WO1999035129A1 - Derives succinimides inhibant le metabolisme de l'acide retinoique - Google Patents

Derives succinimides inhibant le metabolisme de l'acide retinoique Download PDF

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Publication number
WO1999035129A1
WO1999035129A1 PCT/GB1998/003869 GB9803869W WO9935129A1 WO 1999035129 A1 WO1999035129 A1 WO 1999035129A1 GB 9803869 W GB9803869 W GB 9803869W WO 9935129 A1 WO9935129 A1 WO 9935129A1
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WO
WIPO (PCT)
Prior art keywords
pyrrolidine dione
pyrrolidine
dione
pharmaceutical formulation
pharmaceutically acceptable
Prior art date
Application number
PCT/GB1998/003869
Other languages
English (en)
Inventor
Paul Joseph Nicholls
Harold John Smith
Masoud Ahmadi
Original Assignee
University College Cardiff Consultants Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University College Cardiff Consultants Limited filed Critical University College Cardiff Consultants Limited
Priority to AU17726/99A priority Critical patent/AU1772699A/en
Publication of WO1999035129A1 publication Critical patent/WO1999035129A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide

Definitions

  • the present invention is concerned with pyrrolidine dione derivatives useful as inhibitors of retinoic acid metabolism.
  • Retinoic acid supports cellular growth and differentiation and has been shown to attenuate or completely reverse the malignant phenotype for many cell lines. Retinoic acid is also implicated in cell proliferation in skin conditions. Synthetic retinoids have shown promise in the treatment of oral leukoplakia and head and neck cancer, although their use may be associated with significant toxicity. Retinoids have also been used topically and orally for the treatment of skin diseases, i.e. actinic keratoses (precursors to squamous cell carcinoma), nonmelanoma skin cancer, acne vulgaris, psoriasis and disorders of keratinisation. More recently, the benefit of retinoids to photodamaged skin has led to their use in anti- wrinkle cosmetic preparations.
  • Vitamin A is oxidised through retinal by dehydrogenases in the cytoplasm of target cells in low yield to all trans-retinoic acid (.RA).
  • RA is at least 100 fold more active than retinol and is considered to account for its biological action.
  • RA has a short half life (c. 1 hour) and therefore the potency of RA is reduced when administered systemically due to metabolism by human liver and intestine cytochrome P450s to the inactive 4-hydroxy- RA and thence by dehydrogenases to the partially active 4-keto-RA and inactive polar metabolites.
  • P450-RA The specific P450s responsible for 4-hydroxylation of RA in the human liver have not been characterised, but several reconstituted P450s CYP1A2/2B6/2C8/2D6/2E1/3A4, can catalyse the reaction. Repeated exogenous administration of RA leads to a lowering of RA levels due to induction of the metabolising enzymes.
  • a drug which can prolong and intensify the action of endogenous RA on the epidermal cell by inhibiting P450-RA metabolising enzymes would have potential as a clinical agent in the treatment of certain skin conditions.
  • ketoconazole has been reported as inhibitors of RA-metabolising enzymes whilst being studied as inhibitors of 17 -hydroxylase: 17,20-lyase (P450 17 ⁇ ) as agents for the treatment of androgen-dependent prostatic cancer by lowering testosterone levels.
  • P450 17 ⁇ 17,20-lyase
  • Ketoconazole lacks specificity towards P450 17 and inhibits several other cytochrome P450 enzymes on the steroidogenic pathway of androgen synthesis and has a poor pharmacokinetic profile.
  • Liarozole (R75251) also inhibits testicular (but not adrenal) P450 17 ⁇ and similarly lowers testosterone levels in human volunteers, but its effect on androgen-independent carcinoma has been partially attributed to inhibition of P450-RA with an associated increase in RA levels (ketoconazole is also an inhibitor of this enzyme).
