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WO1986006068A1 - Nouveaux composes - Google Patents

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Publication number
WO1986006068A1
WO1986006068A1 PCT/GB1986/000205 GB8600205W WO8606068A1 WO 1986006068 A1 WO1986006068 A1 WO 1986006068A1 GB 8600205 W GB8600205 W GB 8600205W WO 8606068 A1 WO8606068 A1 WO 8606068A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
compound
chlorophenyl
formula
Prior art date
Application number
PCT/GB1986/000205
Other languages
English (en)
Inventor
Roger Edward Markwell
Stephen Allan Smith
Original Assignee
Beecham Group P.L.C.
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 Beecham Group P.L.C. filed Critical Beecham Group P.L.C.
Publication of WO1986006068A1 publication Critical patent/WO1986006068A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 to carbon atoms of the nitrogen-containing ring

Definitions

  • This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of mammals.
  • n 1 or 2.
  • the present invention provides a compound of formula (I) or a salt or solvate thereof:
  • R 1 and R 2 are independently hydrogen, C 1-6 alkyl or together are a group X which is C 3 -6 polymethylene optionally interrupted by O, S or NR 6 wherein R 6 is hydrogen or C 1-6 alkyl;
  • R 3 is phenyl, optionally substituted by one or more substituents selected from halogen, CF 3 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-7 alkanoyl, carboxyl, C 1-6 alkoxycarbonyl, cyano, CONR 7 R 8 wherein R 7 and R 8 are selected from hydrogen or C 1-6 alkyl or together are a group X;NR 9 R 10 wherein R 9 and R 10 are selected from hydrogen, C 1-6 alkyl, C 2-7 alkanoyl or C 1-6 alkylsulphonyl or together are a group X; SO 2 NR 11 R 12 wherein R 11 and R 12 are selected from hydrogen or C 1-6 alkyl or together are a group X; or S(O) m R 13 wherein m is 1 or 2 and R 13 is C 1-6 alkyl;
  • R 4 and R 5 are independently selected from hydrogen, C 1-6 alkyl, cyano, amino, aminocarbonyl, or aminocarbamoyl optionally substituted by one or two C 1-6 alkyl groups or together are a group X, halogen, CF 3 , nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 2-7 alkanoyloxy or hydroxy, or together are methylenedioxy or C 3-5 polymethylene.
  • R 1 and R 2 include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec and tert-butyl, or R 1 and R 2 together are ⁇ 1 which is C 4 or C 5 polymethylene or -(CH 2 ) 2 -O-(CH 2 ) 2 -.
  • R 1 is hydrogen or methyl and R 2 is methyl.
  • Suitable values for R 3 include phenyl and phenyl substituted by one or more of fluoro, chloro, bromo, CF 3 , nitro, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, acetyl, propionyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, CONH 2 ,NR 9 1 R 10 1 wherein R 9 1 and R 10 1 are selected from hydrogen, methyl, methylsulphonyl or together are a group ⁇ 1 as defined; SO 2 NR 11 1 R 12 1 wherein R 11 1 and R 12 1 are selected from hydrogen or methyl, methylsulphonyl, ethylsulphonyl, methylsulphiny
  • R 3 is phenyl optionally substituted by one or two of fluoro, chloro, bromo, CF 3 , nitro, methyl, cyano, methoxy, or methylthio, for example 2-chlorophenyl, 2-bromophenyl, 2-fluorophenyl, 2-chloro-6-fluorophenyl, or 4-chlorophenyl.
  • Suitable values for R 4 and R 5 include hydrogen, methyl, ethyl, n- and iso-propyl, cyano, amino, aminocarbonyl or aminocarbamoyl optionally substituted by one or two methyl groups, fluoro, chloro, bromo, nitro, methoxy, hydroxy, acetoxy, n-butyryloxy or 2,2-dimethylpropionyloxy, or together are methylenedioxy.
  • R 4 and R 5 are selected from hydrogen, methoxy or hydroxy.
  • R 3 1 is phenyl optionally substituted by one or two of halo, nitro, cyano or methyl; and the remaining variables are as defined for formula (I). Suitable and preferred values for R 1 , R 2 and R 3 1 are as described for the corresponding variables in formula (I).
  • R 4 1 is hydrogen, halogen, C 1-6 alkoxy, C 2-7 alkanoyloxy or hydroxy and R 5 1 is C 1-6 alkoxy, C 2-7 alkanoyloxy or hydroxy; or R 4 1 and R 5 1 together are methylenedioxy; and R 3 1 is as defined for formula (II)
  • variable groups are as described for the corresponding variables under formula (I) .
  • R 3 2 is phenyl substituted by one or two of fluoro, chloro or bromo or cyano and the remaining variables are as defined for formula (I).
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form and/or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • pharmaceutical additives such as diluents and carriers
  • additional ionic and solvent moieties must also be non-toxic.
  • a substantially pure form will generally be at least 50% pure, excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95% pure.
  • One preferred pharmaceutically acceptable form is the crystalline form.
  • Examples of a pharmaceutically acceptable salt of a compound of formula (I) include the acid addition salts for example the hydrochloride and hydrobromide salts.
  • Examples of a pharmaceutically acceptable solvate of a compound of formula (I) include the hydrate.
  • the compounds of the formula (I) can form acid addition salts with acids, such as the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • acids such as the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • acids such as the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Such salts preferably the pharmaceutically acceptable salts, form an aspect of
