CA2005759A1 - N-aryl-azetidinones, their preparation process and their use as elastase inhibitors - Google Patents
N-aryl-azetidinones, their preparation process and their use as elastase inhibitorsInfo
- Publication number
- CA2005759A1 CA2005759A1 CA002005759A CA2005759A CA2005759A1 CA 2005759 A1 CA2005759 A1 CA 2005759A1 CA 002005759 A CA002005759 A CA 002005759A CA 2005759 A CA2005759 A CA 2005759A CA 2005759 A1 CA2005759 A1 CA 2005759A1
- Authority
- CA
- Canada
- Prior art keywords
- aryl
- formula
- azetidinone
- radical
- alkyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
Abstract
DESCRIPTIVE ABSTRACT
The invention relates to N-aryl-azetidinones, their preparation process and their use as active serine elastase inhibitors.
The N-aryl-azetidinones are in accordance with formula:
(I) in which R1 and R2 can be a halogen atom or an organic radical, R3 represents a halogen atom or another good starting group and R4 represents H or an organic radical.
The compounds with R3=C1 or OSO2CH3, R4=H and Rl=R2=F or R1=F
and R2=Br are irreversible and selective elastase inhibitors,
The invention relates to N-aryl-azetidinones, their preparation process and their use as active serine elastase inhibitors.
The N-aryl-azetidinones are in accordance with formula:
(I) in which R1 and R2 can be a halogen atom or an organic radical, R3 represents a halogen atom or another good starting group and R4 represents H or an organic radical.
The compounds with R3=C1 or OSO2CH3, R4=H and Rl=R2=F or R1=F
and R2=Br are irreversible and selective elastase inhibitors,
Description
;
.
N-ar~l-azetidinones, their preParation process and their use as elastase inhibltors.
The present invention relates to novel-aryl-azetidinones, their -- preparation process and their use as active serine elastase inhibitors.
It more specifically relates to N-aryl-azetidinones function-alized by appropriate substituents giving them selectivity prop-erties with respect to elastases, particularly leucocytic elast-aqe and pancreatic elastase and giving them the capacity to inhibit these elastases in an irreversible manner.
The non-equilibrium between the concentrations of the elastases and their natural macromolecular inhibitors leads to numerous pathological processes.
Thus, the increased deteriorstion of the elastin of the con~-unctive tissue and cartilages by leucocytic elastase i8 illYOlVed in pulmonary emphysema, rheumatoid arthritis, various other inflammator~ processes and in cutaneous ageing.
In addition, research has been carried out to find irreversible synthetic inhibitors for leucoc~tic elastase able to remedy the deficiency or ineffectivene~s of natural inhibitors and which would therefore have great interest in therapy. Synthetic inhibitors of this type are described by W.C. Groutas in Med.
Res. Review, 1987, 7, No. 2, pp. 227-241 and by Trainor in Trends in Pharmacological Sciences, August 1987, Vol. 8, No. 8, pp.
303-307.
These inhibitors include modified cephalosporins, ~hich are able to inhibit human leucocytic elastase, as iq described by Doherty et al in Nature, Vol. 322, 1986, pp. 192-194 and by Navia et al in Nature, Vol. 327, 1987, pp. 79-82.
20(~S9 mese cephalosporins are in accordance with the following formula:
.
( )n 5 y ~ S ~
.~L N~OAC
z in which X can be an atom of hydrogen, fluorine or chlorine or other radicals, such as alkoxy, aryl, CH3CONH, CF3CONH or HCONH radicals, Y can be an atom of hydrogen or other organic radical~ and Z is a carboxyl, ester or amide radical or a hydr-ogen atom.
Zrihen et al in Eur. J. Med. Chem. - Chim. Ther., 1983, 18, No. 4, pp. 307-314 describe a possible mechsnism for the irrev- -ersible deactivation of g-lactamases by functionalized-N-aryl-azetidinones. However, the results of Table 1 show that the halomethylate~ derivatives of N-aryl-azetidinones having a latent electrophilic function are not irreversible inhibitors, but competitive inhibitors of said enzymes.
Subsequent research carried out on certain activated N-sryl-azetidinones demonstrated that these compounds could also be competitive inhibitors of ~-lactamases, as is described by Joyeau et al in Journal of Medicinal Chemistry, 1988, Vol. 31, No.
.
N-ar~l-azetidinones, their preParation process and their use as elastase inhibltors.
The present invention relates to novel-aryl-azetidinones, their -- preparation process and their use as active serine elastase inhibitors.
It more specifically relates to N-aryl-azetidinones function-alized by appropriate substituents giving them selectivity prop-erties with respect to elastases, particularly leucocytic elast-aqe and pancreatic elastase and giving them the capacity to inhibit these elastases in an irreversible manner.
The non-equilibrium between the concentrations of the elastases and their natural macromolecular inhibitors leads to numerous pathological processes.
Thus, the increased deteriorstion of the elastin of the con~-unctive tissue and cartilages by leucocytic elastase i8 illYOlVed in pulmonary emphysema, rheumatoid arthritis, various other inflammator~ processes and in cutaneous ageing.
In addition, research has been carried out to find irreversible synthetic inhibitors for leucoc~tic elastase able to remedy the deficiency or ineffectivene~s of natural inhibitors and which would therefore have great interest in therapy. Synthetic inhibitors of this type are described by W.C. Groutas in Med.
Res. Review, 1987, 7, No. 2, pp. 227-241 and by Trainor in Trends in Pharmacological Sciences, August 1987, Vol. 8, No. 8, pp.
303-307.
These inhibitors include modified cephalosporins, ~hich are able to inhibit human leucocytic elastase, as iq described by Doherty et al in Nature, Vol. 322, 1986, pp. 192-194 and by Navia et al in Nature, Vol. 327, 1987, pp. 79-82.
20(~S9 mese cephalosporins are in accordance with the following formula:
.
( )n 5 y ~ S ~
.~L N~OAC
z in which X can be an atom of hydrogen, fluorine or chlorine or other radicals, such as alkoxy, aryl, CH3CONH, CF3CONH or HCONH radicals, Y can be an atom of hydrogen or other organic radical~ and Z is a carboxyl, ester or amide radical or a hydr-ogen atom.
Zrihen et al in Eur. J. Med. Chem. - Chim. Ther., 1983, 18, No. 4, pp. 307-314 describe a possible mechsnism for the irrev- -ersible deactivation of g-lactamases by functionalized-N-aryl-azetidinones. However, the results of Table 1 show that the halomethylate~ derivatives of N-aryl-azetidinones having a latent electrophilic function are not irreversible inhibitors, but competitive inhibitors of said enzymes.
Subsequent research carried out on certain activated N-sryl-azetidinones demonstrated that these compounds could also be competitive inhibitors of ~-lactamases, as is described by Joyeau et al in Journal of Medicinal Chemistry, 1988, Vol. 31, No.
2, pp. 370_374.
The latter N-aryl-azetidinones are in accordance with the formula:
.
;20()5759 x2 x1 ~ C~3 o~ ~
OOH
In which Xl and X2 can represent Br and H, Br and F, F and H
or F and F.
These compounds hsve an affinity for beta-lactamase, but they are not substrates of this enzyme.
The present invention relates to novel substituted N-aryl-aze-tidinones, which have the property of being irreversible inhib-itors of sctive serine elastaseq, such as leucocytic elastase and pancreatic ela~tase.
According to the invention the N-aryl-azetidinones according to the formuls:
.
