CA1056834A - 3-(4-bromophenyl)-n-methyl-3-(3-pyridyl)-allylamine - Google Patents
3-(4-bromophenyl)-n-methyl-3-(3-pyridyl)-allylamineInfo
- Publication number
- CA1056834A CA1056834A CA240,075A CA240075A CA1056834A CA 1056834 A CA1056834 A CA 1056834A CA 240075 A CA240075 A CA 240075A CA 1056834 A CA1056834 A CA 1056834A
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- bromophenyl
- pyridyl
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
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Abstract
ABSTRACT OF THE DISCLOSURE
3-Phenyl- 3-pyridylprop-2-enamines of formula
3-Phenyl- 3-pyridylprop-2-enamines of formula
Description
3~
Depressive disorders have with more or less success been treated with various compounds.
The antidepressive agents having the most widespread7 clinical use are the tricyclic tertiary amines imipramine having the st~ctural formula I CH
CH2CH2CH2-~<
and amitriptyline having the structural formula ~ ':.
CHCH2CH2-N < 3 Secondary amines such as desipramine having the structural formula ~ ~ ~ ~ / H
and nortriptyline having the structural formula ~ H
CHCH2CH2N ~ CH
~ -are used to a somewhat less extent. These substances have, however, side effects that are not desired at therapeutic use, such as orthostatism, . ,~ , anticholinergic effects and above all, an arrhythmogenic i.e. heart arrhythmia developing effect, on administration in large doses to elderly patients.
Moreover,all the substances mentioned show the disadvantage that the -1- , ,:
~56~
antidepressive effect starts first after some weeks of treatmentO
Further, it is known from the literature that certain l,l-diphenyl-3-aminoprop-1-enes~ such as the compound haYing the formula \
(~CHCH2 \
~ / C~3 have an antidepressive effect; see J. Med. Chem. 14, 161-4 (19 Compounds having the formula ~ '~ - .' ' ,. "
X ~ R
CHch2C~
.' wherein X is chlorine or bromine and R is hydrogen or methyl~ are described to have antidepressive effect, see United States Patent No. 3,423,510. These : . .
compounds however also have a strong antihistaminic effect. From the literature it is also known that a compound having the formula Br ~
C=CHCH2N'\
M
' ' ',' '' ' has an antidepressi~e activity in animals see Belgian Patent Specification ;
No. ~81glO5.
In clinical practice different types of depressive disorders are ' ~' _2- :
3L/~
recognized. Depressed patients respond in different ways to the various anti-depressants clinically used. Most of these substances inhibit the neuronal uptake of noradrenaline, and some of them additionally inhibit the uptake of 5-hydroxytryptamine. It is believed that inhibition of the uptake of 5-hydroxy~ryptamine is the mechanism behind a mood eleva~ing property seen in some of these anti-depressants. In addition to the absolute values for inhibition of the uptake of either 5 hydroxytryptamine or noradrenaline the selectivity towards uptake of either of these two amines is of great interest.
The present invention seeks to provide a new compo~d having a good antidepressive effect. The invention also seeks to provide a compound having an antidepressive effect, and giving rise to only minor side-effects, in particular arrhythmogenic effects; additionally this compound usefully has a therapeutical effect against an~iety.
The compound of the invention is characterized by the formula ~r Il /H
Pharmaceutically a¢ceptable salts of this compound are included within this invention.
Due to the lack of free rotation in the double bond the compound of this invention may exist in different stereoisomeric forms, that is in cis-trans isomers or, according to the IUPAC nomenclature (J. Org. Chem.
35~ 2849~2867, September 1970)~ in an E-form and a Z-form. The compound may be used therapeutically as a mixture of geometrical isomers or in pure E or Z form. The pure geometrical isomers may be prepared from an isomer , ,,, ~ , ~ ., , . .
. , . - , . . .
~S~3'~
mixture~ from an isomer-pure starting material or directly by a stereoselective synthesis.
The compound of this invention may be administered in the form of a Eree base or as a salt thereof. Some typical examples of these salts are the hydrobromide, hydrochloride, phosphate, sulphate, sulphamate, lactate, acetate~ citrate, tartrate, malate and maleate.
In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable, acid addition salt, e~g. as one of those suggested abo-ve in association with a pharmaceutically acceptable carrier. ~ccordingly, terms relating to the novel compound of this invention are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent, or a capsule. These pharmaceutical preparations constitute a further aspect of this inventionO Usually the active substance will constitute from 0 1 to 95%
by weight of the preparation, more specifically from 0.5 to 20% by weight for preparations intended for injection and from 2 to 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected ~-compound may be mixed with a solid pulverulent carrier, eOg, lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above~ may be coated with a concentrated sugar ~ ;
3~
solution which may contain, e.g. gum arabic, gelatine, talcum or titanium dioxide. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatilc organic solvent or mixture of organic sol~ents.
Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances of different amounts of the active compo~md.
For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelat~ne and, for example, glycerol, or similar closed capsules, the active substance may be admixed with a vegetable oil.
Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulve~ulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin)~
cellulose derivatives or gelatiMe.
Dosage units for rectal application can be prepared in the form of suppositories comprising the active substa~cein admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with ~egetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of -syrups or suspensions for example, solutions containing from about nO2% to about 2G% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol~ ;
Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 10% by ~eight~ These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
,, , ., , ,: . :
- . :, ............ .
Suitable daily doses of the compo~mds of the invention at therapeutical treatment is 25 to 250 mg at peroral administration, preferably 50 to 150 mg and 5 to 50 mg at parenteral administra~ion, preferably 10 to 30 mg. A preparation in dosage unit form for oral administration may contain 10-50 mg, preferably 10 to 25 mg of active substance per dosage unit.
The preferred isomer of the compound of the invention is the Z-isomer having the structural formula ~ ~ ' C
/ \ -Preferably the compound of the invention will be prepared and used in the ~orm of its salt.
Method of ~re~aration .
A. Dehydration of a compound of the formula ~3~ e)fBr ;~
to a compound of the form~la I. ;
The dehydration of the starting material may for example be done by means of treatment with sulphuric acid and heating of the reacting mixture.
The dehydration of the starting material may also be done by means of other types of acid-catalysis~ such as by means of hydrochloric acid, HCl~
phosphoric acid, H3P04, potassium hydrogen sulphate, KHS04, or oxalic acid ~COOH)2. Other methods for the dehydration of the starting material to ~3~ 3~ :
the formation of a compound of the formula I are dehydration using phosphor-oxichloride PoC13 in pyridine, and dehydration with thionylchloride, SOC12~ in pyridine. Also a catalytic dehydration of the starting material may be used. The dehydration is in this case carried out at a temperature of about 300 to 500 C using a catalyst such as kaolin, alumina or aluminium oxide.
B. Demethylation of a compound of the formula Br C
CHCH2N ~ ' : ' to the formation of a compound of the formula I.
C. AIkylation of monomethylamine with a compound of the formula r wherein Y is a leaving group to the formation of a compound of the formula I.
Illustrative examples of Y are halogens such as Cl, Br and I or sulphonates such as methanesulphonate, toluenesulphonate and benzene-sulphonate.
D. Introduction of a methyl group into a compound of the formula 13~
18 to the formation of a compound of the formula I.
.
