DE1620020A1 - (3-aminopyrazinoyl) guanidine-4-oxide compounds and process for their preparation - Google Patents

Description

DR.-ING. WALTER ABITZ PR. DIETER F. MOBF DR. HANS-A. BROWN

Patent attorneys

Monks, * .-

Postal address & Mönchen 86, P.O. Box 860109

PienzenauersfraBe 28
Telephone 483225 and 486415 iegrams: Gheminciys; Monks

-to is ©)

P 16 20 02a. 7th

New

MEKSK & CO », -INC. ■■; ■■ -. ■ V Um Jersey .Ö7065 _a V. -St * Ä ■

whose

The invention relates to : Verbiad «iigen. _fi the atsrch,

can- * '. '. -

da ^ g®stt'üt t-ierden

as well as the 'phamnaseuttsch.' v@r-fer.Sglihabenh^a d'ere.

ynieriagen · (* »£ 71 ■» A * 2 No. BATH

In the formula, the individual symbols have the following meanings s .- ■■■ _.

means

Hydrogen, '., ..,'. ''.
Chlorine, bromine or 3! Rifluoromethyl _e

. Alkoxy _t - '. .. - '■'.

low- * Cyel © alkyl _s

mononuclear ATyI ₃ da © either unsubstituted or substituted iat, preferably'- with a halogen

atom _f especially oil or bromine »niectrig-ll & ylmereapto or phenyl-lower-alkylmer-

low; "Älkjlsulfon ^ l or Pheny!" low-alkyleulfonyl ": and

BIC
Λ

C Il

Hydrogen ρ & ® · £ acyl d @ r formula RC- _f in which E ^ hydrogen _{9 is} lower-alkyl or PJienyl;

H means hydrogen or low-alkyl »

Hydrogen,. -; .. - '

Alkyl can be "saturated or unsaturated and substituted or the! ^ Substituted _e where"

- 2 _ SO 9 8 8 7/1 S Z BAD ORIGINAL

with the substituent groups preferably the following one

Hydroxyl,

Aryl, as either single or binuclear aryl

is "such as phenyl or naphthyl, and is entwederunaubstltuiert or one or more Subθtituenten _s contains in particular the following halogen, lower alkyl,

lower alkoxy, or any combination of these substituent groups, Mono- or di-lower-alkylamino, in which ' the alkyl groups forming a hetero structure with the amino ticket off, to which they are bound can be linked, for example to form an asacycloalkyl group heterocyclic groups, especially the Pyri-

Halogen, Aryl or bubated aryl,

where the subatituent group (s),

Halogen and

9 Q 9 8 8 7 7 1 66 2

_S AD

9198

are,

Best _r - formerly white ice cream

rest,

wad

covered

Hydrogen _r

lower alkyl which is either saturated or unsaturated and substituted or unsubstituted is described above for E ^ or

.00 * 887/1 $ 12

BATH

• 9198 ■ .. -; ■■ .. ■■ -. 'ν. ;;. ■. ■■■ :. '.-->-:;^:;V; : - R ^ and & f can be low * AlJ% igruppen that directly or? during which a S [© teröatoa _9, in particular acidic acid or nitrogen, are linked with the formation of a 5- to, 8-gärigeneyclisonen structure and thus ait dejn stiokstoffatoiss. that they are bound to one

1-pyrrolidinyl », *

Piperidino,

Äliyl - 1 «* piperääinylregt -.-- aaet Morphoilno rest and dergl · solved

and E and E ** (or R ^) can "if Bie represent a low alkyl group · _f jaiteinander under a cyclic structure atoms with the nitrogens to which they are attached, be linked, in particular to form a 2- (2-Xmidazolinyl ) Remainder *

The compounds obtainable according to the invention are valuable because they have no diuretic and natriuretic properties. However, you untsrscheiden from most known effective ßlur ©-Nazi agents is "that the Yerbindimgen erfindungsgömäß available selectively Bxkretion γοη Natrimnionen Incr @ n _s without Zunah-

0Q9887 / 1I $ 2

me in the excretion of xalium ions. The Kaliunry @ rlust _$ which is known by; © Diuretica caused, often leads to severe muscle weakness. Since the © rfindungsgemäß gets hired compounds are substantially free from this Kaliumausschwemmuiig, they have this decided advantage as diuretics · As diuretic agents they can for the treatment of edema, hypertension and other diseases, which are known, tHe they respond to this therapy used ₉ will"

The compounds obtainable according to the invention can be prepared by the following procedure, where X, H, Η »R ₉ R and ISr have the meanings given above»

-O

-NH,

JSOOR

Method a

+ HH ₉ -O-HR ³ R ⁴

II

JL — COHHC-NR ^ R *

III

909837/1882

BATH ORIGINAL

$? means low-alkyl, It can be seen that this

^ in the desired, padprodutet stands out.

occurs · .Γ ΐ -: ■ - ^ - '''Ii]). ■■■■ ^Λ \; ■■ ->; ■ "....; ^: ';'■■".';;; - - ..