Rl R2 --h CH2R3 ~ N~ (I) in which Rl and R2, which can be the qame or different, represent an atom of F, Br, Cl or I, or a radical of formula CF3, CooR5, CN, CoNHR5 or CoR5 with R5 representing an alkyl or aryl radical, R represents a fluorine, chlorine, bromine or iodine a;om, or a radical of formula OC(O)R6, OS02R6, OP(O)R62 or S R62 with R representing an alkyl, perfluoroalkyl or aryl radi-cal and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula CooR7, CoNHR7, N02, CF3, CN, So2R7, (CH2)noR7 and oR7 wlth R7 represe~ting a hydrogen atom or an alkyl or aryl radical and n being an inte8er between 1 and 18.
In the formula of the N-aryl-azetidinones according to the inven-tion, the choice of the substituents Rl, R2 and R3 makes it possible on the one hand to give the molecule a selectivity -relative to elastases compared with other proteases and on the other hand make it serve the function of the suicide inhibitor.
The action mechanism a~ the inhibitor probably corresponds to the unmasking of the latent electrophilic function and the sub-stitution by a nucleophilic residue present in the active centre, in accordance with the following diagram:
Rl R
I . E _ I .E ~R2 ~ ~R3 R2 ~ ~Ht R2 ~ ~ ~
OH OH O 0 ~ H~R3 ~ ~ O l3 ~ ~
Enzyme E 24 E ~ E~
Acyl-enzyme Acyl-enzyme Deactiva'~ enzyme Thus, in the acyl-enzyme, the aminobenzyl halide haq a good startin8 group, so that R3 is very reactive. The substitution by a nucleophilic residue Nu of the active centre of the enzyme takes place rapidly by a dissociative mechanism (elimination - addition) with as the intermediary a methylene quinonimine.
The inhibitor is retained in the active centre, as a result of the covalent connection, throughout the life of the acyl-enzyme. The alkylation of the residue Nu consequently leads to an irreversible inhibition of the elastase.
In this mechanism of the "suicide" type, the reactive function is latent and i9 only released during the catalytic process of the target enzyme within the active centre, which considerabl~
limits the possibilitr of reactions between the inhibitor and other compounds present on its path in vivo.
In order that the N-aryl-azetidinones in question can serve as a suicide inhibitor, it is necessary for the -C~2R3 substit-uent to be in the ortho or para position relative to N. Prefer-ably the -CH2R3 sub~tituent i8 in the ortho position relative to N.
Although R4 can represent several substituents, good results can be obtained when using a hydrogen atom for R4.
The substituents R3 used in the invention are chosen so as to constitute good starting groups favouring the substitution mech-anism by a nucleophilic residue. Good results are obtained when R represents Cl or OS02CH3.
When the N-aryl-azetidinones according to the invention are not used as elastase inhibitors, R3 can represent a fluorine atom. Such N-aryl-azetidinones can in particular be used as elastase substrates.
;~ 7S9 In the lnvention, Rl and R2 are chosen 80 as to give the N-aryl-azetidinone a selectivity with respect to the elastases to be inhibited. For example, when the elastase is leucocytic or pancreatic elastase, Rl and R2 can both represent a fluorine atom or Rl can represent a fluorine atom and R2 a bromine atom.
In the invention, the alkyl or perfluoroalkyl radicals used for R5 and R6 can be strai8ht or branched radicals and generally have 1 to 18 carbon atoms.
When R5 or R6 represents an aryl radical, the latter can have 6 to 14 carbon atoms. As an example of such radicals, reference can be made to phenyl and naphthyl radicalQ.
When in the invention R4 or R7 represents an alkyl radical, the latter can be straight or branched. In general, use is made of an alkyl radical with 1 to 18 carbon atoms. When R7 represents an aryl radical, it is pos~ible to use the aryl radi-cals deQcribed hereinbefore.
The N-aryl-azetidinones of the invention complying with formula (I) can be prepared by conventional processes. For example, it is firstly possible to prepare a N-aryl-azetidinone of formula:
R1 -~
R2~ CH20H
~ N~ (Il) in which Rl, R2 and R4 have the meanin8s given hereinbefore, in order to transform said N-aryl-azetidinone of formula tII) into N-aryl-azetidinone of formula (I) by reaction with an appropriate rea8ent chosen as a function of the R3 group to be introduced.
The N-aryl-azetidinone of formula (II) can be prepared:
a) by reacting a p-halogenopropanoyl halide of formula:
5XlOC-C(RlR2)-CH2X2 (III) in which Xl represents F, Cl, Br or I, x2 represents Cl, Br or I and Rl and R2 have the meanings given hereinbefore, with a silyloxymethylaniline of formula:
. . ~
10H2H ~ CH20Sl(CH
~ CH3 3 to obtain a halopropionanilide of formula:
R2-C-CH2X2 ~~ ~
0 NH ~ CH20Si(CH3)2 ~V) ~ c~cH3)3 and then b) by forming a N~aryl-azetidinone of formula:
200~59 .
Rl R2_ 1 CH2 ¦ CH~0S;(CH3)2 CtCH3?3 ~VI) by ehe cyclization of said halopropionanillde of formula (V) and c) transforming said N-aryl-azetidinone of formula (VI) into N-aryl-azetidinone of formula (II) by reacting with a mix-ture of hydrofluoric scid and water.
As has been shown hereinbefore, the reagent for transforming the N-aryl-azetidinone of formula ~II) into N-aryl-~zetidinone of formula (I) is dependent on the substituent R to be introd-uced. When R represents Cl, the reagent used can be SOC12.When R3 represents F, the rea8ent used can be diethylamino sulphur trifluoride. When R3 represents Br or I, the reagent used can be PBr3, SOBr2, R3SiX(X~Br or I and R~alkyl), ~3P+I2+
imidazole.
When R3 representq OC(O)R6, OS02R6 or OPOR62, it is possible to use as the reagents the chlorides or anhydrides of the corr-esponding acids. For example, for introducing a- substituent R3 of formula OS02R6, it is possible to use 8S the reagent ClS02R -When R3 represents S+R62 the reagent used can be that of the corresponding halogenated deri~ative with a dialkyl sulphide.
g The starting rea8ents used for the preparation of N-aryl-aze-tidinones are commercially available products, or can be prep-ared by standard processes.
For exa~ple, the beta-bromopropanoyl halides of formula (III) can be prepared from esters of formula BrCH2COC02C2H5 by fluor-ination and/or chlorination reactions. They are described in J. Med. Chem. 1988, 31, p.370 in the csse where X is Cl and Rl and R2 are F. In the case where X is Br and Rl and R2 are respectively Br and F, it is possible to use the process desc-ribed by Molines et al in Synthesis, 1985, p.755.
The silyloxymethylanilines of formula (IV) can be prepared fromthe co~responding aminobenzyl alcohols by reacting with a silyl halide in the presence of imidazole.
The N-aryl-azetidinones of formula (I) in which R3 i8 a bromine atom and R4 represents a hydrogen atom or a radical chosen from among the radicals of formula CooR7, CoNHR7, N02, CF3, CN and S02R with R representing a hydrogen atom or an alkyl or aryl radical and n being an inte8er between 1 and 18 can also be prepared by a process consisting of reacting a N-aryl-azetidinone of formula:
.. . . . _ ~2 _ ~ ~ C~ 3 (V~l~
in which Rl, R2 and R4 have the mean~ngs given hereinbefore with N-bromosuccinimide.
Z005~759 The N-aryl-azetldlnone of formuls (VII) used in the process csn be prepsred by a process ldentical to that used for N-aryl-azetidinone of formula tVI) by reactlng a ~-halogenopropanoyl halide accordlng to formula (III) with a toluidine of formula:
H2 ~ ~ R4 in which R has the meaning gi~en hereinbefore.
As has been shown hereinbefore, the N-aryl-azetidinones according to the invention csn be used in phsrmaceutical compositions as elastase inhibitors.
