WO2000018745A1 - Derives d'oxazolidine utiles pour le traitement et la prevention de troubles metaboliques des os - Google Patents
Derives d'oxazolidine utiles pour le traitement et la prevention de troubles metaboliques des os Download PDFInfo
- Publication number
- WO2000018745A1 WO2000018745A1 PCT/EP1999/007253 EP9907253W WO0018745A1 WO 2000018745 A1 WO2000018745 A1 WO 2000018745A1 EP 9907253 W EP9907253 W EP 9907253W WO 0018745 A1 WO0018745 A1 WO 0018745A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- signifies
- oxazolidin
- thioxo
- oxazolidine
- dione
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
- C07D263/44—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
- C07D263/46—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention is concerned with oxazolidine derivatives for the treatment and prevention of metabolic bone disorders, a process for their manufacture as well as medicaments which contain these compounds.
- bone resorption inhibitors such as oestrogens, calcitonin and biphosphonates have primarily been used for the treatment of metabolic bone disorders.
- the use of these substances is, however, limited and also does not show the desired effect in all cases.
- Compounds which have a stimulating activity on bone synthesis and in addition contribute to an increase in an already reduced bone mass are accordingly of especial significance for the treatment of metabolic bone disorders.
- antidiabetics Compounds having the oxazolidine structural element are known as antidiabetics, cytostatics inflammation inhibitors and for the treatment of cardiovascular illnesses and bacterial infections, with the treatment of osteoporosis in addition to an antidiabetic activity also being described in Applications EP 708098 and EP-A-676398.
- the parathyroid hormone (PTH) is the natural ligand of the receptor and an important regulator for the maintenance of the calcium level in the body.
- PTH can stimulate bone formation or bone resorption. In this, it acts as a regulatory hormone on a series of enzymes, inter alia, on adenylate cyclase (cAMP synthesis) and on ornithine decarboxylase.
- cAMP synthesis adenylate cyclase
- PTH mobilizes calcium from bones in the case of calcium deficiency, reduces calcium excretion from the kidneys and simultaneously improves the resorption of calcium from the intestine by an increased synthesis of l,25-(OH) 2 D 3 .
- a normalization of the calcium level is achieved by the action on these target organs.
- oxazolidine derivatives of the present invention stimulate the PTH receptor-mediated cAMP formation.
- Compounds of the present invention are accordingly suitable for the broad treatment of metabolic bone disorders. They can be used primarily to good effect where the bone synthesis is disturbed, i.e. they are especially suitable for the treatment of osteopenic disorders of the skeletal system such as e.g. osteoporosis, inter alia, osteogenesis imperfecta as well as for the local assistance in bone regeneration and osteoinduction such as e.g. in orthopedic and maxillary medical indications, in fracture healing, osteosyntheses, pseudoarthroses and for the healing in of bone implants.
- A signifies a single or double bond
- R signifies hydroxyl, lower alkoxyl or the NR ⁇ R 2 residue, whereby Ri and R 2 can be the same or different
- R 5 signifies hydrogen or methyl
- X signifies oxygen or sulphur
- W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms
- lower alkyl signifies linear or branched alkyl residues with one to six carbon atoms, preferably methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl, particularly methyl.
- Alkoxy groups signify a combination of a Ci-Cio-alkyl group in accordance with the above definition with an oxygen atom, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups.
- phenyl phenyl ether diphenylmethane and bipheny
- substituents there come into consideration primarily lower alkyl, alkoxy, amino, dialkylamino, dioxymethylene, benzonitrile, benzyl, benzyloxy, carboxyl, hydroxy, mercaptoalkyl, styryl, phenoxy, and halogen.
- this is preferably a residue such as the naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, chromane, chromene, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofiiranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinyl residue, especially the indolyl, naphthyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl benzothiophenyl and benzofiiranyl residue, which optionally can be mono- or polysubstituted.
- this is preferably a residue such as the anthracene, dibenzooxepine, phenanthrene, fluorene, dibenzofuran or carbazole residue.
- A signifies a single or double bond
- R 4 signifies hydroxyl, lower alkoxyl or the NR.R 2 residue, whereby Rj and R 2 can be the same or different
- R 5 signifies hydrogen or methyl X signifies oxygen or sulphur
- W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms
- W is not phenol or 2-hydroxypyridine or its bicyclic derivatives, if m equals 0 and g unequal 0,
- W is not phenol and benzofuran, if A is a single bond, X is oxygen and g is 1 or 2,
- W is not phenyl, benzofuran, benzoxazol, if m and g together equal 0,
- m signifies a number between 0 and 2
- q signifies the number 0 or 1
- A signifies a double bond
- Ri signifies hydrogen
- R 2 /R 3 signify hydrogen or methyl
- R 5 signifies hydrogen or methyl
- X signifies sulphur
- W signifies an optionally mono- or polysubstituted phenyl, phenanthrene, benzofuran, benzothiophene, biphenyl, cyclohexenyl or naphthalene residue.