` ~1S~3~
E. Treatment under hydrolytic conditions of an acyl or sulphonyl compound of the fomula ~ Br /\
wh0rein Z is an acyl or sulphonyl group to a compound of the fo = la I
either directly or via an intermediate of the fo = la ~C~~
` CHCH NCH -Z
::: :- .
Illustrative examples of Z are acetyl, benzoyl, methanesulphonyl, benzoylmethanesulphonyl and toluenesulphonyl.
Intermediates For the preparation of the compounds of formNla I it has been found that certain hitherto unlmown compounds may be valuable.
: When preparing the compounds of fo = la I according to process A, the compound C .- :. .
HO CH2C~ZEHCH3 . . .
` is used as starting material.
. .
This starting materia1 can be prepared according to the reaction ~-scheme . ~
::: ' . . --8~
' /~ + Y-C~12COO-~
red >
/C\ / \ , In the reaction scheme Y has the previously given definition and R
is a lower alkyl group with 1-5 carbon atoms, preferably an ethyl group.
The reduction in the last step is preferably carried out with a hydride reagen~.
When preparing the compounds of the formula I according to process C compounds of the formula ~f ~
CHCH~-Y
wherein Y is a leaving group are used as star~ing material.
Thls starting material can be prepared according to the reaction scheme > ~ ~
dehydration and ~ ~ "Br introduction of a leaving group Y ~ N ~ ~
Il .
In the reaction scheme above Y and R have the previously given definition. The reduction in the first step is preferably carried out using LiAlH4. The last step is preferably accomplished using PBr3, which means that the leaving group Y is Br.
The same starting material in which the leaving group is a halogen may also be obtained by the following reaction scheme:
Br ~ Br ~ ~ Br CHCH
allylic halogenati,on N ,l ~ ,J
, _ ..... ,~ ~ \~ ~ ~.
wherein ~ is a halogen such as Cl, Br and I. The allylic halogenation is carried out with a suitable halogenating agen1; such as a halogen succinimide.
When preparing the compound of the in~ention aceording to process D a compound o~ the formula 3~Br . .
11 '` . ':
:. ... . .
is used as starting material. This compound may be prepared aecording to methods similar to methods A, B, C and E described in paragraph d). '~r. .. ,, -.
Still further methods exist for the preparation of the starting materials, so for instance according to the reaction seheme:
;' ' ', "
--10~
3~
Li CH2CN
ll H0 CH2CN
O .'' . ~:
r ~ ~ ~ dr ~' ~ ~ ~ N
H0 CH2CH2NH2 H0 CH2 ~H2 NHC00-aIkyl 3 Examples Pr~paration of intermediates _ _ _ _ _ _ _ _ _ _ _ _ Example A.
Step 1 BrC1~2COalC2Hs ~ )3~ Br Cl / \
A mixture of 4-bromophenyl-3-p~ridyIketone ~CA 66, 37125 (1967); 50 g, 0.19 moles] and activated zinc (20 g~ in benzene (100 ml) was heated to reflux.
Ethyl bromoacetate (56 g, 0.35 moles) dissolved in benzene (50 ml) was added carefully during 30 minutes. Another portion of zinc ~50 g) was added and the ixture was refluxed~for 14 hours. After cooling and filtration, benzene (300 ~1) was added to the ~iltrate, which was washed three times with 10% aqueous acetic acid solution.
Ethyl ether (200 ml)was added and the solution acidified with 10% hydrochloric acid. The precipitate was filtered off~ washed with ether and dried. Yield: 75%. M.p~ 168-175 C~ -' ,: ' ' 3~
LiAlH4 ~ ~
~C\ / C ~ . .
The base (9.5 g, 0.027 moles) from ethyl 3-(4-bromophenyl)-3--hydroxy-3-(3-pyridyl~propanoate hydrochloride (step 1) was prepared and dissolved in ethyl ether (50 ml). This solution was added dropwise to an ice-cold mixture of lithium aluminum hydride (1.0 g, 0.027 moles) and ethyl ether (150 ml). The reaction mixture was refluxed for 5 hours, cooled and a saturated sodium sulphate solution was added until a white precipitate ~-was formed. This was filtered off and the ~iltrate evaporated. The residue was crystallized from chloroform. 1-(4-bromophenyl)-1-(3-pyridyl)-1,3-propanediol was obtained. Yield: 39%. M.p. 130-132 C.
~xam~_e B
Step 1 J~ ~C
C /\
/ \ HO CH2CONHCH
HO~ ~CH2COOC2N5 3 ~4-bromophenyl)-3-h~droxy-N-meth~1-3-(3-pyridyl)-propionamide 19,4 g (0.05 mole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-, _pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and 30 ml of absolute ethanol was stirred for 24 hours at room temperature.
The precipitate was ~iltered off and recrystallized from isopropyl alcohol, which ga~e 13.2 g (79%~ of the amide. M.p~ 188-191 C. The formula C15H15BrN202 was yerified through elemental analysis. (The elemental .~ . .
analyses throughout this application were carried out for all elements of the ,:
'..'.
3~ :~
compounds prepared, and are within ~ 0.4 per cent of the theoretical ~alues if not otherwise stated.) ~ r ~ ~ r HO \ CH CONHCH / \
~ 3 HO CH2CH2NHCH3 3-(4-bromophenyl)-3-hydroxy-N-meth~1-3-~pyridyl)-propylamine To 1.0 g (3.1 mmole) of 3-(4-bromophenyl)-3 hydroxy-N-methyl--3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at 0 and under N2, was added dropwise over 20 minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred over night at room temperature, and then cautiously hydrolyzed with water. Alcalization with 2M NaOH and extraction with ether gave after evaporation C)~9 g of a semicrytsalline residue. Recrystallization from ether-petroleumether gave 2.0 g (23%) of the amine. M.p. 81-88 C.
Example C
~ ~ '.
Br /.C C ', 3-(4~bromop_enyl)-3-hydroxy-3_(3 pyr dyl)-propionamide 0.8 g (2.5 mmole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3_(3_ -pyridyl)-propanoate, 50 ml of aqueous an~lonia and lO ml of absolute ethanol .
was stirred at room temperature for 24 hours. The white precipitate obtained was collected by filtration. Recrystalli ation from isopropyl : ~ ',.
';
, ~ . : . : . . . .
3~
alcohol gave 0~45 g (56%), m.p~ 213-214 C. The formula C14H13BrN202 was verified through elemental analysis, C calculated 52r4, found 51.9.
Ste~p 2 N
HO CH2CONH2 HO CH2CH2N~2 3-(4-bromo~henyl)-3-hydrox~ 3-pyridyl~-propylamine To loO g (3.1 mmole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)--propionamide and 0.8 g ~0~02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at O C and under N2, was added dropwise over 20 minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred for ~8 hours at room temperature, and then cautiously hydrolyzed with water. ALcalization with 2M NaOH and extraction with ether gave after evaporation a semi-crystalline residue.
Recrystallization from ether-petroleumether gave 0.6 g (63~) of the amine, m.p. 95-115 C NMR-spectrum (COC13); 2H(2.4~ 1-CH2)m: 2H(3-0, 2-CH2) :
.
3H~3.6~ -OH, -NH2)b : 6H(7.1-8.0 ArH)m: 2H(8.6)m ~ -Step 3 Ac~O ~
/ \ CHCH NH
HO \ CH2CH2~H2 2 2 3-(4-bromo~henvl~ 3-~3-~vridvl)-allYlamine ~..... . .
