EP1387687A2 - Nouvelle utilisation - Google Patents

Nouvelle utilisation

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Publication number
EP1387687A2
EP1387687A2 EP02731870A EP02731870A EP1387687A2 EP 1387687 A2 EP1387687 A2 EP 1387687A2 EP 02731870 A EP02731870 A EP 02731870A EP 02731870 A EP02731870 A EP 02731870A EP 1387687 A2 EP1387687 A2 EP 1387687A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
pharmaceutically acceptable
conditions
irritable bowel
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.)
Withdrawn
Application number
EP02731870A
Other languages
German (de)
English (en)
Other versions
EP1387687A4 (fr
Inventor
Douglas William Pierre Hay
Gareth J. Sanger
Tadataka Yamada
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0112208A external-priority patent/GB0112208D0/en
Priority claimed from GB0129268A external-priority patent/GB0129268D0/en
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1387687A2 publication Critical patent/EP1387687A2/fr
Publication of EP1387687A4 publication Critical patent/EP1387687A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • This invention relates to a novel use, in particular to a use in a method for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain.
  • the mammalian peptide Neurokinin B belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA).
  • TK Tachykinin
  • SP Substance P
  • NKB Neurokinin A
  • NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J.Phisiol, 410, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J. Neurosci, 14 (2), 712-720; Arenas et al. 1991, J.Neuroscl, 11, 2332-8).
  • the Rome diagnostic criteria recognise that functional bowel disorder includes the following distinct groups: irritable bowel syndrome (IBS), functional abdominal bloating, functional constipation and functional diarrhea. IBS is generally acknowledged to include discomfort and/or pain along with disorders such as diarrhoea-predominant irritable bowel syndrome, constipation- predominant irritable bowel syndrome and alternater irritable bowel syndrome. (Gut, 1999; 45 (Suppl. II) 1169 -1177). In addition the Rome diagnostic criteria recognise that functional abdominal pain is distinct from functional bowel disorder and that functional abdominal pain includes functional abdominal pain syndrome and unspecified functional abdominal pain.
  • Gastroenterology 1999, 116, 1124-1131 discloses the role of NK3 receptors on responses to colorectal distention in the rat via electrophysiological and behavioral studies.
  • International Patent Application, Publication numbers 98/18762 and 00/21931 disclose certain NK3 receptor antagonists stated to be useful for treating disorders involving NK3 receptors including irritable bowel syndrome (IBS) amongst a list of other disorders.
  • IBS irritable bowel syndrome
  • Certain selective NK3 antagonists are disclosed in International Patent Application, Publication number 95/32948. These compounds are disclosed as having activity in the treatment of: pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety and psychosis); and also the treatment of: convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression.
  • pulmonary disorders asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough
  • skin disorders and itch for example, atopic dermatitis and cutaneous wheal and flare
  • Compound (I) has activity in the treatment of conditions characterised by altered bowel function and/or visceral pain. This includes, in particular, functional bowel disorders and functional abdominal pain.
  • the functional bowel disorders include particular irritable bowel syndrome conditions, especially, diarrhoea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome and alternater irritable bowel syndrome.
  • Compound (I) has been indicated to be particularly useful for treating diarrhoea-predominant irritable bowel syndrome.
  • the invention provides a method for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain in humans or non-human mammals, which method comprises the administration of an effective, non- toxic and pharmaceutically acceptable amount of an NK3 receptor antagonist, such as Compound (I), or a pharmaceutically acceptable derivative thereof, wherein the condition characterised by altered bowel function and/or visceral pain is selected from certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel conditions and functional abdominal pain.
  • an NK3 receptor antagonist such as Compound (I)
  • a pharmaceutically acceptable derivative thereof wherein the condition characterised by altered bowel function and/or visceral pain is selected from certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel conditions and functional abdominal pain.
  • the invention provides a method for the treatment and/or prophylaxis of conditions characterised by altered bowel function.
  • the invention provides a method for the treatment and/or prophylaxis of conditions characterised by visceral pain.
  • Suitable conditions characterised by altered bowel function and/or visceral pain are selected from certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea and functional abdominal pain.
  • Particular irritable bowel syndrome conditions include diarrhoea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome and alternater irritable bowel syndrome.
  • a suitable irritable bowel syndrome condition is constipation-predominant irritable bowel syndrome.
