GB1572271A - Creación de Inventos y Patentes con Inteligencia Artificial

GB1572271A – 5-acetyl-4-hydroxy-(3(1-phenylaminoethylidene)-2h-pyran-2,6(3h)-dione derivatives
– Google Patents

GB1572271A – 5-acetyl-4-hydroxy-(3(1-phenylaminoethylidene)-2h-pyran-2,6(3h)-dione derivatives
– Google Patents
5-acetyl-4-hydroxy-(3(1-phenylaminoethylidene)-2h-pyran-2,6(3h)-dione derivatives

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Publication number
GB1572271A

GB1572271A
GB22233/77A
GB2223377A
GB1572271A
GB 1572271 A
GB1572271 A
GB 1572271A
GB 22233/77 A
GB22233/77 A
GB 22233/77A
GB 2223377 A
GB2223377 A
GB 2223377A
GB 1572271 A
GB1572271 A
GB 1572271A
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GB
United Kingdom
Prior art keywords
compound
composition
pyran
amino
formula
Prior art date
1976-06-16
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired

Application number
GB22233/77A
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GlaxoSmithKline LLC

Original Assignee
SmithKline Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1976-06-16
Filing date
1977-05-26
Publication date
1980-07-30

1977-05-26
Application filed by SmithKline Corp
filed
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SmithKline Corp

1980-07-30
Publication of GB1572271A
publication
Critical
patent/GB1572271A/en

Status
Expired
legal-status
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Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings

C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members

C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P37/00—Drugs for immunological or allergic disorders