This syntbs & e includes the tJmeetgwii ^ eiaes j ^ i oarbojäfiäus ^ eetes' - ^ ßxydo ά © 3 · dü ^ üjä, Yerbind ^ mg I with a guanidine of the type shown by compound II ge et eil tea »■ ; _} _ ::]. '- \' ^: - _ ■ \;: ■■■ "_."',

The synthesis by Method A is preferably carried out below anhydrous conditions, either with or without dissolving

'Mt ⁵ ^ lV'1 | fi # vJS6 ^ il ^ l _r ; Ä öder -.andertat \ ■'

Dissolving agent, carried out. i) The reaction can be Λ »β ± ziiaffed temperature or by heating on a steam bath for. t;? 3Hau1? e; W ^ U StmüMti ^: odop longer durciigeführ «erdeziy, Bse geiÄ46elate Proöuki% jbed usually from the cooled part Heaktionageniisoh / Äiθ ^^: TriturateΔ ^ & Λi :; VuSeT-JeVOa- ''';

can be. The base can be added by aqueous

B 's 3-Axaiiiopyra2inoarbonaäureester-4-oxide compound {I) may be prepared by oxidation of the corresponding 3 ^J AminopyrazincarbonsäureeBter, as in the DAS

77 ί

β i * es »

(Patent application M 66 431 IVd / i2p), and can by direct oxidation of miserable 5-Amiaopjraalaearbonßäureestera, z, B «from nopyraalnear & oasaureesfees *, with. an Osydationmiti m-Cäilorperbeazoäure, take place »if the substituent is 6-position is oxidation sensitive ₉ the preparation is preferably carried out from compounds of the following formula IV by reaction with a

Am © tw © its method _d the v / @ riiT © ll äsur the production of required terms is “especially those with an aoyl substituent on which _s can be shown as t9lg%

Method B.

Xl

'■■ *

BAD ORSQlNAL

162002Q

9198 ..: '.- ;. . _: -. . -.-The synthesis according to method B is carried out by dissolving the 2- R ⁵ -6-X-4H- £ yrazinp ^ 2 \ 3 ^ §7 ^ Τ * ^ oxazin-i-oji-S-pxyds, (compound IV) in a LSsTOgsaittels as zBJtthylaeetat, and heating in SticfcstoffatfflospMre with eiriöni ßaanidin (compound II) to form the tJ-Aeylaminö-e ^ J noyl) ~ guanidine "4 *" oxyfis (compound V) is carried out can be seen ₉ that compound V is a erfindungsgeiaäß available compound _f is the acyl radical containing one to the amino group in the 3-position of the nucleus bound ■ piping acyl group may be facilitated ^, ^ t * by hydrolysis ter formation of im- (3rAaiiao "6 ^ X" pyra0inoyl) -guanidine ^ - oxide (Compound III) are removed The reaction mixture is made basic, for example by adding an alkali metal hydroxide the precipitation of the product. It can be obtained by filtering ^

Making the 2-B-6 ~ Χ-4ϊΜ
oxaain ⁱ -4 ⁱ -pn-8-oxide (compound XV) is described in the JDAS * -.- /. ** ■ »♦ <, (patent application M 66 3-31 lVd / 12p) ^ ₉ unökaan by heating a ^ Aminopyrazinsarbonsäiiiye ^^ px ^ ds with an acid hydride _} such as acetic acid, propionic acid =, butyric acid anhydride 3 or an aralkyl acid anhydride ₈ like phenyl = · acetic anhydride, required for the production of "" compounds

90 98877 1δδ2.

■ '. ; - "* - · ⁸ '" - BAD ORIGINAL-

According to the formula IV with Ir «H, the 3-aminopyrazine carboxylic acid is heated with a mixture of formic acid and acetic anhydride

The products obtainable according to the invention can be administered to humans or (animals in the form of pills _- tablets, capsules, elixirs, injectable preparations and the like) and can contain one or more of the compounds obtainable according to the invention as the only active ingredient of the pharmaceutical preparation, or the new (n ) CompoundCen) can be combined in pharmaceutical preparations with other diuretic agents or other therapeutic agents

The compounds obtained according to the present invention are advantageously used at a dosage in the range of about 5 mg / sag to about 750 mg / day or at slightly higher or Lower doses at the discretion of the doctor, preferably in divided amounts, 2 to 4 times daily Gave ©, administered.

The following examples illustrate the invention without restricting it. All melting points are corrected values. .

Be is ρ ie 1 1 (3-Ajainopyrazinoyl) -guanidin-4-oxy d

■ Stage A Production of methyl 3- aminopyraginoate-4-oxide

~ 9 - BAD ORiQINAL

A suspension of 3.0 g (0.02 mol) of methyl 3-amiäiopyrasinoat "ad 3.6 .g (O ₉ 02 MoX) is ~ 0hX © rperfeensoic acid Iu 50 al Qhlurcforja - is" stirred at the same temperature "until the dissolution The reaction gel is heated for 1 hour suis liiulcfliiS and the solvent is washed through the distillate. In vacuo, the oil substitute is obtained, stirred with 50 ml of warm methanol and filtered off. The yield is 2.4 g (? 3 ^) Substance from?, »233 ^Ü C (Sersetaiixig) * H & eh Uiokrist & llise from aeetonitrile aohailst the compound at 235 to 237 ^ö 0 (decomposition) *

Der, s Cs 42.60; Hs 4.17; Ns 24, found t 42 * 81? 4.32 5 24 _e 68 _e

Stage B division of (3-aminopyrazinoyl) "guanidine

0.46 g (0.02 mol) of sodium are dissolved in 50 ml of methanol, and 2.0 g (0.02 mol) of guanidine hydrochloride are dissolved, and the mixture is 30 μm in flow

. 2uxa cooled mixture will be 1.7 g (0.01 mol) ·.

Methyl-3-aminopyraainoat-4-oxide given, and the reac- |

tion chlaoh is vigorously at room temperature for 2 hours

- 10 - =

909887/1682

1820020

long stirred. Uas si oh. separating product is filtered off * Mt --Wfessex · --washed and dried «The yield is!» 8 g ($ 92) Subötanss from F. over 30O ⁰ O. The product is purified by reprecipitation, ie « dm -uh Aoflitaen itt'Yerdfonteir hydrochloric acid and anashliesssnde sugaoe of dilute sodium hydroxide.

