DE1695890C3 - 3- (2-Lower alkyl-4-aminopyrimidinyl-5-methyl) -4-methyl-5-lower alkylthiazolium salts - Google Patents

Description

nh; χ

NU,

N "

cn. N
χ

N ·

N-

CH. N

III

CH,

in the R and R 'alkyls with 1 to 3 carbon atoms and X is a nitrate or rhodinide ion

2 Process / for the preparation of 3- (2-Nicderulk) I -4 -aminop> rimidin \ l - 5 · nwih) Ii · 4 · nicth) I-5 -lower alkyl-thia / olium salts of the general formula
·; ■■ ·. ■ ■ \ \ NH. '■. ■ - ■ "-X' ·. '. ■■■■■ ■■' where R is a lower alkyl radical with I to 3 carbon atoms and X is an inorganic acid radical, are effective against coccidium (Eimcriu sp.) and since this B Disal / e (U terms preventing and curing / idiosc have a remarkable effect of Kok and (2) no adverse side effects on the growth \ poultry after treatment / own.

The invention relates to 3- (2-lower alkyl-4 -amino-pyrimiclinyl.5-methyl) -4-methyl-5-nicdcralkyl-thiaz'oIiumsalVe of the general formula I.

NII,

NN ¹

., "- S

αι.,

lit

-CH, -N

\, J

CU ₁ , R

in which R and R 'are an alkyl radical with 1 to 3 carbon atoms, in R and R' an alkyl group with 1 to 3 carbon atoms and X is a nitrate or rhodanide atom and X is a nitrate or rhodanide! on bc -Ion means characterized in that in a known manner a compound of

general formula

NH,

R-

N-

indicates.

These compounds can be prepared according to the invention by being better known in tin Way a compound of the general formula II

'■. '■ - ■' NII,: ■■ '- ■■ "-". S ¹ "^;". ■: "■ ^; ...

-CH, ~ N I IID

HO CH, R

-CH ₁ -N
-

_N "

in which R and R 'have theobigo meaning, with Hydrogen peroxide unisetzt and the obtained Solution after neutralization with nitrate or Rhodanidioncn added.

3. Agent for the treatment and prevention of coccidiosis in poultry, consisting of one Thiazojium salt according to Claim 1 and customary auxiliaries and carriers.

4S

The invention relates to 3- (2-lower alkyl-4-amino- $ 5-pyrimidinyl. 5 · methyl) · 4-methyl> 5 · lower alkylthiazolium salts, a process for their preparation and an agent consisting of these compounds and customary auxiliaries and carriers Treatment and prevention of coccidiosis in poultry, do The Kqk / idiosc is a frightening and fatal infectious disease in poultry, and its treatment and prevention is known to be one of the most important problems in poultry farming. Various agents have heretofore been used to treat the disease, but these known agents have drawbacks. eg low effectiveness and strong, unpleasant side effects.

HO CH ₁ R

in which R and R 'have the above meaning, are reacted with hydrogen peroxide and, after neutralization, nitrate or rhodanide ions are added to the solution obtained. ^!

The compounds according to the invention have an equally strong effect in terms of prevention and cure coccidiosis such as the Disalzc mentioned above, which according to DT-AS 1692498 dem known sulfathiazole, as well as the following additional benefits:

1. They have a higher storage stability than that Disalzc

2. They are less hygroscopic than the disalzc.

3. As they have no electrostatic properties they can be easily mixed with the feed. . · ■ '

The diiich R and R 'in the above .Formula I represented lower alkyl radicals with 1 to. ^. Carbon atoms can, for example, methyl, ethyl, pro ·', be pyl and isopropyl radicals.

