WO1994009770A1 - The use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents - Google Patents

The use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents Download PDF

Info

Publication number
WO1994009770A1
WO1994009770A1 PCT/EP1993/002975 EP9302975W WO9409770A1 WO 1994009770 A1 WO1994009770 A1 WO 1994009770A1 EP 9302975 W EP9302975 W EP 9302975W WO 9409770 A1 WO9409770 A1 WO 9409770A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
acids
compounds
optionally substituted
aryl
Prior art date
Application number
PCT/EP1993/002975
Other languages
French (fr)
Inventor
Carmelo A. Gandolfi
Lorella Cotini
Marco Mantovanini
Gianfranco Caselli
Gaetano Clavenna
Claudio Omini
Original Assignee
Dompe' Farmaceutici S.P.A.
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 Dompe' Farmaceutici S.P.A. filed Critical Dompe' Farmaceutici S.P.A.
Priority to AU53712/94A priority Critical patent/AU5371294A/en
Publication of WO1994009770A1 publication Critical patent/WO1994009770A1/en

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide

Definitions

  • the present invention relates to the use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents. More particularly, the present invention rela ⁇ tes to the use as therapeutical agents of aryl-, hete ⁇ roaryl- and alkyltartronic acids of general formula
  • Ra and Rb are independently a hydrogen atom, an alkali or alkaline-earth metal cation, an ammonium or C-.-c ⁇ n alkylammonium cation, a C j ⁇ -c ⁇ alkyl group, a C ⁇ C ⁇ alkoxyethyl group;
  • A is a straight or branched C,-c 18 alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.
  • alkyl groups are methyl, ethyl, isopropyl, butyl, neopentyl, 4-methyl-pentyl, hexyl, 2- ethylpentyl, heptyl, iso-octyl, dodecyl, pentadecyl.
  • aryl groups are phenyl, ( -naphthyl, ⁇ - naphthyl.
  • heteroaryl groups are 2-furyl, 2-thia- zolyl, 2-imidazolyl, 3-benzofuryl, &-, ⁇ - and V- pyridyl, 2- and 3-thienyl.
  • one or more substituents such as hydroxy, C,-c. alkoxy, mono- and di-C ⁇ -c * alkylammino, ⁇ ⁇ 4 alkyl, cyano, halogen, free or esterified carboxy, C,-c 4 car- boalkoxy, can be present on the aromatic rings.
  • acids and the esters thereof of formula (I) are (2-furyl)tartronic, (4- hydroxy)phenyltartronic, (3-methoxy-4-hydroxy)phenyl- tartronic, (4-dimethylamino)phenyltartronic, (4-(C,-
  • C 5 alkyl)phenyltartronic, (2,5-dimethyl)phenyltartro ⁇ nic, (2,4,6-trimethyDphenyltartronic, (3-methyl-4- methoxy)phenyltartronic, (2-methoxy-4,6-dimethyD- phenyltartronic, (2-methoxy-5-cyanomethyl)phenyltartro- nic, (3-fluoro)phenyltartronic, [4-(2-acetoxyethyl) ]- phenyltartronic, (4-ethoxycarbonyl)phenyltartronic, k- naphthlenetartronic.
  • Tartronic acids and the derivatives thereof have been known for a long time.
  • Eskola and Muotinen disclose the prepa ⁇ ration of diethyl methylhydroxymalonate by oxidation of diethyl methylmalonate with potassium permanganate.
  • Ames and Bauram disclose tartronic acid ethers as intermediates in the synthesis of olephinic acids.
  • the compounds of formula (I) can be obtained by oxidation of an alkylmalonic acid with oxidizing agents such as potassium permanganate, peroxides and hydrope- roxides according to conventional methods.
  • the compounds of formula (I) exert a surprising therapeutical activity in bone dysmetabolism, particularly such compounds are useful in the treatment of osteoporosis, malignat hypercalcemias and Paget's disease.
  • esters of the compounds of formula (I) which are characterised by a very good bioavailability, after oral administra- tion, which is at least comparable to that of the cor ⁇ responding free acids after parenteral administration.
  • the compounds of the invention Compared with alkyl and aminoalkyl-gem-bisphospho- nates already known and widely used in therapy, the compounds of the invention have the advantages of a better oral bioavailability and an higher activity.
  • the compounds of the invention are suitably formulated in pharmaceu ⁇ tical compositions using conventional techniques and excipients, as described in "Remington's Pharmaceutical Sciences Handbook", Mack Publishing Co., New York, USA, 17th Ed., 1985.
  • the compositions of the invention can be administered intramuscularly, intravenously, by bolus and orally, in form of capsules, tablets, syrups and optionally as controlled-release forms.
  • the daily dosage will depend on various factors, such as severity of the disease and conditions of the patient (sex, weight, age): the dose will generally range from 10 to 1500 mg of the compounds per day, optionally divided in multiple administrations. Higher dosages, even for more prolonged times, can be admini- stered thanks to the low toxicity of the compounds of the invention.

