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WO1992018115A1 - Use of heterocyclic compounds for the treatment of inflammatory pain - Google Patents

Use of heterocyclic compounds for the treatment of inflammatory pain Download PDF

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Publication number
WO1992018115A1
WO1992018115A1 PCT/EP1992/000838 EP9200838W WO9218115A1 WO 1992018115 A1 WO1992018115 A1 WO 1992018115A1 EP 9200838 W EP9200838 W EP 9200838W WO 9218115 A1 WO9218115 A1 WO 9218115A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
group
hydrogen
optionally substituted
halogen
Prior art date
Application number
PCT/EP1992/000838
Other languages
French (fr)
Inventor
Geoffrey Douglas Clarke
Roberto Colle
Giuseppe Giardina
Vittorio Vecchietti
Original Assignee
Dr Lo Zambeletti S.P.A.
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
Priority claimed from GB919108326A external-priority patent/GB9108326D0/en
Priority claimed from GB919115143A external-priority patent/GB9115143D0/en
Application filed by Dr Lo Zambeletti S.P.A. filed Critical Dr Lo Zambeletti S.P.A.
Publication of WO1992018115A1 publication Critical patent/WO1992018115A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to the use of certain
  • Compounds of the present invention are, therefore, of potential use as peripheral analgesics in the treatment of a range of inflammatory painful conditions - such as arthritis and low back pain - since they may reduce both the causes and consequences of local inflammation.
  • a compound, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammation pain
  • the compound is selected from compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or (XVI): in which R is an acyl group containing a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring and R 1 and R 2 are independently C 1-6 alkyl groups or together form a C 1-6 polymethylene or alkenylene group;
  • R, R 1 and R 2 are as defined for formula (I), and p is 1, 2, 3 or 4;
  • R 3 is Br, NO 2 or CF 3 ; and R 1 and R 2 are as defined in formula (I);
  • R 1 and "Br each independently represents an alkyl, alkenyl or alkynyl group or R 1 together with R 2 represents a C 3-6 polymethylene or alkenylene group;
  • R 3 represents hydrogen or alkyl
  • R 4 represents hydrogen, halogen, alkyl, hydroxy, alkoxy, nitrile, nitro, amino or mono or disubstituted amino;
  • n 0 or 1
  • R 1 and R 2 are independenlty hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 4-6 cycloalkyl or C 4-12 cycloalkylalkyl or
  • Rx is C 1-6 alkyl or phenyl, or Rx together with R ⁇ form a -(CH 2 ) 3 - or -(CH 2 ) 4 - group;
  • R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups, or together form a C 2-8 branched or linear
  • polymethylene or C 2-6 alkenylene group optionally
  • R 3 is hydrogen, C 1-6 alkyl, or phenyl, or R 3 together with R-L form a _ (CH 2 ) 3 - or -(CH 2 ) 4 - group;
  • p 1, 2, 3 or 4
  • R is a group of formula
  • X is a direct bond, or O, S or NR a in which R a is hydrogen or C 1-6 alkyl;
  • each of R 5 and R 6 is C 1-6 alkyl, or R 5 and R 6 are linked together and Re represents -(Z) m - where m is 0 or 1 and Z is O, S or NR 7 where R 7 is hydrogen or C 1-6 alkyl;
  • R 6 represents -(CH 2 ) q - where q is an integer of from 1 to 4, and in which one or more of the -(CH 2 )- groups is optionally substituted by a C 1-6 alkyl group;
  • R1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group, optionally substituted with a
  • R 3 is hydrogen, C 1-6 alkyl, or phenyl or R 3 together with R 1 form a -(CH 2 ) 3 - or -(CH 2 ) 4 - group;
  • R 4 is C 1-6 alkyl, or phenyl
  • Het' is an optionally substituted single or fused ring heterocyclic group, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur;
  • R is as defined in formula (I) and R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group optionally substituted with a hetero-atom;
  • R 3 is hydrogen, C 1-6 alkyl, or phenyl or R 3 together with R 1 forms a -(CH 2 ) 3 - or -(CH 2 ) 4 -, group;
  • R 4 and R 5 which may be the same or different and may be attached to the same or different carbon atoms of the isoquinoline nucleus, are each hydrogen, halogen, hydroxy, C 1-6 alkyl, aryl, or R 4 together with R 5 form a - (CH 2 ) group, where p is an integer of from 1 to 5 and one or more of the -(CH 2 )- moieties is optionally substituted by a C 1-6 alkyl group.
  • R 6 and R 6a which may be the same or different, are each hydrogen, C 1-6 alkyl, -CH 2 OR 6b , halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, thiol, C 1-6 alkylthio, , - NHCOR 6d , -NHSO 2 R 6e , -CH 2 SO 2 NR 6f R 6g , in which each of R 6b to R 6g is independently hydrogen, C 1-6 alkyl, aryl or aralkyl;
  • R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups, or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group, optionally substituted with a hetero- atom;
  • R 3 is hydrogen, C 1-6 alkyl or phenyl, or R3 together with R-y form a -(CH 2 ) 3 - or -(CH 2 ) 4 - group;
  • R 4 and R 5 are independently hydrogen, hydroxyl, halogen, C 1-6 alkyl or aryl, provided both R 4 and R 5 are not
  • R x is the remainder of a heterocyclic group, or an optionally substituted phenyl group
  • R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups, or together form a C 2-6 branched or linear polymethylene or C 2-6 alkenylene group, optionally substituted with a hetero- atom;
  • R 3 is hydrogen, C 1-6 alkyl, or phenyl, or R 3 together with
  • R 1 form a -(CH 2 ) 3 _ or -(CH 2 ) 4 - group
  • R 4 and R 5 which may be located on the same or different carbon atoms, are independently hydrogen, C 1-6 alkyl, or phenyl;
  • n 1, 2 or 3;
  • R 7 is hydrogen or C 1-6 alkyl
  • n 0, 1 and 2;
  • X is direct bond, or O, S or NRg is hydrogen or C 1-6 alkyl
  • each of R 8 and R 9 is C 1-6 alkyl, or
  • Rg and Rg are linked together and Rg represents -(Z) p - where p is 0 or 1 and Z is O, S or NR Z where R z is hydrogen or C 1-6 alkyl;
  • Rg represents -(CH 2 ) q - where q is an integer of from 1 to 4;
  • R is as defined in formula (I) and R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group optionally substituted with a hetero-atom;
  • R 3 is hydrogen, C 1-6 alkyl, or phenyl, or R 3 together with
  • R 1 forms a -(CH 2 ) 3 - or -(CH 2 ) 4 , group
  • R 4 and R 5 are identical and are hydrogen or C 1-6 alkyl, or together form a C 2-5 linear polymethylene group;
  • R 6 and R 7 are indentical and are hydrogen or C 1-6 alkyl, or together form a C 2-5 linear polymethylene group;
  • R 5 and R 6 are together -CH 2 - when each of R 4 and R 7 is hydrogen or C 1-6 alkyl;
  • R 8 and R 9 which may be the same or different, are each hydrogen, C 1-6 alkyl, -CH 2 OR 10 , halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, thiol, C 1-6 alkylthio, f -NHCOR 12 , -NHSO 2 R 13 , -CH 2 SO 2 NR 14 R 15 , in which each
  • R 10 to R 15 is independently hydrogen, C 1-6 alkyl, aryl or aralkyl
  • p 1, 2 or 3;
  • ROC- is an acyl group linked to the nitrogen atom of group (A) in which the group R contains a substituted or
  • R 1 and R 2 are substituents on the same or different carbon atoms and are independently hydrogen or C 1-6 alkyl;
  • R a is a fused substituted or unsubstituted heterocyclic or carbocyclic aromatic ring
  • W which may be attached to the same or different carbon atom as R 1 , is hydroxy, C 1-6 alkoxy (preferably methoxy), halogen (preferably fluorine), thiol, C 1-6 alkylthio, hydroxy C 1-6 alkyl, methylidene, hydroxycarbonyl, aminocarbonyl, C 1-3 alkoxycarbonyl, NHR 1a or NHCOR 1a where R 1a is H or C 1-6 alkyl; R 1 is hydrogen, halogen (preferably fluorine), C 1-6 alkyl (preferably methyl) or together with W forms a keto-group or a cyclic ether or thioether containing from 1 to 4 carbon atoms;
  • A represents
  • each of R 2 and R 3 which may be attached to the same or different carbon atom, is hydrogen, C 1-6 alkyl, hydroxy, thiol, C 1-6 alkoxy, C 1-6 alkylthio or halogen
  • R 4 is C 1-6 alkyl
  • R 5 is hydrogen or together with R 4 forms a -(CH 2 ) c - group optionally substituted by one or two C 1-6 alkyl groups and attached to the same or different carbon atom;
  • R x is the remainder of an optionally substituted single or fused ring heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur;
  • R x is the remainder of an optionally substituted phenyl group; a is 1 or 2, b is 1, 2 or 3; c is 1, 2 or 3; and RCO, which is linked to the nitrogen atom of the group A, is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring, with the provisos that: i) When A represents, , R represents a tetralone
  • W is halogen or C 1-6 alkoxy, or R 1 is other than hydrogen or a keto group with W;
  • R 3 is other than hydrogen
  • R x , R 4 and R 5 together form an unsubstituted tetrahydroisoquinoline group, R represents a tetralone moiety or R 1 is other than hydrogen or a keto group with W, or W is halogen or C 1-6 alkoxy;
  • R 1 and R 2 are each linear or branched C 1-4 alkyl
  • R 3 and R 4 are identical, and each is hydrogen or C 1-4 alkyl
  • R 5 is hydrogen or C 1-3 alkyl
  • each of R 1 and R 2 which may be the same or different, is C 1-6 alkyl with at least one of them being substituted by at least one of halogen, (preferably fluorine or chlorine), hydroxy, C 1-6 alkoxy (preferably methoxy), acyloxy
  • R 3 is hydrogen or C 1-3 alkyl, preferably methyl
  • A represents
  • each of R c and R d which may be attached to the same or different carbon atom, is hydrogen, C 1-6 alkyl, hydroxy, thiol, C 1-6 alkoxy, C 1-6 alkylthio or halogen (preferably fluorine);
  • R e is C 1-6 alkyl
  • R f is hydrogen or together with R e forms a -(CH 2 ) b - group optionally substituted by one or two C 1-6 alkyl groups and attached to the same or different carbon atom;
  • R x is the remainder of an optionally substituted single or fused ring heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur; or R x is the remainder of an optionally substituted or unsubstituted phenyl group; a is 1, 2 or 3; b is 1, 2 or 3; and RCO, which is linked to the nitrogen atom of the group A, is an acyl group in which the group R contains a
  • compositions for use in the treatment of inflammation pain in mammals which comprises a compound of formulae (I) to (XVI) (as hereinbefore defined) or a
  • the invention further provides a method for the treatment and/or prophylaxis of inflammation pain in mammals
  • compositions which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of the Compound.
  • the Compounds may be prepared as described in the
  • Medicaments and compositions containing the Compounds may be prepared by admixture of a Compound with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • an appropriate carrier which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • these conventional excipients may be employed for example as in the preparation of compositions of known agents for the treatment of inflammation pain.
  • a medicament or pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as a an agent for the treatment of inflammation pain.
  • the suitable dosage range for a Compound depends on the Compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the Compound may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single
  • the Compound is in pharmaceutically acceptable or
  • 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.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the Compound.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • crystalline form including such form in a pharmaceutical composition.
  • Examples of the Compound in the form of a pharmaceutically acceptable salt include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • composition is suitable for oral, rectal, topical, parenteral, intravenous or
  • Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin,
  • sorbitol tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrrolidone, sodium starch glycollate or
  • microcrystalline cellulose or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
  • compositions When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible
  • capsule for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
  • compositions may also be administered by a non-oral route.
  • the compositions may be formulated, for example, for rectal administration as a suppository or for topical
  • compositions for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an
  • the effective dose of Compound depends on the particular Compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose 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, and 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 20mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • inflammation pain may be demonstrated using the paw pressure test in the monoarthritic rat as described in Eur. J. Pharm. 155, 255-264, 1988.
  • the Compounds produce an enhanced analgesic effect in the inflamed paw compared to the non-inflamed paw.
  • the analgesic effect in the inflamed paw is completely reversed by a low intraplantar dose of the opioid antagonist, naloxone, but not by a similar dose of naloxone administered subcutaneously.
  • Examples of preferred Compounds are:

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Azacyclic and heterocyclic derivatives having kappa agonist activity are useful in the treatment of inflammatory pain.

Description

USE OF HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY PAIN
The present invention relates to the use of certain
compounds for the manufacture of medicaments for the
treatment of inflammatory pain; to a method of treatment of inflammatory pain; and to pharmaceutical compositions for the treatment of such pain.
EP-A-228246, 232612, 232989, 260041, 261842, 275696, 330360, 333315, 333427, 361791, 370732, 409489, WO 91/08205, WO
91/08206, WO 91/17116 and WO 91/17981 (all Dr. Lo.
Zambeletti S.p.a.) describe classes of heterocyclic
derivatives which exhibit kappa receptor agonism and are of potential therapeutic utility as analgesics.
It has now been found that compounds of these classes activate peripheral kappa opioid receptors located on sensory nerve terminals. Activation of such receptors can lead to a reduction in the release of neurogenic
inflammatory mediators released from the nerve terminals and to a reduction in transmission of nociceptive information to the CNS. Compounds of the present invention are, therefore, of potential use as peripheral analgesics in the treatment of a range of inflammatory painful conditions - such as arthritis and low back pain - since they may reduce both the causes and consequences of local inflammation.
According to the present invention there is provided the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammation pain, wherein the compound is selected from compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or (XVI):
Figure imgf000004_0001
in which R is an acyl group containing a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring and R1 and R2 are independently C1-6 alkyl groups or together form a C1-6 polymethylene or alkenylene group;
Figure imgf000004_0002
in which R, R1 and R2 are as defined for formula (I), and p is 1, 2, 3 or 4;
Figure imgf000004_0003
in which R, R1 and R2 and as defined for formula (I) ;
Figure imgf000004_0004
in which R is a group:
Figure imgf000005_0001
in which R3 is Br, NO2 or CF3; and R1 and R2 are as defined in formula (I);
Figure imgf000005_0002
in which R is as defined in formula (I) ;
R1 and "Br each independently represents an alkyl, alkenyl or alkynyl group or R1 together with R2 represents a C3-6 polymethylene or alkenylene group;
R3 represents hydrogen or alkyl;
R4 represents hydrogen, halogen, alkyl, hydroxy, alkoxy, nitrile, nitro, amino or mono or disubstituted amino;
and
n represents 0 or 1;
Figure imgf000005_0003
in which R is as defined in formula (I);
R1 and R2 are independenlty hydrogen, C1-6 alkyl, C2-6 alkenyl, C4-6 cycloalkyl or C4-12 cycloalkylalkyl or
together form a C2-6 polymethylene or C2-6 alkenylene group, optionally substituted with a hetero-atom, provided that R1 and R2 are not simultaneously hydrogen;
Rx is C1-6 alkyl or phenyl, or Rx together with R^ form a -(CH2)3- or -(CH2)4- group;
Figure imgf000006_0001
in which R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups, or together form a C2-8 branched or linear
polymethylene or C2-6 alkenylene group optionally
substituted with a hetero-atom, provided that R1 and R2 are not simultaneously hydrogen;
R3 is hydrogen, C1-6 alkyl, or phenyl, or R3 together with R-L form a _(CH2)3- or -(CH2)4- group;
p is 1, 2, 3 or 4, and
R is a group of formula
Figure imgf000006_0002
in which the group -(CH4)n-X- is in the meta- or para-position with respect to YR5 or R6, R4 is hydrogen or C1-6 alkyl; n is 0, 1 or 2;
X is a direct bond, or O, S or NRa in which Ra is hydrogen or C1-6 alkyl;
Y is >C=O, >CHOH.>S=O or >SO2;
each of R5 and R6 is C1-6 alkyl, or R5 and R6 are linked together and Re represents -(Z)m- where m is 0 or 1 and Z is O, S or NR7 where R7 is hydrogen or C1-6 alkyl;
and R6 represents -(CH2)q- where q is an integer of from 1 to 4, and in which one or more of the -(CH2)- groups is optionally substituted by a C1-6 alkyl group;
Figure imgf000007_0001
in which R is as defined in formula (I)
R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group, optionally substituted with a
heteroatom; R3 is hydrogen, C1-6 alkyl, or phenyl or R3 together with R1 form a -(CH2)3- or -(CH2)4- group;
R4 is C1-6 alkyl, or phenyl;
R5 is hydrogen or together with R4 forms a -(CH2)n- group in which n = 1, 2 or 3; and
'Het' is an optionally substituted single or fused ring heterocyclic group, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur;
Figure imgf000008_0001
in which R is as defined in formula (I) and R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group optionally substituted with a hetero-atom;
R3 is hydrogen, C1-6 alkyl, or phenyl or R3 together with R1 forms a -(CH2)3- or -(CH2)4-, group;
R4 and R5, which may be the same or different and may be attached to the same or different carbon atoms of the isoquinoline nucleus, are each hydrogen, halogen, hydroxy, C1-6 alkyl, aryl, or R4 together with R5 form a - (CH2) group, where p is an integer of from 1 to 5 and one or more of the -(CH2)- moieties is optionally substituted by a C1-6 alkyl group. R6 and R6a, which may be the same or different, are each hydrogen, C1-6 alkyl, -CH2OR6b, halogen, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, thiol, C1-6 alkylthio,
Figure imgf000009_0001
, - NHCOR6d, -NHSO2R6e, -CH2SO2NR6fR6g, in which each of R6b to R6g is independently hydrogen, C1-6 alkyl, aryl or aralkyl;
with the proviso that R4, R5, R6 and R6a are not
simultaneously hydrogen;
Figure imgf000009_0002
in which R is as defined in formula (I);
R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups, or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group, optionally substituted with a hetero- atom;
R3 is hydrogen, C1-6 alkyl or phenyl, or R3 together with R-y form a -(CH2)3- or -(CH2)4- group;
R4 and R5 are independently hydrogen, hydroxyl, halogen, C1-6 alkyl or aryl, provided both R4 and R5 are not
simultaneously hydrogen: and p is an integer from 1 to 4;
Figure imgf000009_0003
in which R represents a group of formula
Figure imgf000010_0001
in which Rx is the remainder of a heterocyclic group, or an optionally substituted phenyl group;
R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups, or together form a C2-6 branched or linear polymethylene or C2-6 alkenylene group, optionally substituted with a hetero- atom;
R3 is hydrogen, C1-6 alkyl, or phenyl, or R3 together with
R1 form a -(CH2)3 _ or -(CH2)4- group;
R4 and R5, which may be located on the same or different carbon atoms, are independently hydrogen, C1-6 alkyl, or phenyl;
m is 1, 2 or 3;
R7 is hydrogen or C1-6 alkyl;
n is 0, 1 and 2;
X is direct bond, or O, S or NRg is hydrogen or C1-6 alkyl;
Y is >C=O, >CHOH, >S=O or >SO2;
each of R8 and R9 is C1-6 alkyl, or
Rg and Rg are linked together and Rg represents -(Z)p- where p is 0 or 1 and Z is O, S or NRZ where Rz is hydrogen or C1-6 alkyl;
and Rg represents -(CH2)q- where q is an integer of from 1 to 4;
Figure imgf000011_0002
in which R is as defined in formula (I) and R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group optionally substituted with a hetero-atom; R3 is hydrogen, C1-6 alkyl, or phenyl, or R3 together with
R1 forms a -(CH2)3- or -(CH2)4, group;
R4 and R5 are identical and are hydrogen or C1-6 alkyl, or together form a C2-5 linear polymethylene group;
R6 and R7 are indentical and are hydrogen or C1-6 alkyl, or together form a C2-5 linear polymethylene group;
or R5 and R6 are together -CH2- when each of R4 and R7 is hydrogen or C1-6 alkyl;
with the proviso that R4, R5, R6 and R7 are not
simultaneously hydrogen;
R8 and R9, which may be the same or different, are each hydrogen, C1-6 alkyl, -CH2OR10, halogen, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, thiol, C1-6 alkylthio, f -NHCOR12, -NHSO2R13, -CH2SO2NR14R15, in which each
Figure imgf000011_0003
of R10 to R15 is independently hydrogen, C1-6 alkyl, aryl or aralkyl;
Figure imgf000011_0001
in which:
(A) is
or
Figure imgf000012_0001
Figure imgf000012_0002
p is 1, 2 or 3;
ROC- is an acyl group linked to the nitrogen atom of group (A) in which the group R contains a substituted or
unsubstituted carbocyclic aromatic or heterocyclic aromatic ring;
R1 and R2 are substituents on the same or different carbon atoms and are independently hydrogen or C1-6 alkyl;
Ra is a fused substituted or unsubstituted heterocyclic or carbocyclic aromatic ring;
Figure imgf000012_0003
in which W, which may be attached to the same or different carbon atom as R 1 , is hydroxy, C1-6 alkoxy (preferably methoxy), halogen (preferably fluorine), thiol, C1-6 alkylthio, hydroxy C1-6 alkyl, methylidene, hydroxycarbonyl, aminocarbonyl, C1-3 alkoxycarbonyl, NHR1a or NHCOR1a where R1a is H or C1-6 alkyl; R1 is hydrogen, halogen (preferably fluorine), C1-6 alkyl (preferably methyl) or together with W forms a keto-group or a cyclic ether or thioether containing from 1 to 4 carbon atoms; A represents
or
Figure imgf000013_0001
Figure imgf000013_0002
in which each of R2 and R3, which may be attached to the same or different carbon atom, is hydrogen, C1-6 alkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio or halogen
(preferably fluorine);
R4 is C1-6 alkyl;
R 5 is hydrogen or together with R4 forms a -(CH2)c- group optionally substituted by one or two C1-6 alkyl groups and attached to the same or different carbon atom;
Rx is the remainder of an optionally substituted single or fused ring heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur;
or Rx is the remainder of an optionally substituted phenyl group; a is 1 or 2, b is 1, 2 or 3; c is 1, 2 or 3; and RCO, which is linked to the nitrogen atom of the group A, is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring, with the provisos that: i) When A represents, , R represents a tetralone
Figure imgf000014_0002
moiety, or W is halogen or C1-6 alkoxy, or R1 is other than hydrogen or a keto group with W;
ii) When R2 is C1-6 alkyl, R3 is other than hydrogen;
iii) When Rx, R4 and R5 together form an unsubstituted tetrahydroisoquinoline group, R represents a tetralone moiety or R1 is other than hydrogen or a keto group with W, or W is halogen or C1-6 alkoxy;
iv) When Rx, R4 and R5 together form a substituted tetrahydroisoquinoline group, substitution only occurs in the -(CH2)c- group formed by R4 and R5;
Figure imgf000014_0001
in which: R1 and R2 are each linear or branched C1-4 alkyl,
C3-6 cycloalkyl, C4-6 cycloalkylalkyl, C3-4 alkenyl, C3-6 cycloalkenyl or C3-4 alkynyl,
R3 and R4 are identical, and each is hydrogen or C1-4 alkyl; and
R5 is hydrogen or C1-3 alkyl;
Figure imgf000015_0001
in which:
each of R1 and R2, which may be the same or different, is C1-6 alkyl with at least one of them being substituted by at least one of halogen, (preferably fluorine or chlorine), hydroxy, C1-6 alkoxy (preferably methoxy), acyloxy
(preferably acetoxy), thiol, C1-6 alkylthio (preferably methylthio), acylthio (preferably acetylthio) halo-C1-6 alkoxy (preferably fluoro-alkoxy), CORh, COORh, CONHRh or NCHORh where Rh is hydrogen or C1-6 alkyl, preferably methyl or ethyl;
R3 is hydrogen or C1-3 alkyl, preferably methyl;
A represents
or
Figure imgf000015_0002
Figure imgf000015_0003
in which each of Rc and Rd, which may be attached to the same or different carbon atom, is hydrogen, C1-6 alkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio or halogen (preferably fluorine);
Re is C1-6 alkyl;
Rf is hydrogen or together with Re forms a -(CH2)b- group optionally substituted by one or two C1-6 alkyl groups and attached to the same or different carbon atom;
Rx is the remainder of an optionally substituted single or fused ring heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur; or Rx is the remainder of an optionally substituted or unsubstituted phenyl group; a is 1, 2 or 3; b is 1, 2 or 3; and RCO, which is linked to the nitrogen atom of the group A, is an acyl group in which the group R contains a
substituted or unsubstituted carbocyclic aromatic or
heterocyclic aromatic ring.
In a further aspect of the invention there is provided a pharmaceutical composition for use in the treatment of inflammation pain in mammals which comprises a compound of formulae (I) to (XVI) (as hereinbefore defined) or a
pharmaceutically acceptable salt or solvate thereof,
(hereinafter referred to as the Compound) and a
pharmaceutically acceptable carrier.
The invention further provides a method for the treatment and/or prophylaxis of inflammation pain in mammals,
particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of the Compound. The Compounds may be prepared as described in the
aforementioned documents, EP-A-228246, 232612, 232989,
260041, 261842, 275696, 330360, 333315, 333427, 361791, 370732, 409489, WO 91/08205, WO 91/08206, WO 91/17116 and WO 91/17981 (the subject matter of which is incorporated herein by reference) or by analogous methods thereto.
Medicaments and compositions containing the Compounds may be prepared by admixture of a Compound with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner. These conventional excipients may be employed for example as in the preparation of compositions of known agents for the treatment of inflammation pain.
Preferably, a medicament or pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as a an agent for the treatment of inflammation pain.
The suitable dosage range for a Compound depends on the Compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
The Compound may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single The Compound is in pharmaceutically acceptable or
substantially pure form. By 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.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the Compound.
One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the
additional ionic and solvent moieties must also be
non-toxic. Examples of the Compound in the form of a pharmaceutically acceptable salt include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
An example of the Compound in the form of a pharmaceutically acceptable solvate includes a hydrate. The Compounds have at least one asymmetric centre and therefore exist in more than one stereoisomeric form. The invention extends to the use of all such forms and to mixtures thereof, including racemates. dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or
intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin,
sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or
microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible
capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. The Compounds may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example, for rectal administration as a suppository or for topical
administration as a cream or lotion. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile
pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other
pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an
injectable formulation. The effective dose of Compound depends on the particular Compound employed, the condition of the patient and on the frequency and route of administration. A unit dose 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, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
Within the above indicated dosage range, no adverse
toxicological effect are observed with the Compounds in tests which are indicative of compounds of potential use in treating inflammation pain.
The effects of the Compounds in protecting against
inflammation pain may be demonstrated using the paw pressure test in the monoarthritic rat as described in Eur. J. Pharm. 155, 255-264, 1988.
Following subcutaneous administration, the Compounds produce an enhanced analgesic effect in the inflamed paw compared to the non-inflamed paw. The analgesic effect in the inflamed paw is completely reversed by a low intraplantar dose of the opioid antagonist, naloxone, but not by a similar dose of naloxone administered subcutaneously. Examples of preferred Compounds are:
4-(pyrrolidin-1-yl)methyl-5-(3,4-dichlorophenyl) acetyl- 4,5,6,7-tetrahydroimidazo [4,5-c] pyridine
(Example 23 of EP-A-333427);
(2)-1-(4-trifluoromethyl phenylacetyl)-2-(1-pyrrolidinylmethyl) piperidine
(Example 3 of EP-A-260 041);
and
(2S)-1-[1-oxo-3,4,-dihydro-(2H)-naphth-6-yl]acetyl-2-dimethylaminomethyl piperidine hydrochloride
(Example No. 1 of WO 91/17116).
Example 23 of EP-A-333427 shows no evidence of brain penetration by comparing cerebral and plasma levels after subcutaneous administration (1 mg/Kg) of the testing drug. This property, which is in agreement with the very low lipophilicity of the compound [assessed by measuring the ΔLogP=logP (n-octanol/acq. buffer) - logP
(cyclohexane/acq. buffer) = 4.12 at pH=12, 25°C], renders the compound particularly suitable for obtaining a
peripherally selective antinociceptive action.

Claims

Claims
Use of a compound, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammation pain, wherein the compound is selected from compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or (XVI):
Figure imgf000023_0001
in which R is an acyl group containing a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring and R1 and R2 are independently C1-6 alkyl groups or together form a C3-6 polymethylene or alkenylene group;
Figure imgf000023_0002
in which R, R1 and R2 are as defined for formula (I), and p is 1, 2, 3 or 4;
Figure imgf000024_0001
in which R, R1 and R2 and as defined for formula (I) ;
Figure imgf000024_0002
in which R is a group :
Figure imgf000024_0003
in which R3 is Br, NO2 or CF3; and R1 and R2 are as defined in formula (I);
Figure imgf000024_0004
in which R is as defined in formula (I);
R1 and R2 each independently represents an alkyl, alkenyl or alkynyl group or R1 together wi.th R2 represents a C3-6 polymethylene or alkenylene group; R3 represents hydrogen or alkyl;
R4 represents hydrogen, halogen, alkyl, hydroxy, alkoxy, nitrile, nitro, amino or mono or disubstituted amino;
and
n represents 0 or 1;
Figure imgf000025_0001
in which R is as defined in formula (I);
R1 and R2 are independenlty hydrogen, C1-6 alkyl, C2-6 alkenyl, C4-6 cycloalkyl or C4-12 cycloalkylalkyl or together form a C2-6 polymethylene or C2-6 alkenylene group, optionally substituted with a hetero-atom, provided that R1 and R2 are not simultaneously
hydrogen;
Rx is C1-6 alkyl or phenyl, or Rx together with R1 form a -(CH2)3- or -(CH2)4- group;
Figure imgf000025_0002
in which R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12
cycloalkylalkyl groups, or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group optionally substituted with a hetero-atom, provided that R1 and R2 are not simultaneously hydrogen;
R3 is hydrogen, C1-6 alkyl, or phenyl, or R3 together with R1 form a -(CH2)3- or -(CH2)4- group;
p is 1, 2, 3 or 4, and
R is a group of formula
Figure imgf000026_0001
in which the group -(CH4)n-X- is in the meta- or para-position with respect to YRc or R6, R4 is hydrogen or C1-6 alkyl; n is 0, 1 or 2;
X is a direct bond, or O, S or NRa in which Ra is hydrogen or C1-6 alkyl;
Y is >C=O, >CHOH.>S=O or >SO2;
each of R5 and R6 is C1-6 alkyl, or
R5 and R5 are linked together and R5 represents -(Z)m- where m is 0 or 1 and Z is O, S or NR7 where R7 is hydrogen or C1-6 alkyl; and R6 represents -(CH2)q- where q is an integer of from 1 to 4, and in which one or more of the -(CH2)- groups is optionally substituted by a C1-6 alkyl group;
Figure imgf000027_0001
in which R is as defined in formula (I)
R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group, optionally substituted with a heteroatom;
R3 is hydrogen, C1-6 alkyl, or phenyl or R3 together with R1 form a -(CH2)3- or -(CH2)4- group;
R4 is C1-6 alkyl, or phenyl;
Rg is hydrogen or together with R4 forms a -(CH2)n- group in which n = 1, 2 or 3; and
'Het' is an optionally substituted single or fused ring heterocyclic group, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur;
Figure imgf000027_0002
in which R is as defined in formula (I) and R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group optionally substituted with a hetero-atom;
R3 is hydrogen, C1-6 alkyl, or phenyl or R3 together with R1 forms a -(CH2)3- or -(CH2)4-, group;
R4 and R5, which may be the same or different and may be attached to the same or different carbon atoms of the isoquinoline nucleus, are each hydrogen, halogen, hydroxy, C1-6 alkyl, aryl, or R4 together with R5 form a -(CH2)p group, where p is an integer of from 1 to 5 and one or more of the -(CH2)- moieties is optionally substituted by a C1-6 alkyl group.
R6 and R6a. which may be the same or different, are each hydrogen, C1-6 alkyl, -CH2OR6b, halogen, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, thiol, C1-6
alkylthio,
Figure imgf000028_0001
- , - NHCOR6d, -NHSO2R6e, -CH2SO2NR6fR6g, in which each of R6b to R6g is independently hydrogen, C1-6 alkyl, aryl or aralkyl;
with the proviso that R4, R5, R6 and R6a are not simultaneously hydrogen;
Figure imgf000028_0002
in which R is as defined in formula (I);
R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups, or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group, optionally substituted with a hetero-atom;
R3 is hydrogen, C1-6 alkyl or phenyl, or R3 together with R1 form a -(CH2)3- or -(CH2)4- group;
R4 and R5 are independently hydrogen, hydroxyl, halogen, C1-6 alkyl or aryl, provided both R4 and R5 are not simultaneously hydrogen: and p is an integer from 1 to 4;
Figure imgf000029_0002
in which R represents a group of formula
Figure imgf000029_0001
in which Rx is the remainder of a heterocyclic group, or an optionally substituted phenyl group; R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups, or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group, optionally substituted with a hetero-atom;
R3 is hydrogen, C1-6 alkyl, or phenyl, or R3 together with R1 form a -(CH2)3- or -(CH2)4- group;
R4 and Rg, which may be located on the same or
different carbon atoms, are independently hydrogen, C1-6 alky l, or Phenyl;
m is 1, 2 or 3;
R7 is hydrogen or C1-6 alkyl;
n is 0, 1 and 2;
X is direct bond, or O, S or NR6 is hydrogen or C1-6 alkyl;
Y is >C=O, >CHOH, >S=O or >SO2;
each of R8 and R9 is C1-6 alkyl, or
R8 and R9 are linked together and R8 represents -(Z)p- where p is 0 or 1 and Z is O, S or NRZ where Rz is hydrogen or C1-6 alkyl;
and R9 represents -(CH2)q- where q is an integer of from 1 to 4;
Figure imgf000030_0001
in which R is as defined in formula (I) and R1 and R2 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or C4-12 cycloalkylalkyl groups or together form a C2-8 branched or linear polymethylene or C2-6 alkenylene group optionally substituted with a hetero-atom; R3 is hydrogen, C1-6 alkyl, or phenyl, or R3 together with R1 forms a -(CH2)3- or -(CH2)4, group;
R4 and R5 are identical and are hydrogen or C1-6 alkyl, or together form a C2-5 linear polymethylene group;
R6 and R7 are indentical and are hydrogen or C1-6 alkyl, or together form a C2-5 linear polymethylene group;
or R5 and R6 are together -CH2- when each of R4 and R7 is hydrogen or C1-6 alkyl;
with the proviso that R4, R5, R6 and R7 are not simultaneously hydrogen;
R8 and R9, which may be the same or different, are each hydrogen, C1-6 alkyl, -CH2OR10, halogen, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, thiol, C1-6
alkylthio, , -NHCOR12, -NHSO2R13, -CH2SO2NR14R15, in which
Figure imgf000031_0004
each of R10 to R15 is independently hydrogen, C1-6 alkyl, aryl or aralkyl;
Figure imgf000031_0001
in which :
(A) is
or
Figure imgf000031_0002
Figure imgf000031_0003
p is 1, 2 or 3;
ROC- is an acyl group linked to the nitrogen atom of group (A) in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring;
R1 and R2. are substituents on the same or different carbon atoms and are independently hydrogen or C1-6 alkyl;
Ra is a fused substituted or unsubstituted
heterocyclic or carbocyclic aromatic ring;
Figure imgf000032_0001
in which W, which may be attached to the same or different carbon atom as R1, is hydroxy, C1-6 alkoxy (preferably methoxy), halogen (preferably fluorine), thiol, C1-6 alkylthio, hydroxy C1-6 alkyl,
methylidene, hydroxycarbony1, aminocarbonyl, C1-3 alkoxycarbonyl, NHR1a or NHCOR1a where R1a is H or C1-6 alkyl;
R1 is hydrogen, halogen (preferably fluorine), C1-6 alkyl (preferably methyl) or together with W forms a keto-group or a cyclic ether or thioether containing from 1 to 4 carbon atoms; or
Figure imgf000033_0001
Figure imgf000033_0002
in which each of R2 and R3, which may be attached to the same or different carbon atom, is hydrogen, C1-6 alkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio or halogen (preferably fluorine);
R4 is C1-6 alkyl;
R5 is hydrogen or together with R4 forms a -(CH2)c- group optionally substituted by one or two C1-6 alkyl groups and attached to the same or different carbon atom;
Rx is the remainder of an optionally substituted single or fused ring heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur;
or Rx is the remainder of an optionally substituted phenyl group; a is 1 or 2, b is 1, 2 or 3; c is 1, 2 or 3; and RCO, which is linked to the nitrogen atom of the group A, is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring. with the provisos that: i) When A represents, N-, R represents a tetralone moiety, or W is halogen or C1-6 alkoxy, or R1 is other than hydrogen or a keto group with W;
ii) When R2 is C1-6 alkyl, R3 is other than hydrogen; iii) When Rx, R4 and Rg together form an unsubstituted tetrahydroisoquinoline group, R represents a tetralone moiety or R1 is other than hydrogen or a keto group with W, or W is halogen or C1-6 alkoxy;
iv) When Rx, R4 and R5 together form a substituted tetrahydroisoquinoline group, substitution only occurs in the -(CH2)c- group formed by R4 and R5;
Figure imgf000034_0001
in which: R1 and R2 are each linear or branched C1-4 alkyl, C3-6 cycloalkyl, C4-6 cycloalkylalkyl, C3-4 alkenyl, C3-6 cycloalkenyl or C3-4 alkynyl,
R3 and R4 are identical, and each is hydrogen or C1-4 alkyl; and
R5 is hydrogen or C1-3 alkyl; in which:
Figure imgf000035_0003
each of R1 and R2, which may be the same or different, is C1-6 alkyl with at least one of them being
substituted by at least one of halogen, (preferably fluorine or chlorine), hydroxy, C1-6 alkoxy
(preferably methoxy), acyloxy (preferably acetoxy), thiol, C1-6 alkylthio (preferably methylthio),
acylthio (preferably acetylthio) halo-C1-6 alkoxy
(preferably fluoro-alkoxy), CORh, COORh, CONHRh or NCHORh where Rh is hydrogen or C1-6 alkyl, preferably methyl or ethyl;
R3 is hydrogen or C1-3 alkyl, preferably methyl;
A represents
or
Figure imgf000035_0002
Figure imgf000035_0001
in which each of Rc and Rd, which may be attached to the same or different carbon atom, is hydrogen, C1-6 alkyl, hydroxy, thiol, C1-6 alkoxy, C1-6 alkylthio or halogen (preferably fluorine); Re is C1-6 alkyl;
Rf is hydrogen or together with Re forms a "(CH2)b- group optionally substituted by one or two C1-6 alkyl groups and attached to the same or different carbon atom;
Rx is the remainder of an optionally substituted single or fused ring heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur; or Rx is the remainder of an optionally substituted or unsubstituted phenyl group; a is 1, 2 or 3; b is 1, 2 or 3; and RCO, which is linked to the nitrogen atom of the group A, is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring.
2. A use according to claim 1 in which the compound is selected from:
4-(pyrrolidin-1-yl)methyl-5-(3,4-dichlorophenyl) acetyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine;
(2)-1-(4-trifluoromethyl phenylacetyl)-2-(1- pyrrolidinyl methyl)piperidine;
and
(2S)-1-[1-oxo-3,4,-dihydro-(2H)-naphth-6-yl]acetyl-2- diraethylaminomethyl piperidine hydrochloride.
3. A pharmaceutical composition for use in the treatment of inflammation pain in mammals, which comprises a compound of formulae (I) to (XVI) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
4. A method for the treatment and/or prophylaxis of
inflammation pain in mammals, which comprises
administering to a mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formulae (I) to (XVI) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.
PCT/EP1992/000838 1991-04-18 1992-04-08 Use of heterocyclic compounds for the treatment of inflammatory pain WO1992018115A1 (en)

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GB919115143A GB9115143D0 (en) 1991-07-13 1991-07-13 Novel use

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