AU612470B2 - Novel benzimidazol(1,2-c)quinazolines, their preparation and their use - Google Patents

Novel benzimidazol(1,2-c)quinazolines, their preparation and their use Download PDF

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AU612470B2
AU612470B2 AU30932/89A AU3093289A AU612470B2 AU 612470 B2 AU612470 B2 AU 612470B2 AU 30932/89 A AU30932/89 A AU 30932/89A AU 3093289 A AU3093289 A AU 3093289A AU 612470 B2 AU612470 B2 AU 612470B2
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yield
quinazoline
acid
benzimidazo
benzimidazole
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AU3093289A (en
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Jose Maria Castellano Berlanga
Miguel Fernandez Brana
Maria Del Carmen Redondo Gonzalez
Gerhard Keilhauer
Erich Schlick
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Abbott GmbH and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

L I-1 I 61247 0, COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: v Int. Class Name of Applicant: Address of Applicant: '4 4 KNOLL AKTIENGESELLSCHAFT 6700 Ludwigshafen, Federal Republic of Germany MIGUEL FERNANDEZ BRANA, JOSE MARIA CASTELLANO BERLANGA, MARIA DEL CARMEN REDONDO GONZALEZ, ERICH SCHLICK and GERHARD KEILHAUER Actual Inventor: EDWD. WATERS SONS, Address for ervice 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: NOVEL BENZIMIDAZOL[1,2-c]QUINAZOLINES, THEIR PREPARATION AND THEIR USE The following statement is a full description of this invention, including the best method of performing it known to US company ana Signatures of MOO 7 by 033/ Its Artlaes of Associatioln.
6 L' S Louis 'ebhardt Registered Patent Attorney c--f
~L
L
O.Z. 0480/01046 Novel benzimidazo[l,2-clauinazolines, their preparation and their use The present invention relates to novel benzimidazo[1,2-c]quinazolines, processes for their preparation and their use in drugs having antitumor and antiviral properties.
Some benzimidazo[l,2-c]quinazolines are known (cf. Heterocyclic Chem. 3 (1966), 289, ibid. 10 (1973), Ukr. Klim. Zh 45 (1979), 225, Acta Ciencia Indica [Ser.] Chem. 10 (1984), 178, Aust. J. Chem. 38 (1985), 1685, Acta Pharm. Yugosl. 36 (1986), 281). However, these compounds have not been described as having an antitumor or antiviral action.
We have found that benzimidazo[l,2-c]quinazolines 15 of the formula I a o0 00 00 0 0 D 0 0o 0 0 0 0 0 X N 4x14_
Y
x 1z where X and Y are identical or different and are each o0 "o C-C 4 -alkyl, nitro, amino, hydroxyl, Cl-C 4 -hydroxyalkyl, °o0 o cyano, C-C4-alkoxy, C-C 4 -alkoxycarbonyl, carbamyl, C-C 4 020 haloalkyl, C-C 4 -trihaloalkyl or halogen and Z is a dialkyl-aminoalkyl, cycloalkylideneaminoalkyl, dialkylaminoalkylideneamino or cycloalkylideneamino-alkylideneamino group, each of which has not more than 4 carbon atoms in the alkyl or alkyl-idene groups and 2 to 5 carbon atoms in the cycloalkyl-idene groups, and their salts with physiologically tolerated acids have an advantageous action.
Preferred compounds are those in which X and Y are each amino or nitro and the alkyl or alkylidene groups in Z have not more than 2 carbon atoms, and those whose cycloalkylideneamino group is a pyrrolidine radical.
Suitable physiologically tolerated acids for salt formation are organic and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic respect of the invention the subject of the application.
DECLARED atLudwi.gshafen.- this 2 d day of Feb 19 i II 2 O.Z. 0480/01046 acid, citric acid, oxalic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, ascorbic acid, malic acid, methanesulfonic acid, isethionic acid, lactic acid, gluconic acid, glucuronic acid, amidosulfonic acid, benzoic acid, tartaric acid and pamoaic acid.
The novel compound may be in the solvated form.
Such forms may be produced, for example, with water or ethanol.
The novel compounds are prepared by a method in which a) where Z is dialkylaminoalkyl, a) water is eliminated from a compound of the formula
II
I 4 4 4 e 4 r a a o I O B) 4 4 fl I o 4444 olor a s e 4 o 16 o I 4 4
N
X-f I H ."-NM-co-(CH 2
-R
where X and Y have the stated meanings, R is di-Ci-C 4 alkylamino or cyclo-C 2
-C
5 -alkylideneamino and n is 1, 2, 3 or 4, or B) a compound of the formula III M CHZ -Hal m
III
where m is 1, 2, 3 or 4, is reacted with a di-Cl-C 4 alkylamine or cyclo-C 2
-C
5 -alkylideneamine, or b) where Z is dialkylaminoalkylideneamino or cycloalkylideneaminoalkylideneamino, a compound of the formula
IV
IV
SH
where X and Y have the stated meanings, is reacted with a dialkylaminoalkylidenediamine or cycloalkylideneaminoalkylideneamine, and, if required, the resulting 3 O.Z. 0480/01046 compound is then converted into its salts with physiologically tolerated acids.
The reaction according to a) a) is advantageously carried out with the aid of an inorganic acid halide in the presence of a base at room temperature or elevated temperatures, advantageously in the presence of a solvent.
