WO1999054278A1 - CETONES INSATUREES 1-(2-ALCOXY-5-CARBOXYPHENYL)-α,β, ELABORATION, ET APPLICATION THERAPEUTIQUE - Google Patents

CETONES INSATUREES 1-(2-ALCOXY-5-CARBOXYPHENYL)-α,β, ELABORATION, ET APPLICATION THERAPEUTIQUE Download PDF

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Publication number
WO1999054278A1
WO1999054278A1 PCT/EP1999/002835 EP9902835W WO9954278A1 WO 1999054278 A1 WO1999054278 A1 WO 1999054278A1 EP 9902835 W EP9902835 W EP 9902835W WO 9954278 A1 WO9954278 A1 WO 9954278A1
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WO
WIPO (PCT)
Prior art keywords
formula
group
γûá
defined above
pharmaceutically acceptable
Prior art date
Application number
PCT/EP1999/002835
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English (en)
Inventor
Andréas TSOTINIS
Theodora Kalogeropoulou
Christos Roussakis
Vassilios Roussis
Original Assignee
Corneal Industrie
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 Corneal Industrie filed Critical Corneal Industrie
Publication of WO1999054278A1 publication Critical patent/WO1999054278A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups

Definitions

  • the present invention relates to the l-(2-alkoxy-5-carboxyphenyl)-or, ?- unsaturated ketone compounds of general formula (I) below, to their geometrical isomers, and to their addition salts, particularly pharmaceutically addition salts, as novel products. It further relates to a method of preparing said compounds and to their application in therapeutics.
  • chalcone derivatives and drugs containing same are disclosed.
  • Said chalcone derivatives are of the following formula :
  • A is phenyl, quinolyl or the like ; W is vinylene or the like ; and R 1 to R 5 are each carboxyl, cyano, alkyloxycarbonyl or the like).
  • the compounds exhibit an excellent antagonism against cys-LT receptors and are useful as anti-allergic agents or the like.
  • l-(2-alkoxy-5-carboxyphenyl)- ⁇ , ⁇ -unsaturated ketone compounds of the present invention are characterised in that they are of general formula (I) :
  • ⁇ Ri represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms ;
  • R 2 and R 3 independently represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms ;
  • ⁇ X represents an -OH , -OR , -NH 2 , -NHR , or -NRR' group, in which R and R' independently represent a lower alkyl group having 1 to 6 carbon atoms ; with the proviso that in the case in which R 2 and R 3 both represent a methyl group and X represents an -OH group or an -OCH 3 group, Ri does not represent a hydrogen atom.
  • the invention also relates to their geometrical isomers ; as well as their addition salts, particularly their pharmaceutically acceptable addition salts.
  • lower alkyl group is understood as meaning a linear or branched hydrocarbon chain having 1 to 6 carbon atoms.
  • a lower alkyl group is, for example, a methyl, ethyl, propyl, isoproopyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or isohexyl group.
  • Methyl and ethyl groups are particularly preferred as lower alkyl groups.
  • the compounds according to the present invention are advantageously the compounds of formula (I) above in which :
  • ⁇ Ri represents a methyl or ethyl group
  • R 2 and R 3 independently represent a hydrogen atom or a methyl or ethyl group ;
  • ⁇ X represents an -OH , -OCH 3 , -OCH 2 CH 3 , -NH 2 , -NHCH 3 , or an - N(CH 3 ) 2 group ; as well as their geometrical isomers ; and their addition salts, particularly their pharmaceutically acceptable addition salts.
  • the particularly preferred compound of the present invention is methyl 3-
  • the compounds of the invention in which Ri represents a hydrogen atom can be prepared either from the compounds of the invention in which Ri represents a lower alkyl group, by customary dealkylation methods known to the person skilled in the art, or, by carrying out the method described above with a compound of formula (III) in which the phenolic -OH group is protected by a protecting group, the product obtained been finally deprotected by customary deprotection methods known to the person skilled in the art.
  • the addition salts of certain compounds of formula (I), in particular those which have an acid function can be obtained by the reaction of these compounds with a base or with an amino acid according to a method known per se.
  • bases which can be used, sodium hydroxide, potassium hydroxide, potassium or sodium carbonate and sodium or potassium bicarbonate can be mentioned, and amongst the amino acids, lysine for example.
  • a series of l-(2-alkoxy-5-carboxyphenyl) ⁇ r, ?-unsaturated ketones has been synthesised and tested.
  • ⁇ Ri represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms ;
  • R 2 and R 3 independently represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms ;
  • ⁇ X represents an -OH , -OR , -NH 2 , -NHR , or -NRR' group, in which R and R' independently represent a lower alkyl group having 1 to 6 carbon atoms, as well as its geometrical isomers, as well as their addition salts, particularly their pharmaceutically acceptable addition salts, incorporated in a pharmaceutically acceptable excipient, vehicle or carrier, exhibit significant antiproliferative activity and cytostatic activity in vitro in the Non Small Cancer Lung Cell (NSCLC) line L16 and its clones C15, C98, C92 and C65, further to their antifungal properties.
  • NSCLC Non Small Cancer Lung Cell
  • the compounds of formula (I) as defined above, their geometric isomers, as well as their addition salts, in particular their pharmaceutically addition salts, have a very valuable pharmacological profile in that they possess cytotoxic, cytostatic, antiproliferative and antifungal activity.
  • diseases of, inter alia, proliferative nature diseases of, inter alia, proliferative nature.
  • An example of their use which may be mentioned is the treatment of, on the one hand, benign cell proliferative diseases such as psoriasis, vaginal dryness, secondary cataracts, glaucoma, vitreo-retinal proliferation, for example, and, on the other hand, anarchic cell proliferative diseases such as cancers of the solid type, such as lung cancer, cancers of the liquid type, such as leukaemia in particular, for example.
