CA1126280A - Benzimidazole and benzimidazolidine derivatives with diuretic and antihypertensive activity - Google Patents
Benzimidazole and benzimidazolidine derivatives with diuretic and antihypertensive activityInfo
- Publication number
- CA1126280A CA1126280A CA324,146A CA324146A CA1126280A CA 1126280 A CA1126280 A CA 1126280A CA 324146 A CA324146 A CA 324146A CA 1126280 A CA1126280 A CA 1126280A
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- Prior art keywords
- substituted
- chloro
- sulfamyl
- lower alkyl
- benzimidazole
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Compounds having diuretic and antihypertensive properties are disclosed which have the following structural formulae:
or or pharmaceutically acceptable salts thereof, wherein:
X = halogen or trifluoromethyl Y1 and Y2 = independently hydrogen, alkyl, acyl, azyl, substituted aryl or heterocycle, R1 = hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle or substituted heterocycle, n = 0 or an integer from 1-4 R2 = amino, substituted amino, guanidino, substituted guandino, halogen, alkyl, substituted alkyl, aryl, substituted aryl or heterocycle, and R3 = hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl aralkyl, heterocycle, substituted heterocycle or acyl.
Methods of preparation are also disclosed.
Compounds having diuretic and antihypertensive properties are disclosed which have the following structural formulae:
or or pharmaceutically acceptable salts thereof, wherein:
X = halogen or trifluoromethyl Y1 and Y2 = independently hydrogen, alkyl, acyl, azyl, substituted aryl or heterocycle, R1 = hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle or substituted heterocycle, n = 0 or an integer from 1-4 R2 = amino, substituted amino, guanidino, substituted guandino, halogen, alkyl, substituted alkyl, aryl, substituted aryl or heterocycle, and R3 = hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl aralkyl, heterocycle, substituted heterocycle or acyl.
Methods of preparation are also disclosed.
Description
~ 1126~80 The inventlon generally relates to compounds having diuretlc and anti-hypertensive properties and which have the following structural formulaq:
Y~
; or X ~ N H
Yl ,, ~\ ~ N ~ ( 2)n 2 Y2Rl or pharmaceutically acceptable salts thereof, wherein:
X - halogen or trifluoromethyl Yl and Y2 ~ independently hydrogen, alkyl, acyl, aryl, substituted aryl or heterocycle, Rl ~ hydrogen, lower alkyl, aryl, substituted aryl, benzyl, ~ubstltuted benzyl, aralkyl, heterocycle or substituted heterocycle, n ~ O or an lnteger from 1-4 R2 ~ amino, substltuted amino, guanidino, substituted guanidino, halogen, alkyl, substituted alkyl, aryl, sub9titutet aryl or heterocycle, and R3 ~ hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle, substituted heterocycle or acyl.
, - 1 - ~ i , '' ' ~ ~
:
''''' :: ;
1126~8~
It 19 a primary ob~ect to provide for new compounds of the above structure.
It i9 a further ob~ect of the present invention to provlde for methods of produclng the above compounds.
It 19 yet a further ob~ect of the present invention to provite a new class of compounds whlch exhlblt dluretlc and antlhypertenslve activity.
Other ob~ects and advantages of the present lnvention will be apparent from a further reading of the ~pecificatlon and of the~appended claims.
The productlon of the compoundæ of the present inventlon may be effect-" 10 ed by varlous methods whlch are known ln prlnciple. The following illustrates two different convenient syntheses which may be used ln the production~of the compounds of the lnventlon:
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--`` 112ti28~
SULFAM~L - lH - BENZIMIDAZOLE HYDROBROMIDE (VII) . O
Cl ~ NH2 Cl ~ NHIC~CH3 (CH3CO)20 ~
1. ClSO3H ¢1 ~ NH2 Cl ~ NHIOC-CH
Y~
; or X ~ N H
Yl ,, ~\ ~ N ~ ( 2)n 2 Y2Rl or pharmaceutically acceptable salts thereof, wherein:
X - halogen or trifluoromethyl Yl and Y2 ~ independently hydrogen, alkyl, acyl, aryl, substituted aryl or heterocycle, Rl ~ hydrogen, lower alkyl, aryl, substituted aryl, benzyl, ~ubstltuted benzyl, aralkyl, heterocycle or substituted heterocycle, n ~ O or an lnteger from 1-4 R2 ~ amino, substltuted amino, guanidino, substituted guanidino, halogen, alkyl, substituted alkyl, aryl, sub9titutet aryl or heterocycle, and R3 ~ hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle, substituted heterocycle or acyl.
, - 1 - ~ i , '' ' ~ ~
:
''''' :: ;
1126~8~
It 19 a primary ob~ect to provide for new compounds of the above structure.
It i9 a further ob~ect of the present invention to provlde for methods of produclng the above compounds.
It 19 yet a further ob~ect of the present invention to provite a new class of compounds whlch exhlblt dluretlc and antlhypertenslve activity.
Other ob~ects and advantages of the present lnvention will be apparent from a further reading of the ~pecificatlon and of the~appended claims.
The productlon of the compoundæ of the present inventlon may be effect-" 10 ed by varlous methods whlch are known ln prlnciple. The following illustrates two different convenient syntheses which may be used ln the production~of the compounds of the lnventlon:
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--`` 112ti28~
SULFAM~L - lH - BENZIMIDAZOLE HYDROBROMIDE (VII) . O
Cl ~ NH2 Cl ~ NHIC~CH3 (CH3CO)20 ~
1. ClSO3H ¢1 ~ NH2 Cl ~ NHIOC-CH
2. NH40H l ll NaOCH3 ¦ 1 3 : ~--N02 ~ N02 IV III
V ~ 2 .BrCN
C~ 3r ; ~ ~ VII H
/
;: - 3 -'~
; ~
,. . . .
'. . ' : ~ . :
.''-' ~
, ~ .
6~8~
SULFAMYL - lH - BENZIMIDAZOLE HYDROCHLORIDE ~VIII?
'.~
I (CH3CO~20 II
/ ~N03 IV NaOCH3 III
~ 1. ClS03H
Z. NH40H
LH]
V ) VI
Cl ~ N / HCl 2 VIII
.
-1126~8~
As indicated above, in the structural formulas of the compounds of the inventlon which were lllustrated X i9 a halogen or trlfluoromethyl.
i Yl and Y2 are each hydrogen, alkyl, acyl, aryl, substltuted aryl or heterocycle. Most pre~erably Yl and ~2 are each either hydrogen and/or lower alkyl.
The substltutent Rl may be hydrogen~ lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle or substituted hetero-cycle. Most preferably Rl is hydrogen, lower alkyl, aryl or substituted aryl, preferably substituted by lower alkyl, alkoxy, or halogen.
As lndicated "n" may be 0 or an integer from 1-4.
Most preferably "n" = 0.
R2 may be amino, substituted amino, guanidino, substituted guanidino, halogen, alkyl, substituted alkyl, aryl, shbstltuted aryl or heterocycle. Most preferably R2 i9 amino, substituted amino substit~ted by lower alkyl or guani-dino.
The substituent R3 may be hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle, su~s~ituted heterocyle or acyl.
Most preferably R3 is hydrogen or lower alkyl.