, \ t Si. 36 ₉ 74 | Hs 4f g © £ * ι 56t68ι

Sine susponion ¥ 0 "5" 8 g ~ CGfGS Möl) -.eiaorpjrasinostnnd % 4 g- '~ (pfO2 mol) acid in 10' isi. Giu-üi ^ foi'n Märä lidl gerOkrt, him nine T ₍ "iflimg erJmji, t" i% wi ^ (15 Miautea} ",

§ & si @ <§ & 1 iltimÄ · MSH®- MGktl'aß «rhitst *

by. Filtration 'recovered' The yield is 3 * 0

■ aeh KvSMtaXltmmtlm aua Methanol 'eohmilzt: t ^: Isei. 20Q-Ms 202 ⁹ O * ¹ "" - - .-. ■ - ■ "■;

BATH ORIGINAL

- 11 ■ ~ 909887/1612

IS

9198 ■ ■. . .; . ■ ;;:;.; - Analysis iO ^ a ^^ O ^ Cl

ber. ' ί Cr 35.40 * Hf 2 »97l K? 2O found ; 35υ ^ ι3 »14γ 20.82.

Level B -. Manufacture; by ^^ J ^ nQ ^ & ^ G ^ QV ^ xr. & miino ^ ■ - guanidine- »4-» Qxyd ^: " ^! - -; ■ - - ■ - ,; ~ ^: -. ^ - .

O 24 g (O ₉ OI mol) of sodium is dissolved in 50 ml of methanol and 1.0 g (0.1 mol) of ouanidine chloride is dispensed, and the mixture takes 30 minutes to let the air flow until the semiseh has cooled down 2 ^ 0 g (0> 01 mol) of methyl-3 "aMno-6- © M © rpyrazi will be given Dasi

Reaktionsgemiech some Mliiüten is heated "to up, solvent effect and below dams sbgeidöilt ₉ Jfes irodukir sehei det is now * Eg ^; is / alifiltrated _t . mi tÄssea? -, washed and dried * Pie yield ^ is 1.8 g (78 ^) of Substana vom Fo- 260 ⁰ G (decomposition). The bond is reprecipitated several times by dissolving it in very dilute salt acid and then adding Terdüniite® sodium hydroxide. Per Sohm © lapmikt, however, remains unchanged «

.Analyser GgH ₇ N ^ O ₂

about «,? Cs 31.25! Hs l, 06i Έι

t 30.83s 3, S5i 35.94

- 12 - 90 988 7/1

B e is ρ i e, 1

-ffl ani di n ^ -

Stage A manufacture; of methyl-S-araino-e-bromopyrazinoate-

A solution of 4 »6 g (0» .02 mol) of methyl - ^ - amino-ß-bromopyrazinoate and 3 »4 g (0.02 mol) of m-chloroperbenzoic acid in 75 μl of chloroform is refluxed for 1 hour and then cooled . The solid matter which separates out is filtered off and recrystallized from ethanol. s. ■

200 to 202 ⁰ C results.

Analysis; CgHgN, O

s Cs 29.055 Hs 2.44; Ks 16.94 # s 29.12; 2 * 27; 17.12.

Stage B Production of (3-amino »6-» bromopyrazinoyl) - »

If the methyl 3-amino-6-chloropyrazinoate-4-oxide used in Example 2, step B, is replaced by an equimolar amount of methyl 3-amino-6-bromopyrazinoate-4-oxide and borrowed in the week according to the example 2, stage B ₉ , if the procedure described is followed, (3-amino-6-bromopyrazinoyl) «guanidine-4-oxide _{β is obtained}

. ₁₅ "809887/1612

ORSQINAL INSPECTED

The in Example l _{t e} Ä stage aiigewandite method is the preparation of other zut

die ef ^ CinättKgageii ^ LÄ erjiältliolien (3 "

by

m & im m & m% X $> cp & n mäh U & t in Seiepiel 1, stage © ^ receives mm \ _ v.

wad p ^^

14 -: - "- '■■■ ■ -'; _-.:.: 80 9887/1112

9198
If di @ gi @

instead of the one in example 1, level B _ff . "Uses®» 3-aminopyrazinosf-4 «'Qxyds can be used and the procedure of stage B is used» one obtains *

_f and

You 4lJ ^ a »3-föiti. ^< uupyrasi2ioat-4 -'- oxy! 3-Svi8chenproduki; e kömien in € 3uttip ^ flc-.e: afta ^ Wöioe sait

umgeeeissst -wer <ä @ n _e ύβι die

Buhat * gus3iidin "4 ^tM 'O3 ^ d - V ^> 6rMndiang ₉ or with ten ^ uaai <lis» 9si9 us' the t ^ gTmlmfX-St ^ - ® & m? «Aubac. IdttnidiA-4 ⁱ -"& a ^ a -V6rbiiV4urigö ^ g ^ 2EÜ to get the · Zn substituted G? Ianidenes _s for this

BADOBIGiNAL,

IB2QU2U

α-methylbenzylguanidine ^

1,1> -l) imethylguanid ± a, 1, i-DiSthylguanidittt 1 t 1-BibutylguanidiKff 1-Amidinopyrrolidisi »

- (Ootahydro-1-szoeia ^ l ^^ ätl ^ igusniäin, tmd 1,2-diguajiidinoethane,

If the above-mentioned substituted guanidines a »B _a instead of guanidine in Example 2, Stiife B _e are used and the method of § ^ uf ^ B is worked, one obtains? . -: - ^; ^:: ^_/:;; "■■ - ■■ ^{^:} _-: -: _\: ■ <?;Z--; ■ ^..--;: x: ^ /.

