EP1594574A2 - Utilisation de composes chimiques pour le traitement de dyspepsie fonctionnelle - Google Patents

Utilisation de composes chimiques pour le traitement de dyspepsie fonctionnelle

Info

Publication number
EP1594574A2
EP1594574A2 EP04705094A EP04705094A EP1594574A2 EP 1594574 A2 EP1594574 A2 EP 1594574A2 EP 04705094 A EP04705094 A EP 04705094A EP 04705094 A EP04705094 A EP 04705094A EP 1594574 A2 EP1594574 A2 EP 1594574A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
hydrogen
integer
nitrogen
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Withdrawn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
EP04705094A
Other languages
German (de)
English (en)
Inventor
George Earl c/o GlaxoSmithKline DUKES
Gareth Andrew c/o GlaxoSmithKline HICKS
Gareth John c/o GlaxoSmithKline Sanger
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0301842A external-priority patent/GB0301842D0/en
Priority claimed from GB0301841A external-priority patent/GB0301841D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1594574A2 publication Critical patent/EP1594574A2/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Withdrawn legal-status Critical Current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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P1/12—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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to the use of NIC, receptor antagonists for the treatment of functional dyspepsia.
  • NIC receptor antagonists
  • NIC receptor antagonists
  • NIC receptor antagonists
  • Preclinical data suggest that NIC; receptor antagonists may be useful in a variety of other disorders including pain, inflammatory diseases, allergic disorders, CNS disorders, skin disorders, cough and gastrointestinal disorders.
  • NIC receptor antagonists are useful in the the treatment of functional dyspepsia.
  • FD Functional dyspepsia
  • the term dyspepsia is defined as the general condition of indigestion and as such encompassed a variety of distinct dyspeptic conditions.
  • There are several recognised types of dyspepia the common being acid-related dyspepsia which is associated with an excess gastric acidity and may lead to peptic ulcers, gastroesophageal reflux disease (GERD) and other conditions characterized by excess gastric acidity.
  • FD is not associated with excess gastric acidity. Rather, the primary pathophysiological causative factor for FD is unclear.
  • FD is a visceral hypersensitivity state characterised by chronic or recurrent upper abdominal symptoms in the absence of any identifiable organic pathology, such as a peptidic ulceration, gastric cancer, chronic pancreatitis or GERD.
  • identifiable organic pathology such as a peptidic ulceration, gastric cancer, chronic pancreatitis or GERD.
  • the absence of identifiable organic pathology is established using conventional tecniques including endoscopy, radiography, histology, and other techniques known to those skilled in the art.
  • the common symptoms for FD are a persistent, recurrent pain or discomfort centred in the upper abdomen, early satiety, nausea and vomiting, bloating, belching and postprandial fullness.
  • FD has been divided into subtypes based upon the predominant symptom(s) observed in the patient. "Ulcer like " FD is characterised primarily by pain. "Reflux-like” FD is primarily characterised by heartburn that is odfen alleviated by acid-suppressing agents. It is PB60019-C
  • reflux-like FD is characterised primarily by discomfort, bloating, nausea, vomiting, early satiety and post-prandial fullness.
  • Unspecified FD refers to FD patient having symptoms that do not fit into the above categories. Typically patients exhibit symptoms across the various sub-types.
  • the invention accordingly provides the use of an N ⁇ receptor antagonist for the treatment of functional dyspepsia
  • the invention provides the use of an Nr ⁇ receptor antagonist in the preparation of a medicament for use in the treatment of functional dyspepsia.
  • the invention provides a method for the treatment of functional dyspepsia, comprising administering to that person an effective amount of an N i receptor antagonist.
  • the invention provides a pharmaceutical composition for functional dyspepsia which comprises at least one NrC, receptor antagonist and is formulated for administration by any suitable route.
  • Such compositions are preferably in a form adapted for use in human medicine and can be conveniently formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the term functional dyspepsia includes "Ulcer like " FD, "Dysmotility-Iike” FD and “Unspecified” FD.
  • NKi receptor antagonists for use in the present invention include those generically and specifically disclosed in the following patent specifications whose disclosures are incorporated by reference:
  • NK1 receptor antagonists for use in the present invention is represented by those compounds described in WO 0125219 having the general formula(l)
  • R represents a halogen atom or a C ⁇ _4 alkyl group
  • represents hydrogen or a C-
  • R2 represents hydrogen, a C1.4 alkyl, C2-6 alkenyl or a C3.7 cycloalkyl group; or R ⁇ and
  • R2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group;
  • R3 represents a trifiuoromethyl, a C-
  • R4 represents hydrogen, a (CH2) R7 or a (CH2)rCO(CH2)pR7 group
  • R5 represents hydrogen, a C-1.4 alkyl or a COR ⁇ group
  • R ⁇ represents hydrogen, hydroxy, amino, methylamino, dimethylamino a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing 1 to 3 nitrogen atoms;
  • R7 represents hydrogen, hydroxy or RsRg wherein Rs and Rg represent independently hydrogen or C-j .4 alkyl optionally substituted by hydroxy or by amino;
  • Rl0 represents hydogen, a C1-4 alkyl group or R-jo together with R2 represents a C3.7 cycloalkyl group
  • m is zero or an integer from 1 to 3
  • n is zero or an integer from 1 to 3
  • both p and r are independently zero or an integer from 1 to 4
  • q is an integer from 1 to 4; provided that, when R-j and R2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group: i) m is 1 or 2; ii) when m is 1, R is not fluorine and iii) when m is 2, the two substituents R are not both fluorine PB60019-C
