WO2008129000A1 - Dérivés de pyridopyrimidine et leur utilisation dans le traitement des démangeaisons et des troubles associés aux démangeaisons - Google Patents

Dérivés de pyridopyrimidine et leur utilisation dans le traitement des démangeaisons et des troubles associés aux démangeaisons Download PDF

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Publication number
WO2008129000A1
WO2008129000A1 PCT/EP2008/054742 EP2008054742W WO2008129000A1 WO 2008129000 A1 WO2008129000 A1 WO 2008129000A1 EP 2008054742 W EP2008054742 W EP 2008054742W WO 2008129000 A1 WO2008129000 A1 WO 2008129000A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
itch
hydrogen
compound
formula
Prior art date
Application number
PCT/EP2008/054742
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English (en)
Inventor
Thomas Jung
Josef Gottfried Meingassner
Original Assignee
Novartis Ag
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
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38038626&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008129000(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis Ag filed Critical Novartis Ag
Publication of WO2008129000A1 publication Critical patent/WO2008129000A1/fr

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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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P17/04—Antipruritics

Definitions

  • the present invention relates to uses of Vanilloid Receptor antagonists, e.g. the use of pyridine derivatives orf formula (I) in the treatment of itch and itch related disorders or diseases, and to pharmaceutical compositions for such uses.
  • R 3 is hydrogen; OH; CN; d-Cealkyl; phenyl; or C(O)OC r C 4 alkyl;
  • R 4 is hydrogen; halogen; NH 2 ; CN; C r C 6 alkyl; C r C 6 alkyl substituted by OH; phenyl; phenyl substituted by OH, halogen, d-C 6 alkyl, C r C 6 haloalkyl or Ci-C 6 alkoxy; benzyl; benzoyl substituted by OH; or C(O)OC 1 -C 6 alkyl; 5 or 6 membered aromatic or aliphatic heterocyclic ring;
  • Compounds for use in the invention exist in free or salt, e.g. acid or base addition salt form.
  • the invention is to be understood as including the use of compounds of formula (I) in free as well as in salt form, e.g. as trifluoroacetate or hydrochloride salt.
  • Suitable pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the invention include in particular the hydrochloride salt.
  • a 5 or 6 membered aromatic or aliphatic heterocyclic ring for R 4 may be e.g. but not limited to thiophenyl, furyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperizinyl and derivatives thereof (e.g. C 1 -C 4 BlKyI, OCrOC 4 alkyl, halogenyl, etc.).
  • Alkyl groups in the compounds of formula (I) may be branched or straight chain.
  • R 1 and R 2 together are a divalent group -NHC(O)NHC(O)- or -NHC(S)NHC(O)-;
  • R 3 is hydrogen
  • R 4 is phenyl; phenyl substituted by OH, halogen, e.g. chloride, fluoride, Ci-C 6 alkyl, C 1 - C 6 haloalkyl or d-Cealkoxy; and
  • R 5 is branched or un-branched Ci-C 6 alkyl, e.g. isopropyl, tert. butyl or C 3 -C 6 cycloalkyl.
  • R 1 and R 2 together are -NH-C(S)-NH- C(O)-;
  • R 3 is hydrogen;
  • R 4 is phenyl; or phenyl substituted by halogen, e.g. by chloro, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl or C r C 4 alkoxy;
  • R 5 is C r C 4 alkyl; or C 3 -C 6 cycloalkyl, e.g. tert.- butyl.
  • compound of formula (I) is 7-tert.-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3- dihydro-1.H.-pyrido[2,3-d.]pyrimidin-4-one.
  • the compounds of formula (I) may be prepared by the processes generally and specifically described in WO02/076946.
  • itch pruritus
  • an itch related disorder or disease includes pruritoceptive itch (originating in the skin, including itching arising from or associated with inflammatory skin diseases, e.g. skin diseases responsive to corticosteroid treatment and/or calcineurin inhibitor treatment, e.g. Elidel, Protopic), neuropathic itch (due to a primary neurological disorder) and neurogenic itch (arising from neurophysiological dysfunction).
  • pruritoceptive itch originating in the skin, including itching arising from or associated with inflammatory skin diseases, e.g. skin diseases responsive to corticosteroid treatment and/or calcineurin inhibitor treatment, e.g. Elidel, Protopic
  • neuropathic itch duee to a primary neurological disorder
  • neurogenic itch arising from neurophysiological dysfunction
  • disorders or diseases include, but are not limited to
