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US3920655A - Nitroimidazolyl benzoquinazolines - Google Patents

Nitroimidazolyl benzoquinazolines Download PDF

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US3920655A
US3920655A US331114A US33111473A US3920655A US 3920655 A US3920655 A US 3920655A US 331114 A US331114 A US 331114A US 33111473 A US33111473 A US 33111473A US 3920655 A US3920655 A US 3920655A
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methyl
imidazolyl
phenyl
alkyl
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Clemens Rufer
Eberhard Schroder
Hans-Joachim Kessler
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the compounds of this invention are nitroimidazolyl pyrimidines of the general Formula I N N II II 0211 I I and physiologically acceptable salts thereof, wherein X is alkyl of 1-4 carbon atoms, R and R which can be alike or different, are a hydrogen atom, alkyl of one to four carbon atoms, phenyl, trifluoromethyl or a thienyl group, and R is a hydrogen atom, alkyl of 1-4 carbon atoms, hydroxyalkoxy of 2-4 carbon atoms, which can be esterified by alkanoic acid of l-4 carbon atoms, i.e., alkanoyloxyalkoxy, oxoalkyl, i.e., keto substituted alkyl, containing a total of 3-6 carbon atoms, or when R;
  • R is phenyl, an alkylene having l-2 carbon atoms in the chain joined to the 2-position of the phenyl ring.
  • alkyl of 1-4 carbon atoms are methyl, ethyl, n-propyl, isobutyl, etc., preferably methyl.
  • hydroxyalkoxy and esters thereof of an alkanoic acid are hydroxyethyl, 2-hydroxypropyl, 3- hydroxypropyl, acetoxyethyl, propionyloxyethyl and 3-acetoxypropy1.
  • oxoalkyl examples include acetylmethyl, acetylethyl and propionylmethyl.
  • physiologically acceptable acids which can be employed to form the acid addition of salts of this invention are inorganic acids, e.g., hydrochloric acid, sulfuric acid, etc., and organic mono-, diand tricarboxylic acids, e.g., acetic acid, propionic acid, lactic acid, citric acid, benzoic acid, succinic acid, heptagluconic acid, etc.
  • inorganic acids e.g., hydrochloric acid, sulfuric acid, etc.
  • organic mono-, diand tricarboxylic acids e.g., acetic acid, propionic acid, lactic acid, citric acid, benzoic acid, succinic acid, heptagluconic acid, etc.
  • the exact nature of the acid is not critical, so long as it forms a physiologically acceptable acid addition salt.
  • novel compounds of this invention can be produced in a conventional manner, for example, by reacting an amidine of the general Formula II N NH 1 l -c 11 OZN N wherein X has the values given above, or a salt thereof, preferably the hydrochloride.
  • R R and R have the values given above, or a reactive functional derivative thereof, and subsequently saponifying any acyloxy groups present in' the condensation product to hydroxy groups, or esterifying free hydroxy groups, and optionally converting the compounds into the salts thereof with inorganic or organic acids.
  • Suitable derivatives of the dicarbonyl compound are reactive derivatives such as, for example, the acetal or, if R and R both are H, an enamine.
  • reaction of the amidine (II) and/or the salt thereof, the latter optionally mixed with ammonium chloride, with the B-dicarbonyl compounds or the derivatives thereof can be effected in the absence or in the presence of a solvent, e.g., acetic acid, acetic anhydride, dimethylformamide, alcohol, to which can be Minimum inhibitory Concentration Against Trichomonas Vaginalis Compound g/ml.)
  • a solvent e.g., acetic acid, acetic anhydride, dimethylformamide, alcohol
