DE1942135A1 - New chemical compounds - Google Patents

Description

Patent attorneys

Dipl. Ing. F. Weickmann, Dipl.lng. H.Weickmann.Dipl.Phys.Dr.K.Fincke Dipl. Ing.FA Weickmann, Dipl. Chem. B. Huber

8 Munich 27, Möhlstr. 22nd

? A 4639/960

LILLY UiDUSSRIBS LIMIiEED, Losdon W. 1 /! England and AHD OQHPAIIT ₉ Indianapolis, Indiana / USA

New chemical compounds

The invention relates to new chemical compounds with a AntiBchis fcosomiasis aliasis.

Duron the invention, compounds of the formula given below (and their pharmaceutically acceptable salts) are available ^:!

Ο 0-9 8 4 0./22 O

OHPORo ^{2 Z}

In this formula, X is a sulfon or carboxyl group, H _{1 is} a halogen atom, a Xrifluomethylgruppe or the group -SB- or -OE ₅ , where Bg is an alkyl radical with 1-4 carbon atoms, K _{2 is} a hydrogen atom, the Group -OO.Bg, where Bg is an alfcyl, aryl, aralkyl or haloalkyl group * or the group -00, NH ₂ * -00.JJHIU or -00.H (Ry) ₂ , where B «is an Al & yl group , H _{5 is} a methylene group that can be substituted with a methyl or ethyl group, B. a hydrogen atom or an ACyl group with 1 - 6 carbon atoms and η 0, V or 2.

Those compounds in which B _{1 is} a chlorine or bromine atom, B is a hydrogen atom, B 1 is an alkyl group with 1-4 carbon atoms and η is 0 or 1 are particularly preferred.

If B _{1 stands} for -SR ₅ or -GR ~ _S then R- is preferably one Methyl group. B _{2 means} the group -CO.R ^, where Rg is a

Is haloal3syl, then Eg torsionally means -CHGl ₂₉ -QQl-T ₉ -OEP ₂ or -03? «.

The invention also provides a method of manufacture created the compounds defined above. The β it Method consists in using a dihalogen sulfone or a hihalogen sulfone of the formula. .

B ₄ .0HI. CB ₃ ) "^. (X).

in which X, "SUg B ₄ and η have the meanings given above and I is a chlorine, bromine or iodine atom, with a 1- (4-hydroxymethylphenyl) -piperaain of the formula

009840/2204

₁ the meaning given above tie si did, In the presence of an ice base to form a compound of the formula

ί I

fe? * - nnä GegeTseneafaH ^ aoBefelie ·: -: - ■ end die »ter Btlil ": '- ^ the YerMndung' - '

¹¹ 1 0FOR OH

0 0 9 8 4 0/2 2 ο 4

where Ag represents the group -CO.R ₆ , where R ^ is an alfcyl, aryl, aralkyl or haloalkyl group, or the group -00.NH ₂ , -GO.HHR ₇ or -00.H (Ry) ₂ , where IU is an AUqrlgruppe, acylate and optionally prepare a pharmaceutically acceptable salt using a suitable acid. A dibromosulfone or dibromoketone is preferably used as the dihalosulfone or dihaloketone,

A tertiary amine is preferably used for the base, triethylamine is particularly preferred.

The acylation of the 4-hydroxy methyl group to the ester or urethane groups, which are represented by -OHgQRg, where R _{2 has} a different meaning than oxygen, can be carried out in a simple manner using customary methods * If an ester group is to be formed, then the 4-Hydroxymethylgrrappa are reacted with the corresponding acylochloride Rg. 00, Gl, where Rg has the meaning given above _p . If a urethane group is to be produced, then the 4-hydroxymethyl group can be made to acidify with the corresponding leocyanate or carbamoyl chloride.