The reaction a) B) is effected by adding the dialkylamine to the halogen compound III. The same applies to the reaction according to except that it is advantageously carried out at elevated temperatures.
The starting materials required for the reactions are known and can be prepared as described in the experimental part under I.
15 The novel compounds are suitable for the treatment of hard tumors, such as carcinomas in the breast, ooo lung, colon and kidney area, and of acute and chronic S° leukemia and viral disorders.
The novel compounds can be administered orally or parenterally in a conventional manner. They can be used 0* in the conventional solid or liquid pharmaceutical forms, 0 00 o0 0o for example as tablets, film tablets, capsules, granules, 0 0 coated tablets or solutions. These are prepared in a 00 00 0 conventional manner and to do so the active compounds are mixed with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents and/or antioxidants (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms thus obtained normally contain the active compound in an amount of from 10 to by weight.
EXAMPLES
I. Preparation of the starting materials A. For process a) a): la. A solution of 5.3 g (0.047 mole) of chloroacetyl -Il~iLI 4 O.Z. 0480/01046 chloride in 10 ml of chloroform was added dropwise to a stirred suspension of 10 g (0.047 mole) of 2- (2-amino-phenyl)-benzimidazole in 125 ml of chloroform. The mixture was stirred for 3 hours at room temperature. The resulting precipitate was filtered off, washed with a 5% strength sodium bicarbonate solution and recrystallized from ethanol.
g of 2-(2-chloroacetamidophenyl)-benzimidazole of melting point 170 0 C were obtained.
The following were prepared in a similar manner: lb. 2-(2-chloroacetimido-5-methylphenyl)-benzimidazole, yield: 30%, mp. 315°C (ethanol) ic. 2-[2-(3-chloropropionamido)-phenyl]-benzimidazole, yield 67%, mp. 170-173 0 C (ethanol) S 15 Id. 2-[2-(3-chloropropionamido)-methylphenyl]-benzimidazole, 4 yield 64%, mp. 174°C (ethanol) le. 2-[2-(2-chloroacetamido)-5-chlorophenyl)-benzimidazole yield 55%, mp. 260-262°C (dimethylformamide/water) Sif. 2-[2-(3-chloropropionamido)-5-chlorophenyl]- 4 benzimidazole, yield 75%, mp. 233-235°C S' ig. 2-[2-(4-chlorobutyramido)-5-chlorophenyl]-benzimidazole, yield 50%, mp. 156-158°C (ethanol/water) lh. 2-[2-(3-chloropropionamido)-phenyl]-benzimidazole, yield 60%, mp. 229-230°C (ethanol/water) li. 2-[2-(3-chloropropionamido)-4-nitrophenyl]-benzimid-azole, yield 79%, mp. 204-206 0 C (acetone) lj. 2-[2-(4-chlorobutyramido)-4-nitrophenyl)-benzimidazole, yield 57%, mp. 161-163 0 C (acetone).
2a. A mixture of 3 g (0.01 mole) of ic and 30 ml of dimethylamine (40% strength aqueous solution) was stirred for 24 hours at room temperature. Excess LI-- "--C-FiDa~ 5 O.Z. 0480/01046 amine was stripped off under reduced pressure and water was added to the residue, a precipitate being formed. This was filtered off under suction and recrystallized from toluene/cyclohexane. 3 g (97%) of 2-[2-(3-dimethylaminopropionamido)-phenyl]benzimidazole of melting point 162-163 0 C were obtained.
The following were prepared similarly: 2b. 2-[2-(3-dinethylaminopropionamido)-5-methyiphenyl]benzimidazole, yield 51%, mp. 233-235'C (ethanol) 2c. 2-[2-(2-dimethylaminoacetamido)-5-chlorophenyl]benzimidazole,
T!
yield 52%, np. 223-225 0 C (ethanol) 2d. 2-[2-(3-dimethylaminopropionamido)-5-chlorophenyl]benzimidazole, yield 71%, mp. 180-182'C (dimethylf ormamide/water) 2e. 2- 3-dimethylaminopropionamido) -4-chlorophenyl] benzimidazole, yield 60%, mp. 194 0 C (ethanol/water) 2f. 3-dimethylaminopropionamido)-4-nitrophenyl]benzimidazole, yield 74%, mp. 210-212 0 C (dimethylformamide/water) 2g. 2-[2-(4-dimethylaminobutyramido)-4-nitrophenyl]benzimidazole, yield 64%, np. 250 0 C (acetone) 3a. A mixture of 2.28 g (0.0073 mole) of Id, 15 ml of ethanol and 3 ml of pyridine was refluxed for 4 hours. The reaction mixture was cooled and left to stand overnight, after which 1.2 g of 2-[2benzimidazole had been precipitated in the form of white crystals. Mp. 120-122 0 C (ethanol).
3b. 2-[2-[2-(l-pyrrolidinyl)-acetamido]-5-chlorophenyl]-benzimidazole, yield 50%, np. 200-202aC (ethanol) 3c. 2-[2-[2-(1-pyrrolidinyl)-propionamido)--chloro- 6 O.Z. 0480/01046 phenyl]-benzimidazole, yield 81%, mp. 184-186 0 C (ethanol).
B. For process a) B) A mixture of 6.4 g (0.022 mole) of la and 0.5 g of sulfuric acid in 150 ml of toluene was refluxed for hours, the water formed being distilled off azeotropically. After the mixture had cooled, the solvent was stripped off under reduced pressure. After the addition of 50 ml of chloroform, the mixture was filtered and the solid residue was recrystallized from toluene/petroleum ether. 7.1 g of 6-chloromethylbenzimidazo[1,2-c]quinazoline of melting point 224-225°C were obtained.