Abstract

The use, as therapeutical agents, of compounds of formula (I), wherein Ra and Rb are independently a hydrogen atom, an alkali or alkaline-earth metal cation, an ammonium or C1-C10 alkylammonium cation, a C1-C4 alkyl group, a C1-C4 alkoxyethyl group; A is a straight or branched C1-C18 alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

Description

THE DSE OF ARYL-, HETEROARYL- AND ALKYLTARTRONIC ACIDS AS THERAPEUTICAL AGENTS
The present invention relates to the use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents. More particularly, the present invention rela¬ tes to the use as therapeutical agents of aryl-, hete¬ roaryl- and alkyltartronic acids of general formula
(I): COORa
I
A-C-O-H (I)
COORb wherein:
Ra and Rb are independently a hydrogen atom, an alkali or alkaline-earth metal cation, an ammonium or C-.-cιn alkylammonium cation, a Cj^-c^ alkyl group, a C^C^ alkoxyethyl group;
A is a straight or branched C,-c18 alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. Examples of alkyl groups are methyl, ethyl, isopropyl, butyl, neopentyl, 4-methyl-pentyl, hexyl, 2- ethylpentyl, heptyl, iso-octyl, dodecyl, pentadecyl.
Examples of aryl groups are phenyl, ( -naphthyl, β- naphthyl. Examples of heteroaryl groups are 2-furyl, 2-thia- zolyl, 2-imidazolyl, 3-benzofuryl, &-, β- and V- pyridyl, 2- and 3-thienyl.
In the case of aryl- and heteroaryltartronic acids, one or more substituents, such as hydroxy, C,-c. alkoxy, mono- and di-C^-c* alkylammino, ~ι~~4 alkyl, cyano, halogen, free or esterified carboxy, C,-c4 car- boalkoxy, can be present on the aromatic rings.
Examples of acids and the esters thereof of formula (I) are (2-furyl)tartronic, (4- hydroxy)phenyltartronic, (3-methoxy-4-hydroxy)phenyl- tartronic, (4-dimethylamino)phenyltartronic, (4-(C,-
C5)alkyl)phenyltartronic, (2,5-dimethyl)phenyltartro¬ nic, (2,4,6-trimethyDphenyltartronic, (3-methyl-4- methoxy)phenyltartronic, (2-methoxy-4,6-dimethyD- phenyltartronic, (2-methoxy-5-cyanomethyl)phenyltartro- nic, (3-fluoro)phenyltartronic, [4-(2-acetoxyethyl) ]- phenyltartronic, (4-ethoxycarbonyl)phenyltartronic, k- naphthlenetartronic. Tartronic acids and the derivatives thereof have been known for a long time. Eskola and Muotinen (Chemical Abstract, vol. 42, 122h) disclose the prepa¬ ration of diethyl methylhydroxymalonate by oxidation of diethyl methylmalonate with potassium permanganate. Ames and Bauram (J. Chem. Soc. (1951) 1079) disclose tartronic acid ethers as intermediates in the synthesis of olephinic acids.
Freon and Tatibouet (Com. Ren. Acad. Sc. 249 (1959) 1361-1363) disclose the preparation of (alkyl)tartronates by reaction of mesoxalates with alkylcadmium.
The preparation of aryltartronic acids is described by Ghosh and al. in J. Org. Chem. 47, (1982), 4692. The compounds of the invention are known and anyhow they can be prepared by conventional methods, among which those cited above.
The compounds of formula (I) can be obtained by oxidation of an alkylmalonic acid with oxidizing agents such as potassium permanganate, peroxides and hydrope- roxides according to conventional methods.
The literature about tartronic acid, up to present day knowledge, does not mention any therapeutical uses of alkyltartronic acids and derivatives thereof.
Now it has been found that the compounds of formula (I) exert a surprising therapeutical activity in bone dysmetabolism, particularly such compounds are useful in the treatment of osteoporosis, malignat hypercalcemias and Paget's disease.
The administration of the compounds of the invention involves no adverse effects on bone growth and on the mineralization thereof. Particularly preferred compounds of the invention are the esters of the compounds of formula (I), which are characterised by a very good bioavailability, after oral administra- tion, which is at least comparable to that of the cor¬ responding free acids after parenteral administration.
Compared with alkyl and aminoalkyl-gem-bisphospho- nates already known and widely used in therapy, the compounds of the invention have the advantages of a better oral bioavailability and an higher activity.
The compounds of the invention when tested in vitro, according to the protocol described by Y.Su et al., Endocrinology, 131, 1497, 1992, in a range of scalar concentrations from 10 to 10~4 M, turned out to be particularly effective in inhibiting the forma¬ tion of bone resorbing pits, without cytotoxic effects on the osteoclasts themselves. Compared with untreated controls, ethydronate, which is a bis-phosphonate used as the control drug, causes a bone resorption, evaluated according to the number (count) and to the consistency of the formed bone cavities, of only 58% of the control values for about 10~° M concentrations, whereas 74% inhibitions are observed only at high concentrations (lxlO-4 M).
On the contrary, its close dicarboxylic analogue: 2-hydroxy-2-methyl-l,3-propanedioic, already at lxlO"10 M concentrations reaches the maximum inhibition (73%), showing a 40% inhibition at about 10 2 M concentra¬ tions, thus calculating an C50 of lxl0~ for the compound. For the envisaged therapeutic uses, the compounds of the invention are suitably formulated in pharmaceu¬ tical compositions using conventional techniques and excipients, as described in "Remington's Pharmaceutical Sciences Handbook", Mack Publishing Co., New York, USA, 17th Ed., 1985. The compositions of the invention can be administered intramuscularly, intravenously, by bolus and orally, in form of capsules, tablets, syrups and optionally as controlled-release forms.
The daily dosage will depend on various factors, such as severity of the disease and conditions of the patient (sex, weight, age): the dose will generally range from 10 to 1500 mg of the compounds per day, optionally divided in multiple administrations. Higher dosages, even for more prolonged times, can be admini- stered thanks to the low toxicity of the compounds of the invention.

