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Patent US4593096 - Novel compounds and process for treating hypertension - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsA process for treating hypertension comprising the systemic administering to a hypertensive subject or a novel compound of the formula: ##STR1## wherein X is alkyl of from 1 to 3 carbon atoms, inclusive, or alkenyl of from 3 to 5 carbon atoms, inclusive. R.sub.1 is --NH.sub.2. R.sub.2 is chloro, bromo,...http://www.google.com/patents/US4593096?utm_source=gb-gplus-sharePatent US4593096 - Novel compounds and process for treating hypertensionAdvanced Patent SearchPublication numberUS4593096 APublication typeGrantApplication numberUS 06/582,674Publication dateJun 3, 1986Filing dateFeb 23, 1984Priority dateJun 9, 1982Fee statusLapsedPublication number06582674, 582674, US 4593096 A, US 4593096A, US-A-4593096, US4593096 A, US4593096AInventorsHarvey I. Skulnick, Wendell WierengaOriginal AssigneeThe Upjohn CompanyExport CitationBiBTeX, EndNote, RefManPatent Citations (6), Non-Patent Citations (6), Referenced by (1), Classifications (7), Legal Events (3) External Links: USPTO, USPTO Assignment, EspacenetNovel compounds and process for treating hypertensionUS 4593096 AAbstract A process for treating hypertension comprising the systemic administering to a hypertensive subject or a novel compound of the formula: ##STR1## wherein X is alkyl of from 1 to 3 carbon atoms, inclusive, or alkenyl of from 3 to 5 carbon atoms, inclusive.
R.sub.1 is --NH.sub.2.
R.sub.2 is chloro, bromo, or iodo.
R.sub.3 is hydrogen or fluorine.
R.sub.4 is hydrogen or fluorine, and
R.sub.5 is hydrogen, fluorine, or CH.sub.3 ; or salt thereof, in association with a pharmaceutical carrier.
I claim: 1. A compound of the formula ##STR4## wherein X is alkyl of from 1 to 3 carbon atoms, inclusive, or alkenyl of from 3 to 5 carbon atoms, inclusive,R.sub.1 is --NH.sub.2, R.sub.2 is chloro, bromo or iodo, R.sub.3 is hydrogen or fluorine, R.sub.4 is hydrogen or fluorine, and R.sub.5 is hydrogen, fluorine or CH.sub.3 ; or a salt thereof. 2. A compound according to claim 1 which is 2-amino-3-methyl-5-bromo-6-phenyl-4-pyrimidinone.
DESCRIPTION BACKGROUND OF THE INVENTION The preparation and use of 2-amino-5-halo-6-alkyl-4-pyrimidinols as antiviral agents is known (U.S. Pat. No. 3,956,302, and Nicols, Weed and Underwood, Antimicrobial Agents, Chemo. Ther. 9 433, 1976). Preparation of 2-amino-5-bromo-6-phenyl-4-pyrimidinol (V, where X.sub.3 is Br and X.sub.1 is phenyl) has been reported (Brown and Stevens, JCS Perkin I, 1023, 1975) but no utility has been described for this material. Snell, Elias and Freeman in Great Britain Patent Number 1,223,686 (1967) disclose a variety of 5,6-disubstituted 2-amino-4-pyrimidinols, such as 2-dimethylamino-5-bromo-6-methyl-4-pyrimidinol. Various 5-unsubstituted 2-amino-6-arylpyrimidinols are known (e.g., Shirahawa, Yakugaku Zasshi 50, 1562, 1960, CA 55, 10651b), Kulkarui et al., J. Sci., Ind. Res. Indil, 19C, 6, 1960, and U.S. Pat. No. 2,776,283. Diuretics and cardioregulatory properties are described for various 2-amino and 2-substituted amino-5-aminomethyl and 5-aryl-6-aryl-4-pyrimidinols (U.S. Pat. Nos. 2,704,285, 2,723,777 and 2,776,283).
BRIEF DESCRIPTION OF THE INVENTION This invention relates to the treatment of hypertension with a group of novel compounds having a unique combination of pharmacological activities, namely diuretic and antihypertensive activities both of which are desirable in healing hypertensive subjects.
DETAILED DESCRIPTION The active compounds of the present invention are represented by the formula: ##STR2## wherein X is alkyl of from 1 to 3 carbon atoms, inclusive, or alkenyl of from 3 to 5 carbon atoms, inclusive.
R.sub.5 is hydrogen, fluorine, or CH.sub.3 ; or the salts thereof.
