WO1991015209A1 - Substituted pyrimidines, pyrimidinones and pyridopyrimidines - Google Patents

Substituted pyrimidines, pyrimidinones and pyridopyrimidines Download PDF

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Publication number
WO1991015209A1
WO1991015209A1 PCT/US1991/001951 US9101951W WO9115209A1 WO 1991015209 A1 WO1991015209 A1 WO 1991015209A1 US 9101951 W US9101951 W US 9101951W WO 9115209 A1 WO9115209 A1 WO 9115209A1
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Prior art keywords
alkyl
heteroaryl
aryl
cycloalkyl
compound
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PCT/US1991/001951
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French (fr)
Inventor
Eric E. Allen
William J. Greenlee
Malcolm Maccoss
Arthur A. Patchett
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Merck & Co., Inc.
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Priority to JP91506652A priority Critical patent/JPH05505609A/en
Publication of WO1991015209A1 publication Critical patent/WO1991015209A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine
  • the compounds of the invention are also useful as ocular antihypertensives.
  • the compounds of this invention also have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
  • CNS central nervous system
  • Renin-angiotensin system plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure.
  • Angiotensin II (A II) an octapeptide hormone is produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS•A II is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
  • ACE angiotensin converting enzyme
  • One of the possible modes of controlling the RAS is angiotensin II receptor antagonism.
  • non-peptide compounds have been described as A II antagonists.
  • Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; and 4,582,847; in European Patent Applications 028,834; 245,637;
  • This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine
  • the compounds of this invention have the general formula (I):
  • the compounds of formula I can also be expressed as compounds having the following formulae (la), (lb), and ((Ic) if R 7 and R 8a are joined)
  • R 1 is (a) -CO 2 R 4 ,
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of 0, N or S and wherein the substituents are members selected from the group consisting of -OH, -SH, -C 1 -C 4 -alkyl, -C 1 -C 4 -alkoxy, -CF 3 , Cl, Br, F, I, -NO 2 , -CO 2 H, -CO 2 -C 1 -C 4 -alkyl, -NH 2 , NH(C 1 -C 4 -alkyl) and
  • R 2a and R 2b are each independently
  • -CO 2 -C 1 -C 4 -alkyl or R 4 is H, C 1 -C 6 -alkyl, benzyl or phenyl;
  • R 5 is H, -CH-O-C-R 4 ;
  • E is a single bond, -NR 13 (CH 2 ) s -, -S(O) X (CH 2 ) s - where x is 0 to 2 and s is 0 to 5, -CH(OH)-, -O-, -CO-;
  • R 7 is (a) hydrogen
  • R 8a is (a) aryl
  • R 7 and R 8a when alkyl groups on adjacent atoms may be joined together with the atoms to which they are bound to form a pyridine ring which may be
  • R 27 is C 1 -C 4 -alkyl, Cl, Br, F, I, -CF 3 , aryl or heteroaryl;
  • R 8b is (a) -OH
  • R 9 is H, C 1 -C 5 -alkyl, phenyl or benzyl;
  • R 10 is H, C 1 -C 4 -alkyl
  • R 11 is H, C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 4 -alkoxy alkyl, or -CH 2 -C 6 H 4 R 20 ;
  • R 12 is -CN, -NO 2 , -CO 2 R 4 , or -CF 3 ;
  • R 13 is H, C 2 -C 4 -alkanoyl, C 1 -C 6 -alkyl, allyl,
  • R 14 is H, C 1 -C 8 -alkyl, C 1 -C 8 -perfluoroalkyl,
  • R 15 is H, C 1 -C 6 -alkyl
  • R 16 is H , C 1 -C 6 -alkyl , C 3 -C 6 -cycloalkyl , phenyl or benzyl ;
  • R 17 is -NR 9 R 10 , -OR 10 , -NHCONH 2 , -NHCSNH 2 ,
  • R 18 and R 19 are independently C 1 -C 4 -alkyl or taken together are -(CH 2 ) q - where q is 2 or 3;
  • R 20 is H, -NO 2 , -NH 2 , -OH or -OCH 3
  • R 21 is (a) -CO-aryl
  • R 22 is the same as R 8a or -H;
  • R 23 is (a) aryl ,
  • aryl selected from the group consisting of aryl, heteroaryl, -OH, -SH,
  • R 25 is (a) H
  • Z is 0, NR 13 or S; or, a pharmaceutically acceptable salt thereof.
  • alkyl alkenyl
  • alkynyl alkynyl
  • specific names for these generic terms shall mean the straight chain species.
  • butyl shall mean the normal butyl substituent, n-butyl.
  • R 1 is -COOH ; -NH-SO 2 CF 3 ; -CO 2 R 4 ;
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or
  • substituents are members selected from the group consisting of OH, SH, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CF 3 , Cl, Br, F, I, NO 2 , CO 2 H, CO 2 -C 1 -C 4 -alkyl, NH 2 , NH(C 1 -C 4 -alkyl) and N(C 1 -C 4 -alkyl) 2 ;
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,
  • E is a single bond, -O- or -S-; R 6 is
  • X is a C-C single bond.
  • R 2a , R 2b , R 3a and R 3b are each H;
  • X is a single bond.
  • R 1 is -COOH; -NH-SO 2 CF 3 ; CO 2 R 4 ;
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or 6-membered aromatic ring comprising contain 1 to 3
  • heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C 1 -C 4 -alkyl,
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,
  • R 7 and R 8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which can be substituted with R 26 and R 27 ;
  • X is a C-C single bond.
  • R 2a , R 2b , R 3a and R 3b are each H;
  • X is a single bond.
  • R 1 is -COOH; -NH-SO 2 CF 3 ; CO 2 R 4 ;
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted 5-or 6-membered aromatic ring
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 5 -C 6 - cycloalkyl, -COOCH 3 , -COOC 2 H 5 , -SO 2 CH 3 ;
  • E is a single bond, -O- or -S-; R 6 is
  • R 7 and R 8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be substituted with R 26 and R 27 ;
  • X is a C-C single bond.
  • R 2a , R 2b , R 3a and R 3b are each H;
  • X is a single bond.
  • FAB-MS Fast atom bombardment mass spectroscopy
  • Pyrimidinones substituted in the 2,4,5, and 6 positions may be prepared as shown in Scheme 1.
  • the dianion of ethyl hydrogen malonate is made using two equivalents of butyllithium in THF at - 78°C. It is then quenched with an acyl chloride then acidified giving the necessary ⁇ -ketoester as shown. 1
  • the ⁇ -ketoester is then alkylated with the appropriate sidechain using sodium hydride in DMSO (or other suitable base in a suitable solvent) to give
  • Intermediate 1 may then be treated with an appropriate R 7 -amidine, guanidine, 0-alkyl or aryl isourea, or S-alkyl or aryl isothiourea, to give the 2,5,6-trisubstituted pyrimidin-4(3H)-one 2.
  • Pyrimidin-4(3H)-one 2 itself may be an A-II antagonist but may also be used as an
  • Scheme 3 illustrates an alternative preparation of pyrimidinone 3.
  • An R 7 nitrile can be converted to an imidate then to an amidine with an R 8a amine. This can then be condensed with ⁇ -ketoester 1 to give 3.
  • Similar procedures also exist for the preparation of isoureas, isothiuronium salts, and guanidines. 4
  • Other methods are also available for the introduction of substituents at the 2-position of the pyrimidine. 5
  • Scheme 4 shows how pyrimidinone 2 can be converted to 4-chloropyrimidine 4, which is a useful intermediate for the preparation of other
  • nucleophile which could be an amine, alcohol, thiol, or carbon nucleophile with or without a Ni 2+ or Pd 0 catalyst, to give the 2,4,5,6-tetrasubstituted
  • 4-aminopyrimidine 7 The 4-aminopyrimidines such as 7 can be converted to pyrimidin-4(3H)-ones simply by diazotizing them with nitrous acid. 9
  • Scheme 8 shows an alternative pyrimidinone synthesis via an intermediate isoxazole. 1 0
  • the ⁇ -ketonitrile 6. can be converted to the
  • Pyridopyrimidinones such as 1.0 can be obtained by condensing variously substituted
  • Scheme 10 illustrates a preparation of a 4-carboxy or 4-carboalkoxy pyrimidine.
  • Ethyl hydrogen malonate can be doubly deprotonated using two equivalents of butyllithium.
  • the dianion can then be used as a nucleophile on which to add the electrophile sidechain to give ethyl ester 11.
  • the ester can then be deprotonated and be added to diethyl oxalate to give the diethyl oxalacetate derivative 12.
  • nucleophile such as an amine, alkoxide , or thiol
  • thiol a nucleophile such as an amine, alkoxide , or thiol
  • hydrolysis of the ester would give the corresponding 4-carboxypyrimidine.
  • Scheme 11 shows how the 2,3,5,6-tetrasubstituted pyrimidin-4(3H)-one 16 could be prepared from pyrimidinone 15.
  • Scheme 13 shows how the 2,4,5,6-tetrasubstituted pyrimidine 17 can be prepared from intermediate 15 with the R 8b nucleophile as described above.14 Alternatively, one could use triflic anhydride and hindered amine base in place of POCl 3 .
  • Scheme 14 illustrates how the pyrimidine ring system can be built onto what would become the 5-sidechain. Conversion of the bromide 18 to a
  • Grignard reagent organo-zinc reagent, organo-lithium reagent, or other related organo-metal reagent
  • Scheme 15 describes the preparation of 4-methoxy-5-bromopyrimidines 25 that may either be converted into nucleophiles and added to the
  • electrophilic sidechain as shown in Scheme 16 or used as electrophiles as illustrated in Scheme 17.
  • Scheme 17 provides a route to the same intermediate 22 by conversion of the bromide 18. to the organo-metal reagent followed by addition to the electrophilic 5-bromopyrimidine 25.
  • Scheme 21 illustrates one specific method used to prepare two of the more preferred compounds in Table 1.
  • Scheme 22 illustrates another specific method used to prepare a preferred compound in Table 3. IDENTIFICATION OF REFERENCES CITED IN SCHEMES W. Wierenga, H.I. Skulnick, Org. Syn. (1982) 615. D.J. Brown, The Pyrimidines, (1962), J. Wiley & Sons, pp. 48-51.
  • N-C-N group amidines, isoureas, isothiuronium salts, etc.
  • C-C-C group generally the ⁇ -keto esters
  • the ⁇ -keto esters may be
  • Scheme 19 provides a route for the
  • acid can be activated by conversion to the acid
  • imidazole can be achieved upon treatment of acid 26
  • Scheme 20 provides a route to the isomeric acyl sulfonamides 33.
  • bromobenzenesulfonyl chloride 28 may be converted to
  • triphenylmethyl group gives sulfonamide 29.
  • ** base can be NaH, KH, DBU
  • the compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.
  • Such salts include ammonium salts, alkai metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine, and the like.
  • salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 , methanesulfonic,
  • toluensulfonic maleic, fumaric, camphorsulfonic.
  • the non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
  • the salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze- drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
  • Antiotensin II (All) is a powerful arterial vasoconstrictor, and it exerts its action by
  • Bovine adrenal cortex was selected as the source of All receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HCl (50mM), pH 7.7 buffer and homogenized. The
  • 3H-angiotensin II was presented as a measure of the efficacy of such compounds as All antagonists.
  • mice Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p.). The trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 strokes per minute, volumn - 1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37°C by a thermostatically
  • propranolol (1 mg/kg i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30-minute intervals and the increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
  • the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic conditions.
  • congestive heart failure in the treatment of secondary hyperaldosteronism, primary and secondarv pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis,
  • the compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables and the like as well as topical ocular formulations in the form of
  • intraocular pressure would typically contain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, of a compound of this invention.
  • compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or
  • the compounds of this invention can be administered to patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such patients (animals and human) in need of such
  • the dosage range will generally be about 1 to 1000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day.
  • the compounds of this invention can also be administered in combination with other antihyper- tensives such as diuretics, angiotensin converting enzyme inhibitors, clacium channel blockers or ⁇ -blockers.
  • antihyper- tensives such as diuretics, angiotensin converting enzyme inhibitors, clacium channel blockers or ⁇ -blockers.
  • the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflu- methiazide, chlorothalidone, chlorothiazide,
  • clonidine cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochloro- thiazide, metolazone, metoprolol tartate, methy- clothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina,
  • captopril delapril hydrochloride, enalapril,
  • teprotide zofenopril calcium, diflusinal. diltiazem. felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.
  • the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
  • one of the angiotensin II antagonist of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the
  • hydrochlorothiazide (15-200 mg) chloro- thiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),
  • propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine 5-60 mg), and nitrendipine (5-60 mg).
  • angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control bllod pressure in hypertensive patients.
  • these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of
  • compositions or preparations of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
  • a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, flavor, etc.
  • the amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
  • Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient sich as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintegreen or cherry.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient sich as microcrystalline cellulose
  • a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such
  • unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • a liquid carrier such as fatty oil.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac , sugar or both .
