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WO1998047861A1 - Composes de type retinoide - Google Patents

Composes de type retinoide Download PDF

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Publication number
WO1998047861A1
WO1998047861A1 PCT/US1998/006214 US9806214W WO9847861A1 WO 1998047861 A1 WO1998047861 A1 WO 1998047861A1 US 9806214 W US9806214 W US 9806214W WO 9847861 A1 WO9847861 A1 WO 9847861A1
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WO
WIPO (PCT)
Prior art keywords
compound
compounds
treatment
formula
agents
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.)
Ceased
Application number
PCT/US1998/006214
Other languages
English (en)
Inventor
Fred C. Zusi
Peter R. Reczek
Jacek Ostrowski
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.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
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 Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to EP98912117A priority Critical patent/EP0971883A4/fr
Priority to CA002286252A priority patent/CA2286252A1/fr
Priority to JP54604598A priority patent/JP2001523247A/ja
Priority to AU65911/98A priority patent/AU729174B2/en
Publication of WO1998047861A1 publication Critical patent/WO1998047861A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention provides compounds having retinoid-like activity. More specifically, the compounds of the present invention are useful as antiinflammatory agents for chronic skin inflammatory diseases such as psoriasis and atopic dermatitis, as agents for the treatment of rheumatic diseases such as rheumatoid arthritis, as antitumor agents for the treatment of various tumors, and as agents for the treatment of non- malignant proliferative skin conditions.
  • Retinoic acids and its natural and synthetic analogs exact a wide variety of biological effects. They have been found to affect cellular growth
  • R 1 , R 2 , R 3 , R 4 , and R 5 independently are hydrogen, alkyl, or C 3 . 7 cycloalkyl or two adjacent residues R 1 to R 5 taken together with adjacent carbons of the phenyl ring form a 5-7 membered ring optionally substituted by one or more lower alkyl groups;
  • X is -NR 7 -CO- or -CO-NR 7 -;
  • R 6 is hydroxy, lower alkoxy or -NR 8 R 9 ;
  • R 7 , R 8 and R 9 independently, are hydrogen or lower alkyl, and where R 6 is hydroxy, their pharmaceutically usable salts for the treatment of inflammatory and rheumatic diseases.
  • R ⁇ , R 2 , R 3 , R 4 and R 5 may be the same or different, each represents hydrogen, middle and lower alkyl and /or cycloalkyl having 3-7 atoms, with the proviso each cannot be hydrogen simultaneously, and both neighboring substituents may be combined with each other to form a ring having 5-12 carbon atoms, R 6 represents hydroxyl, lower alkoxyl, lower alkylamino of the formula — NR 7 R 8 ', wherein R 7 ' and R 8 ' each represent
  • R 7 and R 8 represent hydrogen or lower alkyl. Such compounds are said to be capable of inducing the differentiation of premalignant and
  • malignant cells to morphologically and functionally mature cells which cannot proliferate further and can therefore be used in the therapy of premalignant and malignant diseases.
  • the present invention relates to novel compounds of the formula
  • the compounds of the present invention are useful as antiinflammatory agents for treatment of chronic skin inflammatory diseases such as psoriasis and atopic dermatitis, as agents for the treatment of rheumatic diseases such as rheumatoid arthritis, as antitumor agents for the treatment of various tumors, and as agents for the treatment of nonmalignant proliferative skin diseases.
  • compositions comprising a therapeutically effective amount of one or more of the compounds of the present invention in combination with a pharmaceutically acceptable excipient.
  • the present invention relates to a compound of the formula
  • Compounds of formula I may form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. These salts are also part of the present invention.
  • Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred.
  • Amines which are capable of forming stable salts group include trialkylamines such as triethylamine,
  • procaine dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine,
  • the compounds of formula I contain a carboxy group and so can
  • esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. They are
  • esters of compounds of formula I include ⁇ alkyl, benzyl, 4-methoxybenzyl, indanyl, phthalidyl, methoxymethyl, C. ⁇ alkanoyloxy, C 1 . 6 alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C ⁇ alkoxycarbonyloxy, C ⁇ alkyl, e.g.
  • esters methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-l-3-dioxolen-4- yl)-methyl and other well-known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters are prepared by conventional techniques known in the art.
  • the compounds of the present invention can be made by a variety of methods well-known to those skilled in the art. Examples 1-2 below illustrate one embodiment of their synthesis.
  • Example 1 was tested for its antitumor activity in the following model system:
  • HL 60 cells were evaluated for the effect of retinoic acid and the compound of Example 1 on both differentiation and apoptosis end points by the method described in Molecular and Cellular Biology, 15, 3540-3551 (1995).
  • Cells were grown in culture for times up to 9 days in the presence of 1 ⁇ M all-trans retinoic acid (t-RA) or l ⁇ M compound of Example 1.
  • t-RA all-trans retinoic acid
  • l ⁇ M compound of Example 1 At the end of each day of the culture period, cells were washed and stained with NBT (nitro blue tetrazolium) and counted. NBT staining reveals distinct changes in nuclear morphology and can easily be compared with treatment by t-RA or compound of Example 1.
  • the EC 50 is defined as the culture day necessary to convert cells into a differentiated or apoptosed phenotype and is given below in Table I.
  • the compound of Example 1 is comparable to t-RA in this assay.