  • the compounds of formula (I) have at least one asymmetric centre and therefore exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the present invention also provides a process for the preparation of a compound of formula (I), which process comprises the reaction of a compound of formula (V):
  • R 3 ', R 4 ' and R 5 ' are R 3 , R 4 and R 5 or groups or atoms convertible thereto; with either
  • R 1 ' R 2 ', R 3 ', R 4 'and/or R 5 ' to R 1 , R 2 , R 3 , R 4 and/or R 5 respectively; and/or forming a salt or solvate thereof.
  • a compound of formula (la) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I), by interconversion of suitable substituents.
  • certain compounds of formula (I) are useful intermediates in forming other compounds of the present invention.
  • salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • Suitable values for Q include halogen, such as chloro or bromo, preferably chloro.
  • the reaction i) of a compound of formula (V) with R 1 'R 2 'NCOQ 1 may either take place in an inert solvent, such as xylene or higher boiling solvent or, more preferably in neat R 1 'R 2 'NCOQ 1 at high temperature, for example 150-180oC, preferably 170-175°C.
  • Suitable values for the alkyl group in ii) (a) include methyl, ethyl, n- and iso-propyl.
  • the alkyl group is methyl or ethyl.
  • Suitable alkylating agents include dialkylsulphate, alkyl iodide or trialkyloxonium tetrafluoroborate.
  • the reaction is preferably carried out in an inert solvent such as dichloromethane and the alkylating agent is preferably triethyloxonium tetrafluoroborate.
  • the reaction proceeds through an intermediate of formula (VI) or a salt thereof:
  • Alk is an alkyl group and the remaining variables are as defined in formula (VI).
  • the intermediate of formula (VIla) is the tetrafluoroborate salt when the alkylating agent is a trialkyloxonium tetrafluoroborate.
  • HNR 1 'R 2 ' may then be added to the compound of formula (VI), without isolation, and the compound of formula (I) extracted by conventional methods.
  • the compound of formula (VI) may be isolated, and, for example, converted to a salt, such as its hydrochloride salt, before reaction with HNR 1 'R 2 '.
  • Suitable halogenating agents in ii) b) include phosgene or phosphorous oxychloride. The reaction proceeds through an intermediate of formula (VII):
  • Hal is a halogen atom, in particular chlorine, and the remaining variables are as defined for formula (VI).
  • the intermediate of formula (VII) may then be reacted with HNR 1 'R 2 ', with or without prior isolation of the intermediate. If isolated, the intermediate may be converted to a salt, for example its hydrochloride, before reaction.
  • R 1 ' and R 2 ' may be alkyl or acyl groups and converted to R 1 /R 2 hydrogen atoms by conventional amine dealkylation or deacylation.
  • R 1 ' or R 2 ' is benzyl or substituted benzyl it may be converted to an R 1 or R 2 hydrogen atom by catalytic hydrogenation or other method of reduction.
  • Ri'and R 2 as hydrogen atoms may be converted to R 1 and R 2 alkyl groups by conventional amine alkylation, or by acylation followed by reduction.
  • R 1 ' and R 2 ' are preferably R 1 and R 2 respectively.
  • R 3 ' Conversions of substituents on an aromatic group R 3 ' to obtain R 3 are generally known in the art of aromatic chemistry.
  • a nitro substituent may be converted to an amino group by conventional catalytic hydrogenation.
  • R 3 ' is preferably R 3 .
  • L is a leaving group, for example a hydroxyl group, with an acid catalyst, especially polyphosphoric acid, or
  • A is CN or CONH 2 , with formaldehyde or paraformaldehyde and an acid or with a dihalomethane and a Lewis acid.
  • the groups R 3 ', R 4 ' and R 5 ' are as defined for the compound of formula (V).
  • the compound of formula (VIII) may be prepared by reaction of a compound of formula (X):
  • the compounds of formula ( I ) exist in more than one stereoisomeric form and the processes of the invention produces mixtures thereof.
  • the individual isomers may be separated one from another by resolution using an optically active acid such as tartaric acid.
  • an asymmetric synthesis would offer a route to the individual form.
  • the compounds of this invention are indicated as of ulitity in the treatment of rheumatism and arthritis and in the treatment of pain and other inflammatory conditions and also in the treatment of and prophylaxis of bronchial asthma, rhinitis, hay fever and allergic eczema, by their activity in relevant animal disease models.
  • the present invention further provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaeutically acceptable carrier.
  • a composition of the invention which may be prepared by admixture, may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant, preservative in conventional manner.
  • a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant, preservative in conventional manner.
  • these conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of ketoprofen, indomethacin, naproxeh, acetylsalicyclic acid and other analgesic or anti-inflammatory agents.