  • a suitable irritable bowel syndrome condition is alternater irritable bowel syndrome.
  • a preferred irritable bowel syndrome condition is diarrhoea-predominant irritable bowel syndrome.
  • functional abdominal pain includes functional abdominal pain syndrome and unspecified functional abdominal pain.
  • functional abdominal pain includes functional abdominal pain syndrome.
  • Suitable NK3 antagonists include the compounds specifically and generically disclosed in International Patent Application, Publication number 95/32948 the contents of which are included herein by reference, as if the specific contents of WO 95/32948 were fully set forth herein.
  • a favoured NK3 antagonist is a compound of formula (I):
  • Ar is an optionally substituted phenyl, naphthyl or C5.7 cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
  • R is linear or branched C- g alkyl, 03.7 cycloalkyl, 04.7 cycloalkylalkyl, optionally substituted phenyl or phenyl C ⁇ g alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatom selected from O and N, hydroxy C- g alkyl, amino C ⁇ . alkyl, C ⁇ .g alkylaminoalkyl, di C _ alkylaminoalkyl, C ⁇ . acylaminoalkyl, C ⁇ .g alkoxyalkyl, C . ⁇ alkylcarbonyl, carboxy, C ⁇ alkoxyxcarbonyl, C ⁇ .
  • alkoxycarbonyl C- ⁇ g alkyl, aminocarbonyl, C _6 alkylaminocarbonyl, di Cj.g alkylaminocarbonyl, halogeno ⁇ _ alkyl; or is a group -(CH2)p- when cyclized onto Ar, where p is 2 or 3.
  • Rj and R2 which may be the same or different, are independently hydrogen or C ⁇ _6 linear or branched alkyl, or together form a -(CH2)n- group in which n represents 3, 4, or 5; or R together with R forms a group -(CH2)n-» in which q is 2, 3, 4 or 5;
  • R3 and R4 which may be the same or different, are independently hydrogen, Cj.g linear or branched alkyl, Cj.g alkenyl, aryl, C ⁇ alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, . alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C j .g alkylamino, -O(CH2) r -NT2, in which r is 2, 3, or 4 and T is hydrogen or C _ alkyl or it forms with the adjacent nitrogen a group
  • V and V ⁇ are independently hydrogen or oxygen and u is 0,1 or 2; -O(CH-2) s -OW in which s is 2, 3, or 4 and W is hydrogen or .
  • the invention relates to a method for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain in humans or non-human mammals, which method comprises the administration of an effective, non- toxic and pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof.
  • the invention relates to the treatment and/or prophylaxis of conditions characterised by altered bowel function in particular diarrhoea-predominant irritable bowel syndrome.
  • the invention relates to the treatment and/or prophylaxis of diarrhoea.
  • Ar are phenyl, optionally substituted by hydroxy, halogen, C ⁇ _6 alkoxy or Cj.g alkyl.
  • halogen are chlorine and fluorine, an example of Cj.g alkoxy is methoxy and an example of C . alkyl is methyl.
  • Examples of Ar as a heterocyclic group are thienyl and pyridyl.
  • Examples of Ar as a 05.7 cycloalkdienyl group is cyclohexadienyl.
  • Examples of R are as follows: C j .g alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl; phenyl C ⁇ _6 alkyl: benzyl; hydroxy C ⁇ _ 6 alkyl: - CH 2 OH, -CH 2 CH 2 OH, CH(Me)OH; amino C ⁇ alkyl: -CH2NH2; di Cj_6 alkylaminoalkyl: -CH2NMe2; C ⁇ _6 alkoxylalkyl: CH 2 OMe; Cj_6 alkylcarbonyl: COMe; C ⁇ . ⁇ alkoxycarbonyl: COOMe; C ⁇ g alkoxycarbon
  • Example of R and R2 as C g alkyl is methyl; example of Rj together with R forming a group-(CH2)q- is spirocyclopentane.
  • R3 and R4 are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine, acetyloxy, 2-(dimetylamino)ethoxy, 2-(phthalimido)ethoxy, aminoethoxy, 2-(l-pyrrolidinyl)ethoxy, phthalimido, dimethylaminopropoxy, dimethylaminoacetylammo, acetylamino, dimethylaminomethyl and phenyl.
  • R5 are cyclohexyl, phenyl optionally substituted as defined for Ar above; examples of R5 as a heterocyclic group are furyl, thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl.
  • a preferred group of compounds of formula (I) are those in which:
  • Ar is phenyl, optionally substituted by C _ alkyl or halogen; thienyl or a 5-7 cycloalkdienyl group;
  • R is C ⁇ _6 alkyl, C ⁇ _ alkoxycarbonyl, C ⁇ . alkylcarbonyl, hydroxy _ alkyl;
  • R- and R2 are each hydrogen or ⁇ . alkyl;
  • R3 is hydrogen, hydroxy, halogen, Cj.g alkoxy, . alkyl;
  • R4 is hydrogen, C- g alkyl, ⁇ . alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, phthalimidoalkoxy, mono- or di-alkylaminoacylamino and acylamino;
  • R5 is phenyl, thienyl, furyl, pyrryl and thiazolyl.
  • a further preferred group of compounds of formula (I) are those in which:
  • Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl
  • R is methyl, ethyl, n-propyl, -COOMe, -COMe;
  • R ⁇ and R2 are each hydrogen or methyl
  • R3 is hydrogen, methoxy, or hydroxy
  • R4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2-(phthalimido)ethoxy, aminoethoxy, 2-(l- pyrrolidinyl)ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, and dimethylaminomethyl.
  • R5 is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl and 3-thienyl; and X is oxygen.
  • a preferred sub-group of compounds within the scope of formula (I) above is of formula
  • R, R2, R3 and R4 are as defined in formula (I), and Y and Z, which may be the same or different, are each Ar as defined in formula (I).
  • a particularly preferred group of compounds of formula (la) are those of formula (lb) in which the group R is oriented downward and H upward.
