SE452462B - NEW 2-GUANIDINOTIAZOLD DERIVATIVES - Google Patents
NEW 2-GUANIDINOTIAZOLD DERIVATIVESInfo
- Publication number
- SE452462B SE452462B SE8102683A SE8102683A SE452462B SE 452462 B SE452462 B SE 452462B SE 8102683 A SE8102683 A SE 8102683A SE 8102683 A SE8102683 A SE 8102683A SE 452462 B SE452462 B SE 452462B
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- Prior art keywords
- optionally substituted
- phenyl
- formula
- halogen
- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
15- 20 25 30 40 452 462 C1-C6-alkansulfonamido omfattar metansulfonamido, etansnlfon- amído, propansulfonamido, ísopropansulfonamído, butansulfonamído, isobutansulfonamido, pentansulfonamído och hexansulfonamido; C]-C6-alkylsulfonyl omfattar metylsulfonyl, etylsulfonyl, propyl- sulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl och hexylsulfonyl; CZ-C10-dialkylamino omfattar dimetylamino, dietylamíno, dipropyl- amino, dibutylamino, dipentylamino, metyletylamino, metylpropyl- amino, etylpropylamino, etylbutylamíno och metylbutylaminog C6-C12-aryl omfattar fenyl, tolyl, xylyl, naftyl, metylnaftyl och etylnaftyl; 5-ledad heterocykel omfattar tienyl, isotiazolyl; i 6-ledad heterocykel omfattar pyridyl; och halogen omfattar klor, brom och jod. furyl, isoxazolyl och Såsom sådana H2-receptorantagoníster av 2-guanidinotiazoltyp har amerikanska patentskriften 4 165 377 (1979) beskrivit tioti- din, som har N-metylcyanoguanidingrupp, eventuellt omvandlingsbar till den karcinogena nitroso-N-metylcyanoguanidinogruppen i dägg- djurskroppen [?ool, et al, Toxícology, 15, 69 (1979)]. Vidare har den japanska ogranskade patentpublíkatíonen 141 271/1978 beskri-g vit N-[2-((2-pyridyl)metyltio)-etyljacetamid, som inte har någon verkan såsom histamin-H2-receptorantagonist. C 1 -C 6 alkanesulfonamido includes methanesulfonamido, ethanesulfonamido, propanesulfonamido, isopropanesulfonamido, butanesulfonamido, isobutanesulfonamido, pentanesulfonamido and hexanesulfonamido; C 1 -C 6 alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl and hexylsulfonyl; C 2 -C 10 dialkylamino includes dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, methylethylamino, methylpropylamino, ethylpropylamino, ethylbutylamino and methylbutylamino and C 6 -C 12 aryl includes phenyl, tolyl, xylphenyl; 5-membered heterocycle includes thienyl, isothiazolyl; in the 6-membered heterocycle comprises pyridyl; and halogen includes chlorine, bromine and iodine. furyl, isoxazolyl and As such 2-guanidinothiazole type H2 receptor antagonists, U.S. Patent No. 4,165,377 (1979) discloses thiotidine having the N-methylcyanoguanidine group optionally convertible to the carcinogenic nitroso-N-methylcyanoguanidino group in the mammalian group. , et al., Toxicology, 15, 69 (1979)]. Furthermore, Japanese Unexamined Patent Publication 141 271/1978 discloses white N- [2 - ((2-pyridyl) methylthio) ethyl] acetamide which has no action as a histamine H 2 receptor antagonist.
De först lämpliga föreningarna med formeln I är de vari n betecknar ett heltal från 2 till 3, R betecknar fenyl eventuellt- substituerad med en eller tre substituenter, som utväljes frän halogen, cyano, nitro, amino, C2~C10-dialkylamino, tetrazolyl, hydroxi, C1-C6-alkoxi, bensoyloxi, CZ-C7-alkoxikarbonyl, sulfamoyl, C1-C6-alkylsulfonyl, C1-C6-alkansulfonamido och C1-C6-alkanoyl, och X betecknar tia.The first suitable compounds of formula I are those in which n represents an integer from 2 to 3, R represents phenyl optionally substituted by one or three substituents selected from halogen, cyano, nitro, amino, C 2 -C 10 dialkylamino, tetrazolyl, hydroxy, C 1 -C 6 alkoxy, benzoyloxy, C 2 -C 7 alkoxycarbonyl, sulfamoyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkanesulfonamido and C 1 -C 6 alkanoyl, and X represents ten.
De för det andra lämpliga föreningarna med formeln I är de betecknar ett heltal frán 2 till 3, R betecknar 5-ledad heterocykel eventuellt substituerad med halogen, C1-C6-alkyl el- ler fenyl, och X betecknar tia. vari n De för det tredje lämpliga föreningarna med formel I är de n betecknar ett heltal från 2 till 3, R betecknar 6-ledad heterocykel eventuellt substítuerad med halogen, C1-C6-alkyl el-_ ler fenyl, och X betecknar tia. vari De för det fjärde lämpliga föreningarna med formeln I är de vari n betecknar ett heltal från 2 till 3,^R betecknar väte, 452 462 C]-C6-a1kyl'(eventue11t substítuerad med cyano, amíno eller fen- oxi), C3-Cójcykloalkyl, CZ-C7-alkenyl (eventuellt substítuerad med fenyl eller CZ-C7-alkoxikarbonyl) eller C4-C7-alkadíenyl, _och X betecknar tia. 5 2-guanidínotíazolderívaten (I) kan framställas í enlighet med följande schema: HN=c-NH2 É l : NH ä ,l§ Rcooa (III)' I É 5 N 1 1 L Sätt A) °H2X(CH2)nNH2 (II) HN=q-NH NH Hs(cH ) NHcoR(v) L___§ ______¿à¿1_______._s S N CH2_B ( Sätt B)(X=s) _m.J cH2X(cH2)nNHcoR ......-._« HN=C-NH2 | NH S=è-NH2 A~cH cocH,s(cH 2 2)nNHcoR (VII) (âsärr c)(x=s) (VI) [vari A och B vardera betecknar en reaktiv grupp, såsom halogen F eller resten av en aktiv ester (t.ex. tosyloxíl, och n, R och X har ovan angiven betydelse].The second suitable compounds of formula I are they represent an integer from 2 to 3, R represents a 5-membered heterocycle optionally substituted by halogen, C 1 -C 6 alkyl or phenyl, and X represents ten. wherein n The third suitable compounds of formula I are the n represents an integer from 2 to 3, R represents a 6-membered heterocycle optionally substituted by halogen, C 1 -C 6 alkyl or phenyl, and X represents ten. wherein the fourth suitable compounds of formula I are those wherein n represents an integer from 2 to 3, R 1 represents hydrogen, 452 462 C 1 -C 6 -alkyl '(optionally substituted by cyano, amino or phenoxy), C 3 -C 10 cycloalkyl, C 2 -C 7 alkenyl (optionally substituted with phenyl or C 2 -C 7 alkoxycarbonyl) or C 4 -C 7 alkadienyl, and X represents thia. The 2-guanidinothiazole derivatives (I) can be prepared according to the following scheme: HN = c-NH2 É 1: NH ä, l§ Rcooa (III) 'I É 5 N 1 1 L Method A) ° H2X (CH2) nNH2 ( II) HN = q-NH NH Hs (cH) NHcoR (v) L ___ § ______ ¿à¿1 _______._s SN CH2_B (Set B) (X = s) _m.J cH2X (cH2) nNHcoR ...... -._ «HN = C-NH2 | NH S = è-NH 2 A ~ cH cocH, s (cH 2 2) nNHcoR (VII) (âsärr c) (x = s) (VI) [wherein A and B each represent a reactive group, such as halogen F or the rest of an active ester (eg tosyloxyl, and n, R and X are as defined above].