C. For process b): 4a. A mixture of 3.1 g (0.0147 mole) of 2-(2-aminophenyl)-benzimidazole, 1.5 g (0.026 mole) of carbon disulfide, 50 ml of ethanol and 1 g of potassium hydroxide in 6 ml of water was refluxed for 3 hours in a water bath. Excess carbon disulfide and ethanol were stripped off under reduced pressure, and the residue was washed with acetic acid and recrystal- °o lized from ethanol. 2 g of 6-mercaptobenzimidazo[1,2-c]-quinazoline of melting point S 303-305°C were obtained.
The following were prepared similarly: 4b. 2-methyl-6-mercaptobenzimidazo[l,2-c]quinazoline, yield 46%, mp. 321-323 0 C (ethanol) 4c. 2-chloro-6-mercaptobenzimidazo[l,2-c]quinazoline, yield 45%, mp. 322-324°C (dimethylformamide/water) 4d. 3-chloro-6-mercaptobenzimidazo[1,2-c]quinazoline, yield 57%, mp. 350°C (dimethylformamide/water) 4e. 3-nitro-6-mercaptobenzimidazo[l,2-c]quinazoline, yield 48%, mp. 350C (dimethylformamide/water) II. Preparation of the end products EXAMPLE 1 11.52 g (0.096 mole) of thionyl chloride were added dropwise to a stirred solution of 2.5 g (0.008 i 7 O.Z. 0480/01046 mole) of 3-dimethylaminopropionamido)-phenyl]benzimidazole (2a) and pyridine in 43 ml of alcohol-free chloroform. After stirring had been carried out for 24 hours, the solvent was stripped off under reduced pressure and the residue was washed with 100 ml of strength sodium hydroxide solution. The residue was then filtered off and recrystallized from cyclohexane. 2 g of 6-dimethylaminoethylbenzimidazo 1 c quinazoline of melting point 112°C were obtained.
The following were prepared similarly: EXAMPLE 2 2-methyl-6-dimethylaminomethylbenzimidazo [1,2-c]-quinazoline, yield 65%, mp. 163-165°C (cyclohexane) 15 EXAMPLE 3 2-methyl-6-[2-(1-pyrrolidinyl)-ethyl]-benzimidazo[1,2-c]quinazoline, o0" yield 89%, mp. 147-149°C (cyclohexane) EXAMPLE 4 2-chloro-6-(2-dimethylaminoethyl)-benzimidazo[1,2-c]quinazoline, a 00 o 0o yield 75%, mp. 118°C (cyclohexane) EXAMPLE 4 9 44 3-chloro-6-(2-dimethylaminoethyl)-benzimidazo 1,2-c]quinazoline, yield 25%, mp. 194-196°C (cyclohexane) SEXAMPLE 6 3-nitro-6- (3-dimethylaminopropyl) -benzimidazo 1,2-c]quinazoline, yield 66%, mp. 205-207°C (cyclohexane) EXAMPLE 7 0.37 g of silica gel 60 was added to a solution of 0.51 g (0.0014 mole) of 2-[2-(3-(1-pyrrolidinyl)- (3c) in 30 ml of toluene. 0.3 ml of phosphorus oxychloride was added to the suspension at 80 0 C. The mixture was then kept for a further 1.5 hours at 80 0 C. After the mixture had 8 O.Z. 0480/01046 cooled, it was decanted and the residue was suspended in ml of water with the addition of 25% strength sodium hydroxide solution (to pH 10). The suspension was filtered and the residue was extracted 4 times with 25 ml of hot ethanol, the silica gel remaining behind. The ethanol solutions were evaporated to dryness and the residue was recrystallized from cyclohexane. 100 mg of 2chloro-6-[2-(1-pyrrolidinyl)-ethyl]-benzimidazo[1,2-c]quinazoline of melting point 140-142°C were obtained.
The following were prepared similarly: EXAMPLE 8 3-nitro-6-[2-dimethylaminoethyl]-benzimidazo[1,2-c]- S, quinazoline, yield 39%, mp. 208°C (cyclohexane) EXAMPLE 9 A mixture of 2.7 g (0.01 mole) of 6-chloromethylbenzimidazo[1,2-c]quinazoline and 25 ml of o'e*o strength dimethylamine in water was stirred for 48 hours at room temperature. The resulting precipitate was filtered off, washed with water and recrystallized from io cyclohexane. 2 g of 6-dimethylaminomethylbenzimidazo[l,2-c]quinazoline of melting point 135-137 0 C were obtained.
S" EXAMPLE A solution of 0.5 g (0.002 mole) of 6-mercaptobenzimidazo[1,2-c]quinazoline (4a) in 3 ml of N,N-di- A methylethylenediamine was refluxed for 6 hours. After the mixture had cooled, 60 ml of water were added and the precipitate was filtered off and recrystallized from cyclohexane. 0.48 g of 6-[2-(dimethylamino)-ethylamino)-benzimidazo-l,2-c]quinazoline of melting point 137-139 0 C was obtained.
The following were prepared similarly: EXAMPLE 11 6-[2-(l-pyrrolidinyl)-ethylamino]-benzimidazo[1,2-c]quinazoline, yield 70%, mp. 112-113°C (cyclohexane) 9 0480/01046 EXAMPLE 12 2-methyl-6-[2-(dimethylamino)-ethylamino]-benzimidazo- [1,2-c]quinazoline, yield 77%, mp. 167-169'C (cyclohexane) EXAMPLE 13 2-methyl-6- -pyrrolidinyl) -ethylamino]-benzimidazo- [1,2-c]quinazoline, yield 72%, mp. 155-156'C (cyclohexane) EXAMPLE 14 2-chloro-6-[2-(dimethylamino)-ethylamino]-benzimidazo- [1,2-c]quinazoline, yield 76%, mp. 196-198'C (cyclohexane) EXAMPLE 3 -chloro-6-[2-(dimethylamino)-ethylamino]-benzimidazo- [1,2-c]quinazoline, yield 55%, mp. 162-164'C (cyclohexane) EXAMPLE 16 3-amino-6-[2-(2-(dimethylamino)-ethylamino]-benzimidazo- [l,2-c]quinazoline, yield 80%, mp. 168-170'C (cyclohexane) 11 11 B, t