  • a most preferred compound of formula (I) is Compound (I).
  • the compounds of formula (I) or their derivatives such as salts or solvates are in pharmaceutically acceptable 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.
  • 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 of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts and/or solvates.
  • pharmaceutically acceptable salts of a compound of formula (I) 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.
  • Examples of pharmaceutically acceptable solvates of a compound of formula (I) include hydrates.
  • the compounds of formula (I) may have at least one asymmetric centre and therefore may exist in more than one stereoisomeric form.
  • the treatment of the invention extends to all such forms and to mixtures thereof, including racemates.
  • NK3 antagonists are those disclosed in published patent applications WO99/36424, WO00/39114, WO95/28931, WO96/05203, EP776893, WO98/54191, EP673928, WO94/26735 and WO97/10229.
  • the contents of the above mentioned patent publications are incorporated herein as if each individual publication were specifically and individually incorporated by reference herein as though fully set forth.
  • a particular NK3 antagonist is ([[dichlorophenyl)(trimethoxybenzoy)morpholinyl]ethyl]spiro[benzo(c)thiophenepiperidine] oxide.
  • a particular NK3 antagonist is Rl 13281.
  • a particular NK3 antagonist is N10A.
  • a particular NK3 antagonist is N5A1.
  • a particular NK3 antagonist is SR-142801.
  • a particular NK3 antagonist is SSR-146977.
  • a particular NK3 antagonist is Cam-2425.
  • a particular NK3 antagonist is MDL-105212.
  • the NK3 antagonist is prepared according to known methods for the particular compound chosen, for example compounds of formula (I) and Compound (I) are prepared according to methods disclosed in WO95/32948 or WO99/14196.
  • NK3 antagonists such as Rl 13281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 and MDL-105212 are prepared, as appropriate, according to published methods for example those disclosed in WO99/36424, WOOO/39114, WO95/28931, WO96/05203, EP776893, WO98/54191, EP673928, WO94/26735 and WO97/10229.
  • the compounds of the method of the invention such as Compound (I), may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of the method of the invention such as Compound (I), may be formed by crystallization or recrystallization from the appropriate solvent.
  • hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • Pharmaceutically acceptable derivatives of other NK3 antagonists such as
  • Rl 13281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 and MDL-105212 include, as appropriate, those disclosed in WO99/36424, WOOO/39114, WO95/28931, WO96/05203, EP776893, WO98/54191, EP673928, WO94/26735 and WO97/ 10229.
  • NK3 receptor antagonists are assessed in standard tests indicates that they are of potential therapeutic utility in the treatment of certain clinical conditions characterized by overstimulation of the tachykinin receptors, in particular the conditions disclosed herein.
  • the relevant tests include those disclosed herein.
  • condition characterised by altered bowel function includes diarrhoea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, alternater irritable bowel syndrome, functional abdominal bloating, functional constipation and functional diarrhea
  • conditions characterised by altered bowel function includes diarrhoea-predominant irritable bowel syndrome.
  • conditions characterised by altered bowel function includes constipation-predominant irritable bowel syndrome.
  • conditions characterised by altered bowel function includes other bowel conditions.
  • other bowel conditions includes conditions presenting with symptoms such as abdominal pain, urgency, bloating, incomplete evacuation and straining, especially urgency, bloating, incomplete evacuation and straining.
  • the present invention also provides a method for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain, in humans or non-human mammals, which method comprises the administration of an effective, non- toxic and pharmaceutically acceptable amount of an NK3 antagonist , such as Compound (I), or a pharmaceutically acceptable derivative thereof
  • an NK3 antagonist such as Compound (I) or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain.
  • an NK3 antagonist such as Compound (I) or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain.
  • the condition characterised by altered bowel function and/or visceral pain is selected from certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel conditions and functional abdominal pain.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an NK3 antagonist, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof or a or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor, for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain suitably wherein the condition characterised by altered bowel function and/or visceral pain is selected from certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel conditions and functional abdominal pain.
  • Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • compositions of known agents for treating the conditions may be employed for example as in the preparation of compositions of known agents for treating the conditions.
  • a 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 an agent in the treatment of the conditions.