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic faffy vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
  • cholinomimetics such as physostigmine and nootropic agents are known to be active.
  • rats are trained to inhibit their natural tendency to enter dark areas.
  • the test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet.
  • the test animals are pretreated with 0.2 mg/kg of the
  • muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
  • the anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay.
  • CER conditioned emotional response
  • Diazepam is a clinically useful anxiolytic which is active in this assay.
  • male Sprague-Dawley rats 250-350 g
  • VI variable interval
  • All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed L1D1L2D2L3
  • lever presses in the dark (D), lever presses also elicit mild footshock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed during the dark periods reflecting the formation of a conditioned emotional response (CER).
  • CER conditioned emotional response
  • Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, response rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice.
  • a clinically useful antidepressant which serves as a positive control in this assay is desipramine.
  • the method is based on the observations that a mouse suspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation. Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity code and to measure latency, duration and frequency of immobile periods.
  • Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced sterotypy model.
  • a clinically useful antipsychotic drug that is used as a positive control in this assay is haloperidol.
  • the assay method is based upon the observation that stimulation of the dopaminergic system in rats produces stereotyped motor behavior.
  • Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer.
  • Compounds of the invention should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the dosage range will generally be about 5 to 6000 mg. per patient per day which can be administered in single or multiple doses.
  • the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg . per patient per day.
  • the compounds of this invention may be combined with other cognition-enhancing agents
  • acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (THA; tacrine)
  • TAA tetrahydroacridine
  • muscarinic agonists such as tacrine
  • oxotremorine inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers and as nimodipine, and nootropic agents such as piracetam.
  • the compounds of this invention may be combined with other anxiolytic agents such as
  • alprazolam lorazepam, diazepam, and busipirone.
  • tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone
  • monoamine oxidase inhibitors such as tranylcypromine
  • the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.
  • 1,10-phenanthroline in 500 mL THF at -78°C was added 60 mL 2.5 M n-butyllithium in hexanes ( ⁇ one half of the total).
  • the indicator color persisted at this point.
  • the solution was warmed to -5° to +5°C after which the indicator color disappeared.
  • Another 55 mL 2.5 M n-butyllithium in hexanes was added until the indicator color again persisted.
  • the mixture was cooled to -78°C then 10.0 mL valeroyl chloride in 10 mL THF was added over 3 minutes. After 10 minutes the now yellow solution was allowed to warm to room temperature and stir for 1 hour.
  • the mixture was poured into a solution of 50 mL concentrated HCl in 300 mL water.
  • the mixture was extracted 3 times with ether.
  • the combined organic material was washed twice with saturated NaHCO 3 solution then once with brine.
  • the washes were back extracted with ether and the back extracts were washed with brine.
  • the back extracts were combined with the other organic
  • the title compound is prepared by dissolving 1.0 equivalent of ethyl 2-[2'-(N-triphenyl- methyl-tetrazol-5-yl)biphen-4-yl)methyl]-3-oxoheptan- oate in THF so that the solution is -0.1-0.3 M. To this is added 1.3 equivalents of sodium hydride.
  • the title compound may be prepared by dissolving 1-5 equivalents of acetamidine
  • the title compound may be prepared by dissolving 6-butyl-2-methyl-5-[(2'-(N-triphenylmethyl- tetrazol-5-yl)biphen-4-yl)methyl]pyrimidin-4(3H)-one in methanol and adding excess concentrated HCl and stirring for 10-30 minutes. An indicator quantity of phenolphthalein is added followed by 10% NaOH
  • Step A Ethyl 2-[(4-iodophenyl)methyl]-3-oxohep- tanoate
  • Step B 6-Butyl-2-methyl-5-[(4-iodophenyl)methyl]
  • 6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl]- pyrimidine in 10 mL acetone were added 0.119 mL 57% HI (0.900 mmol) and 851 mg (5.68 mmol) Nal.
  • the mixture was warmed to 40°C for 2.5 hours. As the reaction proceeds, NaCl can be seen precipitating out of solution.
  • the mixture was diluted with brine and saturated NaHCO 3 solution.
  • the mixture was extracted 3 times with ether.
  • the combined organic material was dried over MgSO 4 and decolorized with activated charcoal, was stripped of solvent in vacuo.
  • Step A 2-Butyl-3- [ (4-iodophenyl )methyl]-6-methyl-
  • Step B 2-Butyl-6-methyl-3-[(2'-(tetrazol-5-yl)- biphen-4-yl)methyl]-4H-pyrido[1,2-a]- pyrimidin-4-one
  • a typical tablet would contain 6-butyl-4- carboxy-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)- methyl]pyrimidine (25 mg), pregelatinized starch USP (82 mg), microcrystaline cellulose (82 mg) and
  • a typical combination tablet would contain, for example, 6-butyl-4-carboxy-2-methyl-5-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine a
  • hydrochlorothiazide such as hydrochlorothiazide and consist of hydrochlorothiazide (50 mg) pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).
  • Typical suppository formulations for rectal administration can contain 6-butyl-4-carboxy-2-methyl- 5-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg).
  • Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol.
  • these suppository formulations can also include another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme and/or a calcium channel blocker in pharmaceutically effective amounts as described, for example, in C above.
  • another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme and/or a calcium channel blocker in pharmaceutically effective amounts as described, for example, in C above.
  • a typical injectible formulation would contain 6-butyl-4-carboxy-2-methyl-5-[(2'-(tetrazol- 5-yl)biphen-4-yl)methyl]pyrimidine, sodium phosphate dibasic anhydrous (11.4 mg) benzylalcohol (0.01 ml) and water for injection (1.0 ml).
  • Such an injectible formulation can also include a pharmaceutically effective amount of another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme inhibitor and/or a calcium channel blocker.

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Abstract

Substituted pyrimidines, pyrimidinones and pyridopyrimidines of formula (I) are as angiotensin II antagonists useful in the treatment of hypertension, ocular hypertension and certain CNS ailments; in the said formula, K is -N(R8a)-C(=M) or -N=C(R8b) where M is O or NR22.

Description

TITLE OF THE INVENTION
SUBSTITUTED PYRIMIDINES, PYRIMIDINONES AND PYRIDO-
PYRIMIDINES
SUMMARY OF THE INVENTION
The is a continuation-in-part of copending Application S. N. 501,580, filed March 30, 1990.
This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine
compounds and derivatives thereof which are useful as angiotensin II antagonists in the treatment of elevated blood pressure and congestive heart
failure. The compounds of the invention are also useful as ocular antihypertensives.
The compounds of this invention also have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
BACKGROUND OF THE INVENTION
Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II), an octapeptide hormone is produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS•A II is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr. - Handbook of Hypertension, Clinical
Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science
Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; and 4,582,847; in European Patent Applications 028,834; 245,637;
253,310; 291,969; 323,841; and 324,377; and in articles by A.T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 157, 13-21 (1988)] and by P.C. Wong, et al.
[J. Pharm. Exp. Therap, 247, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted
phenyl. European Patent Application 245,637
discloses derivatives of 4,5,6,7-tetrahydro-2H- imidazo[4,5-c]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine
compounds and derivatives thereof which are useful as angiotensin II antagonists, as antihypertensives, in the treatment of congestive heart failure and in the treatment of elevated intraocular pressure. The compounds of this invention have the general formula (I):
Figure imgf000006_0001
wherein:
K is -N(R8a)-C(=M) or -N=C(R8b)-wherein M is 0 or
NR22.
Thus, the compounds of formula I can also be expressed as compounds having the following formulae (la), (lb), and ((Ic) if R7 and R8a are joined)
Figure imgf000007_0001
wherein:
R1 is (a) -CO2R4,
(b) -SO3R5,
(c) -NHSO2(C1-C4-polyfluoroalkyl)
(d) -PO(OR5)2,
(e) -SO2-NH-R9,
(f) -CONHOR5 ,
OH O
Figure imgf000008_0001
(g) -C--P-OR5,
Figure imgf000008_0002
Figure imgf000008_0003
R9 OR5
(h) -CN,
(i) -SO2NH-heteroaryl,
(j) -CH2SO2NH-heteroaryl,
(k) -SO2NH-CO-R23,
(1) -CH2SO2NH-CO-R23,
(m) -CONH-SO2R23,
(n) -CH2CONH-SO2R23,
(o) -NHSO2NHCO-R23,
(p) -NHCONHSO2-R23,
Figure imgf000009_0001
wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of 0, N or S and wherein the substituents are members selected from the group consisting of -OH, -SH, -C1-C4-alkyl, -C1-C4-alkoxy, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, NH(C1-C4-alkyl) and
-N(C1-C4-alkyl)2;
R2a and R2b are each independently
(a) H,
(b) Cl.Br, I or F,
(c) NO2,
(d) NH2,
(e) C1-C4-alkylamino,
(f) di-(C1-C4-alkyl)amino
(g) SO2NHR9,
(h) CF3,
(i) C1-C4-alkyl, or
(j) C1-C4-alkoxy;
R 3a is
(a) H,
(b) Cl, Br, I, F
(c) C1-C6-alkyl,
(d) C1-C6-alkoxy,
(e) C1-C6-alkoxy-C1-C4-alkyl; R3 b is
(a) H
(b) Cl, Br, I, F
(c) NO2,
(d) C1-C6-alkyl,
(e) C2-C6-alkanoyloxy,
(f) C3-C6-cycloalkyl,
(g) C1-C6-alkoxy,
(h) -NHSO2R4,
(i) hydroxy-C1-C4-alkyl,
(j) aryl-C1-C4-alkyl,
(k) C1-C4-alkylthio,
(1) C1-C4-alkylsulfinyl,
(m) C1-C4-alkylsulfonyl,
(n) NH2,
(o) C1-C4-alkylamino,
(p) C1-C4-dialkylamino,
(q) CF3,
(r) -SO2-NHR9,
(s) aryl or
(t) furyl; wherein aryl is phenyl or naphthyl unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, Br, I, F,
C1-C4-alkyl, C1-C4-alkoxy, NO2 , CF3, C1-C4-alkylthio, OH, NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, C1-C4 polyfluoroalkyl, C3-C6-polyfluorocycloalkyl. -CO2-C1-C4-alkyl or
Figure imgf000011_0001
R4 is H, C1-C6-alkyl, benzyl or phenyl;
R4 0
R5 is H, -CH-O-C-R4;
E is a single bond, -NR13(CH2)s-, -S(O)X(CH2)s- where x is 0 to 2 and s is 0 to 5, -CH(OH)-, -O-, -CO-;
R6 is
(a) C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group
consisting of aryl, C3-C7-cycloalkyl, Cl, Br, I, F, -OH, CF3, CCl3, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2,
-NH-SO2R4, -COOR4, -SO2NHR9, C1-C4-alkoxy, C1-C4-alkyl-S, -CF2CF3;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl;
R7 is (a) hydrogen,
(b) aryl,
(c) heteroaryl,
(d) Cl, Br, I, F,
(e) -CO2H,
(f) -CO2R4,
(g) -NH2,
(h) -NH(C1-C4-alkyl),
(i) -N(C1-C4-alkyl)2,
(j) -SO2NR9R10,
(k) -NHSO2-C1-C4-alkyl,
(l) -S(O)X-C1-C4-alkyl, (m) -OH,
(n) -SH,
(o) -S(O)X-aryl,
(p) -C1-C4-alkyl or -O(C1-C4-alkyl) or -S(C1-C4-alkyl) each of which can be substituted with aryl, heteroaryl, -OH, -NH2, -CF3, C3-C5-cycloalkyl, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, -CO2R4, Cl, Br, I, or F,
(q) C3-C5-cycloalkyl or
(r) -CF3;
R8a is (a) aryl,
(b) heteroaryl,
(c) C1-C4-alkyl either unsubstituted or substituted with aryl, heteroaryl, -OH, -NH2, -NH(C1-C4-alkyl),
N(C1-C4-alkyl)2, -CO2H, -CO2R4 Cl, Br, I, or F, or
(d) C1-C4-alkylaryl either unsubstituted or substituted with CO2R4;
or R7 and R8a when alkyl groups on adjacent atoms may be joined together with the atoms to which they are bound to form a pyridine ring which may be
unsubstituted or substituted with R26 or R27 or R26 and R27 wherein R26 is
(a) R7
(b) -NHCO(C1-C5-alkyl),
(c) -NHCO(C3-C6-cycloalkyl),
(d) -NHCO(aryl),
(e) -NHCO(heteroaryl),
(f) -N(C1-C5-alkyl)CO(C1-C5-alkyl), (g) -N(C1-C5-alkyl)CO(C3-C6-cyclo- alkyl),
(h) -N(C1-C5-alkyl)CO(aryl),
(i) -N(C1-C5-alkyl)CO(heteroaryl). and R27 is C1-C4-alkyl, Cl, Br, F, I, -CF3, aryl or heteroaryl;
R8b is (a) -OH,
(b) -NH2,
(c) -NH(C1-C4-alkyl),
(d) -N(C1-C4-alkyl)2,
(e) -NHCO2-C1-C4-alkyl,
(f) -NHCO-C1-C4-alkyl,
(g) -NHSO2-C1-C4-alkyl,
(h) -NHSO2-aryl,
(i) -NHSO2(C1-C4-polyfluoroalkyl),
(j) -CO2H,
(k) -CO2R4,
(l) Cl, Br, I, F,
(m) -CONHSO2-aryl,
(n) -CONHSO2-heteroaryl,
(o) -CONHSO2-C1-C4-alkyl,
(p) -CONHSO2(C1-C4-polyfluoroalkyl),
(q) -CH2OH,
(r) -CH2OCOR4,
(s) -O-C1-C4-alkyl, unsubstituted or substituted with CO2R4,
(t) -S(O)X-aryl unsubstituted or
substituted with CO2R4,
(u) -S(O)X-C1-C4-alkyl unsubstituted or substituted with CO2R4,
(v) -SO2NHR25,
(w) -CN, (x) tetrazol-5-yl;
R9 is H, C1-C5-alkyl, phenyl or benzyl;
R10 is H, C1-C4-alkyl;
R11 is H, C1-C6-alkyl, C2-C4-alkenyl, C1-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -NO2, -CO2R4, or -CF3;
R13 is H, C2-C4-alkanoyl, C1-C6-alkyl, allyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, C1-C8-alkyl, C1-C8-perfluoroalkyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R 15 is H, C1-C6-alkyl;
R16 is H , C1-C6-alkyl , C3-C6-cycloalkyl , phenyl or benzyl ;
R17 is -NR9R10 , -OR10 , -NHCONH2 , -NHCSNH2 ,
Figure imgf000015_0001
R18 and R19 are independently C1-C4-alkyl or taken together are -(CH2)q- where q is 2 or 3;
R20 is H, -NO2, -NH2, -OH or -OCH3
R21 is (a) -CO-aryl,
(b) -CO-C1-C4-alkyl,
(c) -COCF3,
(d) -CO-heteroaryl,
(e) heteroaryl;
R 22 is the same as R8a or -H; R23 is (a) aryl ,
(b) heteroaryl,
(c) C3-C7-cycloalkyl,
(d) C1-C6-alkyl unsubstituted or substituted with a substituent
selected from the group consisting of aryl, heteroaryl, -OH, -SH,
-C1-C4-alkyl, -O(C1-C4-alkyl),
-S(C1-C4-alkyl),-CF3, Cl, Br, F, or I, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -PO3H2, or -PO(OH)(O-C1-C4-alkyl);
R25is (a) H,
(b) C1-C4-alkyl; X is
(a) a carbon-carbon single bond,
(b) -CO-,
(c) -O-,
(d) -S-,
(e) -N-,
R13
(f) -CON-,
R15
(g) -NCO-,
R15
(h) -OCH2-,
(i) -CH2O-
(j) -SCH2-,
(k) -CH2S-,
(l) -NHC(R9)(R10)-, (m) -NR9SO2-,
(n) -SO2NR9-,
(0) -C(R9)(R10)NH-,
(P) -CH=CH-,
(q) -CF=CF-,
(r) -CH=CF-,
(s) -CF=CH-,
(t) -CH2CH2-,
(u) -CF2CF2-,
(v)
Figure imgf000017_0001
OR14
Figure imgf000017_0005
(w) -CH-,
OCOR16
Figure imgf000017_0004
(x) -CH-,
NR17
Figure imgf000017_0003
(y) -C-, or
R180 OR19
(z)
Figure imgf000017_0002
Z is 0, NR13 or S; or, a pharmaceutically acceptable salt thereof.