  • a composition of the invention may be adapted for oral, topical, rectal or parenteral - intravenous or intramuscular - administration but oral administration is preferred.
  • a composition of the invention will preferably be in the form of a unit dose, such as a tablet or capsule or a sachet containing reconstitutable powder.
  • a unit dose for inflammatory diseases will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg.
  • the composition may be administered once or more times a day, for example 2, 3 or 4 times daily, so that the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of a compound of the invention and be administered in multiples, if desired, to give the preceding daily dose.
  • a suitable dosage unit may contain 0.01 to 500 mg of active ingredient, more suitably 1 to 500 mg for use via the oral route, 0.01 to 10 mg via inhalation, which is preferred.
  • the effective dose of compound depends on the particular compound employed, the condition of the patient and the frequency and route of administration, but in general is in the range of from 0.001 mg/day to 100 mg/day per kilogram of the patient's body weight.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
  • xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH
  • ACTH adrenal stimulants
  • a particular composition of the invention for inflammatory diseases is a hard gelatin capsule containing the required amount of a compound of the invention in the form of a powder or granulate in intimate mixture with a lubricant, such as magnesium stearate, a filler, such as microcrystalline cellulose, and a disintegrant, such as sodium starch glycollate.
  • a lubricant such as magnesium stearate
  • a filler such as microcrystalline cellulose
  • a disintegrant such as sodium starch glycollate.
  • Preparations especially suitable for administration to the respiratory tract include, for example, a snuff, an aerosol, a solution for a nebulizer, or a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns.
  • the preparations may also be presented as an ointment, cream, lotion, gel, gelstick, spray, aerosol, mouth wash or skin paint or in any other vehicle suitable for topical application.
  • the present invention additionally provides a method of treating an inflammatory and/or a painful condition such as rheumatism and/or allergic conditions in mammals, such as humans, which comprises administering an effective amount of a compound, pharmaceutically acceptable salt or solvate, or composition of the invention to the mammal.
  • the present invention also provides a compound, pharmaceutically acceptable salt or solvate, or composition of the invention for use as an active therapeutic substance, particularly in the treatment of inflammatory and/or painful conditions, such as rheumatism, and/or allergic conditions in mammals.
  • the present invention further provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory and/or painful conditions, and/or allergic conditions.
  • 0.2 ml of a 2.0% solution of ⁇ -carrageenin (Viscarin 402) in saline was injected intrapleurally in anaesthetised rats (wt. approx. 175-200g).
  • Compounds were administered 1 hour before carrageenin and at 24 and 48 hours after carrageenin.
  • 72 hours after carrageenin injection 4.0 ml of EDTA solution (5g EDTA in 100 ml of 0.9% saline and 325 mg phenol red added together with saline to 1 litre) was injected intrapleurally after killing the animals, and the exudate removed with a syringe through the diaphragm.
  • Exudate volume was measured spectrophotometrically (560 nm) and cellular content estimated with a DNA assay [Karsten U. and Wollenberger A. Anal. Biochem. 77, 464-470, 1977].
  • Example 2 9 mg/kg (p.o.)
  • Example 4 12 mg/kg (p.o.)
  • Example 7 15 mg/kg (p.o.)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule générale (I) dans laquelle R1 et R2 représentent, individuellement, l'hydrogène, C1-6 alkyl ou forment ensemble un groupe X qui est C3-6 polyméthylène éventuellement interrompu par O, S ou NR6 où R6 représente l'hydrogène ou C1-6 alkyl; R3 représente un phényle éventuellement substitué par un ou plusieurs substituants sélectionnés parmi l'halogène, CF3, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-7 alcanoyle, carboxyle, C1-6 alkoxycarbonyle, cyano, CONR7R8 où R7 et R8 sont sélectionnés parmi l'hydrogène ou C1-6 alkyl ou forment ensemble un groupe X; NR9R10 où R9 et R10 sont sélectionnés parmi l'hydrogène, C1-6 alkyl, C2-7 alcanoyle ou C1-6 alkylsulfonyle ou forment ensemble un groupe X; SO2 NR11 R12 où R11 et R12 sont sélectionnés parmi l'hydrogène ou DC1-6 alkyl ou forment ensemble un groupe X; ou S(O)mR13 où m est égal à 1 ou 2 et R13 représente C1-6 alkyl; R4 et R5 sont sélectionnés individuellement parmi l'hydrogène, C1-6 alkyl, cyano, amino, aminocarbonyle, ou aminocarbomoyle éventuellement substitué par un ou deux groupes C1-6 alkyl ou forment ensemble un groupe X, un halogène, CF3, nitro, C1-6 alkoxy, C1-6 alkylthio, C2-7 alkanoyloxy ou hydroxy, ou représentent ensemble un méthylène dioxy ou C3-5 polyméthylène; ces composés sont utiles dans la prophylaxie et le traitement de troubles allergiques et inflammatoires.
PCT/GB1986/000205 1985-04-17 1986-04-11 Nouveaux composes WO1986006068A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8509834 1985-04-17
GB858509834A GB8509834D0 (en) 1985-04-17 1985-04-17 Compounds