1- (3 '-amino-6'-chlorpyrazinöyl) -3- (S-guanidine-4 * -osyd,

1 - (3'-Amino-6 '-chlorpyrazinoyX) ^ 3 ^ 1 - (3 V-AMno-6 ^! -Chl <jrpp ^ zittöyl) * ^ ben2y ^ u 1- (2 · -Amino-6' - » ohlorpyrasiinQyll - ^ - (p «Äuorbenzyl) -

guani din-4 * -oicyd, 1 «(3 · -amino-6« -chlorpyrszinoyl> -3- <p-chlorobenzyl): - "' ^:

guanidine-4 -

ORSGSHAL INSPECTED

1820020

. 1- {3 ⁸ -Amino-S * -eiilorpyrazinoyl) -3- (p-methoxybenzyl) * -

guaniäia-4 * «oxide,
1- (3 ^! »Affliine» 6 ^r -cliiorpyra2iiioyl) -3- (o-ohiorbenzyl) -

guanidl2i-4 * ~ oxide _s
1 - (3'-amino-6 "-clilorpyrazixioyl) -3- (a-methylbenayl) -

guanidIn-4 * »oaqyd,
1 - (3 ' ^4- Aiaino-6 · -eiilorpyrazinoyl) -3- (2-naphthylmethyl) »

guanidine-4 * -oxide,
1 * (3 * -amino-6 ¹ »chlorpyraz ± aoyl) -3- (3-pyridy! Methyl) -

guanidine 4 * oxide ₉
1- (3 ¹ -amino-6 ⁹ -elilorpyrazinoyl) ~ 2 _f 3-dimethylguanidine-

1- (3 * -Amino-6'-chloropyrazinoyl) -3,3-dimethylguanidine

4 * -ozyd. _v
1- (3 * -Amiao-6 ⁹ -chlorpyrazinoyl) -3 »3-diethylguanidine-

1- (3'-Amino-β ' -eftlorpyrazinoyl) -3 ₉ 3-dibutylguanidine-

1- (3'-Ämino-ö'-chloropyrazindyl) -3 »3-tetramethylene

guanidine «> 4 ^t -oa ^ d,
1-C3 ¹ -Aiaino-6 ¹ -ehlorpyrazinoyl) -3 »3- (3-oxapenta-

1- (3 · -isainp-e'-clilbodyrazinoyi) -3- / 5- (octahydro-1-asocinyl) -ethyl7-guanldine-4 ^l -oxide, and

ORIGINAL INSPECTED «17 .-

909887/1012

165 $ %% &

~ i3k ± Bp ± ®t 2 wögäea su \ 8ÖÖ ml- one 2.5a

Suspension £ θΕ Ba - ^^ ajcisalsea the

18th

, «■ ίο ω

9198 ■,; -.

Stage B production of 2-methyl-6-chloro-4H-pyrazino-

139 g (O ₉ 73 mol) of 3-AisinQ-6-0iaorpyrazinearboxylic acid-4-oxide and 550 ml of acetic anhydride are heated for 1 hour on a steam bath with stirring. The solid substance is triturated with 200 ecm of ethyl acetate, collected on a filter and dried to constant weight in a vacuum cleaner, which gives 2-methyl-6-chloro-4H * pyrazino- ^ 2 _t 3-d7 ^ T _t 27-oxazine-4 "On- 8-oxide of F ₀ = 23O ⁰ C (decomposition) gives «,

Analysis: C «H JM ^ Cl

ber, ί Cs 39.361 Hi 1.89? Nj 19.68? P found : 39.33} 1.98.; - 19.68.

Stage C Production of (g-Acetamido-6-chloropyrazinoyl) -guanidine-4- »Q3cyd

0.54 g (0.0217 mol) Katriujametall are dissolved in 30 ml of methanol, and 2 _f Og (0 _g 021 moles) of guanidine hydrochloride are added to the ömaltenen solution .. To this solution

Mol) 2 «Met23yl-6-chloro-4H-pyrazino- / §, 3-d7-given, and the reaction mixture

BATH 909887/1 ** 2

is stirred for 3 hours at room temperature "The solvent is removed sugefügt by Mndampfen ₉ and then 50 ml of water," It separates a yellow fixed "substance, from which filtered -is" - 'Di © moist learns sub = · stand is suspended in water and through. Adding solved by several drops of acetic acid, "The clear solution is filtered and in a JBi-SBAD _-g@küh3.t>: .and then several drops Essigsäure'.angegeben" Time is the red Nitratsals of (S

Stage D manufacture- ¥ ob ^: '

Its solution τοπ 3 ₀ 85 g ^Λ (α ₉ 015 mol) -pjraKinoyl) "guanidia" 4 ^ o3 £ jä ia 10 ial- lO ^ Lgex ¹ SÄl-aäur © is on a Daapfbaä-10 Mimten @ rM, tst _{; 0} Thi © iJSs is then ab & iüilf and carefully, siit neutralized «The siah .aMöhei-öende- P @ stsubstasis on Biiwwi Sri.chter 'g © samrael *» _s ".ia £ t fealtsm -Wstssep. And then what iJ

ibt »-

Stage A Production of N-methyl »3» amino-6-chloro » pyrazinamide

20 g (0 ₉ 107 mol) of methyl 3-amino-6-chloropyrazinoate are suspended in 200 ml of 40% aqueous methylamine and the mixture is stirred vigorously at room temperature for 20 hours. The reaction mixture is filtered and the solid substance is washed with water and drunk. What 17? 5 S ($ 87) M ~ methyl-3-amin0-6 <»chlQrpyrazinamid results» after recrystallization from ethanol at 152.5 to - 154 »5 ° O sehmilst *

'ber. s Qi 38.62? Hs 3.78} Ni 3O ₉ 035 * s 38 _f 62ι 3 ₉ 82; 29.71.