The terms "alkyl", "alkenyl", "alkynyl" and the like include both the straight chain and branched chain species of these generic terms wherein the number of carbon atoms in the species permit. Unless otherwise noted, the specific names for these generic terms shall mean the straight chain species. For example, the term "butyl" shall mean the normal butyl substituent, n-butyl. One embodiment of the novel compounds is that of formula lb wherein K is -N=C(R8b)
In a class of this embodiment,
R1 is -COOH ; -NH-SO2CF3; -CO2R4;
Figure imgf000018_0001
-SO2NH- heteroaryl or CH2SO2NH- heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or
6-membered aromatic ring 1 to 3 heteroatoms selected from O, N and S and wherein the
substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl, C1-C4-alkoxy, CF3, Cl, Br, F, I, NO2, CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2;
-SO2NHCOR23 ;-CH2SO2NHCOR23; -CONHSO2R23;
-CH2CONHSO2R23; -NHSO2NHCOR23; or -NHCONHSO2R23;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C1-C4-alkoxy,
-COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -O- or -S-; R6 is
(a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group
consisting of, CF3, CF2CF3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl and C3-C5-cyclo- alkyl;
(b) C3-C5-cycloalkyl; and
(c) polyfluoro-C1-C4-alkyl;
X is a C-C single bond.
In a more preferred class of this embodiment are those compounds wherein:
E is a single bond;
R2a, R2b, R3a and R3b are each H; and
X is a single bond.
Exemplifying this embodiment are the following compounds of the Formula II shown in Table 1:
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
In another embodiment of the novel compounds is that of formula la (M=O) wherein K is -N(R8a)-CO-.
In a class of this embodiment *
R1 is -COOH; -NH-SO2CF3; CO2R4;
Figure imgf000024_0001
-SO2NH- heteroaryl or CH2SO2NH- heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or 6-membered aromatic ring comprising contain 1 to 3
heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl,
C1-C4-alkoxy, CF3, Cl, Br , F, I, NO2, CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and
N(C1-C4-alkyl)2; -SO2NHCOR23;-CH2SO2NHCOR23;
-CONHSO2R23; -CH2CONHSO2R23; -NHSO2NHCOR23; and -NHCONHSO2R23;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C1-C4-alkoxy,
-COOCH3, -COOC2H5, -SO2-CH3, NH2. -N(C1-C4-alkyl)2 or -NH-SO2CH3; E is a single bond, -O- or -S-;
R6 is
(a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group
consisting of Cl, CF3, CF2CF3, CCl3,
-O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl and C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which can be substituted with R26 and R27; and
X is a C-C single bond.
In a more preferred class of this embodiment are those compounds wherein:
E is a single bond;
R2a, R2b, R3a and R3b are each H; and
X is a single bond.
Exemplifying this embodiment are the following compounds of the Formula III shown in Table 2:
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0001
Also exemplifying this embodiment are the following compounds of the Formula IV shown in Table 3:
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000029_0001
In another embodiment of the novel compounds of this invention is that of formula la
(M is NR22) wherein K is -N(R8a)- C(=NR22)-.
In a class of this embodiment:
R1 is -COOH; -NH-SO2CF3; CO2R4;
Figure imgf000030_0001
-SO2NH-heteroaryl or -CH2SO2NH-heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5-or 6-membered aromatic ring
comprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl, C1-C4-alkoxy, CF3, Cl.Br, F, I, NO2,CO2H, CO2-C1-C4- alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2;
-SO2NHCOR23; -CH2SO2NHCOR23; -CONHSO2R23;
-CH2CONHSO2R23; -NHSO2NHCOR23; and - NHCONHSO2R23;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C5-C6- cycloalkyl, -COOCH3, -COOC2H5, -SO2CH3;
NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -O- or -S-; R6 is
(a) C1-C5-alkyl, C2-C5-alkenyl or
C2-C5-alkynyl each of which can be
substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl, and C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl;
(c) perfluoro-C1-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be substituted with R26 and R27; and
X is a C-C single bond.
In a more preferred class of this embodiment are those compounds wherein:
E is a single bond;
R2a, R2b, R3a and R3b are each H; and
X is a single bond.
Exemplifying this embodiment are the following compounds of the Formula V shown in Table 4:
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0002
Also exemplifying this embodiment are the following compounds of the Formula VI shown in Table 5:
Figure imgf000033_0001
Figure imgf000033_0003
Figure imgf000034_0001
Several methods for preparing the compounds of this invention are illustrated in the ensuing Schemes.
Abbreviations Used in Schemes
Reagents:
NBS N-bromosuccinimide
AIBN Azo(bis)isobutyronitrile
DDQ Dichlorodicyanoquinone
Ac2O acetic anhydride
TEA triethylamine DMAP 4-dimethylaminopyridine
PPh3 triphenylphosphine
TFA trifluroacetic acid
TMS-Cl trimethylsilyl chloride
Im imidazole
AcSK potassium thioacetate p-TsOH p-toluenesulfonic acid
Solvents:
DMF dimethylformamide
HOAc (AcOH) acetic acid
EtOAc (EtAc) ethyl acetate
Hex hexane
THF tetrahydrofuran
DMSO dimethylsulfoxide
MeOH methanol
iPrOH isopropanol
Others:
rt room temperature
TBDMS t-butyldimethylsilyl
OTf OSO2CF3
OTs OSO2-(4-methyl)phenyl
OMs OSO2CH3
Ph phenyl
FAB-MS (FABMS) Fast atom bombardment mass spectroscopy
NOE Nuclear Overhauser Effect
SiO2 silica gel
trityl triphenylmethyl
Pyrimidinones substituted in the 2,4,5, and 6 positions may be prepared as shown in Scheme 1. The dianion of ethyl hydrogen malonate is made using two equivalents of butyllithium in THF at - 78°C. It is then quenched with an acyl chloride then acidified giving the necessary β-ketoester as shown. 1 The β-ketoester is then alkylated with the appropriate sidechain using sodium hydride in DMSO (or other suitable base in a suitable solvent) to give
intermediate 1. Intermediate 1 may then be treated with an appropriate R7-amidine, guanidine, 0-alkyl or aryl isourea, or S-alkyl or aryl isothiourea, to give the 2,5,6-trisubstituted pyrimidin-4(3H)-one 2.2
Pyrimidin-4(3H)-one 2 itself may be an A-II antagonist but may also be used as an
intermediate for the preparation of
2,3,5,6-tetrasubstituted pyrimidin-4(3H)-ones as indicated in Scheme 2. Intermediate 2 may be
deprotonated in DMF with sodium hydride (or other suitable solvent and base) and alkylated with an R8a electrophile to afford the pyrimidin-4(3H)one 3.3
Scheme 3 illustrates an alternative preparation of pyrimidinone 3. An R7 nitrile can be converted to an imidate then to an amidine with an R8a amine. This can then be condensed with β-ketoester 1 to give 3. Similar procedures also exist for the preparation of isoureas, isothiuronium salts, and guanidines.4 Other methods are also available for the introduction of substituents at the 2-position of the pyrimidine.5
Scheme 4 shows how pyrimidinone 2 can be converted to 4-chloropyrimidine 4, which is a useful intermediate for the preparation of other
4-substituted pyrimidines. One could also envision using triflic anhydride and a suitably hindered amine base to give the corresponding pyrimidine triflate that could be used in a similar fashion to the
4-chloropyrimidine.6 Scheme 5 shows how nucleophilic
displacement would be achieved using an R8b
nucleophile which could be an amine, alcohol, thiol, or carbon nucleophile with or without a Ni2+ or Pd0 catalyst, to give the 2,4,5,6-tetrasubstituted
pyrimidine 5.7
Scheme 6 provides a route to the useful intermediate β-ketonitrile 6 . Cyanoacetic acid can be condensed with an R6 acyl chloride to give the
α-unsubstituted R6 β-ketonitrile.8 This can then be α-alkylated using NaH in DMSO (or other suitable base and solvent) and the appropriate sidechain
electrophile to afford 6..
Scheme 7 shows how the β-ketonitrile 6. can be condensed with an amidine or isourea to give
4-aminopyrimidine 7 . The 4-aminopyrimidines such as 7 can be converted to pyrimidin-4(3H)-ones simply by diazotizing them with nitrous acid.9
Scheme 8 shows an alternative pyrimidinone synthesis via an intermediate isoxazole.1 0 The β-ketonitrile 6. can be converted to the
5-aminoisoxazole 8. upon treatment with hydroxyl- amine. Acylation with an R7 acyl halide gives
intermediate isoxazole 9 which upon reduction and heating gives pyrimidinone 2 .
Pyridopyrimidinones such as 1.0 can be obtained by condensing variously substituted
2-aminopyridines with β-ketoesters 1 as shown in
Scheme 9.11
Scheme 10 illustrates a preparation of a 4-carboxy or 4-carboalkoxy pyrimidine. Ethyl hydrogen malonate can be doubly deprotonated using two equivalents of butyllithium. The dianion can then be used as a nucleophile on which to add the electrophile sidechain to give ethyl ester 11. The ester can then be deprotonated and be added to diethyl oxalate to give the diethyl oxalacetate derivative 12.12
Condensation of this material with an R7 amidine or isourea would give the 6-carbo-ethoxypyrimidin-4(3H)- one 13.13 Conversion of this material to the 4-chloro (or 4-trifluoromethane- sulfonato) derivative
followed by nucleophilic displacement by an R6-E:
nucleophile such as an amine, alkoxide , or thiol , would give the 2 , 5 , 6-tr i substituted-4-carboethoxy- pyrimidine 14. Hydrolysis of the ester would give the corresponding 4-carboxypyrimidine.
