US3766263A - Substituted 2-phenoxyphenylacetic acids - Google Patents

Substituted 2-phenoxyphenylacetic acids Download PDF

Info

Publication number
US3766263A
US3766263A US00132891A US3766263DA US3766263A US 3766263 A US3766263 A US 3766263A US 00132891 A US00132891 A US 00132891A US 3766263D A US3766263D A US 3766263DA US 3766263 A US3766263 A US 3766263A
Authority
US
United States
Prior art keywords
acid
chloro
mole
percent
compounds
Prior art date
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 - Lifetime
Application number
US00132891A
Other languages
English (en)
Inventor
K Godfrey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Reckitt Benckiser Healthcare UK Ltd
Original Assignee
Reckitt and Colman Products Ltd
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.)
Filing date
Publication date
Application filed by Reckitt and Colman Products Ltd filed Critical Reckitt and Colman Products Ltd
Application granted granted Critical
Publication of US3766263A publication Critical patent/US3766263A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/807—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen all halogen atoms bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups

Definitions

  • This invention relates to phenylalkane derivatives and to processes for their production.
  • the invention also relates to therapeutic compositions comprising as the active ingredient one or more of these phenylalkane derivatives.
  • Acetyl salicyclic acid has been in use for over 50 years for the relief of pain and the alleviation of inflammatory states.
  • stomach ulceration and gastrointestinal bleeding could occur in patients taking aspirin, particularly those patients suflering from various inflammatory states such as rheumatoid arthritis, osteoarthritis, rheumatic fever and ankylosing spondylitis in which the treatment necessitated continued high dosages of the drug.
  • Arylacetic acids have been investigated extensively for anti-inflammatory activity, and this work has led to the introduction of Ibuprofen, for example.
  • novel arylacetic acid derivatives in particular ortho phenoxy phenylacetic acid derivatives, which possess anti-inflammatory activity, and certain of which possess to a minimal extent only the ulcerogenic side effects encountered with known anti-inflammatory drugs.
  • rrnooon which are di-, trior tetrasubstituted in the B ring, and wherein R is hydrogen or methyl;
  • R is hydrogen, methyl or chlorine
  • R is alkyl of from 1 to 4 carbon atoms or chlorine
  • R is alkyl of from 1 to 6 carbon atoms at position 4, trifluoromet-hyl at position 5, or hydrogen or chlorine;
  • R is hydrogen or chlorine
  • R is alkyl of from 1 to 4 carbon atoms and p is 0 or 1,
  • R when R is alkyl of from 1 to 6 carbon atoms at position 4, R may be hydrogen and in this case R is chlorine or trifiuoromethyl at position 3 and p is 1; provided that the B ring does not have two alkyl groups containing more than one carbon atom in adjacent positions and that in a compound with alkyl substituents at positions 2 and 6 of the B ring at least one of these alkyl substituents is methyl or ethyl; and also provided that the compound does not have more than 3 chlorine substituents.
  • R when R is alkyl of from 1 to 6 carbon atoms at position 4 or chlorine then R may also represent alkoxy of from 1 to 4 carbon atoms or hydroxy;
  • R may also represent alkyl of from 7 to 18 carbon atoms at position 4 when R is chlorine and there are no other substituents in the B ring;
  • R may also represent alkoxy of from 1 to 4 carbon atoms or hydroxy when R is chlorine; and one or more chlorine substituents in the compound may be replaced by bromine.
  • di-, triand tetra-substituted we mean that there are two, three or four substituents in the B ring in addition to the ether linkage.
  • R is hydrogen or methyl
  • R is chlorine at position 4 or 5, alkyl of from 1 to 6 carbon atoms at position 4, trifiuoromethyl at position 5 or methyl at position 6;
  • n 0, 1 or 2.
  • R when R is chlorine at position 4, R may also represent a methoxy group; and one or more chlorine substituents in the molecule may be replaced by bromine.
  • the present invention provides 2 (2 chloro 4 a1kyl(C to )phenoxy) phenyl acetic acids which may be optionally substituted by methyl at position 5' of Ring A and 2-(2,4-dichlorosubstituted phenoxy) phenylacetic acids which may be optionally substituted by one or two methyls in Ring B and methyl at position 5' of Ring A.