  • Thenovel compounds can be administered topically or systemically in the pharmaceutically customary forms of application, such as pills, dragees, capsules,
  • PREPARATION 9.9 g. (50 millimoles) of the ethyl ester of S-nitro-lmethyl-2-imidazolyl-iminocarboxylic acid and 2.7 g. (50 millimoles) of pulverized ammonium chloride are boiled for 72 hours in methanol. After evaporation of the solvent, the residue is digested in the hot state with 100 ml. of ethyl acetate; yield: 6.1 g. (47% of theory) of an equimolar mixture of 5-nitro-l-methyl-2-imidazolylcarboxamidinium chloride and ammonium chloride; m.p. 225-227 C.
  • EXAMPLE 1 4,6-Dimethyl-2-( 5 -nitrol -methyl-2-imidazolyl pyrimidine 0.52 g. (2 millimoles) of an equimolar mixture of 5- nitro-l -methyl-2-imidazolyl-carboxamidinium chloride and ammonium chloride, 0.21 g. (2.1 millilmoles) of acetylacetone, and 0.33 g. of anhydrous sodium acetate are boiled in 4 ml. of acetic acid for 2 hours. Thereafter, the reaction mixture is concentrated to dryness, the residue is triturated with water, and recrystallized from isopropanol. Yield: 0.32 g. (69% of theory), m.p. l48l 50 C.
  • EXAMPLE 3 5-( 2-Acetoxyethoxy)-2-( 5-nitrol -methyl-2- imidazolyl )-pyrimidine
  • the compound is obtained analogously to Example 1 with 3-dimethylamino-2(2-hydroxyethoxy)-acrolein; in this process, acetic anhydride can also be employed in place of acetic acid.
  • acetic anhydride can also be employed in place of acetic acid.
  • the residue is mixed with water, the product is extracted with ethyl acetate, and the residue of the ethyl acetate extract is triturated with methanol; m.p. l48l50 C.
  • EXAMPLE 5 5-( 2-Hydroxyethoxy)-2-( S-nitrol -methyl-2- imidazolyl)-pyrimidine Hydrochloride 0.78 g. (5 millimoles) of 3-dimethylamino-2-(2- hydroxyethoxy)-acrolein and 1.3 g. (5 millimoles) of an equimolar mixture of S-nitro-l-methyl-2-imidazolylcarboxamidinium chloride and ammonium chloride are added to 5 ml. of 1N sodium methylate solution in methanol. After refluxing for 20 hours, the methanol is distilled off, the residue is maintained at C. for 30 minutes, and mixed with water.
  • the product is extracted with ethyl acetate, the ethyl acetate is concentrated, and the residue is digested with isopropanol.
  • the thus-obtained free base is converted, with methanolic hydrochloric acid, into the hydrochloride, m.p. l58l60 C.
  • the same product is obtained by heating equimolar amounts of S-nitro-l-methyl-Z-imidazolyl-carboxamidine and 3-dimethylamino-2-(2-hydroxyethoxy)- acrolein in dimethylformamide or without solvent and converting the mixture thus obtained optionally after removing the solvent by evaporation into the hydrochloride.
  • EXAMPLE 6 5-( 2-Acetoxyethoxy )-2-( S-nitrol -methyl-2- imidazolyl )-pyrimidine 0.29 g. (l millimole) of 5-(2-hydroxyethoxy)-2-(5- nitro-l -methyl-2-imidazolyl)-pyrimidine hydrochloride means of preparative layer chromatography; m.p. 1 C. (from ethyl acetate).
  • EXAMPLE 8 4,6-Dimethyl-5-( Z-acetylethyl )-2-( 5-nitrol -methyl-2- imidazolyl )-pyrimidine
  • the compound is obtained analogously to Example 7 with 3-acetyl-2,6-heptanedione; m.p. 142 C. (from ethyl acetate).
  • EXAMPLE 10 4-Trifluoromethyl-2-( S-nitro- 1 -methyl-2-imidazolyl 6-(2-thienyl)-pyrimidine The compound is obtained in accordance with Example 7 with l-thenoyl-3,3,3-trifluoroacetone. Purification is effected by recrystallization from ethyl acetate; m.p. 188 C.
  • EXAMPLE 11 4-Methyl-6-phenyl-2-(S-nitro-1-methyl-2'imidazolyl)- pyrimidine The compound is obtained in analogy to Example 7 with Z-acetylacetophenone. The product is purified by recrystallization from ethyl acetate; m.p. C.
  • X is methyl.