Conversion of the 4-carboxypyrimidine to the 4-acetyl derivative followed by peracid oxidation and hydrolysis would give pyrimidinone 15 as
illustrated in Scheme 11. Scheme 12 shows how the 2,3,5,6-tetrasubstituted pyrimidin-4(3H)-one 16 could be prepared from pyrimidinone 15. Scheme 13 shows how the 2,4,5,6-tetrasubstituted pyrimidine 17 can be prepared from intermediate 15 with the R8b nucleophile as described above.14 Alternatively, one could use triflic anhydride and hindered amine base in place of POCl3.
Scheme 14 illustrates how the pyrimidine ring system can be built onto what would become the 5-sidechain. Conversion of the bromide 18 to a
Grignard reagent, organo-zinc reagent, organo-lithium reagent, or other related organo-metal reagent
followed by addition of diethyl oxalate would give the pyruvate derivative 19. Addition of methoxy- or ethoxymethylenetr iphenyl-phosphorane or related reagent would give the ethyl β-ethoxyacrylate
derivative 20. Condensation of this material with an R7-amidine or isourea would provide pyrimidinone 21. Conversion of the 4-hydroxy function to the methoxy followed by addition of a Grignard reagent or
alkyllithium and oxidation with dichlorodicyanoquinone would afford the 2,5,6-trisubstituted-4-methoxy- pyrimidin-4(3H)-one 23. Conversion of the methoxy back to a hydroxy then provides pyrimidinone 2 .
Scheme 15 describes the preparation of 4-methoxy-5-bromopyrimidines 25 that may either be converted into nucleophiles and added to the
electrophilic sidechain as shown in Scheme 16 or used as electrophiles as illustrated in Scheme 17.
Condensation of β-ethoxyacrylate with R7-amidine or isourea would provide pyrimidinone 24. Conversion of this material to the 4-methoxy-5-bromopyrimidine 25 is straight forward as shown.
In Scheme 16 the 5-bromopyrimidine is converted to a Grignard, organolithium, or related reagent then added to the electrophilic sidechain (a catalyst or stoichiometric reagent such as CuCN may be added to enhance nucleophilicity or selectivity if necessary) to give pyrimidine 22 which may be used as illustrated previously.
Scheme 17 provides a route to the same intermediate 22 by conversion of the bromide 18. to the organo-metal reagent followed by addition to the electrophilic 5-bromopyrimidine 25.
Scheme 21 illustrates one specific method used to prepare two of the more preferred compounds in Table 1. Scheme 22 illustrates another specific method used to prepare a preferred compound in Table 3. IDENTIFICATION OF REFERENCES CITED IN SCHEMES W. Wierenga, H.I. Skulnick, Org. Syn. (1982) 615. D.J. Brown, The Pyrimidines, (1962), J. Wiley & Sons, pp. 48-51.
S. Hirokami, T. Takahashi, K. Kurosawa, M.
Nagata, J. Org. Chem. (1985) 50 166.
T. Takahashi, S. Hirokami, M. Nagata, T.
Yamazaki, J. Chem. Soc. Perkin Trans. I (1988) 2653.
S.S. Ahmad, S.I. Haidea, I. Fatima, Syn. Comm.
(1987) 17 1861.
G.D. Daves Jr., F. Baiocchi, R.K. Robins, C.C.
Cheng, J. Org. Chem. (1961) 26 2756.
J.R. Marshall, J. Walker, J. Chem. Soc. (1951) 1004.
T. Sakamoto, H. Yoshizawa, H. Yamanaka, Chem.
Pharm. Bull. (1984) 32 2005.
J.C. Krauss, T.L. Cupps, D.S. Wise, L.B.
Townsend, Synthesis (1983) 308.
D.J. Brown, The Pyrimidines, (1962), J. Wiley &. Sons, p. 333.
G. Shaw, G. Sugowdz, J. Chem. Soc. (1954) 665.
Y. Honma, Y. Sekine, T. Hashiyama, M. Takeda, Y. Ono, K. Tsuzurahara, Chem. Pharm. Bull. (1982) 30 4314.
M. Shur, S.S. Israelstam, J. Org. Chem. (1968) 33 3015.
F. Fulop, I. Hermecz, Z. Meszaros, G. Dombi, G.
Bernath, J. Het. Chem. (1979) 16 457.
P.L. Ferrarini, C. Mori, 0. Livi, G. Biagi, A.M.
Marini, J. Het. Chem. (1983) 20 1053.
H. Antaki, V. Petrow, J. Chem. Soc. (1951) 551. M.W. Goldberg, F. Hunziker, J.R. Billeter, H.R. Rosenberg, Helv. Chim. Acta. (1947) 10 200.
W.K. Hagmann, F.Z. Basha, M. Hashimoto, R.B.
Frye, S. Kojo, S.M. Hecht, J. Org. Chem. (1981) 46 1413.
T.A. Riley, W.J. Hennen, N.K. Dalley, B.E.
Wilson, R.K. Robins, S.B. Larson, J. Het. Chem.
(1987) 24 955.
Y. Muraoka, T. Takita, K. Maeda, H. Umezawa, J.
Antibiotics (1970) 23 253.
M. Otsuka, S. Kobayashi, M. Ohno, Y. Umezawa, H.
Morishima, H. Umezawa, Chem. Pharm. Bull. (1985)
33515.
G.D. Davies, Jr., R. Baiocchi, R.K. Robins, C.C.
Cheng, J. Org. Chem. (1961) 26 2755.
E. Ochiai, H. Yamanaka, Chem. Pharm. Bull. (1955) 3 173.
X >
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
)
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Where condensations of N-C-N group (amidines, isoureas, isothiuronium salts, etc.) with the C-C-C group (generally the β-keto esters) fail because of initial addition of N-C-N group to the ester rather than the keto group, the β-keto esters may be
converted to β-acetoxy, β-ethoxy, β-enol phosphate, β-enol triflate, or similar β-leaving group
α,β-unsaturated esters. [E. Piers, et al,
Tet.Lett., 25, 3155 (1984); M. Alderdice, etal, Org. Syn. 62, 14 (1984)] Such a reaction is illustrated in Scheme 18. The N-C-N group may then be condensed with the C-C-C group to give the expected
pyrimidinone or pyridopyrimidine.
Figure imgf000063_0001
Scheme 19 provides a route for the
preparation of acyl sulfonamides 27. The carboxylic
acid can be activated by conversion to the acid
chloride by various methods including treatment with
refluxing thionyl chloride or preferably with oxalyl
chloride and a catalytic amount of DMF at low
temperature.1 5 Activation by conversion to the acyl
imidazole can be achieved upon treatment of acid 26
with carbonyldiimidazole. N,N-Diphenylcarbamoyl
anhydride intermediates may be prepared as activated
carbonyls.1 6 Treatment of the activated carbonyls
with alkali metal salts of alkyl or aryl sulfonamides
or with the sulfonamide and DBU will give the
expected acyl sulfonamide 27.17
Scheme 20 provides a route to the isomeric acyl sulfonamides 33. The commercially available
bromobenzenesulfonyl chloride 28 may be converted to
the corresponding sulfonamide upon treatment with
ammonia or ammonium carbonate. Protection with the
triphenylmethyl group gives sulfonamide 29.
Palladium catalyzed cross-coupling gives the biaryl
30.18 Treatment of this material with
N-bromosuccinimide and catalytic AIBN in refluxing
CCI4 will give the alkylating agent 31. The bromide
31 may now be used as the alkylating agent shown in
previous schemes to give intermediate 32.
Deprotection and acylation will give the acyl
sulfonamide 33 .
------------------------------------------------
15 A.W. Burgstahler, L.O. Weigel, C.G. Shaefer, Synthesis (1976) 767.
16 F.J. Brown, et al, European Patent Application # EP 199543 K.L. Shepard, W. Halczenko, J. Het. Chem. (1979) 16 321.
17 J.T. Drummond, G. Johnson, Tet. Lett. (1988) 29 1653.
18 T.R. Bailey, Tet. Lett. (1986) 27 4407.
I. P. Beletskaya, J. Organometallic Chem. (1983) 250 551.
Figure imgf000065_0001
* a. SOCl2, reflux
b. (COCl)2. DMF, -20°C
c. N (N,N- Diphenylcarbanoyl) pyridinium chloride/ agueous. NaOH
d. carbonyl diimidazole
** base can be NaH, KH, DBU
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
c
Figure imgf000069_0001
Figure imgf000070_0001
The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkai metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H2SO4, H3PO4, methanesulfonic,
toluensulfonic, maleic, fumaric, camphorsulfonic. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze- drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
Antiotensin II (All) is a powerful arterial vasoconstrictor, and it exerts its action by
interacting with specific receptors present on cell membranes. The compounds described in the present invention act as competitive antagonists of All at the receptors. In order to identify All antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established. Receptor binding assay using rabbit aortae membrane preparation:
Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5mM
Tris-0.25M Sucrose, pH 7.4 buffer (50 ml),
homogenized, and then centifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4°C. The pellet thus obtained was resuspended in 30 ml of 50mM Tris-5 mM MgCl2 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitracin, and the suspension was used for 100 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 ml) there was added
125l-Sar1Ile8-angiotensin ll [ovtained from New
England Nuclear] (10 μl; 20,000 cpm) with or without the test sample, and the mixture was incubated at 37°C for 90 minutes. The mixture was then diluted with ice-cold 50mM Tris-0.9% NaCl, pH 7.4 (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in
scintillation cocktail (10 ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential All antagonist, which gives 50% displacement of the total specifically bound
125l-Sar1lle8-angiotensin ll, was presented as a measure of the efficacy of such compounds as All antagonists. Receptor assay using Bovine adrenal cortex preparation
Bovine adrenal cortex was selected as the source of All receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HCl (50mM), pH 7.7 buffer and homogenized. The
homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na2HPO4 (10mM)-NaCl
(120mM)-disodium EDTA (5mM) containing phenylmethane sulfonyl fluoride (PMSF)(0. lmM)]. (For screening of compounds generally duplicates of tubes are used).
To the membrane preparation (0.5 ml) there was added 3H-angiotensin II (50 mM) (10 μl), with or without the test sample, and the mixture was incubated at 37°C for 1 hour. The mixture was then diluted with Tris buffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential All antagonist, which gives 50% displacement of the total specifically bound
3H-angiotensin II, was presented as a measure of the efficacy of such compounds as All antagonists.
The potential antihypertensive effects of the compounds described in the present invention may be evaluated using the methodology described below:
Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p.). The trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 strokes per minute, volumn - 1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37°C by a thermostatically
controlled heating pad which received unput from a rectal temperature probe. Atropine ( 1mg/kg i.v.) was then administered and 15 minutes later
propranolol (1 mg/kg i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30-minute intervals and the increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
Using the methodology described above, representative compounds of the invention were evaluated and were found to exhibit an activity of at least IC50 < 50μM, thereby demonstrating and
confirming the utility of the compounds of the invention as effective All antagonists.
Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic
congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondarv pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis,
sclerederma, and the like, renal vascular
hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of vascular disorders such as migraine or Raynaud's disease. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.
The compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables and the like as well as topical ocular formulations in the form of
solutions, ointments, inserts, gels, and the like. Pharmaceutical formulations prepared to treat
intraocular pressure would typically contain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, of a compound of this invention.
In the management of hypertension and the clinical conditions noted above the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or
intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such
treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient, depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication and other factors, which those skilled in the art will recognize the dosage range will generally be about 1 to 1000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day.
The compounds of this invention can also be administered in combination with other antihyper- tensives such as diuretics, angiotensin converting enzyme inhibitors, clacium channel blockers or β-blockers. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflu- methiazide, chlorothalidone, chlorothiazide,
clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochloro- thiazide, metolazone, metoprolol tartate, methy- clothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina,
rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, thrichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, amino- phylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate,
captopril, delapril hydrochloride, enalapril,
enalaprilat, fosinopril sodium, lisinopril,
pentopril, quinapril hydrochloride, ramapril,
teprotide, zofenopril calcium, diflusinal. diltiazem. felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof. Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the angiotensin II antagonist of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the
following compounds at the indicated per day dose range: hydrochlorothiazide (15-200 mg) chloro- thiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),
propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine 5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochlorothiazide (15-200 mg) plus amiloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an
angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control bllod pressure in hypertensive patients. Naturally, these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of
patient, special diets and other factors. Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.