  • the invention also provides therapeutic compositions comprising as active ingredients one or more compounds of Formula I or Formula II in association with a pharmaceutically inactive diluent or carrier.
  • the compounds and compositions of the present invention have anti-inflammatory and analgesic properties.
  • the compounds of Formula I in which R is hydrogen may be prepared by reacting together compounds of Formula III and IV.
  • the copper catalyst used in the above reaction is preferably copper in finely divided form.
  • the hydrolysis of the thioacetmorpholide is conveniently carried out under basic conditions, but where there is a trifiuoromethyl substituent in the molecule acidic conditions may be necessary, for example it has been found that 2-(2-chloro-5-trifluoromethylphenoxy)- S-methylpheuylacetic acid must be hydrolysed under acidic conditions.
  • R or R represent hydroxy
  • the compounds in which either R or R represent hydroxy may be prepared by O-demethylation of the analogous methoxy compounds, for example by treatment with glacial acetic acid and hydriodic acid.
  • EXAMPLE 1 2 (2,4-dichloro-S-methylphenoxy) -5-chlorophenylacetic acid
  • the methylated malonic acid (6.4 g.) was decarboxylated by heating at 180 C. for 1 hour and then at 200 C. for 1 hour.
  • the product was crystallised twice from n-hexane to give 2.1 g. of 2-[2-(2,4-dichlorophenxy)phenyl]propionic acid, M.P. l0l-l03 C.
  • the table sets out details of further examples of orthophenoxyphenylacetic acid derivatives which may be substituted at position 5 of the A ring and at positions 2, 3, 4, 5 or 6 of the B ring which were prepared by the procedures of the above examples.
  • Antipyretie activity has been assessed in yeast-fevered rats, using a modification of the method of Winder et al. (J. Pharmac. exp. therap. 133, 117 (1961)).
  • the unsubstituted analogue, o-phenoxyphenylacetic acid is devoid of anti-inflammatory activity and produces no ulceration after six hours and only slight ulceration 24 hours after administration of 1 g./kg.
  • o-phenoxyphenylacetic acid no anti-arthritic activity
  • the analogous p-(2,4-dichlorophenoxy)-phenylacetic acid there was severe ulceration 24 hours after administration of 1 g./ kg.
  • o-Phenoxyphenylacetic acid is therefore much less ulcerogenic than mand p-isomers. This property is retained in the substituted compounds, which also display anti-inflammatory activity.
  • compositions of this invention are well known.
  • the compositions may be in a form suitable for oral, topical or parenteral use but the preferred method of administration is orally.
  • Such oral compositions may take the form of capsules, tablets, lozenges or granules or liquid preparations such as elixirs, syrups or suspensions.
  • the oral compositions may also incorporate flavouring agents, colouring matter, disintegrating agents, tabletting aids and other diluents as required.
  • Tablets or capsules for oral administration contain from 25 to 500 mg. of a compound according to the invention as active ingredient.
  • a preferred tablet or capsule contains from to 500 mg. of 2-(2,4-dichlorophenoxy)phenylacetic acid, 2-(2,4-dichloro-3,S-dimethylphenoxy)phenylacetic acid 2 (2-chloro-4-ethylphenoxy) S-methylphenylacetic acid, 2-(2-methoxy 4 chlorophenoxy)-5-methylphenylacetic acid, or 2-(2-chloro 4 tertbutylphenoxy)-5-methyl phenylacetic acid.
  • a suitable oral daily dose of these preferred compounds for the relief of inflammatory states in human beings would be from 250 mg. to 3 g. of the active ingredient.
  • the compounds of the invention may also be incorporated into novel therapeutic compositions with other known therapeutically active compounds such as, for example, codeine.
  • R is selected from the group consisting of chlorine, bromine and methoxy, provided that R is methoxy only when R is selected from the group consisting of chlorine at position 4 and bromine at position 4;
  • R is selected from the group consisting of chlorine at position 4, bromine at position 4, chlorine at position 5, bromine at position 5, alkyl of from 1 to 6 carbon atoms at position 4, trifluoromethyl at position 5 and methyl at position 6; and n is 0, 1 or 2.
  • R is chlorine
  • R is selected from the group consisting of chlorine at position 4, chlorine at position 5, alkyl of from 1 to 6 carbon atoms at position 4, trifluorornethyl at position 5 and methyl at position 6 and n is 0, l or 2.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00132891A 1970-04-14 1971-04-09 Substituted 2-phenoxyphenylacetic acids Expired - Lifetime US3766263A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB1783270 1970-04-14

