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Publication numberUS3927023 A
Publication typeGrant
Publication dateDec 16, 1975
Filing dateMay 24, 1974
Priority dateMay 24, 1974
Publication numberUS 3927023 A, US 3927023A, US-A-3927023, US3927023 A, US3927023A
InventorsRichard E Brown, Jr John Shavel
Original AssigneeWarner Lambert Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Imidazolyl benzofurans
US 3927023 A
Abstract
Imidazolyl and tetrahydropyrimidyl benzofurans of the formula:
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United States Patent [191 Brown et al.

[ Dec. 16, 1975 IMIDAZOLYL BENZOFURANS [73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22 Filed: May24, 1974 21 Appl. No.: 473,253

[52] US. Cl. 260/309.6; 424/251; 424/269;

260/251 R, 260/256.4 C; 260/2564 H [.51] Int. Cl. C07D 233/04 [58] Field of Search 260/309.6

[56] References Cited UNITED STATES PATENTS 3,818,035 6/1974 Binon et al 260/309.6

Primary Examiner-Lewis Gotts Assistant Examiner-D. R. Phillips Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow [57] ABSTRACT lmidazolyl and tetrahydropyrimidyl benzofurans of the formula:

are disclosed. In the abo e structure A, B, and C are hydrogen or lower alkyl of l to 6 carbon atoms, halogen, lower alkoxy of l to 6 carbon atoms, or an aromatic ring; R is hydrogen, lower alkyl of l to 6 carbon atoms, hydroxy, amino or an aromatic ring; D is hydrogen or lower alkyl of l to 6 carbon atoms, E is hydrogen, lower alkyl of l to 6 carbon atoms, or hydroxy; F is hydrogen, lower alkyl of l to 6 carbon atoms, or B-hydroxyethyl and n is O or 1.

These compounds are useful in the management of gastric hyperacidity and gastric ulcers.

17 Claims, No Drawings IMIDAZOLYL BENZOFURANS The present invention relates to imidazolyl and tetrahydropyrimidyl benzofurans having the following structural formula:

wherein A, B, and C are hydrogen or lower alkyl of 1 to 6 carbon atoms, halogen, lower alkoxy of l to 6 carbon atoms, or an aromatic ring; R is hydrogen, lower alkyl of l to 6 carbon atoms, hydroxy, amino or an aromatic ring; D is hydrogen or'lower alkyl of 1 to 6 carbon atoms, E is hydrogen, lower alkyl of l to 6 carbon atoms, or hydroxy; F is hydrogen, lower alkyl of 1 to 6 carbon atoms, or B-hydroxyethyl and n is O or I.

As stated in the above definition for A, B, C, D, E, F and R the terms lower alkyl and lower alkoxy are meant to have 1 to 6 carbon atoms in the chain. These include, for example, methyl, ethyl, propyl, isopropyl, and methoxy, ethoxy, propoxy, isopropoxy, and the like. The term aromatic ring is preferably a mono cyclic aromatic hydrocarbon radical of 6 to 10 carbon atoms such as phenyl or tolyl. The aromatic ring may be further substituted by groups such as nitro, amino, halogen, alkyl or alkoxy.

The compounds of this invention exhibit gastric antisecretory effects when they are administered to a mammalian host. For example, utilizing a laboratory animal such as a rat at an oral dose of mg/kg, the compounds of this invention were found to reduce the gastric volume up to 80%. This reduction in gastric volume is accompanied by a concommitant lowering of the gastric acidity. These compounds are indicated in the management of conditions resulting from gastric hyperacidity such as, for example, gastric ulcer. In the management of gastric ulcer an oral dose of about 20 mg/ kg two or three times daily is recommended. This dose regimen may be varied by methods known to the art.

In order to use these compounds they may be combined with an inert dilutent such as lactose and then encapsulated. Alternatively, they may be compressed into tablets by conventional pharmaceutical techniques.

According to the present invention, the above compounds are prepared from substituted phenols in which A, B, and C are as defined above, G is formyl (in such a case R becomes hydrogen in compound I); acyl, i.e., alkanoyl of 2 to 7 carbon atoms (in which Among the bases which maybe used for this alkylation step are sodium hydride, sodium methoxide, or, preferably, potassium carbonate. Among the solvents which may be used are methanol, benzene, acetone, DMF, or, preferably, DMSO.

In the second step of this invention, the compound 3 is treated with an alkylene diamine or substituted alkylene diamine of structure 4 whereby compounds of l are formed.