Satt A" 10 Avsedda föreningar (I) kan framställas genom att bringa aminen (II) att reagera med karboxylsyra (III) eller dess reak- tíva derivat (t.ex. halogeníd, blandad syraanhydríd eller aktiv ester såsom tosylat) i ett ínert lösníngmedel, om nödvändigt i närvaro av en bas eller ett kondensationsmedel (t.ex. DCC, 10 15 20 25 35 40 452 462 trifenylfosfin/2,2'-dipyridyl-dísulfid). Denna acylering_utföres på konventionellt sätt sàsom blandad syraanhydridmetod, syrahalo- genidmetod, DCC-metod eller trifenylfosfinmetod, på följande sätt: (1) Blandad syraanhydridmetod Amínen (II) bringas att reagera med en blandad syraanhyd- rid innehållande en acyldel (RCO) av karboxylsyra1(IlI), som fram- ställts i förväg. Reaktionen kan vanligen utföras vid en tempera- tur från -200 till 60°C. Ytterligare framställning av den blandade syraanhydriden utföres genom att bringa karboxylsyræ1(III) att reagera med alkylklorokarbonat såsom metylklorokarbonat, etylkloro- karbonat eller liknande, i närvaro av en bas såsom tríetylamin, pyridin eller liknande, i ett inert lösningsmedel vid en tempera- tur från -300 till OOC. Exempel på lösningsmedel är tetrahydro- furan, metylenklorid, dioxan, dimetylsulfoxid,dimetylformamid, acetonitril, hexametylfosfortríamid eller liknande. (2) Syrahalogenidmetod: Amínen (Il) bringas att reagera med en syrahalogenid av karboxylsyran(III) i närvaro av en bas, såsom trietylamin, pyri- din eller liknande. Denna reaktion kan utföras i ett lämpligt lös- ningsmedel, såsom dimetylformamid, acetonitril, hexametylfosfor- tríamid, tetrahydrofuran, eller liknande vid en temperatur från -zo° ci11 6o°c. (3) DCC-metod: Amínen (II) bríngas att reagera med karboxylsyra1(lII) í närvaro av DCC (dicyklohexylkarbodiimid) i ett lämpligt lös- ningsmedel, såsom kloroform, dimetylformamid, dimetylsulfoxid eller liknande. Denna reaktion kan utföras vid en temperatur från -zo° tili 6o°c. ' (4) Trífenylfosfinmetod: _ Amínen (II) bringas att reagera med karboxy1syrax(III) i närvaro av trifenylfosfin och 2,2'-dipyridyl-disulfíd i ett lämpligt lösningsmedel, såsom dimetylformamid eller liknande vid en temperatur från -zo° :iii ßo°c.The intended compounds (I) can be prepared by reacting the amine (II) with carboxylic acid (III) or its reactive derivatives (eg halide, mixed acid anhydride or active ester such as tosylate) in an inert solvent. , if necessary in the presence of a base or a condensing agent (eg DCC, triphenylphosphine / 2,2'-dipyridyl disulfide) This acylation is carried out in a conventional manner such as mixed acid anhydride method, acid halide method , DCC method or triphenylphosphine method, as follows: (1) Mixed acid anhydride method The amine (II) is reacted with a mixed acid anhydride containing an acyl moiety (RCO) of carboxylic acid1 (III), which has been prepared in advance. is usually carried out at a temperature of from -200 to 60 ° C. Further preparation of the mixed acid anhydride is carried out by reacting carboxylic acid (III) with alkyl chlorocarbonate such as methyl chlorocarbonate, ethyl chlorocarbonate or the like, in the presence of a base such as triethylamine, pyridine or the like, in an inert solvent at a temperature from -300 to 0 ° C. Examples of solvents are tetrahydrofuran, methylene chloride, dioxane, dimethyl sulfoxide, dimethylformamide, acetonitrile, hexamethylphosphoric triamide or the like. (2) Acid halide method: The amine (II) is reacted with an acid halide of the carboxylic acid (III) in the presence of a base such as triethylamine, pyridine or the like. This reaction can be carried out in a suitable solvent, such as dimethylformamide, acetonitrile, hexamethylphosphoric triamide, tetrahydrofuran, or the like at a temperature of -60 ° C to 60 ° C. (3) DCC method: The amine (II) is reacted with carboxylic acid (II) in the presence of DCC (dicyclohexylcarbodiimide) in a suitable solvent such as chloroform, dimethylformamide, dimethylsulfoxide or the like. This reaction can be carried out at a temperature from -zo ° to 60 ° C. (4) Triphenylphosphine method: The amine (II) is reacted with carboxylic acid (III) in the presence of triphenylphosphine and 2,2'-dipyridyl disulfide in a suitable solvent such as dimethylformamide or the like at a temperature from -zo °: iii ßo ° c.
Utgångsaminen (II) framställes i enlighet med metoden som beskrives i amerikanska patentskriften 4 165 377.The starting amine (II) is prepared according to the method described in U.S. Patent No. 4,165,377.
Sätt B Avsedda föreningar (I) kan framställas genom att bringa 2-guanidino-4-(aktiverad)metyltiazol (IV) att reagera med merkap- tan (V) i närvaro av en bas. Reaktionen.utföres i ett inert lös~ níngsmedel (t.ex. metanol, etanol, díetyleter, tetrahydrofuran, 10 15 20 25 30 452 462 dimetylformamid, dimetylsulfoxid, aceton, kloroform) víd.en tempe- ratur fràn 0° till 60°C. Exempel på basen är alkalimetallhydroxi- der (t.ex. natríumhydroxid), alkalimetallkarbonater (t.ex. kalium- karbonat, natriumkarbonat) och alkalimetallalkoxider (t.ex. nat- riummetoxid, kalíumetoxíd).Method B Intended compounds (I) can be prepared by reacting 2-guanidino-4- (activated) methylthiazole (IV) with mercaptan (V) in the presence of a base. The reaction is carried out in an inert solvent (eg methanol, ethanol, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, chloroform) at a temperature of from 0 ° to 60 ° C. . Examples of the base are alkali metal hydroxides (eg sodium hydroxide), alkali metal carbonates (eg potassium carbonate, sodium carbonate) and alkali metal alkoxides (eg sodium methoxide, potassium methoxide).
Utgàngstiazolen (IV) framställes exempelvis genom att behand- la guanyltiokarbamíd med 1,3-dikloroaceton i ett inert lösnings- medel såsom aceton [amerikanska patentskriften 4 165 3771.The starting thiazole (IV) is prepared, for example, by treating guanylthiourea with 1,3-dichloroacetone in an inert solvent such as acetone [U.S. Patent No. 4,165,3771.
En annan utgängsmerkaptan (V) framställes genom att behandla en disulfid (VIII) med karboxylsyra (III) eller dess reaktiva de- rivat enligt acyleringssteget ovan, och reducera erhàllen acyl- amínoalkyldisulfid (IX) med natriumborhydríd i ett inert lösnings- medel (t.ex. etanol eller metanol) på följande sätt: fflçflfinyqfl; 2 (VIII) .I Lsmnzynnacoiz] 2 (IX) NaBH4 -----§> HS(CH2) NHCOR Il (V) och R har ovan angiven betydelse).Another starting mercaptan (V) is prepared by treating a disulfide (VIII) with carboxylic acid (III) or its reactive derivatives according to the acylation step above, and reducing the acylaminoalkyl disulfide (IX) obtained with sodium borohydride in an inert solvent (t). eg ethanol or methanol) as follows: f fl ç flfi nyq fl; 2 (VIII) .I Lsmnzynnacoiz] 2 (IX) NaBH4 ----- §> HS (CH2) NHCOR II (V) and R have the meaning given above).
Sätt C ~e«~ (vari n Avsedd förening (I) kan framställas genom att bringa guanyl- tiokarbamid (VI) att reagera med ketonderivatet (VII) i närvaro av en bas, såsom trietylamin, pyridin eller liknande.Reaktionen utföres i ett inert lösningsmedel, såsom etanol, tetrahydrofuran, dimetylsulfoxid, dimetylformamid, kloroform eller liknande, vid en temperatur från 0°C till det använda lösningsmedlets kokpunkt.The process C (e) (wherein n Intended compound (I) can be prepared by reacting guanylthiourea (VI) with the ketone derivative (VII) in the presence of a base such as triethylamine, pyridine or the like. The reaction is carried out in an inert solvents such as ethanol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, chloroform or the like, at a temperature from 0 ° C to the boiling point of the solvent used.