The invention also provides a process for the preparation of those compounds according to the invention in which η stands for 1. This procedure consists in making a divinyl sulfone or divinyl acetone from Pomiel;

B ₄ .CHeOHg. (X) .OfigaGH.R ^

wherein X and R. have the meanings given above and Rg is a hydrogen atom or a methyl or itby! group isii, with an lsin from Pormel

.009840 / 2.204

CH ₂ OH

wherein B _{1 has} the meaning given above, with formation of a compound of the formula

OH.Bj.iX)

OH ₂ OH

GH ₂ OH

wherein B ^ ₉ Β ·, B * and X the meanings given above, reversed and optionally subsequently the 4-hydroxyethyl group with a corresponding aoylating agent to form the compound

? 4? 4

CH.Hj. (X). B ₅ . CH

009840 / 220A

where B _{2 stands} for the group -GO.Rg, where Eg denotes an alkyl, an aryl, aralkyl or halogen-substituted alkyl group »or the group -00.HH ₂ V -00.HHE, or -00.9 ( Ey) ₂ * where E »is an alkyl group, acylate su and, if necessary, produce a pharmaceutically compatible sale using a suitable acidic.

The acylation of the 4-hydroxymethyl group can be carried out in the manner described above.

The flubstituted 1- (4-hydroxyethylpheisyl) -piperai! III starting materials can be prepared by suitable methods. A method which has been shown to be mveokmäseig is illustrated by Example I below. This example describes the production \. 2-BrosM- (1-peraainyl) -ben ~ eyl alcohol. An aniline, which is _{substituted by the group E 1} in the J position, is treated with dietary alanine to obtain the H- (3-subst _e - ^ enyl) -piperasine, whereupon the last-mentioned combination of ionnsrlderiiraits is fonaylated. Me IMaateung with Phoephorozyohlorid and Bioethylfoxm & mid has subsequently the oroqrlierung of the Bensolring in the p-position on the Piporaziaring but follow. The hydrolysis of the IT-formyl group gives the 2-substituted-4- (1-PiperaBiayl) -ben »aldehyde. Reduction with sodium borohydride results in the formation of the desired substituted bensyl alcohol.

Other suitable synthetic methods can also be used for HatUrlioh.

You erf indungsgemässen compounds and their Säareadditiomesalze are extremely effective Kittel sur treating Soiii- stosoioiasis at Xieren _y such as Mgasen and monkeys.

0098AO / 220A

In addition, binds are effective when they are either up administered by the oral or parenteral route.

The compounds are used to control sohistosomlasia in such a way that they are administered to the infected host animal in therapeutically effective amounts, the amounts usually being about 10 and about 1000 mg / kg of the body weight of the host animal per sag. Bio preferred levels vary between about 50 and about 500 Hg / leg. The compounds can be administered in one dose of Bosieren. The active ingredient can be used alone or in combination with a pharmassutisottem carrier, for example "a fast or liquid Verditeniingemittelf Puffes * Biademittel, Besofaiohtusgßisatsrialp itoilgiermittel or Äergl © ioheii ₉ TerWöMen. The solid B © pien! Ngefo3raien are especially for the ge _ö SemSss an AusfÜhEusgafo ^ ia drr eats charge ^ der;? ew © 3-ligö ¥ irtetoff lh a «, jJhyßS.el: egieoh SirSger eiügßnieisgt» for example lit esfne Eompöaönte in a rembination of Εοηιρο · ■ ηΐ ^l ttt1i "er0 ^; de & ^:? -Wii? 'TB' tieres «Wiihlweiß can be used as Ϊ3?% © ε Jeaeß * inerte _f ^ send wiiMeende feterlal, that of. the Wi ^ tstiele is "" vext & hands $ -Will * Where this IFE1;? e5 £ al-eelbet pfcygslölGgiBöiie effect has "ÄEWäimt be be ± spi®lßw © iee ioaenauetauscherharae Other solid Boeißrungsformen _p as beiBpielawsißs Cable tablets and / or-!.! Filled capsules, which contain anti-seizures, as well as one or more of the substances that are sometimes used, such as egel0W @ le @ SaIk, xaotose, starch, magnesium stearate or methylsellulose, can be used with equally good results

The following examples illustrate the invention without it su restrict.