The present invention also relates to a pharmaceutical comp-osition incorporating an elaetase inhibitor, characterized in that said elasta4e inhibitor is a N-aryl-azetidinones according to the formula:
.
R~
R2 1 ----' ~ H~ (I) in which Rl and R2, which can be the same or different, repre~ent an atom of F, Br, Cl or I, or a radical of formula CF3, ;~005~'~9 CooR5, CN, CoNHR5 or CoR5 with R5 representing an alkyl or ar~Yl radical, R represents a fluorine, chlorlne, bromine or iodine atom, or a radical of formula OC(O)R6, OS02R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoroalkyl or aryl radi-cal and R4 represents a hvdrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula CooR7, coNHR7, N02, CF3, CN, So2R7, (CH2)noR7 and oR7 with R7 representing a hydrogen atom or an alk~l or aryl radical and n being an integer between 1 and 18.
mese pharmaceutical compo~itions can be in the form of solu-tions, suspensions, powders or solubili~able granules, syrups or elixirs, auricular, nasal or ophthalmic drops, tablets, gel-atin-coated pills, aerosols, ointments, transdersal applications or suppositories, in dosed presentations containing non-tosic supports, ad~uYants and excipients. The in~ections can e.g. be intra~enous, intramuscular, subcutaneous, intradermal, intra-sternsl or intra-articular. It is also possible to use infusion or inst~llation methods ~e.g. intratracheal).
In order to more particularl~ target the pulmonar~ ti~sue, solu-tions containing albumin microspheres to which N-arYl-azetidinones are covalently connected can be produced.
The preparations for oral use can contain one or more sugaring, aromatizing and pre~erYing agents. Tablets contain the acti~e molecule of N-aryl-azetidinone mixed with non-toxic excipients, which are acceptable from the pharmaceutical standpoint. Examples of excipients are inert diluents, such as calcium or sodium car-bonate, calcium or sodium phosphate and lactose; agents permitting ;::005~759 the granulation and disintegration, e.g. corn starch; fi%in8 agents, e.g. gelatin and starch; and lubricating agents, e.g.
talc or magnesium stearate. The tablets may be coated or not (e.g. with the aid of glycerol monostearate or distearate) ln order to delay their disintegration and absorption.
me gelatin-coated pills can have a hard gelatin capsule cont-aining the active molecule mixed with an inert solid (e.g. cal-cium carbonate or kaolin), or a soft gelatin capsule in which the N-aryl-azetidinone is mixed with water or fatty sub~tances (e.g. liquid paraffin).
Aerosols of three types can in particular be envisaged: (a) aqueous aerosols (administered with the aid of atomizer~) for which a better solubilization of the N-aryl-azetidinones can be obtained by adding a cosolvent or by forming micelle3; (b) pressurized aerosols hsving e.g. as vector gases chlorinated and fluorinated hydrocarbons of different formulas (or their substitutes) in which the N-ar~l-azetidinones can be dissol~ed or suspended; and (c) powder aerosols with N-aryl-azetidinones in fine particles in e.g. a gelatin capsule.
Aqueous suspensions containing N-aryl-azetidlnones and approp-riate excipients, with optionally one or more preservatives (e.g. ethyl p-hydroxybenzoate), colouring agents, sugared agents and aromatizing agents can be produced. Among the excipients reference can be made to suspending agents (e.g. methyl cellu-lose, acacia gum), dispersing and wetting agents, e.g. naturalphosphatides (e.g. lecithin) or products for condensing ethylene oxide with ~arious partial esters of fatty acids or aliphatic alcohols. Oily suspensions of the acti~e molecule can be prep-ared by using a ~egetable oil (e.g. oli~e oil) or a mineral oil (e.g. liquid paraffin), optionally in the presence of ~ugaring and aromatizing agents, like those given in exemplified manner hereinbefore, together with preser~atiYes (in particular an Z0057~9 antioxidant).
Syrups and elixlrs could contain sugaring agents (e.g. sucro~e or sorbitol), one or more preservati~es and also aromatizing agents. Granules or powders which can be suspended in water can be obtained by mixing N-aryl-azetidinones with a wetting or dispersing agent, one or more preser~ati~es and various exci-pients. Emulsions of N-aryl-azetidinones in water can be prod-uced by using a mineral or ~egetable oil and ~arious emulsifying agents, such as e.g. natural gums, natural phosphatides and ~arious esterified fatty acids.
The N-aryl-azetidinones can also be in the form of sterile in~e-ctable, aqueous or oily suspensions using suspending or wetting agents of the types described hereinbefore. The solvents~ dilu-ent~ or excipients can e.g. be 1,3-butane diol, an isotonic solution of sodium chloride, water, etc. Suppositories cont-aining the acti~e principle can be prepared with con~entional excipients such as pol~eth~lene gl~col or e.g. cacao butter.
For local uses, it is possible to prepare ointments, crears, ~ellies, suspensions, solutions, etc. containing the active principle.
Doses of 0.1 to 40 mg/kg of bod~ weight/da~ can be appropriate.
~owe~er, the dose for a given patient can depend on a certain number of factors, such as e.g. the effectiveness of the N-ar~l-azetidinone in question, the age, weight, administration method, diet, medicamentus interactions and the seriousness of the ill-ness.
These compositions can be used in particular for the treatment of acute or chronic inflammatory processes and degenerati~e processes, no matter which organ is in~olved, such as pul~onary emphysema, bronchial inflammation, rheumatoid arthritis, infect-ious arthritis, rheumatic fe~er, cutaneous ageing, periodontitis, 2005~759 gingivitis, arterial sclerosis, glomerulonephritis, respiratory distress syndrome, septic shock, Crohn's disease, gout, pancreatis and similar illnesses.
Other characteristics and advantages of the invention can be better gathered from the following examples.
Examples 1 to 7.
These examples disclose the preparation of 3 N-aryl azetidinones of the invention according to the following reaction diagrams :
CH
osi ~ C (tN3) 3 f 0~ F 1l~
H2N ~ 0 ~1 \ tH3 f tH~ ~ tH3 f ~ r oSi_ t(CH~)3 f . H(compound 2~) ~ c~ _ r ~ r 20 (compound 3~) ( compound /f ~ t F ~ tl ~p r' ' ~ SO2~
( compOund 5b) (compound Se (compound 5a) ' ~ r~' /
( compound Sd) Example 1: PreParation of N-ttert-2,butYldlmethYlsilylox~meth~l-phen~l) 2,2-difluoro-3-bromopropionamide (comPound 2a).
For this synthesis use i9 made of tert butyl 2-dimethylsilyl-oxymethyl-aniline prepared according to the method described by G. Ju3t and R. Zamboni in Canad. J. Chem., 1978, 5b, p.2720 and 3-bromo-2,2-difluoropropanoyl chloride prepared by the proc-ess described by Joyeau et al in Journal of Medicinal Chemistr~, 1988, Vol. 319 No. 2, pp. 372-373.
Dropwise addition takes place at 4C to a solution of 3-bromo-2,2-difluoropropanoyl chloride (1.1 eq) in dry toluene (2 ml/
mmole) of an equimolar mixture of triethylamine and tert butyl-2-dimethylsilyloxymethyl aniline dissolved in toluene (1 ml/
mmole). The temperature is maintained at 15 to 20C for 35 minutes. The reaction mi~ture is taken up with ether, washed with a saturated aqueous Na~C03 solution and then by a 3aturated aqueous NaCl solution to neutrality. The organic phase is dried on MgS04 and i9 evaporated.
me residue obtained is purlfied by flash chromatography using an ether/pentane mixture with a ~olume ratio of 1:6. mis gi~es 560 mg of N-(tert-2,butyldimethylsilylo~ymethyl-phen~l) 2,2-difluoro-3-bromopropionamide, which corresponds to a 68% yield.
me prod~ct obtained has the following characteristics:
Melting point : 36.8C
Infrared analysis : IR(CH2C12~ : 3400 ; 1700 cm 1 '~005~59 Analysis by nuclear magnetlc resonance : lHMMR (CD3)2C0) :
0.17 ppm (6H, 8) ; 0.96 (9H, 8) ; 4.16 (2H, t, J~14.07Hz) ;
4.94 (2H, 8) ; 7.4 (3Harm, m) ; 8.07 (lH, NH).