Utgångsketonderivatet (VII) framställes genom att bringa 1,3-di(aktiverad)keton (X) att reagera med merkaptan (V) í närvaro av en bas, såsom trietylamin, pyrídin eller jonbytarharts (OH-typ), lämpligen jonbytarharts (OH-typ),í ett ínert lösningsmedel såsom etanol, aceton, dimetylsulfoxid eller liknande vid en temperatur från -zo° :in 3o°c.The starting ketone derivative (VII) is prepared by reacting 1,3-di (activated) ketone (X) with mercaptan (V) in the presence of a base such as triethylamine, pyridine or ion exchange resin (OH type), preferably ion exchange resin (OH- type), in an inert solvent such as ethanol, acetone, dimethyl sulfoxide or the like at a temperature from -zo °: in 30 ° C.
A-CHZCOCH2-A+ HS(CH2)nNHCOR -¿> ACH3COCH2S(CH2)nNHC0R (X) (V) (VII) (vari A, n och R har ovan angiven betydelse).A-CH2COCH2-A + HS (CH2) nNHCOR -¿> ACH3COCH2S (CH2) nNHCOR (X) (V) (VII) (wherein A, n and R have the meaning given above).
Om nödvändigt kan nitrogruppen på bensenringen i föreningar: na (I) (R = aryl) reduceras med ett milt reduktíonsmcdel, såsom titantríkloríd eller liknande i vattenhaltig ättiksyra vid rums- temperatur för omvandling till motsvarande amínogrupp. Varje 10 15 20 ZS 35 452 462 amínoskyddande grupp, såsom karbobensoxi eller trityl, somfnödvän- digtvis införts i produkten (I) genom ovanstående sätt, kan av- lägsnas därifrån på konventionellt sätt.If necessary, the nitro group on the benzene ring of compounds: (I) (R = aryl) can be reduced with a mild reducing agent, such as titanium trichloride or the like in aqueous acetic acid at room temperature to convert to the corresponding amino group. Any amino protecting group, such as carbobenzoxy or trityl, which is necessarily introduced into the product (I) by the above method, may be removed therefrom by conventional means.
Produkten (I) kan omvandlas till farmaceutiskt godtagbara syraadditionssalter, såsom de med oorganisk syra (t.ex. saltsyra, svavelsyra, salpetersyrlighet, fosforsyra, tiocyansyra) eller de med organisk syra (t.ex. ättiksyra, bärnstenssyra, oxalsyra, male- insyra, äpplesyra, ftalsyra, metansulfonsyra),för behov vid fram- ställning, krístallisation, solubilisation eller förbättring av stabiliteten.The product (I) can be converted into pharmaceutically acceptable acid addition salts, such as those with inorganic acid (eg hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid) or those with organic acid (eg acetic acid, succinic acid, oxalic acid, maleic acid , malic acid, phthalic acid, methanesulfonic acid), for use in the preparation, crystallization, solubilization or improvement of stability.
Sålunda erhållet 2-guanídinotiazolderivat (I) och deras far- maceutiskt godtagbara syraadditionssalter är användbara såsom antipeptiska magsårsmedel eller histamin-H2-receptor-antagoníster.The 2-guanidinothiazole derivatives (I) thus obtained and their pharmaceutically acceptable acid addition salts are useful as antipeptic gastric ulcers or histamine H2 receptor antagonists.
Exempelvis visade 2-guanidíno-4-[?-(formamido)etyltiometyl]tiazol- maleat följande farmakolgiska verkningar: a) Histamin-H2-antagonism in vítro under användning av extra- herat marsvinsatrium på grund av förbehandlíng med försöksföre- ningen: pA2 = 7,05 [Äriens, Molecular Pharmacology, vol. 1, Academic Press, New York, 1964]; b) Hämning av peptisk sekretion beroende på histamin in vivo under användning av hanrâttor av Donryu-stammen: ED50 0,25 mg/kg (i.v.) [Chosh, et al, Brit. J. Pharmacol., (1958), lå, 542; c) Letal dos hos möss: - LD50 148 mg/kg (i.v.); 7691 mg/kg (p.o.) [Bliss; Ann. Appl. Biol., gå, 134-307 (1935]; Quant. J. Pharmacol., ll, 192 (l938l].For example, 2-guanidino-4 - [? - (formamido) ethylthiomethyl] thiazole maleate showed the following pharmacological effects: a) In vitro histamine H2 antagonism using extracted guinea pig sodium due to pretreatment with the test compound: pA2 = 7.05 [Ariens, Molecular Pharmacology, vol. 1, Academic Press, New York, 1964]; b) Inhibition of peptic secretion due to histamine in vivo using male rats of the Donryu strain: ED50 0.25 mg / kg (i.v.) [Chosh, et al, Brit. J. Pharmacol., (1958), lay, 542; c) Lethal dose in mice: - LD50 148 mg / kg (i.v.); 7691 mg / kg (p.o.) [Bliss; Ann. Appl. Biol., Ga, 134-307 (1935]; Quant. J. Pharmacol., Ll, 192 (1938l].
De andra föreningarna visade liknande farmakologiska verk- ningar. 2-guanídínotiazolderivaten (I) och deras farmaceutiskt god- tagbara syraaddítionssalter tillföres ensamma eller i kombination med farmaceutiskt lämpliga bärare, såsom vetestärkelse, majsstär- kelse, potatisstärkelse, gelatín, etc. Valet av bärare bestämmas av det lämpliga administrationssättet, substansens löslighet och farmaceutisk standardpraxis. Exempel på farmaceutiska preparat är tabletter, kapslar, piller, suspensioner, siraper, pulver och 10 15 20 25 30 35 40 452 462 lösningar.:Dessa kompositioner kan framställas pá konventionellt sätt.The other compounds showed similar pharmacological effects. The 2-guanidinothiazole derivatives (I) and their pharmaceutically acceptable acid addition salts are administered alone or in combination with pharmaceutically acceptable carriers, such as wheat starch, corn starch, potato starch, gelatin, etc. The choice of carrier is determined by the appropriate route of administration and the pharmaceutical standard, substance and substance. . Examples of pharmaceutical preparations are tablets, capsules, pills, suspensions, syrups, powders and solutions. These compositions can be prepared in a conventional manner.
En lämplig daglig dos av Zfguanidinotiazolderivaten (I) eller farmaceutískt godtagbara syraadditionssalter därav för vuxna män- niskor är i storleksordningen från cirka 1,0 till cirka 40,0mg/kg, lämpligen cirka 1,0 till cirka 15,0 mg/kg i en enda eller delade portioner.A suitable daily dose of the Zfguanidinothiazole derivatives (I) or pharmaceutically acceptable acid addition salts thereof for adults is in the range of from about 1.0 to about 40.0 mg / kg, preferably about 1.0 to about 15.0 mg / kg in a single or divided portions.
Histamin-H2-receptor-antagonism rappmïerades av Black et al [Black et al, Nature, åäö, 385 (1972)].Histamine H2 receptor antagonism was reported by Black et al [Black et al., Nature, A, 385 (1972)].
Utan vidare lämpliga och praktiska utföringsformer av före- liggande uppfinning belyses i följande exmepel.Without further ado suitable and practical embodiments of the present invention are illustrated in the following examples.
Exempel 1. En blandning av p-sulfamoylbensoesyra (201 mg), tri- fenylfosfin (262 mg) och 2,2'-dipyridyldisulfid (220 mg) i torr dimetylformamid (4 ml) omrördes vid rumstemperatur i 1 timme.Example 1. A mixture of p-sulfamoylbenzoic acid (201 mg), triphenylphosphine (262 mg) and 2,2'-dipyridyl disulfide (220 mg) in dry dimethylformamide (4 ml) was stirred at room temperature for 1 hour.
Till erhållen lösning sattes 2-guanidino-4-(2-aminoetyltiometyl} tiazol-dihydroklorid (304 mg) (amerikanska patentskriften 4165 STÜ och tríetylamin (0,4 ml) Efter omröring vid rumstemperatur i 20 timmar avdunstades lösningsmedlet i vakuum och återstoden under- kastades silikagel (50 g) kolonnkromatografi under eluering med etylacetat/metanol (20/5 volym/volym) för att ge 2-guanidino-4- [2-(4-sulfamoylbensamído)etyltíometyljflazol (274 mg) i 67-procen- tigt utbyte. Behandling av produkten med maleinsyra (300 mg) i aceton gav i utbyte monomaleat (297 mg) såsom kristaller, som smälte vid z1s-z17°c, sönderdeining (metanol).To the resulting solution was added 2-guanidino-4- (2-aminoethylthiomethyl} thiazole dihydrochloride (304 mg) (U.S. Patent 4,165 STU and triethylamine (0.4 mL). After stirring at room temperature for 20 hours, the solvent was evaporated in vacuo and the residue was evaporated. silica gel (50 g) was subjected to column chromatography eluting with ethyl acetate / methanol (20/5 v / v) to give 2-guanidino-4- [2- (4-sulfamoylbenzamido) ethylthiomethyl] flazole (274 mg) in 67% yield Treatment of the product with maleic acid (300 mg) in acetone yielded monomaleate (297 mg) as crystals, melting at 70 DEG-17 DEG C., decomposing (methanol).