Claims (2)

1. A benzimidazo[l,2-c]quinazoline of the formula I I I where X and Y are identical or different and are each Ci-C 4 -alkyl, nitro, amino, hydroxyl, Ci-C 4 -hydroxyalkyl, cyano, C 1 -C 4 -alkoxy, Ci-C 4 -alkoxycarbonyl, carbamyl, C 1 -C 4 haloalkyl, Ci-C 4 trihaloalkyl or halogen and Z is a dialkyl-aminoalkyl, cycloalkylideneaminoalkyl, dialkylam- inoalkyl-ideneamino or cycloalkylideneamino alkylidene- S 10 amino group, each of which has not more than 4 carbon atoms in the alkyl or alkyl-idene groups and 2 to carbon atoms in the cycloalkyl-idene groups, and its salts with physiologically tolerated acids.
2. The method of treating tumors and/or leukemia in a patient suffering therefrom, which comprises adminis- tering to said patient an effective amount of a com-pound as claimed in claim 1. DATED this 2nd day of March 1989. KNOLL AKTIENGESELLSCHAFT EDWD. WATERS SONS PATENT ATTORNEYS QUEEN STREET MELBOURNE. VIC. 3000.
AU30932/89A 1988-03-04 1989-03-03 Novel benzimidazol(1,2-c)quinazolines, their preparation and their use Ceased AU612470B2 (en)