The raw product of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)- ~ --propylam~e (from 0.4 g of 3-(4-bromophenyl)-3-hydroxy-3_pyridyl)_ -propionamide) was added with stirring to 50 ml of acetic anhydride and 0.2S ml of concentrated sulphuric acid and the mixture was heated at 130 ,.''~ :
~35~13~
for 45 minutes The mixture was then cooled, poured on to crushed ice, alcalized with 30% NaOH and extracted with ether. Evaporation gave 0.36 g of an oil. After hydrolysis with 15 ml of concentrated hydrochloric acid for four hours 0.2S g of an oil was obtained, thin layer chromatography showed two spots with Rf=O.l and 0.8. CO1D chromatography on Silica Gel with methanol as eluant gave 0.06 g of the faster moving fraction and 0.19 g of the slower one, which was the amine. The oxalate of this compound was prepared. It was recrystallized from ethanol~ M.p. 153.5-155.5 C.
The NMR spectrum shows the vinyl proton as a double triplet at lo 6.1-6.5 ppm indicating an isomer ratio 1:1.
The formula: C14H13BrN2 . 1 H~O was ~erified through elemental analysisO
The oxalate was further recrystallized from a mixture of equal volumes of methanol and isopropyl alcohol and once from pure methanol. A
substance melting at 160-162 C was obtained. The NMR spectrum showed it to be the Z isomer.
Example D
S_e~_l W ~.W ~ ~r 3-~-bromophenyl~-3-hydroxy-3-(3-p2~idyl)-propionit_ile A mixture of 6.5 g (0.16 mole) of acetonitrile and SO ml of dry tetrahydrofuran (T~F) was slowly added under N2-atm to a mixture of 100 ml of 1.5 M n-buthyllithium in hexane and 50 ml of dry THF at -50C. After stirring for 35 minutes a solution of 36.5 g (0.14 mole) of 4-bromophenyl-3-pyridylketone in 250 ml of dry THF was added at -50 C. The temperature was kept at -70 C for 15 minutes, then the reaction mixture became viscous and it was allowed to reach ambient temperature. The product was poured into a 3 ~
stirred mixture of 500 g of ice-water and 500 ml of methylene chloride. The layers were separated and the a~ous layer was extracted with 2x200 ml of CH2C12. The combined organic layers were washed with water and dried. The solvent was evaporated giving 39.7 g of an oil. It was dissolved in 550 ml of hot i-PrOH a~d a solution of 35 ml of 4M HCl-ether (0.14 mole~ in 100 ml of i-PrOH was added, After coolirg there was collected 34.6 (74 %) of the hydrochloride of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile.
M.p. 158-161 C.
Step 2 ~ ~ Br 3-(4-bromophenyl-3-hydroxy-3-(3-pyridyl3-propylamine 17.2 g (0.056 mole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile was dissolved in 175 ml of T~ and diluted with 200 ml of ether. The solution was cooled ~o -35 C and 4.0 g (0.112 mole) of LiAlH4 was added in portions under N2-atm. The mixture was held at 0C for 2 hours then at 15 C for 2 hours. 20ml of a solution o~ saturated Na2S04 was slowly added.
After 30 minutes the mixture was filtered and the inorganic salts were washed with 2xlOO ml of ether. The filtrate was collected and the solvent -was evaporated giving 14.7 g of an oil. It was diluted with 500 ml of hot i-PrOH and 4.3 g ~0.048 mole~ of oxalic acid in 300 ml of hot i PrOH was dropwise added. After cooling over night 11.8 g of crystals, m.p.
98-105 C were collected. An analytical sample of the free amine had m.p.
118-120 C from i-PrOH. Yield 51%.
-]6-.
3'~
Step 3 ~ ~Br ~ r 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine To 0.80 g (0.002 mole) of the oxalate of 3-(4-bromophenyl)-3--hydroxy-3-(3-pyridyl)-propylamine was added 6 ml of 70% H2S04 for 35 minutes.
Ice-waker was added, then 30 ml of 30% NaOH and the mixture was extracted with 3xlOO ml of ether. Drying and evaporation of the solvent gave O.62 g of an oil. This was dissolved in 10 ml of hot ethanol and a hot solution of 0.20 g of oxalic acid in 5 ml of ethanol was added. Upon cooling 0.49 g of crystals were collected. NMR showed the product to be a mixture of the . .
E and z isomers of 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine as in Example C step 3.
Preparation of the end product Example 1~ (Method C) C NH2CH3 lC
\ CHCH,NHCH
HO CH2C~2H 3 1-(4-bromophenyl)-1-(3-pyrid~1)-1,3-propanediol (prepared in accordance with Example A, 7.2 g, 0.023 moles) was dissolved in dry acetone (70 ml)7 Hydrogen bromide was bubbled through the solution and the solvent was removed in ~acuum. Methylene chloride (50 ml) and phosphorus tribromide (6~4 g, 0.047 mole) w0re added to the residue and the mixture was refluxed for 14 hours, poured into ice and made aIkaline with sodium carbonate, Methanol (50 ml) ;
was added to the organic phase and the solution was evaporated in vacuum at ~30 C to 30 ml, The solution was heated with monomethylamine (14 g, 0.47 -~ -.. ~: .
: ' ' ' ' .
~ f~
mole~ in an autoclave at 110C for 15 hours. After coo]ing, the solvent was evaporated and the residue was dissolved in ether (25 ml) and water (25 ml).
~he pH of the mixture was adjusted to 9.0 with ammonia and the layers were separated. Another portion of water was added to the etheral layer and pH
was adjusted to 2.1 with HCl. The water-phase was treated with carbon black and then made alkaline with ammonia and extracted with ether. The organic-phase was dried with sodium sulphate and evaporated in vacuum. The residual base was dissolved in ether (40 ml) and cooled on an ice bath. Hydro-chloric acid in ether was added dropwise whereby a slightly yellow lo precipitate was obtained. The precipitate was filtered off, washed with ether and dried in vacuum. The hydrochloride of 3-~(4-bromophenyl)-N-methyl-3~(3-pyridyl) ally~Lamine was obtained.
Yield: 43%. M.p. 138-1~4 C.
Example 2. (Method A~
H SO ~ ~ Br ~ :
N ~ ~ 2 4 ~ ~ ~
C\ 11 The raw product of 3-(4-bromophenyl~-3-hydroxy-N-methyl_3_(3_pyridyl) _prop~lamine (prepared in accordance with Example B from 5.0 g of 3-(4-bromophenyl)-3-hydroxy-N-methyl-3-pyridyl~-propionamide) was added with stirring to 50% sulphuric acid (50 ml) and the mixture was heated at 110 for 10 minutes. me mixture was then cooled, poured on to crushed ice, basified by the addition of 30% NaOH and extracted with ether~ Evaporation gave 4~9 g of semicrystalline residue. lSG ml acetone was added and the solution was clarified by filtration. 0.9 g (0.01 mole) of oxalic acid dissolved in 25 ml of acetone was added dropwise to the filtrate. The white precipitate was collected and recrystallized from 350 ml isopropyl alcohol to yield 1.7 g of white crystals of the oxalate of 3-~4-bromophenyl)-N-methyl-3-~ '' _18-J, ' ' ~ ' '.
~35~3~
(3-pyridyl)-allylamine. M.p. 180-208 CO The NMR spectrum shows the vinyl proton as a double triplet at 6.1-6~4 ppm, indicating a mixture of E and Z
isomers.