Analys, beräknat för cmnzzonwóss: c 40,74 n 4,18 funnet ' 40,63 4,08 Monohydroklorid, smältpunkt ZZOOC (sönderdelníng) Exempel 2. let för p-sulfamoylbensoesyra utfördes reaktionen såsom i exempel 1, varvid 2-guanidino-4-[2-(4-(N)-tetrazolylbensamido)etyltio- N1s,s4_(%> 15,74 (t) Under användning av p-(N)-tetrazolylbensoesyra i stäl- metyljtiazol erhölls i 28-procentigt utbyte. Monomaleatet, smält~ punkt 211°C (sönderdelning) (metanol). ' Analys, beräknat för C10H21O5N9S2: C 43,92 H 4,07 (%) funnet 43,85 4,15 (%) Exempel 3. Till en lösning av p-(metylsulfonyl)bensoesyra (S52 mg) i torr tetrahydrofuran (10 ml) sattes trietylamin (0,24 ml) och etylklorokarbonat (191 mg) vid OOC under omröring. Efter omröring vid denna temperatur i 30 minuter behandlades erhållen suspension med 2-guanidino-4-(2-aminoetyltiometyl)tiazol-dihydroklorid (500 mg) och trietylamin (0,5 ml) och fick antaga rumstemperatur över 10 452 462 natten under omröring. Utfällt fast ämne avfiltrerades och filt- ratet índunstades i vakuum för att ge en olja, som renades genom silíkagel (40 g) kromatografi under eluering med etylacetatlmeta- nol (20:5) för att ge 2-guanídíno-4-[?-(4-metylsulfonylbensamido)- etyltiometylj-tiazol (154 mg) i 82-procentigt utbyte. Behandling av produkten med maleínsyra (500 mg) i aceton gav monomaleatet (600 mg) såsom kristaller som smälte vid 192-194°C (sönderdelning) (metanol).Analysis calculated for concentration: 40.74 n 4.18 Found 40.63 4.08 Monohydrochloride, melting point Z 2 OOC (decomposition) Example 2 The reaction for p-sulfamoylbenzoic acid was carried out as in Example 1, substituting 2-guanidino-4 - [2- (4- (N) -tetrazolylbenzamido) ethylthio- N1s, s4- (%> 15.74 (t) Using p- (N) -tetrazolylbenzoic acid in stalemethylthiazole was obtained in 28% yield. melting point 211 ° C (decomposition) (methanol). Analysis, calculated for C 10 H 21 O 5 N 9 S 2: C 43.92 H 4.07 (%) found 43.85 4.15 (%) Example 3. To a solution of p (methylsulfonyl) benzoic acid (S52 mg) in dry tetrahydrofuran (10 ml), triethylamine (0.24 ml) and ethyl chlorocarbonate (191 mg) were added at 0 DEG C. with stirring. After stirring at this temperature for 30 minutes, the resulting suspension was treated with 2-guanidino- 4- (2-Aminoethylthiomethyl) thiazole dihydrochloride (500 mg) and triethylamine (0.5 ml) and allowed to warm to room temperature over 452,462 overnight with stirring, the precipitated solid was filtered off and the filtrate was evaporated. was evaporated in vacuo to give an oil which was purified by silica gel (40 g) chromatography eluting with ethyl acetate / methanol (20: 5) to give 2-guanidino-4 - [? - (4-methylsulfonylbenzamido) ethylthiomethyl] thiazole (154 mg) in 82% yield. Treatment of the product with maleic acid (500 mg) in acetone gave the monomaleate (600 mg) as crystals melting at 192-194 ° C (dec.) (Methanol).
Analys, beräknat för C O S N 7 3 S: C 43,08 H 4,38 N 13,22 (%) funnet 42,81 4,20 13,33 (%) Exemgel 4-22. Under användning av karboxylsyra (III) utfördes reaktionen såsom i exempel 3, varvid produkten (I) erhölls såsom visas i tabell 1. 19Hzs HN=ï-NH2 HN=c-Nnz NH fm s,l§¿I ncooH(III) S,i§N O %\ CH2S(CH2)2NH2 cH2s(on2)2NHcn (II) (I) Tabell 1 Ex- I ' 93 ~ R Sal* åfflfl°C) uubyre(%) n ._<:::>_cN maieat 175-176 sogz 5 -1@šï>_C0CH3 maleat 161-163 87,h 6 -cH=c(cH3)2 ï§:É:š"' 175-176d. 91 7 3 H Ph maieat. 212-ziha. 43,3 \o Tabell :1 , forts. 452 462 Exø I nr R salt âïåiïvc) Utbyte s _.@_1\'Hso2cr13 maleaf 197-198 35 9 _¿flšzï ma1ear- 183-185 63 1 1o -@_F ma1ear 175-177 71 ' oocH __<° ß 11 <9/ mama: 173-175 76 coocH 3 12 maleat 181-183 55 :oz 2- 13 .<:)>_o-co-Ph ma1eat 207-209 34 11» C113 ma1eaf 1314-136 62,5 - i v H l .kn- v 4 .- 15 -cH-chz 95-964 30, 5 maieat- 16 -Qocfiß 1/21120 154-1566 58,5 ocH 3 _ _ = . . maleat- ._ _ Q 17 cfl-cn cn chcaß l/üfizo 1,9 1.06 81,6 vem.. ... ~ 1:13' 452 462 10 Tabell 1, forts. --F Ex.É . I I nr R salt âï臨°o) Utbyte (%) I i 1 mal at-- . I _ 18 H'““"H 1/2:20 1s1-1s2d. l ,2,s å 0 .Analysis calculated for C 0 S N 7 3 S: C 43.08 H 4.38 N 13.22 (%) found 42.81 4.20 13.33 (%) Exemgel 4-22. Using carboxylic acid (III), the reaction was carried out as in Example 3, the product (I) being obtained as shown in Table 1. 19Hzs HN = 1 H-NH 2 HN = c-Nnz NH fm s, 1§¿I ncooH (III) S , i§NO% \ CH2S (CH2) 2NH2 cH2s (on2) 2NHcn (II) (I) Table 1 Ex- I '93 ~ R Sal * åf fl fl ° C) uubyre (%) n ._ <:::> _ cN maieat 175-176 sogz 5 -1 @ šï> _C0CH3 maleat 161-163 87, h 6 -cH = c (cH3) 2 ï§: É: š "'175-176d. 91 7 3 H Ph maieat. 212-ziha . 43,3 \ o Table: 1, cont. 452 462 Exø I nr R salt âïåiïvc) Yield s _. @ _ 1 \ 'Hso2cr13 maleaf 197-198 35 9 _¿fl šzï ma1ear- 183-185 63 1 1o - @ _ F ma1ear 175-177 71 'oocH __ <° ß 11 <9 / mama: 173-175 76 coocH 3 12 maleat 181-183 55: oz 2- 13. <:)> _ o-co-Ph ma1eat 207-209 34 11 »C113 ma1eaf 1314-136 62,5 - iv H l .kn- v 4 .- 15 -cH-chz 95-964 30, 5 maieat- 16 -Qoc fi ß 1/21120 154-1566 58.5 ocH 3 _ _ = .. maleat- ._ _ Q 17 c fl- cn cn chcaß l / ü fi zo 1,9 1.06 81.6 vem .. ... ~ 1:13 '452 462 10 Table 1, cont. --F Ex.É. II nr R salt âï臨 ° o) Yield (%) I i 1 mal at--. I _ 18 H '““ "H 1/2: 20 1s1-1s2d. 1, 2, s å 0.