Stage © B Production of If-Me thy! - »3-amino- 6- chi or-

For © iner Suspensioa of S Q g ₉ (O ₉ O5 mole) of N-Hethyl-3-aaLae-S-elalörpyrasiiiajaid In 100 ml of chloroform are 8.6 g of (O ₃ OS mol) fi6M3hlorpex * "feengoesäure given _p and Reakti .öasgeffliseis "is one 'hour to Eüokflnß heated" Laoli. "bkühlen' a Festsubstans selieidet from which abfiltriertο washed with ether and dried.

Biese- iB & tmub & tmis will ®eiu? Aais aas ethanol umkriatal »

BAD ORIQiNAL

'. ■ '■ ■' - - "'' ..." 909887/1612

I can tell what 8.4 g (8A-Ji) N-methyl ^ -aaino-e-chlprpyrazInaaid-4 ^ oxide from P. » 170 to 172 ⁰ C results.

Analyzes

ber *: Cs 55 _f 57i H; 3 * 48 | It's $ 27.66,; 35.66 | 3.55f 27.74.

Stage C Production of you 3-methyl-6-ohlor * 4 (3H) pterldtnon a-ojqrd

To a mixture of 20 ml Triätfeylorthoformi.at and 20 ml Acetic anhydride becomes 3 »24 g (0.016 mol) of N-methyl-3-amino-6-chloropyra2inamid-4-oxide given. The resulting solution is heated in the sun for 2 hours and the reaction mixture then cooled and the product which separates out is filtered off »washed with ethyl acetate and dried, resulting in 3-methyl-6-chloro-4 (3H) pteridinone> -8-oxide results. '

Stage B Preparation of 3 ~ methyl "-6-dimethylamino> -4 (3H) -pt eri dinon-6-O3cy d

To a solution iron 5 * 0 ml 25% lg of aqueous dimethyl gain

in 4Θ al - l- »M © tßOxyät & aiiol werdga 4 _ff 35 g (0.0205 Hol) 3-'6-ehl © r-4C3H) ptes ^t iclia © a '= - 8'-02 £ yä -given * and It will take 2 1/2 hours in a bath

- ^: SQJ: 8 877ii§2 -

heated * The reaction mixture is then placed in an ice bath cooled, whereupon a Feeisubstans is deposited. This product is filtered off, washed with cold methanol and dried what 3-Hethyl-6-dimethylan & no-4 (3H) pteridinon-8-o3QTd results.

Stage E Production of 5-Ag & no-6-dimethylaminopyraginoarponic acid ° »4 ~ oxide

15 ml to ^ igee sodium hydroxide and 1.04 g (0.0049 Hol) 3-Ethyl-6-aimethylamino-4 (3H) pteridon-8-oxide mixed and then under carrots 2 1/2 hours on one Steam bath heated · The reaction mixture is cooled to room temperature and then carefully neutralized with formic acid «whereupon the product separates out, which is filtered off and air dried, wae 3-Anino-6-dimethylaminopyra2inearboxylic acid-4-oxide gives

Step .? Preparation of 2-Methy l ~ 6-diaiethylaminO "4H- pyrazlno- ^ S, 3

A mixture of 2.19 g (0.011 hol) 3-aino-6-dimethyl "» · aminopyrasincaxboxylic acid 4-oxide and 25 ml of acetic anhydride is 2 1/2 hours ^ while stirring on the steam bath heated. The solution obtained is then cooled in an ice bath, whereupon an ice dust substance separates out «

9098 87 / 1SS 2

9198 ■■ ..; ■■ -, - ·.;. r \ ■ '"-

This product is filtered off with cold ether wash and dry »was 2-KetSi ^ l-6-diflieth3rlamino-4H ·»

results

Stage 6 Manufacture : of (ff-Acetamid ^

O "5 g (0.217 Q _v Hol) .H'a $ ia 30 rliuimetall.werden al released and 2 ₉ 0 g (0 021 mol _v) *. dttanidinohydraohlor obtained 'solution "geltigt-e ^ Zti. this solution vreyden; 1 _g 0? g (0g0048" M © 1) 2-ethyl-6rdti ^ thylamln6 «^ - pyra.t» inp- ^ ₉ 3 <-d / ^r · - './T _s 27-oxazIn.-4-on-8 «-ö23rd g © gefeeii _e -und ..- das- Heaktionsge» "mixed, becomes-at 2imme'rtei8p @ 3patur 3-Stisaden' Stirred Bsi solvent will be added in the Yakusm ab®dampit _e wonaefe 50 Hl V / ater E "-Bs -" .- a-yellow solid substance separates out, which is "filtered off - you fire-ohte Pestsub". - 'punch is suspended in water- taad by adding "vom mekreren Kröpfen""acetic acid - dissolved» the clear solution - is filtered' and in general a "bisbad - cooled _s - and" asam weväm. several drops ■ Satlpitric acid © eye adds ₀ f acii shortBV time the nitrate-saXs * This material is "filtered off" ad g © traeknet _r . was (^ = "Aö © tamido" »6 ™ diiae-thy-laffiiao «Pyrazinojl} -guanidine ⁱ -'4 ' ⁱ * osyd <« »nitrate gives«: - ..- "-,;'

o 8 ae 7 / \ t $ 2- _BAD

Stage H Production of (3-amino-6-dimethylaminopyragynoyl) - »guanldine-4-oxide

A solution of O ₉ 52 g (O ₅ OO15 mol) (3-acetamido-6-dimethyl aminopyrazinoyl-guani din-4-oxy d-nitrate in 10 ml 10% hydrochloric acid is heated on a steam bath for 10 minutes the solution is cooled and carefully neutralized with sodium hydroxide. The orange solid substance which separates out is collected on a suction filter »washed with cold water and then dried? What (5-amino-6-diiaethylaniinopyrazinoyl)

gives _β

The method used in Example 5 can be used to "produce other"; (3-aminopyrazinoyl) -guanidine-4-oxide compounds and 1- (5 ^D * ainopyrazinoyl) ^ "3-subst. guanidine bonds _? ~ AI® in. D # r 6-St @ llung 'by other di- (subst «) - amino groups and substituted, used

~ If the dimethylaaiin'-Ϋοη Example 5 ₉ Step D, durolx an a ^ uiisolare amount of aa diethylamine, morpholine »BenzyliasthylaiBin © the piperidine is replaced, m.an:

4 C 3H) pt@rIdinoB.-8-oxyd _s

BAD ORfQINAL

- ■ 25 - ^:.