Publications (1)

Publication Number Publication Date
US3766263A true US3766263A (en) 1973-10-16

Family

ID=10101999

Family Applications (1)

Application Number Title Priority Date Filing Date
US00132891A Expired - Lifetime US3766263A (en) 1970-04-14 1971-04-09 Substituted 2-phenoxyphenylacetic acids

Country Status (13)

Country Link
US (1) US3766263A (enExample)
JP (1) JPS536143B1 (enExample)
BE (1) BE842952Q (enExample)
CA (1) CA935438A (enExample)
FR (1) FR2092044B1 (enExample)
GB (1) GB1308327A (enExample)
HK (1) HK51576A (enExample)
IE (1) IE35123B1 (enExample)
KE (1) KE2633A (enExample)
MY (1) MY7600176A (enExample)
NL (1) NL157006B (enExample)
SE (1) SE372254B (enExample)
ZA (1) ZA712345B (enExample)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976673A (en) * 1974-01-14 1976-08-24 Isf Spa 4-Cyclopropylmethyleneoxy-3-chlorophenylacetic acid and salts thereof
US3985779A (en) * 1973-10-29 1976-10-12 Eisai Co., Ltd. M-phenoxyphenyl propionic acid derivatives and preparation thereof
US4065503A (en) * 1974-09-30 1977-12-27 Sandoz, Inc. P-Phenoxy-alkylphenones and corresponding alcohols
US4430510A (en) 1981-06-18 1984-02-07 Schering Corporation Process for the preparation of 2-(2,4-dichlorophenoxy)-phenylacetic acid
US4468469A (en) * 1981-11-04 1984-08-28 Miles Laboratories, Inc. Substituted phenylacetic acids and salts as TBP blocking agents in iodothyronine immunoassays
US5145790A (en) * 1990-05-04 1992-09-08 Abbott Laboratories Reagents and method for detecting polychlorinated biphenyls
US5538852A (en) * 1992-10-02 1996-07-23 Ecochem Research, Inc. Immunoassay for polychlorinated biphenyls
US5686589A (en) * 1990-11-06 1997-11-11 Cell Pathways, Inc. Esters and amides of substituted phenyl and pyridyl amino carboxylates
US6544556B1 (en) 2000-09-11 2003-04-08 Andrx Corporation Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor
WO2003043625A1 (en) * 2001-11-20 2003-05-30 Dompe S.P.A. 2-aryl-propionic acids and pharmaceutical compositions containing them
WO2007103540A2 (en) 2006-03-08 2007-09-13 Pharmena North America Inc. Combination therapy with non-selective cox inhibitors to prevent cox-related gastric injuries

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2093021B (en) * 1981-01-24 1985-10-02 Reckitt & Colman Product Ltd 2-(2,4-dichlorophenoxy) phenylacetic acid
JPS60103906U (ja) * 1983-12-20 1985-07-16 株式会社ヨコオ アンテナ接続装置
GB8715242D0 (en) * 1987-06-29 1987-08-05 Wood E M Fenclofenac as immunosuppressant drug