The means according to the invention contain the as Active ingredients against coccidiosis quaternized thiazolium alcohol salts of the formula I in dispersion or mixture with suitable carriers oiler Thinners. Depending on the different Conditions, e.g. B; Type of poultry, feed

! '»' Dci-AUvr«! I "s. (Jv'iV.ijvls. V.nuten tlii 'W'f (Vvtö (left:
in ZtiK'reituii ^ iT !, wy powder, iii.inu1.it. labie'tcti,

wedge administered ihKm mixed with the Gviliigvlfuttet

''. or ιϊη drinking water can be drawn. Preferably s

. now uses Ti agermittel »nler 'thinner,'
who often do not react with the act and with certainty MannhCrV wesik * I evltoniktikci) ^l > '! ", rv atf

hay can be given to the poultry

dgnct are, for example, kitchen dishes. Weizentuehl * Infeklutscs O ^ yiduim

Mauniehl. Soybean-based feed. Soy- m Sporulated Oovystcn Mm Ίνΐηκπ; * "iene.Ha.
bohftenmeh !. Vegetables. Muse meal, fish meal, soy

KihncnNChrot. Grain, fermentation residues, rice- ^{: J} > Verahioluse yethimhii ^ en

bran. Potash, starch. Lactose. Sucrose .: GIu- As Tesivcrindunueit the Mononiinif and

cose. Fructose. Molasses. Antibiotic mycelium. Vitamins. Monorhodanid von, Vi2-Mcth> I> 4nimiiu> p> rimidinvli.räuhkner Lime. TiMUi like iy 5-methyl) -4,5-dimethylihiazolium (iiiu of a concentration

The * optimal concentration of the means depends in a tralion of 0.0063% in the feed. animal poultry species and the handdinyl · 5 · methyl) · 4,5 · dimethyl Vthiazoliumchtond · lunüs / weck, ie prophylaxis or therapy. Supply hydnKhlorid (Disalzl in a concentration son ^■: bereitun'gen any desired concentration kön-: o 0. (1063% in the feed used,
by appropriate choice of the diluent · Λ · ι ι «

and determining the appropriate ratio of ⁴ experimental methods

Carrier to active ingredient. In general, the chicks mentioned above are 8'lage. '

mine are preparations that are about 0.001 to separated! held and on their GesuhdhciNzuttan.d

-'0.05 "-O. Preferably about O.rt) 5 to 0.025 weight 5 chicks divided Ls.'wird daratii pefutter or water for treating or preventing respects, the DAT lnitlleie ^weight: Eder group "is equal to the disease. The quaternary is used for therapy. One group each serves as a test group and control thiolium monosalts, preferably in the higher group. There is also one included and one non-included group from O.OI25 to 0.05% used. According to the classification, intermediate preparations are divided into the groups: the test group and the consumption concentration, using a suitable control group, the feed containing the compound diluents or carriers mentioned beforehand, and the infected Group and those who do not provide and then the finished feed in the required group receive the normal! Feed. As a concentration of a feeding period of 24 hours in the intermediate preparations, all animals with the exception of about 1 to 30 percent by weight of the quaternary thia / or the uninfected group were given orally with 00 '(H. ) 0 OoeyMen liummonosalzc in question. infected by Eimeria tenella.

For a better understanding of the invention.; will ,. r,. .

the major experiments and examples are described. 4 "5. Beol seals

The quantities given relate to the mortal wedge and blood drop in each group Weight unless otherwise stated. CeWiehiseile are noted daily until the end of the experiment. 8 location relate to parts of space like gram to mule ·. after infection with Oocystei) all became over liter. living animals killed and pathologically examined

. '.. ■: & Explanation of the' results' mentioned in TaMIe I

Growth rate Vf M; "^,], _{| (H)}

y Average body weight at the start of the experiment J

.., -, ■. '.. ■, - ■■'., »'Ι. Growth rate of test group ,, «,

Ratio of growth rate -. ,,; v-. Γ t> n - 1 € X>

Control group growth rate

Blood drop: Average B. Oocysts in the diluted λ mi ^ lU-nio 'are never given

Number of drops of blood which come from the intestines each-is _J5 Caccal content ·) '. '

Chicks of the group were excreted. None in 20 fields .. ,,, ,,.: .... 0

I to 5 per F'cld ...... '.' ■ ',. -, ,,, ..:, .... I

6 to 50 per field, .., ...;.,.-... 2

7, efficiency index according to J E. Johnson et al 51 to 150 per field,. ,,, ... . ... 4

-to Mehrais I50 per field; .., ..;., ..., .. H
The effect indev is calculated as follows: • i.tticcaUntali-wird-auf Λ »lofaviic" wnliinnt '»nd u» w dem

; ".». Micro> l (<ip utttcrsueht.

