein T is a metallic component, with an ester of formula (XVI) R OOCtCH2)2 ~

R (xvI) wherein R3 and R4 are as defined in a) (i) above and R5 is an alkyl group of 1 to 4 carbon atoms; or D) when Q is hydroxyl group, G is a hydrogen atom, Rl and R2 are the same or different, and M is said group of formula CH2NR3R4 where R3 and R4 are as defined in a) (i) above, reacting an organo~
metallic reagent of formula RlT, wherein T is a metallic ~.
component, with a ketone of formula (XVII) :

( 2)2 \ R (XVII) wherein R2, R and R4 are as defined above; or E) when Q and G

taken together represent a single bond and M is a nitrile group or a group of formula -CO~R R , reacting a ketone of formula R
C = O

wherein Rl ~nd R are as defined above with a phosphorus compound of formula I
O = P - CH2X
~ OR

~04~)647 where X is -CN or -coNR3R4 and R6 is a lower alkyl group,. or F) when Q and G taken together represent a single bond and M
is CH2A where A represents a group -NR COR where R and R are defined above, reacting a compound of formula (I) Rl R

C = CH.CH2.N (I) :-R2 / ~ R4 ~ :
with an appropriate carboxylic acid of formula R9CooH.

In the case where M represents a nitrile group and Q and G represent a single bond, the compound of formula ; (V) has the structure (IX) (c.f. method (A) (a) (i)) ~ -~ 8a-- ,- : . : ' : '' - . , -, ,, . .
,:
, 10406i47 -C = CH CN (IX) R 2 : .
- '~' . ;'' Reduction of this compound leads only to the primary amine of formula (I) where R and R both represent hydrogen atoms. This reduction can be carried out using the process described by Jones and Maisey in J. Med. Chem. 1971, 4, 161.
When M represents the group CYNR R and Q and G
represent a single bond the compound of formula (V) has the structure C = CH. CYN (X) \
R2~ R4 When Y is an oxygen atom, (X) then being an amide, reduction may be carried out, for example, by means of a metallic hydride, such as sodium borohydride, lithium aluminium hydride, or by diborane. When Y is a sulphur atom, reduction may be carried out, for example, by means of a Raney nickel catalyst. The amides can be prepared using a procedure similar to that outlined in Chemical Abstracts 65, 615 g.
1966. The corresponding sulphur compounds can be prepared ` by reacting the appropriate nitrile with hydrogen sulphide in ethanol under pressure or by reacting the corresponding amide with P2S5.
When M represents the group CH2A and Q and G
represent a single bond the compound of formula (V) has the - structure (XII) (c.f. method (A) (a) (i)) :

_ g _ .' ~

.

~0406~7 R

C = CH. CH2A (XII) The compounds can be obtained from the correspond-ing amines using any appropriate conventional technique known to those skilled in the art. Reduction can be accomplished using, for example, lithium aluminium hydride.
When M represents a group of formula CH2Z and Q
and G represent a single bond the compound of formula (V) has the structure (XIII) (c.f. method (A) (a) (i)).
R \
C = CH. CH2z (XIII) R2,, : .

Compounds where Z rPpresents a bromine atom can be prepared from the corresponding prop-l-ene using N - bromo succinimide and azobisisobutyronitrile. Compounds where Z
represents a tosyloxy group can be prepared from the corres-ponding alcohol using p-toluene sulphonyl chloride. This alcohol, which has the structure RlR2C = CH.CH2OH can be prepared by the reduction of the ~,~ - unsaturated ester of formula RlR2C = CHCO2CH3 which can itself be prepared by a ~;
Wittig reaction between a ketone of formula RlR CO and di-ethylphosphonoacetate.

When M represents a group of formula CH2NR R where one or both R3 and R4 represent hydrogen atoms, and Q and G
represent a single bond, the compound of formula (V) has the structure (XI) (c.f. method (A) (a) (iii)) .
.

~ R~ ~ ~040647 R3 C = Cl-I. Cll2 N~ (XI) R2/ ``R4 Mono or dialkylation of this compound, as appropriate, can be carried out by methods well-known in the art. For example, monoalkylation can be carried out using the Forester- -Decker reaction (C.F. Name Index of Organic Reactions by Gowan and Wheeler, London 1960 Page 92). Complete alkylation can be carried out by treating the amine with a mixture of formaldehyde and formic acid. Obviously, this method can only be used to provide compounds of formula (I) in which one or both of R and ~ -R represent alkyl groups.
When M represents a group of formula CH2NR B and Q
and G represent a single bond the compound of formula (V) can be represented by the formula (XIV) (c.f. method (A) (a) (iv)) R
C = CH.CH2~NR B (XIV) R ~
; As examples of protecting groups there may be mentioned acyl and phenyl groups (the former being removable by any technique conventional in the art and the latter being removable by nitrosoation and subsequent treating with sodium ~i hydroxide). These compounds of formula (XII) can be easily prepared from the corresponding amines using standard , techniques.
When M represents a group of formula CH2NR R , Q
represents a nucleophilic group and G represents a hydrogen atom the compound of formula (V) can be represented hy the ; formula (XV) (c.f. method (A) (b)) l R3 R2~ C ~ 2 H2 / \ R4 (XV) .1, , ~ , , . . :
.
: . . .. . .

10406~ ~

In the above compound, it is preferred that Q be a hydroxyl group since the elements of water can be removed from :-such compounds simply by treatment with a strong acid such as ~ -.: .
concentrated hydrochloric acid in glacial acetic acid. Thus 1,1-di(4-biphenylyl)-3-dimethylamino-prop-1-ene can be pre- ~ .
pared by the dehydration of 1,1-di(4-biphenylyl)-3-dimethyl-amino-propan-l-ol.
Compounds of formula (XV) where Rl and R2 are the same and Q is a hydroxy gr~up, can be prepared by the reaction of an organometallic reagent of formula RlZ, where Rl is as defined previously and where Z is, for example, a magnesium halide or lithium, with an ester of formula (XVI) ~ ..

: j R3 . R OOC(CH2)2N .

\ R (XVI) or when Rl and R are the same or different a ketone of formula ~:
(XVII) R ::.
~ R2co ( CH2 ) 2N ~ .
` ~ 4 (XVII) R5 being an alkyl group, preferably one containing from 1 to 4 carbon atom~.

.
~, ' .

- 12 _ .
, , . ,, : . .... - .: `
.; , 104~647 Compounds of formula (V) in which Q is a hydroxyl group, G is a hydrogen atom, Rl and R2 are the same or different and are as defined previously, and M is a group of formula CH2NR3R4 where R3 and R are both hydrogen, can be prepared by reacting a nitrile of formula (XVIII) .: . .
Rl / C.CH2.CN (XVIII) R OH
.
with a mixed metal hydride.

When the preparation of compounds of formula (I), where both R3 and R4 represent hydrogen-atoms is-envisaged, the preferred routes of preparation are those classified . under the headings (A) (a) (i), (A) (a) (ii), or (A) (a) (iv~

~ as defined above.

.1, .

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

- 12a -:' ~ .
~.

. , : .
- .

~040647 For use in treating human infections of T. cruzi, it is estimated from data obtained from in vivo experiments with mice that doses of the compound of formula (I) which could be administered daily are of the order of 5 mg to 500 mg/kg, preferably 25 mg to 200 mg/kg, more preferably 50 mg to 100 mg/kg. For example, it is estimated that a dose of 50 mg/kg given daily for a month will prove effective against infections of T. cruzi.
Naturally, the dosage levels indicated above will be varied at the discretion of the physician according to the degree of infection and other attendant circumstances.
- The invention will now be illustrated with reference to the following Examples.

To the Grignard reagent prepared from magnesium (7.3 gO~ and 4-bromodiphenyl (69.9 g.) in ether (300 ml.) was added, at 0C, ethyl ~-dimethylaminopropionate (14~5 g.) ;~ in ether (50 ml.). After stirring under reflux for 3 hours the mixture was cooled and decomposed by addition of water (50 ml.), 25% aqueous ammonium chloride (50 ml.) and glacial acetic acid (42 ml.).
After standing overnight at 0C, the crude 1,1-di(4-biphenylyl)-3-dimethylamino-propan-1-ol hydrobromide was filtered off and washed with ether and water. The base, re-- crystallised from ethanol, had m. p. 160C.
The carbinol base (15 g.) was boiled under reflux for ' half an hour with glacial acetic acid (100 ml.) and con-centrated hydrochloric acid (30 ml.~. The solvent wa~ removed in vacuo and the residue basified to give 1, 1-di(4-biphenylyl)-

3-dimethylaminoprop-1-ene, m.p. 94-95C~ after recrystalli~ation from light petroleum (b.p. 40-60C)o The hydrochloride (colour-les~ prisms from ethanol, m.p~ 228C.) was identical with that - dascribed in Example 1 of Canadian Patent 1,009, 255~
B~ - 13 -- . -~ ';.' Fro~m ethyl ~-methylaminopropionate by the method of Example 1 was prepared 1,1-di(4-biphenylyl)-3-methylamino-propan-l-ol, needles from benzene, m.p. 154-156C. On de-hydration this gave l,l-di(4-biphenylyl)-3-methylaminoprop-1- ~¦
ene m.p. 94C. Its hydrochloride monohydrate, needles from ethanol, had m.p. 160C.

Di-4-biphenylyl ketone (6.68 g.) was added to a mixture of N,N-di-methylcarbamoylmethyl phosphonic acid diethyl ester (C.A. 65, 615 g. 1966) (4.46 g.), sodium hydride (60~/o) (0.8g.) and benzene (400 ml.). The mixture was boiled under reflux for sixty hours. The benzene layer, decanted and çvaporated, gave an oil, from which by column chromatography on silica gel MFC in benzene and elution by ethyl acetate, was isolated N,~-dimethyl-3,3-di(4-biphenylyl) ' acrylamide, m.p. 121C after recrystallisation from light petroleum (b.p. 80-100C). This, reduced with lithium aluminium hydride in ether/tetrahydrofuran at -30C, gave 1,1-di(4-bi-phenylyl)-3-dimethylaminoprop-1-ene identical with that described in Example 1.

Di-4-biphenylyl ketone was reacted with acetonitrile I in benzene in the presence of sodamide by the method of ¦ Lettre and Wick (Annalen, 1957, 603, 194) to give 3-hydroxy-3,3-di(4-biphenylyl) propionitrile, m.p. 168-170C, after re-crystallisation from benzene. The nitrile ~8.0 g.) dissolved in a mixture of tetrahydrofuran (80 ml.) and ether (80 ml.) was added over 30 minutes at room temperature under nitrogen to a stirred suspension of lithium aluminium hydride (2.88 g.) in ether (75 ml.). After stirring a further hour the mixture was , decomposed by addition of water (2.8 ml.) and aqueous N sodium i hydroxide ~12 ml.). After filtration, the organic layer was .

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

separated and evaporated to give a solid which recrystallised from benzene/light petroleum (b.p. 80-100C), gave 1,1-di(4-biphenylyl)-3-aminopropan-1-ol, prisms, m.p. 176-8C, ~max (ethanol) = 260 nm. The carbinol (6.5 g.) boiled under reflux for one hour with glacial acetic acid (40 ml.) and concentrated hydrochloric acid (10 ml.) gave 1,1-di(4-biphenylyl)-3-amino-prop-1-ene hydrochloride, needles from n-propanol, m.p. 231-232C. The base, from éthanol, had m.p. 127-8C, ~max (ethanol) = 274 nm.

_. :, To 1,1-di(4-biphenylyl)prop-1-ene (Pfeiffer and Schneider, J. prakt. chem., 1931 129, 129) (0.85 g.) in carbon tetrachloride (25 ml.) heated under nitrogen at 50C were added finely ground N-bromo succinimide (0.45 g.) and azobis-isobutyronitrile (50 mg.) and the mixture stirred at 50C for 24 hours. The succinimide formed was filtered off, and the filtrate evaporated to give l,l-di(4-biphenylyl)-3-bromoprop- ,~
! l-ene dS a cream solid. It was dissolved in acetone (10 ml.) ~, and 25% aqueous dimethylamine (1 ml.). The mixture was warmed on the steam bath for 10 minutes and the solvent evaporated. The residue was dissolved in ether, the ether -solution washed twice with water, dried and acidified with ethereal HC1. The precipitated hydrochloride was filtered off and recrystallised from ethanol to give l,l-di(4-biphenylyl)-$
3-dimethylaminoprop-1-ene hydrochloride as colourless prisms, , m.p. 228C.
;i EXAMPLE 6 ;~ To sodium hydride (6~/o) (3.75 g.), suspended in dry ~ -dimethoxyethane (75 ml.) and stirred under N2 was added drop-wise at 0C diethoxyphosphono-acetonitrile (15.9 g.) followed by a suspension of dibiphenylyl ketone (25 g.3 in dimethoxy-ethane (200 ml.) over one hour. Stirring was continued for one ' ''''":' ' ' ' :: . ~ , . ~ . . ..
.
. ' : ' ~ , , , , , . , : . ~ ~ ':

hour at room ten~perature and a ~urther hour at 50-60C. The mixture was cooled, decomposed by addition of water, extracted with ether, the solvent removed, and the residual solid recrystallised from n-propanol/benzene to give 3,3-di(4-bi-phenylyl)acrylonitrile, m.p. 154C. This was reduced with lithium aluminium hydride at -20C by the method of Jones, Maisey et al., (J. Med. Chem., 1971 14, 161) to give material from which l,l-di(4-biphenylyl)-3-aminoprop-1-ene having a m.p. of 127-128C. and ~max (ethanol) of 274 nm~

Acetic anhydride (1 ml.) was added to a solution of J 1,1-di(4-biphenylyl)-3-amino-prop-1-ene (1 g.) in 99/O formic acid (5 ml~) and the mixture was refluxed for 1 hour then ;
poured onto ice. The solid was collected, washed with water, ;~
, dried and then recrystallised from benzene/n-propanol to furnish 1,1-di(4-biphenylyl)-3-formamido-prop-1-ene (m.p. 171-~ 173C.). This compound, reduced with lithium aluminium Z hydride in ether/tetrahydrofuran at -30C, afforded 1,1-di-(4-biphenylyl)-3-methylamino-prop-1-ene, m.p. 94C.

1,1-di(4-biphenylyl)-3-amino-prop-1-ene (1 g.) was ' added to a mixture of anhydrous sodium acetate (1 g.) acetic j acid (10 ml.) and acetic anhydride (l ml.) and the mixture was refluxed for one hour then evaporated in vacuo. The residue was washed with water and dried and recrystallised from n-propanol to give 1,1-di(4-biphenylyl)-3-acetamido-prop-1-ene.
(M.p. 246 - 249C). This compound was reduced in a similar ~;
, manner to the method described in Example 7 to yield 1,1-di(4-9 biphenylyl)-3-ethylamino-prop-1-ene. <

:j ' ' ~!
., ' .

~ - 16 -. - . ~ . - - - ~ . .

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

104~647 ~XAMPLE 9 A tablet containing 1,1-di(4-biphenylyl)-3-dimethyl-amino-prop-l-ene was made up from the following components.

(I) 1,1-di(4-biphenylyl)-3-dimethyl-amino-prop-l-ene 250 mg.
(II) Lactose B. P. ` 125 mg.
(III) Starch B. P. 40 mg. ~`~
(IV) Methyl hydroxyethyl cellulose6 mg.
(V) Magnesium stearate B. P. 2 mg.
Components (I) and (II) were granulated and mixed together with a 5% solution of component (IV) in 5~/O aqueous alcohol. The granules were dried at 50C and components , ; . ! ~.
(III~ and (V) added. Mixing was then carried out, followed by compression into tablets.

A hard capsule contalnlng 1,1-dl(4-blphenylyl)-3 dimethylamino-prop-l-ene was formed from the foll~owing components.

(I) l,l-di(4-biphenylyl)-3-dimethyl-amino-prop~l-ene 100 mg.
(II) Talc B. P. 10 mg.
(III) Starch B. P. 40 mg-Component (I) was ground up and then mixed with - -components (II) and (III). The mixed powder was used to fill hard gelatin capsules. ~ -~

A tablet containing cis-1-(4'-chloro-4-biphenylyl)--chlorophenyl-3-dimethylamino-prop-1-ene hydrochloride as ~; the active ingredient was made up from the following ingredients. -~

:, .

~. .

' .. . . . .. : .: .. .... . :.... .. . .. . ..... .

(I) Cis-1-(4'-chloro-4-biphenylyl)-1-p-chlorophenyl-3-dimethylamino-prop-l.ene hydrochloride 500 mg.
(II) Microcrystalline cellulose 150 mg.
(III) Starch B.~P. 50 mg.
(IV) Gelatin B. P. 10 mg.
(V) Magnesium stearate B . P . 2 mg.
Component (I) was granulated with half of components (II) and (III) with a l~/o solution of component (IV) in 5~/
aqueous alcohol. The mixture was dried at 50C. The remainder of components (II) and (III) and also component (V) were then added to the dried granules and mixing carried out. The mixture was then compressed into tablets.

A syrup was made up from the following ingredients.

', (I) Cis-1-(4'-chloro-4-biphenylyl)-1-~-chlorophenyl-3-dimethylamino-prop-l-ene hydrochloride 500 mg.
,, (II) Sucrose B . P. 30 g.
~III) Glycerin B . P. 15 g.
'~ (IV) Methyl hydroxybenzoateB. P. 0.1 g.
(V) Saccharin Sodium B. P. 0.1 g.
(VI) Amaranth B. P. C. 1954 1.0 ~g.
(VII) Purified water B. P.to 100 ml.
Components (II), (IV) and (V) were dissolved in puri-fied water and components (III) and (VI) then added. To this '~
aqueous mixture was added component (I) which was dissolved therein. Sufficient purified water was then added to adjust ~i the volume to 100 ml. After filtration, the syrup was ready for use.

~ ~ .

,, .

., .
., .

1040~;47 To~ (4,4'-dibiphenylyl)prop-1-en-3-ol (1~8 g.) in ~ry pyridine (10 ml) at -5C to 0C was added, with stirring, 4-toluenesulphonyl chloride (1 g.) over 15 minutes.
The mixture was stirred at 0 C. for 30 minutes until solid and then left at the same temperature overnight. It was then . ~ . . . . .
poured into 2N HCl (50 ml), filtered and washed with water.
The solid was dried and extracted with boiling ethyl acetate, filtered and washed with boiling ethyl acetate. The yield of dry product was 1.2 g., m. p. 170 - 172C.
BXAMPLE 14 ~

4'-Chloro-4-biphenylyl 4-chlorophenyl ~etone (16.4 g) -and acetonitrile (2.25 g.) were reacted in benzene with ;~
presence of sodamide ~2.5 g.) by the method of Example 4 to give 3-hydroxy-3-(4'-chloro-4-biphenylyl)-3-~-chlorophenyl- -propionitrile, m. p. 123C. after recrystallization from ~-benzene, AmaX (ethanol) = 260 nm.
The nitrile was reduced with lithium aluminium hydride by the method of Bxample 4 to give 1-(4'-chloro-4-biphenylyl)-1-(4-chlorophenyl)-3-aminopropan-1-ol, m.p.
131-2C. after recrystallization from ethanol, ~max (ethanol) =
261 nm. ~ `
The aminopropanol, dehydrated by the method of Bxample 4, gave a mixture of cis- and trans-1-(4'-chloro-4-biphenylyl)-1-~-chlorophenyl-3-aminoprop-1-enes. The mixture

5' was converted to hydrochlorides which were separated by fractional crystallization from ethanol to give the sparingly soluble trans-isomer hydrochloride, m. p. 224 - 226C., ~max (ethanol) =
284 nm., isomeric purity by n.m.r., >98%, and the more soluble cis-isomer hydrochloride, m. p. 204-206, ~max (ethanol) = 260 nm, isomeric purity by n.m.r., 85%. ~ -: :: - 19.-:, '' . . ' '. ,'. . :. . , :,: .:
" . . . ..
.
: :, , : . : . ,

Claims (30)

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

1. A method of preparing a compound of formula (V) (V) wherein R1 and R2 are the same or different and can each represent a halo-substituted or unsubstituted biphenylyl, or halo- substituted or unsubstituted phenyl group, with the proviso that both of R1 and R2 cannot represent a halo-substituted biphenylyl group or a halo- substituted or unsub-stituted phenyl group, and that when one of R1 and R2 represents a halo-substituted biphenylyl group the other represents a halo-substituted or unsubstituted phenyl group, and either (a) Q and G taken together represent a single bond, when M represents:
(i) a nitrile group; a group of formula CONR3R4;
a group of formula CH2A where A represents a nitrile group or a group - NR3COR9 where R9 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and where R3 and R4 are the same or different and can each represent a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, or (ii) a group of formula CH2Z where Z represents a tosyloxy group or a bromo atom, (b) Q represents a hydroxyl group, G represents a hydrogen atom and M represents a group of formula CH2NR3R4, where R3 and R are defined in (a) (i), which comprises:
A) when Q and G taken together represent a single bond, and M is a group of formula CH2Z where Z
is a tosyloxy group, reacting an alcohol of formula with p-toluene sulphonyl chloride; or B) when Q and G taken together represent a single bond, and M is a group of formula CH2Br, reacting a prop-1-ene of formula (XXX) (XXX) with bromo succinimide and azobisisobutyronitrile;
or C) when Q is a hydroxyl group, G is a hydrogen atom and M is a group of formula CH2NR3R4 where R3 and R4 are as defined in a)(i) above, and R1 and R2 are the same, reacting an organometallic reagent of formula R1T wherein T is a metallic component, with an ester of formula (XVI) (XVI) wherein R3 and R4 are as defined in a)(i) above and R5 is an alkyl group of 1 to 4 carbon atoms;
or D) when Q is a hydroxyl group, G is a hydrogen atom, R1 and R are the same or different and are as defined above, and M is said group of formula CH2NR3R4 where R3 and R4 are as defined in a)(i) above, reacting an organometallic reagent of formula R1T, wherein T is a metallic component with a ketone of formula (XVII) (XVII) E) when Q and G taken together represent a single bond and M is a nitrile group or a group of formula -CONR3R4, reacting a ketone of formula wherein R1 and R2 are as defined above with a phosphorus compound of formula where X is -CN or -CONR3R4 and R6 is a lower alkyl group; or F) when Q and G taken together represent a single bond and M is CH2A where A represents a group -NR3COR9 where R3 and R9 are defined above, reacting a compound of formula (I) (I) with an appropriate carboxylic acid of formula R9COOH; or G) when Q is a hydroxyl group, G is a hydrogen atom, R1 and R2 are the same or different and are as defined above, and M is a group of formula CH2NR3R4 where R3 and R4 are both hydrogen, reacting a nitrile of formula (XVIII) (XVIII) with a mixed metal hydride.

2. A method as defined in claim 1 A) where Z represents a tosyloxy group comprising reacting an alcohol of formula R1R2C = CH.CH2OH with p-toluene sulphonyl chloride.

3. A method as defined in claim 1 B) where Z represents a bromine atom comprising reacting said prop-1-ene compound of formula (XXX) with bromo succinimide and azobisisobutyronitrile.

4, A method as defined in claim 1 C) comprising reacting said organometallic reagent of formula R1T with said ester of formula (XVI).

5. A method as defined in claim 1 D) where R1 and R2 are the same or different comprising reacting said organometallic reagent of formula R1T with said ketone of formula (XVII).

6. A method according to claim 4 or 5, wherein T is magnesium halide or lithium.

7. A method as defined in claim 1 E) comprising reacting said ketone with said phosphorus compound.

8. A method as defined in claim 1F) comprising reacting said compound of formula (I) with said carboxylic acid.

9. A method according to claim 1, wherein M is other than a nitrile group and wherein (i) either both of R1 and R2 represent unsubstituted 4-biphenylyl groups, or (ii) R1 represents a substituted or unsubstituted 4-biphenylyl group when R2 represents a substituted or unsubstituted phenyl group;
and wherein R3 and R4 represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, provided that R3 and R4 cannot both represent hydrogen atoms.

10. A method according to claim 4, for preparing 1,1-di-(4-biphenylyl)-3-dimethylamino-propan-1-ol comprising reacting ethyl .beta.-dimethylaminopropionate with 4-biphenylyl magnesium bromide.

11. A method according to claim 4, for preparing 1,1-di-(4-biphenylyl)-3-methylaminopropan-1-ol comprising reacting ethyl .beta.-methylaminopropionate with 4-biphenylyl magnesium bromide.

12. A method according to claim 7, for preparing N,N-dimethyl-3,3-di(4-biphenylyl)acrylamide comprising reacting di-4-biphenylyl ketone with N,N-di-methylcarbamoyl methyl phosphonic acid diethyl ester.

13. A method according to claim 3, for preparing 1,1-di(4-biphenylyl)-3-bromopro-1-ene comprising reacting 1,1-di(4-biphenylyl)prop-1-ene with N-bromo succinimide and azobisisobutyronitrile.

14. A method according to claim 7, for preparing 3,3-di(4-biphenylyl)acrylonitrile comprising reacting dibiphenylyl ketone with diethoxyphosphono-acetonitrile.

15. A method according to claim 8, for preparing 1,1-di-(4-biphenylyl)-3-formamido-prop-1-ene comprising reacting 1,1-di(4-biphenylyl)-3-amino-prop-1-ene with formic acid.

16. A method according to claim 8, for preparing 1,1-di-(4-biphenylyl)-3-acetamido-prop-1-ene comprising reacting 1,1-di(4-biphenylyl)-3-amino-prop-1-ene with acetic acid.

17. A method according to claim 2, for preparing 1,1-di(4-biphenylyl-3-tosyloxyprop-1-ene comprising reacting 1,1-(4,4'-dibiphenylyl)prop-1-ene-3-ol with 4-toluene-sulphonyl chloride,

18, A compound of formula (V) (V) wherein R1 and R2 are the same or different and can each represent a halo-substituted or unsubstituted biphenylyl, or halo-substituted or unsubstituted phenyl group, with the proviso that both of R1 and R2 cannot represent a halo-sub-stituted biphenylyl group or a halo-substituted or unsubstituted phenyl group and that when one of R1 and R2 represents a halo-substituted biphenylyl group the other represents a halo-sub-stituted or unsubstituted phenyl group and either (a) Q and G taken together represent a single bond, when M represents:
(i) a nitrile group; a group of formula CONR3R4;
a group of formula CH2A where A represents a nitrile group or a group -NR3COR9 and where R9 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and where R3 and R4 are the same or different and can each represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms:
(ii) a group of formula CH2Z where Z represents a tosyloxy group or a bromo atom; or (b) Q represents a hydroxy group, G represents a hydrogen atom and M represents a group of formula CH2NR3R4, where R3 and R4 are defined in (a) (i), whenever prepared by the method of claim 1, or by an obvious chemical equivalent,

19. A compound of formula (V), as defined in claim 1, whenever prepared by the method of claim 2, 3 or 4, or by an obvious chemical equivalent.

20. A compound of formula (V), as defined in claim 1, whenever prepared by the method of claim 4, 5 or 7, or by an obvious chemical equivalent.

21. A compound of formula (V), as defined in claim 1, whenever prepared by the method of claim 8, or by an obvious chemical equivalent.

22. A compound of formula (V) as defined in claim 1, wherein M is other than a nitrile group and wherein (i) either both of R1 and R2 represent unsubstituted 4-biphenylyl groups, or (ii) R1 represents a substituted or unsubstituted 4-biphenylyl group when R2 represents a substituted or unsubstituted phenyl group;

and wherein R3 and R4 represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, provided that R3 and R4 cannot both represent hydrogen atoms, whenever prepared by the method of claim 9, or by an obvious chemical equivalent.

23. 1,1-Di(4-biphenylyl)-3-dimethylamino-propan-1-ol whenever prepared by the method of claim 10 or by an obvious chemical equivalent.

24, 1,1-Di(4-biphenylyl)-3-methylaminopropan-1-ol whenever prepared by the method of claim 11 or by an obvious chemical equivalent.

25. N,N-Dimethyl-3,3-di(4-biphenylyl)acrylamide whenever prepared by the method of claim 12 or by an obvious chemical equivalent.

26. 1,1-Di(4-biphenylyl)-3-bromoprop-1-ene whenever prepared by the method of claim 13 or by an obvious chemical equivalent.

27. 3,3-Di(4-biphenylyl)acrylonitrile whenever prepared by the method of claim 14 or by an obvious chemical equivalent.

28. 1,1-Di(4-biphenylyl)-3-formamido-prop-1-ene whenever prepared by the method of claim 15 or by an obvious chemical equivalent.

29. 1,1-Di(4-biphenylyl)-3-acetamido-prop-1-ene whenever prepared by the method of claim 16 or by an obvious chemical equivalent.

30. 1,1-Di(4-biphenylyl-3-tosyloxyprop-1-ene whenever prepared by the method of claim 17 or bv an obvious chemical equivalent.