I i 1 l '19 II H malear 168-17od. ' 66,3 É Sf/ Br | E 1 t- _ 20 -cH=cH-cooau ï?2§:O 99-lold. ,u,u l.25male- at- _ lhl-lhjd. 11,1 _@_m2 22 'íššià ma1ear 179-181 39 ' NH2 21 Anm: Förkortningarna har följande betydelse: Bu Cbutyl), Ph (fenyl), d (sönderdelning).I i 1 l '19 II H malear 168-17od. '66.3 É Sf / Br | E 1 t- _ 20 -cH = cH-cooau ï? 2§: O 99-lold. , u, u l.25male- at- _ lhl-lhjd. 11.1 _ @ _ m2 22 'íššià ma1ear 179-181 39' NH2 21 Note: The abbreviations have the following meanings: Bu Cbutyl), Ph (phenyl), d (decomposition).
Exempel 23. Till en suspension av 2-guanidino-4~[2-(amino)etyl- tíometyl]tíazol-díhydroklorid (500 mg) i torr Qímetylformamid _ (5 ml) sattes p-nítrobensoylkloríd (300 mg) och trietylamin (0,74 ml) vid OOC under omröríng. Erhållen suspension omrördes och fick antaga rumstemperatur över natten. Lösningsmedlet avduns- tades i vakuum och återstoden underkastades kromatografí pà sili- ' kagel-(40 g) kolonn, eluerades med etylacetat/metanol (Z0:5 volym/ volym) för att ge 2-guanídino-4-[?-(4-nitrobensamído)-etyltíome- tyl]tíazol (614 mg) i 98-procentígt utbyte. Monomaleatet, smält- punkt 180-181OC (síntríng vid 170°C) (omkrístallíserat från meta- nol).Example 23. To a suspension of 2-guanidino-4- [2- (amino) ethylthiomethyl] thiazole dihydrochloride (500 mg) in dry Dimethylformamide (5 ml) were added p-nitrobenzoyl chloride (300 mg) and triethylamine (0 mg). , 74 ml) at 0 ° C with stirring. The resulting suspension was stirred and allowed to warm to room temperature overnight. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel (40 g) column, eluting with ethyl acetate / methanol (Z0: 5 v / v) to give 2-guanidino-4 - [? - (4- nitrobenzamido) -ethylthiomethyl] thiazole (614 mg) in 98% yield. Monomaleate, m.p. 180 DEG-181 DEG C. (sintering at 170 DEG C.) (recrystallized from methanol).
Analys, beräknat för C 18H2 o?N6s¿: c 43,43 H 4,06' N 16,92 (2) funnet : 45,Q8 4,14 16,76 (%) Exemgel Z4-É4. Under användñíng av karboxylsyraklorid (IIIÖ ut- 11 452 462 fördes rèaktíonen såsom i exempel 23, varvid produkten (I) èr- hölls såsom visas i tabell 2. gabell 2 Ex . s "lr- m. R salt pïkt (°c) ~ Utbyregä) 21» @.coocH3 maleac 189-190 22 25 -q maleat 1881159 73 ,s 26 ß-naftyl maleat l75-l77a. 39 l;l-l52d 27 °CH20--@ maleat (slntring 95 vld 145°C) š 28 -@ malear zoo-zozfl. 69 ,8 29 -@\ male-at lsz-lshd i ,7 ,8 N' 2 30 . Cl maleat 177-178 i #8 ,¿|- 31 I] J maleaf l9l-l92d. 62 ,l _.\u maleat~ 32 -<(â/\_0CH3 H20 lul-llßd. 6o,h 33 -CHëCH-Ph maleat lS3-l85d . 55 5 5 34 -@.\*(CH3)Z malea: 188-190, 21, l --;-:: ::-g--=f. :=:r-:rf-:ff-v=vv-ftífitffyïztyrïftrßfïiïïfift? 10 15 20 25 30 35 40 12 452 462 Exemgel 35; Till en blandning av 2-guanidino-4-[2-(aminoletyl- tiometyljtiazol (800 mg), myrsyra (132 mg) och DCC (590 mg) i torr dimetylformamid (15 ml) sattes trietylamin (0,8 ml) under omröring. Därefter omrördes erhållen blandning vid rumstemperatur i 16 timmar, det utfällda fasta ämnet avfiltrerades och filtratet indunstades i vakuum för att ge en oljig återstod, som kromatogra- ferades på en kolonn av silikagel (70 g), eluerades med etylacetat/ metanol (2025 volym/volym) för att ge en blandning (706 mg) av den fria basen och karbonatet av 2-guanidino-4-[2-(formamido)- etyltiometyl]tiazo1. Den löstes i metanol och koldioxidgas passe- rade genom lösningen. Avdunstning av lösningsmedlet gav karbona- tet (720 mg) i 85-procentigt utbyte såsom kristaller som smälte vid 138-14o°c.Analysis calculated for C 18 H 21 N 6 O 5: c 43.43 H 4.06, N 16.92 (2) Found: 45, Q8 4.14 16.76 (%) Exemgel Z4-É4. Using carboxylic acid chloride (IIIÖ), the reaction was carried out as in Example 23, the product (I) being obtained as shown in Table 2. Table 2 Ex. S "lr- m. R salt point (° c) ~ Utbyregä) 21 »@ .coocH3 maleac 189-190 22 25 -q maleate 1881159 73, s 26 ß-naphthyl maleate l75-l77a. 39 l; l-l52d 27 ° CH20 - @ maleate (slntring 95 vld 145 ° C) š 28 - @ malear zoo-zozfl. 69, 8 29 - @ \ male-at lsz-lshd i, 7, 8 N '2 30. Cl maleat 177-178 i # 8, ¿| - 31 I] J maleaf l9l -l92d. 62, l _. \ u maleat ~ 32 - <(â / \ _ 0CH3 H20 lul-llßd. 6o, h 33 -CHëCH-Ph maleat lS3-l85d. 55 5 5 34 - @. \ * (CH3) Z malea: 188-190, 21, l -; - :: :: - g - = f.: =: R-: rf-: ff-v = vv-ftí fi tffyïztyrïftrßfïiïïfift? 10 15 20 25 30 35 40 12 To a mixture of 2-guanidino-4- [2- (aminolethylthiomethylthiazole (800 mg), formic acid (132 mg) and DCC (590 mg) in dry dimethylformamide (15 ml) was added triethylamine (0, 452 462). 8 ml) with stirring, then the resulting mixture was stirred at room temperature for 16 hours, the precipitated solid filtered off The filtrate was evaporated in vacuo to give an oily residue, which was chromatographed on a column of silica gel (70 g), eluted with ethyl acetate / methanol (2025 v / v) to give a mixture (706 mg) of the free the base and the carbonate of 2-guanidino-4- [2- (formamido) ethylthiomethyl] thiazole. It was dissolved in methanol and carbon dioxide gas passed through the solution. Evaporation of the solvent gave the carbonate (720 mg) in 85% yield as crystals melting at 138-140 ° C.
Analys, beräknat för C H 9 15O4N5S2-1,5 HZCO3-1 H20: C 30,41 H 4,82 (%) funnet: 30,55 4,66 (%) Exemgel 36. Till en lösning av metalliskt natrium (cirka 'D mg) i etanol (5 ml) sattes droppvis en lösning av N-bensoylcystamin (268 mg) i etanol (5 ml) vid 0°C under omröring och erhállen bland- ning omrördes vid OOC i 2 timmar. En lösning av 2-guanidino-4- klorometyltiazol (239 mg) i etanol (5 ml) sattes droppvis till blandningen, som omrördes vid rumstemperatur i 15 timmar. Reak- tionsblandningen koncentrerades i vakuum och blandningen blanda- des med aceton. Olösligt material avfiltrerades och filtratet blandades med maleinsyra/aceton för att ge 2-guanidino-4-[2-(bens- amido)etyltiometyljtiazol-maleat (414 mg) i 91,4 % såsom kristal- ler, som smälter vid 200-202°C (sönderdelning}.Analysis calculated for CH 9 15O 4 N 5 S 2 -1.5 H 2 CO 3 -1 H 2 O: C 30.41 H 4.82 (%) Found: 30.55 4.66 (%) Example gel 36. To a solution of metallic sodium (ca. D mg) in ethanol (5 ml) was added dropwise a solution of N-benzoylcystamine (268 mg) in ethanol (5 ml) at 0 ° C with stirring and the resulting mixture was stirred at 0 ° C for 2 hours. A solution of 2-guanidino-4-chloromethylthiazole (239 mg) in ethanol (5 ml) was added dropwise to the mixture, which was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the mixture was mixed with acetone. Insoluble material was filtered off and the filtrate was mixed with maleic acid / acetone to give 2-guanidino-4- [2- (benzamido) ethylthiomethylthiazole maleate (414 mg) in 91.4% as crystals melting at 200-202 ° C (decomposition}.
