LT4482B - Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anticonvulsive effect, and process for their production - Google Patents
Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anticonvulsive effect, and process for their production Download PDFInfo
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- LT4482B LT4482B LT98-047A LT98047A LT4482B LT 4482 B LT4482 B LT 4482B LT 98047 A LT98047 A LT 98047A LT 4482 B LT4482 B LT 4482B
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- morpholinimidazolin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
Description
kurioje: X yra vandenilis, CpC^alkilas, CpC^alkoksilas, trifluormetilas arba halogenas: R1 ir R2 yra C)-C4-alkilas, cikloalkilas arba heteroalkilas.wherein: X is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl or halogen: R 1 and R 2 are C 1 -C 4 alkyl, cycloalkyl or heteroalkyl.
Šis išradimas yra susijęs su 1-aril(alkil)imidazolin-2-onais, turinčiais dipakeistą aminogrupę 4 padėtyje, su jų gavimo būdais ir jų panaudojimu kaip įo farmacinių priemonių centrinės nervų sistemos susirgimų, konkrečiai, įvairių formų epilepsijos, gydymui.The present invention relates to 1-aryl (alkyl) imidazolin-2-ones having a disubstituted amino group at the 4-position, processes for their preparation and their use as pharmaceuticals for the treatment of central nervous system disorders, in particular various forms of epilepsy.
Pagal žinomą technikos lygį 1-aril(alkil)imidazolin-2-onus, turinčius nepakeistą amino arba metilaminogrupę 4 padėtyje, gauna aril(alkil)aminoacetamidams reaguojant su bromcianu. N-alkilinant tokiu būdu gautus 4-amino-1-aril(alkil)imidazolin-2-onus, gauna 3-alkil- arba 1-iminoalkil-3alkil-1 -aril(alkil)imidazolin-2-onus, be to aminogrupe 4 padėtyje tautomerizuojasi j iminogrupę. To pasėkoje tolesnis N-alkilinimas, siekiant gauti bendros 1 formulės junginius, yra neįmanomas, ir ryšium su tuo atitinkančių šį išradimą junginių tokiu būdu gauti negalima (JAV patentas Nr. 4044021; Vokietijos patentas Nr.In the prior art, 1-aryl (alkyl) imidazolin-2-ones having an unsubstituted amino or methylamino group at the 4-position are obtained by reacting aryl (alkyl) aminoacetamides with bromocyano. N-alkylating the 4-amino-1-aryl (alkyl) imidazolin-2-one thus obtained gives 3-alkyl- or 1-iminoalkyl-3alkyl-1-aryl (alkyl) imidazolin-2-one, in addition to amino group 4. position tautomerizes to the iminogroup. As a result, further N-alkylation to obtain compounds of general formula 1 is not possible, and the corresponding compounds of the present invention cannot be obtained in this way (U.S. Patent No. 4,404,402;
2251354).2251354).
-Aril(alkil)imidazolin-2-onai, turintys dipakeistą aminogrupę 4 padėtyje, iki šiol nėra aprašyti.-Aryl (alkyl) imidazolin-2-ones having a substituted amino group at the 4-position are not yet described.
Žinoma daugybė junginių, pasižyminčių antispazminiu veikimu. Tačiau dar ir dabar ne visų epileptinių sindromų gydymas duoda patenkinamus rezultatus.Numerous compounds with antispasmodic activity are known. However, the treatment of all epileptic syndromes is still not satisfactory.
Tokiu būdu, šio išradimo tikslas yra naujų junginių, pasižyminčių palankiomis farmakologinėmis savybėmis, kuriuos galima naudoti, pavyzdžiui, kaip farmacinius preparatus, ir pasižyminčių antispazminiu veikimu, pateikimas.Thus, it is an object of the present invention to provide novel compounds having favorable pharmacological properties which can be used, for example, as pharmaceutical preparations, and which possess antispasmodic activity.