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Abstract

Nitroimidazolyl pyrimidines of the formula

AND PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF WHEREIN X is alkyl of 1-4 carbon atoms, R1 and R2 each are a hydrogen atom, alkyl of 1-4 carbon atoms, phenyl, trifluoromethyl or a monocyclic heterocyclic ring and R3 is a hydrogen atom, alkyl of 1-4 carbon atoms, hydroxyalkoxy of 2-4 carbon atoms or an ester thereof of an alkanecarboxylic acid of 1-4 carbon atoms, oxoalkyl of 3-6 carbon atoms, or, when R1 or R2 is phenyl, alkylene having 1-2 carbon atoms in the chain joined to the 2position of the phenyl ring possess trichomonacidal activity.

Description

United States Patent 1191 Rufer et a].
[ Nov. 18, 1975 NITROIMIDAZOLYL BENZOQUINAZOLINES [75] Inventors: Clemens Rufer; Eberhard Schriider;
Hans-Joachim Kessler, all of Berlin, Germany [73] Assignee: Schering Aktiengesellschaft, Berlin and Bergkamen, Germany 22 Filed: Feb. 9, 1973 [211 App]. No.2 331,114
'[30 Foreign Application Priority Data Feb. 19, 1972 Germany 2208518 Nov. 7, 1972 Germany 2255079 52 us. 01 ..260 2's6.4 Q; 260/2564 c; v I 2 60/256.4 424/251 51 int. cm C07D 403/04 58 Field of Search 260/2564 Q, 256.4 R
Primary Examiner.lames A. Patten Attorney, Agent, or Firm-Millen, Raptes & White [57] ABSTRACT Nitroimidazolyl pyrimidines of the formula 1 N II I O'2N IFHN R3 1 X B2 carbon atoms, oxoalkyl of 36 carbon atoms, or, when R or R is phenyl, alkylene having 1-2 carbon atoms in the chain joined to the 2-position of the phenyl ring possess trichomonacidal activity.
5 Claims, No Drawings NITROIMIDAZOLYL BENZOQUINAZOLINES BACKGROUND OF THE INVENTION The effectiveness of nitroimidazoles against trichomonads has been known since the discovery of the antibiotic azomycin (2-nitroimidazole, S. Nakamura and H. Umezawa, J. Antibiotics (Tokyo), 9 A, 66 [1955]). However, this compound and other 2-nitroimidazoles proved to be no more effective in vitro than metronidazole (-nitro-2-methyl-1-(2-hydroxyethyl)-imidazo1e), G. C. Lancini, E. Lazzari, R. Pallanea, Il Farmaco Ed Sc. 21, 278 [1966]) and the ED and LD -values were considerably less favorable (E. Grunberg, E. Titsworth, Antimicrobial Agents and Chemotherapy, 1965, 1966, 478). Only from the S-nitroimidazoles evolved the best among a large number of synthesized compounds, viz., the commercial preparation metronidazole (C. Cosar, "Arzneimittelforschung, 16, 23 [1966]). See also French Pat. No. 1,212,028 which has a minimum inhibitory concentration of 2.5 'y/ml. against Trichomonas vaginalis.
It has now been discovered that the known l-substituted 5-nitro-2-imidazolyl-iminocarboxylic acid esters can be reacted with ammonia or ammonium salts to produce novel l-substituted 5-nitro-2-imidazolylcarboxamidines, which also have trichomonacidal activity, which compounds can then be reacted with B- dicarbonyl compounds and/or the derivatives thereof to produce 2-(5-nitro-2-imidazolyl)-pyrimidines, which are more effective than metronidazole in trichomonacidal activity.
SUMMARY OF THE INVENTION The compounds of this invention are nitroimidazolyl pyrimidines of the general Formula I N N II II 0211 I I and physiologically acceptable salts thereof, wherein X is alkyl of 1-4 carbon atoms, R and R which can be alike or different, are a hydrogen atom, alkyl of one to four carbon atoms, phenyl, trifluoromethyl or a thienyl group, and R is a hydrogen atom, alkyl of 1-4 carbon atoms, hydroxyalkoxy of 2-4 carbon atoms, which can be esterified by alkanoic acid of l-4 carbon atoms, i.e., alkanoyloxyalkoxy, oxoalkyl, i.e., keto substituted alkyl, containing a total of 3-6 carbon atoms, or when R;
or R is phenyl, an alkylene having l-2 carbon atoms in the chain joined to the 2-position of the phenyl ring.
DETAILED DISCUSSION Examples of alkyl of 1-4 carbon atoms are methyl, ethyl, n-propyl, isobutyl, etc., preferably methyl.