  • particularly preferred compounds include those wherein R is selected independently from halogen or methyl, R3 is trifiuoromethyl both at the 3 and 5 position, R1 is hydrogen or methyl, R2 is hydrogen, methyl, 2-propenyl, or a cyclopropyl group or together with R- j is a 3,6-dihydro-2H-pyridin-1yl, a piperidin-1-yl or a pyrrolidin 1-yl group, R-10 represents hydrogen, a methyl or R-jg together with R2 is a cyclopropyl group, R4 is hydrogen, an aminoacetyl or amino ethyl group and R5 is hydrogen or a methyl group.
  • a particularly preferred compound of formula (I) for use in the invention is
  • R represents a halogen atom or a C -1.4 alkyl group
  • R-l represents a C-
  • R2 represents hydrogen or a C-
  • R3 represents hydrogen, or a C-1.4 alkyl group
  • R4 represents a trifiuoromethyl group
  • R5 represents hydrogen, a C ⁇ alkyl group or C(O)R 6 ;
  • R ⁇ represents C1..4 alkyl, C3.7 cycloalkyl, NH(C ⁇ alkyl) or N(C1-4alkyI)2; m is zero or an integer from 1 to 3; PB60019-C
  • n is an integer from 1 to 3;
  • a particularly preferred compound of formula (II) for use in the present invention is 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fIuoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide and pharmaceutically acceptable salts (e.g. hydrochloride, methanesulphonate, sulphate, p-toluensulphonate) or solvates thereof.
  • pharmaceutically acceptable salts e.g. hydrochloride, methanesulphonate, sulphate, p-toluensulphonate
  • NK1 receptor antagonists for use in the present invention is that described in WO03/066635 having general formula(lll)
  • R represents halogen or C-1.4 alkyl ;
  • R ⁇ represents C ⁇ _4 alkyl;
  • R2 or R3 independently represent hydrogen or C ⁇ _4 alkyl
  • R4 represents trifiuoromethyl, C-
  • R5 represents hydrogen, C-
  • R ⁇ is hydrogen and R7 is a radical of formula (W):
  • R ⁇ is a radical of formula (W) and R7 is hydrogen;
  • X represents CH2, NR5 or O
  • Y represents Nitrogen and Z is CH or Y represents CH and Z is Nitrogen;
  • A represents C(O) or S(O)q, provided that when Y is nitrogen and Z is CH, A is not S(O)q; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p and q are independently an integer from 1 to 2; PB60019-C
  • Particularly preferred compounds of formula (III) include those in which Rg is hydrogen, R7 is a radical of formula (W) and Y is CH and Z is nitrogen or wherein RQ is a radical of formula (W), R7 is a hydrogen and Y is nitrogen and Z is CH; A is C(O) and X is CH2.
  • a particularly preferred compound of formula (III) for use in the invention is 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2- yl)-piperidine-1 -carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide and pharmaceutically acceptable salts (e.g. hydrochloride, methanesulphonate or maleate) and solvates thereof.
  • pharmaceutically acceptable salts e.g. hydrochloride, methanesulphonate or maleate
  • a preferred embodiment of the invention provides a method for the treatment of functional dyspepsia in a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a NK1 receptor antagonists selected from 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis- trifluoromethyl-phenyl)-ethyl]-methyl-amide and pharmaceutically acceptable salts thereof ( e.g. methansulphonate and hydrochloride);
  • a NK1 receptor antagonists selected from 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis- trifluoromethyl-phenyl)-ethyl]-methyl-amide and pharmaceutically acceptable salts thereof (e.g. methansulphonate and hydrochloride);
  • NK 1 receptor antagonists for use according to the present invention may be administered as the raw chemical but the active ingredients are preferably presented as a pharmaceutical formulation. Suitable pharmaceutical formulations are described in the above referenced patent specifications.
  • N , receptor antagonists for use according to the present invention may be formulated for oral, buccal, parenteral, depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). Oral and parenteral formulations are preferred.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • PB60019-C PB60019-C
  • N i receptor antagonists for use according to the present invention may be formulated for parenteral administration by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the NK, receptor antagonists for use according to the present invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • NKi receptor antagonists for use according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • receptor antagonists for use according to the present invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the NK receptor antagonists for use according to the present invention may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • Suitable dose ranges are also described in the above referenced patent specifications, that is to say that for use in the treatment of functional dyspepsia, compounds may be used at doses appropriate for other conditions for which NK receptor antagonists are known to be useful. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient, and the precise dosage will be ultimately at the discretion of the attendant physician. The dosage will also depend on the route of administration and the particular compound selected. A suitable oral dose range will typically be within the range 1 to 300 mg e.g 1 to 100 mg.
  • the NK receptor antagonists are administered either once or twice a day, preferably twice a day.
  • NK receptor antagonists for use according to the present invention may, if desired, be administered in combination with one or more other therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses and formulations will be readily appreciated by those skilled in the art.
  • Nk1 antagonists in the treatment of FD are supported by appropriate clinical trials.
  • the primary endpoint is adequate relief of FD pain or discomfort.
  • Secondary endpoints includes 1)changes in daily upper abdominal pain severity ratings 2) proprtion of pain free days 3) changes in self-ratings of nausea, early PB60019-C
  • the study is double-blinded and placebo-matched.