Pagal šj išradimą tie nauji junginiai yra 1-ari(alkil)imidazolin-2-onai, kurių bendra formulė yra 1:According to the present invention, those novel compounds are 1-ary (alkyl) imidazolin-2-ones of the general formula 1:
n = O, 1; m = 0,1, 2, 3, 4, 5; kurioje:n = 0.1; m = 0.1, 2, 3, 4, 5; where:
X yra vandenilis, CrCA-alkilas, CrC^alkoksilas, trifluormetilas arba halogenas;X is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl or halogen;
R1 ir R2 yra CpCA-alkilas, eikloalkilas arba heteroalkilas, kur alkilo grupė pasirinktinai apima 5-7 anglies atomus, arbaR 1 and R 2 are CpCA-alkyl, eicycloalkyl or heteroalkyl, wherein the alkyl group optionally contains 5 to 7 carbon atoms, or
R1 ir R2 kartu sudaro alkileno grupę, turinčią 2-6 anglies atomus, kur -CH2io grupė gali būti pakeista deguonim, azotu arba siera.R 1 and R 2 together form an alkylene group having from 2 to 6 carbon atoms, wherein the -CH 2 io group may be replaced by oxygen, nitrogen or sulfur.
CH2 grupių skaičius lygus arba 0 (1-arilimidazolin-2-onai), arba 1 (1arilalkilimidazolin-2-onai).The number of CH 2 groups is equal to either 0 (1-arylimidazolin-2-one) or 1 (1-arylalkylimidazolin-2-one).
Junginių, turinčių bendrą formulę 1, pavyzdžiai yra šie: 1-fenil-4-morfolinimidazolin-2-onasExamples of compounds of general formula 1 are: 1-phenyl-4-morpholinimidazolin-2-one
1-(4-metoksi)-4-piperidinimidazolin-2-onas1- (4-Methoxy) -4-piperidinimidazolin-2-one
1-(4-chlorfenil)-4-morfolinimidazolin-2-onas 1-(4-chlorfenil)-piperidinimidazolin-2-onas 1-(4-chlorfenil)-4-dimetilaminoimidazolin-2-onas 1-(4-bromfenil)-4-morfolinimidazolin-2-onas1- (4-Chlorophenyl) -4-morpholinimidazolin-2-one 1- (4-chlorophenyl) -piperidinimidazolin-2-one 1- (4-chlorophenyl) -4-dimethylaminoimidazolin-2-one 1- (4-bromophenyl) -4-morpholinimidazolin-2-one
1 -(3-chlorfenil)-4-morfolinimidazolin-2-onas1- (3-chlorophenyl) -4-morpholinimidazolin-2-one
1-(4-chlorfenil)-4-heksametileniminoimidazolin-2-onas1- (4-Chlorophenyl) -4-hexamethyleniminoimidazolin-2-one
1-(4-chlorfenil)-4-(4-metilpiperazino)imidazolin-2-onas1- (4-Chlorophenyl) -4- (4-methylpiperazino) imidazolin-2-one
1-(4-metilfenil)-4-morfolinimidazolin-2-onas1- (4-Methylphenyl) -4-morpholinimidazolin-2-one
1-(4-chlorfenil)-4-(cikloheksilmeti!amino)imidazolin-2-onas1- (4-Chlorophenyl) -4- (cyclohexylmethylamino) imidazolin-2-one
1 -(4-fluorfenil)-4-morfolinimidazolin-2-onas1- (4-Fluorophenyl) -4-morpholinimidazolin-2-one
1-benzil-4-morfolinimidazolin-2-onas.1-Benzyl-4-morpholinimidazolin-2-one.
Pagal šį išradimą bendrą formulę 1 turintys junginiai gali būti gauti nauju būdu, reaguojant bendros formulės 2 junginiamsThe compounds of the general formula 1 according to the present invention can be obtained in a novel manner by reacting the compounds of the general formula 2
H n = 0,1; m = 0,1,2, 3, 4, 5;H n = 0.1; m = 0,1,2,3,4,5;
kurioje X yra vandenilis, CrC^alkilas, Ci-C4-alkoksilas, trifluormetilas arba halogenas;wherein X is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl or halogen;
su antriniu aminu.with a secondary amine.
Alternatyviai, formulę 1 turintys junginiai gali būti gauti tirpiklyje arba antrinio amijo pertekliuje nuo 50 iki 160 °C temperatūroje. Tinkami tirpikliai, kuriems teikiama pirmenybė, yra aromatiniai angliavandeniliai, tokie kaip benzenas, toluenas, chlorbenzenas arba dichlorbenzenas.Alternatively, the compounds of Formula 1 may be obtained in a solvent or in an excess of secondary amide at 50 to 160 ° C. Suitable preferred solvents are aromatic hydrocarbons such as benzene, toluene, chlorobenzene or dichlorobenzene.
