Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reissue Patent
1999-08-03
2001-02-27
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S077000
Reissue Patent
active
RE037078
ABSTRACT:
The present invention relates to new thiophene compounds.
It relates especially to compounds of formula I:
wherein
X
1
, X
2
, Y
1
and Y
2
, which are identical or different, each represents a hydrogen or halogen atom, an alkyl or alkoxy radical each having from 1 to 5 carbon atoms in straight or branched chain, or a trifluoromethyl radical;
X
1
and Y
1
, which are identical or different, each represents an alkoxy radical having
1
to
5
carbon atoms in straight or branched chain,
X
2
and Y
2
each represents hydrogen,
R
1
represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms in straight or branched chain;
A represents a straight hydrocarbon chain having from 1 to 5 carbon atoms each of which carbon atoms is optionally mono- or di-substituted by an alkyl radical having from 1 to 5 carbon atoms; and
R
2
represents a hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms in straight or branched chain, a cyclohexyl radical or a benzyl radical;
and their physiologically tolerable addition salts with appropriate bases.
The closest prior art to the present invention is illustrated especially by the PCT patent application 91/19708, which relates to compounds of formula:
having an anti-inflammatory activity, which reference neither describes nor suggests the compounds of formula I forming the subject of the present invention; the compounds of formula I have a pharmacological and therapeutic activity of particular value in the inflammation field.
The present invention relates also to a process for the preparation of compounds of formula I which is characterised in that:
the ester of formula II:
wherein X
1
, X
2
, Y
1
, Y
2
, R
1
and A are defined above and n represents 1 or 2 is hydrolysed
to form an acid of formula III:
wherein X
1
, X
2
, Y
1
, Y
2
, R
1
and A are as defined above.
which acid is converted into a corresponding activated compound of formula IV:
wherein
X
1
, X
2
, Y
1
, Y
2
, R
1
and A are as defined above, and
Z represents a chlorine atom or an imidazol-1-yl radical,
with which the O-silylated hydroxylamine of formula V:
wherein R
2
is as defined above is reacted
to obtain the compound of formula VI:
wherein X
1
, X
2
, Y
1
, Y
2
, A, R
1
and R
2
are as defined above,
which is hydrolysed to obtain the corresponding compound of formula I.
The hydrolysis of the ester of formula II is expediently carried out by means of sodium hydroxide in aqueous alcohol medium.
The conversion of the acid of formula III into an activated compound of formula IV is advantageously carried out either in a chloroform medium, by means of oxalyl chloride, to obtain compounds of formula IV wherein Z represents a chlorine atom, or in a dichloromethane medium, by means of carbonyldiimidazole, to obtain the compounds of formula IV wherein Z represents an imidazol-1-yl radical.
The reaction of the compounds IV and V to yield compounds of formula VI is carried out especially expediently by operating in an appropriate solvent, such as, for example:
acetonitrile, in the presence of dimethylaminopyridine and triethylamine in the case where, in the formula of the compound IV used, Z represents a chlorine atom, and
dichloromethane in the case where, in the formula of the compound IV used, Z represents an imidazol-1-yl radical.
The hydrolysis of the compound of formula VI to obtain a compound of formula I is advantageously carried out by operating in a mixture of dichloromethane and trifluoroacetic acid.
The ester of formula II, used as starting material, was prepared in accordance with the following reaction scheme:
it being understood that in that scheme:
Ar
1
represents:
Ar
2
represents:
PPA=polyphosphoric acid,
DMF=dimethylformamide,
Et=—C
2
H
5
,
Me=—CH
3
,
n=1 or 2,
R
1
and A are as defined for formula I, and
A is such that A=—HA′—
The compounds of formula I may be converted into physiologically tolerable addition salts with appropriate bases. Prepared according to conventional methods, as described in the Examples hereinafter, those salts, as such, form part of the present invention.
The compounds of the present invention have valuable pharmacological and therapeutic properties especially in the inflammation field.
During the course of inflammation, arachidonic acid, released from the phospholipids of the cellular membrane by phospholipase A2, is rapidly metabolised by two main enzymatic pathways: that of cyclooxygenase, which leads to the formation of prostaglandins, and that of lipoxygenase, which leads to the formation of leukotriene. The prostaglandins, especially PGE
2
, play an important role in the vascular phenomena associated with inflammation as well as in inflammatory pain, while at the same time exerting a protective effect on the gastric mucosa. Two types of cyclooxygenases have been demonstrated recently: constitutive type 1 cyclooxygenase (COX1), which is found in the physiological state in various tissues of the stomach, and type 2 cyclooxygenase (COX2), which is induced during inflammatory processes. The leukotrienes—notably 5HETE and leukotrienes B4—powerful neutrophil chemoattractants, which are capable of increasing vascular permeability and have immunological properties, contribute to the progressive tissue destruction of immunoinflammatory diseases, such as rheumatoid polyarthritis; they furthermore appear to be implicated in gastric ulceration processes. The inhibition of cyclooxygenase by non-steroidal anti-inflammatories (NSAI) is responsible for their beneficial effect on the symptoms of the initial phase of inflammation, but it also has the undesirable effects that belong to that class of medicaments, especially in respect of the gastrointestinal mucosa. Those NSAIs have no effect on the progression of the tissue destruction associated with leukocyte migration.
The compounds of the present invention inhibit both the enzymatic pathway of cyclooxygenase and that of lipoxygenase. In addition, they exert a preferential inhibition of COX2 compared with COX1. That particular profile gives them powerful anti-inflammatory effects, which act in particular on the symptoms of chronicity, and an improved gastrointestinal tolerance compared with conventional NSAIs.
The compounds of the invention also prove to be powerful anti-inflammatory agents capable of inhibiting both the early vascular phase and the chronic tissue destruction phase associated with inflammation.
Their therapeutic effect will therefore be effective in rheumatological inflammation of an acute or chronic nature, such as, for example, rheumatoid polyarthritis and ankylosing spondylitis, and in inflammation of the intestinal type (Crohn's disease) or of the cutaneous type (psoriasis) in which leukotrienes are found to be implicated.
The present invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula I or a physiologically tolerable salt thereof, mixed with or in association with an appropriate pharmaceutical excipient, such as, for example, glucose, starch, talc, ethylcellulose, magnesium stearate, cocoa butter or distilled water.
The so-obtained pharmaceutical compositions are generally presented in a dosage form, which may contain from 10 to 300 mg of active ingredient; they may, for example, take the form of tablets, dragées, gelatin capsules, suppositories, injectable or drinkable solutions or ointments and, depending on the case in question, may be administered by the oral, rectal, parenteral or local route.
The dosage may vary in accordance with the age and weight of the patient, the route of administration, the nature of the disorder and associated treatments.
By way of example, the dosage by the oral route may range from 10 to 300 mg of active ingredient per day.
The following Examples illustrate the invention. Unless specified to the contrary, the melting points are determined using a Kofler hot plate.
REFERENCES:
patent: 5571810 (1996-11-01), Matsuo et al.
Bonnet Jacqueline
Sauveur Frederic
Tordjman Charles
Wierzbicki Michel
Adir et Compagnie
Lambkin Deborah C.
The firm of Gordon W. Hueschen
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