Examples of hydroxyalkoxy and esters thereof of an alkanoic acid are hydroxyethyl, 2-hydroxypropyl, 3- hydroxypropyl, acetoxyethyl, propionyloxyethyl and 3-acetoxypropy1.
Examples of oxoalkyl are acetylmethyl, acetylethyl and propionylmethyl.
0 ene joined thereto, especially those wherein X is methyl.
Examples of physiologically acceptable acids which can be employed to form the acid addition of salts of this invention are inorganic acids, e.g., hydrochloric acid, sulfuric acid, etc., and organic mono-, diand tricarboxylic acids, e.g., acetic acid, propionic acid, lactic acid, citric acid, benzoic acid, succinic acid, heptagluconic acid, etc. The exact nature of the acid is not critical, so long as it forms a physiologically acceptable acid addition salt.
The novel compounds of this invention can be produced in a conventional manner, for example, by reacting an amidine of the general Formula II N NH 1 l -c 11 OZN N wherein X has the values given above, or a salt thereof, preferably the hydrochloride.
with a B-dicarbonyl compound of the general Formula 111 wherein R R and R have the values given above, or a reactive functional derivative thereof, and subsequently saponifying any acyloxy groups present in' the condensation product to hydroxy groups, or esterifying free hydroxy groups, and optionally converting the compounds into the salts thereof with inorganic or organic acids.
Suitable derivatives of the dicarbonyl compound are reactive derivatives such as, for example, the acetal or, if R and R both are H, an enamine.
The reaction of the amidine (II) and/or the salt thereof, the latter optionally mixed with ammonium chloride, with the B-dicarbonyl compounds or the derivatives thereof can be effected in the absence or in the presence of a solvent, e.g., acetic acid, acetic anhydride, dimethylformamide, alcohol, to which can be Minimum inhibitory Concentration Against Trichomonas Vaginalis Compound g/ml.)
.4',6-Dimethyl-2-(S-nitro-l-methyl-2- imidazolyl)-pyrimidine 0.4 2-(5-Nitro-l-methyl-2-imidazolyl)- 4-methyl-5 ,6-dihydrobenzo[ h ]quinazoline 0. l 4-Trifluoromethyl-2-( S-nitrol -methyl- Z-imidazolyl)-6-(2-thienyl)-pyrimidine 0.2 4-M ethyl-6-phenyl-2-( S-nitro- 1 -methyl- 2-imidazolyl)-pyrimidine 0.2 Metronidazole (in own test) 1.6
Thenovel compounds can be administered topically or systemically in the pharmaceutically customary forms of application, such as pills, dragees, capsules,
, N NH I IV 0 on wherein X has the values given above and R is alkyl of l-4 carbon atoms, with ammonia or an ammonium salt analogously to the preparation below.
Without further elaboration, it is believed that one skilled in the art cam-using the preceding description,
vutilize {the present invention to its fullest extent. The
following preferred specific embodiments are, therefore,,to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
PREPARATION 9.9 g. (50 millimoles) of the ethyl ester of S-nitro-lmethyl-2-imidazolyl-iminocarboxylic acid and 2.7 g. (50 millimoles) of pulverized ammonium chloride are boiled for 72 hours in methanol. After evaporation of the solvent, the residue is digested in the hot state with 100 ml. of ethyl acetate; yield: 6.1 g. (47% of theory) of an equimolar mixture of 5-nitro-l-methyl-2-imidazolylcarboxamidinium chloride and ammonium chloride; m.p. 225-227 C.
0.52 g. (2 millimoles) of this mixture and 0.55 g. (4 millimoles) of potassium carbonate are agitated in ml. ofacetone for 48 hours to give the free amidine, 5- nitro-l-methyl-2-imidazo'lyl-carboxamidine. After filtration, the filtrate is concentrated and the remaining free amidine is recrystallized from ethyl acetate. Yield: 0.14 g. 40% of theory, m.p. l44l46 C.
EXAMPLE 1 4,6-Dimethyl-2-( 5 -nitrol -methyl-2-imidazolyl pyrimidine 0.52 g. (2 millimoles) of an equimolar mixture of 5- nitro-l -methyl-2-imidazolyl-carboxamidinium chloride and ammonium chloride, 0.21 g. (2.1 millilmoles) of acetylacetone, and 0.33 g. of anhydrous sodium acetate are boiled in 4 ml. of acetic acid for 2 hours. Thereafter, the reaction mixture is concentrated to dryness, the residue is triturated with water, and recrystallized from isopropanol. Yield: 0.32 g. (69% of theory), m.p. l48l 50 C.