Exemgel 37. Under användning av N-nikotinoylcystamin (273 mg), utfördes reaktionen såsom i exempel 36, varvid 2-guanídino-4-[É- (nikotinamido)etyltiometyljtiazol-maleat (0,35 g) erhölls i TT,4% utbyte.Example Gel 37. Using N-nicotinoylcystamine (273 mg), the reaction was carried out as in Example 36 to give 2-guanidino-4- [E- (nicotinamido) ethylthiomethylthiazole maleate (0.35 g) in TT, 4% yield .
Exempel 38. des reaktionen såsom i exempel 3, varvid Z-fluanídino-4-¿?-(3,4,S- trimetoxibensamido(etyltíometyl]tiazol-maleat erhölls såsom kris- taller, som smälter vid l63-165oC (sönderdelning) i 66 % utbyte.Example 38, the reaction was carried out as in Example 3, where Z - fluanidino-4-β- (3,4,5-trimethoxybenzamido (ethylthiomethyl] thiazole maleate was obtained as crystals melting at 186 DEG-165 DEG C. (decomposition) in 66% yield.
Exemgel 39. Under användning av p-metylsulfonylbensoesyra utför- des reaktionen sàsom i exempel 3, varvid Z-guanidino-4-[É-(4-me- tylsulfonylbensamido)etyltiometyl]tiazol-hydroklorid erhölls såsom kristaller som smälter vid 196-198°C.Example 39. Using p-methylsulfonylbenzoic acid, the reaction was carried out as in Example 3, yielding Z-guanidino-4- [E- (4-methylsulfonylbenzamido) ethylthiomethyl] thiazole hydrochloride as crystals melting at 196-198 ° C.
Exemgel 40. Till en lösning av 1-kloro-3-[2-(acetamido)etyltiq7- Under användning av 3,4,5-trimetoxibensoesyra utför- 10 15 20 25 30 35 40 13 452 462 2-propanon¿(607 mg) i absolut etanol (25 ml) sattes guanyltio- karbamid (320 mg) och erhàllen blandning àterloppskokades under omröring i.3 timmar. Efter kylning blandades reaktionsblandningen med trietylamín (1,5 ml) och koncentrerades i vakuum. Återstoden kromatograferades på en kolonn av silikagel (25 g), som eluerades med etylacetat/metanol (20:5 volym/volym). Eluatet koncentrerades för att ge 2-guanidino-4-[2-(acetamido)etyltiometyljtiazol (196mg), som var identisk med produkten i exempel 14. Utbytet var 25 %.Example gel 40. To a solution of 1-chloro-3- [2- (acetamido) ethyl] 7- Using 3,4,5-trimethoxybenzoic acid perform 2-propanone (607 mg ) in absolute ethanol (25 ml) was added guanylthiourea (320 mg) and the resulting mixture was refluxed with stirring for 3 hours. After cooling, the reaction mixture was mixed with triethylamine (1.5 ml) and concentrated in vacuo. The residue was chromatographed on a column of silica gel (25 g), which was eluted with ethyl acetate / methanol (20: 5 v / v). The eluate was concentrated to give 2-guanidino-4- [2- (acetamido) ethylthiomethylthiazole (196mg), which was identical to the product of Example 14. The yield was 25%.
Framställning av 1-kloro-3-[2-(acetamido)etyltiq]-2-propanon: Till en lösning av 2-acetamidoetantíol (667 mg) i absolut etanol (25 ml) sattes'%mberlite IR4B"(OH-typ) (2 g). Erhällen blandning kyldes vid OQC, blandades med 1,3-dikloraceton (908 mg), omrördes vid 0°C i 1 timme, fick stå vid 3-5°C över natten. Hart- set avfiltnerades och filtratet koncentrerades i vakuum vid en temperatur under 35°C. Den oljiga återstoden kromatograferades på en kolonn av silikagel som eluerades med etylacetat/metanol (2015 volym/volym). Eluatet koncentrerades i vakuum för att ge 1-k1oro-3-[2-(acetamido)etyltiQ]-Z-propanon (607 mg) såsom en olja.Preparation of 1-chloro-3- [2- (acetamido) ethyl] -2-propanone: To a solution of 2-acetamidoethanethiol (667 mg) in absolute ethanol (25 ml) was added 1% mberlite IR4B "(OH type) The resulting mixture was cooled to 0 DEG C., mixed with 1,3-dichloroacetone (908 mg), stirred at 0 DEG C. for 1 hour, allowed to stand at 3-5 DEG C. overnight, the resin was filtered off and the filtrate was concentrated. in vacuo at a temperature below 35 ° C. The oily residue was chromatographed on a column of silica gel eluting with ethyl acetate / methanol (2015 v / v) The eluate was concentrated in vacuo to give 1-chloro-3- [2- (acetamido) ) ethyl] -Z-propanone (607 mg) as an oil.
Utbytet var 52 %.The yield was 52%.
NMR, ¿CDC13; 1,98 (sus), 2,65 (zur, Ja? H1), 3,45 (zfls), 4,28 (ZHS), 6,22 (1H, brs) Exemgel 41. Till en suspension av 2~guanidino-4-[2-(amino)ety1- tiometyljtiazol-dihydroklorid (30 g) och N,N-dimetylformamid-dí- metylacetal (13 g) i torr tetrahydrofuran (550 ml) sattes trietyl- amin (S0 g). Erhâllen blandning àterloppskokades under omröring i 5 timmar och koncentrerades i vakuum. Återstoden blandades med 10-procentig vattenhaltig kalíumkarbonatlösning (500 ml) och om- rördes vid rumstemperatur i 3 dagar. Reaktionsblandníngen neutra- liserades med utspädd saltsyra approximativt till pH 7 och kroma- tograferades på en kolonn av "Amberlite IRC-50" (H+-typ), som eluerades med 10-procentig vattenhaltig ammoniaklösning. Eluatet koncentrerades i vakuum för att ge 2-guanidino-4-[2-(formamido)- etyltíometyljtiazol (11,6 g) såsom en viskös olja. Oljan löstes i aceton och blandades med en lösning av maleinsyra (11 g) i aceton för att ge det råa maleatet (15,3 g) såsom kristaller, som omkris- talliserades från etanol för att ge monomaleatet (11,8 g), smält- punkt 146-148oC. Utbytet var 32 %.NMR, δ CDCl 3; 1.98 (sus), 2.65 (zur, Ja? H1), 3.45 (z fls), 4.28 (ZHS), 6.22 (1H, brs) Exemgel 41. To a suspension of 2-guanidino -4- [2- (amino) ethyl-thiomethylthiazole dihydrochloride (30 g) and N, N-dimethylformamide dimethyl acetal (13 g) in dry tetrahydrofuran (550 ml) were added triethylamine (SO g). The resulting mixture was refluxed with stirring for 5 hours and concentrated in vacuo. The residue was mixed with 10% aqueous potassium carbonate solution (500 ml) and stirred at room temperature for 3 days. The reaction mixture was neutralized with dilute hydrochloric acid approximately to pH 7 and chromatographed on an Amberlite IRC-50 column (H + type) eluting with 10% aqueous ammonia solution. The eluate was concentrated in vacuo to give 2-guanidino-4- [2- (formamido) ethylthiomethylthiazole (11.6 g) as a viscous oil. The oil was dissolved in acetone and mixed with a solution of maleic acid (11 g) in acetone to give the crude maleate (15.3 g) as crystals, which were recrystallized from ethanol to give the monomaleate (11.8 g), melted - 146-148 ° C. The yield was 32%.