  • Example 1 4.0 days Table II shows the percentage of either differentiated or apoptosed HL60 cells after treatment with all-trans retinoic acid or the compound of Example 1.
  • the compounds of the present invention are shown to be useful in the treatment of tumors in mammals.
  • the compounds of the present invention are also useful for treating a host animal, preferably a mammal and most preferably a human, for chronic skin inflammatory diseases (e.g. psoriasis), rheumatic diseases and non-malignant proliferative skin conditions.
  • a host animal preferably a mammal and most preferably a human
  • chronic skin inflammatory diseases e.g. psoriasis
  • rheumatic diseases e.g. psoriasis
  • non-malignant proliferative skin conditions e.g. psoriasis
  • composition thereof is administered to said host animal in the same manner as with other retinoid compounds.
  • the compounds of formula I above may be used topically or systemically, as anticancer agents and in the treatment, amelioration or prevention of the skin disorders and rheumatic illnesses (including rheumatoid arthritis) described in U.S. Patent 5,618,839.
  • they may be used for therapy in animals, including humans, of premalignant epithelial cell lesions, as a prophylaxis against tumor promotion in epithelial cells and treatment for dermatoses such as ichthyoses, follicular disorders, benign epithelial disorders and other
  • proliferative skin diseases such as psoriasis, eczema, atopic dermatitis, non-specific dermatosis and the like. They may also be used in reversing and preventing the effects of irradiation damage to skin. When used for the above purposes, they will usually be formulated with a pharmaceutically acceptable liquid, semi-solid, or solid carrier.
  • pharmaceutically acceptable carrier is a material that is nontoxic and generally inert and does not affect the functionality of the active
  • the carrier may be organic or inorganic
  • Examples of pharmaceutically acceptable carriers that may be used to formulate a compound of formula I are water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, orbital, mannitol, gum
  • the formulation may include acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers.
  • the formulation may include
  • additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
  • the dosages and dosage regimen in which the compounds of formula I are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through routine experimentation.
  • concentrations of the active compound or compounds ranging from 0.0005% to 2% by weight can generally be used. It is of course possible to use higher concentrations if
  • the preferred concentration of active principle are from 0.002% to 1% by
  • the compounds of formula I are conveniently provided in the form of unguents, gels, creams, ointments, powders, dyeing compositions, solutions, suspensions, emulsions, lotions, sprays, adhesive plasters and impregnated pads.
  • the compounds according to the invention can be mixed with inert nontoxic, generally liquid or pasty, bases suitable for topical treatment. Preparation of such topical formulations is well described in the art of pharmaceutical formulations as exemplified, for example, in Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.
  • Other medicaments can be added to such formulation for such secondary purposes as treating skin dryness, providing protection against light; other medications for treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
  • the compounds according to the invention can also be used.
  • the required dose can be administered in one or more portions.
  • suitable forms are, for example, tablets, pills, dragees,
  • a preferred method of administration consists in using pills containing
  • Isotretinoin (Accutane®) and etretinate (Tegison®) are used
  • the compounds according to the invention can also be any organic compound according to the invention.
  • the compounds according to the invention can also be any organic compound according to the invention.
  • the compounds according to the invention are generally administered at the
  • method of administration consists of using solutions or suspensions containing approximately from 0.01 mg to 1 mg of active substance per ml.
  • all-trans retinoic acid can be used to treat acute promyelocytic leukemia.
  • Isotretinoin has been shown to be useful in prevention of second primary tumors in squamous-cell carcinoma of the head and neck.
  • the compounds of formula I can be used in a substantially similar manner to retinoids for treating (both chemopreventively and
  • the anti-tumor dose to be administered whether a single dose, multiple doses
  • the dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects.
  • An oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compounds of this present invention, such as by referring to the earlier published studies on retinoids found to have anti-tumor properties.
  • an oncologist may refer to the study by Hong, W.K. et al. in N. Engl. I. Med., 1990, 323, p. 795.
  • the oncologist may refer to the study by Huang, M. et al. in Blood. 1988, 72, p. 567.
  • NMR nuclear magnetic resonance
  • TMS tetramethylsilane
  • the relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule.
  • the nature of the shifts as to multiplicity is reported as broad singlet (bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quarter (dq).
  • the solvents employed for taking NMR spectra are DMSO-d 6 (perdeuterodimethylsulfoxide), D 2 0 (deuterated water), CDC1 3 (deuterochloroform) and other conventional deuterated solvents.
  • DMSO-d 6 perdeuterodimethylsulfoxide
  • D 2 0 deuterated water
  • CDC1 3 deuterochloroform
  • the infrared (IR) spectral description include only absorption wave numbers (cm 1 ) having functional group identification value. All melting points were not corrected.
  • keto-ester II which is hydrolyzed using base to give keto acid III.
  • Ill is oxidatively decarboxylated using aqueous hydrogen peroxide to give acid IV, which is activated by conversion to its acid chloride using thionyl chloride and