  • the suitable dosage range for the compounds of the invention 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 or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may self-administer it in a single dosage.
  • 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.
  • compositions 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, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • 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, polyvinyl-pyrrolidone
  • 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.
  • 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 colour
  • compositions may be formulated, for example for rectal administration as a suppository. 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.
  • 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 active compounds of this invention may also be administered by inhalation, via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles.
  • the compound particle size is from about 2 to 10 microns.
  • a further mode of administration of the active compounds of this invention comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or • silicone can be used.
  • 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 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • Dosages and formulations of particular NK3 antagonists include those disclosed in the above mentioned patent applications.
  • NK3 ligands are determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [125l]- [Me-Phe ⁇ j-NKB or [ ⁇ Hj-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
  • the binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [ 125 I]-[Me-Phe 7 ]-NKB and [ 3 H]-Senktide specific binding to NK3 receptor in equilibrium conditions (IC50).
  • Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the NK 3 - antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J.
  • Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean Kg value of 3- 8 separate experiments, where Kg is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide.
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca ++ mobilization induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.
  • the therapeutic potential of the compounds of the present invention in treating the conditions mentioned above can be assessed using rodent disease models.
  • FIGURES The invention is illustrated, but not limited by, the following experimental data.
  • Figure 1 shows inhibition by Compound (I) of the ascending excitory reflex
  • Figure 2 shows the lack of significant effect of Compound (I) on small intestinal transit in normal non-sensitised animals
  • Figure 3 shows the effect of Compound (I) on small intestinal transit in egg-albumen sensitisation model
  • Figure 4 shows the effect of Compound (I) on rat colorectal sensitivity and tone.
  • Compound (I) at oral doses of 5, 15 and 50 mg/kg produced no marked or statistically significant effects on rat gastric emptying, as determined using the phenol red method.
  • the high doses used in this study are similar to those that exerted intestinal antinociceptive activity (see below) and are consistent with the low affinity of Compound (I) for the rat NK-3 receptor, relative to its higher affinity for the human or guinea-pig variants of this receptor.
  • the reference standard, morphine sulfate administered orally at 20 mg/kg produced a marked and statistically significant decrease in gastric emptying (see Table 1). This effect was expected and demonstrated the validity of the test system.
  • Table 1 Proportion of gastric emptying in rats after administration of Compound (I), morphine sulfate, phenol red and vehicle only
  • Oral administration of Compound (I) at doses of 5, 15 and 50 mg/kg also produced no marked or statistically significant effect on gastrointestinal motility in the rat, as determined using the charcoal meal test.
  • the distance travelled by the charcoal meal in each Compound (I)-treated group was similar to the vehicle-treated group at each tested dose.
  • morphine sulfate at an oral dose of 10 mg/kg produced a marked and statistically significant decrease in gastrointestinal motility compared with the vehicle-treated group (see Table 2). This effect was expected and demonstrated the validity of the test system.
  • the slowEPSP was elicited by high frequency (20 Hz) electrical stimulation for 1 s, applied to a circumferential internodal strand connecting to the ganglion.
  • a baseline slowEPSP was obtained and once it subsided, Compound (I) at a concentration of 0.1 microM was perfused through the preparation. It was perfused continuously and the slowEPSP was tested at various intervals, hi all four neurons there was a decrease of peak amplitude of depolarisation of over 50% when compared with baseline, once the drug had circulated for at least 30 minutes. There was 100% blockade in one neuron and it even revealed an inhibitory post-synaptic potential (IPSP) on stimulation.
  • IIPSP inhibitory post-synaptic potential
  • the other three neurons showed a blockade, based on the amplitude of depolarisation, of 60-80%.
  • Two of the neurons were filled with biocytin and reacted with streptavidin and Texas Red revealing a Dogiel type II morphology on fluorescence microscopy.
  • NK3 receptor antagonism by Compound (I) 15 mg/ kg po. has been shown to inhibit the increase in rat small intestinal transit time evoked by an egg-albumin challenge.