» N.-r.fA., ι -iti.wi.tn <\ i | imiiienie ν ■ Durchwlitiiit de <Weric« A tl) iiivliM.hinit %)?> VSVno Il

A.taecait uastontn is called the inli / iertcn (iruppc.

None,., .-., -.......... ... ,, .. ,, v » _v ., Durchwhnitl de» Wertes Λ »OurchH-linm de- Work". Il

"· ■ '■.''■.;Track,.'.>. ,,., ......... ■ · ι. ...,., .... '. ·· I 65 'at the'Tmyruppch ^.: '

Easy . ,, ....,. · · '2 Wirkuniitimlci ■ »■■''■' - ■ ii. *»

MaBlg,, .. ,, .., 4 If the wetl of »- fiiev'iiliv hl'Aii'l fiirilon W iVimpiindcv

Strong ./,,.,.,:·. S .. _; · - .. the value ο «!

! 6 95 890

■ Piyfi V ^ iS ^ ίΜ \ ■:

S & t-

'■ -itinjfi.tk

it- ₍ ; _f s! V'ίΙ'ίιΒΐΏ '. hi :.

Mononitr.i ¹ . «HK« ι "*

'-t ^ rtippe

KLmHri »iL'j! I; <[V Chlordhydfochlond t!) T» i) /:
tnfi / ieMe KontroMjimppe
nichi tnh / icrte Konirollgiuppv-

»J Vd

U ·:. ■ · ■ : ■ «» IV ^: · '-'. ' mi. ' ■ '. ,; if ^: it ^:

ί.1, Λ

W ic viie Hrüchni'iso in the part I / own, are d.is Miunvinr.il and MoRorhiHijn.it \ on 3-42-Methyl- ■>-jmiiiopvnmidin> i-5-tncth% li-4.5- « liinc (h \ lthi.i / o · Hum. ie the crnndungsgemalkn compounds, the disal / in the effect «.'gen 1 inieria tenella essentially '.μ Ic i who tip and hi (vn none." tjfisiünvii- ■ t : en effects .tiif the poultry

Attempt:

Mannhchcweilk Leehorn chicks. 12 location all!

2. Infectious Coccidiuni
Sporulated oocysts of Himeria tenella.

3. Connections administered

As ■ a test connection! (a) .V (2 -. \ lhyl-4-aminopyrimidin - 5 - .lambda..sub.i - methyl) - 4.5 · dimelhylthiazoliummononitrai in a concentration of () (X) 3I ^o i>, (MXW ¹ O and 0.0125%.. in a ;; u see well-known Cietiügelfutter \ used.

The \ t> r \! E! U * iuS ^ en.tnnten Kükec. “Eider I! ! '. (·.' (. ■ separated eehalteü «in! .isit iliren tie »» nJt · ~ it% / usi.iu>!

ίο 'bcoKichtct You will »pe * oj: en and in five groups / u divided into five chicks each. l> “I pay attention to it. that means the mean weight of each Ottippe 'equals κ. Three and five groups are test dummies and /WC! are KonUoilsmippcn (mfi / ierie group and

J5 not, infi / ier'ie group). The chicks in every teNt group receive a feed. d.K die Verbiiuhms: iai m den Contains jien ^ nnten terms, and the bumps Control groups receive a normal poultry fmtc. After 24 hours each chick will. with exit,

jo would take the animals of the non-infected control group inoculated orally with 50 (XX) oocytes of Eimeria tenella.

5. Observations

Mortality and blood drops in each group are recorded up to the end of the trial. 8 days After ίηΐϊ / ation with oocysts, all surviving animals are soldered and pathologically examined.

The explanation of the results mentioned in Tabe '! E2 isi. the same as for experiment I.