000840/2204

BATH

1 9-21 35

example 1

ethyl} sulfone

A ₉ H - * (5? * Bromophenyl) -

69 g of 3-bromoaniline _e 47 g DIMthanolamin and 93 ml of a 48 T gen BreimR ^ serstoffsäurelösung be slowly heated, wherein the aqueous fhase distilled 1 1/2 hours under a temperature rise of the Eealrtionsmlschung from 110 to 180 ⁰ C for a tent range sound. The light brown mixture is axially heated to 180-200 ° for a period of 3 hours, the dark brown liquid obtained is poured onto ice, made strongly alkaline using a 5N solution and extracted with ither. The ether extracts are combined and dried over Kaliiaohydro ^ d ^ Plätsolien, evaporate, the oil, the brown viscous oil is distilled under reduced pressure. In this case, 52.8 g of N- (3-bromophenyl} "piperasin in the form of a straw colored viscous oil (Ep. Obtain 116 to 12O ⁰ G moji mm).

B. 2-Bromo-4-C i-

27t 4 g of the H- (Brosaplssnyl) -piperazine prepared in the manner described above in 50 ml of 'Bensol are under Use your own bean tsnd Stark separator to collect dee Beaktionswagsers with β ml of 98 to 100 pounds of formic acid cooked on the Etek River. Eaoh 3 hours the mixture will cooled, whereupon the benzene tea is removed. Be there 29 »2 g of the F-form derivative in the form of a very light yellow color Oil dispensing.

BADORIQlNAt

'«■ Q" -

20.3 g Phosphoirexyehlorid are added dropwise to 75 al dimethylformamide »during which the temperature is maintained at 40 ⁰ C over a period of 30 mewed. After cooling, the solution is added, with vigorous drilling, to the aforementioned IT-fformyl derivative, dissolved in 50 ml of dimethylformamide, which is heated on a steam bath. The ear and heating to 90-95 ° C are continued for 1 hour. After cooling, approximately 60 ml of the pear thylfoxmamide are removed under reduced pressure. The product obtained is poured onto 400 ml of a bis / water mixture, made alkaline with a 35% (weight / volume) sodium hydroxide solution and extracted with chloroform. The chloroform extracts are combined, washed with water and evaporated to give a dark brown mobile oil. This oil is heated on a steam bath for a period of 30 minutes with 100 ml of 2.5 N hydrochloric acid. After cooling to Ö ° C overnight, the slightly brown crystalline product is filtered off, washed with isopropanol and dried. This gives 16.3 g of 2-ÄPom-4-Ci-piperazinyl) benzaldehyde boron chloride.

C. 2-Bromo-4 - (1-pjperazinyl) ~ benzyl alcohol

16.2 g of prepared in the manner described above 2-BrOnM ** (i-piperazinyll-benzaldehyde Härdrochlorids be slurried in 100 ml of methanol, äbgektthlt to 0 ⁰ C and a solution of 1.55 g of sodium hydroxide in 5 ml Water is added, followed by the addition of a solution of 2.15 g of sodium borohydride in 20 ml of water. For 30 minutes, the methanol is removed under reduced pressure the solution with chloroform

009840/2204

- ίο -

ι - ■ ■ ■ - ■■ '-.-

is extracted. 2He OMorofosmextrakte are combined, with activity beliaafielt, evaporated over an anhydrous mid · Bafcei an oil is obtained, Oa® large solids also is waisted, Bine ΐΜ-from Itliylaeeiiat lies 6 _f 4 g dee Gewüasoiir ·