309887/1002

1820020

-H-iae taylaxain © -

3-amino -6-

Each of the above compounds can be used in the same way as described in Example _5, Levels E to H 5,

The following end products are created & ru

(3-Aoetaaaido-6-BiorphoiinopyraEinoyl) - (3-Ace tamidp * 6 * K-benssyl-K-methylaminopyrazinoyl) -

(J-Acetiamido-ö-piperidinopyraisinoyl) -guanidine-4-oxide, (3-Amino-6-dietl ^ laininopyrazinoyl) -guanidine-4-oaiyä » (S-Amino-ö-morpholinopyrazinoyl) -guanidin-4-oxy d, (3-Aιnino-6-lί-benzyl-K-methylaminopyΓazinoyl) .- guani ^ din

4-oxide *
(-3-Amiao-e ^ piperidinopyrazinoyl) -guanidine-4-oxide,

Be i β ρ i e 1 6

-6 ^ iae thoxy pyrazinoyl) - <»

Stage A, division of 3-methyl ^ 6-metho3cy ~ 4 (311 ) pterjdi · . non ~ e ~ oxide

- 26th

90S887 / 1M2

9198 ■ '■

1.2 g (0.052 gAtom) of sodium are dissolved in 100 ml of methanol dissolved and 0.02 mol of 3-methyl-6-ohlor-4 (3H) pteriäinon-8-oxide from Example 5 »stage 0, added to the solution, the then heated to reflux for 4 hours. Then will 150 ml of water are added to the cooled reaction mixture, which is then acidified with dilute hydrochloric acid, whereupon the product precipitates. The product is recrystallized from aqueous 2-propanol «

Stage B Division of 3-amino- »6-ethoxypyrazine carbon-

Acid-4-oxide

15 al lOj & gee sodium hydroxide and 1.02 g (0.0049 hol) 3-Methyl-6-methoxy-4 (3H) pteridinon-8-ojcyd are mixed and then on a steam bath with stirring for 2 1/2 hours heated. The reaction mixture is brought to room temperature cooled and carefully neutralized with formic acid, whereupon the product separates out, which is filtered off is obtained and air-dried, which gives 3-amino ~ 6-methoxypyrazinecarbonic acid-4-oxide.

Stage 0 Production of 2-methyl'-6 »methoxy ~ 4H» pyrazino- '

37-oxazin-4-on-8-o3cyd

A mixture of 2.04 g (0.011 mol) of 3-amino-6-methoxypyrazine-4-oxide and 25 ml of acetic anhydride

- 27 -

9 0 9 8 8 7/1682

hitat. The received ESsting wii? <I iK an "Eisljad afege * cools what; a pest substance is deposited »This product is filtered off, washed with cold ether. see and dry what 2-, 3-d7 / ^ »37-oxazin-4-» on-8-oxide

Stage B Manufacture of (^ "Aojet ^ ido ^ gj ^ mgthg ^ r; ^

0.5 | . (O ₉ OSt? Mol) latrlumaetall are dissolved in 30 ml of ethanol and Z ₉ Q g (O ₀ O2f times) eaanidia-liydrooiilorid add? _ received liösimg attached »;. 2u- (Sis-s © r "solution" becomes 1 »0g. (0.0049 mol) 2-methyl ^ 6-methoxy-tö-pyrazino - ^? * 3- | 7 ^ T ₉ j / - = oxa2in ° . * 4-Oss, "" 8 ™ öxyd ·; gage "ben ₉ ^\" and the Heaktiongesiisch; --gerührt is at room temperature 3 hours, "the solution" medium is _ff removed by evaporation in vacuum * then 50 ml of water be admitted - »- Bs separates-" see one, gel--

be jestsulastaiis from _s the "filtered off- ■ is- *; Bie." moisture-proof substance ViIrO ⁵ suspended in water .and dureli "-Addition © of several drops of acetic acid dissolved * The" klar® solution is filtered and drained in a bisbath _s ■ and äegm become turns © Tp & -p £ ^ n nitric acid © sug @ füg't * laehaer iSince the Hitrataäls »piping © becomes from £ ilt ^ i @ 2? t and -getro; Ck | iet-. ₈ what {p

ffiethO2 £ yp _r yrasinQyl) -guani «äin-4-O3tyd ~ nitrate gives

Stage ß Manufacture of CS-AminQ-e-methoxypyrazinoyl) -

A solution of 0.5 g (O ₉ OQ15 mol) of O-ethamido-δ-methoatypyrazinoyl) guanidine-4-δaqrd nitrate in 10 ml of 10% hydrochloric acid is heated on a steam bath for 10 hours. The solution is then cooled and carefully neutralized with sodium hydroxide. The solid substance that separates out is collected on a suction filter, washed with cold water and then dried.