Table:

tier connection in lutu-r

Cicuichl's blood droplets according to

/ unahme iniiex

C.) .'Tagen aTagen STagcri

'Test group

K-Mdrollgruppe

Mononitrate (a) 0. (X) 3l
Mortonilrat In "0.006.1" ■
Mononitrate la) 0.0125

ind / ied controls! ruppc
uninfected control influenza 106.9
105.2
109.1

80.7
KX)

0
0
0

1.0
0

0
0
0

2.4
0

0
0
0

3.6
0

9K.8

HX) .O

98.1

^; 'VerMJch

a) The chlorinated hydrochloride iDisal /). Mononilra! fan 4 weeks at 30 (. '. 2 weeks at 35 C and

and then Moiifirliodanal von 3-12-V1elhyl'4.aniini) - ₆₎ I \ Voche b / w, 2 weeks at 40 ° C was stored

pyrinHdinvl-5-methyl) -4,5-dinietl)> llhia / ol will iii den 'is, the remaining amount will be the active ingredient in each

the following con / eimations / u handcK group determined. The results are below

usual WathMUmsfiitiiM '■ - (iegebCHi After that in table ?, called.

Kon /

Mcn »cin **« kt AnUit »

l.jgctung hct'4n V bsi "«

cloth cloth

run;

hey

JMf

Chloride hydro chloride

luvh

4 4

W.the W.when weeks Wmhrti W.nhcn

85.0 85.4 86.7 67.5 75.4

Mono- HI 95.4 93.2 99.8 71.7 85.7

nitrate

Mono- 118 92.7 86.5 9ΙΛ 76.2 79.7

rhodanate

b) The chloride hydrochloride (Disal /). Mononitrate and monorhodanide of 3- (2-McthyM-uminopyrimidinyl-5-nic «hyl) -4.5-dimcthyllhiazolium were each a growth and starter feed in one Concentration of 250 y / g. calculated as free 3- (2-methyl-4-aminopyrimidinyl-5-methyl) -4.5-di

methylthia / olium. added. After this feed 2 Wol-hcn had been kept at 40 ° C. was the the remaining amount of the active ingredient in each group is determined. The results are shown in Table 4 below called.

'Table 4

(actual Menpc insider

St.iiterfuiier Wach »iun» fuiiet

Chloride hydrochloride (Disal /) " Mononilr.it Monorhodanate

67.0

82.4 81.4

67.3

84.0 84.9

Chloride hydrofluoride

Mononitrate

salary / u

Beginning %

5.45

0.8.1

Kelalive
lightly
wedge
(%) * Waucrxchall 1%)
After after
? T «| ten MTaycn 8.34
8.48
8.89 52
63
75 8.26
8.42
8.87 0.70
0.79
1.05 52
63
75 0.50
0.71
0.97 6:00 am
5.99
5.79 52
75 6.06
5.76
5.73

IXr ι iKivhluhe water content tk »Rhodjnatv he * is deceiving about 0.2 hi »03%. da da «Rhodarut I Mol (about 5.8%) KrtMallwaMcr revealed.

The ErgehnK-wr / own that the invention

in the case of the monotal / c a higher shelf life

wedge and lower hygro »kopi / itiit have al« da «

Example I The following ingredients are mixed together:

2. Hygroscopic measurements

Each of the salts listed below will be 7 days b / .w. 14 days at 4'C at a certain relative Allow to stand moisture and determine the water content of each salt. The results are mentioned in Table 5 below.

Table 5

monorhodiinai ................... 25

Wheat flour ................ 75

0.05 parts of the mixture are equal with 99.95 Share a »common chicken feed mixed. The feed obtained in this way is fed to chicks.

Example 2 The following ingredients are mixed:

Parts

3- <2-methyl-4-aminopyrimidiny! S-methylH.S-dimcihylthiazoltum

mononitrate 10

Soybean meal 85 Sucrose .... 5

A homogeneous mixture of 0.05 parts of this Mixture and 99.95 parts of a common filling for hatching hens is produced.

Example 3 The following ingredients are mixed:

Parts

3- (2-Methyl-4-aminopyrimidinyl-S-methylM.S-dimethylthiazolium monorhodanate ... 20

Gürrücksiand 80

A homogeneous mixture of 0.5 parts of this Mixture and 99.95 parts of a standard feed for hatching hens is produced.