Geriausia, kai reakcija vyksta esant medžiagų, surišančių vandenį, pavyzdžiui, esant ceoiitų arba natrio sulfato. Reakciją galima pagreitinti pridedant įprastų kondensacijos katalizatorių, pavyzdžiui, 4-toluensulforūgšties.The reaction is preferably carried out in the presence of water-binding substances such as zeolites or sodium sulfate. The reaction can be accelerated by the addition of conventional condensation catalysts such as 4-toluenesulfonic acid.
Šio išradimo junginiai tinka farmacinių kompozicijų sudarymui. J farmacinių kompozicijų sudėtį gali įeiti vienas ar daugiau šio išradimo junginių. Farmacinių preparatų gavimui gali būti naudojami įprastiniai farmaciniai užpildai ir pagalbinės medžiagos.The compounds of the present invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions may contain one or more compounds of the present invention. Conventional pharmaceutical excipients and excipients may be used in the preparation of pharmaceutical preparations.
Vaistai gali būti įvedami parenteraliai (pavyzdžiui, į veną, į raumenis arba po oda) arba peroraliai.The drugs may be administered parenterally (for example, intravenously, intramuscularly or subcutaneously) or orally.
Vaisto formos gali būti paruoštos žinomais ir plačiai paplitusiais farmacijoje . būdais.The formulations may be formulated according to known and widely used pharmaceutical formulations. ways.
Šio išradimo junginiai pasižymi stipriu antispazminiu veikimu.The compounds of the present invention exhibit potent antispasmodic activity.
Šių preparatų antispazminis veikimas buvo tikrinamas in vivo įvedus pelėms intraperitoniškai arba žiurkėms peroraliai, pagal tarptautinių standartų reikalavimus (Pharmac. VVeekblad, 2nd ed., 14, 132 (1992) ir Antiepileptic drugs, 3rd ed., Raven press, New York (1989)) (1 lentelė).The antispasmodic activity of these preparations has been tested by in vivo administration to mice intraperitoneally or orally in rats according to international standards (Pharmac. Weekblad, 2nd ed., 14, 132 (1992) and Antiepileptic drugs, 3rd ed., Raven press, New York (1989). ) (Table 1).
Pavyzdžiui, junginio 2 (1-(4-chlorfenil)-4-morfolinimidazolin-2-onas) efektyvi dozė ED50 (peroraliai) maksimalaus elektrošoko žiurkėms atveju yra 21 mg/kg, ED50, įvedant pentetrazolą po oda yra 16 mg/kg ir NT50 neurotoksiškumo bandymuose yra >400 mg/kg. Palyginimui, žinomi priešepileptiniai vaistai yra aktyvūs arba maksimalaus elektrošoko modelyje, arba įvedus pentetrazolą, arba, esant santykinai dideliems aktyvumams, jie rodo pernelyg didelį neurotoksiškumą įvedus pentetrazolą.For example, the effective dose of compound 2 (1- (4-chlorophenyl) -4-morpholinimidazolin-2-one) for ED 50 (oral) at maximal electroshock rats is 21 mg / kg, ED 50 for subcutaneous administration of pentetrazole is 16 mg / kg. and NT 50 in neurotoxicity assays is> 400 mg / kg. In comparison, known antiepileptic drugs are active either in the maximal electroshock model, either after administration of pentetrazole or, at relatively high activities, they exhibit excessive neurotoxicity after administration of pentetrazole.
LENTELĖTABLE
Pastabos:Notes:
1) Dėl junginių numeravimo žiūr. pavyzdžius.1) For compound numbering, see marg. examples.
2) Pasiskirstymo koeficientas sistemoje oktanolis-vanduo.2) Partition coefficient in octanol-water system.
3) MES - maksimalus elektrošokas, PTZ - pentetrazolis, įvedimas po oda.3) MES - maximum electroshock, PTZ - pentetrazole, subcutaneous administration.
4) mg/kg4) mg / kg
5) apsaugotų gyvuliukų %.5)% of protected animals.