~ 19FNMR S(CFC13) : - 105.6 ppm (2F, t, J~14.1Hz).
Elementary analysis :
foundcalculated C 47.28 47.06 H 5.94 5.92 N 3.37 3.43 10 m/z : 393-3g5 (M-14) ; (350-352) ; (230-228) ; 13~ ; 91 ; 77.
Example 2 : Preparation of N-(tert butyl-2-dimeth~lsil~loxymethyl phen~l)-3.3-difluoro-2-azetidinone (comPound 3a).
1.5 mmole of compound 2a obtained in example 1 are dissolYed in 9 El of a mixture of dimethyl formamide (DMF) and CH2C12 with a ~olume ratio of 1:6. The solution is then added over a period of 40 minutes and at -10C to a suspension of Na~
(60% dispersed in oil; 3.5 eq) in the same sol~ent ~i~ture of DMF and CH2C12 (9 ~1)-After stirring the reaction ~ixture for 35 to 45 d n., it is rapidl~ washed with an aqueous ~aturated a~monium chloride solu-tion to neutralit~. Drying takes place on MgS04 and evaporation takes place on the vane pump. The residue is then purified on a Florisil column using an ethane:pentane mixture (1:12).
Thic gi~es 303 mg of compound 3a in the form of a white solid corresponding to a 53% yield.
The product obtained has the following characteristics:
s9 melting point : 30.2C
Infrared analysis : IR(CH2C12) : 1775 cm 1 ~ Analysiq by nuclear magnetlc resonance : 1HNMR (CD3)2CO) :
0.13 ppm (6H, ~) 0.95 (9H, 8) ; 4.56 (2H, t, J-6.78Hz) ; 4.91 (2H, A); 7.46 (4H, arom, m).
FNMR - s(CFC13) : - 117 ppm (2F, t, J=6.50Hz).
m/z : 312 (M-15) ; 270 ; 162 ; 148 ; 117 ; 91 ; 77.
Example 3 : Preparation of N-(2-hYdroxYmethYl phenyl) 3.3-diflu-oro-2-azetidinone (compound 4a).
0.19 mmole of compound 3a is dissolved in 1 ml of acetonitrile and this ~olution i8 added dropwise to a 40~ H20/HF mixture corresponding to 3 eq. Stirring is maintained for 5 min. at ambient tempersture, followed by the neutralization of the excesQ
~F by a 5% aqueouq NaH003 solution.
The mixture iq then taken up in ether, the organic phase is rapidly washed with a ~aturated aqueous NaCl qolution, follo~ed by drying on MgS04 and e~aporation. Thi~ give~ compound 4a in the form of a colourles~ oil and having the following chara-cteristicq:
Infrared analysi~ : IR(CH2C12) : 3590-3490 (~ OH) ; 1768 (~CO) cm -Analysis by nuclear magnetic resonance : lHNMR (CD3)2GO) :
4.58 ppm (2H, t, J=6.84Hz) ; 4.76 (2H, m) ; 7.4 (2Harm, m) ;
7.62 (2 & rm, m) FNMR ~(CFC13) : - 112.66 (2F, t, J=6.7Hz).
Example 4 : Preparation of N-(2-chloromethyl phenyl)-3,3-diflu-oro-2-azetidinone (compound 5a).
;~n~
The rea8ent used in this case is the Vilsmaier re~ent and it is prepared by adding 200 yl of thion~l chloride ~JC12) to 1 ml of dr~ dimethyl formamide (DMF) at a temperature of 0 to 4C and whilst stirring for 5 min. This gives a SOC12/DMF
reagent. 53 ~1 of this reagent are then added dropwise to 0.11 mmole of compound 4a dissolved in the minimum of dr~ DMF. The mixture iq then stirred for 20 min. at ambient temperature and vacuum evaporation then takes place of the thionyl chloride.
This is followed by the elimination of the DMF with the vane pump. The residue obtained is purified on a silica gel prep-arative layer using an ether:pentane mixture with a volume ratio of 1:1.5. Thic gives 13 mg of compound 5a in the form of an oil corresponding to a 51% yield.
The characteristic~ of this compound are as follows:
IR(CH2C12) : 1780 cm (~ C0) HNMR (CD3)2C0) : 4.6 ppm (2H, t, J~6.88Hz) ; 4.97 (2H, 8) 7.63 (4Harm' m)-19FNMR - ~(CFC13) : - 112.8 (2F, t, J~6.7Hz).
Molecular ~eight for CloH8ClF2N0 fouDd : 231.0263 calculated : 231.02625.
m/z : 231-233 (M+-- isotopes Cl) ; 165-167 ; 132, 118, 92, 77.
EYample 5 : Preparation of N-(2-fluorometh~l phen~l)-3,3-diflu-oro-2-azetidinone (compound 5b).
An equimolar quantity of diethylamino sulphur trifluoride (DAST) i9 added to a solution of compound 4a in dry meth~lene chloride, at -78C and under a dry atmosphere. The reaction mixture is kept at -40C for 40 to 50 min. The end of the reaction i9 monitored on a silica film. After evaporating the solvent, the residue obtained is purified on a preparative layer using _ 19_ an ether:pentane mixture in a ratio of 1:1.5. This gives 11mg of compound 5b in the form of a colourless oil corresponding to a 41% yield.
The characteristics of this compound are as follovs:
IR (CH2C12) : (1780m (~C0) lHNMR (CD3)2C0) : 4.59 (2H, t, J~7.05Hz) ; 5.64 (2H, d, JHF-47.51 Hz) ; 7.59 (4~, m).
19FNMR - ~(CFC13) : - 112.6 ppm (2F, t, J~6.8 Hz) ; -205(1F, t, J~47.5H~) Molecular weight :
found : 215.0562 calculated : 215.05580 m/z : 215 (M+-) ; 151 ; 109.
ExamPle 6 : PreParation of N-(2-methane sulPhon~lo~ymethyl Phen~1)-3,3-difluoro-2-azetidinone (compound 5c).
0.17 mmole of compound 4a i9 dissol~ed ~n 0.8 ml of 2,6-1utidine at 0C, followed by the sddition of 0.18 m~ole of sulphonyl methane chloride to ~aid solution. After stirrin8 the reaction mixture for 90 min. at a temperature of 4 to 10C, the solution is taken up in 1 ml of ether and then washed twice with 0.5 ml of saturated aqueous NaCl ~olution.
The organic pha~e is dried on MgS04 and then evaporated. The oil obtained is purified on a silica preparati~e la~er using an ether:pentane mixture in a ratio of 1:1. This gi~es 19 mg of compound 5c corresponding to ~ 39% yield.
The compound has the following characteristic~:
IR (CH2C12) : 1780cm 1 (~C0) ; 1350 cm 1 HNMR (tCD3)2C0) : 3.95 (3H, 9) ; 4.6 (2H, t, J-6.31Hz) 4.95 (2H, 9); 7.6 (4N, m).
19FNMR (CFC13) : - 118 ppm (2F, t, J-6.4Hz).
Example 7 : Preparation of N-(2-bromometh~l phen~ 3.3-difluoro-2-szetidinone (comPound 5d).