Example 4 The following ingredients are mixed:

Parts 3- <2-methyl-4-aminopyrimidinyl-

5-methylH, 5-dimethylthiazolium

mononitrite 45

loictosc 35

Sucrose .. 20

Parts of the mixture are in 10 (XK) space share dissolved water. The mixture is used for chicks.

Example The following ingredients are mixed:

■ .... ". T * lle -

.V (2-methyl-4-aminopyrimidinyl 5-melhylH.5-dimcthyllhiiizolium

Cereal flour ...................... 88 Calcium carbonate II

«9644754

16

:. .-. ■; ■■. ■. · ■ 9.. . ■ ■;

A mixture of 0.0? Share this mixture and 99.9? Share a common tuner for laying chickens is produced

Example f.. ■ "* Manufacture of the active ingredient *.

Λ. Exit Maierial

7.5 parts of 2-methyl - ** - amino-5-aminomethylpyrimidine are dissolved in 40 parts by volume of methanol. 23.4 parts of aqueous ammonia are dissolved. 4.2 parts of carbon disulfide and then KI parts of 3-chlorobuianon-2 are added, followed by stirring at 50 ° C. for 4 hours, a reaction taking place. After the reaction, the methanol is distilled off under reduced pressure. 7.2 parts are added to the residue. Added hydrochloric acid, »is heated to 70 ° C. for 1 hour. After cooling, the pH of the solution is adjusted with an aqueous sodium hydroxide solution! set to 7, a solid separating out. This solid is filtered, washed with water and dried, where I λ parts JO-MethyM-aminopyrimidinyl-S-irethylM.s-dimethylthiazol-2-thione with a melting point 223 C "ER t \ will hold. Yield 90%.

-B. Production of the connection according to the invention

■ ·. ' . ■. ■ ■ ■ w

In HK) room parts of water become IO parts 3- (2-Methyl -4 -aminopyrimidinyl -5-ηκ · ΐΙηΓ (-4.5-Λί-meihylthiazol-2-thione) slowly 10.2 weight percent 30% wa. \ ser \ toffpefoxyd given while resting, with the temperature \ < is kept at 20 C. The obtained Crcmisch is agitated for 2 hours, whereby a reaction takes place. The reaction mixture is neutralized by adding 5.5 parts of sodium bicarbonate. By adding one conc. aqueous solution of 2.5 parts ammonium thiocyanate becomes 8.0 parts 3- (2-methyl-4-amino pyrimidinyl- 5 -methyl) - 4.5 - dimethylihiazoliumrhodanid from melting point ISS to I'X) C deposited. Yield 80%. ■ * '

Elementary analysis for C ,, H _M N, S _: ΙΙ, Ο: ^

Calculated ... C46.28, 115.50. N 22.49: .found....; C 45.89. H 5.36. N 22.21.

'If instead of ammonium rhodanide a con /. aqueous solution of 2.5 parts of sodium nitrate is used, 6.5 parts of 3-12-methyl-4-aminopyrimidinyl> 5'Pielltyl) -4.5'-dimethylthia / olium nitrate receive. Yield 68%.

After recrystallization from medicinal water, the nitrate is converted into 1 ^; orm of colorless needles with a melting point of 185 to 188 C iZers.).

l-lementaranalysf for C ₁₁ II ₁ , N, (), S: Calculated., C .44.43, MSM. N 23.5s. found ..-..., ('44 .26. H 5 10. N 23.35. ■ ^to

When the effective amount, i.e. h the measures taken to combat coccidiosis to be administered on 100 g of body weight ■ the weight of the cjelliigcl is calculated ■ result about 0.5 to 10 mg, preferably about 1 to 5 mg per KK) g of body weight,

890

Example 7

Production of 3-t2-rtihyl-4-aminopyrimidine> l S-methylM.S-dimethylthia / olium nitrate