Naujų, turinčių 1 formulę junginių gavimas detaliau iliustruojamas darbiniais pavyzdžiais.The preparation of novel compounds of formula 1 is further illustrated by working examples.
PAVYZDŽIAIEXAMPLES
Bendra 1 formulės junginių pagal 1 lentelę gavimo procedūra, 1-11 pavyzdžiaiGeneral procedure for the preparation of compounds of formula 1 according to Table 1, Examples 1-11
A variantas.Option A.
0,05 molio 1-arilimidazolin-2,4-diono, turinčio bendrą 2 formulę (n=0), 200mg 4-toluensulforūgšties pridėjo j 100 ml tinkamo antrinio amino. Po to mišinį virino kolboje su grįžtamu šaldytuvu Soksleto ekstraktoriuje, kurio ekstrakcinė kapsulė užpildyta 25 g kietos medžiagos, surišančios vandenį (tinka, pavyzdžiui, natrio sulfatas, magnio sulfatas, NaOH, KOH, ceolitai). Po 8-30 vai.karštą mišinį nufiltravo ir distiliavo rotoriniame garintuve iki maždaug pusės tūrio. Skaidresnį tirpalą atšaldė ledo vonioje, o susidariusią tirštą kristalų vandeninę suspensiją atskyrė nuo amino. Pradinę medžiagą, . esančią nevalytame produkte, išekstrahavo 50 ml karšto acetono. Produktą perkristalino iš n-propanolio.0.05 mol of 1-arylimidazoline-2,4-dione of general formula 2 (n = 0), 200 mg of 4-toluenesulphonic acid were added per 100 ml of the appropriate secondary amine. The mixture was then refluxed in a Soxhlet extractor containing 25 g of water-soluble solids (suitable, for example, sodium sulfate, magnesium sulfate, NaOH, KOH, zeolites). After 8-30 hours, the hot mixture was filtered and distilled in a rotary evaporator to about half volume. The clear solution was cooled in an ice bath and the resulting thick crystal aqueous suspension was separated from the amine. Starting material, -. Extract 50 ml of hot acetone in the crude product. The product was recrystallized from n-propanol.
Iš atskirto amino galima išskirti iki 0,02 mol nesureagavusio 1ariliniidazolin-2,4-diono.Up to 0.02 mol of unreacted 1aryl imidazoline-2,4-dione can be isolated from the isolated amine.
B variantas.Option B.
0,05 mol 1-arilalkilimidazolin-2,4-dionas, turintis bendrą 2 formulę (n=1) reaguoja su antriniu aminu, kaip aprašyta A variante. Po 8-30 vai. karštą tirpalą nufiltruoja ir koncentruoja iki sausos liekanos rotoriniame garintuve. Į liekaną prideda 50 ml metilenchlorido ir 50 ml 2 N HCI. Organinę fazę atskiria, vandeninę fazę papildomai du kartus ekstrahuoja metilenchloridu. Atskirtą vandeninę fazę pašarmina, pridėdami 50 ml 10 % NaOH, ir 1,4-amino-1-arilalkilimidazolin-2-oną išekstrahuoja 100 ml metilenchlorido. Ekstraktus džiovina natrio sulfatu. Nudistiliavus metilenchloridą, nevalytą produktą perkristalina iš etanolio arba acetono.0.05 mol of 1-arylalkylimidazoline-2,4-dione of general formula 2 (n = 1) is reacted with a secondary amine as described in variant A. After 8-30 or. the hot solution is filtered and concentrated to dryness in a rotary evaporator. To the residue are added 50 mL of methylene chloride and 50 mL of 2N HCl. The organic phase is separated off and the aqueous phase is further extracted twice with methylene chloride. The separated aqueous phase is made alkaline by the addition of 50 ml of 10% NaOH and the 1,4-amino-1-arylalkylimidazolin-2-one is extracted with 100 ml of methylene chloride. The extracts are dried over sodium sulfate. After distillation with methylene chloride, the crude product is recrystallized from ethanol or acetone.
C variantas.Option C.
0,05 mol 1 -aril(alkil)imidazolin-2,4-diono, turinčio bendrą 2 formulę, reaguoja su 100 ml dimetilamoniodimetilkarbamato, kaip aprašyta A ir B variantuose. Po 40 vai. mišinį apdoroja pagal A arba B variantą.0.05 mol of 1-aryl (alkyl) imidazoline-2,4-dione of general formula 2 is reacted with 100 ml of dimethylammoniodimethylcarbamate as described in variants A and B. After 40 or so. the mixture is treated according to variant A or B.