  • This view has been confirmed by experiments showing that RA metabolism in epidermal cells is inhibited (IC 50 -2 ⁇ M) and also that endogenous RA levels are increased and the elimination rate from the plasma of injected RA is reduced.
  • Liarozole has also been in trials for the treatment of severe psoriasis (oral) and acne (topical and oral) and it seems likely that this action is due to inhibition of epidermal P450-RA.
  • RA-metabolising enzyme inhibitors intended for topical use for skin diseases should show little unwanted systemic effects due to the involvement of other enzymes, e.g. steroidogenic P450 enzymes such as P450 17 ⁇ , CSCC, 21-hydroxylase. This objective should be achievable due to either poor sub-dermal penetration or, should this occur, low dose effects due to plasma dilution of the small load of drug placed on a restricted area of skin.
  • pyrrolidine diones suitable for use as retinoic acid metabolising enzyme inhibitors, which pyrrolidine diones are represented by the general formula (I):
  • R 1 is hydrogen or an alkyl, cycloalkyl or aralkyl group
  • each of R 2 and R 3 is independently hydrogen or an alkyl, cycloalkyl or aryl group
  • each of x and y is independently zero or one; wherein at least one of R 1 , R 2 and R 3 has at least five carbon atoms.
  • R 2 and R 3 can, of course, be the same or different. It is preferred that at least one of R 1 , R 2 and R 3 is a hydrogen atom; when R 1 is an aralkyl group, it is preferably benzyl (H 5 C 6 -CH 2 -). When any of R 1 , R 2 and R 3 is an alkyl group, it preferably has 1 to 7 carbon atoms; when the relevant substituent is cycloalkyl it preferably has 5 or 6 carbon atoms.
  • the compounds according to the invention have low activity against other P450 enzymes involved in cortisol production, which is indicative of low toxicity should systemic absorption occur.
  • the compounds according to the invention also have a short half life in the rat, [about lh] further emphasising their suitability for topical application.
  • the compounds are racemates and it might be expected that one of the resolved enantiomers would possess most of the activity in accordance with general findings for inhibition of P450s.
  • Table 1 lists exemplary compounds according to the present invention, together with their respective values for inhibition of retinoic acid metabolism (according to the protocol described herein under the heading "In vitro inhibition studies”). This shows that the compounds according to the invention have potency comparable to that of ketoconazole: Table 1. Inhibition of P450-RA
  • the pyiTolidine diones according to the present invention are suitable for use as retinoic acid metabolism inhibitors.
  • Pharmaceutically acceptable salts of the pyrrolidine diones of the present invention may also be suitable for use as retinoic acid metabolism inhibitors.
  • the present invention therefore preferably further comprises a pharmaceutical formulation comprising such a pyrrolidine dione (or such a salt), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • the preferred route of administration of the formulation is topical.
  • a formulation suitable for topical use may contain the free base of a pyrrolidine dione according to the invention.
  • the formulation suitable for topical use contains a pharmaceutically acceptable carrier, diluent or excipient which is substantially non-aqueous in nature.
  • the formulation may be in the form of a gel, foam, salve, emollient, cream or ointment, and may, in some cases, contain paraffin wax.
  • the pyrrolidine dione (or salt thereof) can be used for the treatment of dermatological conditions in (i) a dose form designed for topical administration in a dose range of 0.5-10% (w/v) with a concentration of 1 to 3% being preferred, and (ii) a dose form designed for oral administration in a dose range of 50-500mg daily with a daily dose of 150 to 250mg being preferred.