About 1 to 100 mg. of compounds or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient sich as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintegreen or cherry. When the dosage
unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac , sugar or both . A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic faffy vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
The following examples illustrate the preparation of the compounds of formula (I) and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the
invention set forth in the claims appended hereto. All 1H-NMR spectra were recorded on a Varian XL-300 Fourier transform spectrometer or on a Bruker 250 MHz spectrometer. Chemical shifts are reported as (parts per million) downfield from tetramethylsilane. Mass spectra were obtained from the Merck and Co. mass spectral facility in Rahway, N.J. Analytical TLC was conducted on E. Merck precoated silica plates (0.25 mm in glass, Kieselgel 60 F254) with UV
visualization. All chromatography was conducted on E. Merck silica gel. All reactions were carried out under an atmosphere of dry nitrogen under standard conditions for those skilled in the art.
The useful central nervous system (CNS) activities of the compounds of this invention are demonstrated and exemplified by the ensuing assays.
COGNITIVE FUNCTION ASSAY
The efficacy of these compounds to enhance cognitive function can be demonstrated in a rat passive avoidance assay in which cholinomimetics such as physostigmine and nootropic agents are known to be active. In this assay, rats are trained to inhibit their natural tendency to enter dark areas. The test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet. The test animals are pretreated with 0.2 mg/kg of the
muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
Upon return to the illuminated chamber, normal young rats who have been subjected to this training and who have been treated only with control vehicle take longer to re-enter the dark chamber than test animals who have been exposed to the apparatus but who have not received a shock. Rats treated with scopolamine before training do not show this hesitation when tested 24 hours later. Efficacious test compounds can overcome the disruptive effect on learning which scopolamine produces. Typically, compounds of this invention should be efficacious in this passive avoidance assay in the dose range of from about 0.1 mg/kg to about 100 mg/kg.
ANXIOLYTIC ASSAY
The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a clinically useful anxiolytic which is active in this assay. In the CER protocol, male Sprague-Dawley rats (250-350 g)
are trained to press a lever on a variable interval (VI) 60 second schedule for food reinforcement in a standard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed L1D1L2D2L3
sequence. During both periods (L or D), pressing a lever delivers food pellets on a VI 60 second
schedule: in the dark (D), lever presses also elicit mild footshock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed during the dark periods reflecting the formation of a conditioned emotional response (CER).
Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, response rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
DEPRESSION ASSAY
The antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice. A clinically useful antidepressant which serves as a positive control in this assay is desipramine. The method is based on the observations that a mouse suspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation. Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity code and to measure latency, duration and frequency of immobile periods.
Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
SCHIZOPHRENIA ASSAY
The antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced sterotypy model. A clinically useful antipsychotic drug that is used as a positive control in this assay is haloperidol. The assay method is based upon the observation that stimulation of the dopaminergic system in rats produces stereotyped motor behavior. There is a strong correlation between the effectiveness of classical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer. Compounds of the invention should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will generally be about 5 to 6000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg . per patient per day.
In order to obtain maximal enhancement of cognitive function, the compounds of this invention may be combined with other cognition-enhancing
agents. These include acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (THA; tacrine), muscarinic agonists such as
oxotremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers and as nimodipine, and nootropic agents such as piracetam.
In order to achieve optimal anxiolytic activity, the compounds of this invention may be combined with other anxiolytic agents such as
alprazolam, lorazepam, diazepam, and busipirone.
In order to achieve optimal antidepressant activity, combinations of the compounds of this invention with other antidepressants are of use.
These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine oxidase inhibitors such as tranylcypromine.
In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.
PREPARATION OF INTERMEDIATES
2-t-BUTOXYCARB0NYL-4'-METHYLBIPHENYL
To a solution of p-bromotoluene (30g) in dry ether (150 ml) at -78°C, a solution of t-BuLi in pentane (1.7M) (210 ml) was added slowly over a period of 1.5 hr using a dropping funnel. The bath was then removed and the mixture was stirred at room temperature for an additional 2 hours. The content of the flask was then added slowly (using a cannula) at room temperature to a premixed solution of ZnCl2 in ether (1M, 180 ml) and dry THF (360 ml). The mixture was stirred for 2 hr at that temperature and then the slurry was added (using a cannula) to a solution of 2-t-butoxycarbonyl iodobenzene (35.6 g) and NiCl2(Ph3P)2 (2.1 g) in dry THF (360 ml). The mixture, after stirring at room temperature overnight (18 hr), was poured slowly under stirring into ice-cold 0.5N HCl (1500 ml). The organic layer was separated, and the aqueous phase was extracted with ether (3 X 300 ml). The combined organic layer was washed with water, brine and then dried over MgSO4. Removal of the solvent gave the crude product as an oil (32 g). The material was purified on a
silica-gel flash column using ethyl acetate-hexane (1:12) to give the titled compound as an oil (24 g, 76%). 1H NMR (CDCl3): δ 1.24 (s,9H) 2.42 (s,3H), 7.2-7.8 (m,8H); FAB-MS: m/e 269(M+H). 4-BROMOMETHYL-2'-t-BUTOXYCARBONYL-BIPHENYL
To a solution of 2-t-butoxycarbonyl-4'- methylbiphenyl (25.3 g, 95 mmol) in CCI4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (1x50 ml), sat. NaHCO3 (1x50 ml), water (1x50 ml), sat. NaCl (1x50 ml) and dried over MgSO4. The solution was filtered and
concentrated in vacuo. The residue was dissolved in 100 ml of not hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20°C and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1H-NMR (CDCl3):1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
2-CYANO-4'-METHYLBIPHENYL
To a solution of p-bromotoluene (30 g) in dry ether (150 ml) at -78°C, a solution of t-BuLi in pentane (1.7 M) (210 ml) was added slowly over a period of 1.5 hr, using a dropping funnel. The bath was then removed and the mixture was stirred at room temperature for an additional 2 hr . The contents of the flask was then added slowly (using a cannula) at room temperature to a premixed solution of ZnCl2 in ether (1M) (180 ml) and dry THF (360 ml;. The mixture was stirred for 2h at that temperature and then the slurry was added (using a cannula) to a solution of 2-bromobenzonitrile (21.3 g) and NiCl2(Ph3P)2 (2.1 g) in dry THF (300 ml). The mixture, after stirring at room temperature overnight (18h), was poured slowly under stirring into ice-cold IN HCl (1500 ml). The organic layer was separated, and the aqueous phase was extracted with ether (3 X 300 ml). The combined organic layer was washed with water, brine and then dried over MgSO4. Removal of the solvent gave the crude product as a semisolid mass (34 g). The material was purified on a
silica-gel flash column using ethyl acetate-hexane (1:12) to give the desired nitrile as a low-melting solid (28 g, 88%). 1H NMR (CDCl3): 2.42 (s, 3H), 7.2-7.8 (m, 8H); FAB-MS: m/e 194 (M++1).
TRIMETHYLSTANNYL AZIDE
To a concentrated solution of NaN3 (1.2 kg, 18.5 moles) in water (3 L), a solution of
trimethyltin chloride (600 g, 3 moles) in dioxane (400 ml) was added in three portions under vigorous stirring. A precipitate formed instantaneously. The mixture, after stirring overnight at room
temperature, was filtered. The residue was washed with water and dried under suction and then in vacuo over P2O5. Yield 541 g (88%), mp 120-122°C.
5-[2-(4'-METHYLBIPHENYL)]TETRAZOLE
To a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 moles) in toluene (2.3 L) was added trimethyltin azide (525 g, 2.55 moles) at r.t. The mixture was refluxed for 24 h. cooled to r.t., filtered, washed with toluene and sucked dry in a funnel. The precipitate was resuspended in toluene (3.5 L) and THF (250 mL) was added. Anhydrous HCl was bubbled in at a moderate rate at r.t. to give a clear solution (45 min). Addition of HCl gas was continued for another 20 min. with stirring whereupon a white precipitate formed. The reaction mixture was stirred over night. The solid product was filtered, washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrazole. m.p. 152-154°C; 1H-NMR (CDCl3):2.40 (s, 3H), 7.19 (dd, 1H), 7.55 (m, 2H), 8.25 (dd, 1H).
N-TRIPHENYLMETHYL-5-[2-(4'-METHYLBIPHENYL)] TETRAZOLE
To a cloudy solution of 5-[2-(4'-methylbi- phenyl)]tetrazole (250 g (1.06 mole) in CH2Cl2 (4 L) was added triphenylmethylchloride (310 g 1.11 mole) at r.t. The reaction mixture was stirred and
triethylamine (190 mL, 138 g, 1.36 mole) was added portionwise. After addition, the mixture was stirred at reflux for 90 min. The solution was cooled to r.t., washed with water (2x1 L) and dried over MgSO4, filtered through a silica gel plug and concentrated on the rotovap to a solid. This was crystallized from toluene to give the product as an off-white solid (425 g, 84%); m.p. 166-168 °C; 1H-NMR (CDCl3): 2.28 (s, 3H), 6.9-7.05 (m, 10H), 7.2-7.5 (m, 12H), 7.9 (dd, 1H).
N-TRIPHENYLMETHYL-5-[2-(4'-BROMOMETHYLBIPHENYL)]
TETRAZOLE
To a solution of N-triphenylmethyl-5- [2-(4'-methylbiρhenyl)] tetrazole (425 g, 0.89 moles) in CCI4 (4.0 L) were added N-bromsuccinimide (159 g, 0.89 mole) and dibenzoyl peroxide (22 g, 0.089 moles). The mixture was refluxed for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a thick oil. The addition of ether (2.0 L) to this oil resulted in a clear solution. Crystallization, followed by
filtration, gave a white solid (367 g, 74%). m.p. 137-139.5°C; 1H-NMR (CDCl3): 4.38 (s, 2H), 6.9-8.0 (m, 23H).
ETHYL 3-OXOHEPTANOATE
A two liter, three neck, round bottom flask equipped with a mechanical stirrer was charged with 50 g ethyl hydrogen malonate, 875 mL dry THF, and a few milligrams of 1,10-phenanthroline as indicator, under dry nitrogen. The stirred mixture was cooled to -78°C To this was added 308 mL 2.5 M
n-butyllithium in hexanes over 30 minutes until a brown color persisted several minutes. The mixture was warmed to 0°C for -30 minutes then was cooled to -78°C again. To this was added 22.5 mL valeroyl chloride in 25 mL THF over 15 minutes. The mixture was then warmed to room temperature, stirred 15 minutes, and acidified with ~150 mL 5% HCl. The mixture was extracted 3 times with ether. The combined organic material was washed twice with saturated NaHCO3 solution and twice with brine, dried over Na2SO4, stripped of solvent in vacuo, and distilled at ~15 Torr with the title compound
distilling at 80-83°C. The title compound was isolated ss a clear oil, 21.4 g, 667. yield. Rf 0.30 in 7% EtOAc/hexane, vi suali zed by UV and ninhydrin stain; 1H-NMR (250 MHz, CDCl3): δ 4.19 (q, 2H), 3.44 (s, 2H), 2.54 (3 line m, 2H), 1.59 (m, 2H), 1.30 (m, 2H), 1.28 (t, 3H), 0.90 (t, 3H).
3-OXOHEPTANENITRILE
To a mechanically stirred solution of 14.3 g MgSO4-dried cyanoacetic acid and ~100 mg
1,10-phenanthroline in 500 mL THF at -78°C was added 60 mL 2.5 M n-butyllithium in hexanes (~one half of the total). The indicator color persisted at this point. The solution was warmed to -5° to +5°C after which the indicator color disappeared. Another 55 mL 2.5 M n-butyllithium in hexanes was added until the indicator color again persisted. The mixture was cooled to -78°C then 10.0 mL valeroyl chloride in 10 mL THF was added over 3 minutes. After 10 minutes the now yellow solution was allowed to warm to room temperature and stir for 1 hour. The mixture was poured into a solution of 50 mL concentrated HCl in 300 mL water. The mixture was extracted 3 times with ether. The combined organic material was washed twice with saturated NaHCO3 solution then once with brine. The washes were back extracted with ether and the back extracts were washed with brine. The back extracts were combined with the other organic
material and then were dried over MgSO4. The organic material was stripped of solvent in vacuo then was distilled at ~1 Torr with the title compound
distilling at 87-91°C. The title compound was isolated as a clear oil, 6.32 g, 60%, yield. To this material there was added 1%. by weight BHT to prevent polymerization. The material was also kept
refrigerated at 0°C under nitrogen. Rf 0.18 in 20% EtOAc/hexane, visualized by ninhydrin stain; 1H-NMR (300 MHz, CDCl3): δ 3.46 (s, 2H), 2.62 (3 line m, 2H), 1.61 (m, 2H), 1.35 (m, 2H), 0.92 (t, J=7.3Hz, 3H); 13C-NMR (75.4 MHz, CDCl3): δ 197.6, 113.8, 41.9, 31.9, 25.3, 22.0, 13.7.