60mg (0.28 mmole) of compound 4a are treated with 4 equi~slents (0.15 ml) of trimethylsilylbromide at ambient temperature for 35 min. The compound obtained is purified by silica gel plate chromatography using an ether:pentane mixture (1:6). Thi~ gi~es 16mg of compound 5d corresponding to a 25% yield.
This compound has the following characteristics:
IR : (CH2C12) : 1775 cm 1 IH NMR (CD3)2C0 : 7.37 ppm (4H, m) ; 4.72 (2H, 8); 4.47 (2H, t, J-6.7Hz).
19FNMR (/CFC13) : -115.6 ppm (t, J=6.6 Hz).
Precise ~eight: (obser~ed/calculated : 274.9760/274.97579).
m/z : 275-277 (M+ isotopes Br) ; 196(M-Br) ; 132 ; 91 ; 77.
Examp1es 8 to 12.
mese examples correspond to the following reaction diagrams:
'~VOS~59 tH3 ~ osi ~ C~CH3)3 f Br H2N ~ \ CH3 8r ~
0 8r.
F Br 8r ~
O ~ NH O ~ C(CH3)~
(compound 2b) f CH~
8r _ os1 _ CtCN3)3 F
( compound 3b) tcompound 4b) F F
8 r~ r c l B r ~1 ~ F
( compound S~) ( compound ~b) a. 9942 MDT
2005'759 - 22 ~
Example 8 : Preparation of N-(tert but~l 2-dimethylsil~loxy-methYl phenvl)-2,3-dibromo-2-fluoro pro~anamide (compound 2b~.
The same operating procedure as in example 1 i9 adopted for preparing compound 2b, except that 1.1 eq of 2,3-dibromo-2-fluoro S propanoyl bromide i8 u~ed in place of 1.1 eq of 3-bromo-2,2-difluoropropanoyl chloride. This gives 882mg of compound 2b corresponding to a yield of 63%.
The product has the following characteristics:
Melting point : 58.2C
10 IR(CH2C12) : 3290 ; 1695 cm 1 1HNMR (CD3)2CO) : 0.08 (6H, s) ; 0.87 (9H, s) ; 4.40 (lH, dd, J=11.49 ; 9.01Hz); 4.63 (lH, dd, J=11.52 ; 31.06 Hz) ; 7.3 (4H, m) ; 9.2 (lH, NH).
19FNMR ~(CFC13) : -118.6 ppm (ddd ; 30 ; 8Hz) Analysis :
ObservedCslculated C 41.20 40.95 H 5.08 5.16 N 2.98 2.98 20 m/z : 410-412-414 (M-57) ; 252 (M 2Br)130, 91, 77.
..
Example 9 : Preparation of N-(tert butyl-2-dimeth~lsil~loxy-methyl phenyl)-3-bromo-3-fluoro-2-azetidinone (compound 3b).
The operating procedure of example 2 is adopted for preparing compound 3b using 1.5 mmole of compound 2b in place of 1.5 mmole of compound 2a. Following purification on the ~ilica gel prep-arative layer using a mixture of ethylene acetate:pentane in a ratio of 1:10, 93 mg of compound 3b sre obtained in the form 2005~59 of an oil corresponding to a 41% yield.
The product obtained has the following characteristics:
IR(CH2C12) : 1770 cm 1 ;
lHNMR (CD3)2CO) : 0.14 ppm (6H, 9) : 0.95 (9H, s) ; 4-6 (1H~
dd ; J=7.21 (x2)Hz) ; 4.8 (lH, dd, J=7.36 ; 9.29Hz) ; 4.9 (2H;
sys (AB) ; J=13.93Hz) ; 7.35 (2Ham ; m) ; 7.6 (2Ha~ ; m).
19FNMR ~(CFC13) : - 120 ppm (dd ; J=7.52 (x2) Hz) Molecular weight for C16H23BrFN02Si found : 387.0640 calculated : 387.0666 m/z : 388 (M+- low) ; (373-375) (332-335) ; 132 ; 91.
Fxam~le 10 : Preparation of N-(2-hydrox~meth~l phen~l)-3-bromo-3-fluoro-2-azetidinone (comPound 4b).
The operating procedure of example 3 is adopted for preparing compound 4b using 0.19 mmole of compound 3b in place of 0.19 mmole of compound 3a. This gives 32mg of compound 4b in the form of a colourless oil and with a ~ield of 80~.
The product obtained has the following characteristics:
IR(CH2C12) : 3570 - 3460 (~OH) : 1765 (~CO)Cm 1 lHNMR (CD3)2CO) : 4.32 ppm (2H, t, J=5.26Hz) 4.47 (lH, dd, J=7.29 7.24Hz) ; 4.64 (lH, dd, J=7.27 ; 9.34Hz) 19FNMR- ~(CFC13) : - 122.33 (dd, J=7.7 ; 9.4 Hz) m/z : 273-275 (M+~(isotopes Br) : 216-194, 176, 149, 105, 118, 93, 77, 65.
- 24 ~
.
Example 11 : Preparation of N-(2-chlorometh~l phen~ 3-fluoro-3-bromo-2-azetidinone (comPound 5'a).
The operating procedure of example 4 is sdopted for preparing ~ compound 5'a using 0.11 mmole of compound 4b in place of 0.11 mmole of compound 4a. This gi~es 32mg of compound 5'a in the form of a colourless oil corresponding to a 75% yield.
The characteristics of the product obtained are as follows:
IR (CH2C12) : 1770 cm (~C0) lHNMR (CD3)2C0) : 4.47 ppm (lH, dd, J=7.32 ; 6.93Hz) 4.73 (lH, dd, J=7.23 ; 9.37Hz) ; 4.85 (2H, dd, sys (AB) ; J=12Hz) ; 7.4 (4Harm' m) 19FNMR - ~(CFC13) - 118.7 ppm / dd, J=7 : 9.2Hz) Molecular weight for ClOH8FClBrN0 found : 290.9411 calculated : 290.94624 m/z : 290 - 293 - 295 (M~ isotope Cl, Br) ; 216.167 ; 132.148.
Example 12 : Preparation of N-(2-fluoromethyl phen~l)-3-bromo-3-fluoro-2-azetidinone (compound 5'b).
The operating procedure of example 5 is used for preparing comp-ound 5'b using compound 4b in place of compound 4a. This giYes 12mg of compound 5'b in the form of a colourless oil and with a 64% yield.
The product obtained has the following characteristics:
IR (CH2C12) : 1770 cm 1 (~ C0) lHNMR (CD3)2C0) : 4.55 ppm (lH, dd; JAB=7.3 ; 7.17Hz) 4.76 (lH, dd, JAB = 7.3 ; 9.06Hz) ; 5.5 (2H, d, J=47.55Hz).
19FNMR ~(CFC13) : - 204.4 (lF, t, J=47.5Hz) ; - 118.4 (lF~ t, J=7.1 ; 9.23Hz).
2005~59 ~ 25 -Molecular weight:
found : 274.9763 calculated : 274.97579 m/z : (275-277) (M~-) ; 151 ; 123 ; 109 ; 96.
-Examples 13 to 18.
These examples relate to the preparation of N-ar~l-azetidinones according to the invention using the following reaction diagram:
200~759 F llr t H 3 f H2N --~ OSi / C~tH3)3 + ~_ S (compound 6) f llr fl--NH
7 ) ~ t H 3 ~compound F
osl ~ t(CH3)3 --~ tH3 (Compound 8 ) F
oD~ ~) O H ~/
2 5 ~ (compound 10a) (compound 9) `~ f 0/~ f compound 10b) . 9942 MDT
Example 13 : Preparation of tert but~l 4-dimethylsil~loxymethYl aniline (com~ound 6).