  • the pharmaceutical formulation according to the invention may be in a form suitable for oral administration.
  • the formulation suitable for oral administration may comprise a suitable pharmaceutically acceptable salt, or free base, of the pyrrolidine dione according to the invention.
  • the diluent, carrier or excipient may comprise, for example, lactose, microcrystalline cellulose and/or calcium phosphate dihydrate.
  • a preferred compound is compound 6, in which the 3-position of the pyrrolidine dione is substituted with the l-(4-aminophenyl)-2-phenylethyl group.
  • a pyrrolidine dione according to the invention may also be used in the treatment of various dermatological conditions.
  • These dermatological conditions may include ichthyosis, acne, pso ⁇ -asis, wrinl es or photodamaged skin.
  • the pyrrolidine diones of the present invention may be used in anti-ageing preparations and in preparations to protect the skin from the effects of radiation damage caused, for example, by radiation therapy of tumours and to alleviate such damage.
  • Table 2 In vitro activity profiles of (I), .aminoglutethimide and ketoconazole
  • the enzyme reaction was initiated by addition of rat liver microsomes (lO ⁇ l of lOmg/ml) and the mixture incubated at 37°C for 25 min.
  • the enzyme action was arrested by addition of lOO ⁇ l of 1 % formic acid and the tubes were placed in ice for 5 min.
  • 3ml of ethyl acetate containing 0.02% butylated hydroxy anisole was added and the tubes vortexed for 10 s.
  • the tubes were then left for another 5 min at room temperature and the organic layer (2ml) was removed from each tube and transferred to another set of tubes.
  • the ethyl acetate extracts were evaporated using a univap centrifuge connected to a vacuum pump and a multitrap at -80°C.
  • Percentage inhibition was calculated from the conversion rate of the samples containing inhibitors to that of control samples which contained absolute ethanol instead of inhibitor solution. Ketoconazole was used as a standard.
  • test compound 100 ⁇ M, final concentration
  • NADPH generating system 50 ⁇ l
  • [l,2,6,7- 3 H]17 ⁇ - hydroxyprogesterone l ⁇ M final concentration, lO ⁇ l
  • phosphate buffer 50 ⁇ M, pH 7.4
  • Incubation mixture (0.5ml) in phosphate buffer (50mM, pH 7.4) containing a range of concentrations of test compound in ethanol (20 ⁇ l) NADPH generating system (50 ⁇ l) and [26,(27)- 3 H]25-hydroxycholesterol and 25-hydroxycholesterol (0.412 ⁇ M final concentration; 50 ⁇ l) were warmed in a shaking water bath at 37°C for 5 min and the reaction was started by addition of the mitochondrial fraction of bovine adrenal cortex (0.2mg/ml protein final concentration, lO ⁇ l). After incubation at 37°C for 15 min, aliquots (250 ⁇ l) were added separately to tubes containing NaOH (1 M, 0.1ml) and chloroform (1ml).
  • the incubation mixture contained test compound (200 ⁇ M final concentration) in ethanol (20 ⁇ l), NADPH generating system (50 ⁇ l) and [4- 14 C]progesterone (2J2 ⁇ M final concentration, lO ⁇ l) and was made up to a final volume of 0.5ml with phosphate buffer (50mM, pH 7.4). It was warmed in a shaking water bath at 37°C for 5 min and the reaction was started by addition of rat adrenal microsomes (lO ⁇ l, final protein concentration 0.045mg/ml). The experiment was terminated after 15 min by addition of diethyl ether (3ml).
  • phenyl succinic acid (lOg, 0.0515 mol) was added portionwise to fuming nitric acid (50 ml) at -40°C (acetone/cardice bath) at such a rate as to maintain the temperatue at -40°C.
  • ⁇ fter lh the resulting mixture was poured with vigorous stirring into ice/water (300 ml) and the white precipitate formed was filtered off to give 2-(4'-nitrophenyl) butan-l,4-dioic acid (11) (6.8 g, 68%) m.p. 212-216°C.