Example 7,

Stage ^ A Hera division of,

30 g (1 ₉ 6 mol) of methyl 3-amino-6-chloropyrazinoate are added to 2 liters of kunsB & tTlBTtBT Mm@nlumte&ärQxjäl'oBiw.g "and the chemical is stirred for 16 hours at room temperature. The formed® pee & substance is filtered off and dried t @ which results in 2SO g 3 ° Aaiino <"6" * ehlorpyrazinaaiid Tom F ₈ ^ ⁰ .

BAD ORiQINAL

90988-7 / 18I2

1S2ÖÖ2Ö

Analyzei Ο ^ ΟίίίνΟ

ber » s Oi 34 * 80i H: 2.92j Ht 32 _f 47 #

• Gef · s 35.28} 5.38 | 32 * 55.

St life B Manufacture of 3-Amino-6-chloropyrazinamiä-

8.6 g are added to a suspension of 8.65 g (0.05 mol) of 3-amino-6-chloropyrazinamide in 100 ml of chloroform (OrOS Hol) m-Chlorperbenzoeeauie given, and the reaction mixture is refluxed for t hour When it cools down, a pests substance is deposited, which is filtered off, washed with ether and dried. This solid substance is recrystallized several times from ethanol

909887/1682

left what gives the purified product. !

Stage C Division of 4 * Hydroxy ~ 6 ~ Chlorpteridln ~ 8-oxide

Bin mixture van 36.0 g (0.19 mol) j-Amino-e-chlorpyrazinamid-4-O3cydy Eseigeäureanhydrid 200 ml and 200 ml Xthylorthoformiat f, ₀ for 5 hours reflux the mixture was cooled and WITD daö collected precipitated product and recrystallized from aqueous 2-propanol, which gives 4-hydroxy-6-chloΓpteΓidin-8-ΌXJrd.

_S9 . f620020

SZ- -,.-.- ■■

Stage B division of 4 »hydroxy-6-bensylmeroapto-

Sine solution of 6.0 g (0.03 mol) ^ - 8-oxide and 4.4 g (O ₉ O35 Hol) Beazy! Mercaptan In 100 ml 4% sodium hydroxide solution is heated on the steam bath for 90 minutes is cooled and 20 ml of 40 # sodium hyiirojgydiugung are added to precipitate the sodium salt of the product. The salt is collected and dissolved in 2 ^ 0 ml of hot water and the solution acidified »to precipitate the product, which recrystallizes from aqueous 2-propanol becomes what A-Hydroxy-ö -benzylaercaptopteridin-8-03Qrd gives.

Step B herstel l u n g v on S-Ainlno-e-benzylmercapto- "pyrazincarbonBäure * 4-o3tyd

A solution of 45 ₁ 0 g (0.156 mol) of 4-benzyl-6-Hydroagr "mercaptopteridin-8-oxide in 600 ml of 5 ^ strength sodium hydroxide solution is heated for 6 hours on a steam bath. The solution is cooled "in order to precipitate the sodium salt of the product". The salt is dissolved in hot water and the solution acidified to precipitate S-amino-e-benzylmercaptopyrazinoarbonic acid-4-axyd

31 - ORIGINAL BATHROOM

16200213

Level g Manufacturing mip of 2-Metifay 1- e-benzylmer c apt ο-

A solution of 9.0 g (0.0325 mol) of 3-mereaptopyrazinecarbonic acid-4 * "o: eyd in 50 ml of acetic acid anhydride is heated for 5 hours on a steam bath." Volatile materials are distilled off in the Takuuai and the office is out of Ben's ©! recrystallized _B wae 2-methyl-6-beiis2rlmereaptQ »= 4H ^ pyragixio- _< / 2 _i J-dT ^ T, 37 ™

Stage © production tos

SfiO g (Os052.Hol) -_G.uanidine ">hyds" oehlorid are in a solution of iron 1 _{g of} sodium (O ₉ 045 gAtom). 3, ₉ 4 g (0 _s 0t2 mol) of a-Jaetnyl-e to-4H-pyra2ino- ^ 2g 3-C & 7 / T ^^^ oxazinr ^ rOn ^ e ^ ox ^ ut are added in 20 ml nol the 6emia © h - w 1-ird Stmiöe b @ i © Zimmerteffip temperature allowed to stand "Then WLR d'das" ß © JBiseh poured into 100 ml of water and acidified with _& Salzsäur® mm the precipitating gumräiartige prod uct to be loose and _su de »-" acetyüeren * "The" solution is flattened on a basisofe up the product amsisufälleiig which is crystallized from aqueous 2 <-Frepanol _§ what - (3-iiaino- »6 = -benzy! mercapto · = pyraainsyl) -guaiaiäin-> 4 = * O3grd ■ -does «

-.52-. BATH ORIGINAL

»0988-7 / 1it2-

9198
Example 8

(3 »Amino ~ 6-methylaulfonylpyrazinoyl)» guanidine,

Stage A Production of ^ hydroxy- »6 * methylmeroaptopteridin-e-oaard

4.8 g (0.1 mol) of methyl mercaptan are dissolved in 60 ml of 10% sodium hydroxide solution and a solution of 10.0 g (0.05 mol) of hydroxy-6-chloropteridin-S-oxide from Example 7 ₉ Level G, add to 100 ml of a 4% sodium hydroxide solution. The resulting solution is heated for 20 minutes on the steam bath and then cooled in order to precipitate the sodium salt of the product. The salt is dissolved gsaaiamelt and in hot water and the solution angeeäuertfr the product aussufällen the ₉ ~ from aqueous 2 Pr © pas, © l umkristallisieri; becomes what 4- »Hydroxy-6-methylmercaptopteridin-S-osyd results.