123mg (1 mmole) of 4-aminobenzyl alcohol are dissolved in 2ml of dry DMF and to the solution are added 180 mg (1.2 mmole) of tert butyl dimethylsilyl chloride, followed by 170 mg (2.5 mmole) of imidazole.
Stirring takes place for 40 min. at ambient temperature and then the DMF is evaporated with the vane pump. The residue is taken up in 10 ml of ether and the ethereal phase washed with 4x4 ml of water, followed by drying on MgS04 and evapora-tion. The oil obtained is purified by flash chromatog}aphy using an ether:pentane mixture in a volume ratio of 3:2. This gives 173 mg of compound 6 corresponding to a 73% yield.
The product obtained has the follo~ing characteristics:
IR (CH2C12) : 3430-3380 ; 2800 ; I610 ; 1510 ; 1100 cm 1 HNMR (CD3)2C0) : 0.05 pp~ (6H, s) ; 0.85 (9H, 9); 4-4 (2H, NH2 9 wide) ; 4.55 (2H, s) ; 6.35 (2H, d, J=8.8Hz) ; 6.95 (2H, d, Js8.7Hz).
Example 14 : Preparation of N-(tert but~l-4-dimeth~lsil~lox~-methYl phen~l)-2,2-difluoro-3-propionamide (compound 7).
The same operating procedure as in example 1 is used employing compound 6 is place of tert butyl-2-dimethyl3ilyloxymethyl aniline. This gives 230 mg of compound 7 corresponding to a 70% yield.
The characteristics of the product obtained are as follows:
Melting point : 57.3C
IR(CH2C12) 3400 ; 1700 cm 1 _28 _ lHNMR (CD3)C0) : 0.17 ppm (6H, s) ; 1 (9H, 9); 4.16 (2H, t, J~14.3Hz) ; 4,82 (2H, 9); 7.43 (2Ham; d ; J~8.58Hz) ; 7.8 (2H, d, J~8.53Hz).
19FNMR - ~(CFC13) : - 120.8 ppm (t; J314Hz) Molecular weight for C16H24F2BrN02Si :
found : 407.0729 calculated : 407.07283 Elementary analysis :
found calculated C 47.76 47.06 H 5.99 5.92 N 3.33 3.43 m/z : 407 (M+~) weak ; (352-350) isotopes Br ; (230-228) ; 106, 90.
Example 15 : Preparation of N-(tert butyl-4-dimethylsilyloxy-meth~l phen~l)-3,3-difluoro-2-azetidinone (compound 8).
The operating procedure of example 2 is adopted for preparing compound 8 using 1.5 mmole of compound 7 in place of 1.5 mmole of compound 2a. Following purification on a Florisil column using an ether:pentane mixture with a ~olume ratio of 1:6, 72mg of compound 8 are obtained corresponding to a 51~ yield. This compound is a white solid melting at 48C.
The product obtained has the following characteristics:
IR (CH2C12) : 1770 cm 1 lHNMR (CD3)2C0) : 0.2 ppm (6H, s) ; 1(9H, s) ; 4.49 (2H, t, J=6.42Hz) ; 4.87 (2H, s) ; 7.55 (4H, m).
19FNMR i(CFC13) : - 111.6 ppm (2F, t, J-6.4Hz).
200~759 Molecular weight :
found : 327.1471 calculated : 327.14661 m/z : 327 tM+-) : 312 ; 270 ; 196 ; 168.
E~ample 16 : PreParation of N-(4-hvdroxYmethYl phen~l)-3,3-difluoro-2-azetidinone (compound 9).
The operating procedure of example 3 iQ adopted for preparing compound 9 from compound 8 using 0.19 mmole of compound 8 in place of 0.19 mmole of compound 3a. 1`his gives 42mg of compound 9 in the form of a solid, which corresponds to an 82% yield.
The product obtained has the following characteristics:
Melting point : 124C
IR (CH2C12) : 3580-3490 (~OH) : 1768 (~CO) cml lHNMR (CD3)2CO) : 4.68 ppm (2H, d, J=5.7Hz) ; 4.45 (2H, t, J=6.32 Hz) ; 4.35 (lH, t, J=5.76Hz) ; 7.5 (4Ham ; 8) 19FNMR - ~(CFC13) : - 111.6 ppm (2F, t, J=6.4Hz) Molecular weight for CloHgF2N02 ; found : 213.0604 calculated : 213.06014 m/z : 213(M~-) ; 149 ; 106.
Example 17 : Preparation of N-(4-chlorometh~l phen~l)-3,3-difluoro-2-azetidinone (compound lOa).
The operating procedure of example 4 is followed for the prep-aration of compound 10a from compound 9 using 0.11 mmole of compound 9 in place of 0.11 mmole of compound 4a. This gi~eQ
16mg of compound lOa in the form of a white solid corresponding to a ~5~ yield.
ZO()5~59 The compound obtained has the following characteristics:
Melting point : 93C
IR (CH2C12) : 1770 cm 1 ( C0) lHNMR (CD3)2C0) : 4.48 (2H, t, J-6.53Hz) ; 4.79(2H, 9); 7.57 (4Harm, d ; J-8.6Hz).
19FNMR - (CFCl3) : - 111.5 ppm (2F, t, J=6.6Hz) Molecular weight for CloH8F2ClN0 found : 231.0260 calculated : 231.02625 m/z : 231-233 (M+~ isotope Cl) : 196 ; 167 ; 169 ; 168 ; 132 118 ; 90 ; 77.
Example 18 : Preparation of N-(4-fluorometh~l phenyl)-3.3-difluoro-2-azetidinone (compound lOb).
The operating procedure of example 5 i~ used for preparing comp-ound lOb from compound 9, the latter being used instead of com-pound 4a. This gives 16mg of compound lOb in the form of a solid corresponding to a 38% yield.
The product obtained has the following characteristics:
Melting point : 104C
IR (CH2C12) : 1770 cm 1 ( C0) lHNMR - (CD3)C0) : 4.49 ppm (2H, t, J=6.49Hz) ; 5.46 ~2H, d, J=48Hz) ; 7.58 (4H, s) l9FNMR (CFCl3) : - 111.5 ppm (2F, t, J=6.6Hz) ; - 200.39 (lF, t, J=48Hz) Molecular weight found : 215.0559 calculated : 215.05580 m/z : 215 (M+~) ; 151 ; 106 ; 109 B 9 9~ MDT
2005'~59 Examples 19 to 22.
These examples ;llustrate the preparation of N-aryl-azetidinones according to the in~ention using the following reaction diagram :
CH3 ~ ~
H2N ~ CH3 0 Cl Cl CH3 ' C p CH, ~ c~ ¦ c~ r Os~_ C~tH3)3 o\ r~ CtCH3)3 ~ H ~ ~ CN3 ~ ~ ~ tN3 ( Compound 2e) t compound 3e tl Cl.
~ ~~ 0~ ~
tCompound 4e) (compound 5e) ~. 9942 MDT
2005'7~9 Example 19 : Preparation of N(tert butYl-2-dimethYlsil~lox~-meth~l phenyl)-2,2,3-trichloro propionamide (comPound 2e).
For this synthesis, use iq made of tert butyl-2-dimethylsilyl-- oxymethyl aniline prepared according to the method describedby ~. Just and R. Zamboni in Canad. J. Chem. 1978, 5b, p.2720 and trichloropropanoyl chloride prepared in the following way.