EXAMPLE 2 2-( S-Nitrol-methyl-2-imidazolyl)-pyrimidine The compound is obtained analogously to Example 1 with malonic dialdehyde tetraethylacetal', m.p. 194l96 C.
EXAMPLE 3 5-( 2-Acetoxyethoxy)-2-( 5-nitrol -methyl-2- imidazolyl )-pyrimidine The compound is obtained analogously to Example 1 with 3-dimethylamino-2(2-hydroxyethoxy)-acrolein; in this process, acetic anhydride can also be employed in place of acetic acid. After concentration of the reaction solution, the residue is mixed with water, the product is extracted with ethyl acetate, and the residue of the ethyl acetate extract is triturated with methanol; m.p. l48l50 C.
EXAMPLE 4 5-( 2-Hydroxyethoxy)-2-( S-nitrol -methyl-2- imidazolyl)-pyrimidine Hydrochloride 0.2 g. of 5-(2-acetoxyethoxy)-2-(S-nitro-l-methyl-2- imidazolyl)-pyrimidine is refluxed in 5 ml. of ethanol with 2.5 ml. of concentrated hydrochloric acid. After concentration under vacuum, the residue is recrystallized from ethyl acetate; m.p. l58l60 C.
EXAMPLE 5 5-( 2-Hydroxyethoxy)-2-( S-nitrol -methyl-2- imidazolyl)-pyrimidine Hydrochloride 0.78 g. (5 millimoles) of 3-dimethylamino-2-(2- hydroxyethoxy)-acrolein and 1.3 g. (5 millimoles) of an equimolar mixture of S-nitro-l-methyl-2-imidazolylcarboxamidinium chloride and ammonium chloride are added to 5 ml. of 1N sodium methylate solution in methanol. After refluxing for 20 hours, the methanol is distilled off, the residue is maintained at C. for 30 minutes, and mixed with water. The product is extracted with ethyl acetate, the ethyl acetate is concentrated, and the residue is digested with isopropanol. The thus-obtained free base is converted, with methanolic hydrochloric acid, into the hydrochloride, m.p. l58l60 C.
The same product is obtained by heating equimolar amounts of S-nitro-l-methyl-Z-imidazolyl-carboxamidine and 3-dimethylamino-2-(2-hydroxyethoxy)- acrolein in dimethylformamide or without solvent and converting the mixture thus obtained optionally after removing the solvent by evaporation into the hydrochloride.
EXAMPLE 6 5-( 2-Acetoxyethoxy )-2-( S-nitrol -methyl-2- imidazolyl )-pyrimidine 0.29 g. (l millimole) of 5-(2-hydroxyethoxy)-2-(5- nitro-l -methyl-2-imidazolyl)-pyrimidine hydrochloride means of preparative layer chromatography; m.p. 1 C. (from ethyl acetate).
EXAMPLE 8 4,6-Dimethyl-5-( Z-acetylethyl )-2-( 5-nitrol -methyl-2- imidazolyl )-pyrimidine The compound is obtained analogously to Example 7 with 3-acetyl-2,6-heptanedione; m.p. 142 C. (from ethyl acetate).
EXAMPLE 9 2-( S-Nitrol -methyl-2-imidazolyl)-4-methyl-5 ,6-dihydrobenzo[h ]quinazoline The compound is produced analogously to Example 7 with Z-acetyI-I-tetralone; m.p. 147 C. (from i sopropanol).
EXAMPLE 10 4-Trifluoromethyl-2-( S-nitro- 1 -methyl-2-imidazolyl 6-(2-thienyl)-pyrimidine The compound is obtained in accordance with Example 7 with l-thenoyl-3,3,3-trifluoroacetone. Purification is effected by recrystallization from ethyl acetate; m.p. 188 C.
EXAMPLE 11 4-Methyl-6-phenyl-2-(S-nitro-1-methyl-2'imidazolyl)- pyrimidine The compound is obtained in analogy to Example 7 with Z-acetylacetophenone. The product is purified by recrystallization from ethyl acetate; m.p. C.
The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this vinvention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
What is claimed is:
1. A compound of the formula and physiologically acceptable acid addition salts thereof wherein X is alkyl of 1-4 carbon atoms, R is a hydrogen atom, alkyl of 1-4 carbon atoms, phenyl or trifluoromethyl, R is phenyl and R is CH or -CH CH joined to the 2-position of the phenyl 2 A compound of claim 1, wherein X is methyl.
3. A compound of claim 1, wherein R is H or CH;,.
4. A compound of claim 3, wherein X is CH 5. The compound of claim 1, 2-(5-nitro-l-methyl-2-