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé de formule (I), dans laquelle X est CONH ou NHCO, ou bien un sel pharmaceutiquement acceptable, un ester ou un solvate, physiologiquement hydrolysable et non toxique, dudit composé. Les composés de la présente invention, qui possèdent des propriétés de type rétinoïde, sont utiles comme agents anti-inflammatoires permettant de traiter les maladies chroniques de la peau telles que le psoriasis et la dermatite atopique, comme agents permettant de traiter les maladies rhumatismales telles que la polyarthrite rhumatoïde, comme agents antitumoraux permettant de traiter diverses tumeurs et comme agents permettant de traiter les troubles prolifératifs cutanés bénins.
PCT/US1998/006214 1997-04-24 1998-03-30 Composes de type retinoide Ceased WO1998047861A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98912117A EP0971883A4 (fr) 1997-04-24 1998-03-30 Composes de type retinoide
CA002286252A CA2286252A1 (fr) 1997-04-24 1998-03-30 Composes de type retinoide
JP54604598A JP2001523247A (ja) 1997-04-24 1998-03-30 レチノイド様化合物
AU65911/98A AU729174B2 (en) 1997-04-24 1998-03-30 Retinoid-like compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4418697P 1997-04-24 1997-04-24
US60/044,186 1997-04-24

Publications (1)

Publication Number Publication Date
WO1998047861A1 true WO1998047861A1 (fr) 1998-10-29

Family

ID=21930965

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/006214 Ceased WO1998047861A1 (fr) 1997-04-24 1998-03-30 Composes de type retinoide

Country Status (5)

Country Link
EP (1) EP0971883A4 (fr)
JP (1) JP2001523247A (fr)
AU (1) AU729174B2 (fr)
CA (1) CA2286252A1 (fr)
WO (1) WO1998047861A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051382A1 (fr) * 2001-12-14 2003-06-26 Sundory Co., Ltd. Procédé d'induction d'apoptose et compositions pour cette dernière
US6624154B1 (en) 1999-04-23 2003-09-23 Bristol-Myers Squibb Company Compositions and methods for treatment of hyperproliferative diseases
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4725598A (en) * 1983-09-13 1988-02-16 Kureha Kagaku Kogyo Kabushiki Kaisha Derivative of dihydroxybenzamide and a pharmaceutical composition having an anti-inflammatory activity
US4760174A (en) * 1984-09-22 1988-07-26 Basf Aktiengesellschaft Tetralin derivatives, their preparation and their use
US5087743A (en) * 1989-02-10 1992-02-11 Basf Aktiengesellschaft Diphenylheteroalkyl derivatives, the preparation thereof and drugs and cosmetics prepared therefrom
US5216153A (en) * 1989-07-28 1993-06-01 Hoffmann-La Roche Inc. Aromatic carboxamides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4725598A (en) * 1983-09-13 1988-02-16 Kureha Kagaku Kogyo Kabushiki Kaisha Derivative of dihydroxybenzamide and a pharmaceutical composition having an anti-inflammatory activity
US4760174A (en) * 1984-09-22 1988-07-26 Basf Aktiengesellschaft Tetralin derivatives, their preparation and their use
US5087743A (en) * 1989-02-10 1992-02-11 Basf Aktiengesellschaft Diphenylheteroalkyl derivatives, the preparation thereof and drugs and cosmetics prepared therefrom
US5216153A (en) * 1989-07-28 1993-06-01 Hoffmann-La Roche Inc. Aromatic carboxamides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0971883A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6624154B1 (en) 1999-04-23 2003-09-23 Bristol-Myers Squibb Company Compositions and methods for treatment of hyperproliferative diseases
WO2003051382A1 (fr) * 2001-12-14 2003-06-26 Sundory Co., Ltd. Procédé d'induction d'apoptose et compositions pour cette dernière
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof

Also Published As

Publication number Publication date
EP0971883A4 (fr) 2000-06-14
EP0971883A1 (fr) 2000-01-19
CA2286252A1 (fr) 1998-10-29
JP2001523247A (ja) 2001-11-20
AU729174B2 (en) 2001-01-25
AU6591198A (en) 1998-11-13

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