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985779A (en) * 1973-10-29 1976-10-12 Eisai Co., Ltd. M-phenoxyphenyl propionic acid derivatives and preparation thereof
US3976673A (en) * 1974-01-14 1976-08-24 Isf Spa 4-Cyclopropylmethyleneoxy-3-chlorophenylacetic acid and salts thereof
US4065503A (en) * 1974-09-30 1977-12-27 Sandoz, Inc. P-Phenoxy-alkylphenones and corresponding alcohols
US4430510A (en) 1981-06-18 1984-02-07 Schering Corporation Process for the preparation of 2-(2,4-dichlorophenoxy)-phenylacetic acid
US4468469A (en) * 1981-11-04 1984-08-28 Miles Laboratories, Inc. Substituted phenylacetic acids and salts as TBP blocking agents in iodothyronine immunoassays
US5145790A (en) * 1990-05-04 1992-09-08 Abbott Laboratories Reagents and method for detecting polychlorinated biphenyls
US5686589A (en) * 1990-11-06 1997-11-11 Cell Pathways, Inc. Esters and amides of substituted phenyl and pyridyl amino carboxylates
US5538852A (en) * 1992-10-02 1996-07-23 Ecochem Research, Inc. Immunoassay for polychlorinated biphenyls
US6544556B1 (en) 2000-09-11 2003-04-08 Andrx Corporation Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor
US6869615B2 (en) 2000-09-11 2005-03-22 Andrx Labs Llc Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor
WO2003043625A1 (en) * 2001-11-20 2003-05-30 Dompe S.P.A. 2-aryl-propionic acids and pharmaceutical compositions containing them
US20050038119A1 (en) * 2001-11-20 2005-02-17 Marcello Allegretti 2-Aryl-propionic acids and pharmaceutical compositions containing them
CN100376242C (zh) * 2001-11-20 2008-03-26 冬姆佩制药股份公司 2-芳基-丙酸及含有它们的药物组合物
AU2002352052B2 (en) * 2001-11-20 2008-09-04 Dompe' Farmaceutici S.P.A. 2-Aryl-propionic acids and pharmaceutical compositions containing them
EP2229942A1 (en) * 2001-11-20 2010-09-22 Dompe S.p.A. 2-Aryl-propionic acids and pharmaceutical compositions containing them
US8063242B2 (en) 2001-11-20 2011-11-22 Dompe Pha.R.Ma S.P.A. 2-aryl-propionic acids and pharmaceutical compositions containing them
WO2007103540A2 (en) 2006-03-08 2007-09-13 Pharmena North America Inc. Combination therapy with non-selective cox inhibitors to prevent cox-related gastric injuries

Also Published As

Publication number Publication date
NL7104884A (enExample) 1971-10-18
NL157006B (nl) 1978-06-15
FR2092044A1 (enExample) 1972-01-21
IE35123L (en) 1971-10-14
JPS536143B1 (enExample) 1978-03-04
FR2092044B1 (enExample) 1975-08-01
SE372254B (enExample) 1974-12-16
KE2633A (en) 1976-06-11
HK51576A (en) 1976-08-20
IE35123B1 (en) 1975-11-12
DE2117826A1 (de) 1971-10-28
MY7600176A (en) 1976-12-31
ZA712345B (en) 1972-05-31
BE842952Q (fr) 1976-10-01
CA935438A (en) 1973-10-16
GB1308327A (en) 1973-02-21
DE2117826B2 (de) 1975-11-20

Similar Documents

Publication Publication Date Title
US3766263A (en) Substituted 2-phenoxyphenylacetic acids
US3793457A (en) Therapeutically active phenylalkane derivatives
US4585788A (en) 6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives
US3852364A (en) Ethynylbenzene compounds derivatives therefor
US3957850A (en) Phenylacetic acid derivatives
EP0150166B1 (en) Novel arylacitic acid derivatives
US3707549A (en) Alpha-substituted hydrocinnamic acids and derivatives thereof
DE2531456A1 (de) Antiinflammatorisch und analgetisch wirksame stilbenderivate
US3255242A (en) (alpha-alkylideneacyl)naphthyloxy monocarboxylic acids
Pfister et al. Inhibition of histamine-induced gastric secretion by flavone-6-carboxylic acids
US3821289A (en) Tetrahydronaphthylalkanoic acids and their derivatives
US3385887A (en) 4-isobutylphenylacetic acid
US3845215A (en) Phenylalkane derivatives in the treatment of inflammation
US4116972A (en) Anti-inflammatory 1-oxo-isoindoline derivatives and processes for their preparation
CH628014A5 (en) Gamma-aryl-gamma-oxoisovaleric acids having antiphlogistic and antalgic properties
US4020094A (en) 2-Substituted-5-oxo-5H-dibenzo[a,d]cycloheptenes, the salts and esters thereof, having pharmaceutical activity
US3409661A (en) Nuclear polysubstituted[(2-nitro-1-alkenyl)-aryloxy]alkanoic acids
US4219668A (en) 4-Hydroxy,4-biphenylbutyric acid
US3903134A (en) Phenyl propionic acids and derivatives thereof
Durant et al. Nonsteroidal antiinflammatory agents. Some arylacetic acids
JPS6033373B2 (ja) １−ナフチル酢酸誘導体、その製造法ならびに１−ナフチル酢酸誘導体を含有する薬剤
US3755442A (en) Acenaphthyl amides and amines
US3985788A (en) Phenyl propionic acids and derivatives thereof
US4189607A (en) Anilionotropone derivatives
US4562287A (en) 2-(4-Biphenylyl)-4-hexenoic acid and derivatives thereof having anti-inflammatory activity