NO164711B - ETAN-DIIMIDAMID-DERIVATIVES. - Google Patents
ETAN-DIIMIDAMID-DERIVATIVES. Download PDFInfo
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- NO164711B NO164711B NO872504A NO872504A NO164711B NO 164711 B NO164711 B NO 164711B NO 872504 A NO872504 A NO 872504A NO 872504 A NO872504 A NO 872504A NO 164711 B NO164711 B NO 164711B
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- reaction
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- compound
- derivatives
- diimidamid
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- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 6
- RDJGIQPSSNMJPF-UHFFFAOYSA-N ethanediimidamide Chemical compound NC(=N)C(N)=N RDJGIQPSSNMJPF-UHFFFAOYSA-N 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- -1 2-guanidinothiazol-4-yl Chemical group 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003464 sulfur compounds Chemical class 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- IPLXKLUYTPGIPL-UHFFFAOYSA-N 1,2,5-thiadiazole-3,4-diamine Chemical class NC1=NSN=C1N IPLXKLUYTPGIPL-UHFFFAOYSA-N 0.000 description 1
- QYIWBOWEQBEAGP-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)sulfanylisoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1SN1C(=O)C2=CC=CC=C2C1=O QYIWBOWEQBEAGP-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- PXJJSXABGXMUSU-UHFFFAOYSA-N disulfur dichloride Chemical compound ClSSCl PXJJSXABGXMUSU-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Description
Foreliggende oppfinnelse angår etan-diimidamid-derivater med The present invention relates to ethane-diimidamide derivatives with
den generelle formel the general formula
der there
m er 1 eller 2; m is 1 or 2;
n er 2,3 eller 4; samt n is 2, 3 or 4; as well
ikke-toksiske, farmasøytisk akseptable salter derav. non-toxic, pharmaceutically acceptable salts thereof.
Forbindelsene ifølge foreliggende oppfinnelse benyttes for fremstilling av terapautisk aktive 3,4-diamino-l,2,5-tiadiazolderivater med den generelle formel (I) The compounds according to the present invention are used for the production of therapeutically active 3,4-diamino-1,2,5-thiadiazole derivatives with the general formula (I)
der m og n har den ovenfor angitte betydning. where m and n have the meaning stated above.
I denne forbindelse skal det henvises til NO-PS 161856. In this connection, reference should be made to NO-PS 161856.
Forbindelsene med formel I ifølge NO-PS 161856 kan fremstilles ved omsetning av oppfinnelsens etan-diimidamid med formel II The compounds with formula I according to NO-PS 161856 can be prepared by reacting the ethane diimidamide of the invention with formula II
der m og n har den ovenfor angitte betydning, med en svovelforbindelse, for eksempel S2CI2 eller SCI2 eller R-S-R (III), der R er som beskrevet i NO-PS 161856, fortrinnsvis N,N-tiobisftalimid, eller kjemiske ekvivalenter derav. where m and n have the above meaning, with a sulfur compound, for example S2CI2 or SCI2 or R-S-R (III), where R is as described in NO-PS 161856, preferably N,N-thiobisphthalimide, or chemical equivalents thereof.
Ved omsetning av en forbindelse med formel II med S2CI2 eller SC12 bør minst 1 mol S2CI2 eller SCI2 anvendes pr. mol forbindelse II, og det foretrekkes: å anvende et overskudd av S2CI2 eller SC12, for eksempel fra 2 til 3 mol pr., mol forbindelse II. ReakssjioELstemperaturen. er ikke vesentlig: men reaksjonen foretrekkes' utf.ffø.r't vedi em; temperatur I onnrådet fra 0 til 5rØ!°X„ og. det. er m& st bekvemt å utføre reaksjonen ved omgivelises.tempe-ratutf. Reaksjonstiden er ikke kritisk og avhenger av -temperaturen. Vanligvis anvendes en reaksjonstid innen området: 3?0> mdinutter til 6 timer. Ved omgivelsestemperatur foretrekkes vanligvis en reaksjonstid innen området 1,5 til 4 timer. Omsetningen kan utføres i.et inert organisk oppløsningsmiddel og dimetylformamid. Det foretrekkes å gjennomføre omsetningen i dimetylformamid. When reacting a compound of formula II with S2CI2 or SC12, at least 1 mol of S2CI2 or SCI2 should be used per mol of compound II, and it is preferred: to use an excess of S 2 Cl 2 or SC 12 , for example from 2 to 3 mol per mol of compound II. The reaction temperature. is not essential: but the reaction is preferred' utf.ffø.r't vedi em; temperature In the range from 0 to 5rØ!°X„ and. the. it is most convenient to carry out the reaction at omgivelises.tempe-ratutf. The reaction time is not critical and depends on the temperature. Usually, a reaction time in the range: 3?0> mminutes to 6 hours is used. At ambient temperature, a reaction time in the range of 1.5 to 4 hours is usually preferred. The reaction can be carried out in an inert organic solvent and dimethylformamide. It is preferred to carry out the reaction in dimethylformamide.