Abstract

L'invention concerne l'utilisation d'antagonistes du récepteur NK1 pour le traitement de la dyspepsie fonctionnelle.
EP04705094A 2003-01-27 2004-01-26 Utilisation de composes chimiques pour le traitement de dyspepsie fonctionnelle Withdrawn EP1594574A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0301842A GB0301842D0 (en) 2003-01-27 2003-01-27 Medicament
GB0301842 2003-01-27
GB0301841 2003-01-27
GB0301841A GB0301841D0 (en) 2003-01-27 2003-01-27 Use of chemical compounds for the treatment of functional dyspepsia
PCT/EP2004/000752 WO2004067093A2 (fr) 2003-01-27 2004-01-26 Utilisation de composes chimiques pour le traitement de dyspepsie fonctionnelle

Publications (1)

Publication Number Publication Date
EP1594574A2 true EP1594574A2 (fr) 2005-11-16

Family

ID=32827031

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Application Number Title Priority Date Filing Date
EP04705094A Withdrawn EP1594574A2 (fr) 2003-01-27 2004-01-26 Utilisation de composes chimiques pour le traitement de dyspepsie fonctionnelle

Country Status (3)

Country Link
EP (1) EP1594574A2 (fr)
JP (1) JP2006516581A (fr)
WO (1) WO2004067093A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0403005D0 (sv) * 2004-12-09 2004-12-09 Astrazeneca Ab New use
PL2906219T3 (pl) * 2012-10-11 2020-02-28 Nerre Therapeutics Limited Orwepitant do leczenia przewlekłego świądu

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9923748D0 (en) * 1999-10-07 1999-12-08 Glaxo Group Ltd Chemical compounds
GB0025354D0 (en) * 2000-10-17 2000-11-29 Glaxo Group Ltd Chemical compounds
GB0203020D0 (en) * 2002-02-08 2002-03-27 Glaxo Group Ltd Chemical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004067093A2 *

Also Published As

Publication number Publication date
WO2004067093A2 (fr) 2004-08-12
WO2004067093A3 (fr) 2004-10-28
JP2006516581A (ja) 2006-07-06

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