Publications (1)

Publication Number Publication Date
WO1986006068A1 true WO1986006068A1 (fr) 1986-10-23

Family

ID=10577789

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1986/000205 WO1986006068A1 (fr) 1985-04-17 1986-04-11 Nouveaux composes

Country Status (6)

Country Link
EP (1) EP0220226A1 (fr)
AU (1) AU5663786A (fr)
GB (1) GB8509834D0 (fr)
PT (1) PT82410B (fr)
WO (1) WO1986006068A1 (fr)
ZA (1) ZA862791B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064400A1 (fr) * 1998-06-12 1999-12-16 Vertex Pharmaceuticals Incorporated INHIBITEURS DE p38
EP1277740A1 (fr) * 1998-06-12 2003-01-22 Vertex Pharmaceuticals Incorporated Inhibiteurs de p38

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1164192A (en) * 1966-05-05 1969-09-17 Hoechst Ag Tetrahydroisoquinolines and process for preparing them
DE2030675A1 (en) * 1969-06-23 1971-02-11 Arthur D Little, Inc , Cambridge, Mass (V St A) 3-amino-4-phenyl-isoquinoline derivs
FR2207720A1 (fr) * 1972-11-25 1974-06-21 Aspro Nicholas Ltd
EP0139296A2 (fr) * 1983-10-20 1985-05-02 Beecham Group Plc Dérivés de la dihydroisoquinoléine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1164192A (en) * 1966-05-05 1969-09-17 Hoechst Ag Tetrahydroisoquinolines and process for preparing them
DE2030675A1 (en) * 1969-06-23 1971-02-11 Arthur D Little, Inc , Cambridge, Mass (V St A) 3-amino-4-phenyl-isoquinoline derivs
FR2207720A1 (fr) * 1972-11-25 1974-06-21 Aspro Nicholas Ltd
EP0139296A2 (fr) * 1983-10-20 1985-05-02 Beecham Group Plc Dérivés de la dihydroisoquinoléine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064400A1 (fr) * 1998-06-12 1999-12-16 Vertex Pharmaceuticals Incorporated INHIBITEURS DE p38
EP1277740A1 (fr) * 1998-06-12 2003-01-22 Vertex Pharmaceuticals Incorporated Inhibiteurs de p38
US6528508B2 (en) 1998-06-12 2003-03-04 Vertex Pharmaceuticals Incorporated Inhibitors of p38
US6800626B2 (en) 1998-06-12 2004-10-05 Vertex Pharmaceuticals Incorporated Inhibitors of p38
US7151101B2 (en) 1998-06-12 2006-12-19 Vertex Pharmaceuticals Incorporated Inhibitors of p38

Also Published As

Publication number Publication date
GB8509834D0 (en) 1985-05-22
AU5663786A (en) 1986-11-05
ZA862791B (en) 1987-01-28
PT82410A (en) 1986-05-01
EP0220226A1 (fr) 1987-05-06
PT82410B (en) 1988-02-19

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