Analys, beräknat för C8H13N5OS2-C4H4O4: c 38,39 H 4,56 18,66 517,08 (i) funnet ss,ss 4,47 18,45 16,74 (a) 10 15 20 25 30 40 14 452 462 Exemgel 42% Till en lösning av 2-guanidino-4-[2-(4-nítrQbens~ amido)etyltiometyl7tiazol-monomaleat (7,2 g) i 50-procentïg ättik- syra (200 ml) sattes 20-procentig vattenhaltig títantriklorídlös- ning (89 ml) vid rumstemperatur och erhâllen blandning omrördes vid rumstemperatur i 45 minuter. Reaktionsblandningen gjordes basisk med 10-procentig vattenhaltig natríumhydroxídlösning och extraherades med etylacetat. *Det utfällda hartsartade materialet löstes i metanol och lösningen kombinerades med etylacetatskiktet.Analysis calculated for C 8 H 13 N 5 OS 2 -C 4 H 4 O 4: c 38.39 H 4.56 18.66 517.08 (i) found ss, ss 4.47 18.45 16.74 (a) 10 15 20 25 30 40 14 452 462 Example 42% To a solution of 2-guanidino-4- [2- (4-nitrobenzamide) ethylthiomethyl] thiazole monomaleate (7.2 g) in 50% acetic acid (200 ml) was added 20% aqueous titanium trichloride solution. (89 ml) at room temperature and the resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture was basified with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The precipitated resinous material was dissolved in methanol and the solution was combined with the ethyl acetate layer.
Blandníngen torkades över vattenfrítt natríumsulfat och koncentre- rades. Återstoden kromatograferades på en kolonn av silikagel, som eluerades med etylacetat/metanol (20 5 volym/volym). Eluatet koncentrerades för att ge en olja som behandlades med en lösning av maleínsyra (4,6 g) i aceton. Erhàllet rått maleat kristallise- ¿ rades från etanol för att ge 2~guanídíno-4-[2-(4-aminobensamido)- 1 etyltíometyljtiazol-monomaleat (3,1 g), smältpunkt 171-172°C f (sönderdelning). Utbytet var 46 %. 1 Analys, beräknat för CMHWNÖOSZ: C 46,34 H 4,75 N 18,02 S 13,75 (ä) funnet 46,35 4,82 17,65 13,55 (%) å Exemgel 43. Till en lösning av N-karbobensoxi-1-aminosmörsyra (7,8 g) i torr tetrahydrofuran (200 ml) sattes trietylamin (šflg) och metylklorokarbonat (3,1 g) vid -10°C och erhàllen blandning omrördes i 30 minuter vid samma temperatur. Trietylamin (7,0 g) och 2-guanidino-4-[2-(amino)etyltiometyljtiazol-dihydrokloríd (10 g) sattes till blandningen, som omrördes vid rumstemperatur över natten. Fällningen filtrerades och tvättades tillräckligt med tetrahydrofuran. Filtratet kombinerades med tvättlösningarna och koncentrerades i vakuum. Återstoden blandades med 30 % brom- vätesyra)ättiksyra (50 ml) och omrördes vid rumstemperatur i 12 timmar. Reaktionsblandningen späddes med torr eter (1 liter). Er- hållen hygroskopisk fällníng fíltrerades snabbt, löstes i vatten (S0 ml) och neutraliserades med fast natriumkarbonat. Lösningen koncentrerades i vakuum till torrhet. Återstoden eïtraherades med etanol och extraktet koncentrerades för att ge en viskös olja (3,0 g). Oljan behandlades med en lösning av maleinsyra (3,0 g) i etanol för att ge 2-guanidino-4-[?-(4-aminobutyramido)etyltiome- tyl]-tiazol-monomaleat (1,5 g), smältpunkt 87-S9°C_(omkristalli- serat från 95-procentig etanol).The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a column of silica gel, eluting with ethyl acetate / methanol (20 v / v). The eluate was concentrated to give an oil which was treated with a solution of maleic acid (4.6 g) in acetone. The crude maleate obtained was crystallized from ethanol to give 2-guanidino-4- [2- (4-aminobenzamido) -1-ethylthiomethylthiazole monomaleate (3.1 g), m.p. 171-172 ° C (dec.). The yield was 46%. Analysis, calculated for CMHWNÖOSZ: C 46.34 H 4.75 N 18.02 S 13.75 (ä) found 46.35 4.82 17.65 13.55 (%) on Exemgel 43. To a solution of N-Carbobenzoxy-1-aminobutyric acid (7.8 g) in dry tetrahydrofuran (200 ml) was added triethylamine (flflg) and methyl chlorocarbonate (3.1 g) at -10 ° C and the resulting mixture was stirred for 30 minutes at the same temperature. Triethylamine (7.0 g) and 2-guanidino-4- [2- (amino) ethylthiomethylthiazole dihydrochloride (10 g) were added to the mixture, which was stirred at room temperature overnight. The precipitate was filtered and washed sufficiently with tetrahydrofuran. The filtrate was combined with the washing solutions and concentrated in vacuo. The residue was mixed with 30% hydrobromic acid (acetic acid) (50 ml) and stirred at room temperature for 12 hours. The reaction mixture was diluted with dry ether (1 liter). The resulting hygroscopic precipitate was filtered rapidly, dissolved in water (SO ml) and neutralized with solid sodium carbonate. The solution was concentrated in vacuo to dryness. The residue was extracted with ethanol and the extract was concentrated to give a viscous oil (3.0 g). The oil was treated with a solution of maleic acid (3.0 g) in ethanol to give 2-guanidino-4 - [? - (4-aminobutyramido) ethylthiomethyl] -thiazole monomaleate (1.5 g), m.p. S9 ° C (recrystallized from 95% ethanol).
Analys, beräknat för C11H20N6OS2-2C4H404-i H20: C 40,92 H 5,24 N 15,07 S.11,50 (1) funnet 40,50 5,19 15,22 11,86 (%) 10 15 20 25 30 15 452 462 Till en lösning av 2-guanidino-4-(3-aminopr0pyl)- Exempel 44É tíazol (amerikanska patentskriften 4 165 377) (472 mg) och trietyl- amín (0,8 ml) i torr dimetylformamid (8 ml) sattes nikotinylklorid- hydroklorid (500 mg) vid -ZOOC. Erhållen blandning omrördes vid rumstemperatur över natten och koncentrerades i vakuum. Återstoden blandades med vatten (3 ml) och gjordes basisk med 5-procentig vattenhaltíg natríumvätekarbonatlösning. Erhållen fällning filtrerades, tvättades tillräckligt med vatten och torkades för att ge rå produkt. Den råa produkten behandlades med en lösning av maleinsyra (300 mg) i metanol och späddes med aceton för att ge 2-guanidino-4-[3-(nikotinamido)propyljtiazol-monomaleat (300 mg), smäirpunkr 176°c (sönderae1ning) (etanol).Analysis calculated for C 11 H 20 N 6 OS 2 -2C 4 H 4 O 4 -I H 2 O: C 40.92 H 5.24 N 15.07 S.11.50 (1) found 40.50 5.19 15.22 11.86 (%) 452,462,462 To a solution of 2-guanidino-4- (3-aminopropyl) - Example 44E thiazole (U.S. Patent 4,165,377) (472 mg) and triethylamine (0.8 ml) in dry dimethylformamide (8 ml) nicotinyl chloride hydrochloride (500 mg) was added at -ZOOC. The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was mixed with water (3 ml) and basified with 5% aqueous sodium bicarbonate solution. The resulting precipitate was filtered, washed with sufficient water and dried to give crude product. The crude product was treated with a solution of maleic acid (300 mg) in methanol and diluted with acetone to give 2-guanidino-4- [3- (nicotinamido) propylthiazole monomaleate (300 mg), melting point 176 ° C (decomposition) ( ethanol).