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Abstract

L'invention concerne une méthode de traitement et/ou de prévention de troubles caractérisés par une modification de la fonction intestinale et/ou des douleurs viscérales chez les mammifères, y compris l'homme. Cette méthode consiste à administrer une dose pharmaceutiquement acceptable, non toxique et efficace d'un antagoniste du récepteur NK3. Le trouble caractérisé par une modification de la fonction intestinale et/ou des douleurs viscérales est sélectionné dans les pathologies suivantes : certains troubles associés à un syndrome du côlon irritable, ballonnements abdominaux fonctionnels, constipation fonctionnelle, diarrhée fonctionnelle et autres troubles intestinaux et douleurs abdominales fonctionnelles.
EP02731870A 2001-05-18 2002-05-17 Nouvelle utilisation Withdrawn EP1387687A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0112208A GB0112208D0 (en) 2001-05-18 2001-05-18 New use
GB0112208 2001-05-18
GB0129268A GB0129268D0 (en) 2001-12-06 2001-12-06 Novel use
GB0129268 2001-12-06
PCT/US2002/015911 WO2002094187A2 (fr) 2001-05-18 2002-05-17 Nouvelle utilisation

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EP1387687A2 true EP1387687A2 (fr) 2004-02-11
EP1387687A4 EP1387687A4 (fr) 2006-07-05

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KR (1) KR20040016865A (fr)
CN (1) CN1269483C (fr)
AR (1) AR045879A1 (fr)
AU (1) AU2002303811B2 (fr)
BR (1) BR0209662A (fr)
CA (1) CA2447063A1 (fr)
CZ (1) CZ20033115A3 (fr)
HU (1) HUP0400966A2 (fr)
IL (1) IL158701A0 (fr)
MX (1) MXPA03010509A (fr)
MY (1) MY134211A (fr)
NO (1) NO20035121L (fr)
NZ (1) NZ529462A (fr)
PE (1) PE20021067A1 (fr)
PL (1) PL367308A1 (fr)
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WO (1) WO2002094187A2 (fr)