In 4, the groups D, E, F and n are as defined for I. In this second step in which both the nitrogencontaining ring is formed and the ring closure to the benzofuran takes place, a catalytic amount of carbon disulfide is conveniently used to increase the rate of reaction.

In actualv practice when carrying out the steps of this invention, compound 3 need not be purified or separated from unreacted 2, but instead the total crude product of step I may be reacted with the diamine of structure 4. In this way, compounds of structure l are easily isolated as a basic fraction and thereby separated from the non-basis materials 2 and 3.

The starting materials for this invention, i.e., the phenols and the diamines of structure 4, are either commercially available or are known compounds which are synthesized by methods described in the literature (with the exception of 2-hydroxy,4-5- dichlorobenzophenone which is a new compound which is described in example 23). In addition, many of the compounds according to 3 are known compounds.

The compounds of this invention form acid addition salts with pharmaceutically acceptable acids such as hydrochloric, nitric, acetic, sulfuric and so on. These salts are prepared by conventional procedures, i.e., by reacting the base with the selected acid and recovering the desired salt. These salts are also a feature of this invention. I v

In order to further illustrate the practice of this invention, the following examples are included. In the examples temperatures are given in degrees centigrade.

EXAMPLE 1 2-Benzoyl phenoxyacetonitrile EXAMPLE 2 2-( 2-lmidazolin-2-yl )-3-phenylbenzofuran A mixture of 10.5 g (0.044 mole) of 2-benzoyl phenoxyacetonitrile, 3.2 g (.054 mole) of ethylenediamine and 0.2 ml of carbon disulfide was heated for 5 hours on the steam bath. Ammonia was evolved. The mixture was poured into water and the precipitate extracted with ethyl acetate. The organic phase was washed twice with water, then extracted with 4N HCl. The aqueous acid phase was washed with ethyl acetate and made basic with ammonium hydroxide. The precipitated oil crystallized on stirring and was filtered and was recrystallized from ethyl acetate for analysis, mp ll920.

Anal. Calcd for C H N O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.85; H, 5.45; N, 10.70.

EXAMPLE 3 80CH ()C H 2 CN 2-Carbomethoxyp henoxyaceton itrile In the same way as described in example 1, methyl salicylate and bromoacetonitrile were reacted to give the title compound, mp 534 after recrystallization from methylene chloride-hexane.

Anal. Calcd for lUHgNOgI C, 62.82; H, 4.75; N, 7.33. Found; C, 63.04; H, 4.85; N, 7.60.

EXAMPLE 4 2-( 2-Imidazolin-2-yl )-3-benzofuranol In the same way as described in example 2, 2-carbomethoxyphenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp 268-9 after recrystallization from methanol.

Anal. Calcd for C I-1 N 0 C, 65.33; H, 4.98; N,

13.86. Found: C, 65.25; H, 5.04; N 13.98.

EXAMPLE 5 COOCH OCH CN 2-Carbomethoxy-6-chlorophenoxyacetonitrile In the same way as described in example 1, methyl 3-chlorosa1icylate and bromoacetonitrile were reacted to give the title compound, mp 701 after recrystallization from hexane.

Anal. Calcd for C ,,H ClNO C, 53.23; H. 3.57; Cl, 15.71. Found: C, 53.02; H, 3.56; N, 15.45. EXAMPLE 6 7-Chloro-2-(2-imidazo1in-2-yl)-3-benzofuranol In the same way as described in example 2, 2-carbomethoxy-6-chlorophenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp 266-9 after recrystallization from acetonitrile.

Anal. Calcd for CuHgClNgOz: C, 55.83; H, 3.83; N, 11.84. Found: C, 55.84; H, 3.75; N, 11.73.

" EXAMPLE 7 2-Benzoyl-4-chlorophenoxyacetonitrile In the same way as described in example 1, 5-chloro- 2-hydroxybenzophenone and bromoacetonitrile were reacted to givethe title compound, mp 77-78 after recrystallization from methanol.

Anal. Calcd for C, H ClNO C. 66.31; H, 3.71; N, 5.16. Found: C, 66.18; H, 3.62; N, 5.20.

EXAMPLE 8 5-Chloro-2-( 2-imidazolin-2-yl )-3phenylbenzofuran In the same way as described in example 2, 2-benzoyl-4-chlorophenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp l75-6 after recrystallization from ethyl acetate.

Anal. Calcd for C H CIN O: C, 68.81; H, 4.42; N, 9.44. Found: C, 68.99; H, 4.36; N, 9.44.