In addition to compounds (VII) and (VIII) shown above, other specific ; suitable compounds of the above Pormula lnclude:
5-- chloro - 2 - formamido - 6 - sulfamyl - lH - benzlmldazole 2-- carbethoxyamino - 5 - chloro - 6 - ~ulfamyl - lH - benzimidazole 2 - benzylamino - 5 - chloro - 6 sulfamyl - lH - benzimidazUe S - chloro - 6 - N,N - dimethylsulfonamido - 2 - guanidino - 1~ - benzimidazole 5 - chloro - 2 - guanidino - 6 - N - methylsulfonamido - lH - benzimidazole 2 - amino ~ 5 - chloro - 6 - sulfamyl - 1 - (o-tolyl) - lH - benzimidazole 2 - amino - 5 - chloro - 1 - (o-methylbenzyl) - 6 - sulfamyl - lH - benzimidazole ~, ,, , ' ' ~ . , ' ~` 11;~280 5 - chloro - 2 - dlmethylamlno - 6 - sulfamyl - lH - benzlmldazole 2 - dimethylamino - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzlmidazole 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzimidazole 5 - chloro - 2 - guanldlno - 1 - methyl - 6 - sulfa~yl - lH - benzimidazole 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzimldazole - 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzlmidazole 2 - carbethoxyamlno - 5 - chloro - 6 - sulfamyl - lH - benzimidazole 2 - formamido - 6 - sulfamyl - 5 - trlfluoromethyl - lH benzimidazole 2 - carbethoxyamlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimldazole , 10 2 - benzylamlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimidazole : 2 - benzylamlno - 5 - bromo - 6 - sulfa~yl - lH - benzlmidazole 5 - chloro - 2 - (2,6-- dichloro) anilino - 6 - sulfamyl - lH - benzimidazole 2 - (2,6 - dichloro) anllino - 6 - sulfamyl - 5 - trlfluoromethyl - lH -: benzlmldazole 5 - bromo - 2 - (2.6 - dlchloro) anillno - 6 - sulfamyl - lH - benzimidazole 5 - chloro - 2 - (2,6 - dimethyl) anilino - 6 - sulfamyl - lH - benzimldazole 2 - (2,6 - dimethyl) anlllno - 6 - sulfamyl - S - trlfluoromethyl - lH -benzlmldazole 5 - bromo - 2 - (2,6 - dlmethyl) anllino - 6 - sulfamyl - lH - benzimidazole 2 - amino - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzlmidazole 2 - amlno - 5 - bromo - 6 - sulfamyl - lH - benzimldazole 2 - guanldlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzlmldazole 5 - bromo - 2 - guanldino - 6 - sulfamyl - lH - benzimidazole 5 - chloro - 2 - guanldlno - 6 - N - methylsulfonamldo - lH - benzlmldazole 2 - amino - 5 - chloro - 6 - N - methylsulfonamldo - lH - benzlmidazole 2 - amlno - 6 - N - methylsulfonamido - S - trlfluoromethyl - lH - benzimidazole ,, 2 - amino - 5 - chloro - 6 - N,N - dlmethylsulfonamido - lH - benzimldazole .;, ; 2 - guanldino - 6 - N - methylsulfonamido - 5 - ~rlfluoromethyl - lH -benzlmidazole ; 30 5 - bromo - 2 - guanldlno - 6 - N-methylsulfonamido - lH - benzlmidazole ,~, .
.. ~ ~ ... .
' ", ~ ~:
,' . . , ` ' ;.,:., :
- `` 11~6Z8~
' 6 - N,N - dimethylsulfonamldo - 2 - guanidino - 5 - trifluoromethyl - lH -benzimidazole 5 - bromo - 6 - N,N - dimethylsulfonamldo - 2 - guanidino - lH - benzlmidazole 5 - fluoro - 2 - guanldino - 6 - sulfamyl - lH - benzlmidazole 2 - amlno - 5 - fluoro - 6 - sulfamyl - lH - benzimldazole 5 - chloro - 2 - [4 - (2,3~- dlchlorophenoxymethylcarboxyl)] amino - 6 - sulfamyl - lH - benzlmidazole 2 - [4 - 2,3 - dlchlorophenoxymethylcarboxy)] amino - 6 - sulfamyl - 5 - tri-fluoromethyl - lH - benzlmldazole 5 - bromo - 2 - [4 - (2,3 - dlchlorophenoxymethylcarboxy)~ amino - 6 - sulfamyl - 1 H - benzlmltazole 2 - amino - 5 - chloro - 6 - sulfamylbenzimidazolidine : 2 - amino - 6 - sulfamyl - 5 - trifluoromethylbenzlmldazolldlne 2 - amino - 5 - bromo - 6 - sulfamylbenzimidazolidine 5 - chloro - 2 - guanidino - 6 - sulfamylbenzlmidazolldine 2 - guanidlno - 6 - sulfamyl - 5 - trlfluoromethylbenzimidazolidine 5 - bromo - 2 - guanitino - 6 - ~ulfamylbenzlmidazolidlne 2 - amino - 5 - chloro - 6 - sulfamyl - 1 - (3-tolyl) - lH - benzimldazole : 2 - amino - 6 - sulfamyl - 1 - (3-tolyl) - 5 - trifluoromethyl - lH - benzl-: 20 mitazole 2 - amlno - 5 - bromo - 6 - sulfamyl - 1 - (3-tolyl) - lH - benzimldazole 2 - amino - 5 - chloro - 6 - sulfamyl - 1 - (4-tolyl~ - lH - benzimidazole 2 - amino - 6 - sulfamyl - 1 - (4-tolyl) - 5 - trifluoromethyl - lH benzimida-zole 2 - amlno - 5 - bro - 6 - sulfamyl - 1 - (4-tolyl) - lH - benzlmldazole 2 - amlno - 5 - chloro - 1 - (2,6 - dimethylphenyl) - 6 - sulfamyl - lH -benzlmidazole 2 - amino - 1 - (2,6 - dlmethylphenyl) - 6 - sulfamyl - 5 - trifluoromethyl -: lH - benzimldazole ~; 30 2 - amlno - 5 - bromo - 1 - (2,6 - dimethylphenyl) - 6 - sulfamyl - lH -benzimidazole 2 - amino - 5 - chloro - 6 - culfamyl - 1 - (2-tolyl) benzimidazolldlne , ~...... ., ~ . .
~Z6Z8~
2 - amino - 6 - sulfamyl - 1 - (2-tolyl) - 5 - trifluoromethylbenzimidazolidine 2 - amino - 5 - bromo - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine 5 - chloro - 2 - guanidino - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine 2 - guanidino - 6 - sulfamyl - 1 - (2-tolyl)- 5 - trifluoromethylbenzimidazolidine , 5 - bromo - 2 - guanidlno - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine 2 - amlno - 5 - chloro - 1 - (2-methoxyphenyl)- 6 - sulfamyl-lH- benzlmidazole ~4 2 - amino - 1 - (2-methoxyphenyl) - 6 - sulfamyl - 5 - trifluoromethyl - lH -benzimldazole 2 - amino - 5 - bromo - 1 - (2-methoxyphenyl) - 6 - sulfamyl - lH - benzimidazole ?, 2 - amlno - 5-chloro -1 - (2-methoxyphenyl) - 6 - sulfamyl - lH - benzimidazole ; 2 - amino - 1 - (2-chlorophenyl) - 6 - sulfamyl - 5 - trifluoromethyl - lH -benzlmidazole ; 2 - amino - 5 - bromo - 1 - (2-chlorophenyl) - 6 - sulfamyl - lH - benzimidazole ; 5 - chloro - 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamyl - lH - benzi-midazole 1 - (2-chlorophenyl) - 2 - guanldlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH -.~ benzlmidazole 5 - bromo - 1 - (2-chlorophenyl) - 2- guanidlno - 6 - sulfamyl-lH- benzimidazole 2 - amino - 5 - chloro - 1 - (2-chlorophenyl) - 6 - sulfamylbenzimidazolidine 2 - amlno - 1 - (2-chlorophenyl) - 6 - sulfamyl - 5 - trifluoromethylbenzi-midazolldlne 2 - amlno - 5 - bromo - 1 - (2-chlorophenyl) - 6 - sulfamylbenzlmldazolldine :'' , , 5 - chloro - 1 - (2-chlorophenyl) - 2 - guanldino - 6 - sulfamylbenzimazolidine 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamyl - 5 - trlfluoromethyl ;, benzlmldazolitlne , I
;, 5 - bro - 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamylbenzimidazolidine ., 5 - chloro - 2 - (furfurylamino) - 6 - sulfamyl - lH - benzlmldazole 2 - (furfurylamlno) - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzlmidazole ,. 5 - chloro - 2 - (furfurylamino) - 6 - sulfamylbenzimidazolidine 2 - (furfurylamino) - 6 - sulfamyl - 5 - trlfluoromethylbenzlmldazolidine 5 - chloro - 6 - sulfamyl - 2 - (2-tolyl) - lH - benzimldazole .~ 2 - (2-tolyl) - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimldazole : - 8 -, ' ':, , ' , ~, , ~ - -. ~ ' ' , ~ 628~
S - chloro - 6 - sulfamyl - 2 - (2-tolyl) benzlmldazolidine - 6 - sulfamyl - 2 - (2-tolyl) - 5 - trlfluoromethylbenzimidazolidlne 5 - chloro - 6 - sulfamyl - 2 - (3-tolyl) - lH - benzimldazole ~; 6 - sulfamyl - 2 - (3-tolyl) - 5 - trifluoromethyl - lH - benzimidazole 5 - chloro - 2 - phenyl - 6 - sulfamyl - lH - benzimidazole 2 - phenyl - 6 - sulfamyl - S - trlfluoromethyl - lH - benzimidazole 5 - chloro - 6 - sulfamyl - 2 - (3-tolyl) benzimidazolldine 6 - sulfamyl - 2 - (3-tolyl) - 5 - trlfluoromethylbenzimidazolidine 5 - chloro - 2 - phenyl - 6 - sulfamylbenzimidazolidine 2 - phenyl - 6 - sulfamyl - 5 - trlfluoromethylbenzimidazolidine 2 - (3-carboxy-4-hydroxy) anilino - 6 - sulfamyl - 5 - trifluoromethyl - lH -benzimitazole 2 - (3-carboxy-4-hydroxy) anlllno - 5 - chloro - 6 - sulfamyl - lH - benzimida-zole 5 - bromo - 2 - (3-carboxy-4-hydroxy) anllino - 6 - sulfamyl - lH - benzimida-~: zole ': 2 - (4-carboxy-3-hydroxy) anlllno - 5 - chloro - 6 - sulfamyl - lH - benzimida-,~ zole ; 2 - (4-carboxy-3-hydroxy) anilino - 6 - sulfam~l - 5 - trifluoromethyl - lH -benzlmidazole i: 5 - bromo - 2 - (4-carboxy-3-hydroxy) anilino - 6 - sulfamyl - lH -~benzimida-; zole , 5 - chloro - 2 - (N -methylguanidino) - 6 - sulfamyl - lH - benzimidazole 5 - bromo - 2 - (N3-methylguanldino) - 6 - sulfamyl - lH - benzimidazole 2 - (N -methylguanidino) - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzimida-zole , 5 - chloro - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) - lH -benzimidazole ' 5 - bromo - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) - lH -benzlmldazole : 2 - (N3-methylguanidino) - 6 - sulfamy~l - 1 - (2-tolyl) - S - trlfluoromethyl -; lH - benzimidazole . S - bromo - 2 - (N3-methylguanidino) - 6 - sulfamylbenzimidazolidine , ,;
_ 9 _ ',';
... . .
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5 - chloro - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) ben~imida-zolidine 5(6)-chloro-2-methyl-6(5)-sulfamyl-1(3)H-benzimidazole hydrochloride 5(6)-chloro-benzlmldazole-6(5)-sulfonamide 5(6)-chloro-2-(2-furyl)-6(5)-~ulfamyl-1(3)H-benzim~da~ole 2-acetylamlno-5(6)-chloro-benzlmldazole-6(5)-sulfonamide 2,5(6)-dlchloro-6(5)-sulfamyl-1(3)H-benzimidazole HCl ~onohydrate 5(6)-chloro-2-propyl-6(5)-sulfam~l -1(3)H-benzimldazole 2-benzyl-5(6)-chloro-6(5)-sulfamyl-1-(3)H-benzlmldazole HCl monohydrate 10The following examples are given to illustrate the production of compounds according to the lnventlon. The scope of the invention is not, however, meant to be llmlted to the speclflc details of the examples Preparatlon of 3 - Chloroacetanillde (II) To 500 g. of 3 - chloroanlllne ~I) suspended ln 4.5 1. of water heated to 35 was added stream wlse 690 g. of acetic anhydride over a 40 minute period.
After the addltion, the reactlon was stlrred for 4 hours, filtered, and the ; product washed wlth 12 1. of water and drled to provide 620.2 g. of 3-chloro-acetanlllde (II) as whlte crystals, m.p. 72.5 - 73C.
! 20 Preparatlon of 5 - Chloro - 2 - ~ltroacetanillde_(III) ; To 100 g. of 3 - chloroacetanlllde ~II) ln 110 ml. of acetlc acld and 120 ml. of acetlc snhydrlde was added dropwlse at -10 to -5C 44 ml. of 90%
fumlng nltrlc acld ln 50 ml. of glacial acetlc acld. After completlon of the addltlon, the yellow solutlon was stirred for one hour at 0 to +5C and then ; decanted into lce water. The yellow solld was collected by fll~ratlon, stirred 30 mlnutes wlth water, flltered, and then stlrred 20 mlnutes wlth 1 1. of ether and flltered. Drylng of the solld provlded 110 g. of 5 - chloro - 2 - nltro-acetanlllde (III) as a llght tan solid, m.p. 114 - 116C.
' '., ~
1~ 28~
, Preparation of 5 - Chloro - 2 - Nltroanillne (IV) To 3 1. of absolute methanol was slowly added 2.4 g, of sodium. When all the sodlum had dissolved, 68 g. of 5 - chloro - 2 - nltroacetanillde was added with stlrring and the solution refluxed for 7 hours. The solution was allowed to sit overnight and then concentrated in vacuo until crystals formed.
Piltration of the precipitate provlded 51 g. of 5 - chloro - 2 - nitoraniline (IV) as yellow needles, m.p. 124 - 126C.
Pre~aratlon of 5 - Chloro - 2 - Nitro - 4 - Sulfamylanilane (U) To 235 ml. of chlorosulfonic acid at 2 at 10 was added portion wise 83.0 g. of 5 - chloro - 2 - nitroaniline (I~). After the addition, the dark brown solution was stirred at 96 - 98C~for one hour, cooled, and carefully decanted into 2 1. of lce. The precipitate was collected by filtretion, washed with 1 1. of water, and air dried. To 365 ml. of 30~ ammonium hydroxlde was added in 4 portions the crude sulfamyl chloride. The su~pension was stirred for two hours at ambient temperature, heated at 100 for one hour, cooled and set overnight. Filtration of the precipitate followed by recrystallization from ethanol provided 30 g. of 5 - chloro - 2 - nitro - 4 - sulfamylanilane (V3 , as light yellow crystals, m.p. 249 - 251C.
Preparation of 2 - Amino - 5 - Chloro - 4 - Sulfamylanillne (VI) i 20 To 300 ml. of absolute methanol was added 19.25 g. of 5 - chloro - 2 -,. . .
nitro - 4 - sulfamylanilane (V). After flushing with nitrogen, 5.5 g. of 5~
; pallsdium on carbon was added and the mixture hydrogenated for two hours after ; which time no more hydrogen was taken up. The reaction was filtered, the charcoal washed with 100 ml. of absolute methanol, and the filtrate concentrated to yield 10.4 g. of crude product. Recrystallization from ethanol treated with ~; activated carbon provided 10.4 g. of 2 - amino - 5 - chloro - 4 - sulfamylanilane (VI) as brown needles, m.p. 216C.
.. . :
.
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~l12628~
Preparation o 2 ~ Amino - 5 - Chloro - 6 - Sulfamyl - lH - Benzimidazole ` Hydrobromlde (VII?
To 19.38 g. of cyanogen bromlde ln 408 ml. of water at 5 to 10 C was added portion wlse 15 g. of 2 - amino - 4 - chloro - 5 - sulfamylanillne (VI).
The suspenslon was stlrred at amblent temperature for two hours and then set overnight. After concentratlng the reactlon mlxture ln vacuo, the residue was dlssolved in bolllng ethanol and flltered to remove some insoluble material.
The ethanol solutlon was treated wlth charcoal, boiled, flltered, concentrated tq 200 ml. and cooled. Dllutlon wlth ether followed by lce coollng preclpltat-ed the product as off~white cry~tals which upon drying provided 7.30 g. of 2 - amlno - 5 - chloro - 6 - sulfamylbenzimadazole hydrobromide (YII), m.p.
317C, Analy~is: Calculated for C7H8Br CI N4 02S~
25.66% C; 2.46%H; 17.10%N; 9.79%S
Found: 25.78% C; 2,52ZH; 17.25%N; 9,60%S, ? nmr: (DMS0-d6 - CDC13): 7.55 (bd, 4H), 7.78 (S,lH), 8.18 (S,lH), and 8.959 (bd, 2 H) ir (K Br) 1680 cm (NH2) 4, Tlc (Silica gel): Rf ~ 0.60, methanol as eluant.
Preparatlon of 5 - Chloro - 2 - Guanidino - 6 - Sulfamyl - lH - Benzimidazole Hydrochlorlde (VIII) The procedure for maklng compound (VI) ls the same as glven ln Example 1. A mlxture of 2.22 g. of 2 - amlno - 4 - chloro - 5 - sulfamylanillne (VI) 0.84 g. of cyanoguanldlne, 2 ml. of concentrated hydrochlorlc acld, and 8 ml.
of water was refluxed for four hours. The reaction was concentrated in vacuo to a dar~ blue solid whlch was dlssolved ln methanol, treated wlth charcoal, bolled 5 mlnutes, flltered, cooled, and then filtered through celite. Dllutlon ~ ,. . .
' .
~ .
6~8~
!
with ether followed by ice cooling provided 0.2 g. of 5 - chloro - 2 - guanidino - 6 - sulfamyl - lH - benzimidazole hydrochloride (VIII) as off-white crystals, m p 291 292C
Analysis: Calculated for C8HloC12N602S:
; 29.55~C;3.10%H; 21.81%Cl; 25.85~N; 9.86%S
~- Found: 29.42%C; 3.17%H; 21.97%Cl; 25.67%N; 9.70%S
lr (K Br) 1630, 168$ cm (NCNH2) , Tlc (Silica gel): R5 ~ 0.55, methanol as eluant Therapeutically effective salts of the compounds of the invention may be made by methods which are per se known in the art and the resulting salts - are also useful as dluretlcs and antihypertensive agents. The most suitable salts are the acid addition salts of the compounds with physiologically compat-ible aclds to produce, for example, the sulfates, hydrochlorides, hydrobromides, phosphates, cyclohexyl sulfamates, maleates, cltrates, tartrates, succinates, ethane dlsulfonates, etc. The dluretic effectlveness of the compounds of the lnventlon was conflrmed by pharmacologlcal tests run on selected compounds.
For example, lntravenous admlnistration of compound (VIII) to male Sprague Dawley rats, compared to rats receivlng equal volumes of sallne lndicated great-; er urlne volume, greater sodium excretion and greater chloride excretion in the ; case of the animals to which the compound of the invention was administered.
' :
.
Preparation of 5-Chloro-2-Phenyl-6-Sulfamyl-lH-Benzimidazole A mixture of 2.21 g. of 2-amlno-4-chloro-5-sulfamylanllane (VI), 50 ml of glacial acetic acid, and 1.06 g of benzaldehyde was refluxed for 16 hours and then decanted lnto water. The precipitate was collected by filtration, dlssolved ln ethanol, treated with Darco, filtered through fllter paper and then through celite. Concentration in vacuo provided a solid which was dissolved in ethanol, ~lltered, and forced out wlth water. Treatment of thls beige solid ., . :
~Z628~
' with bolling acetronlle provided an off-white solld, mp 314-316. --Analysls: Calculated for C13HlOClN302S
50.73% C; 3.28~H 13.65~N
Found: 50.61% C; 3.54%H; 13.40%N
Preparation of 5-chloro-2-N -methylguanidlno-6-sulfamyl-lH-benzimidazole hydrochloride To 2.22 g of 2-amino-4-chloro-5-sul~amylaniline tYI) in 12 ml of water was adted 2 ml of concentrated hydrochloric acid and 2 ml of methanol. After addlng 1.23 g. of N-methyl-cyanoguanidine, the dark solution was refluxed for 45 mlnutes, cooled, and the resultant solld collected by filtratlon. The solid was dlssolved ln methanol and flltered. Darco was added to the flltrate and the suspenslon bolled 10 minutes, filtered through filter; paper, cooled and flltered through cellne. Dllutlon wlth ether provlded a pink solid which, upon drying, ylelded 0.5 g of light plnk solld, m.p. 284-286.
Analysis: Calculated for CgH12C12N602S
' 31.86~C; 3.57%H; 24.78~N; 9.45%S
Found: 31.44%C; 3.58%H; 24.58%N; 9.62%S
; ln (KBr) 1680 cm (NH2) Tlc (Slllca gel): R - 0.10, ethyl acetate as eluant.
The new compounds of the present lnventlon can be mlxed with any suitable pharmaceutlcal csrrler, solld or liqult to provlde diuretic and antlhypertensive q compositions. These compositions can be made for oral administration or for admlnlstration by lnJection. The active ingredlent can be in the form of the ba~e compound or the pharmaceutlcally acceptable salt thereof.
- 14 - ~
. ~ ,, ' .
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V ~ 2 .BrCN
C~ 3r ; ~ ~ VII H
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SULFAMYL - lH - BENZIMIDAZOLE HYDROCHLORIDE ~VIII?
'.~
I (CH3CO~20 II
/ ~N03 IV NaOCH3 III
~ 1. ClS03H
Z. NH40H
LH]
V ) VI
Cl ~ N / HCl 2 VIII
.
-1126~8~
As indicated above, in the structural formulas of the compounds of the inventlon which were lllustrated X i9 a halogen or trlfluoromethyl.
i Yl and Y2 are each hydrogen, alkyl, acyl, aryl, substltuted aryl or heterocycle. Most pre~erably Yl and ~2 are each either hydrogen and/or lower alkyl.
The substltutent Rl may be hydrogen~ lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle or substituted hetero-cycle. Most preferably Rl is hydrogen, lower alkyl, aryl or substituted aryl, preferably substituted by lower alkyl, alkoxy, or halogen.
As lndicated "n" may be 0 or an integer from 1-4.
Most preferably "n" = 0.
R2 may be amino, substituted amino, guanidino, substituted guanidino, halogen, alkyl, substituted alkyl, aryl, shbstltuted aryl or heterocycle. Most preferably R2 i9 amino, substituted amino substit~ted by lower alkyl or guani-dino.
The substituent R3 may be hydrogen, lower alkyl, aryl, substituted aryl, benzyl, substituted benzyl, aralkyl, heterocycle, su~s~ituted heterocyle or acyl.
Most preferably R3 is hydrogen or lower alkyl.