Broduktss in the form oremöfart) 83i9r Erlstall © (F. 123- ^ -sulfone

10.5 g 2-3rom-4- (1-pipea ^^ i2 ^ 1) -fe © ni ^ lallJX> 1iol be is 1 liter of HHhr © B l? at room temperature dissolved. A © £ & »

atis 2 _e 55 g Mvisylsulfon in 20 si Ethanol wisä drops wise fortune ainer Seitspaima of 20 Mimiten migseetst. Sann is the Misohuog About Haoht feei ZiEsmertei ^ & ratar rülirt tiM abauhllessand ¥ .äiH? Eiiii a gieitspasme of 1 to a de DaiBpfbaa held iiao ^ eisiem AbkQhlesi usasl lieslessezi the solid is gescmsoslt and tmüsristallieiert from ethanol. BaMi yr & raen 6 ₉ 2 g ~ bie- {ß ^ [4'O Brom-4-liyarüsyme thy! Phenyl) -phenyl) -piperasino] -äiaiyl) STilfon (F. 146-148 ° 0)

Analysis:

Bereotoet! 0 47 »28, H 5.50, ¥ 8.47 3έ Found 0 47.00 »H 5.45r H 8.32? Έ

Example 2

Bis- Iß- [4 "(3 ^ chloro-4-lvdroxyiBothylplienyl) -piperas5ino3

A solution of 0.6 g (0.005 mol) divinyl stafoii in 5 au nol Is a ge during a period of time 70η 10 minutes

0 0 9840/2204

Solution (~ 3 ^ hydroxymetE2ylphenyl hlor ° 4) ~ piperazin temperature added 2.26 g of (E _f O1 moles) i- in the minimum volume of 30 ml ItIiSUEU) I in Ziaaaar "That stirring is continued. Small amounts of a we read! Solid fall out of the compartment for 30 minutes. For 16 hours the mixture is refluxed over a period of 1 hour and then cooled. The precipitate is collected and twice converted from ethanol. The product falls into Έοτ®, white prisms in an amount of 2.5 g {?. 140 142 ° 0).

Analysis; ^ gSW ^ gV ^ S
Bereehnets O 54 * 69 * H 6.56, S 9.83
ö 54 »70, H 6.44 · H 9« 52

Biner KiSBßg from 22.5 g "(0.1 hol) 2 * -0hlor-4- {T-piperael & yl ') - benBjlal3coh.ol in 250 mol Xthahol will 12 * 25 g (0.125 mol) 2feiätiäyla? Iiiii sugesetst. This 3jösung vix & drip emieise a solution of 12.2 g (0.05 Hol) 2 _s 4-I> itoiiömpentan-3-one in 50 ml & thzmal KUgesetst. It is heated for a period of 24 hours. "

The 3 & 6 agent is under -missAertam Bruok whereupon the turning oil is poured out with Moroform and water. The Ghlorofona extract is separated, dried over Batriua ^ ulJTat and your removal of the oil is evaporated (Silica gel) _s being with a mixture

009 840/2204

1942131

';■■' ■. · * Η>»' ■■. /. - ■■■. ■■■

Oil croform and methanol (96/4) eluleaft wiiPäl *

A üinla? Ißi; allieai; ion of the combined factioni]. yields> 1.7 g of white crystals (F, 150 - 152 ⁰ O, aioh *

Analyzes

Bereoiuieti G 60.55 * H 6.78 »Ii 1O ₉ 4ß 0 60.20.2 6.77.5

Εβίβρί, βΐ 4

Eiaer IitJsimg from 11.2 g 2-Jiol to 250 hlL Ittenol are added 2.7 g. The HeafctionsmieeiiwBg w: irä isgh & miü. eiae ^? 2 Uagen gerülirt and anscKLleseeiiä wäiiremd ei & er 1 hour before hurry & flow

The Iiösun ^ mitteX will wfeea? yeami at least Bsmofc xriiofclJleiJsezueLe öi ¥ äa? ä An siaer SSpXe the column is filed with stone! Me fS | $ u93ng | B follows υ »* θ3? Terweadung aj?