Isolation of the Z-isomer: After recrystallization three times from ethanol 0.5 g substance was obtained. M.p. 202-205C. The NMR spectrum sho~s the vinyl proton as a single triplet with J = 3.4 Hz ~nd in a position which indicates that the compound is the Z-isomer.
The amine oxalate obtained was converted into the corresponding hydrochloride via the free base. Recrystallization from acetonitrile containing a few per cent of water gave a compound melting at 161-165 C.
Elemental analysis showed it to be a dihydrochloride with the composition C15H15BrN2 2HCl H20.
Isolation of the ~-isomer: Mother liquors from the isolation of the Z isomer, containing both isomers in a ratio of about 60:40 E and Z
respectively~ was used. The oxalate of this amine mixture was recrystalli~ed three times from acetonitrile containing 15% of water, giving a substance melting at 198-201C. According to the NMR spectrum this substance was the E~isomer.
Pharmacolo~cal tes~s -It is not possible by experimental means to induce depressions in laboratory animals. In order to evaluate a possible anti-depressive effect of new substances biochemical-pharmacological test methods must be resorted to.
One such method, which seems to give a good indication of the potential anti- ;
depressive e~fects o~ the test substances, is described in Europ. JO Pharmacol.
7~ 1~7~ 1972.
This method involves the measurement of the decrease in the uptake of C-S-hydroxytryptamine ( C-5-HT) and H-noradrenaline ( H-NA) in brain ;~
slices from mice after in vivo and in vitro administration of the test substance O ' ~19-- ., .,. : .
...... ,,,, .. ,, .. , ,, ., , , , ; . . . .
., , .. , , . , ~ , . . .. .. ..
Inhibition of the uptake of C-5-HT and H-NA in vitro and in vivo, is measured as follows:
The test substances were administered intraperitoneally half an hour before the animals were killed. The midbrair. was taken out, sliced and incubated in a mixture consisting of 0.2 nmole of C-5-HT, 0.2 nmole of H-NA and ll,umole of glucose in 2 ml of Krebs-Henseleit buffer, pH 7.4 per loo mg of brain slices. The incubation time was 5 minutes with 5 minutes of preincubation before the labelled amines were added. The slices were dissolved in Soluene~ and the amounts of radio-active amines taken up were ` 10 determined by liquid ~cintillationO The doses producing 50 per cent decrease ~ -of the active uptake (ED50) of C-5-HT and H-NA were de~ermined graphically from dose response curves. Active uptake is defined as that part of the radioactive uptake which is inhibited by a high concentration of cocaine.
In the in vitro method slices of mouse midbrain were preincubated for 5 minutes with solution of the compound to be tes~ed and then incubated as described above.
' -- .
3~
~ '~
,.:
.~ a~ ,_ ....
C , o ~ ,_ ~
¢ ~ ~ q I O O ~ ~ ~ V
U~ ~ .
~rl ~H ~ ~ O ~ ~ 00 a~ ~ ~ O.
.,, .,, .::
.~ ~a ':' . . .
.~ ~ ~ ~ . .
~ ~C n o ~ coIn ~ a~
~ ~ _~ ~ o ~ a~ ~
h C~
~ ~ q ~ U~ Ln 11~ ~ ~1 ~ ~1 ~=~ ~ ,F~ ' ~ D O O
a~ ~ ~
I ~ ~ I ~ ~ I ~rl ~ , O \ =-Z ~ ~ ~ h h ~--I ' ~d h O .
f-l r-l ~d td~ O t~ ~ O t~ ~1 ~1 u~ u~ o o 3~ o ~ ~ o ~ o ~
o h ::
a~
a) h h ,~ U~ ~ Ul .
E~ , , ~H ~ .~ ~
c ~P ~ N ~ .
.~ ~--J ~
4~ 0 ~D ~
h ~ : ~
g .rl h ~ O ;: ~.
O .S h O .. :
..
--i 2 1 ' ':, As can be seen from the Table the compounds of the invention are potent inhibitors of the neuronal uptake of 5-hydroxytryptamine and noradrenaline. The Z-form of the compound of the invention shows a stronger inhibition of the uptake of 5-HT in vivo than do any of the prior art compounds tested.
The Z-form of the compound of the invention tested as the hydrochloride, is further a more potent inhibitor of the uptake of 5-HT in vitro than any of the prior art compounds. ~The difference appearing between the ~-oxalate and the hydrochloride is believed to be due to the fact that the hydrochloride was prepared from the oxalate whereby a more pure Z-isomer was obtained). The E-form of the compound of the invention primarily inhibits the uptake of noradrenaline. The inhibition of neuronal uptake of 5-hydroxytryptamine and noradrenaline disclosed, may give the compounds of the invention value as anti-depressive agents. Likewise the compounds of the invention may be useful as anxiolytic agents.
.
~.,,.'' ~, .
.'. .: '' ', : ' ,. ".
~ ~ .
Depressive disorders have with more or less success been treated with various compounds.
The antidepressive agents having the most widespread7 clinical use are the tricyclic tertiary amines imipramine having the st~ctural formula I CH
CH2CH2CH2-~<
and amitriptyline having the structural formula ~ ':.
CHCH2CH2-N < 3 Secondary amines such as desipramine having the structural formula ~ ~ ~ ~ / H
and nortriptyline having the structural formula ~ H
CHCH2CH2N ~ CH
~ -are used to a somewhat less extent. These substances have, however, side effects that are not desired at therapeutic use, such as orthostatism, . ,~ , anticholinergic effects and above all, an arrhythmogenic i.e. heart arrhythmia developing effect, on administration in large doses to elderly patients.
Moreover,all the substances mentioned show the disadvantage that the -1- , ,:
~56~
antidepressive effect starts first after some weeks of treatmentO
Further, it is known from the literature that certain l,l-diphenyl-3-aminoprop-1-enes~ such as the compound haYing the formula \
(~CHCH2 \
~ / C~3 have an antidepressive effect; see J. Med. Chem. 14, 161-4 (19 Compounds having the formula ~ '~ - .' ' ,. "
X ~ R
CHch2C~
.' wherein X is chlorine or bromine and R is hydrogen or methyl~ are described to have antidepressive effect, see United States Patent No. 3,423,510. These : . .
compounds however also have a strong antihistaminic effect. From the literature it is also known that a compound having the formula Br ~
C=CHCH2N'\
M
' ' ',' '' ' has an antidepressi~e activity in animals see Belgian Patent Specification ;
No. ~81glO5.
In clinical practice different types of depressive disorders are ' ~' _2- :
3L/~
recognized. Depressed patients respond in different ways to the various anti-depressants clinically used. Most of these substances inhibit the neuronal uptake of noradrenaline, and some of them additionally inhibit the uptake of 5-hydroxytryptamine. It is believed that inhibition of the uptake of 5-hydroxy~ryptamine is the mechanism behind a mood eleva~ing property seen in some of these anti-depressants. In addition to the absolute values for inhibition of the uptake of either 5 hydroxytryptamine or noradrenaline the selectivity towards uptake of either of these two amines is of great interest.
The present invention seeks to provide a new compo~d having a good antidepressive effect. The invention also seeks to provide a compound having an antidepressive effect, and giving rise to only minor side-effects, in particular arrhythmogenic effects; additionally this compound usefully has a therapeutical effect against an~iety.
The compound of the invention is characterized by the formula ~r Il /H
Pharmaceutically a¢ceptable salts of this compound are included within this invention.