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

Abstract

L'invention se rapporte à des dérivés pyrrolidine dione qui peuvent être utilisés comme inhibiteur du métabolisme de l'acide rétinoïque et sont représentés par la formule générale (I), dans laquelle R1 est hydrogène ou un groupe alkyle, cycloalkyle ou aralkyle; R2 et R3 sont chacun indépendamment hydrogène ou un groupe alkyle, cycloalkyle ou aryle; et x et y sont chacun indépendamment égaux à 0 ou 1; l'un au moins des groupes que sont R?1, R2 et R3¿ possédant au moins cinq atomes de carbone. L'invention se rapporte également à un sel pharmaceutiquement acceptable d'une telle pyrrolidine dione.
PCT/GB1998/003869 1998-01-02 1998-12-21 Derives succinimides inhibant le metabolisme de l'acide retinoique WO1999035129A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17726/99A AU1772699A (en) 1998-01-02 1998-12-21 Succinimide derivatives which inhibit retinoic acid metabolism

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9800040.9A GB9800040D0 (en) 1998-01-02 1998-01-02 Pyrrolidine dione derivatives
GB9800040.9 1998-01-02

Publications (1)

Publication Number Publication Date
WO1999035129A1 true WO1999035129A1 (fr) 1999-07-15

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PCT/GB1998/003869 WO1999035129A1 (fr) 1998-01-02 1998-12-21 Derives succinimides inhibant le metabolisme de l'acide retinoique

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AU (1) AU1772699A (fr)
GB (1) GB9800040D0 (fr)
WO (1) WO1999035129A1 (fr)
ZA (1) ZA9811937B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060781A2 (fr) * 2000-02-17 2001-08-23 University College Cardiff Consultants Limited Composes diphenyle, preparations et utilisations associees
WO2002015920A2 (fr) * 2000-08-17 2002-02-28 University Of Sheffield Traitement des maladies d'hyperproliferation
WO2002045704A2 (fr) * 2000-12-04 2002-06-13 Molecular Skincare Limited Traitement de maladie
WO2021049255A1 (fr) * 2019-09-09 2021-03-18 Jsr株式会社 Agent d'orientation de cristaux liquides, film d'orientation de cristaux liquides, et élément à cristaux liquides

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AHMED ET AL: "Synthesis and biological evaluation of novel pyrrolidine-2-5-dione inhibitors as potential anti-tumor agents.", DRUG.DES.DISCOVERY, vol. 12, no. 4, 1995, pages 275 - 287, XP002098113 *
DALY ET AL: "Synthesis and biochemical evaluation of anaolgs of aminoglutethimide based on phenylpyrrolidine-2,5-dione.", J.MED.CHEM., vol. 24, no. 4, 1986, pages 520 - 523, XP002098117 *
KORNET ET AL: "Potential long-acting anticonvulsants", J.MED.CHEM, vol. 20, no. 3, 1977, pages 405 - 409, XP002098118 *
PEPPER C ET AL: "ENANTIOSELECTIVITY OF AROMATASE INHIBITORS: SUBSTITUTED 3-(4-AMINOPHENYL)PYRROLIDINE-2,5-DIONES", CHIRALITY, vol. 7, no. 5, 1995, pages 376 - 380, XP000614300 *
PEPPER ET AL: "Racenization of drug enantiomers by nenzylic proton abstaction at physiological pH:", CHIRALITY, vol. 6, no. 5, 1994, pages 400 - 404, XP002098115 *
WHOMSLEY ET AL: "Some 1-, and 3-substituted 3-(4'-aminophenyl) pyrrolidine-2,5-diones asselective inhibitors of aromatase", J.ENZYME INHIB., vol. 6, no. 4, 1993, pages 317 - 30, XP002098114 *
WHOMSLEY ET: "1-Pentyl-3-(4-aminophenyl)pyrrolidine-2-5-dione, a selective aromatse inhibitor", J.ENZYME INHIB., vol. 7, no. 2, 1993, pages 137 - 145, XP002098116 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060781A2 (fr) * 2000-02-17 2001-08-23 University College Cardiff Consultants Limited Composes diphenyle, preparations et utilisations associees
WO2001060781A3 (fr) * 2000-02-17 2002-03-14 Univ Cardiff Composes diphenyle, preparations et utilisations associees
WO2002015920A2 (fr) * 2000-08-17 2002-02-28 University Of Sheffield Traitement des maladies d'hyperproliferation
WO2002015920A3 (fr) * 2000-08-17 2002-10-17 Univ Sheffield Traitement des maladies d'hyperproliferation
AU2001278632B2 (en) * 2000-08-17 2006-05-25 Vampex Limited Treatment of hyperproliferative diseases
WO2002045704A2 (fr) * 2000-12-04 2002-06-13 Molecular Skincare Limited Traitement de maladie
WO2002045704A3 (fr) * 2000-12-04 2003-05-01 Molecular Skincare Ltd Traitement de maladie
WO2021049255A1 (fr) * 2019-09-09 2021-03-18 Jsr株式会社 Agent d'orientation de cristaux liquides, film d'orientation de cristaux liquides, et élément à cristaux liquides
CN114207085A (zh) * 2019-09-09 2022-03-18 Jsr株式会社 液晶取向剂、液晶取向膜及液晶元件

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Publication number Publication date
AU1772699A (en) 1999-07-26
GB9800040D0 (en) 1998-03-04
ZA9811937B (en) 1999-07-19

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