Claims

1. The use, as therapeutical agents, of the compounds of formula (I) : COORa
I A-C-O-H (I)
I COORb wherein:
Ra and Rb are independently a hydrogen atom, an alkali or alkaline-earth metal cation, an ammonium or Cτ-Cιn alkylammonium cation, a Cι~C4 alkyl group, a Cχ-C4 alkoxyethyl group; A is a straight or branched C,-C-,8 alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.
2. The use of the compounds according to claim 1, for the preparation of a medicament useful for the treatment of bone dysmetabolism.
3. The use of the compounds according to claim 1, for the preparation of a medicament useful for the treatment of osteoporosis, malignant hypercalcemias and Paget's disease.
4. Pharmaceutical compositions containing one compound of formula (I) as the active ingredient.
PCT/EP1993/002975 1992-11-05 1993-10-27 The use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents WO1994009770A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53712/94A AU5371294A (en) 1992-11-05 1993-10-27 The use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI92A002534 1992-11-05
ITMI922534A IT1256300B (en) 1992-11-05 1992-11-05 USE OF ARYL, ETHEROARYL AND ALCHYLTARTRONIC ACIDS AS THERAPEUTIC AGENTS

Publications (1)

Publication Number Publication Date
WO1994009770A1 true WO1994009770A1 (en) 1994-05-11

Family

ID=11364234

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/002975 WO1994009770A1 (en) 1992-11-05 1993-10-27 The use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents

Country Status (4)

Country Link
CN (1) CN1091633A (en)
AU (1) AU5371294A (en)
IT (1) IT1256300B (en)
WO (1) WO1994009770A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0792878A2 (en) * 1996-02-27 1997-09-03 Dompé S.P.A. Geminal carboxylic acids and esters thereof, pharmaceutical formulations containing them useful in the treatment of bone dysmetabolism

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3988470A (en) * 1974-02-25 1976-10-26 Scott Eugene J Van Treatment of palmar and plant disturbed keratosis
EP0056264A1 (en) * 1981-01-12 1982-07-21 Montedison S.p.A. Process for preparing alkyl esters of C-alkyl-tartronic or C-halogenalkyl-tartronic acids
US4698333A (en) * 1982-11-10 1987-10-06 Bayer Aktiengesellschaft Use of substituted malonic acid derivatives as agents for combating pests
EP0304986A2 (en) * 1987-08-28 1989-03-01 Norwich Eaton Pharmaceuticals, Inc. The use of certain Calcium-Citrate-Malate for the manufacture of a medicament for the treatment of osteoporosis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3988470A (en) * 1974-02-25 1976-10-26 Scott Eugene J Van Treatment of palmar and plant disturbed keratosis
EP0056264A1 (en) * 1981-01-12 1982-07-21 Montedison S.p.A. Process for preparing alkyl esters of C-alkyl-tartronic or C-halogenalkyl-tartronic acids
US4698333A (en) * 1982-11-10 1987-10-06 Bayer Aktiengesellschaft Use of substituted malonic acid derivatives as agents for combating pests
EP0304986A2 (en) * 1987-08-28 1989-03-01 Norwich Eaton Pharmaceuticals, Inc. The use of certain Calcium-Citrate-Malate for the manufacture of a medicament for the treatment of osteoporosis