  • Pruritic dermatoses e.g. atopic dermatitis, psoriasis, urticaria, irritant/allergic contact eczema, prurigo nodularis, insect bites, scabies, Lichen ruber, dry skin (xerosis), pruritis ani, pruritus scroti, pruritus vulvae,
  • metabolic disorders including e.g. chronic renal disease, primary billiary cirrhosis, cholestasis, hepatic insufficieny, psychotropic medication
  • endocrine disorders including e.g. thyrotoxicosis, hypothyroidism, hyperparathyroidism, hyperphosphatemia, diabetes mellitus,
  • lymphoma e.g. lymphoma, leukemia, polycythemia, rubra vers,
  • autoimmune diseases including e.g. dermatitis herpetiformis, linear IgA syndrome, multiple sclerosis.
  • the disorder or disease is selected from the group consisting of itch and pruritic dermatoses, especially preferred from the group consisting of itch, atopic dermatitis and psoriasis.
  • the appropriate dosage of the agents of invention will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular agent of invention employed.
  • the amount of active agent required may be determined on the basis of known in vitro and in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
  • satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 mg/kg p.o.
  • an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g.
  • Oral dosage forms accordingly suitably comprise from about 0.2 or 2.0 to about 700 or 1400 mg agent of invention admixed with an appropriate pharmaceutically acceptable diluent or carrier therefore.
  • compositions comprising a compound of formula (I) are provided in a form useful for the topical or local application such as e.g. in the form of a cream, an ointment, a gel, a solution, a semi-solid formulation or a solid or semi-liquid dispersion form.
  • a compound of formula (I) is used for the topical treatment or itch and inflammatory dermatoses associated with itch, e.g. atopic dermatitis.
  • compositions comprising the agents of invention include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, e.g. cyclodextrin, a microemulsion and a suspension of, e.g. a micronized hydrochloride salt of a compound of formula (I) in, e.g. aqueous methyl cellulose in the range of from 0.1 to 1 %, e.g. 0.5 %.
  • the composition may be buffered to, e.g. a pH in the range of from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer, e.g. malic acid.
  • the invention provides a method for the topical treatment of itch or an itch related disorder or disease, e.g. comprising administration to a patient an effective amount of a compound of formula (I) in free base or acid addition salt form, as described above.
  • the present invention also provides:
  • a compound of formula (I) for use of treating itch or an itch related disorder or disease e.g. such as described above.
  • a pharmaceutical composition comprising a compound of formula (I) in free base or pharmaceutically acceptable acid addition salt form as active ingredient together with a pharmaceutically acceptable diluent or carrier therefore, in the treatment of itch or an itch related disorder or disease.
  • Treatment as used herein includes therapeutic treatment and prevention.
  • a combination comprising a therapeutically effective amount of a compound of formula (I) in free base or pharmaceutically acceptable acid addition salt form and a second drug substance, said second drug substance being for example for use in the treatment of itch or an itch related disorder or disease, for the use in the treatment of itch or an itch related disorder or disease.
  • the second drug may be selected from ingredients which are known as being itch-reducers, such as e.g. campher, menthol, phenol, pramoxine, diphenylhydramine, caine anesthetics, e.g. benzocaine, cortisone, hydrocortisone or corticosteroids, or it may be an antiinflammatory agent such as e.g.
  • Elidel ® Protopic ® , diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam, sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib.
  • the preferred compound of formula (I) is the 7-tert.-butyl-6-(4-chlorophenyl)-2-thioxo-2,3- dihydro-1.H-pyrido[2,3-.d.]-pyrimidin-4-one (example 2 of WO02/076946).
  • FIG. 1 The TEST COMPOUND inhibits concentration-dependently capsaicin-induced skin inflammation and scratching: % inhibition vs. vehicle-treated animals, shown are the mean values of groups (see also note to Table 1).
  • Example 1 Capsaicin-induced irritant contact dermatitis
  • Capsaicin is applied at 0.1% in volumes of 15 ⁇ l to both sides of the right auricles of rats.
  • Control animals are treated with capsaicin alone.
  • the animals are observed clinically for ear reddening, scratching, and ear swelling for 40 minutes after challenge. Ear reddening is scored with 0 (not present), 1 (mild), 2 (pronounced) and 3 (severe). Scratching is recorded by counting scratching bouts with right or left hind limb for 40 minutes after the challenge. Ear swelling is determined by differences in left and right ear thickness before challenge and 40 minutes after the challenge. In the first series of studies the minimal effective concentration is evaluated (Table 1 ).
  • TEST COMPOUND inhibits redness, scratching and swelling in capsaicin-induced skin irritation in rats in a concentration dependent way.
  • Example 2 DNFB-induced allergic contact dermatitis in pigs
  • TEST COMPOUND Further activity of the TEST COMPOUND is tested in a swine model.
  • the latter PD model is used to evaluate skin permeability of the TEST COMPOUND in vivo under skin conditions which are similar to the human situation.
  • Challenge reactions in young, DNFB-sensitized domestic pigs are elicited on contralateral test sites of the dorsolateral back.
  • the formulations (verum or placebo) are applied contralateral ⁇ to 2 test sites in each animal 0.5 and 6 hours after the challenge.
  • the test sites are clinically examined 24 hours after the challenge when inflammation peakes.
  • the changes are scored on a scale from 0 to 4 for extent and intensity of redness and infiltration allowing a combined maximal score of 12 per designated site.
  • TEST COMPOUND is compared with hydrocortisone and betamethasone (Table 2).
  • the latter reference compounds are applied as drug substances and prepared in ethanol / propylene glycol at the clinically used concentrations. Marketed formulations are not used because the corresponding placebos are not available to us.
  • Table 2 Clinical efficacy of the TEST COMPOUND against acute ACD in domestic pigs
  • test sites are treated 0.5 hours and 6 hours after DNFB challenge with experimental formulations containing the TEST COMPOUND at 10 to 1 mM.
  • the contralateral left sites are treated similarly with the vehicle.
  • Test sites are clinically examined 24 hours after the DNFB challenge, at the peak of the inflammatory response.
  • Topical application of capsaicin to ears of rats induces scratching, skin reddening and swelling. These symptoms are concentration-dependently inhibited, indicating that topical application of the TEST COMPOUND interferes with capsaicin-induced VR1/TPVR1 activation in the skin (see Figure 1 ).
  • TEST COMPOUND Penetration of the TEST COMPOUND into the skin and permeation through the skin is tested in vitro in static Franz-type diffusion cells at 32° for 48 hours. Thawed samples of human dorsal cadaver skin cut to 700 ⁇ m thickness are used. The TEST COMPOUND is applied epicutaneously as solution in propylene glycol. Samples of 100 ⁇ l are taken from the receptor reservoir 6 times for analysis and replaced by fresh receptor fluid (phosphate buffered saline/ fetal calf serum 2:1). Drug analysis is performed with receptor samples and specimens of the exposed skin (at the end of the experiment), from which the stratum corneum had been removed by 20 strippings with an adhesive tape.
  • fresh receptor fluid phosphate buffered saline/ fetal calf serum 2:1
  • the weighed skin samples are homogenized in 0.2 M ammonium phosphate buffer (pH 7.0).
  • the homogenates are extracted with ethyl acetate and processed for HPLC analysis. Concentrations in the receptor fluid and in the skin extracts are calculated using appropriate calibration curves. The data are shown in Table 3.
  • the TEST COMPOUND exhibits a favorable skin penetration profile.
  • 1% hydrocortisone in propylene glycol results in skin concentrations of 47 ⁇ 6 ⁇ g/g and permeation rates of 23 + 1 ng/cm 2 /hour [Schmook, et al 2001].
  • the amount of the TEST COMPOUND penetrating into skin layers below the stratum corneum is much higher than the in vitro active concentrations which are in the 2 digit nanomolar concentrations.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne l'utilisation d'un composé de formule (I), où R1, R2, R3, R4 et R5 sont tels que définis dans la description, et leurs combinaisons, dans le traitement des démangeaisons et des troubles ou maladies associés aux démangeaisons.
PCT/EP2008/054742 2007-04-20 2008-04-18 Dérivés de pyridopyrimidine et leur utilisation dans le traitement des démangeaisons et des troubles associés aux démangeaisons WO2008129000A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07106648.4 2007-04-20
EP07106648 2007-04-20