Stage 3 3 "AmJnQ ^ o-BIetSw laeroa ptop yragincarbonaäu r8-» 4- * QXyd

A solution you 27 _s 3 g (0 _g 13 mol) of 4-hydroxy-6-methylmeroaptopte ^ idin-'ö-o ^ 'd in 250 ml of Seiger sodium hydroside solution is heated on a steam bath for 12 hours and then cooled down, the sodium salt precipitate the product ,, Sas Sais is gesassaelt us4 in heißesi: solved water and oil © _s solution acidified to precipitate the product, which

ORIGINAL BATHROOM - 33 -

9 0 9 8 8 7/1 $ ■ $ 2

9198. ■ ■■

au8Ithylaeetair uakristaliisiert virdi what 3-Amino-6-

results.

Stage C Production of 5 "ainiao" "e" methylsm € onylpyra2inoarbonsätire-4- "03tyd

A solution of 1.05 g (0.067 mol) * potassium permanganate in 35 ml water becomes a solution of 1.0 g (0.005 mol) 3-amino * 6-methylmercaptopyrazine carboxylic acid * -4-oxide in 15 ml of a 2 _S 55 cell Add sodium hydroxide solution. Manganese dioxide is filtered off and the filtrate is acidified in order to precipitate the product which is recrystallized from 2-propanol, which is J-ABiino-ö-jinethylsulfonylpyrazinecarbyl-i-oxide.

StUiTe D Production of ..- "2-M.ethy 1» 6-methy 1 sulfony 1-4H «» -

A solution of 2.3 g (0.01 mol) of I-amino-e-methylsulfonylpyrazinecarboxylic acid ^ 4-O3qrd in 25 ml acetic anhydride is heated for 5 hours on the steam bath and cooled, and the precipitated product is recrystallized from acetone, around 0.8 "g; 2-methyl-6-methyl3ulfonyl- ■ 4H-pyrazino- ^ 2,3-d7-

to obtain. ^v

BATH

90.9887 / 1 682

Stage E Production of (S-Acetamido-S-methylsulfonylpyrazinoy1) -guanidine-4-oxide

This product is prepared by essentially the same procedure as described in Example 5, step (J, with the exception that an equimolar amount of 2-methyl-6-methylsulfonyl-4H-pyrazino- ^ 5,3-d / ^ T, 27 ^- oxazin-4-one-8-oxide is used instead of the oxazine used in Example 5 in step G. Hau thus receives (3-acetainido-6-methylsulfonylpyrazinoyl) -guanidine-4-oxide, which is obtained from a mixture of 2-propanol and water is recrystallized.

Stage P ' Production of (3 * amino-6-methyl8ulfonyl * -pyraginoyl) -guanldine-4 »oxide

(3-Acetamido-6-methyl9ulfonylpyrazinoyl) -guanidine-4-oxide is poured into water and the mixture is acidified with hydrochloric acid, to dissolve the product and then to deacetylateo After bleaching the solution with dilute sodium hydroxide the product precipitates and is filtered off, which (3-amino-6-methylsulfonylpyrazinoyl) -guanidine-4-oxide

BATH ORIGINAL

- 35 -. ■ '

: = '«H 909887/1662

Claims (1)

Merck 4 Co., Inc. 9198 (M 70 150) P a t e η t a η s ρ r U c h e (3-Amino-pyrazinoyl) «güiuildin * 4-.oxid- _? Connect the general formula -NHR ¹
CO-NH-CN ^ and their pharmaceutically available salts »in which be ~ interpret X is hydrogen chlorine _$ * "bromo" ,, trifluoromethyl Alko ^ r _e low-alkyls low-cycloalkyl "monocyclic aryl, lower-alkylmercapto or phenyl ni = © DRiG-alkylmer ^ eapto, low-Alkylgwlfonyl phenyl or" low "of the alkylsülfonyl © Dl - * (never "drig" alkyl) -amino "- ^; R is hydrogen or the group *, 5- «* in which. R- * denotes hydrogen, low = alkyl or phenyl . " o- "■ - -" ■ '■ ■■■ ""' ■■ R hydrogen or low alkyl and W bäw * R water suffeoffjp low-Ällqyl, Hydroxyalkyl * Phenyl »lower ^ alteylj, (halophenyl) alkyl» lower-alkylphenalkyl (lower »Alko ^ yphenyl5 * (Art ? 11 para. A No. I sentence 3 of the amendment *. Ν, 4. 9098t? / lower-alkyl * naphthyl-lower-alkyl ,, {octahydro-lazoeinyl) »lower-alkyl. Pyridyl-lower «alkyl or Phenyl and, if Έ? and R denotes lower-alkyl "these can be linked * in order to form a 1-fyrrolidinyl" piperidino ", morpholine" or 4-lower alkyl group, and when R and Br ( or R) in each case lower = alkyls mean "these can be linked to one another to form an eye-like structure with the nitrogen atom" to which they are bonded., 2 »A process for the preparation of compounds geraMss claim ₉ characterized in that a guanidine of the formula * NR ² with a low = -allqrlest @ r of a 5-> Amino ° 6-X-pyrazine carboxylic acid ^ 4-oxide the general formula COOR ⁶ in which R denotes lower-alkyl- «or BATH 3T - '■ 9098.87 / 1682 "It _f eitie" S ^^ - X ^ liHH ^ astiw ^ rJ-d ^ I ^ y-oxazte ^ 8-oxld of the general formula converts and the compound obtained of the general formula. . '"" ■ -. - _; v - r - " ^r : '. ■' - ■■ ■ optionally hydrolyzed, where in'den "formulas the Best X and R to R ^ the meaning given above to have. __ Arxneiaitfcelaktivitoff ₉ consisting of a compound as per claim 1. ; ' Ä9887 / 16 «2 _0R1QiNAL