Analys, beräknat för C H N OS'C H 0 ° 13 16 6 4 4 4' _ C 48,56 H 4,79 N 19,99 S 7,63 (%) funnet 48,31 4,59 19,73 7,80 (%) Exempel 45. Till en lösning av natriumhydrid (50-procentig sus- pension i mineralolja, 590 mg) i absolut etanol (20 ml) sattes droppvis en lösning av 2-acetamidoetantíol (755 mg) i abso- lut etanol (3 ml) vid -20°C och erhållen blandning omrördes vid -ZOOC i 10 minuter. Fast 2-guanídino-4-klorometyltía:ol-hydroklo- rid (amerikanska patentskriften 4 165 377) (1,8S g) sattes till blandningen som omrördes vid rumstemperatur över natten. Erhållen fällníng filtrerades och tvättades med etanol. Filtratet kombine- rades med tvättvätskorna och koncentrerades i vakuum till torrhet. Återstoden kromatograferades på en kolonn av silikagel, som_elue- rades med etylacetat/metanol (2025 volym/volym). Eluatet koncen- trerades i vakuum för att ge 2-guanidíno-4-[2-(acetamido)etyltio- metylltíazol (1,5 g) såsom en olja. Utbytet var 89 %.Analysis calculated for CHN OS'C H 0 ° 13 16 6 4 4 4 '- C 48.56 H 4.79 N 19.99 S 7.63 (%) found 48.31 4.59 19.73 7, 80 (%) Example 45. To a solution of sodium hydride (50% suspension in mineral oil, 590 mg) in absolute ethanol (20 ml) was added dropwise a solution of 2-acetamidoethanethiol (755 mg) in absolute ethanol ( 3 ml) at -20 ° C and the resulting mixture was stirred at -ZOOC for 10 minutes. Solid 2-guanidino-4-chloromethylthia: ol hydrochloride (U.S. Patent 4,165,377) (1.8S g) was added to the mixture which was stirred at room temperature overnight. The resulting precipitate was filtered and washed with ethanol. The filtrate was combined with the washings and concentrated in vacuo to dryness. The residue was chromatographed on a column of silica gel, eluting with ethyl acetate / methanol (2025 v / v). The eluate was concentrated in vacuo to give 2-guanidino-4- [2- (acetamido) ethylthiomethyl] thiazole (1.5 g) as an oil. The yield was 89%.
Exempel 46-50. Följande föreningar erhölls i enlighet med Sätt B såsom i exempel 3: HN=C-NH 2 Visa H,s(cH2)nxHcoR Ex s "1t- 1 Utby: (a) nr n R salt pÉfikt(°C) I _) e 47 3 -QÄ) Monomaleat 136-179a 65,1 48 3 -ca; “ 138-159 74,4 49 3 H H 127-129. 39,3 so 4 '-(Ä) " 135-137 33,3 31 4 CH3 " 160-162 ss,sExamples 46-50. The following compounds were obtained according to Method B as in Example 3: HN = C-NH 2 Show H, s (cH2) nxHcoR Ex s "1t- 1 Yield: (a) nr n R salt pÉ fi kt (° C) I _) e 47 3 -QÄ) Monomaleat 136-179a 65,1 48 3 -ca; “138-159 74,4 49 3 HH 127-129. 39,3 so 4 '- (Ä)" 135-137 33,3 31 4 CH3 "160-162 ss, s
Claims (7)
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| US14494680A | 1980-04-29 | 1980-04-29 |
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| AR (1) | AR231538A1 (en) |
| AU (1) | AU540239B2 (en) |
| BE (1) | BE888602A (en) |
| CH (1) | CH646964A5 (en) |
| DE (1) | DE3116890A1 (en) |
| DK (1) | DK188881A (en) |
| ES (1) | ES8206501A1 (en) |
| FR (1) | FR2481280A1 (en) |
| GB (1) | GB2076397B (en) |
| IE (1) | IE51151B1 (en) |
| IL (1) | IL62747A (en) |
| IT (1) | IT1146750B (en) |
| NL (1) | NL8102099A (en) |
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| FR2531705B1 (en) * | 1982-08-13 | 1986-12-05 | Sanofi Sa | AMIDOBENZAMIDES, THEIR SALTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4501747A (en) * | 1982-05-10 | 1985-02-26 | Sanofi | Certain amide derivatives of 2-guanidino-thiazoles and compositions containing same |
| JPS59104370A (en) * | 1982-12-03 | 1984-06-16 | Kotobuki Seiyaku Kk | Thiazole derivative and its production |
| AU563072B2 (en) * | 1983-04-26 | 1987-06-25 | Shionogi & Co., Ltd. | 2-guanidino-4-hydroxymethylthiazole and derivitives thereof |
| US4680300A (en) * | 1985-01-10 | 1987-07-14 | Syntex (U.S.A.) Inc. | Anti-inflammatory guanidines |
| US4837316A (en) * | 1985-08-29 | 1989-06-06 | Fujirebio Kabushiki Kaisha | Alkylamide derivatives with H2 -receptor antagonistic and cytoprotective action |
| EP0385525B1 (en) * | 1989-03-03 | 1994-04-13 | Akzo Nv | Aminoethylthiazole and aminoethyloxazole derivatives. |
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| US4165378A (en) * | 1977-04-20 | 1979-08-21 | Ici Americas Inc. | Guanidine derivatives of imidazoles and thiazoles |
| ZA782129B (en) * | 1977-04-20 | 1979-03-28 | Ici Ltd | Hertocyclic derivatives |
| JPS54132566A (en) * | 1978-01-18 | 1979-10-15 | Ici Ltd | Guanidine derivative*its manufacture and secretion controlling pharmaceutical composition containing it |
| ATE6156T1 (en) * | 1978-10-16 | 1984-02-15 | Imperial Chemical Industries Plc | BRANCH CHAIN HETEROCYCLIC GUANIDE DERIVATIVES WITH ANTISECRETORY ACTIVITY, PROCESS FOR THEIR PREPARATION, INTERMEDIATE PRODUCTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAID DERIVATIVES. |
| US4309435A (en) * | 1978-10-16 | 1982-01-05 | Imperial Chemical Industries Ltd. | Antisecretory guanidine derivatives and pharmaceutical compositions containing them |
| EP0014057B1 (en) * | 1979-01-18 | 1985-01-02 | Imperial Chemical Industries Plc | Guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them |
| PH16099A (en) * | 1979-03-06 | 1983-06-24 | Yamanouchi Pharma Co Ltd | Guanidinothiazole compounds,process for preparing them and medical composition containing them |
| GR71929B (en) * | 1979-11-13 | 1983-08-19 | Ici Ltd | |
| JPS5754177A (en) * | 1980-09-19 | 1982-03-31 | Teikoku Hormone Mfg Co Ltd | Substituted thiazole derivative |
| JPS57102852A (en) * | 1980-12-19 | 1982-06-26 | Shionogi & Co Ltd | Dicarboxylic acid diamide |
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1981
- 1981-04-24 NZ NZ196923A patent/NZ196923A/en unknown
- 1981-04-28 NL NL8102099A patent/NL8102099A/en not_active Application Discontinuation
- 1981-04-28 SE SE8102683A patent/SE452462B/en not_active IP Right Cessation
- 1981-04-28 ES ES501736A patent/ES8206501A1/en not_active Expired
- 1981-04-28 DE DE19813116890 patent/DE3116890A1/en not_active Ceased
- 1981-04-28 JP JP6473981A patent/JPS574977A/en active Granted
- 1981-04-28 DK DK188881A patent/DK188881A/en not_active Application Discontinuation
- 1981-04-28 FR FR8108468A patent/FR2481280A1/en active Granted
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Also Published As
| Publication number | Publication date |
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| DE3116890A1 (en) | 1982-03-04 |
| JPS574977A (en) | 1982-01-11 |
| AR231538A1 (en) | 1984-12-28 |
| IT8167585A0 (en) | 1981-04-29 |
| AU540239B2 (en) | 1984-11-08 |
| BE888602A (en) | 1981-10-28 |
| IL62747A (en) | 1984-10-31 |
| NL8102099A (en) | 1981-11-16 |
| FR2481280B1 (en) | 1983-10-28 |
| SE8102683L (en) | 1981-10-30 |
| IE810956L (en) | 1981-10-29 |
| IL62747A0 (en) | 1981-06-29 |
| ES501736A0 (en) | 1982-08-16 |
| DK188881A (en) | 1981-10-30 |
| AU6996681A (en) | 1981-11-05 |
| JPH027952B2 (en) | 1990-02-21 |
| GB2076397A (en) | 1981-12-02 |
| ES8206501A1 (en) | 1982-08-16 |
| GB2076397B (en) | 1984-02-08 |
| IT1146750B (en) | 1986-11-19 |
| IE51151B1 (en) | 1986-10-15 |
| FR2481280A1 (en) | 1981-10-30 |
| CH646964A5 (en) | 1984-12-28 |
| NZ196923A (en) | 1983-12-16 |
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