4,0jgifsiaeer Isjieiballe Cf _o 142 - H4 ° 0

G 61.01, p. 7 * $ 1 ₉ . M ϋ 61 ^ 75, S? »W # M

Example 5

The effectiveness of bis- £ ß- [4- (3-CMor-4-methylphe »yl) -pipöraslno]" ethyl ^ -siafon opposite Sohistosoma mans on L Clay on experimental ¥ ega infected lieren is in the the following ¥ ei8 © determined:

löiere that Kiosnischen with the Puerto strain have been infected by S.mansonl, are divided into groups, each group 3 - 5 includes animals that are kept Siere 6-7 weeks prior to the treatment to the infection to proceed blank zn. In any case, at least one group of patients is not treated during the whole trial, after the infections have reached an advanced level, the rope is administered to the Xiere, and is carried out by means of a gastric tube or a similar device, after which treatment is necessary The second is held for a further 10-18 seconds. They are then killed, whereupon the remaining worms are counted ₉ The results are given in the following tables

table I ₁

Hospitality from to - ^ [4- (S- ¹
BiBgglgiiagLlrM ^ yl, j ~ aulfon ^ opposite S _ft zaagaoM

liamsbsm

daily oral dose, mg / kg

125 250 400 500

average Number ah l W ürmer / treated gers ™ ~ * "~ Annam 3 W & mer / Vergleiohstiere

number the urinary
eter number
the sun
fail percent
sentence d. the
Cans 3 1 O 5 3 ■ - ,. ■ ί 13th 5 3 ο 4th 1 54. 5

χ loo i>

009840/2204

Table II

volume
piperazine »j-a-thyl \

la mice

daily oral dosage, mg / kg

25th

50

100

150

200

Sheets.

5 5 5

5 5

in the

5 5 6 5 Äusahl
the so «
failures

11 19

62

MscLung © in ©
sits,

argeltsn, eat the Torat © k «fit V generally mice T # n> 1Qü0 mg / kg body weight

The Wirkaaaücelt of

piparaBlao3 ™ ätliyl ^ -sulfoa gellliar Schistoaom B ^ bSqM la Mäiisen will be "aeh the general example 5- ijesaiirieba & eii -Matknde" a You results "siM in the ^ © Igendeii 2ab © lle

. ■ ■ - ■■ ^ --- ■ "belle _III:

daily oral dose is, lasaiil üev number of iBg / kg '-. . ' _ia _ cans

100
150
200

5 5

O 1 ο prosentsata the

30 100 100

0 0 9840/2204 bad ORIGINAL,

of 1, iMp

} pI |> eEasia3 against Schistososa ssanso- Ώ.1 In EamtaxiL , according to the Hetliode "beetiiroit" in Example 5, the results are 1 »of the following table

chapel HT 1 number & l the fo « Prosentsata of the
β- ", iöglioiiö oral dose ,. the
. lametsr Ö 78 SO the
Cans 4th .0 85 100 5 8th 0 54 15 © , 5 * ■ 0 75 * ■ 200 5 4th 5

Claims (1)