Reaksjonsforholdet er ved omsetning av oppfinnelsens forbindelse med formel II med en svovelforbindelse med formel III ikke kritisk. Det foretrekkes å anvende minst en ekvimolar mengde av forbindelsen med formel III men et overskudd kan anvendes. Det foretrekkes å utføre omsetningen med i det alt vesentlige ekvimolare mengder av forbindelsene II og III. Reaksjonstemperaturen ikke kritisk. Ved lavere temperatur forløper omsetningen langsomt mens produksjonen av biprodukter økes ved høyere temperaturer. Den foretrukne reaksjonstemperatur ligger i området 10 til 50° C men det er mest bekvemt å utføre omsetningen ved omgivelsestemperatur. Reaksjonstiden er ikke kritisk og avhenger av reaksjonstemperaturen. Vanligvis anvendes det en reaksjonstid i området 20 minutter til 3 timer. Ved omgivelsestemperatur er en reaksjonstid på ca. 1 time passende og er normalt tilstrekk-elig til å la omsetningen forløpe til ende. Ftalimidet som felles ut fra reaksjonsblandingen kan så ekstraheres med en sterk base, for eksempel 10-20 %- ig vandig KOH, og det organiske oppløsningsmiddel tørkes, filtreres og konsen-treres, noe som gir råforbindelsen med formel I. Omsetningen skjer i et ikke-reaktivt organisk oppløsningsmiddel som metylenklorid, kloroform, karbontetraklorid, dimetylformamid, dimetylacetamid, tetrahydrofuran, diglym, benzen, toluen, xylen eller lignende. The reaction ratio is not critical when reacting the invention's compound of formula II with a sulfur compound of formula III. It is preferred to use at least an equimolar amount of the compound of formula III but an excess may be used. It is preferred to carry out the reaction with essentially equimolar amounts of the compounds II and III. The reaction temperature is not critical. At lower temperatures, turnover proceeds slowly, while the production of by-products is increased at higher temperatures. The preferred reaction temperature is in the range 10 to 50° C. but it is most convenient to carry out the reaction at ambient temperature. The reaction time is not critical and depends on the reaction temperature. Usually, a reaction time in the range of 20 minutes to 3 hours is used. At ambient temperature, a reaction time of approx. 1 hour is appropriate and is normally sufficient to allow the turnover to proceed to completion. The phthalimide that precipitates from the reaction mixture can then be extracted with a strong base, for example 10-20% aqueous KOH, and the organic solvent is dried, filtered and concentrated, which gives the crude compound of formula I. The reaction takes place in a non -reactive organic solvent such as methylene chloride, chloroform, carbon tetrachloride, dimethylformamide, dimethylacetamide, tetrahydrofuran, diglyme, benzene, toluene, xylene or the like.
Forbindelsene med formel II anvendes vanligvis som et syreaddisjonssalt, for eksempel et trihydroklorid. The compounds of formula II are usually used as an acid addition salt, for example a trihydrochloride.
Anvendelsen av syreadlsjonssalter foretrekkes vanligvis når omsetningen skjer med svovelmonoklorid eller svoveldiklorid. Skjønt syreaddisjonssaltet spesielt kan omdannes til den frie base før omsetning med svovelforbindelsen med formel III er dette ikke nødvendig eller ønskelig. Omdanningen skjer In situ ganske enkelt ved tilsetning av en passende mengde av en organisk base til en oppløsning av forbindelsen med formel II før omsetning med forbindelsen med formel III. Ved anvendelse av 1 Hioil av en forbindelse med formel II i form av trihydro-kloiridet bør det for eksempel således tilsettes 3 mol av en passende organisk base. Passende organiske baser omfatter tertiære aminer slik som trimetylamin, trietylamin, tri-n-propylamin, triisopropylamin, tri-n-butylamln, pyridin, N-metylmorfol in, N-metylpiperidin, 1,4-diazabicyklo[2,2,2]-oktan ( "BABC029 ,, 1,8-diazabieyklo[4,3,0]non-5-en ( "DBN" ) og lignende. The use of acid addition salts is usually preferred when the reaction takes place with sulfur monochloride or sulfur dichloride. Although the acid addition salt in particular may be converted to the free base prior to reaction with the sulfur compound of formula III, this is not necessary or desirable. The transformation takes place in situ simply by adding a suitable amount of an organic base to a solution of the compound of formula II before reaction with the compound of formula III. When using 1 Hioil of a compound of formula II in the form of the trihydrochloride, 3 mol of a suitable organic base should be added, for example. Suitable organic bases include tertiary amines such as trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, pyridine, N-methylmorpholine, N-methylpiperidine, 1,4-diazabicyclo[2,2,2]- octane ("BABC029 ,, 1,8-diazabiechlo[4,3,0]non-5-ene ("DBN") and the like.