Due to the lack of free rotation in the double bond the compound of this invention may exist in different stereoisomeric forms, that is in cis-trans isomers or, according to the IUPAC nomenclature (J. Org. Chem.
35~ 2849~2867, September 1970)~ in an E-form and a Z-form. The compound may be used therapeutically as a mixture of geometrical isomers or in pure E or Z form. The pure geometrical isomers may be prepared from an isomer , ,,, ~ , ~ ., , . .
. , . - , . . .
~S~3'~
mixture~ from an isomer-pure starting material or directly by a stereoselective synthesis.
The compound of this invention may be administered in the form of a Eree base or as a salt thereof. Some typical examples of these salts are the hydrobromide, hydrochloride, phosphate, sulphate, sulphamate, lactate, acetate~ citrate, tartrate, malate and maleate.
In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable, acid addition salt, e~g. as one of those suggested abo-ve in association with a pharmaceutically acceptable carrier. ~ccordingly, terms relating to the novel compound of this invention are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent, or a capsule. These pharmaceutical preparations constitute a further aspect of this inventionO Usually the active substance will constitute from 0 1 to 95%
by weight of the preparation, more specifically from 0.5 to 20% by weight for preparations intended for injection and from 2 to 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected ~-compound may be mixed with a solid pulverulent carrier, eOg, lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above~ may be coated with a concentrated sugar ~ ;
3~
solution which may contain, e.g. gum arabic, gelatine, talcum or titanium dioxide. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatilc organic solvent or mixture of organic sol~ents.
Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances of different amounts of the active compo~md.
For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelat~ne and, for example, glycerol, or similar closed capsules, the active substance may be admixed with a vegetable oil.
Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulve~ulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin)~
cellulose derivatives or gelatiMe.
Dosage units for rectal application can be prepared in the form of suppositories comprising the active substa~cein admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with ~egetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of -syrups or suspensions for example, solutions containing from about nO2% to about 2G% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol~ ;
Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 10% by ~eight~ These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
,, , ., , ,: . :
- . :, ............ .
Suitable daily doses of the compo~mds of the invention at therapeutical treatment is 25 to 250 mg at peroral administration, preferably 50 to 150 mg and 5 to 50 mg at parenteral administra~ion, preferably 10 to 30 mg. A preparation in dosage unit form for oral administration may contain 10-50 mg, preferably 10 to 25 mg of active substance per dosage unit.
The preferred isomer of the compound of the invention is the Z-isomer having the structural formula ~ ~ ' C
/ \ -Preferably the compound of the invention will be prepared and used in the ~orm of its salt.
Method of ~re~aration .
A. Dehydration of a compound of the formula ~3~ e)fBr ;~
to a compound of the form~la I. ;
The dehydration of the starting material may for example be done by means of treatment with sulphuric acid and heating of the reacting mixture.
The dehydration of the starting material may also be done by means of other types of acid-catalysis~ such as by means of hydrochloric acid, HCl~
phosphoric acid, H3P04, potassium hydrogen sulphate, KHS04, or oxalic acid ~COOH)2. Other methods for the dehydration of the starting material to ~3~ 3~ :
the formation of a compound of the formula I are dehydration using phosphor-oxichloride PoC13 in pyridine, and dehydration with thionylchloride, SOC12~ in pyridine. Also a catalytic dehydration of the starting material may be used. The dehydration is in this case carried out at a temperature of about 300 to 500 C using a catalyst such as kaolin, alumina or aluminium oxide.
B. Demethylation of a compound of the formula Br C
CHCH2N ~ ' : ' to the formation of a compound of the formula I.
C. AIkylation of monomethylamine with a compound of the formula r wherein Y is a leaving group to the formation of a compound of the formula I.
Illustrative examples of Y are halogens such as Cl, Br and I or sulphonates such as methanesulphonate, toluenesulphonate and benzene-sulphonate.
D. Introduction of a methyl group into a compound of the formula 13~
18 to the formation of a compound of the formula I.
.
` ~1S~3~
E. Treatment under hydrolytic conditions of an acyl or sulphonyl compound of the fomula ~ Br /\
wh0rein Z is an acyl or sulphonyl group to a compound of the fo = la I
either directly or via an intermediate of the fo = la ~C~~
` CHCH NCH -Z
::: :- .
Illustrative examples of Z are acetyl, benzoyl, methanesulphonyl, benzoylmethanesulphonyl and toluenesulphonyl.
Intermediates For the preparation of the compounds of formNla I it has been found that certain hitherto unlmown compounds may be valuable.
: When preparing the compounds of fo = la I according to process A, the compound C .- :. .
HO CH2C~ZEHCH3 . . .
` is used as starting material.
. .
This starting materia1 can be prepared according to the reaction ~-scheme . ~
::: ' . . --8~
' /~ + Y-C~12COO-~
red >
/C\ / \ , In the reaction scheme Y has the previously given definition and R
is a lower alkyl group with 1-5 carbon atoms, preferably an ethyl group.
The reduction in the last step is preferably carried out with a hydride reagen~.
When preparing the compounds of the formula I according to process C compounds of the formula ~f ~
CHCH~-Y
wherein Y is a leaving group are used as star~ing material.
Thls starting material can be prepared according to the reaction scheme > ~ ~
dehydration and ~ ~ "Br introduction of a leaving group Y ~ N ~ ~
Il .
In the reaction scheme above Y and R have the previously given definition. The reduction in the first step is preferably carried out using LiAlH4. The last step is preferably accomplished using PBr3, which means that the leaving group Y is Br.
The same starting material in which the leaving group is a halogen may also be obtained by the following reaction scheme:
Br ~ Br ~ ~ Br CHCH
allylic halogenati,on N ,l ~ ,J
, _ ..... ,~ ~ \~ ~ ~.
wherein ~ is a halogen such as Cl, Br and I. The allylic halogenation is carried out with a suitable halogenating agen1; such as a halogen succinimide.
When preparing the compound of the in~ention aceording to process D a compound o~ the formula 3~Br . .
11 '` . ':
:. ... . .
is used as starting material. This compound may be prepared aecording to methods similar to methods A, B, C and E described in paragraph d). '~r. .. ,, -.
Still further methods exist for the preparation of the starting materials, so for instance according to the reaction seheme:
;' ' ', "
--10~
3~
Li CH2CN
ll H0 CH2CN
O .'' . ~:
r ~ ~ ~ dr ~' ~ ~ ~ N
H0 CH2CH2NH2 H0 CH2 ~H2 NHC00-aIkyl 3 Examples Pr~paration of intermediates _ _ _ _ _ _ _ _ _ _ _ _ Example A.
Step 1 BrC1~2COalC2Hs ~ )3~ Br Cl / \
A mixture of 4-bromophenyl-3-p~ridyIketone ~CA 66, 37125 (1967); 50 g, 0.19 moles] and activated zinc (20 g~ in benzene (100 ml) was heated to reflux.
Ethyl bromoacetate (56 g, 0.35 moles) dissolved in benzene (50 ml) was added carefully during 30 minutes. Another portion of zinc ~50 g) was added and the ixture was refluxed~for 14 hours. After cooling and filtration, benzene (300 ~1) was added to the ~iltrate, which was washed three times with 10% aqueous acetic acid solution.