A61P37/08—Antiallergic agents

Description

PATENT SPECIFICATION ( 11) 1 572 271
1-, ( 21) Application No 22233/77 ( 22) Filed 26 May 1977 ( 19) e ( 31) Convention Application No 696461 ( 32) Filed 16 Jun 1976 in ( 33) United States of America (US) l ( 44) Complete Specification Published 30 Jul 1980 ( 51) INT CL 3 C 07 D 307/32 A 61 K 31/35 ( 52) Index at Acceptance X C 2 C 1671 200 215 220 227 22 Y 253 Y 271 281 292 29 X 29 Y 30 Y 321 322 324 32 Y 332 342 34 Y 351 352 354 355 365 369 36 Y 385 510 515 51 X 591 592 595 597 601 602 611 620 621 623 62 X 630 631 63 X 640 645 660 661 665 672 702 761 802 Y AA KH KT KY LK LP LW MA SA ( 54) 5-ACETYL-4-HYDROXY-3 ( 1-PHENYLAMINOETHYLIDENE)2 H-PYRAN-2,6 ( 3 H) DIONE DERIVATIVES We, SMITHKLINE CORPORATION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following 5 statement:-
This invention relates to substituted 2 H-pyran-2,6 ( 3 H) dione derivatives which are useful for inhibiting the symptoms of an allergic response resulting from an antigenantibody reaction More specifically, the compounds of this invention are believed to be effective by inhibiting the release and/or formation and release of pharmacologically active 10 mediators such as histamine, serotonin and slow-reacting substance of anaphylaxis (SRS-A) from effector cells which are produced and/or released as a result of an interaction of antigen and specific antibody fixed to the cell surface (allergic reaction) These properties enable the subject compounds to be useful in various allergic diseases such as asthma, rhinitis and urticaria 15 Accordingly the invention provides a compound represented by the following general structural formula (I):O OH H 3 R 120 20 CH 3 C’C NH 3 0 «‘ »» O «R 2 25 (I) wherein:
R, and R 2 which are the same or different, represent amino, C, to Cs straight or branched chain alkanoylamino or methyl-sulphonamido; mono and di alkali metal salts of 30 said compounds and pharmaceutically acceptable acid addition salts thereof when at least one of R, or R 2 is amino.
Particular compounds of this invention represented by formula I above are 3,5-bisacetamido: 3,5-bis-propionamido: 3,5-bis-methylsulphonamido; 3,5-diamino and 3-amino5-acetamido derivatives 35 The compounds of formula (I) in which R, and R 2 are C, to Cs straight or branched chain alkanoylamino or methyl-sulphonamido can be prepared by a process which comprises reacting 3,5-diacetvl-4,6-dihydroxy-2 H-pyran-2-one and an appropriately substituted aniline of formula (ii):NH 2 RI, R 2 5 (‘i) wherein R 1 and R 2 and C 2 to C 5 straight or branched chain alkanoylamino or 10 methylsulphonamido The reaction can be suitably carried out by reacting the reagents at reflux in an inert organic solvent, for example benzene, toluene, ethanol or methanol for from one to three hours to give the products To prepare the compounds of formula (I) wherein one or both of RI to R 2 is amino, an aniline of formula (II) above wherein one or both of R 1 and R 2 is nitro is reacted as above 15 with the pyran-2-one to give the corresponding nitro substituted derivative which is hydrogenated catalytically, for example using palladium-on-carbon, to obtain the free amino products.
Mono and di-alkali metal salts of the compounds of formula (I), for example the monoand di-sodium or potassium salts are readily obtainable by reaction with the appropriate 20 alkali metal alkoxide, for example methoxide, in an alkanol solvent such as methanol.
Similarly, the free amino products (R 1/R 2 is amino) may be used in the form of a pharmaceutically acceptable acid addition salt, for example, those formed with either an inorganic or organic acid e g, as maleic, fumaric, methanesulphonic, acetic, hydrochloric, hydrobromic or sulphuric acids 25 The pyran-2-one starting material indicated above can be obtained by reaction of acetonedicarboxylic acid with acetic anhydride in sulphuric acid at elevated temperature.
The reaction product has the tautomeric structure as shown below.
00000 30 (A) OH j OH OH 30 CH/ CH IOH CH 3/ X C 3 CH 3 -3 CH 3 CH 3 C NCH 3 HO O a O O O a O OH 35 O o 40 IIi H Il’I 1 ?H II C C CH 3 C’ C CH 3 HO OH 45 however for convenience it is designated herein as 3,5-diacetyl-4,6dihydroxy-2 H-pyran-2one Accordingly the reaction of this product with an aniline as shown above gives a product having the tautomeric structures as shown below:
(B) 1 OH CH 3 R O OH CH 3 R ( 8 >I II ? CH 3 N CH 3) 290 C.
This nitrobenzene ( 1 3 g, 0 0052 mol) was hydrogenated in a mixture of 200 ml of ethanol and 0 3 g of 10 % palladium-on-carbon in a Parr apparatus at room temperature 10 The aniline product was obtained upon usual workup.
To a refluxing mixture of 0 96 g ( 0 0045 mol) of 3,5-diacetyl-4,6dihydroxy-2 H-pyran-2one in 35 ml of methanol was added a solution of 1 g ( 0 0045 mol) of 3,5bisacetamidoaniline (prepared as above) in 15 ml of methanol After three hours at reflux, the reaction mixture was cooled and filtered to yield 5-acetyl-4-hydroxy3-l 1-( 3,5-bis 15 acetamidophenylamino)ethylidenel-2 H-pyrani-2,6 ( 3 H)-dione, m p 265-267 C (dec).
Both the mono and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.
Example 3 20
To a mixture of 1 8 g of 3,5-diaminonitrobenzene and 20 ml of propionic acid were added 5 ml of propionic anhydride and the resulting mixture was heated at reflux for 30 minutes The cooled reaction mixture was poured over ice/water and stirred for one hour.
Filtration gave the product 3,5-bis-propionamidonitrobenzene, m p 197-198 C.
Following the procedures outlined in Example 2, this nitrobenzene was hydrogenated to 25 the 3,5-bis-propion-amidoaniline and the latter ( 2 15 g, 0 0084 mol) was reacted with 1 75 g ( 0 0084 mol) of 3,5-diacetyl-4,6-dihydroxy-2 H-pyran-2-one to furnish 5-acetyl-4hydroxy-3-l 1 -( 3,5-bis-propionamidophenylamino)ethylidenel-2 H-pyran-2, 6 ( 3 H)-dione, m.p 239-241 (dec).
Similarly, reaction of 3,5-diaminonitrobenzene in isobutyric acid with isobutyric 30 anhydride furnishes the 35-bis-isobutyramidonitrobenzene which is further reacted as outlined in Example 2 to yield 5-acetyl-4-hydroxy-3-l 1-( 3,5-bisisobutyramidophenylamino)ethylidenel-2 H-pyran-2,6-( 3 H)-dione.
Example 4 35
A mixture of 10 g ( 0 0546 mol) of 3,5-dinitroaniline (prepared as in Example 2) and 25 ml of glacial acetic acid was heated until all the solid dissolved Acetic anhydride ( 10 ml) was added and the resulting mixture was refluxed for 10 minutes Cooling followed by diluting to 350 ml with water gave 3,5-dinitroacetanilide, m p 190-191 C.
The acetanilide thus prepared ( 9 5 g, 0 042 mol) was refluxed in a mixture of 140 ml of 40 ethanol and 140 ml of ammonium sulfide solution (prepared as in Example 2) Evaporation of ethanol in vacuo, filtration and treatment of the filtrate with concentrated aqueous ammonia solution gave 3-acetamido-5-nitroaniline, m p 204-205 C.
The nitroaniline ( 3 8 g, 0 0195 mol) was refluxed with 4 1 g ( 0 0195 mol) of 3,5-diacetyl-4,6-dihydroxy-2 H-pyran-2-one in 120 ml of methanol for two hours The 45 reaction mixture was filtered hot, isolating 5-acetyl-4-hydroxy-3-l 1-( 3acetamido-5nitrophenylamino)ethylidenel-2 H-pyran-2,6 ( 3 H)-dione, m p > 270 C.
This dione ( 1 g 0 00256 mol) was hydrogenated at room temperature in a mixture of 100 ml of ethanol 0 3 g of 10 % palladium-on-carbon and 0 3 ml of concentrated hydrochloric acid in a Parr apparatus The reaction mixture was filtered and the filter cake was stirred in 50 ml of dimethylformamide under argon Filtering again and treatment of the filtrate with ml of water yielded 5-acetyl-4-hydroxy-3-l 1-( 3-amino-5acetamidophenylamino)ethylidenel-2 H-pyran-2,6 ( 3 H)-dione, hydrate, m p 227-230 C.
(dec).
Treatment of the product thus obtained, in tetrahydrofuran solution, with etheral 55 hydrogen chloride gives the corresponding hydrochloride salt.
As a specific embodiment of a composition of this invention, an active ingredient such as 5-acetyl-4-hydroxy-3-l 1-( 3,5-bis-methylsulfonamidophenylamino) ethylidene)-2 H-pyran2,6 ( 3 H)-dione is dissolved in sterile water at a concentration of 0 5 % and aerosolized from a nebulizer operating at an-air flow adjusted to deliver the desired aerosolized weight of 60 drug.
For oral administration, a composition such as the following can be prepared.
1 572 271 6 1 572 271 6 Ingredients Mg /Tablet 5-Acetyl-4-hydroxy-3-l 1 10 ( 3,5-bis-propionamidophenylamino)ethylidenel 2 H-pyran-2,6 ( 3 H)-dione 10Calcium sulfate, dihydrate 150 10 1 Sucrose 25 Starch 15 15 Talc 5 Stearic acid 3 The sucrose, calcium sulfate and active ingredient are thoroughly mixed and granulated 20 with hot 10 % gelatin solution The wetted mass is passed through a No 6 mesh screen directly onto drying trays The granules are dried at 120 F and passed through a No 20 mesh screen, mixed with the starch, talc and stearic acid, and compressed into tablets.
Example 5 25
Following the procedures of Example 4 an equimolar mixture of 35dinitroaniline and 3.5-diacetvl-4 6-dihvdroxv-2 H-pvran-2-one in methanol was reacted to give 5-acetyl-4hvdroxy-3-l 1-( 3,5-dinitrophenylamino)ethylidenel-2 H-pvran-2,6 ( 3 H)dione A solution of the latter ( 3 O g 0 008 mol) in 30 ml of dimethvlformamide was hydrogenated over 200 mg of 10 % palladium-on-carbon at 50 psi When absorption of hydrogen stopped, the 30 catalvst was filtered and the filtrate was poured into 200 ml of icewater The resulting product was filtered, washed with water and dried to give 5-acetyl-4hvdroxy-3-l 1-( 3 5diaminophenylamino)ethylidenel-2 H-pyran-26 ( 3 H)-dione m p above 350 C (dec).
Analysis, Calculated C: 55 98 H: 4 86 N: 13 06 35 Found 56 17 5 17 13 14

Claims (1)

WHAT WE CLAIM IS:-
1 A compound represented bv the formula (I):40 OH CH 3 R o 4 CH 3 N H 45 R 2 (I) wherein RI and R, which are the same or different, represent amino C, to C 5 straight or 50 branched chain alkanovlamino or methvlsulphonamido; mono and di-alkali metal salts of said compound and phiarmceutically acceptable acid addition salts of said compound when at least one of RI and R, is amino.
2 A compound as claimed in claim 1 in which RI and R 2 are alkanoylamino 3 A compound as claimed in claim 2 in which Rt and R 2 are acetamido 55 4 A compound as claimed in claim 2 in which RI and R 2 are propionamido.
A compound as claimed in claim 1 in which RI and R 2 are methylsulphonamido.
6 A compound as claimed in claim 1 in which RI is amino and R 2 is acetamido.
7 A compound as claimed in claim 1 wherein RI and R, are amino.
8 A process for the preparation of a compound as claimed in claim 1 wherein RI and R 2 60 are C, to C 5 straight or branched chain alkanovlamino or methylsulphonamido which comprises reacting 3 5 diacetyl-4 6-dihydroxy-2 H-pyran-2-one with a substituted aniline of formula (II):1 572 271 7 1 572 271 7 15 NH R 1 R 2 () wherein RI and R 2 are C 2 to C 9 straight or branched chain alkanoylamino or 10 methylsulphonamido.
9 A process as claimed in claim 8 in which the reactants are heated at reflux in an inert organic solvent for from one to three hours.
A process for the preparation of a compound as claimed in claim 1 wherein one of RI and R, is amino, which comprises reacting 3,5-diacetyl-4,6-dihydroxy-2 H-pyran-2-one 15 with a substituted nitroaniline of formula (II):NH 2 20 R 1 R 2 ( 21:) 25 wherein one of RI or R, is nitro to give the corresponding nitro substituted derivative which is hydrogenated catalytically.
11 A process for the preparation of a compound as claimed in claim 7 which comprises reacting 3,5-diacetyl-4,6-dihydroxy-2 H-pyran-2-one with 3,5dinitroaniline to give the 30 corresponding dinitro substituted derivative which is hydrogenated catalytically.
12 A process as claimed in claim 8 substantially as described in any one of Examples 1 to 3.
13 A process as claimed in claim 10 substantially as described in Example 4.
14 A process as claimed in claim 11 substantially as described in Example 5 35 A compound as claimed in claim 1 whenever prepared by a process as claimed in anv one of claims 8 to 14.
16 A compound of formula (I) as defined in claim 1 substantially as described herein in any one of Examples 1 to 5.
17 A pharmaceutical composition comprising a nontoxic pharmaceutical carrier or 40 diluent and a compound as claimed in any one of claims 1 to 7, 15 or 16.
18 A composition as claimed in claim 17 in a form suitable for administration by inhalation.
19 A composition as claimed in claim 17 comprising a solution or suspension of the active ingredient in sterile water 45 A composition as claimed in claim 17 in the form of an aerosol formulation.
21 A composition as claimed in claim 17 in which the pharmaceutical carrier or diluent is a solid.
22 A composition as claimed in any one of claims 17 to 21 containing a compound as claimed in claim 4 50 23 A composition as claimed in any one of claims 17 to 21 containing a compound as claimed in claim 5.
24 A composition as claimed in any one of claims 17 to 21 containing a compound as claimed in claim 7.
25 A composition as claimed in claim 17 in dosage unit form and in which the 55 compound is present in an amount of from 0 5 mg to 500 mg per dosage unit.
G.H HARGREAVES, Chartered Patent Agent.
Printed for Her Majesty’s Stationery Office, by Croydon Printing Company Limited Croydon, Surrey, 1980.
Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A IAY,from which copies may be obtained.

GB22233/77A
1976-06-16
1977-05-26
5-acetyl-4-hydroxy-(3(1-phenylaminoethylidene)-2h-pyran-2,6(3h)-dione derivatives

Expired

GB1572271A
(en)

Applications Claiming Priority (1)

Application Number
Priority Date
Filing Date
Title

US69646176A

1976-06-16
1976-06-16

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Publication Number
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GB1572271A
true

GB1572271A
(en)

1980-07-30

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Application Number
Title
Priority Date
Filing Date

GB22233/77A
Expired

GB1572271A
(en)

1976-06-16
1977-05-26
5-acetyl-4-hydroxy-(3(1-phenylaminoethylidene)-2h-pyran-2,6(3h)-dione derivatives

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US
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US4127646A
(en)

JP
(1)

JPS52153969A
(en)

DE
(1)

DE2727207C2
(en)

FR
(1)

FR2355013A1
(en)

GB
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GB1572271A
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2005-07-29
2012-02-23
Basf Se
Stabilization of body-care and household products against degradation by UV radiation using merocyanine derivatives

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DK134552B
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1974-07-29
1976-11-29
Smithkline Corp

Analogous process for the preparation of substituted 2H-pyran-2,6 (3H) -dione derivatives.

US4032652A
(en)

1975-04-23
1977-06-28
Smithkline Corporation
Substituted 2h-pyran-2,6(3h)-dione derivatives, pharmaceutical compositions comprising such derivatives and methods of inhibiting the antigen-antibody reaction

1977

1977-05-26
GB
GB22233/77A
patent/GB1572271A/en
not_active
Expired

1977-06-09
FR
FR7717692A
patent/FR2355013A1/en
active
Granted

1977-06-13
JP
JP7042877A
patent/JPS52153969A/en
active
Granted

1977-06-16
DE
DE2727207A
patent/DE2727207C2/en
not_active
Expired

1977-07-05
US
US05/812,550
patent/US4127646A/en
not_active
Expired – Lifetime

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Publication number
Publication date

DE2727207A1
(en)

1978-01-05

FR2355013B1
(en)

1980-10-10

US4127646A
(en)

1978-11-28

FR2355013A1
(en)

1978-01-13

JPS6120550B2
(en)

1986-05-22

JPS52153969A
(en)

1977-12-21

DE2727207C2
(en)

1986-10-23

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