Oppfinnelsens mellomprodukter med formel II kan fremstilles ved forskjellige fremgangsmåter. The intermediate products of the invention with formula II can be prepared by various methods.
Ved en fremgangsmåte behandles det tilsvarende 3-(amino eller substituert amino)-4-(substituert amino)--l,2,5-tiadiazol 1-oksyd med formel IV med en sterk mineralsyre HC1, for å oppnå forbindelsen med formel II. In one method, the corresponding 3-(amino or substituted amino)-4-(substituted amino)-1,2,5-thiadiazole 1-oxide of formula IV is treated with a strong mineral acid HCl, to obtain the compound of formula II.
Omsetningen kan skje i et inert oppløsningsmiddel og utføres fortrinnsvis i metanol. Reaksjonstemperaturen er ikke kritisk og omsetningen skjer mest bekvemt ved romtemperatur. Forbindelsene med formel IV er kjente og kan lett fremstilles ved de i US-PS 4.394.508 omtalte fremgangsmåter. The reaction can take place in an inert solvent and is preferably carried out in methanol. The reaction temperature is not critical and the reaction takes place most conveniently at room temperature. The compounds of formula IV are known and can be easily prepared by the methods mentioned in US-PS 4,394,508.
Ved en alternativ fremgangsmåte kan forbindelsene med formel II fremstilles på den i det følgende reaksjonsskjerna angitte måte: In an alternative method, the compounds of formula II can be prepared in the manner indicated in the following reaction core:
Omsetningen kan skje i et inert oppløsningsmiddel og skjer fortrinnsvis i metanol. Utgangsstoffene med formel V er kjente eller kan lett fremstilles ved kjente fremgangsmåter, for eksempel ved de I US-PS 4.394.508 samt de I EP-publ. 45.155 og 65.823 behandlede fremgangsmåter. The reaction can take place in an inert solvent and preferably takes place in methanol. The starting substances with formula V are known or can be easily prepared by known methods, for example by the I US-PS 4,394,508 and the I EP-publ. 45,155 and 65,823 processes processed.
Eksempel Example
N- < 2- f ( 2 - quanidlnot iazol - 4- vi ) metyltiol etyl >etandiimidamid, trihydroklorid N- < 2- f ( 2 - quanidlnot iazol - 4- vi ) methylthiol ethyl >ethanediimidamide, trihydrochloride
En suspensjon av 3-amino-4-<2-[(2-guanidinotiazol-4-yl)-metyltio]etylamino>-l,2,5-tiadiazol l-oksyd(5,25 g; 13,7 mmol) (fremstilt i henhold til offentliggjort GB-søknad 2.067.987) i 105 ml metanol ble behandlet med 80 ml konsentrert HC1 , noe som ga en øyeblikkelig gul oppløsning. Efter omrøring ved omgivelsestemperatur i 4,25 timer ble oppløs-ningen konsentrert nesten til tørr tilstand og resten triturert med aceton, filtrert og tørket, noe som ga den ønskede forbindelse. A suspension of 3-amino-4-<2-[(2-guanidinothiazol-4-yl)-methylthio]ethylamino>-1,2,5-thiadiazole 1-oxide (5.25 g; 13.7 mmol) ( prepared according to published GB application 2,067,987) in 105 ml of methanol was treated with 80 ml of concentrated HCl, which gave an immediate yellow solution. After stirring at ambient temperature for 4.25 hours, the solution was concentrated to near dryness and the residue triturated with acetone, filtered and dried to give the desired compound.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO872504A NO164711C (en) | 1984-06-22 | 1987-06-16 | ETAN-DIIMIDAMID-DERIVATIVES. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/623,588 US4644006A (en) | 1984-06-22 | 1984-06-22 | Substituted 3,4-diamino-1,2,5-thiadiazoles having histamine H2 -receptor antagonist activity |
| NO852519A NO161856C (en) | 1984-06-22 | 1985-06-21 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3,4-DIAMINO-1,2,5-THIADIAZOL DERIVATIVES. |
| NO872504A NO164711C (en) | 1984-06-22 | 1987-06-16 | ETAN-DIIMIDAMID-DERIVATIVES. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO872504L NO872504L (en) | 1985-12-23 |
| NO872504D0 NO872504D0 (en) | 1987-06-16 |
| NO164711B true NO164711B (en) | 1990-07-30 |
| NO164711C NO164711C (en) | 1990-11-07 |
Family
ID=27352929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO872504A NO164711C (en) | 1984-06-22 | 1987-06-16 | ETAN-DIIMIDAMID-DERIVATIVES. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO164711C (en) |
-
1987
- 1987-06-16 NO NO872504A patent/NO164711C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO872504L (en) | 1985-12-23 |
| NO164711C (en) | 1990-11-07 |
| NO872504D0 (en) | 1987-06-16 |
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