Firstly 2,2,3-trichloropropionitrile is prepared by adding chlor-ine to ~ -chloroacrylonitrile, as described by H. Brintzinger et al in Angew. Chemie, 1948, 60, p.311 and then the 2,2,3-tri-chloropropionitrile undergoes acid hydrolysis with 60% H2S04 at 125C and for 5 hours in order to obtain the corresponding acid, as described by H. Laato in Suomen Kemistilehti, 1968, 41B, p.266. The acid is then treated by SOC12 in the presence of a catalytic quantity of DMF at 40 to 50C and for 1 hour, which gives 2,2,3-trichloropropanoyl chloride, which is distilled at 50C under 2700 Pa (20 mm of Hg), the yield being 66%.
This compuund has the following characteristics:
IR (CH2C12) : 1800 1770 cm 1 (intense band) lHNMR (CDC13) : 4.4 ppm (2H, s).
The same operating procedure as in example 1 is used for prep-aring N-(tert butyl-2-dimethylsilyloxymethyl phenyl)-2,2,3-trichloropropionamide from tert butyl-2-dimethylsilyloxymethyl aniline and 2,2,3-trichloropropanoyl chloride. This gi~es 814 mg of compound 2e corresponding to a 70% yield.
The compound has the following characteristics:
White solid : m.p. 41C ;
IR(CH2Cl2) ; 3300 ; 1690 ; 1585 cm 1 lHNMR : 10.25(1H,NH) ; 8,25(1H,d) ; 7.35(2H,m) ; 4.8(2H,s) ;
The latter N-aryl-azetidinones are in accordance with the formula:
.
;20()5759 x2 x1 ~ C~3 o~ ~
OOH
In which Xl and X2 can represent Br and H, Br and F, F and H
or F and F.
These compounds hsve an affinity for beta-lactamase, but they are not substrates of this enzyme.
The present invention relates to novel substituted N-aryl-aze-tidinones, which have the property of being irreversible inhib-itors of sctive serine elastaseq, such as leucocytic elastase and pancreatic ela~tase.
According to the invention the N-aryl-azetidinones according to the formuls:
.
Rl R2 --h CH2R3 ~ N~ (I) in which Rl and R2, which can be the qame or different, represent an atom of F, Br, Cl or I, or a radical of formula CF3, CooR5, CN, CoNHR5 or CoR5 with R5 representing an alkyl or aryl radical, R represents a fluorine, chlorine, bromine or iodine a;om, or a radical of formula OC(O)R6, OS02R6, OP(O)R62 or S R62 with R representing an alkyl, perfluoroalkyl or aryl radi-cal and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula CooR7, CoNHR7, N02, CF3, CN, So2R7, (CH2)noR7 and oR7 wlth R7 represe~ting a hydrogen atom or an alkyl or aryl radical and n being an inte8er between 1 and 18.
In the formula of the N-aryl-azetidinones according to the inven-tion, the choice of the substituents Rl, R2 and R3 makes it possible on the one hand to give the molecule a selectivity -relative to elastases compared with other proteases and on the other hand make it serve the function of the suicide inhibitor.
The action mechanism a~ the inhibitor probably corresponds to the unmasking of the latent electrophilic function and the sub-stitution by a nucleophilic residue present in the active centre, in accordance with the following diagram:
Rl R
I . E _ I .E ~R2 ~ ~R3 R2 ~ ~Ht R2 ~ ~ ~
OH OH O 0 ~ H~R3 ~ ~ O l3 ~ ~
Enzyme E 24 E ~ E~
Acyl-enzyme Acyl-enzyme Deactiva'~ enzyme Thus, in the acyl-enzyme, the aminobenzyl halide haq a good startin8 group, so that R3 is very reactive. The substitution by a nucleophilic residue Nu of the active centre of the enzyme takes place rapidly by a dissociative mechanism (elimination - addition) with as the intermediary a methylene quinonimine.
The inhibitor is retained in the active centre, as a result of the covalent connection, throughout the life of the acyl-enzyme. The alkylation of the residue Nu consequently leads to an irreversible inhibition of the elastase.
In this mechanism of the "suicide" type, the reactive function is latent and i9 only released during the catalytic process of the target enzyme within the active centre, which considerabl~
limits the possibilitr of reactions between the inhibitor and other compounds present on its path in vivo.
In order that the N-aryl-azetidinones in question can serve as a suicide inhibitor, it is necessary for the -C~2R3 substit-uent to be in the ortho or para position relative to N. Prefer-ably the -CH2R3 sub~tituent i8 in the ortho position relative to N.
Although R4 can represent several substituents, good results can be obtained when using a hydrogen atom for R4.
The substituents R3 used in the invention are chosen so as to constitute good starting groups favouring the substitution mech-anism by a nucleophilic residue. Good results are obtained when R represents Cl or OS02CH3.
When the N-aryl-azetidinones according to the invention are not used as elastase inhibitors, R3 can represent a fluorine atom. Such N-aryl-azetidinones can in particular be used as elastase substrates.
;~ 7S9 In the lnvention, Rl and R2 are chosen 80 as to give the N-aryl-azetidinone a selectivity with respect to the elastases to be inhibited. For example, when the elastase is leucocytic or pancreatic elastase, Rl and R2 can both represent a fluorine atom or Rl can represent a fluorine atom and R2 a bromine atom.
In the invention, the alkyl or perfluoroalkyl radicals used for R5 and R6 can be strai8ht or branched radicals and generally have 1 to 18 carbon atoms.
When R5 or R6 represents an aryl radical, the latter can have 6 to 14 carbon atoms. As an example of such radicals, reference can be made to phenyl and naphthyl radicalQ.
When in the invention R4 or R7 represents an alkyl radical, the latter can be straight or branched. In general, use is made of an alkyl radical with 1 to 18 carbon atoms. When R7 represents an aryl radical, it is pos~ible to use the aryl radi-cals deQcribed hereinbefore.
The N-aryl-azetidinones of the invention complying with formula (I) can be prepared by conventional processes. For example, it is firstly possible to prepare a N-aryl-azetidinone of formula:
R1 -~
R2~ CH20H
~ N~ (Il) in which Rl, R2 and R4 have the meanin8s given hereinbefore, in order to transform said N-aryl-azetidinone of formula tII) into N-aryl-azetidinone of formula (I) by reaction with an appropriate rea8ent chosen as a function of the R3 group to be introduced.
The N-aryl-azetidinone of formula (II) can be prepared:
a) by reacting a p-halogenopropanoyl halide of formula:
5XlOC-C(RlR2)-CH2X2 (III) in which Xl represents F, Cl, Br or I, x2 represents Cl, Br or I and Rl and R2 have the meanings given hereinbefore, with a silyloxymethylaniline of formula:
. . ~
10H2H ~ CH20Sl(CH
~ CH3 3 to obtain a halopropionanilide of formula:
R2-C-CH2X2 ~~ ~
0 NH ~ CH20Si(CH3)2 ~V) ~ c~cH3)3 and then b) by forming a N~aryl-azetidinone of formula:
200~59 .
Rl R2_ 1 CH2 ¦ CH~0S;(CH3)2 CtCH3?3 ~VI) by ehe cyclization of said halopropionanillde of formula (V) and c) transforming said N-aryl-azetidinone of formula (VI) into N-aryl-azetidinone of formula (II) by reacting with a mix-ture of hydrofluoric scid and water.
As has been shown hereinbefore, the reagent for transforming the N-aryl-azetidinone of formula ~II) into N-aryl-~zetidinone of formula (I) is dependent on the substituent R to be introd-uced. When R represents Cl, the reagent used can be SOC12.When R3 represents F, the rea8ent used can be diethylamino sulphur trifluoride. When R3 represents Br or I, the reagent used can be PBr3, SOBr2, R3SiX(X~Br or I and R~alkyl), ~3P+I2+
imidazole.