ETHYL 2-[(2'-(N-TRIPHENYLMETHYL-TETRAZOL-5-YDBIPHEN-
4-YL)METHYL]-3-OXOHEPTANOATE
To a solution of 370 mg ethyl 3-oxoheptan- oate in 10 mL DMSO was added 86 mg 60% NaH in oil. After two minutes 600 mg N-triphenylmethyl-5-[2-(4'- bromomethylbiphenyl)]tetrazole was added all at once to the solution. After 20 minutes the solution was poured into brine and extracted 3 times with ether. The organic material was dried over MgSO4, stripped of solvent in vacuo. and MPLC'd in 10% EtOAc/hexane. The title compound was isolated as a white foam. Rf 0.30 in 20% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain; dialkylated material was observed at Rf 0.21; 1H-NMR (300 MHz, CDCl3): δ 8.19 (4 line m, 1H), 7.57 (11 line m, 2H), 7.40 (4 line m, 1H), 7.19 (m, 4H), 4.17 (4 line m, 2H), 3.79 (3 line m, 1H), 3.19 (d, J=8.3 Hz, 2H), 2.66-2.32 (m, 2H), 1.54 (m, 2H), 1.28 (m, 2H), 1.24 (3 line m, 3H), 0.88 (3 line m, 3H). Spectrum recorded after detritylation in MeOH/HCl.
2-[(2'-(N-TRIPHENYLMETHYL-TETRAZOL-5-YL)BIPHEN-4-
YL)METHYL]-3-OXOHEPTANENITRILE
To a solution of 225 mg 3-oxoheptanenitrile in 10 mL DMSO was added 144 mg 60% NaH in oil. After two minutes 500 mg N-triphenylmethyl-5-[2-(4'- bromomethylbiphenyl)]tetrazole was added all at once to the solution. After 20 minutes the solution was poured into brine and extracted 3 times with ether. The organic material was dried over MgSO4, stripped of solvent in vacuo, and MPLC'd in 15% EtOAc/hexane. The title compound was isolated as a white foam, 125 mg, 23% yield. Rf 0.23 in 20% EtOAc/hexane,
visualized by UV and ammonium molybdate/ceric sulfate stain; 1H-NMR (300 MHz, CDCl3): δ 7.93 (m, 1H), 7.47 (10 line m, 2H), 7.40-7.20 (m, 10H), 7.04 (m, 4H), 6.90 (m, 6H), 3.44 (X of ABX, 1H), 3.03 (AB of ABX,
JAB=13-8 Hz, JAX=8.6 Hz, JBX=5.3 Hz, Δv=43.5 Hz, 2H), 2.59 (sym. 12 line m, 2H), 1.55 (m, 2H), 1.28 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).
EXAMPLE 1
Ethyl 2-[(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen- 4-yl)methyl]-3-(trifluoromethanesulfonato)-2(Z)- heptenoate
The title compound is prepared by dissolving 1.0 equivalent of ethyl 2-[2'-(N-triphenyl- methyl-tetrazol-5-yl)biphen-4-yl)methyl]-3-oxoheptan- oate in THF so that the solution is -0.1-0.3 M. To this is added 1.3 equivalents of sodium hydride.
After 10 minutes a room temperature, 1.2 equivalents of trifluoromethanesulfonic anhydride is added. When the reaction is complete the mixture is neutralized with saturated NaHCO3 solution and extracted with ether. The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound. EXAMPLE 2
6-Butyl-2-methyl-5-[(2'-(N-triphenylmethyl-tetrazol-5- yl)biphen-4-yl)methyl]pyrimidin-4(3H)-one
The title compound may be prepared by dissolving 1-5 equivalents of acetamidine
hydrochloride and an equal mole-equivalent of sodium methoxide or sodium acetate in DMF. To this mixture is added 1.0 equivalent of ethyl 2-[(2'-(N-triphenyl- methyl-tetrazol-5-yl)biphen-4-yl)methyl]-3- (trifluoromethanesulfonato)-2(Z)-heptenoate. Enough DMF is used so the the solution is -0.1-1.0 M in the heptenoate compound. The mixture is either stired at RT or is heated to reflux, until complete. The mixture is poured into brine and extracted with ether. The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound.
EXAMPLE 3
6-Butyl-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl')- methyl]pyrimidin-4-(3H)-one
The title compound may be prepared by dissolving 6-butyl-2-methyl-5-[(2'-(N-triphenylmethyl- tetrazol-5-yl)biphen-4-yl)methyl]pyrimidin-4(3H)-one in methanol and adding excess concentrated HCl and stirring for 10-30 minutes. An indicator quantity of phenolphthalein is added followed by 10% NaOH
solution until pink. Excess acetic acid is added and the mixture is extracted three times with ether.
The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound. EXAMPLE 4
6-Butyl-2-methyl-5-[(2'-(tetrazol-5-yl')biphen-4-yl) methyl]-4-trifluoromethanesulfonatopyrimidine
To a solution of 1.0 equivalents of 6-butyl-2-methyl-5-[(2'-(tetrazol-5-yl)biρhen-4-yl) methyl]pyrimidine-4(3H)-one and 5.0 equivalents of 2,4,6-collidine in methylene chloride at 0°C is added 2.4 equivalents of trifluoromethanesulfonic
anhydride. When the reaction is complete, the
mixture is washed twice with saturated CuSO4
solution, dried over MgSO4, and stripped of solvent in vacuo.
EXAMPLE 5
6-Butyl-4-cyano-2-methyl-5-[(2'-(tetrazol-5-yl)biphen- 4-yl)methyl]pyrimidine
A solution of CuCN and 6-Butyl-2-methyl-5- [(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-4-trifluoromet hanesulfonatopyrimidine in pyridine is heated to give the title compound with standard brine workup.
EXAMPLE 6
6-Butyl-4-carboxy-2-methyl-5-[(2'-(tetrazol-5-yl)bi- phen-4-yl)methyl]pyrimidine
Heating 6-Butyl-4-cyano-2-methyl-5-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine with several equivalents of sodium hydroxide and excess hydrogen peroxide in methanol provides the
corresponding primary amide after workup. Treatment of this material with concentrated HCl with warming following by an neutralization and extractive workup gives the title compound. EXAMPLE 7
6-Butyl-4-methoxycarbonyl-2-methyl-5-[(2'(tetrazol-5- yl)biphen-4-yl)methyllpyrimidin
Step A: Ethyl 2-[(4-iodophenyl)methyl]-3-oxohep- tanoate
To a solution of 3.77 g (43.8 mmol) ethyl 3-oxoheptanoate in 200 mL DMSO was added 1.75 g (43.8 mmol) 65% NaH in oil. After 10 minutes, 6.5 g (21.9 mmol) α-bromo-4-iodotoluene was added. The mixture was allowed to stir for 2 hours. It was then poured into an ice/brine mixture and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgSO4, stripped of solvent in vacuo. then Still flash chromatographed in 40%
CH2Cl2/hexane to give 2.46 g of the title compound, 29% yield. Rf 0.23 in 40% CH2Cl2/hexane, visualized by UV and ninhydrin stain;
1H-NMR (300 MHz, CDCl3): δ 7.58 (m,2H), 6.93 (m, 2H), 4.14 (m,2H), 3.72 (3 line m, 1H), 3.09 (m, 2H), 2.44 (12 line m, 2H), 1.50 (m, 2H), 1.22 (m, 2H), 1.21 (3 line m, 3H), 0.86 (3 line m, 3H).
Step B: 6-Butyl-2-methyl-5-[(4-iodophenyl)methyl]
pyrimidine-4(3H)-one
A solution of 2.46 g (6.33 mmol) ethyl
2-[(4-iodophenyl)methyl]-3-oxoheptanoate, 6.0 g (63.3 mmol) acetamidine hydrochloride, 5.2 g (63.3 mmol) sodium acetate, and 84 mg (0.381 mmol) 2,6-di-tert- butyl-4-methylρhenol in 30 mL DMF was heated to 153°C for 12 hours. The cooled reaction mixture was poured into brine and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 1/65/34 AcOH/EtOAc/hexane to give 485 mg of the title compound, 20% yield. Unreacted ethyl 2-[(4- iodophenyl)methyl]-3-oxoheptanoate was recycled. Rf 0.25 in 1/65/34 AcOH/EtOAc/hexane, visualized by UV and ninhydrin stain;
1H-NMR (300 MHz, CDCl3): δ 7.56 (m, 2H), 6.98 (m, 2H), 3.83 (s, 2H), 2.54 (3 line m, 2H), 2.38 (s, 3H), 1.52 (m, 2H), 1.43 (m, 2H), 0.89 (3 line m, 3H).
Step C: 6-Butyl-4-cyano-2-methyl-5-[(4-iodophenyl)
methyl]pyrimidine
A solution of 485 mg (1.27 mmol) 6-butyl-2- methyl-5-[(4-iodophenyl)methyl]pyrimidine-4(3H)-one in 7 mL POCl3 was refluxed for 60 minutes. After cooling to room temperature, excess POCl3 was
stripped off in vacuo. The crude product was
partitioned between CH2CI2 and a mixture of brine and NaHCO3. The organic layer was removed and the aqueous layer was extracted three more times with CH2Cl2. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 10% EtOAc/hexane to give 380 mg of 6-butyl-4-chloro-2- methyl-5-[(4-iodophenyl)methyl]pyrimidine, 75% yield.
To a solution of 380 mg (0.947 mmol)
6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl]- pyrimidine in 10 mL acetone were added 0.119 mL 57% HI (0.900 mmol) and 851 mg (5.68 mmol) Nal. The mixture was warmed to 40°C for 2.5 hours. As the reaction proceeds, NaCl can be seen precipitating out of solution. The mixture was diluted with brine and saturated NaHCO3 solution. The mixture was extracted 3 times with ether. The combined organic material was dried over MgSO4 and decolorized with activated charcoal, was stripped of solvent in vacuo. then was medium pressure chromatographed on silica gel using 10% EtOAc/hexane to give 440 mg of 6-butyl-4-iodo-2- methyl-5-[(4-iodophenyl)methyl]pyrimidine, 94% yield.
A mixture of 800 mg (8.94 mmol) CuCN and 10 mL pyridine was heated to 110°C until all of the CuCN went into solution ( 7 minutes). To this mixture was added a solution of 440 mg (0.894 mmol) 6-butyl-4- iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 3 mL pyridine. After 5 minutes, the reacton mixture was cooled to room temperature, diluted with CH2CI2, filtered through powdered cellulose flock, stripped of solvent in vacuo, and was medium pressure
chromatographed on silica gel using 13%. EtOAc/hexane to give 306 mg of the title compound, 87% yield. Rf 0.29 in 15% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain;
1H-NMR (300 MHz, CDCl3): δ 7.63 (m, 2H), 6.84 (m, 2H), 4.16 (s, 2H), 2.73 (s, 3H), 2.68 (3 line m, 2H), 1.53 (m, 2H), 1.31 (m, 2H), 0.87 (3 line m, 3H).
Step D: 6-Butyl-4-methoxycarbonyl-2-methyl-5-
[(4-iodophenyl)methyl]pyrimidine
To a solution of 306 mg 6-butyl-4-cyano-2- methyl-5-[(4-iodophenyl)methyl]pyrimidine in 6 mL methanol was added 0.885 mL (~7.81 mmol) 30% H2O2 and 0.937 mL (2.34 mmol) 2.5 N NaOH. The mixture was allowed to stir for 1 hour at room temperature. To the mixture was added ~1 mL HOAc. Solvent was removed in vacuo. The crude material (409 mg) was dissolved in ~20 mL methanol. To this was added 4.0 g Amberlyst-15®. The mixture was heated to 60° for 18 hours. After cooling to room temperature, ~5 mL pyridine was added. After stirring for 1 hour, the mixture was f iltered through powdered cellulose flock, stripped of solvent in vacuo, stripped from toluene to remove remaining pyridine, then was medium pressure chromatographed on silica gel using 25% EtOAc/hexane to give 152 mg of the title compound, 46% yield. Rf 0.21 in 30% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain; 1H-NMR (300 MHz, CDCl3); δ 7.58 (m, 2H0, 6.81 (m, 2H), 4.12 (s, 2H), 3.87 (s, 3H), 2.75 (s, 3H), 2.67 (3 line m, 2H), 1.53 (m, 2H), 1.31 (m, 2H), 0.86 (3 line m, 3H).
Step E: 6-Butyl-4-methoxycarbonyl-2-methyl-5-
[(2'-tetrazol-5-yl)biphen-4-yl)methyl]- pyrimidine
To -25°C solution of 278 mg .0.717 mmol; 5-phenyl-2-triphenylmethyltetrazole in 4 mL THF was added dropwise a solution of 1.7 M tert-butyllithium in pentane until a faint red color persisted (drying process). Then 0.420 mL (0.717 mmol) of the 1.7 M tert-butyllithium in pentane was added. After 2 minutes the solution was blood red. After 25 minutes, the organolithium salt was precipitating from the THF. At this time, 0.358 mL (0.358 mmol) 1.0 M ZnCl2 in ether was added. The color changed from blood red to medium yellow and the precipitate went back into solution . The mixutre was warmed to room temperature. To the solution was added 13 mg (0.018 mmol) (Ph3P)2PdCl2 followed by 152 mg (0.358 mmol) 6-butyl-4-methoxycarbonyl-2-methyl-5-[(4- iodophenyl)methyl]pyrimidine. The mixture was refluxed for 3.25 hours then cooled to room
temperature, diluted with water and brine, and was extracted 3 times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silican gel using 30% EtOAc/hexane to give 146 mg of the trityl protected title compound, 60% yield. Rf 0.18 in 30% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain.