In addition to compounds (VII) and (VIII) shown above, other specific ; suitable compounds of the above Pormula lnclude:
5-- chloro - 2 - formamido - 6 - sulfamyl - lH - benzlmldazole 2-- carbethoxyamino - 5 - chloro - 6 - ~ulfamyl - lH - benzimidazole 2 - benzylamino - 5 - chloro - 6 sulfamyl - lH - benzimidazUe S - chloro - 6 - N,N - dimethylsulfonamido - 2 - guanidino - 1~ - benzimidazole 5 - chloro - 2 - guanidino - 6 - N - methylsulfonamido - lH - benzimidazole 2 - amino ~ 5 - chloro - 6 - sulfamyl - 1 - (o-tolyl) - lH - benzimidazole 2 - amino - 5 - chloro - 1 - (o-methylbenzyl) - 6 - sulfamyl - lH - benzimidazole ~, ,, , ' ' ~ . , ' ~` 11;~280 5 - chloro - 2 - dlmethylamlno - 6 - sulfamyl - lH - benzlmldazole 2 - dimethylamino - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzlmidazole 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzimidazole 5 - chloro - 2 - guanldlno - 1 - methyl - 6 - sulfa~yl - lH - benzimidazole 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzimldazole - 2 - acetamido - 5 - chloro - 6 - sulfamyl - lH - benzlmidazole 2 - carbethoxyamlno - 5 - chloro - 6 - sulfamyl - lH - benzimidazole 2 - formamido - 6 - sulfamyl - 5 - trlfluoromethyl - lH benzimidazole 2 - carbethoxyamlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimldazole , 10 2 - benzylamlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimidazole : 2 - benzylamlno - 5 - bromo - 6 - sulfa~yl - lH - benzlmidazole 5 - chloro - 2 - (2,6-- dichloro) anilino - 6 - sulfamyl - lH - benzimidazole 2 - (2,6 - dichloro) anllino - 6 - sulfamyl - 5 - trlfluoromethyl - lH -: benzlmldazole 5 - bromo - 2 - (2.6 - dlchloro) anillno - 6 - sulfamyl - lH - benzimidazole 5 - chloro - 2 - (2,6 - dimethyl) anilino - 6 - sulfamyl - lH - benzimldazole 2 - (2,6 - dimethyl) anlllno - 6 - sulfamyl - S - trlfluoromethyl - lH -benzlmldazole 5 - bromo - 2 - (2,6 - dlmethyl) anllino - 6 - sulfamyl - lH - benzimidazole 2 - amino - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzlmidazole 2 - amlno - 5 - bromo - 6 - sulfamyl - lH - benzimldazole 2 - guanldlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzlmldazole 5 - bromo - 2 - guanldino - 6 - sulfamyl - lH - benzimidazole 5 - chloro - 2 - guanldlno - 6 - N - methylsulfonamldo - lH - benzlmldazole 2 - amino - 5 - chloro - 6 - N - methylsulfonamldo - lH - benzlmidazole 2 - amlno - 6 - N - methylsulfonamido - S - trlfluoromethyl - lH - benzimidazole ,, 2 - amino - 5 - chloro - 6 - N,N - dlmethylsulfonamido - lH - benzimldazole .;, ; 2 - guanldino - 6 - N - methylsulfonamido - 5 - ~rlfluoromethyl - lH -benzlmidazole ; 30 5 - bromo - 2 - guanldlno - 6 - N-methylsulfonamido - lH - benzlmidazole ,~, .
.. ~ ~ ... .
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- `` 11~6Z8~
' 6 - N,N - dimethylsulfonamldo - 2 - guanidino - 5 - trifluoromethyl - lH -benzimidazole 5 - bromo - 6 - N,N - dimethylsulfonamldo - 2 - guanidino - lH - benzlmidazole 5 - fluoro - 2 - guanldino - 6 - sulfamyl - lH - benzlmidazole 2 - amlno - 5 - fluoro - 6 - sulfamyl - lH - benzimldazole 5 - chloro - 2 - [4 - (2,3~- dlchlorophenoxymethylcarboxyl)] amino - 6 - sulfamyl - lH - benzlmidazole 2 - [4 - 2,3 - dlchlorophenoxymethylcarboxy)] amino - 6 - sulfamyl - 5 - tri-fluoromethyl - lH - benzlmldazole 5 - bromo - 2 - [4 - (2,3 - dlchlorophenoxymethylcarboxy)~ amino - 6 - sulfamyl - 1 H - benzlmltazole 2 - amino - 5 - chloro - 6 - sulfamylbenzimidazolidine : 2 - amino - 6 - sulfamyl - 5 - trifluoromethylbenzlmldazolldlne 2 - amino - 5 - bromo - 6 - sulfamylbenzimidazolidine 5 - chloro - 2 - guanidino - 6 - sulfamylbenzlmidazolldine 2 - guanidlno - 6 - sulfamyl - 5 - trlfluoromethylbenzimidazolidine 5 - bromo - 2 - guanitino - 6 - ~ulfamylbenzlmidazolidlne 2 - amino - 5 - chloro - 6 - sulfamyl - 1 - (3-tolyl) - lH - benzimldazole : 2 - amino - 6 - sulfamyl - 1 - (3-tolyl) - 5 - trifluoromethyl - lH - benzl-: 20 mitazole 2 - amlno - 5 - bromo - 6 - sulfamyl - 1 - (3-tolyl) - lH - benzimldazole 2 - amino - 5 - chloro - 6 - sulfamyl - 1 - (4-tolyl~ - lH - benzimidazole 2 - amino - 6 - sulfamyl - 1 - (4-tolyl) - 5 - trifluoromethyl - lH benzimida-zole 2 - amlno - 5 - bro - 6 - sulfamyl - 1 - (4-tolyl) - lH - benzlmldazole 2 - amlno - 5 - chloro - 1 - (2,6 - dimethylphenyl) - 6 - sulfamyl - lH -benzlmidazole 2 - amino - 1 - (2,6 - dlmethylphenyl) - 6 - sulfamyl - 5 - trifluoromethyl -: lH - benzimldazole ~; 30 2 - amlno - 5 - bromo - 1 - (2,6 - dimethylphenyl) - 6 - sulfamyl - lH -benzimidazole 2 - amino - 5 - chloro - 6 - culfamyl - 1 - (2-tolyl) benzimidazolldlne , ~...... ., ~ . .
~Z6Z8~
2 - amino - 6 - sulfamyl - 1 - (2-tolyl) - 5 - trifluoromethylbenzimidazolidine 2 - amino - 5 - bromo - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine 5 - chloro - 2 - guanidino - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine 2 - guanidino - 6 - sulfamyl - 1 - (2-tolyl)- 5 - trifluoromethylbenzimidazolidine , 5 - bromo - 2 - guanidlno - 6 - sulfamyl - 1 - (2-tolyl) benzimidazolidine 2 - amlno - 5 - chloro - 1 - (2-methoxyphenyl)- 6 - sulfamyl-lH- benzlmidazole ~4 2 - amino - 1 - (2-methoxyphenyl) - 6 - sulfamyl - 5 - trifluoromethyl - lH -benzimldazole 2 - amino - 5 - bromo - 1 - (2-methoxyphenyl) - 6 - sulfamyl - lH - benzimidazole ?, 2 - amlno - 5-chloro -1 - (2-methoxyphenyl) - 6 - sulfamyl - lH - benzimidazole ; 2 - amino - 1 - (2-chlorophenyl) - 6 - sulfamyl - 5 - trifluoromethyl - lH -benzlmidazole ; 2 - amino - 5 - bromo - 1 - (2-chlorophenyl) - 6 - sulfamyl - lH - benzimidazole ; 5 - chloro - 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamyl - lH - benzi-midazole 1 - (2-chlorophenyl) - 2 - guanldlno - 6 - sulfamyl - 5 - trlfluoromethyl - lH -.~ benzlmidazole 5 - bromo - 1 - (2-chlorophenyl) - 2- guanidlno - 6 - sulfamyl-lH- benzimidazole 2 - amino - 5 - chloro - 1 - (2-chlorophenyl) - 6 - sulfamylbenzimidazolidine 2 - amlno - 1 - (2-chlorophenyl) - 6 - sulfamyl - 5 - trifluoromethylbenzi-midazolldlne 2 - amlno - 5 - bromo - 1 - (2-chlorophenyl) - 6 - sulfamylbenzlmldazolldine :'' , , 5 - chloro - 1 - (2-chlorophenyl) - 2 - guanldino - 6 - sulfamylbenzimazolidine 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamyl - 5 - trlfluoromethyl ;, benzlmldazolitlne , I
;, 5 - bro - 1 - (2-chlorophenyl) - 2 - guanidlno - 6 - sulfamylbenzimidazolidine ., 5 - chloro - 2 - (furfurylamino) - 6 - sulfamyl - lH - benzlmldazole 2 - (furfurylamlno) - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzlmidazole ,. 5 - chloro - 2 - (furfurylamino) - 6 - sulfamylbenzimidazolidine 2 - (furfurylamino) - 6 - sulfamyl - 5 - trlfluoromethylbenzlmldazolidine 5 - chloro - 6 - sulfamyl - 2 - (2-tolyl) - lH - benzimldazole .~ 2 - (2-tolyl) - 6 - sulfamyl - 5 - trlfluoromethyl - lH - benzimldazole : - 8 -, ' ':, , ' , ~, , ~ - -. ~ ' ' , ~ 628~
S - chloro - 6 - sulfamyl - 2 - (2-tolyl) benzlmldazolidine - 6 - sulfamyl - 2 - (2-tolyl) - 5 - trlfluoromethylbenzimidazolidlne 5 - chloro - 6 - sulfamyl - 2 - (3-tolyl) - lH - benzimldazole ~; 6 - sulfamyl - 2 - (3-tolyl) - 5 - trifluoromethyl - lH - benzimidazole 5 - chloro - 2 - phenyl - 6 - sulfamyl - lH - benzimidazole 2 - phenyl - 6 - sulfamyl - S - trlfluoromethyl - lH - benzimidazole 5 - chloro - 6 - sulfamyl - 2 - (3-tolyl) benzimidazolldine 6 - sulfamyl - 2 - (3-tolyl) - 5 - trlfluoromethylbenzimidazolidine 5 - chloro - 2 - phenyl - 6 - sulfamylbenzimidazolidine 2 - phenyl - 6 - sulfamyl - 5 - trlfluoromethylbenzimidazolidine 2 - (3-carboxy-4-hydroxy) anilino - 6 - sulfamyl - 5 - trifluoromethyl - lH -benzimitazole 2 - (3-carboxy-4-hydroxy) anlllno - 5 - chloro - 6 - sulfamyl - lH - benzimida-zole 5 - bromo - 2 - (3-carboxy-4-hydroxy) anllino - 6 - sulfamyl - lH - benzimida-~: zole ': 2 - (4-carboxy-3-hydroxy) anlllno - 5 - chloro - 6 - sulfamyl - lH - benzimida-,~ zole ; 2 - (4-carboxy-3-hydroxy) anilino - 6 - sulfam~l - 5 - trifluoromethyl - lH -benzlmidazole i: 5 - bromo - 2 - (4-carboxy-3-hydroxy) anilino - 6 - sulfamyl - lH -~benzimida-; zole , 5 - chloro - 2 - (N -methylguanidino) - 6 - sulfamyl - lH - benzimidazole 5 - bromo - 2 - (N3-methylguanldino) - 6 - sulfamyl - lH - benzimidazole 2 - (N -methylguanidino) - 6 - sulfamyl - 5 - trifluoromethyl - lH - benzimida-zole , 5 - chloro - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) - lH -benzimidazole ' 5 - bromo - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) - lH -benzlmldazole : 2 - (N3-methylguanidino) - 6 - sulfamy~l - 1 - (2-tolyl) - S - trlfluoromethyl -; lH - benzimidazole . S - bromo - 2 - (N3-methylguanidino) - 6 - sulfamylbenzimidazolidine , ,;
_ 9 _ ',';
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,~
6Z8~
5 - chloro - 2 - (N3-methylguanidino) - 6 - sulfamyl - 1 - (2-tolyl) ben~imida-zolidine 5(6)-chloro-2-methyl-6(5)-sulfamyl-1(3)H-benzimidazole hydrochloride 5(6)-chloro-benzlmldazole-6(5)-sulfonamide 5(6)-chloro-2-(2-furyl)-6(5)-~ulfamyl-1(3)H-benzim~da~ole 2-acetylamlno-5(6)-chloro-benzlmldazole-6(5)-sulfonamide 2,5(6)-dlchloro-6(5)-sulfamyl-1(3)H-benzimidazole HCl ~onohydrate 5(6)-chloro-2-propyl-6(5)-sulfam~l -1(3)H-benzimldazole 2-benzyl-5(6)-chloro-6(5)-sulfamyl-1-(3)H-benzlmldazole HCl monohydrate 10The following examples are given to illustrate the production of compounds according to the lnventlon. The scope of the invention is not, however, meant to be llmlted to the speclflc details of the examples Preparatlon of 3 - Chloroacetanillde (II) To 500 g. of 3 - chloroanlllne ~I) suspended ln 4.5 1. of water heated to 35 was added stream wlse 690 g. of acetic anhydride over a 40 minute period.
After the addltion, the reactlon was stlrred for 4 hours, filtered, and the ; product washed wlth 12 1. of water and drled to provide 620.2 g. of 3-chloro-acetanlllde (II) as whlte crystals, m.p. 72.5 - 73C.
! 20 Preparatlon of 5 - Chloro - 2 - ~ltroacetanillde_(III) ; To 100 g. of 3 - chloroacetanlllde ~II) ln 110 ml. of acetlc acld and 120 ml. of acetlc snhydrlde was added dropwlse at -10 to -5C 44 ml. of 90%
fumlng nltrlc acld ln 50 ml. of glacial acetlc acld. After completlon of the addltlon, the yellow solutlon was stirred for one hour at 0 to +5C and then ; decanted into lce water. The yellow solld was collected by fll~ratlon, stirred 30 mlnutes wlth water, flltered, and then stlrred 20 mlnutes wlth 1 1. of ether and flltered. Drylng of the solld provlded 110 g. of 5 - chloro - 2 - nltro-acetanlllde (III) as a llght tan solid, m.p. 114 - 116C.
' '., ~
1~ 28~
, Preparation of 5 - Chloro - 2 - Nltroanillne (IV) To 3 1. of absolute methanol was slowly added 2.4 g, of sodium. When all the sodlum had dissolved, 68 g. of 5 - chloro - 2 - nltroacetanillde was added with stlrring and the solution refluxed for 7 hours. The solution was allowed to sit overnight and then concentrated in vacuo until crystals formed.
Piltration of the precipitate provlded 51 g. of 5 - chloro - 2 - nitoraniline (IV) as yellow needles, m.p. 124 - 126C.
Pre~aratlon of 5 - Chloro - 2 - Nitro - 4 - Sulfamylanilane (U) To 235 ml. of chlorosulfonic acid at 2 at 10 was added portion wise 83.0 g. of 5 - chloro - 2 - nitroaniline (I~). After the addition, the dark brown solution was stirred at 96 - 98C~for one hour, cooled, and carefully decanted into 2 1. of lce. The precipitate was collected by filtretion, washed with 1 1. of water, and air dried. To 365 ml. of 30~ ammonium hydroxlde was added in 4 portions the crude sulfamyl chloride. The su~pension was stirred for two hours at ambient temperature, heated at 100 for one hour, cooled and set overnight. Filtration of the precipitate followed by recrystallization from ethanol provided 30 g. of 5 - chloro - 2 - nitro - 4 - sulfamylanilane (V3 , as light yellow crystals, m.p. 249 - 251C.
Preparation of 2 - Amino - 5 - Chloro - 4 - Sulfamylanillne (VI) i 20 To 300 ml. of absolute methanol was added 19.25 g. of 5 - chloro - 2 -,. . .
nitro - 4 - sulfamylanilane (V). After flushing with nitrogen, 5.5 g. of 5~
; pallsdium on carbon was added and the mixture hydrogenated for two hours after ; which time no more hydrogen was taken up. The reaction was filtered, the charcoal washed with 100 ml. of absolute methanol, and the filtrate concentrated to yield 10.4 g. of crude product. Recrystallization from ethanol treated with ~; activated carbon provided 10.4 g. of 2 - amino - 5 - chloro - 4 - sulfamylanilane (VI) as brown needles, m.p. 216C.
.. . :
.
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~l12628~
Preparation o 2 ~ Amino - 5 - Chloro - 6 - Sulfamyl - lH - Benzimidazole ` Hydrobromlde (VII?
To 19.38 g. of cyanogen bromlde ln 408 ml. of water at 5 to 10 C was added portion wlse 15 g. of 2 - amino - 4 - chloro - 5 - sulfamylanillne (VI).
The suspenslon was stlrred at amblent temperature for two hours and then set overnight. After concentratlng the reactlon mlxture ln vacuo, the residue was dlssolved in bolllng ethanol and flltered to remove some insoluble material.
The ethanol solutlon was treated wlth charcoal, boiled, flltered, concentrated tq 200 ml. and cooled. Dllutlon wlth ether followed by lce coollng preclpltat-ed the product as off~white cry~tals which upon drying provided 7.30 g. of 2 - amlno - 5 - chloro - 6 - sulfamylbenzimadazole hydrobromide (YII), m.p.
317C, Analy~is: Calculated for C7H8Br CI N4 02S~
25.66% C; 2.46%H; 17.10%N; 9.79%S
Found: 25.78% C; 2,52ZH; 17.25%N; 9,60%S, ? nmr: (DMS0-d6 - CDC13): 7.55 (bd, 4H), 7.78 (S,lH), 8.18 (S,lH), and 8.959 (bd, 2 H) ir (K Br) 1680 cm (NH2) 4, Tlc (Silica gel): Rf ~ 0.60, methanol as eluant.
Preparatlon of 5 - Chloro - 2 - Guanidino - 6 - Sulfamyl - lH - Benzimidazole Hydrochlorlde (VIII) The procedure for maklng compound (VI) ls the same as glven ln Example 1. A mlxture of 2.22 g. of 2 - amlno - 4 - chloro - 5 - sulfamylanillne (VI) 0.84 g. of cyanoguanldlne, 2 ml. of concentrated hydrochlorlc acld, and 8 ml.
of water was refluxed for four hours. The reaction was concentrated in vacuo to a dar~ blue solid whlch was dlssolved ln methanol, treated wlth charcoal, bolled 5 mlnutes, flltered, cooled, and then filtered through celite. Dllutlon ~ ,. . .
' .
~ .
6~8~
!
with ether followed by ice cooling provided 0.2 g. of 5 - chloro - 2 - guanidino - 6 - sulfamyl - lH - benzimidazole hydrochloride (VIII) as off-white crystals, m p 291 292C
Analysis: Calculated for C8HloC12N602S:
; 29.55~C;3.10%H; 21.81%Cl; 25.85~N; 9.86%S
~- Found: 29.42%C; 3.17%H; 21.97%Cl; 25.67%N; 9.70%S
lr (K Br) 1630, 168$ cm (NCNH2) , Tlc (Silica gel): R5 ~ 0.55, methanol as eluant Therapeutically effective salts of the compounds of the invention may be made by methods which are per se known in the art and the resulting salts - are also useful as dluretlcs and antihypertensive agents. The most suitable salts are the acid addition salts of the compounds with physiologically compat-ible aclds to produce, for example, the sulfates, hydrochlorides, hydrobromides, phosphates, cyclohexyl sulfamates, maleates, cltrates, tartrates, succinates, ethane dlsulfonates, etc. The dluretic effectlveness of the compounds of the lnventlon was conflrmed by pharmacologlcal tests run on selected compounds.
For example, lntravenous admlnistration of compound (VIII) to male Sprague Dawley rats, compared to rats receivlng equal volumes of sallne lndicated great-; er urlne volume, greater sodium excretion and greater chloride excretion in the ; case of the animals to which the compound of the invention was administered.
' :
.
Preparation of 5-Chloro-2-Phenyl-6-Sulfamyl-lH-Benzimidazole A mixture of 2.21 g. of 2-amlno-4-chloro-5-sulfamylanllane (VI), 50 ml of glacial acetic acid, and 1.06 g of benzaldehyde was refluxed for 16 hours and then decanted lnto water. The precipitate was collected by filtration, dlssolved ln ethanol, treated with Darco, filtered through fllter paper and then through celite. Concentration in vacuo provided a solid which was dissolved in ethanol, ~lltered, and forced out wlth water. Treatment of thls beige solid ., . :
~Z628~
' with bolling acetronlle provided an off-white solld, mp 314-316. --Analysls: Calculated for C13HlOClN302S
50.73% C; 3.28~H 13.65~N
Found: 50.61% C; 3.54%H; 13.40%N
Preparation of 5-chloro-2-N -methylguanidlno-6-sulfamyl-lH-benzimidazole hydrochloride To 2.22 g of 2-amino-4-chloro-5-sul~amylaniline tYI) in 12 ml of water was adted 2 ml of concentrated hydrochloric acid and 2 ml of methanol. After addlng 1.23 g. of N-methyl-cyanoguanidine, the dark solution was refluxed for 45 mlnutes, cooled, and the resultant solld collected by filtratlon. The solid was dlssolved ln methanol and flltered. Darco was added to the flltrate and the suspenslon bolled 10 minutes, filtered through filter; paper, cooled and flltered through cellne. Dllutlon wlth ether provlded a pink solid which, upon drying, ylelded 0.5 g of light plnk solld, m.p. 284-286.
Analysis: Calculated for CgH12C12N602S
' 31.86~C; 3.57%H; 24.78~N; 9.45%S
Found: 31.44%C; 3.58%H; 24.58%N; 9.62%S
; ln (KBr) 1680 cm (NH2) Tlc (Slllca gel): R - 0.10, ethyl acetate as eluant.
The new compounds of the present lnventlon can be mlxed with any suitable pharmaceutlcal csrrler, solld or liqult to provlde diuretic and antlhypertensive q compositions. These compositions can be made for oral administration or for admlnlstration by lnJection. The active ingredlent can be in the form of the ba~e compound or the pharmaceutlcally acceptable salt thereof.
- 14 - ~
. ~ ,, ' .
~.
, , '' . ''
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a sulfamyl benzimidazole of formula and pharmaceutically acceptable acid addition salts thereof wherein n is 0 or an integer from 1 to 4, X is halogen or trifluoromethyl and R2 is amino, furyl, halogen, lower alkyl, lower alkyl substituted by phenyl, phenyl, phenyl substituted by lower alkyl, formamido, guanidino, guanidino substituted by lower alkyl, and amino substituted by lower alkyl, by carboxy, by carboxy-lower alkyl, by lower alkyl-carboxy, by phenyl, by benzyl, by phenyl substituted by carboxy, by phenyl substituted by hydroxy, by phenyl substituted by lower alkyl, by phenyl substituted by halogen, by furfuryl, by carboxy substituted by phenoxy lower alkyl and by carboxy substituted by dihalogeno phenoxy lower alkyl;
which comprises subjecting a compound of formula wherein X is as already defined to ring closure with a compound that will add the substituent - (CH2)nR2 wherein n and R2 are as defined, at the 2-position of the formed sulfamyl benzimidazole and recovering the required sulfamyl benzimidazole.
which comprises subjecting a compound of formula wherein X is as already defined to ring closure with a compound that will add the substituent - (CH2)nR2 wherein n and R2 are as defined, at the 2-position of the formed sulfamyl benzimidazole and recovering the required sulfamyl benzimidazole.
2. The process of claim 1 wherein the compound that will add a substituent -(CH2)nR2 is a cyanide or an aldehyde.
3. A compound of the formula and pharmaceutically acceptable acid addition salts thereof wherein n is 0 or an integer from 1 to 4, X is halogen or trifluoromethyl and R2 is amino, furyl, halogen, lower alkyl, lower alkyl substituted by phenyl, phenyl, phenyl substituted by lower alkyl, formamido, guanidino, guanidino substituted by lower alkyl, and amino substituted by lower alkyl, by carboxy, by carboxy-lower alkyl, by lower alkyl-carboxy, by phenyl, by benzyl, by phenyl substituted by carboxy, by phenyl substituted by hydroxy, by phenyl substituted by lower alkyl, by phenyl substituted by halogen, by furfuryl, by carboxy substituted by phenoxy lower alkyl and by carboxy substituted by dihalogeno phenoxy lower alkyl;
when prepared by the process of claim I or an obvious chemical equivalent.
when prepared by the process of claim I or an obvious chemical equivalent.
4. A process for the preparation of the compound 2-amino-5-chloro-6-sulf-amyl-1H-benzimidazole hydrobromide, which comprises reacting 2-amino-4-chloro-5-sulfamylaniline with cyanogen bromide in suspension and recovering the required compound.
5. 2-amino-5-chloro-6-sulfamyl-1H-benzimidazole hydrobromide when prepared by the process of claim 4 or an obvious chemical equivalent.
6. A process for the preparation of the compound 5-chloro-2-guanidino-6-sulfamyl-1H-benzimidazole hydrochloride which comprises reacting 2-amino-4-chloro-5-sulfamylaniline with cyanoguanidine in the presence of HCl and water and recovering the required compound.
7. 5-chloro-2-guanidino-6-sulfamyl-1H-benzimidazole hydrochloride when prepared by the process of claim 6 or an obvious chemical equivalent.
8. A process for the preparation of the compound 5-chloro-2-phenyl-6-sulf-amyl-1H-benzimidazole which comprises reacting 2-amino-4-chloro-5-sulfamylan-iline with benzaldehyde in glacial acetic acid and recovering the required compound.
9. 5-chloro-2-phenyl-6-sulfamyl-1H-benzimidazole when prepared by the process of claim 8 or an obvious chemical equivalent.
10. A process for the preparation of the compound 5-chloro-2-N3-methyl-guanidino-6-sulfamyl-1H-benzimidazole hydrochloride which comprises reacting 2-amino-4-chloro-5-sulfamylaniline with N-methyl cyanoguanidine in the presence of HCl in solution and recovering the required compound.
11. 5-chloro-2-N3-methylguanidino-6-sulfamyl-1H-benzimidazole hydrochloride when prepared by the process of claim 10 or an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89504878A | 1978-04-10 | 1978-04-10 | |
| US895,048 | 1978-04-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1126280A true CA1126280A (en) | 1982-06-22 |
Family
ID=25403870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA324,146A Expired CA1126280A (en) | 1978-04-10 | 1979-03-26 | Benzimidazole and benzimidazolidine derivatives with diuretic and antihypertensive activity |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS54138561A (en) |
| AT (1) | AT372951B (en) |
| AU (1) | AU531086B2 (en) |
| BE (1) | BE875425A (en) |
| CA (1) | CA1126280A (en) |
| DE (1) | DE2914084A1 (en) |
| DK (1) | DK139079A (en) |
| ES (1) | ES479446A1 (en) |
| FI (1) | FI74461C (en) |
| FR (1) | FR2422644A1 (en) |
| GB (1) | GB2018766B (en) |
| GR (1) | GR68483B (en) |
| IL (1) | IL57105A (en) |
| IT (1) | IT1193755B (en) |
| NL (1) | NL7902802A (en) |
| NZ (1) | NZ190136A (en) |
| PT (1) | PT69458A (en) |
| SE (1) | SE446532B (en) |
| ZA (1) | ZA791726B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070466A (en) * | 2010-12-28 | 2011-05-25 | 天津市筠凯化工科技有限公司 | Preparation method of 5-chiorine-2-nitroaniline |
| CN108558712A (en) * | 2018-06-20 | 2018-09-21 | 新乡市锦源化工有限公司 | It is a kind of using antifebrin as the method and P-aminobenzene-sulfonamide of Material synthesis high-purity P-aminobenzene-sulfonamide |
| CN110305018B (en) * | 2019-06-06 | 2022-07-15 | 浙江普洛家园药业有限公司 | Preparation method of 3-bromo-2-fluoronitrobenzene |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH404675A (en) * | 1961-06-29 | 1965-12-31 | Siegfried Ag | Process for the preparation of new heterocyclic sulfonamido compounds |
| FR1469504A (en) * | 1964-10-22 | 1967-02-17 | Fisons Pest Control Ltd | Insecticidal compounds |
| FR1477792A (en) * | 1965-03-24 | 1967-04-21 | Fisons Pest Control Ltd | New benzimidazoles |
| GB1163711A (en) * | 1966-01-13 | 1969-09-10 | Fisons Pest Control Ltd | Substituted Benzimidazoles and Biocidally-Active Compositions |
| GB1356244A (en) * | 1970-07-29 | 1974-06-12 | Fisons Ltd | Substituted benzimidazole parasiticides |
-
1979
- 1979-03-26 CA CA324,146A patent/CA1126280A/en not_active Expired
- 1979-04-02 AU AU45675/79A patent/AU531086B2/en not_active Ceased
- 1979-04-02 SE SE7902911A patent/SE446532B/en not_active IP Right Cessation
- 1979-04-02 FI FI791083A patent/FI74461C/en not_active IP Right Cessation
- 1979-04-03 GR GR58771A patent/GR68483B/el unknown
- 1979-04-04 DK DK139079A patent/DK139079A/en not_active IP Right Cessation
- 1979-04-06 GB GB7912255A patent/GB2018766B/en not_active Expired
- 1979-04-07 DE DE19792914084 patent/DE2914084A1/en not_active Withdrawn
- 1979-04-09 NZ NZ190136A patent/NZ190136A/en unknown
- 1979-04-09 PT PT69458A patent/PT69458A/en unknown
- 1979-04-09 JP JP4211979A patent/JPS54138561A/en active Granted
- 1979-04-09 ES ES479446A patent/ES479446A1/en not_active Expired
- 1979-04-09 FR FR7908945A patent/FR2422644A1/en active Granted
- 1979-04-09 BE BE0/194480A patent/BE875425A/en not_active IP Right Cessation
- 1979-04-09 AT AT0263379A patent/AT372951B/en not_active IP Right Cessation
- 1979-04-10 NL NL7902802A patent/NL7902802A/en not_active Application Discontinuation
- 1979-04-10 ZA ZA791726A patent/ZA791726B/en unknown
- 1979-04-10 IT IT48686/79A patent/IT1193755B/en active
- 1979-04-22 IL IL57105A patent/IL57105A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI791083A (en) | 1979-10-11 |
| IT7948686A0 (en) | 1979-04-10 |
| IT1193755B (en) | 1988-08-24 |
| DE2914084A1 (en) | 1979-10-25 |
| SE7902911L (en) | 1979-10-11 |
| NZ190136A (en) | 1982-11-23 |
| AT372951B (en) | 1983-12-12 |
| NL7902802A (en) | 1979-10-12 |
| GB2018766A (en) | 1979-10-24 |
| ES479446A1 (en) | 1979-08-01 |
| AU531086B2 (en) | 1983-08-11 |
| DK139079A (en) | 1979-10-11 |
| JPS54138561A (en) | 1979-10-27 |
| FR2422644A1 (en) | 1979-11-09 |
| JPH0250904B2 (en) | 1990-11-05 |
| BE875425A (en) | 1979-07-31 |
| ZA791726B (en) | 1980-05-28 |
| SE446532B (en) | 1986-09-22 |
| FR2422644B1 (en) | 1982-12-17 |
| IL57105A (en) | 1983-10-31 |
| FI74461C (en) | 1988-02-08 |
| ATA263379A (en) | 1983-04-15 |
| GR68483B (en) | 1982-01-04 |
| FI74461B (en) | 1987-10-30 |
| GB2018766B (en) | 1982-09-22 |
| PT69458A (en) | 1979-05-01 |
| IL57105A0 (en) | 1979-07-25 |
| AU4567579A (en) | 1979-10-18 |
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