- ⁇ -halocarboxylic acids and aldehydes used as starting materials are either commercially available, known or can be prepared analogously to the generally known processes.
- Compounds of formula (I) can be administered (sic) in liquid, solid or aerosol form orally, enterally, parenterally, topically, nasally, pulmonary or rectally in all usual non- toxic pharmaceutically acceptable carrier materials, adjuvants and additives.
- the compounds of formula (I) can also be applied locally to/in the bones (optionally with surgical intervention).
- parenteral embraces subcutaneous, intravenous,and intramuscular delivery or infusions.
- Oral administration forms can be e.g. tablets, capsules, dragees, syrups, solutions, suspensions, emulsions, elixirs etc., which can contain one or more additives from the following groups, such as flavourings, sweeteners, colouring agents and preservatives.
- Oral administration forms contain the active ingredient together with non-toxic, pharmaceutically acceptable carrier materials which are suitable for the production of tablets, capsules, dragees etc., such as e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose, talc, highly dispersible silicic acids, high molecular fatty acids (such as stearic acid), groundnut oil, olive oil, paraffin, miglyol, gelatine, agar-agar, magnesium stearate, beeswax, cetyl alcohol, lecithin, glycerol, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycol).
- carrier materials which are suitable for the production of tablets, capsules, dragees etc., such as e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose,
- Tablets, capsules, dragees etc. can be provided with an appropriate coating, e.g. glyceryl mono- stearate or glyceryl distearate, in order to prevent undesired side effects in the gastrointestinal tract or to give a longer duration of action by the delayed absorption in the gastrointestinal tract.
- an appropriate coating e.g. glyceryl mono- stearate or glyceryl distearate
- sterile injectable aqueous or oily solutions or suspensions which contain the usual additives such as stabilizers and solubilizers.
- additives can be e.g. water, isotonic saline, 1,3- butanediol, fatty acids (such as oleic acid), mono- and diglycerides or miglyol.
- non-irritating additives which are solid at normal temperatures and liquid at rectal temperatures, such as e.g. cocoa butter and polyethylene glycol.
- Pharmaceutically usual carrier media are used for appUcation as aerosols.
- Creams, tinctures, gels, solutions or suspensions etc. with the pharmaceutically usual additives are used for external application.
- the dosage can depend n a variety of factors such as mode of administration, species, age and/or individual condition.
- the doses to be administered daily or at intervals lie at 1- 1000 mg/individual, preferably at 10-250 mg/individual, and can be taken at one time or divided over several times.
- the compounds of formula (I) can also be applied locally to/in the bones (optionally with surgical intervention).
- the application directly to/in the bones (optionally with surgical intervention) can be effected locally or carrier-bonded either in solution or suspension, conveniendy by infusion or injection.
- Carrier-bonded compounds of formula (I) can be administered, for example, as gels, pastes, solids or as a coating on implants.
- Biocompatible and preferably biodegradable materials are used as the carrier. Preferably, the materials themselves also induce wound healing or osteogenesis.
- the compounds of formula (I) are imbedded in polymer gels or films in order to immobilize them and to apply these preparations directly on the site of the bone to be treated.
- polymer-based gels or films consist, for example, of glycerine, methylcellulose, hyaluronic acid, polyethylene oxides and/or poloxamers.
- collagen, gelatines and alginates are described, for example, in WO 93/00050 and WO 93/20859.
- Further polymers are polylactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLPG) (Hollinger el al., J. Biomed. Mater. Res.
- DBM Demineralized Bone Matrix
- suitable as carriers for the compounds of formula (I) are materials which are usually used for the implantation of bone substitutes or otherwise of therapeutically active substances. Such carriers are based, for example, on calcium sulphate, tricalcium phosphate, hydroxylapatite (sic) and its biodegradable derivatives and polyanhydrides. Apart from these biodegradable carriers there are also suitable carriers which are not biodegradable, but which are biocompatible. Such carriers are, for example, sintered hydroxylapatite, bioglass, aluminates or other ceramic materials (e.g. calcium aluminium phosphate). These materials are preferably used in combination with the biodegradable materials, such as especially polylactic acid, hydroxylapatite, collagen or tricalcium phosphate. Further non-degradable carriers are described, for example, in US Patent 4,164,560.
- a carrier which liberates the compounds of formula (I) continuously at the target site is especially preferred.
- a carrier which liberates the compounds of formula (I) continuously at the target site are especially suitable for this.