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SI1594517T1 (sl) 2003-01-28 2007-10-31 Microbia Inc Sestavki za zdravljenje gastrointestinalnih motenj
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
KR20060135000A (ko) * 2004-03-30 2006-12-28 스미스클라인 비참 코포레이션 분무 건조 제약 조성물
WO2005100997A2 (fr) * 2004-04-16 2005-10-27 Bayer Healthcare Ag Moyens diagnostiques et therapeutiques pour maladies associees au recepteur de tachykinine 3 (tacr3)
US20080255193A1 (en) * 2005-09-30 2008-10-16 Jeffrey Brum Pharmaceutical Composition
TW201018662A (en) 2005-12-12 2010-05-16 Astrazeneca Ab Alkylsulphonamide quinolines
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2170930B3 (fr) 2007-06-04 2013-10-02 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
JP2011522828A (ja) 2008-06-04 2011-08-04 シナジー ファーマシューティカルズ インコーポレイテッド 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト
AU2009270833B2 (en) 2008-07-16 2015-02-19 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
ES2657938T3 (es) 2008-12-31 2018-03-07 Ardelyx, Inc. Compuestos y métodos para inhibir el antipuerto mediado por NHE en el tratamiento de trastornos asociados a la retención de líquidos o a la sobrecarga de sales y trastornos del tracto gastrointestinal
KR200452372Y1 (ko) * 2010-05-14 2011-02-22 서일수 건설용 리프트의 통신선 지지장치
KR101034774B1 (ko) * 2010-07-30 2011-05-17 (주)챔피온코리아 와이어로프를 이용한 리프트 장치
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
BR112015003527A2 (pt) 2012-08-21 2017-07-04 Ardelyx Inc compostos e métodos para inibição de antiporte mediado por nhe no tratamento de desordens associadas à retenção de fluido ou sobrecarga de sal e desordens do trato gastrointestinal
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
CA2905435A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2983667B1 (fr) 2013-04-12 2019-03-20 Ardelyx, Inc. Composés de liaison à nhe3 et procédés d'inhibition du transport de phosphate
WO2014170648A1 (fr) 2013-04-19 2014-10-23 Astrazeneca Ab Composé antagoniste du récepteur nk3 (nk3ra) utilisé dans une méthode pour traiter le syndrome des ovaires polykystiques (sopk)
EP3004138B1 (fr) 2013-06-05 2024-03-13 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
MA47203A (fr) 2017-01-09 2019-11-13 Ardelyx Inc Inhibiteurs d'antiport à médiation par nhe
MX2019008170A (es) 2017-01-09 2020-02-07 Ardelyx Inc Compuestos útiles para tratar transtornos del tracto gastrointestinal.

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EP0673928A1 (fr) * 1994-03-18 1995-09-27 Sanofi Nouveaux dérivés de la N-(3,4-dichlorophényl-propyl)-pipéridine comme antagonistes sélectifs du récepteur NK3 humain
WO1995028931A1 (fr) * 1994-04-26 1995-11-02 Merck & Co., Inc. Azacycles spiro-substitues utilises en tant qu'antagonistes de neurokinine-3
WO1997019926A1 (fr) * 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
WO1998052942A1 (fr) * 1997-05-23 1998-11-26 Smithkline Beecham S.P.A. Nouveaux composes
WO2000031037A1 (fr) * 1998-11-20 2000-06-02 Smithkline Beecham S.P.A. Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2

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EP0673928A1 (fr) * 1994-03-18 1995-09-27 Sanofi Nouveaux dérivés de la N-(3,4-dichlorophényl-propyl)-pipéridine comme antagonistes sélectifs du récepteur NK3 humain
WO1995028931A1 (fr) * 1994-04-26 1995-11-02 Merck & Co., Inc. Azacycles spiro-substitues utilises en tant qu'antagonistes de neurokinine-3
WO1997019926A1 (fr) * 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
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WO2000031037A1 (fr) * 1998-11-20 2000-06-02 Smithkline Beecham S.P.A. Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2

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CA2447063A1 (fr) 2002-11-28
CZ20033115A3 (cs) 2004-09-15
MXPA03010509A (es) 2004-03-02
NO20035121D0 (no) 2003-11-17
KR20040016865A (ko) 2004-02-25
HUP0400966A2 (hu) 2004-08-30
TWI243678B (en) 2005-11-21
IL158701A0 (en) 2004-05-12
AU2002303811B2 (en) 2005-07-07
NZ529462A (en) 2005-07-29
PE20021067A1 (es) 2003-02-02
AR045879A1 (es) 2005-11-16
PL367308A1 (en) 2005-02-21
MY134211A (en) 2007-11-30
NO20035121L (no) 2003-11-17
EP1387687A4 (fr) 2006-07-05
CN1509175A (zh) 2004-06-30
JP2004534761A (ja) 2004-11-18
BR0209662A (pt) 2004-04-20
WO2002094187A2 (fr) 2002-11-28
CN1269483C (zh) 2006-08-16
WO2002094187A3 (fr) 2003-05-30

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