LENTELĖTABLE
1) įvertinant išeigą, įskaityta išskirta pradinė medžiaga.(1) isolated starting material is included in the yield assessment.
Claims (7)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19532668A DE19532668A1 (en) | 1995-09-05 | 1995-09-05 | Novel, anticonvulsant 1-ar (alk) yl-imidazolin-2-ones which contain a disubstituted amine radical in the 4-position, and process for their preparation |
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LT98047A LT98047A (en) | 1998-10-26 |
LT4482B true LT4482B (en) | 1999-03-25 |
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LT98-047A LT4482B (en) | 1995-09-05 | 1998-04-03 | Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anticonvulsive effect, and process for their production |
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EP (1) | EP0863880B1 (en) |
JP (1) | JP4030578B2 (en) |
CN (1) | CN1103762C (en) |
AR (1) | AR003502A1 (en) |
AT (1) | ATE254606T1 (en) |
AU (1) | AU700602B2 (en) |
BG (1) | BG63917B1 (en) |
BR (1) | BR9610359A (en) |
CA (1) | CA2184871C (en) |
CZ (1) | CZ291839B6 (en) |
DE (2) | DE19532668A1 (en) |
DK (1) | DK0863880T3 (en) |
EA (1) | EA000535B1 (en) |
EE (1) | EE03562B1 (en) |
ES (1) | ES2208758T3 (en) |
FR (1) | FR13C0049I2 (en) |
GE (1) | GEP20022652B (en) |
HK (1) | HK1015776A1 (en) |
HU (1) | HU225956B1 (en) |
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TR (1) | TR199800476T1 (en) |
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UA (1) | UA46790C2 (en) |
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DE19721580A1 (en) * | 1997-05-23 | 1998-11-26 | Dresden Arzneimittel | Use of 1-ar (alk) yl-imidazolin-2-one for the treatment of anxiety and tension |
US20050070537A1 (en) * | 2002-10-10 | 2005-03-31 | Chris Rundfeldt | Use of dihydroimidazolones for the treatment of dogs |
CN101254189A (en) * | 2003-07-11 | 2008-09-03 | 埃尔比昂股份公司 | Method of treating or preventing central nervous system disorders with compounds having selectivity for the alpha 3 subunit of the benzodiazepine receptor |
EP2093218A1 (en) * | 2008-02-22 | 2009-08-26 | Ruggero Fariello | Arylalkyl substituted imidazolidinones |
BR112014003117A2 (en) | 2011-08-12 | 2017-06-13 | Boehringer Ingelheim Vetmedica Gmbh | funny (if) current inhibitors for use in a method of treatment and prevention of feline heart failure |
US9820988B2 (en) | 2014-03-24 | 2017-11-21 | Boehringer Ingelheim Vetmedica Gmbh | Treatment of epileptic disorders in feline animals |
IT202100000782A1 (en) | 2021-01-18 | 2022-07-18 | Procos Spa | PROCESS FOR THE SYNTHESIS OF IMEPITOIN |
Citations (2)
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DE2251354A1 (en) | 1971-10-21 | 1973-04-26 | American Cyanamid Co | NEW DIURETICA AND AGENTS FOR TREATMENT OF HYPERAL DOSTERONISM |
US4044021A (en) | 1971-10-21 | 1977-08-23 | American Cyanamid Company | Tetrasubstituted imidazolidine diuretics useful in the treatment of hyperaldosteronism |
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US3932452A (en) * | 1975-02-07 | 1976-01-13 | Morton-Norwich Products, Inc. | 1-Arylmethyl-2-imidazolidinones |
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1995
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1998
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1999
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2013
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2251354A1 (en) | 1971-10-21 | 1973-04-26 | American Cyanamid Co | NEW DIURETICA AND AGENTS FOR TREATMENT OF HYPERAL DOSTERONISM |
US4044021A (en) | 1971-10-21 | 1977-08-23 | American Cyanamid Company | Tetrasubstituted imidazolidine diuretics useful in the treatment of hyperaldosteronism |
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