- Preferred in the scope of the present invention are, apart form the compounds named in the Examples and compounds derivable by a combination of all of the significances of the substituents set forth in the claims, the following derivatives as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments,
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU63311/99A AU6331199A (en) | 1998-09-30 | 1999-09-30 | Oxazolidine derivatives for the treatment and prevention of metabolic bone disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98118522 | 1998-09-30 | ||
EP98118522.6 | 1998-09-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000018745A1 true WO2000018745A1 (fr) | 2000-04-06 |
Family
ID=8232724
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1999/007253 WO2000018745A1 (fr) | 1998-09-30 | 1999-09-30 | Derives d'oxazolidine utiles pour le traitement et la prevention de troubles metaboliques des os |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU6331199A (fr) |
WO (1) | WO2000018745A1 (fr) |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2169334A1 (en) * | 1972-01-26 | 1973-09-07 | Boehringer Sohn Ingelheim | Biaxially stretched injection mouldings - esp hollow articles such as bottles |
GB2083810A (en) * | 1980-07-28 | 1982-03-31 | Pfizer | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
EP0097453A2 (fr) * | 1982-06-23 | 1984-01-04 | Pfizer Inc. | Oxazolidines-2, 4-dione contenant un substituant alicyclique à activité hypoglycémique |
EP0343643A2 (fr) * | 1988-05-25 | 1989-11-29 | Warner-Lambert Company | Dérivés arylméthyléniques, sélectionnés de thiazolidinones, d'imidazolidinones et d'oxazolidinones utiles comme agents anti-allergiques et comme agents anti-inflammatoires |
EP0428312A2 (fr) * | 1989-11-13 | 1991-05-22 | Pfizer Inc. | Oxazolidinedione comme agents hypoglycémiques |
WO1992002520A1 (fr) * | 1990-08-06 | 1992-02-20 | Beecham Group P.L.C. | Derives d'oxazolidine dione |
EP0612743A1 (fr) * | 1993-02-26 | 1994-08-31 | Takeda Chemical Industries, Ltd. | Dérivés de l'oxazolidinedione, leurs production et leurs utilisation pour réduire les niveaux de sucres et lipides dans le sang |
EP0643050A1 (fr) * | 1993-09-14 | 1995-03-15 | Takeda Chemical Industries, Ltd. | Dérivés d'oxazolidinedione et leur utilisation comme agents hypoglycémiques |
US5468762A (en) * | 1994-05-18 | 1995-11-21 | American Home Products Corporation | Azolidinediones as antihyperglycemic agents |
US5498621A (en) * | 1992-05-01 | 1996-03-12 | Pfizer Inc. | Oxazolidinedione hypoglycemic agents |
WO1997000249A1 (fr) * | 1995-06-16 | 1997-01-03 | Takeda Chemical Industries, Ltd. | Composes heterocycliques et production et utilisation de ces derniers |
EP0783888A1 (fr) * | 1995-12-26 | 1997-07-16 | Sankyo Company Limited | Utilisation de la troglitazone et de thiazolidinediones apparentées dans la fabrication d'un médicament destiné au traitement et la prévention de l'ostéoporose |
WO1998001445A1 (fr) * | 1996-07-09 | 1998-01-15 | Smithkline Beecham S.P.A. | Derives d'indole pour le traitement de l'osteoporose |
-
1999
- 1999-09-30 AU AU63311/99A patent/AU6331199A/en not_active Abandoned
- 1999-09-30 WO PCT/EP1999/007253 patent/WO2000018745A1/fr active Application Filing
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2169334A1 (en) * | 1972-01-26 | 1973-09-07 | Boehringer Sohn Ingelheim | Biaxially stretched injection mouldings - esp hollow articles such as bottles |
GB2083810A (en) * | 1980-07-28 | 1982-03-31 | Pfizer | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
EP0097453A2 (fr) * | 1982-06-23 | 1984-01-04 | Pfizer Inc. | Oxazolidines-2, 4-dione contenant un substituant alicyclique à activité hypoglycémique |
EP0343643A2 (fr) * | 1988-05-25 | 1989-11-29 | Warner-Lambert Company | Dérivés arylméthyléniques, sélectionnés de thiazolidinones, d'imidazolidinones et d'oxazolidinones utiles comme agents anti-allergiques et comme agents anti-inflammatoires |
EP0428312A2 (fr) * | 1989-11-13 | 1991-05-22 | Pfizer Inc. | Oxazolidinedione comme agents hypoglycémiques |