A solution of 146 mg of the trityl protected title compound in 4/1/1 ACOH/H2O/CH2CI2 was stirred for 6 hours at room temperature. The mixture was diluted with brine and extracted 3 times with CH2Cl2. The combined organic material was dried over MgS04, stripped of solvent in vacuo, stripped from toluene, then was Still flash chromatographed in 1/13/86 NH4OH/MeOH/CH2Cl2 to give 92 mg of the title compound, 97% yield. Rf 0.18 in 1/50/49 AcOH/EtOAc/ hexane; Rf 0.22 in 1/13/86 NH4OH/MeOH/CH2Cl2,
visualized by UV; 1H-NMR (300 MHz, CDCl3): δ 8.10 (m, 1H), 7.57 (m, 2H), 7.37 (m, 1H), 7.04 (m, 4H), 4.24 (s, 2H), 3.79 (s, 3H), 2.67 (3 line m, 2H), 2.53 (s, 3H), 1.58 (m, 2H), 1.34 (m, 2H), 0.88 (3 line m, 3H); MS (FAB) m/e 443 (M+1).
EXAMPLE 8
6-Butyl-4-carboxy-2-methyl-5-[(2'-(tetrazol-5-yl)- biphen-4-yl)methyl]pyrimidine
To a solution of 68.4 mg (0.155 mmol)
6-butyl-4-methoxycarbonyl-2-methyl-5-[(2'-(tetrazol- 5-yl)biphen-4-yl)methyl]pyrimidine in 5 mL methanol was added ~0.300 mL 10% NaOH. After stirring at room temperature for 2.5 hours, the mixture was acidified with ~0.500 mL HOAc. Volatiles were removed in vacuo, The crude material was redissolved in methanol along with a couple of drops of TFA, then was HPLC'd using the following conditions: Rainin Dynamax® C-18
column, 25 x 2.14 cm w/Guard Column; gradient of acetonitrile in water 5 to 100% over 40 minutes at 5 mL/minute; gradient held at 82% for 7 minutes. A yield of 66.1 mg (100%) of the title compound was obtained. Rf 0.14 in 1/30/69 NH4OH/MeOH/CH2Cl2, visualized by UV;
1H-NMR (300 MHz, CDCl3): δ~9.7-8.8 (v br s, 2H), 7.97 (m, 1H), 7.52 (m, 2H), 7.37 (m, 1H), 7.00 (br s, 4H), 4.51 (br s, 2H), 2.86 (3 line m, 2H), 2.75 (br s, 3H), 1.62 (m, 2H) , 1 . 36 (m , 2H) , 0 . 88 ( 3 line m , 3H ) ; MS (FAB ) m/e 429 (1+1). EXAMPLE 9
6-Butyl-6-methyl-3-[ (2 ' -(tetrazol-5-yl )biphen-4-yl )- methyl ]-4H-pyri2do [ 1, 2-a]pyrimidine-4-one
Step A : 2-Butyl-3- [ (4-iodophenyl )methyl]-6-methyl-
4H-pyrido[1,2-a]pyrimidin-4-one
A mixture of 1.59 g (4.09 mmol) ethyl 2-[(4- iodophenyl)methyl]-3-oxoheptanoate, 487 mg (4.50 mmol) 2-amino-5-methylρyridine, and 3 g PPA was heated to 160°C for 1 hour. The mixture was cooled to room temperature then NH4OH was added with
cooling. When all of the PPA had reacted, the
mixture was extracted e times with ether. The
cominbed organic material was dried over MgSO4, stripped of solvent in vacuo, then Still flash
chromatographed in 10/50/40 EtOAc/CH2Cl2/hexane to give 177 mg of the title compound, 10% yield. Rf 0.21 in 10/50/40 EtOAc/CH2Cl2/hexane, visualized by UV;
1H-NMR (300 MHz, CDCl3): δ 8.80 (s, 1H), 7.55 (m, 2H), 7.51 (s, 2H), 7.02 (m, 2H), 4.05 (s, 2H), 2.72 (3 line m, 2H), 2.40 (s, 3H), 1.61 (m, 2H), 1.39 (m, 2H), 0.91 (3 line m, 3H).
Step B: 2-Butyl-6-methyl-3-[(2'-(tetrazol-5-yl)- biphen-4-yl)methyl]-4H-pyrido[1,2-a]- pyrimidin-4-one
To -25°C solution of 318 mg (0.819 mmol) 5- phenyl-2-triphenylmethyltetrazole in 5 mL THF was added dropwise a solution of 1.7 M tert-butyllithium in pentane until a faint red color persisted (drying process). Then 0.482 mL (0.819 mmol) of the 1.7 M tert-butyllithium in pentane was added. After 2 minutes the solution was blood red. After 30
minutes, the organolithium salt was precipitating from the THF. At this time, 0.410 mL (0.410 mmol) 1.0 M ZnCl2 in ether was added. The color changed from blood red to medium yellow and the precipitate went back into solution. The mixture was warmed to room temperature. To the solution was added 14 mg (0.020 mmol) (Ph3P)2PhCl2 followed by 177 mg (0.410 mmol) 2-butyl-3-[(4-iodophenyl)methyl]-6-methyl-4H- pyrimidin-4-one. The mixture was refluxed for 4 hours then was cooled to room temperature, diluted with water and brine, and was extracted 3 times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 40%
EtOAc/hexane to give 159.4 mg of the trityl protected title compound, 56% yield. Rf 0.18 in 40%
EtOAc/hexane, visualized by UV and ammonium molybdate/ eerie sulfate stain.
To a solution of 159.4 mg of the trityl protected title compound in 5 mL methanol was added 10 drops concentrated HCl. After 30 minutes, an indicaor quantity of phenolphthalein was added and the mixture was basified with 10%. NaOH then
reacidified with HOAc. Ether was added and the mixture was dried over MgSO4. stripped of solven in vacuo, then was Still flash chromatographed in
1/12/87 NH4OH/MeOH/CH2Cl2 to give 95.7 mg of the title compound as its ammonium salt, 89% yield. Rf 0.22 in 1/13/86 NH4OH/MeOH/CH2Cl2, visualized by UV; 1H-NMR (300 MHz, CDCl3): δ 8.78 (s, 1H), 8.13 (m, 1H), 7.53 (m, 4H), 7.37 (m, 1H), 7.17 (m, 2H), 7.06 (m, 2H), ~6.1-5.0 (v br s, 4H), 4.06 (s, 2H), 2.75 (3 line m, 2H), 2.39 (s, 3H), 1.67 (m, 2H), 1.41 (m, 2H), 0.92 (3 line m, 3H); MS (FAB) m/3 451 (M+1).
EXAMPLE 10
Typical Pharmaceutical Compositions Containing a
Compound of the Invention
A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule
Ingredient Amount per capsule (mg)
6-butyl-4-carboxy-2- 50
methyl-5-[(2'-(tetrazol- 5-yl)biphen-4-yl)methyl]- pyrimidine
Lactose 149
Magnesium stearate 1
Capsule (size No. 1) 200
The 6-butyl-4-carboxy-2-methyl-5-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine
can be reduced to a No. 60 powder and the lactose and magnesium stearate can then be passed through a No. 60 blotting cloth onto the powder. The combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry gelatin capsule. B : Tablet
A typical tablet would contain 6-butyl-4- carboxy-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)- methyl]pyrimidine (25 mg), pregelatinized starch USP (82 mg), microcrystaline cellulose (82 mg) and
magnesium stearate (1 mg).
C: Combination Tablet
A typical combination tablet would contain, for example, 6-butyl-4-carboxy-2-methyl-5-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine a
diuretic such as hydrochlorothiazide and consist of hydrochlorothiazide (50 mg) pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).
D: Suppository
Typical suppository formulations for rectal administration can contain 6-butyl-4-carboxy-2-methyl- 5-[(2'- (tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol. Further, these suppository formulations can also include another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme and/or a calcium channel blocker in pharmaceutically effective amounts as described, for example, in C above.
E: Injection
A typical injectible formulation would contain 6-butyl-4-carboxy-2-methyl-5-[(2'-(tetrazol- 5-yl)biphen-4-yl)methyl]pyrimidine, sodium phosphate dibasic anhydrous (11.4 mg) benzylalcohol (0.01 ml) and water for injection (1.0 ml). Such an injectible formulation can also include a pharmaceutically effective amount of another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme inhibitor and/or a calcium channel blocker.

Claims

WHAT IS CLAIMED IS:
1. A method of treating cognitive
dysfunctions, anxiety, depression and schizaphrenia which comprises administring to a patient in need of such treatment a therapeutically effective amount of a compound having the formula:
Figure imgf000106_0001
wherein:
K is -N(R8a)-C(=M) or -N=C(R8b)-wherein M is O or
NR 22;
R1 is (a) -CO2R4,
(b) -SO3R5, (c) -NHSO2CF3,
(d) -PO(OR5)2,
(e) -SO2-NH-R9,
(f) -CONHOR5,
OH O
Figure imgf000107_0002
(g) -C--P-OR5,
Figure imgf000107_0003
R9 OR5
(h) -CN,
(i) -SO2NH-heteroaryl,
(j) -CH2SO2NH-heteroaryl,
(k) -SO2NH-CO-R23,
(l) -CH2SO2NH-CO-R23,
(m) -CONH-SO2R23,
(n) -CH2CONH-SO2R23,
(o) -NHSO2NHCO-R23,
(p) -NHCONHSO2-R23,
Figure imgf000107_0001
(t) -CONHNHSO2CF3 ,
Figure imgf000108_0001
wherein hetaroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of -OH, -SH, -C1-C4-alkyl, -C1-C4-alkoxy, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, NH(C1-C4-alkyl) and
-N(C1-C4-alkyl)2;
R2a and R2b are each independently
(a) H,
(b) halogen,
(c) NO2,
(d) NH2, (e) C1-C4-alkylamino,
(f) di-(C1-C4-alkyl)amino
(g) SO2NHR9,
(h) CF3,
(i) C1-C4-alkyl, or
(j) C1-C4-alkoxy;
R 3a is
(a) H,
(b) Cl, Br, I, F,
(c) C1-C6-alkyl,
(d) C1-C6-alkoxy,
(e) C1-C6-alkoxy-C1-C4-alkyl;
R3bi is
(a) H
(b) halo (Cl, Br, I, F)
(c) NO2,
(d) C1-C6-alkyl,
(e) C2-C6-alkanoyloxy,
(f) C3-C6-cycloalkyl,
(g) C1-C6-alkoxy,
(h) -NHSO2R4,
(i) hydroxy-C1-C4-alkyl,
(j) aryl-C1-C4-alkyl,
(k) C1-C4-alkylthio,
(l) C1-C4-alkylsulfinyl,
(m) C1-C4-alkylsulfonyl,
(n) NH2,
(o) C1-C4-alkylamino,
(p) C1-C4-dialkylamino, (q) CF3 ,
( r ) -SO2-NHR9
( s ) aryl or
(t ) furyl ; wherein aryl is phenyl or naphthyl unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, Br, I, F,
C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH, NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, C1-C4-polyfluoroalkyl, C3-C6-polyfluorocycloalkyl, -CO2-C1-C4-alkyl or *
Figure imgf000110_0001
R4 is H, C1-C6-alkyl, benzyl or phenyl;
R4 0
Figure imgf000110_0002
R5 is H, -CH-O-C-R4;
E is a single bond, -NR13(CH2)s-, -S(O)X(CH2)s- where x is 0 to 2 and s is 0 to 5, -CH(OH)-, -O-, CO-;
R6 is
(a) C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynvl each of which can be optionally substituted with a substituent selected from the group consisting of aryl as defined above, C3-C7-cycloalkyl, Cl, Br, I, F, -OH, CF3, CCI3, -NH2, -NH(C1-C4-alkyl),
-N(C1-C4-alkyl)2, -NH-SO2R4, -COOR4, -SO2NHR9, C1-C4-alkoxy, C1-C4-alkyl-S, and -CF2CF3;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl; R7 is (a) hydrogen,
(b) aryl,
(c) heteroaryl,
(d) Cl, Br, I, F,
(e) -CO2H,
(f) -CO2R4,
(g) -NH2,
(h) -NH(C1-C4-alkyl),
(i) -N(C1-C4-alkyl)2,
(j) -SO2NR9R10,
(k) -NHSO2-C1-C4-alkyl,
(l) -S(O)χ-C1-C4-alkyl,
(m) -OH,
(n) -SH,
(o) -S(O)χ-aryl,
(P) -C1-C4-alkyl or -O(C1-C4-alkyl) or
-S(C1-C4-alkyl) each of which can be substituted with aryl, heteroaryl, -OH, -NH2, -CF3. C3-C5-cycloalkyl> -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, -CO2R4 or Cl, Br, I, F,
(q) C3-C5-cycloalkyl, or
(r) -CF3; R8a is (a) aryl ,
(b) heteroaryl,
(c) C1-C4-alkyl unsubstituted or substituted with aryl, heteroaryl, -OH, -NH2, -NH(C1-C4-alkyl),
N(C1-C4-alkyl)2, -CO2H, -CO2R4 or Cl, Br, I, or F,
(d) C1-C4-alkylaryl unsubstituted or
substituted with CO2R4; or R7 and R8a when alkyls on adjacent atoms may be joined together with the atoms to which they are bound to form a pyridine ring which may be
substituted with R26 and/or R27 wherein
R26 is (a) R7
(b) -NHCO(C1-C5-alkyl)
(c) -NHCO(C3-C6-cycloalkyl),
(d) -NHCO(aryl),
(e) -NHCO(heteroaryl),
(f) -N(C1-C5-alkyl)CO(C1-C5-alkyl),
(g) -N(C1-C5-alkyl)CO(C3-C6-cycloalkyl), (h) -N(C1-C5-alkyl)CO(aryl),
(i) -N(C1-C5-alkyl)CO(heteroaryl), and R27 is C1-C4-alkyl, Cl, Br, F, I, -CF3, aryl or heteroaryl;
R8b is (a) -OH,
(b) -NH2,
(c) -NH(C1-C4-alkyl).