Patentsiisprttcii © 1. Compounds of the general formula where for a sulfon or carbonyl group, H _{1 is} a halogenator, a SriCLuormei ^ yl group or the group or ~ 0Be t? ed © tttet _t where R- is an AByIr it t with ί · ■ * 4 material atoms- _r R ^ is a hydrogen atom »the group where Rg is an allqrl-i aryl« - »Ατβΐϊψΐ ·" or, or the group "00; KH ₂ , -Ö0.HER" or R _{7 is} an alfcyl group, represents R ^ a die durcli a Metfcyl- odor itiQägn ^ pe 0Uti> stittt £ 0ai? ii can, Trersiniibildliclit, R ^, a water st offatöiH öö # 3? 0l «ne Alliy! group with t - β Eoliiensteffat omen is taafi | tf Ut Of ί or 2 stands »as well as the pMraaeeiitiBcai Tertr% lie | iöin salts of these compounds. 2, according to Verbinöimgen Aaßpruch 1, characterized gekemizeio | inet ₉ that R ₁ for a Ghlor- ODSR Broiastom, R ^ is a hydrogen atom, R ^ © ine Allqrlgruppe Mt t -4 KoiLlenstoffstOiaeii tet and η O or 1. 0984 0/2104 - .17 - 3. Compounds according to Anspmoh 1 or 2, characterized in that R _{2 is} the group -OO.Rg, where Rg ₂ , ₅ , -CHP ₂ or f ^ ^. , .. .. 4. Connections »acli one of the preceding claims, characterized in that the IW füa? one methjl © ngrnpp9 stands, ^ ,. ¹ V-; '.'_; ? »J 5 "Terfahren s" r Heass division ¥ on; 7ea? ^ Indiaiigs "gssaäes An sprach 1.-4" äadiarQli gak@2msslohiie.ij5 ü & bb Bin keton or Dlhalaganstalfoa dar ^ R ₄₀ OHIo wherein X ₉ R ^ ₉ R ₄ and η represent the regrets mentioned in claim 1 and Y © in Ghlorr. »'Brom- © represents iodine atom with an i - ^' - ^ ydroxyaethjlphönyll-piparssia OH ₂ OH. wherein R _{1 is} the in claim 1 © ugegabsna B8de »fe ^ sag in the presence of a base under Bil & iassg a Yerbindimg der 009840/220 s-Jird, worais? aoseiiXiLeSend ■■ if necessary- tile 4 «. & srlg ^ uppe rait a "suitable. eylation withfcel ■ untei · education -der 3. rn where Bg-fIiF oils group -S (KB ^ * -. MOböl Rg a © Ailcyl Aral ^ rl «or haloalksrlgz'uppe '... or et Is group -CO.HHFU.oddr -00.H (IU) ₂ , 'wotoai R-' sine Äll ^ lgruppe represents j aeyliert is läHd 'if necessary nnfcer use of a sssigaaten Sä »r © a pharmaceutical% -artpMglielies SaIs is produced from it» δ, method naoh'Anepruoh 5 * daduroh gsk @ Bnseiülinet _s ciai the dihalogeiiketone or bihalosulfone used is a di- ρ - BADORtGINAL 09840/2 204 "bromketon or DlbroiasulfOn is" 7 «¥ er £ afaren according to Claim 5 October 6 _V daüurcli gekenaseionnetj that triethylamine is used as the base 8. Yerfateen aur producing a YerfeincLiing iiaeli claim woria a for 1 stelit _f dadurcii geke5mi? Eicimet _P «fees a or Divinyllcetoa der R ₄ . CH = OR ₈ . (X) ₄ X oxide R ^ which imgegeteiiea in Anspruoii 1 "τζαο Rg have a Waeeeretoffatom or a» Mai & jrl- or is _s rait a 1 - * ( Formation of a Yerbinfinng äer formula ¹ GHgOH OH ₂ OH 009840/2204 where R | , Rr ₉ R *. and 2 that have in-tuations, only if subsequently the 4H suitable aoylating agents under the formula 1 given © & Beaeu is given slightly en- with © l »em © iner i ^ where Rg stands for the group -SO _# Rg _e where Rg is an alkyl «· _{f /} -AryX—, ■ - © of the Ealogenallqrlgruppe iet _# or the group gt -OO.HHR ™ or -ΟΟ.Η (Ε») _2β where E "© inegruppe is, provides, is aoylated and possibly pbarmaseutieo ?! The contracted acid is produced using a suitable acid. 9 * Terf almen naoh one of the AiaeprSie & © 5 indicates that the ^^ drox ^ methjlgrup ohlorid Rg.CO ₄ Ol ₀ where Rg has the definition in the claim, is ao ^ lated. Bg daiureh ιώθ with