  • benign cell proliferative diseases such as psoriasis, vaginal dryness, secondary cataracts, glaucoma, vitreo-retinal proliferation
  • anarchic cell proliferative diseases such as cancers of the solid type, such as lung cancer, cancers of the liquid type, such as leukaemia in particular, for example.
  • the invention also covers a pharmaceutical composition characterised in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined above (not including the disclaimer), a geometrical isomer thereof, or one of its pharmaceutically acceptable addition salts incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
  • compositions can be administered by the buccal, rectal, parenteral, transdermal, ocular, nasal or auricular route.
  • compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatine capsules, granules, suppositories, injectable preparations, transdermal systems, eye drops, aerosols and sprays, and ear drops. They are prepared by the customary methods.
  • the active principle which consists of a pharmaceutically effective amount of at least one compound of formula (I) as defined above, a geometrical isomer thereof, or one of its pharmaceutically acceptable addition salts can be incorporated therein together with excipients normally employed in pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavourings and colours.
  • the preferred pharmaceutical form is an injectable form.
  • the invention also covers a pharmaceutical composition with cytotoxic, cytostatic, anti-proliferative or antifungal activity which can be used especially as a favourable treatment of diseases such as psoriasis, vaginal dryness, secondary cataracts, glaucoma, vitreo-retinal proliferation, cancer of the solid type, such as lung cancer, cancer of the liquid type, such as leukaemia in particular, said composition being characterised in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) above, a geometrical isomer thereof, or one of its pharmaceutically acceptable addition salts incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
  • cytotoxic, cytostatic, anti-proliferative or antifungal activity which can be used especially as a favourable treatment of diseases such as psoriasis, vaginal dryness, secondary cataracts, glaucoma, vitreo-retinal proliferation, cancer of the solid type, such as lung cancer, cancer of the liquid type, such as leuk
  • the invention also covers a method of therapeutic treatment of mammals, characterised in that a therapeutically effective amount of at least one compound of formula (I) as defined above or one of its pharmaceutically acceptable addition salts is administered to the said mammal.
  • This method affords especially a favourable treatment of diseases of proliferative nature.
  • the compounds of formula (I) can be administered by themselves or in association with a physiologically acceptable excipient, in any form, in particular orally in the form of gelatine capsules or tablets, or parenterally in the form of injectable solutions. It is possible to envisage other forms of administration such as suppositories, ointments, creams, gels or aerosol preparations.
  • Step 1 Preparation of 3-acetyl-4-hydroxybenzoic acid.
  • Step 2 Preparation of 3-acetyl-4-methoxybenzoic acid methyl ester.
  • Step 3 Preparation of l-(2-methoxy-5-carboxymethyphenyl)-l-trimethyl- silyloxyethylene.
  • Step 4 Preparation of l-(2-methoxy-5-carboxymethylpheny ⁇ )-3-hydroxy-3- methyl-1-butanone.
  • Titanium tetrachloride (0.0183 moles, 2 ml) was added to ice-chilled methylene chloride (26 ml) followed by the dropwise addition of a solution of acetone (0.021 moles, 1.5 ml) in methylene chloride (5.5 ml).
  • a solution of 1 -(2-methoxy-5-carboxymethylphenyl)- 1 -trimethylsilyloxyethylene 0.0183 moles, 5.13 g
  • methylene chloride 2.5 ml
  • the reaction mixture was poured onto ice water with vigorous stirring and the organic layer was separated. The aqueous layer was extracted with methylene chloride.
  • Step 5 Preparation of methyl 3-(l'-oxo-3'-methyl-2'-butenyI)-4-methoxy- benzoate.
  • the compound of Example 1 exhibits cytostatic activity towards the bronchopulmonary human carcinoma (non-small cell lung) in vitro and in vivo.
  • the preliminary biological studies in vitro indicate that this cytostatic activity is due to the irreversible blocking of the Gl phase of the cell cycle.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés nouveaux à base de cétones insaturées 1-(2-alcoxy-5-carboxyphényl)-α,β représentés par la formule générale (I), ainsi que leurs isomères géométriques, leurs sels d'addition, en particulier les sels d'addition pharmaceutiques. L'invention concerne également des procédés relatifs à l'élaboration de ces composés et à leur application thérapeutique. Lesdits composés ont des propriétés cytotoxiques, cytostatiques, antiprolifératives et antifongiques.
PCT/EP1999/002835 1998-04-16 1999-04-16 CETONES INSATUREES 1-(2-ALCOXY-5-CARBOXYPHENYL)-α,β, ELABORATION, ET APPLICATION THERAPEUTIQUE WO1999054278A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR980100137 1998-04-16
GR98100137 1998-04-16

Publications (1)

Publication Number Publication Date
WO1999054278A1 true WO1999054278A1 (fr) 1999-10-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/002835 WO1999054278A1 (fr) 1998-04-16 1999-04-16 CETONES INSATUREES 1-(2-ALCOXY-5-CARBOXYPHENYL)-α,β, ELABORATION, ET APPLICATION THERAPEUTIQUE

Country Status (1)

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WO (1) WO1999054278A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044306A1 (fr) * 1996-05-17 1997-11-27 Kowa Co., Ltd. Derives de chalcone et medicaments les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044306A1 (fr) * 1996-05-17 1997-11-27 Kowa Co., Ltd. Derives de chalcone et medicaments les contenant
EP0902007A1 (fr) * 1996-05-17 1999-03-17 Kowa Co. Ltd. Derives de chalcone et medicaments les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 9804, Derwent World Patents Index; AN 98-041745, XP002085640 *

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