Claims (5)

1. A COMPOUND OF THE FORMULA
2. A compound of claim 1, wherein X is methyl.
3. A compound of claim 1, wherein R1 is H or CH3.
4. A compound of claim 3, wherein X is CH3.
5. The compound of claim 1, 2-(5-nitro-1-methyl-2-imidazolyl)-4-methyl-5,6-dihydrobenzo(h)quinazoline.
US331114A 1972-02-19 1973-02-09 Nitroimidazolyl benzoquinazolines Expired - Lifetime US3920655A (en)

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DE19722208518 DE2208518A1 (en) 1972-02-19 1972-02-19 Nitro imidazolylpyrimidines - as anti protozoal agents
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4055642A (en) * 1975-05-12 1977-10-25 Sandoz Ltd. Imidazolyl-2-quinazoline derivatives
US4256887A (en) * 1978-04-06 1981-03-17 Merck & Co., Inc. 1,2,4-Triazoles and a method for their preparation
US4323570A (en) * 1978-11-15 1982-04-06 Beiersdorf Aktiengesellschaft Substituted aminopyrimidines
US4434167A (en) 1979-11-07 1984-02-28 Beiersdorf Aktiengesellschaft Pyrimidyl thioureas useful for the treatment of hypertension and hyperlipidemia
US4769378A (en) * 1986-03-31 1988-09-06 Eli Lilly And Company Indenopyrimidine aromatase inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1920635C3 (en) * 1969-04-19 1979-06-28 Schering Ag, 1000 Berlin Und 4619 Bergkamen 2- (1-methyl-5-nitro-2-imidazolyl) benzimidazoles
IT1043840B (en) * 1971-05-08 1980-02-29 Poli Ind Chimica Spa PYRIMIDINES 2 5 REPLACED AND PROCESS FOR THEIR PREPARATION

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4055642A (en) * 1975-05-12 1977-10-25 Sandoz Ltd. Imidazolyl-2-quinazoline derivatives
US4256887A (en) * 1978-04-06 1981-03-17 Merck & Co., Inc. 1,2,4-Triazoles and a method for their preparation
US4323570A (en) * 1978-11-15 1982-04-06 Beiersdorf Aktiengesellschaft Substituted aminopyrimidines
US4434167A (en) 1979-11-07 1984-02-28 Beiersdorf Aktiengesellschaft Pyrimidyl thioureas useful for the treatment of hypertension and hyperlipidemia
US4769378A (en) * 1986-03-31 1988-09-06 Eli Lilly And Company Indenopyrimidine aromatase inhibitors

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