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DE3807084 1988-03-04
DE3807084A DE3807084A1 (en) 1988-03-04 1988-03-04 NEW BENZIMIDAZO (1,2-C) CHINAZOLINE, THEIR PRODUCTION AND USE

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU640708B2 (en) * 1989-11-21 1993-09-02 F. Hoffmann-La Roche Ag Substituted pyrimidobenzimidazole derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8088928B2 (en) 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7855289B2 (en) 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
EP2388263A1 (en) 2005-08-04 2011-11-23 Sirtris Pharmaceuticals, Inc. Imidazo[2,1-b]thiazole derivatives as sirtuin modulators
CA2637530A1 (en) * 2006-01-18 2007-09-07 Siena Biotech S.P.A. Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof
FR2916763B1 (en) * 2007-05-31 2013-11-15 Biomerieux Sa NEW PEPTIDASE SUBSTRATES
CL2008001822A1 (en) 2007-06-20 2009-03-13 Sirtris Pharmaceuticals Inc Compounds derived from thiazolo [5,4-b] pyridine; pharmaceutical composition comprising said compounds; and use of the compound in the treatment of insulin resistance, metabolic syndrome, diabetes, among others.
BRPI0922435A2 (en) 2008-12-19 2018-09-11 Sirtris Pharmaceuticals Inc "sirtuine modulatory thiazolopyridine compound, pharmaceutical composition comprising the same and its use."

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* Cited by examiner, † Cited by third party
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DE3612440A1 (en) * 1986-04-12 1987-10-22 Bayer Ag BENZIMIDAZOLO CHIANZOLINE

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU640708B2 (en) * 1989-11-21 1993-09-02 F. Hoffmann-La Roche Ag Substituted pyrimidobenzimidazole derivatives

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DK103889D0 (en) 1989-03-03
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DK103889A (en) 1989-09-05
AU3093289A (en) 1989-09-07
JPH01268689A (en) 1989-10-26

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