Preparation 1 2-Amino-5-iodo-3-methyl-6-phenyl-4-pyrimidinone Part 1 3-methyl-6-phenyl-4-pyrimidinone to 7.0 g (36.4 mM) of 2-amino-6-phenyl-4-pyrimidinone was added 350 ml of abs. EtOH+3.30 g KOH (57 mM). When all the solid had dissolved, 18.2 g (7.98 ml≈0.129M) of CH.sub.3 I was added and the reaction mixture heated at reflux for 5 hours. At this point an additional 0.5 g KOH was added and heating was continued for an additional 3 hours followed by the addition of 25.0 ml of H.sub.2 O. The mixture was cooled and evaporated to dryness under vacuum. To the solid was added 150 ml of H.sub.2 O, and at 50 was added to dissolve solid. The solution was cooled to 20 NaHCO.sub.3 solution added until no further precipitation occurred. The solids were filtered, washed well with H.sub.2 O and dried at 60 C. in a vacuum oven to yield 5.4 g (74%) of title compound. Recrystallization of an analytical sample from MeOH/Et.sub.2 O gave crystals, m.p. 240
Calculated for C.sub.11 H.sub.11 N.sub.3 O: C, 65.65-H, 5.51-N, 20.85. Found: C, 65.40-H, 5.39-N, 20.81.
NMR (D.sub.6 MSO) δ: 7.88-8.05 (m, 2H, φ), 7.38-7.58 (m, 3H, φ), 7.05-7.31 (b, 2H,NH.sub.2), 6.23 (s, 1H, vinyl H), 3.33 (s, 3H, N-CH.sub.3).
Part 2 2-Amino-5-iodo-3-methyl-6-phenyl-4-pyrimidinone To 1.8 g (8.95 mM) of 2-amino-3-methyl-6-phenyl-4-pyrimidinone was added 75 ml glacial acetic acid and 1.98 g N-iodosuccinimide (8.8 mM). The reaction mixture was heated to 70 cool to room temperature and evaporated to dryness under vacuum. The residual solid was azeotroped twice from absolute EtOH, heated to reflux with 50 ml absolute EtOH and allowed to cool to room temperature. The solids were filtered, washed well with absolute EtOH, and dried at 80
Calculated for C.sub.11 H.sub.10 IN.sub.3 O: C, 40.38-H, 3.08-N, 12.84-I, 39.79. Found: C, 40.30-H, 3.31-N, 12.98-I
NMR (D.sub.6 MSO/TMS): 7.45 (s, 5H, φ), 3.38 (s, 3H, NCH.sub.3).
Preparation 2 5-Bromo-3-methyl-6-phenyl-4-pyrimidinone To 1.8 g (8.95 mM) of 2-amino-3-N-methyl-6-phenyl-4-pyrimidinone was added 40 ml CH.sub.3 COOH and 0.535 ml Br.sub.2 (1.64 g≈10.3 mM). The reaction mixture was allowed to stir at ambient temperature for 18 hours. The solution was evaporated to dryness and the residual solid azeotroped from EtOH (2X). The solids were heated to reflux with 100 ml of H.sub.2 O, cooled to 5 hot, and allowed to crystallize at room temperature for 18 hours. The crystals were filtered and washed well with H.sub.2 O to yield 1.0 g (40%) of title compound. Cooling of mother liquors gave an additional 0.6 g (24%) of title compound.
Calculated for C.sub.11 H.sub.10 BrN.sub.3 O: C, 47.15-H, 3.59-N, 15.00-Br, 28.52. Found: C, 47.14-H, 3.45-N, 15.14-Br, 28.50.
NMR(D.sub.6 MSO/TMS): 7.33-7.70 (m, 5H, φ), 3.36 (s, 3H, N-CH.sub.3).
Preparation 3 Part 1 Following the procedure of the preceding Preparation 1, part 1, but substituting for the methyl iodide an equimolar amount of ethyl iodide, isopropyl iodide, or n-propyl iodide there is respectively obtained:
Part 2 Following the procedure of the preceding Preparation 1, Part 2 but substituting each of the above pyrimidinones there is respectively obtained:
Preparation 4 Part 1 Following the procedure of the preceding Preparation 1, Part 2 but substituting for the methyl iodide an equimolar amount of propenyl iodide, 2-butenyl iodide, isobutenyl iodide, or 2-pentenyl iodide there is respectively obtained:
EXAMPLE 1 Hard Gelatin Capsules One thousand two piece hard gelatin capsules for oral use, each capsule containing 100 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone, are prepared from the following types and amounts of ingredients:
EXAMPLE 2 Soft Gelatin Capsules One piece soft gelatin capsules for oral use, each containing 250 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone, finely divided by means of an air micronizer, are prepared by first suspending the compound in 0.5 ml of corn oil to render the material capsulatable and then capsulating in the above manner.