Publications (1)

Publication Number Publication Date
WO2008129000A1 true WO2008129000A1 (fr) 2008-10-30

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PCT/EP2008/054742 WO2008129000A1 (fr) 2007-04-20 2008-04-18 Dérivés de pyridopyrimidine et leur utilisation dans le traitement des démangeaisons et des troubles associés aux démangeaisons

Country Status (3)

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CL (1) CL2008001112A1 (fr)
TW (1) TW200902014A (fr)
WO (1) WO2008129000A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8940753B1 (en) 2012-12-14 2015-01-27 Trevi Therapeutics, Inc. Methods for treating pruritis
US8987289B2 (en) * 2012-12-14 2015-03-24 Trevi Therapeutics, Inc. Methods for treating pruritus
US10064871B2 (en) 2014-01-22 2018-09-04 Biomimetix Jv, Llc Methods of treating skin disorders
US10080759B2 (en) 2014-01-22 2018-09-25 Duke University Methods of treating pruritus
CN114605408A (zh) * 2022-03-30 2022-06-10 沈阳药科大学 5-羟基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制法和应用
US11660296B2 (en) 2018-07-23 2023-05-30 Trevi Therapeutics, Inc. Treatment of chronic cough, breathlessness and dyspnea

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076946A2 (fr) * 2001-03-26 2002-10-03 Novartis Ag Derivee de la pyridine
WO2005023807A2 (fr) * 2003-09-09 2005-03-17 Neurogen Corporation Derives de quinazolin-4-ylamine bicyclique substitue

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076946A2 (fr) * 2001-03-26 2002-10-03 Novartis Ag Derivee de la pyridine
WO2005023807A2 (fr) * 2003-09-09 2005-03-17 Neurogen Corporation Derives de quinazolin-4-ylamine bicyclique substitue

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CULSHAW ANDREW J ET AL: "Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain.", JOURNAL OF MEDICINAL CHEMISTRY 26 JAN 2006, vol. 49, no. 2, 26 January 2006 (2006-01-26), pages 471 - 474, XP002434835, ISSN: 0022-2623 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8940753B1 (en) 2012-12-14 2015-01-27 Trevi Therapeutics, Inc. Methods for treating pruritis
US8987289B2 (en) * 2012-12-14 2015-03-24 Trevi Therapeutics, Inc. Methods for treating pruritus
US10238646B2 (en) 2012-12-14 2019-03-26 Trevi Therapeutics Inc. Methods for treating pruritus
US10064871B2 (en) 2014-01-22 2018-09-04 Biomimetix Jv, Llc Methods of treating skin disorders
US10080759B2 (en) 2014-01-22 2018-09-25 Duke University Methods of treating pruritus
US11065259B2 (en) 2014-01-22 2021-07-20 Duke University Methods of treating pruritus
US11660296B2 (en) 2018-07-23 2023-05-30 Trevi Therapeutics, Inc. Treatment of chronic cough, breathlessness and dyspnea
CN114605408A (zh) * 2022-03-30 2022-06-10 沈阳药科大学 5-羟基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制法和应用

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TW200902014A (en) 2009-01-16
CL2008001112A1 (es) 2008-12-19

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