WO1992002520A1 (fr) * | 1990-08-06 | 1992-02-20 | Beecham Group P.L.C. | Derives d'oxazolidine dione |
US5498621A (en) * | 1992-05-01 | 1996-03-12 | Pfizer Inc. | Oxazolidinedione hypoglycemic agents |
EP0612743A1 (fr) * | 1993-02-26 | 1994-08-31 | Takeda Chemical Industries, Ltd. | Dérivés de l'oxazolidinedione, leurs production et leurs utilisation pour réduire les niveaux de sucres et lipides dans le sang |
EP0643050A1 (fr) * | 1993-09-14 | 1995-03-15 | Takeda Chemical Industries, Ltd. | Dérivés d'oxazolidinedione et leur utilisation comme agents hypoglycémiques |
US5468762A (en) * | 1994-05-18 | 1995-11-21 | American Home Products Corporation | Azolidinediones as antihyperglycemic agents |
WO1997000249A1 (fr) * | 1995-06-16 | 1997-01-03 | Takeda Chemical Industries, Ltd. | Composes heterocycliques et production et utilisation de ces derniers |
EP0783888A1 (fr) * | 1995-12-26 | 1997-07-16 | Sankyo Company Limited | Utilisation de la troglitazone et de thiazolidinediones apparentées dans la fabrication d'un médicament destiné au traitement et la prévention de l'ostéoporose |
WO1998001445A1 (fr) * | 1996-07-09 | 1998-01-15 | Smithkline Beecham S.P.A. | Derives d'indole pour le traitement de l'osteoporose |
Non-Patent Citations (13)
Title |
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AKITO NAGATSU ET AL: "Novel antioxidants from roasted perilla sees", CHEMICAL AND PHARMACEUTICAL BULLETIN., vol. 43, no. 5, 1995, TOKYO JP, pages 887 - 889, XP002093527 * |
BARRIE C.C. CANTELLO ET AL: "[[Omega-(heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents", JOURNAL OF MEDICINAL CHEMISTRY., vol. 37, no. 23, 1994, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 3977 - 3985, XP002127022, ISSN: 0022-2623 * |
CHEMICAL ABSTRACTS, vol. 111, no. 17, 23 October 1989, Columbus, Ohio, US; abstract no. 153681h, N.A.SHENBERG ET AL: "5-arylidene-2-thio-4-oxazolidinones in hydroxy and aminomethylation reactions" page 710; XP002093532 * |
CHEMICAL ABSTRACTS, vol. 48, no. 19, 10 October 1954, Columbus, Ohio, US; abstract no. 11391b, N.K.USHENKO ET AL: "Substitution in the azolidine ring. V. Preparation of 2-thiono-4-oxazolidinone and its transformations" XP002093531 * |
CHEMICAL ABSTRACTS, vol. 89, no. 13, 25 September 1978, Columbus, Ohio, US; abstract no. 109198j, N.A.SHENBERG ET AL: "Study of the reactivity and tautomerism of azolidines.XXIII. Alkylation of salts of 5-benzylidene-2-thiooxazolidin-4-ones" page 894; XP002093533 * |
FRIEDRICH WEYGAND ET AL: "Über die Umsetzung von alpha-chlor-alpha-äthylmercapto-ketonen mit Kaliumrhodanid.Ein neuer Weg zu Oxazolthionen", CHEMISCHE BERICHTE., vol. 91, 1958, WEINHEIM DE, pages 2537 - 2542, XP002093528 * |
KHIM.GERETEROTSIKL.SOEDIN, no. 1, 1989, pages 106 - 108 * |
PAUL C. UNANGST ET AL: "Synthesis and biological evaluation of 5-[[3,5-Bis(1,1dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles,-thiazoles,and -imidazoles: Novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity", JOURNAL OF MEDICINAL CHEMISTRY., vol. 37, no. 2, 1994, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 322 - 328, XP002127023, ISSN: 0022-2623 * |
ROBERT L.DOW ET AL: "Benzyloxazolidine-2,4-diones as potent hypoglycemic agents", JOURNAL OF MEDICINAL CHEMISTRY., vol. 34, no. 5, 1991, WASHINGTON US, pages 1538 - 1544, XP002093529 * |
TAKASHI SOHDA ET AL: "Studies on antidiabetic agents.I. Synthesis of 5-[4-(2-methyl-2-phenylpropoxy)-benzyl]thiazolidine-2,4-dione (AL-321) and related compou nds.", CHEMICAL AND PHARMACEUTICAL BULLETIN., vol. 30, no. 10, 1982, TOKYO JP, pages 3563 - 3573, XP002093530 * |
THOMAS R. HERRIN ET AL: "Antimalarial.Synthesis and antimalarial activity of 1-(4-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine and derivatives", JOURNAL OF MEDICINAL CHEMISTRY., vol. 18, no. 12, 1975, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 1216 - 1223, XP002127021, ISSN: 0022-2623 * |
UKRAIN.KHIM.ZHUR., vol. 16, 1950, pages 545 - 551 * |
ZH.ORG.KHIM., vol. 14, no. 6, 1978, pages 1323 - 1327 * |
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