EXAMPLE 9 CH30 OCHZCN 2-( p-Chlorobenzoyl )-5-methoxyphenoxyacetonitrile In the same way as described in example 1, 4-chloro- 2-hydroxy-4-methoxybenzophenone and bromoacetonitrile were reacted to give the title compound as a yellow oil.

EXAMPLE 3-(p-Chloropheny1)-2-( 2-imidazolin-2-yl )-6-methoxybenzofuran .In the same way as described in example 2, 2-(pc'hlorobenzo yl )-5-methoxy phenoxyacetonitrile and ethylenediamine were reacted to give the title compound. mp 128-9 after recrystallization from ethyl acetate-hexane.

Anal. Calcd. for C H CIN O C, 66.16; H, 4.63; N, 8.57. Found: C, 65.97; H. 4.47; M866.

EXAMPLE 1 1 Cl 2. H

OCH CN 2-Formyl-4,6-dichlorophenoxyacetonitrile EXAMPLE 12 5,7-Dichloro-2-( 2-imidazolin-2-yl )benzofuran In the same way as described in example 2. 2-formyl- 4,6-dichlorophenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp l8 after recrystallization from ethyl acetate.

Anal. Calcd for C H CI H O: C,- 51.79; H. 3.16; N, 10.98. Found: C, 51.58; H, 3.19; N-, 11.10.

EXAMPLE 13 OCHZCN' Z-Cyanophenoxyacetonitrile In the same way as described in example 1, Z-cyanophenol and bromoacetonitrile were reacted to give the title compound, mp 645 after recrystallization from ethyl acetate-hexane.

Anal. Calcd for C H N- O: C, 68.35; H. 3.82; N. 17.71. Found: C, 68.12; H, 3.77; N, 17.41.

EXAMPLE 14 3-Amino-2-( 2-imidazolin-2yl )benzofuran In the same way as described in example 2, 2-cyanophenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp 99100 after recrystallization from methylene chloride-hexane.

Anal. Calcd for C H N O: C. 65.67; H, 5.51; N, 20.88. Found: C, 65.45; H, 5.62; N, 20.80.

EXAMPLE 15 c11 OCHZCN 2-Benzoyl-S-methoxyphenoxyacetonitrile In the same way as described in example 1, 2- hydroxy-4-methoxybenzophenone and bromoacetonitrile were reacted to give the title compound as an oil which was used directly in example 16.

EXAMPLE l6 2-( 2-Imidazolin-2-yl )-6-methoxy-3-phenylbenzofuran In the same way as described in example 2, 2-benzoy1-5-methoxyphenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp 1468 after recrystallization from ethyl acetate.

Anal. Calcd for C,,,H ,N O C, 73.95; H, 5.52; N, 9.58. Found: C, 74.03; H, 5.51; N, 9.28.

EXAM PLE l 7 Br C0OCH &0 CH 2 CN 2-Carbomethoxy-4-bromophenoxyacetonitrile In the same way as described in example 1, methyl-- bromosalicylate and bromoacetonitrile were reacted to give the title compound, mp 889 after recrystallization from methylene chloride-hexane.

Anal. Calcd for C I-I BrNO C, 44.47; H, 2.99; N, 5.19. Found: C, 44.60; H, 2.83; N, 5.32.

EXAMPLE l8 EXAMPLE l9 2-( Phenylcarbamoyl )-phenoxyacetonitrile In the same way as described in example 1, salicylanilide and bromoacetonitrile were reacted to give the title compound, mp 1567 after recrystallization from methanol.

Anal. Calcd for C H N O C, 71.41; H, 4.80; N, 11.11. Found: C, 71.32; H, 4.71; N, 10.91.

EXAMPLE 20 2-(4,5-dimethyl-2-imidazolin-2-yl)-3-benzofuranol In the same way as described in example 2, 2- (phenylca rbamoyl )phenoxyacetonitrile and 2 ,3 diaminobutane were reacted to give the title compound, mp 270-3 after recrystallization from isopropanol.

Anal. Calcd for C ,,H N O C, 67.81; H, 6.13; N, 12.17. Found: C, 67.85; H, 6.04; N, 12.18.

EXAMPLE 21 OCHZQN Z-Carbomethoxy-6-phenylphenoxyacetonitrile In the same way as described in example 1, methyl-3- phenylsalicylate and bromoacetonitrile were reacted to give the title compound as an oil used directly in example 22.

EXAMPLE 22 2-( 2-1midazolin-2-yl )-7-phenyl-3-benzofuranol hydrochloride In the same way as described in example 2, 2-carbomethoxy-6-phenylphenoxyacetonitrile and ethylenediamine were reacted to give the title compound. The hydrochloride salt formed on treatment with 2N HCl 7 and had mp 2469 after recrystallization from isopropanol.

Anal. Calcd for C H ClN O C, 64.87; H, 4.90; N, 8.90. Found: C, 64.56; H, 4.78; N, 9.02.

EXAMPLE 23 [I] OH 2-Hydroxy-4,5-dichlorobenzophenone To a suspension of 67.5 g (0.5 mole) of aluminum chloride in 81.5 g (0.5 mole) of 3,4-dichlorophenol was added with stirring at 100 70.5 (0.5 mole) of benzoyl chloride. The reaction mixture was then heated to 180 for 35 minutes. The reaction was cooled, the complex decomposed with 750 ml of HCl, and the mixture extracted with chloroform. The chloroform layer was washed with water, dilute NaOH, water, dried and concentrated to a solid. The solid was recrystallized from ethanol for analysis, mp 1 l6.

Anal. Calcd for C H Cl O C, 58.46; H, 3.02; CI, 26.55. Found: C, 58.69; H, 2.98; Cl, 26.36.

EXAMPLE 24 (31 OCH CN 2-Benzoyl-4,5-dichlo rophenoxyacetonitrile In the same way as described in example 1, 2- hydroxy-4,5-dichlorobenzophenone and bromoacetonitrile were reacted to give the title compound as an oil used directly in examples 25 and 26.

EXAMPLE 25 5,6-Dichloro-2-( 2-imidazolin-2-yl)-3-phenylbenzofuran In the same way as described in example 2, 2-benzoyl-4,5-dichlorophenoxyacetonitrile and ethylenediamine were reacted to give the title compound, mp 6 after recrystallization from methanol.

Anal. Calcd for C H Cl ON C, 61.65; H, 3.65; N, 8.46; CI, 21.41. Found: C, 61.53; H, 3.65; N, 8.67; Cl, 21.41.

EXAMPLE 26 2-(5,6 Dichloro-3-phenyl-Z-benzofuranyl)-1,4,5,6-tetrahydro5-pyrimidinol hydrochloride EXAMPLE 27 1,4,5 ,6-Tetrahydro-2-( 3-hydroxy-2-benzofuranyl )-5- pyrimidinol In the sameway as described in example 2, 2-carbomethoxyphenoxyacetonitrile and 2-hydroxy-1,3-propane'diamine were reacted to give the title compound, mp 2535 after recrystallization from methanol.

Anal. Calcd for C I-1 N 0 C, 62.06; H, 5.21; N, 12.06. Found: C, 61.96; H, 5.30; N, 12.10.

EXAMPLE28 2-( 5-Chloro-3-phenyl-2-benzofuranyl 1 ,4,5,6-Tetrahydropyrimidine In the same way as described in example 2, 2-benzoyl-4-chlorophenoxyacetonitrile and 1,3-propane diamine were reacted to give the title compound, mp l645 after recrystallization from ethyl acetate.

Anal. Calcd for C,,,H ClN O: C, 69.57; H, 4.87; N, 9.01. Found: C, 69.52; H, 4.98; N, 8.75.

EXAMPLE 29 2-( -Chloro-3-phenyl-2-benzofuranyl l ,4,5,6-tetrahydro-5-pyrimidinol In the same way as described in example 2, Z-benzoyl-4-chlorophenoxyacetonitrile and 2-hydroxy-l,3- propane diamine were reacted to give the title compound, mp l99200 after recrystallization from acetonitrile.

Anal. Calcd for C ,,H ClN O C, 66.16; H, 4.63; N, 8.57. Found: C, 65.95; H. 4.72; N, 8.54.

EXAMPLE 30 l CH2CH20H 2-( 5-Chloro-3-phenyl-2- benzofuranyl l ,4,5,6-Tetrahydro-l-pyrimidine ethanol hydrochloride In the same way as described in example 2, 2-benzoyl-4-chlorophenoxyacetonitrile and 1,3-diamino-N- ,B-hydroxyethyD-propane were reacted to give the title compound. The hydrochloride salt had mp 127-30 after recrystallization from acetonitrile.

Anal- Calcd for CgoHgqClgNgOzl C, l H, 5.3 N, 7.39. Found: C, 60.39; H, 5.30; N, 7.20.

EXAMPLE3I EXAMPLE 32 2-( 5 -Chlo ro-3-phenyl-2-benzofuranyl )-4,5-dimethyl-2- imidazoline hydrochloride In the same way as described in example 2, 2-benzoyl-4-chlorophenoxyacetonitrile and 2,3-diaminobutane were reacted to give the title product. The hydrochloride salt was recrystallized from ethanol, mp 232-4". 7

Anal. Calcd for C H Cl N O: C, 63.17; H, 5.02; N, 7.75. Found: C, 62.90; H, 5.07; N, 8.02.

EXAMPLE 33 2-( 5-Chloro-3-phenyl-2-benzofuranyl l -methyl-2- imidazoline In the same way as described in example 2, 2-benzoyl-4-chlorophenoxyacetonitrile and N-methylethylenediamine were reacted to give the title compound, mp l056 after recrystallization from methylene chloride-hexane.

Anal. Calcd for C ,,H ClN O: C, 69.57; H. 4.87; N, 9.01. Found: C, 69.77; H, 5.03; N, 9.26.

EXAMPLE 34 2-Acetyl phenoxyacetonitrile 1n the same way as described in example 1. o-hydroxyacetophenone and bromoacetonitrile were reacted to give the title compound as a solid which was used as is for the next step.

EXAMPLE 35 2-( 2-lmidazolin-2-yl )-3-methylbenzofuran in which A. B, and C are hydrogen or lower alkyl of 1 to 6 carbon atoms. halogen, lower alkoxy of l to 6 carbon atoms. or an aromatic ring: R is hydrogen. lower alkyl of l to 6' carbon atoms. hydroxy. amino or an aromatic ring; D is hydrogen or lower alkyl of l to 6 carbon atoms. E is hydrogen. lower alkyl of l to 6 carbon atoms. or hydroxy; F is hydrogen. lower alkyl of l to 6 carbon atoms. or B-hydroxyethyl and n is O and the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1 which is 2-(2- imidazolin-Z-yl)3-phenylbenzofuran.

3. A compound according to claim 1 which is 2-(2- imidazolin-Z-yl)-3-benzofuranol.

4. A compound according to claim 1 which is 7 chloro-2-( Z-imidazolin-Z-yl )-3-benzofuranol.

5. A compound according to claim 1 which is 5' chloro-Z- Z-imidazolin-Z-yl )-3-phenylbenzofuran.

6. A compound according to claim 1 which is 3-(pchlorophenyl)- 2-( 2-imidazolin-2-yl )-6-methoxy-benzofuran.

7. A compound according to claim 1 which is 5.7- Dichloro-2-( 2-imidazolin-2-yl )benzofuranv 8. A compound according to claim 1 which is 3- amino-2- Z-imidazolin-Z-yl )benzofuran.

9. A compound according to claim 1 which is 2-(2- imidazolin-Z-yl)-6-methoxy-3-pheny1benzofuran.

10. A compound according to claim 1 which is 5- Bromo-2( Z-imidazolin-Z-yl )-3-benzofuranol hydrochloride.

11. A compound according to claim 1 which is 2- (4.5-dime thyl-Z-imidazolin-Z-yl )-3-benzofuranol.

12. A compound according to claim 1 which is 2-(2- imidazolin-2-yl)-7phenyl-3-benzofuranol and its hydrochloride.

13. A compound according to claim 1 which is 5.6

and its

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4021444 *May 10, 1976May 3, 1977Morton-Norwich Products, Inc.2-[5-(3,4-Dimethoxyphenyl)-2-furyl]imidazoline hydrochloride
US4022798 *May 10, 1976May 10, 1977Morton-Norwich Products, Inc.2-(5-Phenyl-2-furyl)imidazolines
US4225711 *Oct 2, 1978Sep 30, 1980Schering CorporationSubstituted 2-[(methylsulfinyl)acetyl]-3-heterocyclicindoles and their use as immunosuppressants
US4342769 *Apr 25, 1980Aug 3, 1982Schering Corporation2-[(Methylsulfinyl)acetyl]-3-heterocyclicindoles and derivatives thereof as immunosuppressants
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US4895867 *Jan 19, 1988Jan 23, 1990Norwich Eaton Pharmaceuticals, Inc.2-(5-phenyl-2-furanyl)imidazoles useful as cardiotonic agents
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Classifications
U.S. Classification548/311.4, 544/298, 544/333, 514/927
International ClassificationC07D405/04
Cooperative ClassificationY10S514/927, C07D405/04
European ClassificationC07D405/04