Ethyl ether (200 ml)was added and the solution acidified with 10% hydrochloric acid. The precipitate was filtered off~ washed with ether and dried. Yield: 75%. M.p~ 168-175 C~ -' ,: ' ' 3~
LiAlH4 ~ ~
~C\ / C ~ . .
The base (9.5 g, 0.027 moles) from ethyl 3-(4-bromophenyl)-3--hydroxy-3-(3-pyridyl~propanoate hydrochloride (step 1) was prepared and dissolved in ethyl ether (50 ml). This solution was added dropwise to an ice-cold mixture of lithium aluminum hydride (1.0 g, 0.027 moles) and ethyl ether (150 ml). The reaction mixture was refluxed for 5 hours, cooled and a saturated sodium sulphate solution was added until a white precipitate ~-was formed. This was filtered off and the ~iltrate evaporated. The residue was crystallized from chloroform. 1-(4-bromophenyl)-1-(3-pyridyl)-1,3-propanediol was obtained. Yield: 39%. M.p. 130-132 C.
~xam~_e B
Step 1 J~ ~C
C /\
/ \ HO CH2CONHCH
HO~ ~CH2COOC2N5 3 ~4-bromophenyl)-3-h~droxy-N-meth~1-3-(3-pyridyl)-propionamide 19,4 g (0.05 mole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-, _pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and 30 ml of absolute ethanol was stirred for 24 hours at room temperature.
The precipitate was ~iltered off and recrystallized from isopropyl alcohol, which ga~e 13.2 g (79%~ of the amide. M.p~ 188-191 C. The formula C15H15BrN202 was yerified through elemental analysis. (The elemental .~ . .
analyses throughout this application were carried out for all elements of the ,:
'..'.
3~ :~
compounds prepared, and are within ~ 0.4 per cent of the theoretical ~alues if not otherwise stated.) ~ r ~ ~ r HO \ CH CONHCH / \
~ 3 HO CH2CH2NHCH3 3-(4-bromophenyl)-3-hydroxy-N-meth~1-3-~pyridyl)-propylamine To 1.0 g (3.1 mmole) of 3-(4-bromophenyl)-3 hydroxy-N-methyl--3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at 0 and under N2, was added dropwise over 20 minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred over night at room temperature, and then cautiously hydrolyzed with water. Alcalization with 2M NaOH and extraction with ether gave after evaporation C)~9 g of a semicrytsalline residue. Recrystallization from ether-petroleumether gave 2.0 g (23%) of the amine. M.p. 81-88 C.
Example C
~ ~ '.
Br /.C C ', 3-(4~bromop_enyl)-3-hydroxy-3_(3 pyr dyl)-propionamide 0.8 g (2.5 mmole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3_(3_ -pyridyl)-propanoate, 50 ml of aqueous an~lonia and lO ml of absolute ethanol .
was stirred at room temperature for 24 hours. The white precipitate obtained was collected by filtration. Recrystalli ation from isopropyl : ~ ',.
';
, ~ . : . : . . . .
3~
alcohol gave 0~45 g (56%), m.p~ 213-214 C. The formula C14H13BrN202 was verified through elemental analysis, C calculated 52r4, found 51.9.
Ste~p 2 N
HO CH2CONH2 HO CH2CH2N~2 3-(4-bromo~henyl)-3-hydrox~ 3-pyridyl~-propylamine To loO g (3.1 mmole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)--propionamide and 0.8 g ~0~02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at O C and under N2, was added dropwise over 20 minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred for ~8 hours at room temperature, and then cautiously hydrolyzed with water. ALcalization with 2M NaOH and extraction with ether gave after evaporation a semi-crystalline residue.
Recrystallization from ether-petroleumether gave 0.6 g (63~) of the amine, m.p. 95-115 C NMR-spectrum (COC13); 2H(2.4~ 1-CH2)m: 2H(3-0, 2-CH2) :
.
3H~3.6~ -OH, -NH2)b : 6H(7.1-8.0 ArH)m: 2H(8.6)m ~ -Step 3 Ac~O ~
/ \ CHCH NH
HO \ CH2CH2~H2 2 2 3-(4-bromo~henvl~ 3-~3-~vridvl)-allYlamine ~..... . .
The raw product of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)- ~ --propylam~e (from 0.4 g of 3-(4-bromophenyl)-3-hydroxy-3_pyridyl)_ -propionamide) was added with stirring to 50 ml of acetic anhydride and 0.2S ml of concentrated sulphuric acid and the mixture was heated at 130 ,.''~ :
~35~13~
for 45 minutes The mixture was then cooled, poured on to crushed ice, alcalized with 30% NaOH and extracted with ether. Evaporation gave 0.36 g of an oil. After hydrolysis with 15 ml of concentrated hydrochloric acid for four hours 0.2S g of an oil was obtained, thin layer chromatography showed two spots with Rf=O.l and 0.8. CO1D chromatography on Silica Gel with methanol as eluant gave 0.06 g of the faster moving fraction and 0.19 g of the slower one, which was the amine. The oxalate of this compound was prepared. It was recrystallized from ethanol~ M.p. 153.5-155.5 C.
The NMR spectrum shows the vinyl proton as a double triplet at lo 6.1-6.5 ppm indicating an isomer ratio 1:1.
The formula: C14H13BrN2 . 1 H~O was ~erified through elemental analysisO
The oxalate was further recrystallized from a mixture of equal volumes of methanol and isopropyl alcohol and once from pure methanol. A
substance melting at 160-162 C was obtained. The NMR spectrum showed it to be the Z isomer.
Example D
S_e~_l W ~.W ~ ~r 3-~-bromophenyl~-3-hydroxy-3-(3-p2~idyl)-propionit_ile A mixture of 6.5 g (0.16 mole) of acetonitrile and SO ml of dry tetrahydrofuran (T~F) was slowly added under N2-atm to a mixture of 100 ml of 1.5 M n-buthyllithium in hexane and 50 ml of dry THF at -50C. After stirring for 35 minutes a solution of 36.5 g (0.14 mole) of 4-bromophenyl-3-pyridylketone in 250 ml of dry THF was added at -50 C. The temperature was kept at -70 C for 15 minutes, then the reaction mixture became viscous and it was allowed to reach ambient temperature. The product was poured into a 3 ~
stirred mixture of 500 g of ice-water and 500 ml of methylene chloride. The layers were separated and the a~ous layer was extracted with 2x200 ml of CH2C12. The combined organic layers were washed with water and dried. The solvent was evaporated giving 39.7 g of an oil. It was dissolved in 550 ml of hot i-PrOH a~d a solution of 35 ml of 4M HCl-ether (0.14 mole~ in 100 ml of i-PrOH was added, After coolirg there was collected 34.6 (74 %) of the hydrochloride of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile.
M.p. 158-161 C.
Step 2 ~ ~ Br 3-(4-bromophenyl-3-hydroxy-3-(3-pyridyl3-propylamine 17.2 g (0.056 mole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile was dissolved in 175 ml of T~ and diluted with 200 ml of ether. The solution was cooled ~o -35 C and 4.0 g (0.112 mole) of LiAlH4 was added in portions under N2-atm. The mixture was held at 0C for 2 hours then at 15 C for 2 hours. 20ml of a solution o~ saturated Na2S04 was slowly added.
After 30 minutes the mixture was filtered and the inorganic salts were washed with 2xlOO ml of ether. The filtrate was collected and the solvent -was evaporated giving 14.7 g of an oil. It was diluted with 500 ml of hot i-PrOH and 4.3 g ~0.048 mole~ of oxalic acid in 300 ml of hot i PrOH was dropwise added. After cooling over night 11.8 g of crystals, m.p.
98-105 C were collected. An analytical sample of the free amine had m.p.
118-120 C from i-PrOH. Yield 51%.
-]6-.
3'~
Step 3 ~ ~Br ~ r 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine To 0.80 g (0.002 mole) of the oxalate of 3-(4-bromophenyl)-3--hydroxy-3-(3-pyridyl)-propylamine was added 6 ml of 70% H2S04 for 35 minutes.
Ice-waker was added, then 30 ml of 30% NaOH and the mixture was extracted with 3xlOO ml of ether. Drying and evaporation of the solvent gave O.62 g of an oil. This was dissolved in 10 ml of hot ethanol and a hot solution of 0.20 g of oxalic acid in 5 ml of ethanol was added. Upon cooling 0.49 g of crystals were collected. NMR showed the product to be a mixture of the . .
E and z isomers of 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine as in Example C step 3.
Preparation of the end product Example 1~ (Method C) C NH2CH3 lC
\ CHCH,NHCH
HO CH2C~2H 3 1-(4-bromophenyl)-1-(3-pyrid~1)-1,3-propanediol (prepared in accordance with Example A, 7.2 g, 0.023 moles) was dissolved in dry acetone (70 ml)7 Hydrogen bromide was bubbled through the solution and the solvent was removed in ~acuum. Methylene chloride (50 ml) and phosphorus tribromide (6~4 g, 0.047 mole) w0re added to the residue and the mixture was refluxed for 14 hours, poured into ice and made aIkaline with sodium carbonate, Methanol (50 ml) ;
was added to the organic phase and the solution was evaporated in vacuum at ~30 C to 30 ml, The solution was heated with monomethylamine (14 g, 0.47 -~ -.. ~: .
: ' ' ' ' .
~ f~
mole~ in an autoclave at 110C for 15 hours. After coo]ing, the solvent was evaporated and the residue was dissolved in ether (25 ml) and water (25 ml).
~he pH of the mixture was adjusted to 9.0 with ammonia and the layers were separated. Another portion of water was added to the etheral layer and pH
was adjusted to 2.1 with HCl. The water-phase was treated with carbon black and then made alkaline with ammonia and extracted with ether. The organic-phase was dried with sodium sulphate and evaporated in vacuum. The residual base was dissolved in ether (40 ml) and cooled on an ice bath. Hydro-chloric acid in ether was added dropwise whereby a slightly yellow lo precipitate was obtained. The precipitate was filtered off, washed with ether and dried in vacuum. The hydrochloride of 3-~(4-bromophenyl)-N-methyl-3~(3-pyridyl) ally~Lamine was obtained.
Yield: 43%. M.p. 138-1~4 C.
Example 2. (Method A~
H SO ~ ~ Br ~ :
N ~ ~ 2 4 ~ ~ ~
C\ 11 The raw product of 3-(4-bromophenyl~-3-hydroxy-N-methyl_3_(3_pyridyl) _prop~lamine (prepared in accordance with Example B from 5.0 g of 3-(4-bromophenyl)-3-hydroxy-N-methyl-3-pyridyl~-propionamide) was added with stirring to 50% sulphuric acid (50 ml) and the mixture was heated at 110 for 10 minutes. me mixture was then cooled, poured on to crushed ice, basified by the addition of 30% NaOH and extracted with ether~ Evaporation gave 4~9 g of semicrystalline residue. lSG ml acetone was added and the solution was clarified by filtration. 0.9 g (0.01 mole) of oxalic acid dissolved in 25 ml of acetone was added dropwise to the filtrate. The white precipitate was collected and recrystallized from 350 ml isopropyl alcohol to yield 1.7 g of white crystals of the oxalate of 3-~4-bromophenyl)-N-methyl-3-~ '' _18-J, ' ' ~ ' '.
~35~3~
(3-pyridyl)-allylamine. M.p. 180-208 CO The NMR spectrum shows the vinyl proton as a double triplet at 6.1-6~4 ppm, indicating a mixture of E and Z
isomers.
Isolation of the Z-isomer: After recrystallization three times from ethanol 0.5 g substance was obtained. M.p. 202-205C. The NMR spectrum sho~s the vinyl proton as a single triplet with J = 3.4 Hz ~nd in a position which indicates that the compound is the Z-isomer.
The amine oxalate obtained was converted into the corresponding hydrochloride via the free base. Recrystallization from acetonitrile containing a few per cent of water gave a compound melting at 161-165 C.
Elemental analysis showed it to be a dihydrochloride with the composition C15H15BrN2 2HCl H20.
Isolation of the ~-isomer: Mother liquors from the isolation of the Z isomer, containing both isomers in a ratio of about 60:40 E and Z
respectively~ was used. The oxalate of this amine mixture was recrystalli~ed three times from acetonitrile containing 15% of water, giving a substance melting at 198-201C. According to the NMR spectrum this substance was the E~isomer.
Pharmacolo~cal tes~s -It is not possible by experimental means to induce depressions in laboratory animals. In order to evaluate a possible anti-depressive effect of new substances biochemical-pharmacological test methods must be resorted to.
One such method, which seems to give a good indication of the potential anti- ;
depressive e~fects o~ the test substances, is described in Europ. JO Pharmacol.
7~ 1~7~ 1972.
This method involves the measurement of the decrease in the uptake of C-S-hydroxytryptamine ( C-5-HT) and H-noradrenaline ( H-NA) in brain ;~
slices from mice after in vivo and in vitro administration of the test substance O ' ~19-- ., .,. : .
...... ,,,, .. ,, .. , ,, ., , , , ; . . . .
., , .. , , . , ~ , . . .. .. ..
Inhibition of the uptake of C-5-HT and H-NA in vitro and in vivo, is measured as follows:
The test substances were administered intraperitoneally half an hour before the animals were killed. The midbrair. was taken out, sliced and incubated in a mixture consisting of 0.2 nmole of C-5-HT, 0.2 nmole of H-NA and ll,umole of glucose in 2 ml of Krebs-Henseleit buffer, pH 7.4 per loo mg of brain slices. The incubation time was 5 minutes with 5 minutes of preincubation before the labelled amines were added. The slices were dissolved in Soluene~ and the amounts of radio-active amines taken up were ` 10 determined by liquid ~cintillationO The doses producing 50 per cent decrease ~ -of the active uptake (ED50) of C-5-HT and H-NA were de~ermined graphically from dose response curves. Active uptake is defined as that part of the radioactive uptake which is inhibited by a high concentration of cocaine.
In the in vitro method slices of mouse midbrain were preincubated for 5 minutes with solution of the compound to be tes~ed and then incubated as described above.
' -- .
3~
~ '~
,.:
.~ a~ ,_ ....
C , o ~ ,_ ~
¢ ~ ~ q I O O ~ ~ ~ V
U~ ~ .
~rl ~H ~ ~ O ~ ~ 00 a~ ~ ~ O.
.,, .,, .::
.~ ~a ':' . . .
.~ ~ ~ ~ . .
~ ~C n o ~ coIn ~ a~
~ ~ _~ ~ o ~ a~ ~
h C~
~ ~ q ~ U~ Ln 11~ ~ ~1 ~ ~1 ~=~ ~ ,F~ ' ~ D O O
a~ ~ ~
I ~ ~ I ~ ~ I ~rl ~ , O \ =-Z ~ ~ ~ h h ~--I ' ~d h O .
f-l r-l ~d td~ O t~ ~ O t~ ~1 ~1 u~ u~ o o 3~ o ~ ~ o ~ o ~
o h ::
a~
a) h h ,~ U~ ~ Ul .
E~ , , ~H ~ .~ ~
c ~P ~ N ~ .
.~ ~--J ~
4~ 0 ~D ~
h ~ : ~
g .rl h ~ O ;: ~.
O .S h O .. :
..
--i 2 1 ' ':, As can be seen from the Table the compounds of the invention are potent inhibitors of the neuronal uptake of 5-hydroxytryptamine and noradrenaline. The Z-form of the compound of the invention shows a stronger inhibition of the uptake of 5-HT in vivo than do any of the prior art compounds tested.
The Z-form of the compound of the invention tested as the hydrochloride, is further a more potent inhibitor of the uptake of 5-HT in vitro than any of the prior art compounds. ~The difference appearing between the ~-oxalate and the hydrochloride is believed to be due to the fact that the hydrochloride was prepared from the oxalate whereby a more pure Z-isomer was obtained). The E-form of the compound of the invention primarily inhibits the uptake of noradrenaline. The inhibition of neuronal uptake of 5-hydroxytryptamine and noradrenaline disclosed, may give the compounds of the invention value as anti-depressive agents. Likewise the compounds of the invention may be useful as anxiolytic agents.
.
~.,,.'' ~, .
.'. .: '' ', : ' ,. ".
~ ~ .
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
or a pharmaceutically acceptable salt thereof, which process comprises (a) dehydration of a compound of the formula to provide a compound of the formula I, or (b) alkylation of monomethylamine with a compound of the formula wherein Y is a leaving group to provide a compound of the formula I, or (c) introduction of a methyl group into the compound of the formula to provide a compound of the formula I, or (d) treatment under hydrolytic conditions of an acyl or sulphonyl compound of the formula wherein Z is an acyl or sulphonyl group, to provide a compound of formula I either directly or via an unsaturated acyl or sulphonyl compound; and (e) if desired separating an E - Z isomeric mixture obtained by any of the processes (a) to (d) to provide the E- and Z- isomers in substantially pure form; and (f) if desired converting either an E - Z isomeric mixtures or the E- and Z- isomers in substantially pure form into a pharmaceutically acceptable acid addition salt.
or a pharmaceutically acceptable salt thereof, which process comprises (a) dehydration of a compound of the formula to provide a compound of the formula I, or (b) alkylation of monomethylamine with a compound of the formula wherein Y is a leaving group to provide a compound of the formula I, or (c) introduction of a methyl group into the compound of the formula to provide a compound of the formula I, or (d) treatment under hydrolytic conditions of an acyl or sulphonyl compound of the formula wherein Z is an acyl or sulphonyl group, to provide a compound of formula I either directly or via an unsaturated acyl or sulphonyl compound; and (e) if desired separating an E - Z isomeric mixture obtained by any of the processes (a) to (d) to provide the E- and Z- isomers in substantially pure form; and (f) if desired converting either an E - Z isomeric mixtures or the E- and Z- isomers in substantially pure form into a pharmaceutically acceptable acid addition salt.
2. A compound of the formula or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.
3. A compound of formula I according to claim 1 in the form of a geometrical isomer, whenever prepared by the process of claiml,or by an obvious chemical equivalent thereof.
4. A compound according to claim 2 characterized by the formula or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7414622A SE388854B (en) | 1974-11-21 | 1974-11-21 | PROCEDURE FOR THE PREPARATION OF PHENYLPYRIDYLAMINE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1056834A true CA1056834A (en) | 1979-06-19 |
Family
ID=20322772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA240,075A Expired CA1056834A (en) | 1974-11-21 | 1975-11-20 | 3-(4-bromophenyl)-n-methyl-3-(3-pyridyl)-allylamine |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS5176278A (en) |
| AR (2) | AR211921A1 (en) |
| AT (1) | AT346328B (en) |
| AU (1) | AU501915B2 (en) |
| BE (1) | BE835802A (en) |
| CA (1) | CA1056834A (en) |
| CH (4) | CH614937A5 (en) |
| DD (1) | DD122528A5 (en) |
| DE (1) | DE2550005A1 (en) |
| DK (1) | DK147179C (en) |
| ES (4) | ES442758A1 (en) |
| FI (1) | FI61484C (en) |
| FR (1) | FR2291751A1 (en) |
| GB (1) | GB1530804A (en) |
| HU (1) | HU171206B (en) |
| IE (1) | IE42615B1 (en) |
| IL (1) | IL48409A (en) |
| LU (1) | LU73844A1 (en) |
| NL (1) | NL7513648A (en) |
| NO (1) | NO149775C (en) |
| NZ (1) | NZ179247A (en) |
| PL (2) | PL103999B1 (en) |
| SE (1) | SE388854B (en) |
| SU (1) | SU686614A3 (en) |
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| ZA (1) | ZA756893B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2857020A1 (en) * | 1977-07-04 | 1981-01-08 | Astra Laekemedel Ab | A NOVEL INTERMEDIATE FOR PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDINE COMPOUNDS |
| SE409860B (en) * | 1977-07-04 | 1979-09-10 | Astra Laekemedel Ab | A NEW INTERMEDIATE PRODUCT FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDINE COMPOUNDS |
| SE7909514L (en) | 1979-11-16 | 1981-05-17 | Astra Laekemedel Ab | NEW HALOPHENYL-PYRIDYL-ALLYLAMINE DERIVATIVES |
| US4312368A (en) * | 1980-02-20 | 1982-01-26 | Philip Morris, Incorporated | Smoking compositions |
| US5148817A (en) * | 1980-11-07 | 1992-09-22 | Philip Morris Incorporated | Smoking compositions |
| CA1150269A (en) * | 1980-11-14 | 1983-07-19 | Carl B. J. Ulff | Process for preparing 3-(4-bromophenyl)-3-(3-pyridyl)-allylamines |
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|---|---|---|---|---|
| CH83A (en) * | 1888-11-17 | 1889-01-10 | Fontainemelon Horlogerie | Improvements made to the construction of watches of all calibers |
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1974
- 1974-11-21 SE SE7414622A patent/SE388854B/en unknown
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1975
- 1975-11-03 ZA ZA00756893A patent/ZA756893B/en unknown
- 1975-11-04 IL IL48409A patent/IL48409A/en unknown
- 1975-11-07 DE DE19752550005 patent/DE2550005A1/en not_active Withdrawn
- 1975-11-14 NZ NZ179247A patent/NZ179247A/en unknown
- 1975-11-14 AU AU86627/75A patent/AU501915B2/en not_active Expired
- 1975-11-17 NO NO753849A patent/NO149775C/en unknown
- 1975-11-18 ES ES442758A patent/ES442758A1/en not_active Expired
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- 1975-11-19 FI FI753260A patent/FI61484C/en not_active IP Right Cessation
- 1975-11-19 YU YU02939/75A patent/YU39153B/en unknown
- 1975-11-19 SU SU2189809A patent/SU686614A3/en active
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- 1975-11-20 CA CA240,075A patent/CA1056834A/en not_active Expired
- 1975-11-20 FR FR7535539A patent/FR2291751A1/en active Granted
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1979
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