(d) -N(C1-C4-alkyl;2,
(e) -NHCO2-C1-C4-alkyl,
(f) -NHCO-C1-C4-alkyl,
(g) -NHSO2-C1-C4-alkyl, (h) -NHSO2-aryl,
(i) -NHSO2(C1-C4-polyfluoroalkyl),
(j) -CO2H,
(k) -CO2R4,
(l) Cl, Br, I, F,
(m) -CONHSO2-aryl,
(n) -CONHSO2-heteroaryl,
(o) -CONHSO2-C1-C4-alkyl,
(p) -CONHSO2(C1-C4~polyfluoroalkyl),
(q) -CH2OH,
(r) -CH2OCOR4,
(s) -O-C1-C4-alkyl unsubstituted or
substituted with CO2R4,
(t) -S(O)X-aryl unsubstituted or substituted with CO2R4,
(u) -S(O)X-C1-C4-alkyl unsubstituted or substituted with CO2R4.
(v) -SO2NHR25,
(w) -CN,
(x) tetrazol-5-yl;
R9 is H, C1-C5-alkyl, phenyl or benzyl;
R10 is H, C1-C4-alkyl;
R11 is H, C1-C6-alkyl, C2-C4-alkenyl, C1-C4-alkoxy alkyl, or -CH2-C6H4R20;
R12 is -CN, -NO2, -CO2R4, or -CF3;
R13 is H, C2-C4-alkanoyl, C1-C6-alkyl, allyl,
C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, C1-C8-alkyl, C1-C8-perfluoroalkyl .
C3-C6-cycloalkyl, phenyl or benzyl;
R15 is H, C1-C6-alkyl;
R16 is H, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl or benzyl; R17 i s -NR9R10 , -OR10 , -NHCONH2 , -NHCSNH2 , O O
Figure imgf000114_0001
R18 and R19 are independently C1-C4-alkyl or taken together are -(CH2)q- where q is 2 or 3; R20 is H, -N02, -NH2, -OH or -OCH3;
R21 is (a) -CO-aryl,
(b) -CO-C1-C4-alkyl,
(c) -COCF3,
(d) -CO-heteroaryl, or
(e) heteroaryl;
R22 is the same as R8a or -H;
R23 is (a) aryl,
(b) heteroaryl,
(c) C3-C7-cycloalkyl,
(d) C1-C6-alkyl unsubstituted or substituted with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH,
-C1-C4-alkyl, -O(C1-C4-alkyl),
-S(C1-C4-alkyl), -CF3, Cl, Br , F, I, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -PO3H2, or -PO(OH)(O-C1-C4-alkyl);
R25 is (a) H,
(b) C1-C4-alkyl; X is
(a) a carbon-carbon single bond,
(b) -CO-,
(c) -O-,
(d) -S-,
(e) -N-,
R 13
(f) -CON- ,
R15
(g) -NCO-,
R15
(h) -OCH2-,
(i) -CH2O-
(j) -SCH2-,
(k) -CH2S-,
(l) -NHC(R9)(R10)-,
(m) -NR9SO2-,
(n) -SO2NR9-,
(o) -C(R9)(R10)NH-,
(p) -CH=CH-,
(q) -CF=CF-,
(r) -CH=CF-,
(s) -CF=CH-,
(t) -CH2CH2-,
(υ) -CF2CF2-,
CH2 CH
(v) C
Figure imgf000115_0001
or
Figure imgf000115_0002
CH
" CH2 CH
OR14
Figure imgf000115_0003
(w) -CH-, OCOR16
Figure imgf000116_0002
(x) -CH-,
NR 17
Figure imgf000116_0003
(y) -C-, or
R18O OR 19
(z)
Figure imgf000116_0004
Z is O, NR13 or S; or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 wherein K is -N=C(R8b) of structure
Figure imgf000116_0001
3. The method of Claim 2 wherein:
R1 is -COOH; -NH-SO2CF3; -CO2R4;
Figure imgf000117_0001
-SO2NH- heteroaryl or CH2SO2NH- heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or
6-membered aromatic ring conprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl,
C1-C4-alkoxy, CF3, Cl, Br, F, I, NO2, CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and
N(C1-C4-alkyl)2; -SO2NHCOR23;-CH2SO2NHCOR23; -CONHSO2R23; -CH2CONHSO2R23; -NHSO2NHCOR23; and -NHCONHSO2R23 ;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C1-C4-alkoxy,
-COOCH3, -COOC2H5, -SO2-CH3, NH2 , -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -0- or -S-:
R6 is
(a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of CF3, CF2CF3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl and
C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl; and
X is a C-C single bond.
4. The method of Claim 3 wherein:
E is a single bond;
R2a, R2b, R3a and R3b are each H; and
X is a single bond.
5. The compound of Claim 4 which is a member of the group of compounds of Formula II and described in Table I:
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
6. The compound of Claim 1 wherein
K is -N(R8a)-CO- of structure
Figure imgf000123_0001
7. The compound of Claim 6 wherein *
R1 i s -COOH ; -NH-SO2CF3 ; CO2R4 ;
Figure imgf000123_0002
-SO2NH- heteroaryl or CH2SO2NH- heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or 6-membered aromatic ring comprising 1 to 3 heteroatoms selected from O, N and S and wherein the
substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl, C1-C4-alkoxy, CF3, Cl, Br, F, I, NO2, CO2H, CO2-C1-C4-alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2;
-SO2NHCOR23;-CH2SO2NHCOR23; -CONHSO2R23;
-CH2CONHSO2R23; -NHSO2NHCOR23; and -NHCONHSO2R23; R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C1-C4-alkoxy,
-COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -O- or -S-;
R6 is
(a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group
consisting of Cl, CF3, CF2CF3, CCI3,
-O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl and C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl;
(c) polyfluoro-C1-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be substituted with R26 and/or R27;
X is a C-C single bond.
8. The compound of Claim 7 wherein: E is a single bond;
R2a, R2b, R3a and R3b are each H; and
X is a single bond.
9. The compound of Claim 8 which is a member of the group of Formula III and described in Table 2:
Figure imgf000125_0001
Figure imgf000125_0002
Figure imgf000126_0001
10. The compound of Claim 8 whichis a member of the group of compound of Formula IV and described in Table 3:
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000128_0001
Figure imgf000129_0002
11. The compound of Claim 1 wherein K is -N(R8a)-C(=NR22)- of structure K
Figure imgf000129_0001
12. The compound of Claim 11 wherein:
R1 is -COOH; -NH-SO2CF3; CO2R4;
Figure imgf000130_0001
-SO2NH-heteroaryl or -CH2SO2NH-heteroaryl wherein the heteroaryl is an unsubstituted, monosubstituted or disubstituted 5-or 6-membered aromatic ring comprising 1 to 3 heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C1-C4-alkyl, C1-C4- alkoxy, CF3, Cl.Br, F, I, NO2,CO2H, CO2-C1-C4- alkyl, NH2, NH(C1-C4-alkyl) and N(C1-C4-alkyl)2;
-SO2NHCOR23; -CH2SO2NHCOR23; -CONHSO2R23;
-CH2CONHSO2R23; -NHSO2NHCOR23 ; and - NHCONHSO2R23;
R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or
C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C5-C6- cycloalkyl, -COOCH3, -COOC2H5, -SO2CH3;
NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3; E is a single bond, -O- or -S-; R6 is
(a) C1-C5-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of Cl, CF3, CCI3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5, phenyl, and
C3-C5-cycloalkyl;
(b) C3-C5-cycloalkyl; or
(c) polyfluoro-C1-C4-alkyl;
R7 and R8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be optionally substituted with R26 and R27; and
X is a C-C single bond.
13. The compound of Claim 12 wherein:
E is a single bond;
R2a, R2b, R3a and R3b are each H; and
X is a single bond.
14. The compound of Claim 13 which is a member of the group consisting of compounds of
Formula V and described in Table 4:
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0002
15. The compound of Claim 13 which is a member selected from the group consisting of compounds of Formula VI and described in Table 5:
Figure imgf000133_0001
Figure imgf000133_0003
Figure imgf000134_0001
Figure imgf000135_0001
16. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a
pharmaceutically effective amount of a compound of Claim 1.
17. The composition of Claim 14 which includes another antihypertensive agent selected from an angiotension converting anzyme inhibitor, a calcium channel blocker, or a β-blocker selected from the group consisting of:
amilor ide , atenolol , bendrof lumethiazide,
chlorothalidone, chlorothiazide, clonidine,
cryptenamine acetates and cryptenamide tannates, deserpidine, diazoxide, guanethidene sulfate,
hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serepentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline,
cyclothiazide, ethacrynic acid, furosemide,
merethoxylline procaine, sodium ethacrynate,
captopril, delapril hydrochloride, enalapril,
enalaprilat, fosinopril sodium, lisinopril,
pentopril, quinapril hydrochloride, ramapril,
teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, as well as admistures and combinations thereof.
18. A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of Claim 1.
19. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an
effective ocular antihypertensive amount of a
compound of Claim 1.
20. A method of treating ocular
hypertension comprising administering to a patient in need of such treatment an effective ocular
antihypertensive amount of a compound of Claim 1.
21. A method of treating cognitive dysfunction, anxiety, or depression comprising administering to a patient in need of such treatment an effective therapeutic amount of a compound of Claim 1.
PCT/US1991/001951 1990-03-30 1991-03-27 Substituted pyrimidines, pyrimidinones and pyridopyrimidines WO1991015209A1 (en)

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US5324729A (en) * 1990-03-30 1994-06-28 Merck & Co., Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
WO1994017067A1 (en) * 1993-01-22 1994-08-04 Istituto Luso Farmaco D'italia S.P.A. Pyrimidinone derivatives fused to nitrogen heterocycles having a ii antagonistic activity
US5358950A (en) * 1991-07-05 1994-10-25 Laboratoires Upsa Triazolopyrimidine derivatives which are angiotensin II receptor antagonists
US5387747A (en) * 1992-02-24 1995-02-07 Laboratoires Upsa Triazolopyrimidine derivatives which are angiotensin II receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are present
US5389660A (en) * 1989-07-03 1995-02-14 Merck & Co., Inc. Substituted imidazo-fused 5-membered ring heterocycles as angiotensin II antagonists
US5472967A (en) * 1991-02-20 1995-12-05 Synthelabo 4-pyrimidinone derivatives their preparation and their application in therapy
US5491172A (en) * 1993-05-14 1996-02-13 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents
US5496835A (en) * 1992-12-22 1996-03-05 Takeda Chemical Industries, Ltd. Heterocyclic compounds having angiotensin II antagonistic activity and use thereof
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US5633287A (en) * 1993-05-14 1997-05-27 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0407342A2 (en) * 1989-07-06 1991-01-09 Ciba-Geigy Ag Pyrimidine derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0424317A3 (en) * 1989-10-19 1991-09-25 Ciba-Geigy Ag Pyrimidines
EP0435827A3 (en) * 1989-12-28 1991-11-13 Ciba-Geigy Ag Diaza compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0407342A2 (en) * 1989-07-06 1991-01-09 Ciba-Geigy Ag Pyrimidine derivatives

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US5965592A (en) * 1990-02-19 1999-10-12 Novartis Corporation Acyl compounds
US5324729A (en) * 1990-03-30 1994-06-28 Merck & Co., Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
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US5250548A (en) * 1990-09-10 1993-10-05 Abbott Laboratories Angiotensin II receptor antagonists
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