Λ. .Input material

In 3n parts of a mixture of water / ethanol II: 5) 56.2 parts of 2 * ftih> M-: tntini> -5-iimintimc • thylpyrimid-nhydrichlorid are suspended. The suspension is made by adding 50% aqueous sodium hydroxide solution! Then 23.5 parts of carbon disulfide are neutralized. 26 parts 28% igcs w; iB. The mixture is stirred and left to stand overnight to form crystals. The crystals are filtered off, washed with water and dried, especially 3- »2-AthyM.aminopyrimidinyl 5-methyl) -4-hydroxy-4.5-dimethylt'hiazolidin-thione is obtained in 64% yield with a melting point of 253 to 260 ° C. ^{9 % 4 parts of the compound} are dissolved in 60 parts of hydrogen chloride, and the solution is heated on a water bath for 20 to 30 minutes, cooled and neutralized with aqueous sodium hydride solution, 51 parts of crystals of 3'2-ethyl -4-aminopynnmlmvl-5-methyl) -4.5-dimethylthiazol-2-lhione with a melting point of 2 (W to 211 ° C. in a yield of 1%

B. llerstelliini; the crfmdgemaUcn connection

«» -Γ » ⁴ ' ^{7 parts lk <r Krisl; lll} <-' are in 1.50 parts''• - .."' for ^{r (} li>"rwasserst.> Ffsäure Mispendierl. Whereupon M) rush M)"" is slowly added IGCS hydrogen peroxide with stirring and auUcrcm cooling with ice water, to form cmc yellow transparent solution. After the solution .st been see overnight. will her a I "isuiig i-ESpecify. _ ^{'L' tlu, RCH} Dissolve 21.6 parts of Hanumcl'ilond in '«> eile-n« ..rmcm of water. »Ml of theKilu-n · ,: mixture is stirred. Drausgelullic Bar: utuMilfai is separated and the I esting mn activated charcoal Ivha. ! ukl and concentrated under reduced wnick to give a syrup; irtiger residue is obtained, is added to the ethanol The mixture is gekühl, preceded 17.1 parts D crystals are formed, _c K.istalle be in a small amount xVassc, ·..!. dissolved and a iu | iiimolar amount of rsattium hydrogen carbonate added to neutralize until the monohydrochloride has been formed A liquid quantity of sodium nitrate dissolved in water is added and the mixture is stirred, from which crystals of the mononitrate are formed. The crystals are filtered off and recrystallized from a very small amount of water. vvorvi .1 -1. -Aihsl -4 -aminopyrimulinyl- 5-methylhyl) · - ».. Vdiincthylihiazolinemnitrat of melting point 157 •>'s 160 C in a yield of 72'!; will echo.

Llemenial analysis nir (',, H ₁₇ N ^ O (S:

Calculate cluiulcn

C46.2 <), Il 5.50. N 22.49. S 10 30; C 46.27. 115.68, N 22.49. S 10.28.

Effectiveness against coccidiosis Adopted verbimltmgeii

^ " ^l , '^{<? sl} , ^vcr - ^b i ^llllu i ^{1 |! cn} « •' ••• «Jcnilns Mononilrat and ί ϊΐ i; (2-Ethy | .4.aminopyrimidiny |.

^ "hiaZoliiim used in a con / en-11% i _m Fuiicr.

irS ί * iraiton of

The dinitrate and d; is dirhodanide of 3- (2v \ thyl-4-aminopyrimidinyl-5-methyl) -4,5-dimelhyllhiazolium in one concentration 0.0031% used in the rear.

12th

The test for effectiveness against coc / idiosis was carried out in the same way as in Experiment I. The Hr.ucbnissc are listed in the table below practice:

dor connection

Tesigruppc Control group

in l-'uucr

Mononitrate 0.0031 monorhodanate 0.0031

Dinitrate 0.0031 Dirhodanate O. (X) 3l infected control uninfected control /tin.ihmc

Blimropfcn after 4 Τίΐμοη 5 repayments

2.1 2.8 3.8 0

3.3 4.1 6.3 0

0 0

1.8 .2.2 4.2 0

Impact index

08.1 06.8

31.2 23.1

KX)

The results in the table show the consistency of the mononitrate and monorhodanide of 3- (2-EthyM-aniinop_vrimidinyl-5-nieth> IM.5-dimethylthiazolium.

Claims (1)

P.iicntai ^ priiche: tli>ii-4.moth>l-5-Niederjlk> l-lhi.i / oliunKilA '
general foime! The registration agent has already been found. that quatcrnarc not / belonging to the state of the art Thiazolium sal / c (Disal / c) of the formula