EXAMPLE 3 Tablets One thousand tablets, each containing 500 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone, are prepared from the following types and amount of ingredients:
EXAMPLE 4 Oral Suspension One thousand ml of an aqueous suspension for oral use, containing in each teaspoonful (5 ml) dose, 500 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone, is prepared from the following types and amounts of ingredients:
EXAMPLE 5 Parenteral Injectable A sterile aqueous suspension for parenteral injection, containing in 1 ml, 300 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone, is prepared from the following types and amounts of ingredients:
EXAMPLE 6 Suppository, Rectal and Vaginal One thousand suppositories, each weighing 2.5 gm and containing 150 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone are prepared from the following types and amounts of ingredients:
The 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone is finely divided by means of an air micronizer and added to the propylene glycol and the mixture passed through a colloid mill until uniformly dispersed. The polyethylene glycol 4000 is melted and the propylene glycol dispersion added slowly with stirring. The suspension is poured into unchilled molds at 40 removed from the mold and each suppository foil wrapped.
EXAMPLE 7 Intranasal Suspension One thousand ml of a sterile aqueous suspension for intranasal instillation containing in each ml 150 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone is prepared from the following types and amounts of ingredients:
EXAMPLE 8 Animal Feed One thousand grams of feed premix is prepared from the following types and amounts of ingredients:
EXAMPLE 9 Oral Powder One thousand grams of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone in bulk form is finely divided by means of an air micronizer. The micronized powder is divided into individual doses of 250 mg and packaged.
EXAMPLE 10 Insufflation One thousand grams of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone in bulk form is finely divided by means of an air micronizer.
EXAMPLE 11 Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 100 mg of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone, are prepared from 100 grams of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone.
EXAMPLE 12 Following the procedure of the preceding Examples 1 through 11, inclusive, compositions are prepared substituting equivalent amounts of the pharmaceutically acceptable acid addition salts of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone for the free base of the examples.
EXAMPLE 13 Following the procedure of the proceding Examples 1 through 11, inclusive, compositions are prepared substituting equivalent amounts of 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone or the pharmaceutically acceptable acid addition salts or the alkali metal or alkaline earth metal salts of each of the foregoing compounds for 2-amino-3-methyl-5-bromo-6-metafluorophenyl-4-pyrimidinone of each of the examples. Those compositions are useful for treating hypertension where administered as described above and in Examples 1 through 12, inclusive.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS2704285 *Jun 17, 1954Mar 15, 1955Searle & Co2-amino-5-(lower alkyl)-6-substituted phenyl-4-pyrimidolsUS2723277 *Aug 14, 1953Nov 8, 1955Hoffmann La RocheMalonic acid derivatives and process for the manufacture thereofUS2776283 *Jun 1, 1954Jan 1, 1957Searle & Co5-dialkylaminomethyl and 5-heterocyclylmethyl substituted 2-amino-6-aryl-4-pyrimidolderivativesUS3956302 *May 24, 1974May 11, 1976The Upjohn CompanySubstituted pyrimidinesBE882315A1 * Title not availableGB1223686A * Title not available* Cited by examinerNon-Patent CitationsReference1 *Brown and Stevens, JCS Perkin I, 1023, 1975.2 *Kulkarni et al., J. Sci. and Ind. Research (India), 19C, 6 8 (1960), CA.3Kulkarni et al., J. Sci. and Ind. Research (India), 19C, 6-8 (1960), CA.4 *Nicols, Weed and Underwood, Antimicrobial Agents, Chemo. Ther., 9, 433 (1976).5 *Sirakawa, Yakugaku Zasshi, 80, 1542, 1960 CA 55, 10651b.6 *United States application Ser. No. 022,205 (Case 3621).* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS5902789 *May 26, 1995May 11, 1999Fisons CorporationNasal administration of drugs* Cited by examinerClassifications U.S. Classification544/321International ClassificationA23K1/16, C07D239/46Cooperative ClassificationC07D239/47, A23K1/1628European ClassificationA23K1/16F4, C07D239/47Legal EventsDateCodeEventDescriptionAug 14, 1990FPExpired due to failure to pay maintenance feeEffective date: 19900603Jun 3, 1990LAPSLapse for failure to pay maintenance feesFeb 15, 1990REMIMaintenance fee reminder mailedRotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google