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
J. THOMAS ET AL.: "ETUDES SUR L'ACTION ANTILITHOGENE DES ACIDES DIHYDROXYMALEIQUE, CETOMALONIQUE (MESOXALIQUE) ET TARTRONIQUE VIS-A-VIS DE LA LITHIASE EXPERIMENTALE DU RAT", ANNALES D'UROLOGIE, vol. 23, no. 5, 1989, pages 444 - 452 *
J.E.F.REYNOLDS: "MARTINDALE THE EXTRA PHARMACOPOEIA", 1989, THE PHARMACEUTICAL PRESS, LONDON *
L. CIMA: "ACUTE AND SUBACUTE TOXICITY OF ISOMALIC ACID", TOXICOLOGY AND APPLIED PHARMACOLOGY, vol. 9, 1966, pages 274 - 278 *
S. GHOSH ET AL.: "ESTER ENOLATES FROM alpha-ACETOXYESTERS", J. ORG. CHEM., vol. 47, 1982, pages 4692 - 4702 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0792878A2 (en) * 1996-02-27 1997-09-03 Dompé S.P.A. Geminal carboxylic acids and esters thereof, pharmaceutical formulations containing them useful in the treatment of bone dysmetabolism
EP0792878A3 (en) * 1996-02-27 1998-03-18 Dompé S.P.A. Geminal carboxylic acids and esters thereof, pharmaceutical formulations containing them useful in the treatment of bone dysmetabolism

Also Published As

Publication number Publication date
ITMI922534A1 (en) 1994-05-05
AU5371294A (en) 1994-05-24
CN1091633A (en) 1994-09-07
ITMI922534A0 (en) 1992-11-05
IT1256300B (en) 1995-11-29

Similar Documents

Publication Publication Date Title
JP4614884B2 (en) Pyridone derivatives and their use
IE49902B1 (en) 4-substituted-3-hydroxy-3-pyrroline-2,5-dione compounds,process for their preparation and pharmaceutical compositions containing the same
EP0551230A1 (en) Cyano-2-hydroxy-3-enamide derivatives, process for their preparation, their use as drugs, pharmaceutical compositions containing them and intermediates obtained
US4595695A (en) 1'-ethoxycarbonyloxyethyl ester of valproic acid, its preparation and pharmaceutical compositions containing it
KR900006724B1 (en) Benzothiazine dioxide derivatives
WO1994009770A1 (en) The use of aryl-, heteroaryl- and alkyltartronic acids as therapeutical agents
US4176193A (en) Therapeutic isobutyramides
WO1990006931A1 (en) Organometallic compounds, process for producing them and pharmaceutical compositions containing them
EP0117959A2 (en) Nitrosourea derivatives, process for their preparation and pharmaceutical compositions containing them
EP0138272B1 (en) Diarylindane-1,3-diones, their preparation and use
EP0002635B1 (en) Process for the preparation of thieno (2,3-c) and (3,2-c) pyridine derivatives, thieno (2,3-c) pyridine derivatives thus obtained, and their therapeutical use
JPS60104084A (en) 4h-benzo(4,5)cyclohepta(1,2-b)thiophene derivative
CZ20021433A3 (en) Prodrug based on 6-methoxy-2-naphthylacetic acid
HU191681B (en) Process for preparing pyridil-n-oxide-carboxylic acid esters and pharmaceutical preparations comprising the same as active substance
FR2479820A1 (en) 4- (4-CHLOROPHENYL) -2- (4-ACYLOXY- OR HYDROXYPHENYL) -THIAZOLE-5-ACETIC OR ACETATE-LIKE COMPOUND, PROCESS FOR PREPARATION THEREOF AND APPLICATION AS MEDICAMENT
US4722940A (en) Aminoalkyl phenyl selenides for the treatment of hypertension and nervous system dysfunctions
JP3043118B2 (en) Conjugated γ-hydroxybutenolide compound and anticancer agent containing the same as an active ingredient
JP3154298B2 (en) Pharmaceutically active 3-aryl and 3-heteroaryl-2-fluoro-1-olefins
US5084464A (en) Conjugated γ-hydroxybutenolide compounds and antiulcer agents containing the same as an effective ingredient
JPH0454160A (en) Tetracycline derivative
EP0210886B1 (en) Tertiary halogenated biphenyl alcohols therapeutically useful in the treatment of atheriosclerosis
LU82421A1 (en) NEW TAURINE DERIVATIVE, PREPARATION METHOD THEREOF AND THERAPEUTIC APPLICATION THEREOF
CS261894B2 (en) Method of 7-oxo-prostacycline's analogues salts production
BE877096R (en) DERIVATIVES OF METHYL-2 PHENOXY-2 PROPIONIC ACIDS, THEIR PROCESS OF PREPARATION AND THEIR APPLICATIONS IN THERAPEUTICS
JPH0742274B2 (en) Hydantoin derivative and aldo-reductase inhibitor containing the same as active ingredient

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA