WO1994026279A1 - Esters de biphosphonate pour traiter les troubles gastriques - Google Patents

Esters de biphosphonate pour traiter les troubles gastriques Download PDF

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Publication number
WO1994026279A1
WO1994026279A1 PCT/US1994/003873 US9403873W WO9426279A1 WO 1994026279 A1 WO1994026279 A1 WO 1994026279A1 US 9403873 W US9403873 W US 9403873W WO 9426279 A1 WO9426279 A1 WO 9426279A1
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WO
WIPO (PCT)
Prior art keywords
bis
pyrimidinyl
methyl
dimethyl
ethylidene
Prior art date
Application number
PCT/US1994/003873
Other languages
English (en)
Inventor
Colin J. Dunn
Richard A. Nugent
Original Assignee
The Upjohn Company
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 The Upjohn Company filed Critical The Upjohn Company
Priority to AU65568/94A priority Critical patent/AU6556894A/en
Publication of WO1994026279A1 publication Critical patent/WO1994026279A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds

Definitions

  • the subject invention is directed toward the discovery that bisphosphonate esters are useful in the treatment of gastric diseases characterized by irritation, ulceration and acid hypersecretion and are useful as cytoprotective agents against gastric irritation and ulceration.
  • this class of chemical compounds was known to be useful for the treatment of arthritis and cardiovascular diseases and; therefore, the discovery that these compounds are useful in treating gastric diseases is unexpected.
  • the present invention comprises the use of these compounds in humans and lower animals as a safe and effective treatment of diseases characterized by irritation, ulceration and acid hypersecretion in the gastric tract.
  • PCT International Application PCT/US92/05398; WO 93/01198 discloses the preparation and structures for bisphosphonate esters having a pyrazolopyrimidine and pyrimidinyl heterocyclic structure useful as anti-inflammatories and anti-arthritic agents.
  • PCT International Application PCT/US90/01106; WO 90/12017 (18 October 1990) discloses the preparation and structures for bisphosphonate acid, esters and salts useful as anti-arthritic agents.
  • PCT International Application PCT/US91/05554; WO 92/03451 discloses the preparation and structures for acyclic and cyclic bisphosphonate esters useful as antiarthritic agents.
  • the present invention is directed toward a method for treating gastric diseases characterized by irritation, ulceration and acid hypersecretion by administering a therapeutically effective amount of a bisphosphonate ester or a pharmaceutically acceptable acid salt thereof to an animal or human in need thereof.
  • the mode of administration can be intravenously, intramuscularly, topically, transdermally, bucally, orally or parenterally as best determined by the severity and type of patient being treated.
  • a typical dosage depending on the route of administration can vary from about 0.001 mg to about 1.0 grams per dose.
  • a bisphosphonate ester or a pharmaceutically acceptable acid salt thereof are generally known in the art except not as a medicament for treating gastric diseases.
  • a bisphosphonate comprises two phosphorus atoms joined together by a carbon atom wherein each phosphorus atom has a doubly bonded oxygen and two hydroxy, alkyoxy or various other oxygen bonded groups such as those depicted for R 1 , below, or combinations thereof.
  • the carbon atom joining the two phosphorus groups is bonded to various other chemical entities such as halogen atoms, amine groups or heterocyclic ring structures.
  • the present invention disclosed the use of bisphosphonate esters, acids and their pharmaceutically acceptable salts for treating gastric diseases characterized by irritation, ulceration, and acid hypersecretion.
  • the bisphosphonate compounds are also useful as cytoprotective agents against gastric irritation and/or ulceration.
  • Typical bisphosphonate compounds that may be used in methods or treatments for gastric diseases are those disclosed in PCT/US92/05398, WO 93/01198 (21 January 1993), herein incorporated by reference; PCT/US90/01106, WO 90/12017 (18 October 1990), herein incorporated by reference; PCT/US91/05554, WO 92/03451 (5 March 1992), herein incorporated by reference; US Patent 3,683,080, herein incorporated by reference for the formula X 2 C- (PO(OR 1 ) 2 ) 2 wherein X is H, F, Cl, Br, and R 1 is as defined below; and bisphosphonate esters, acids and their pharmaceutically acceptable salts which are structurally represented by Formula I:
  • R 1 are the same or different and are selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, CH 2 Ph, or where both OR 1 on the same P are taken together along with CH 2 -CH 2 , CH 2 -CH 2 -CH 2 , or CH 2 -C(CH 3 ) 2 -CH 2 to form a heterocyclic ring containing one P, two O and two to three carbon atoms;
  • R 2 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl optionally substituted with 1 or 2 phenyls, or 1 through 5 F, Cl, Br, I, NO 2 , CN, CF 3 , C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, OH, SH, NH 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, or N(R 5 ) 2 ;
  • R 3 is H, phenyl, F, Cl, Br, I, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, or N(R 5 ) 2 ;
  • X is O or S when R 4 is phenyl or phenyl substituted with 1 or 2 phenyls, or 1 through 5 F, Cl, Br, I, NO 2 , CN, CF 3 , C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, OH, SH, NH 2 , C 1 -C 6 alkoxy, C 1 - C 6 alkylthio, or N(R 5 ) 2 ; or
  • X is N when R 4 X is a heterocyclic ring containing n atoms of which n-1 to 1 are carbon, 1 to 3 nitrogen, 0 or 1 oxygen, or 0 or 1 sulfur where n is 5 or 6; and
  • R 5 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or N(R 5 ) 2 is a heterocyclic ring of 4 to 7 members containing 3 to 6 carbons, 1 to 3 nitrogens, 0 to 2 oxygens, and 0 to 2 sulfurs.
  • C i -C j defines the number of carbon atoms present from the integer "i" to "j" inclusive.
  • C 1 -C 3 alkyl refers to alkyls of one to three carbon atoms, inclusive, including isomers thereof such as methyl, propyl, ethyl and isopropyl.
  • C 3 -C 7 cycloalkyl is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and isomeric forms thereof.
  • halo includes fluoro, chloro, bromo and iodo.
  • C 1 -C 6 alkylthio are methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio
  • C 1 -C 6 alkylthio are methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and isomeric forms thereof.
  • C 1 -C 6 alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and isomeric forms thereof.
  • Ph phenyl
  • Pharmaceutically acceptable salts means salts useful for administering the compounds of this invention or useful forms the compounds may take in vitro and in vivo and include potassium, sodium, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malonate, succinate, tartrate, citrate and the like. These salts may be in hydrated form.
  • the subject invention provides a method for treating gastric diseases characterized by irritation, ulceration and acid hypersecretion and are useful as cytoprotective agents against gastric irritation and ulceration by administering to an animal or human (patients) in need thereof a therapeutically effective amount of a bisphosphonate compound.
  • Routes of administration include oral, intramuscular, intravenous, transdermal, intra-articular, subcutaneous, or intraperitoneal.
  • An effective amount is an amount whereby the symptoms such as the pain and gastric discomfort are relieved or reduced and, for irritation or ulceration reduced or ameliorated.
  • a typical dosage is about 0.001 mg to 1.0 gram with dose determined by the particular mode of administration, use and frequency of administration.
  • the compounds can be administered intravenously, intramuscularly, topically, transdermally, such as by skin patches, bucally or orally to humans or animals.
  • compositions of the present invention can be presented for administration in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil in water and water in oil emulsions containing suitable quantities of the compound, suppositories and in fluid suspensions or solutions.
  • either solid or fluid unit dosage forms can be prepared.
  • the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared.
  • the forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth,
  • fluid unit dosage forms can be prepared utilizing the compound and a sterile vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • Adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into a vial and the water removed under vacuum.
  • the dry lyophilized powder can then be sealed in the vial and reconstituted prior to use.
  • the compounds of Formula I can be prepared by selecting the appropriately substituted
  • 2-amino pyrimidines synthesized by means familiar to those skilled in the art, and involve the reaction of 6-halo-2-amino pyrimidines with the desired alkoxide, phenoxide, thiophenoxide, or amine in an inert solvent such as toluene, THF, DMSO, or DMF or the solvent can be the corresponding alcohol, phenol, or thiophenol. Temperatures can range between 0°C and reflux. The preferred temperature is room temperature. If the alcohol is low molecular weight, the preferred solvent is the corresponding alcohol or else is DMF. The products are isolated by dilution with water, and collection of the solid. This material can be recrystallized if needed.
  • the bisphosphonates are synthesized through the reaction of the above 2-amino pyrimidines with vinylidene bisphosphonate esters, which have previously been described in published PCT Application WO 9012 017 and by Degenhardt, C.R.; Burdsall, D.C.
  • reaction occurs in an inert solvent, such as THF, benzene, toluene, or xylene at elevated temperatures. It is preferred that the reaction be run in toluene at reflux.
  • inert solvent such as THF, benzene, toluene, or xylene
  • Bisphosphonate ester compounds were tested in models of gastric ulcers induced by ethanol, aspirin (+4°C), flurbiprofen (+4°C), also against gastric hypersecretion induced by ligation of the gastric pylorus. These assays demonstrated the usefulness of bisphosphonate therapy for gastric disorders or diseases not heretobefore known.
  • Table 1 The aspirin-induced ulcer study (Table 1) was performed to determine whether the compounds exerted antiulcer activity. After an overnight fast, gastric ulcers were produced by aspirin administered orally at 50 mg/kg contained in 1 ml, homogenized in water containing
  • Tween 80 (1 drop/20 ml).
  • the animals were exposed to cold temperatures (4°C) in order to increase the ulcerogenicity of aspirin.
  • the compounds were given orally thirty minutes before aspirin and the animals were killed one hour after aspirin plus cold. Gastric ulcers were counted and scored in Table 1. There were 10 animal controls, and 6 animals in each of the experimental groups.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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 concerne l'utilisation d'esters de biphosphonate pour le traitement de maladies gastriques caractérisées par des irritations, des ulcérations et l'hypersécrétion d'acide. Ce sont des agents cytoprotecteurs utiles contre l'irritation ou l'ulcération gastrique. On administre au patient atteint de tels troubles des esters, des acides de biphosphonate, ou encore les sels de ces derniers acceptables sur le plan pharmaceutique.
PCT/US1994/003873 1993-05-18 1994-04-12 Esters de biphosphonate pour traiter les troubles gastriques WO1994026279A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65568/94A AU6556894A (en) 1993-05-18 1994-04-12 Bisphosphonate esters for treating gastric disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6375893A 1993-05-18 1993-05-18
US08/063,758 1993-05-18

Publications (1)

Publication Number Publication Date
WO1994026279A1 true WO1994026279A1 (fr) 1994-11-24

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AU (1) AU6556894A (fr)
WO (1) WO1994026279A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5652227A (en) * 1995-01-30 1997-07-29 Teronen; Olli Pekka Inhibition of the degradation of connective tissue matrix protein components in mammals
WO2014162123A1 (fr) * 2013-04-02 2014-10-09 The University Of Sheffield Utilisations thérapeutiques des biphosphonates
WO2014162124A1 (fr) * 2013-04-02 2014-10-09 The University Of Sheffield Utilisations thérapeutiques des biphosponates

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0007326A1 (fr) * 1978-07-18 1980-02-06 Smith Kline & French Laboratories Limited Amidines, leur préparation et compositions pharmaceutiques les contenant.
WO1988003921A1 (fr) * 1986-11-21 1988-06-02 Aktiebolaget Hässle Nouveaux derives de benzimidazole, procede de production desdits derives et composition pharmaceutique les contenant
WO1992003451A1 (fr) * 1990-08-21 1992-03-05 The Upjohn Company Derives d'acide bisphosphonique utilises comme agents anti-arthritiques
WO1992019610A1 (fr) * 1991-04-30 1992-11-12 Allergan, Inc. 4- (1-hydroxy, 1-acyloxy ou 1-carbamoyloxy)-5-hydroxy-2(5h)-furanones a substitution alkyle et phenyle en position 2 et 5 en tant qu'agents anti-inflammatoires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0007326A1 (fr) * 1978-07-18 1980-02-06 Smith Kline & French Laboratories Limited Amidines, leur préparation et compositions pharmaceutiques les contenant.
WO1988003921A1 (fr) * 1986-11-21 1988-06-02 Aktiebolaget Hässle Nouveaux derives de benzimidazole, procede de production desdits derives et composition pharmaceutique les contenant
WO1992003451A1 (fr) * 1990-08-21 1992-03-05 The Upjohn Company Derives d'acide bisphosphonique utilises comme agents anti-arthritiques
WO1992019610A1 (fr) * 1991-04-30 1992-11-12 Allergan, Inc. 4- (1-hydroxy, 1-acyloxy ou 1-carbamoyloxy)-5-hydroxy-2(5h)-furanones a substitution alkyle et phenyle en position 2 et 5 en tant qu'agents anti-inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIDDER G. W.: "Effects of the ATP Analog 5'-Adenyl Methylendiphophonate on Acid Secretion in Frog Gastric Mucosa", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 298, 1973, pages 732 - 742 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5652227A (en) * 1995-01-30 1997-07-29 Teronen; Olli Pekka Inhibition of the degradation of connective tissue matrix protein components in mammals
WO2014162123A1 (fr) * 2013-04-02 2014-10-09 The University Of Sheffield Utilisations thérapeutiques des biphosphonates
WO2014162124A1 (fr) * 2013-04-02 2014-10-09 The University Of Sheffield Utilisations thérapeutiques des biphosponates

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Publication number Publication date
AU6556894A (en) 1994-12-12

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