When R3 representq OC(O)R6, OS02R6 or OPOR62, it is possible to use as the reagents the chlorides or anhydrides of the corr-esponding acids. For example, for introducing a- substituent R3 of formula OS02R6, it is possible to use 8S the reagent ClS02R -When R3 represents S+R62 the reagent used can be that of the corresponding halogenated deri~ative with a dialkyl sulphide.
g The starting rea8ents used for the preparation of N-aryl-aze-tidinones are commercially available products, or can be prep-ared by standard processes.
For exa~ple, the beta-bromopropanoyl halides of formula (III) can be prepared from esters of formula BrCH2COC02C2H5 by fluor-ination and/or chlorination reactions. They are described in J. Med. Chem. 1988, 31, p.370 in the csse where X is Cl and Rl and R2 are F. In the case where X is Br and Rl and R2 are respectively Br and F, it is possible to use the process desc-ribed by Molines et al in Synthesis, 1985, p.755.
The silyloxymethylanilines of formula (IV) can be prepared fromthe co~responding aminobenzyl alcohols by reacting with a silyl halide in the presence of imidazole.
The N-aryl-azetidinones of formula (I) in which R3 i8 a bromine atom and R4 represents a hydrogen atom or a radical chosen from among the radicals of formula CooR7, CoNHR7, N02, CF3, CN and S02R with R representing a hydrogen atom or an alkyl or aryl radical and n being an inte8er between 1 and 18 can also be prepared by a process consisting of reacting a N-aryl-azetidinone of formula:
.. . . . _ ~2 _ ~ ~ C~ 3 (V~l~
in which Rl, R2 and R4 have the mean~ngs given hereinbefore with N-bromosuccinimide.
Z005~759 The N-aryl-azetldlnone of formuls (VII) used in the process csn be prepsred by a process ldentical to that used for N-aryl-azetidinone of formula tVI) by reactlng a ~-halogenopropanoyl halide accordlng to formula (III) with a toluidine of formula:
H2 ~ ~ R4 in which R has the meaning gi~en hereinbefore.
As has been shown hereinbefore, the N-aryl-azetidinones according to the invention csn be used in phsrmaceutical compositions as elastase inhibitors.
The present invention also relates to a pharmaceutical comp-osition incorporating an elaetase inhibitor, characterized in that said elasta4e inhibitor is a N-aryl-azetidinones according to the formula:
.
R~
R2 1 ----' ~ H~ (I) in which Rl and R2, which can be the same or different, repre~ent an atom of F, Br, Cl or I, or a radical of formula CF3, ;~005~'~9 CooR5, CN, CoNHR5 or CoR5 with R5 representing an alkyl or ar~Yl radical, R represents a fluorine, chlorlne, bromine or iodine atom, or a radical of formula OC(O)R6, OS02R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoroalkyl or aryl radi-cal and R4 represents a hvdrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula CooR7, coNHR7, N02, CF3, CN, So2R7, (CH2)noR7 and oR7 with R7 representing a hydrogen atom or an alk~l or aryl radical and n being an integer between 1 and 18.
mese pharmaceutical compo~itions can be in the form of solu-tions, suspensions, powders or solubili~able granules, syrups or elixirs, auricular, nasal or ophthalmic drops, tablets, gel-atin-coated pills, aerosols, ointments, transdersal applications or suppositories, in dosed presentations containing non-tosic supports, ad~uYants and excipients. The in~ections can e.g. be intra~enous, intramuscular, subcutaneous, intradermal, intra-sternsl or intra-articular. It is also possible to use infusion or inst~llation methods ~e.g. intratracheal).
In order to more particularl~ target the pulmonar~ ti~sue, solu-tions containing albumin microspheres to which N-arYl-azetidinones are covalently connected can be produced.
The preparations for oral use can contain one or more sugaring, aromatizing and pre~erYing agents. Tablets contain the acti~e molecule of N-aryl-azetidinone mixed with non-toxic excipients, which are acceptable from the pharmaceutical standpoint. Examples of excipients are inert diluents, such as calcium or sodium car-bonate, calcium or sodium phosphate and lactose; agents permitting ;::005~759 the granulation and disintegration, e.g. corn starch; fi%in8 agents, e.g. gelatin and starch; and lubricating agents, e.g.
talc or magnesium stearate. The tablets may be coated or not (e.g. with the aid of glycerol monostearate or distearate) ln order to delay their disintegration and absorption.
me gelatin-coated pills can have a hard gelatin capsule cont-aining the active molecule mixed with an inert solid (e.g. cal-cium carbonate or kaolin), or a soft gelatin capsule in which the N-aryl-azetidinone is mixed with water or fatty sub~tances (e.g. liquid paraffin).
Aerosols of three types can in particular be envisaged: (a) aqueous aerosols (administered with the aid of atomizer~) for which a better solubilization of the N-aryl-azetidinones can be obtained by adding a cosolvent or by forming micelle3; (b) pressurized aerosols hsving e.g. as vector gases chlorinated and fluorinated hydrocarbons of different formulas (or their substitutes) in which the N-ar~l-azetidinones can be dissol~ed or suspended; and (c) powder aerosols with N-aryl-azetidinones in fine particles in e.g. a gelatin capsule.
Aqueous suspensions containing N-aryl-azetidlnones and approp-riate excipients, with optionally one or more preservatives (e.g. ethyl p-hydroxybenzoate), colouring agents, sugared agents and aromatizing agents can be produced. Among the excipients reference can be made to suspending agents (e.g. methyl cellu-lose, acacia gum), dispersing and wetting agents, e.g. naturalphosphatides (e.g. lecithin) or products for condensing ethylene oxide with ~arious partial esters of fatty acids or aliphatic alcohols. Oily suspensions of the acti~e molecule can be prep-ared by using a ~egetable oil (e.g. oli~e oil) or a mineral oil (e.g. liquid paraffin), optionally in the presence of ~ugaring and aromatizing agents, like those given in exemplified manner hereinbefore, together with preser~atiYes (in particular an Z0057~9 antioxidant).
Syrups and elixlrs could contain sugaring agents (e.g. sucro~e or sorbitol), one or more preservati~es and also aromatizing agents. Granules or powders which can be suspended in water can be obtained by mixing N-aryl-azetidinones with a wetting or dispersing agent, one or more preser~ati~es and various exci-pients. Emulsions of N-aryl-azetidinones in water can be prod-uced by using a mineral or ~egetable oil and ~arious emulsifying agents, such as e.g. natural gums, natural phosphatides and ~arious esterified fatty acids.
The N-aryl-azetidinones can also be in the form of sterile in~e-ctable, aqueous or oily suspensions using suspending or wetting agents of the types described hereinbefore. The solvents~ dilu-ent~ or excipients can e.g. be 1,3-butane diol, an isotonic solution of sodium chloride, water, etc. Suppositories cont-aining the acti~e principle can be prepared with con~entional excipients such as pol~eth~lene gl~col or e.g. cacao butter.
For local uses, it is possible to prepare ointments, crears, ~ellies, suspensions, solutions, etc. containing the active principle.
Doses of 0.1 to 40 mg/kg of bod~ weight/da~ can be appropriate.
~owe~er, the dose for a given patient can depend on a certain number of factors, such as e.g. the effectiveness of the N-ar~l-azetidinone in question, the age, weight, administration method, diet, medicamentus interactions and the seriousness of the ill-ness.
These compositions can be used in particular for the treatment of acute or chronic inflammatory processes and degenerati~e processes, no matter which organ is in~olved, such as pul~onary emphysema, bronchial inflammation, rheumatoid arthritis, infect-ious arthritis, rheumatic fe~er, cutaneous ageing, periodontitis, 2005~759 gingivitis, arterial sclerosis, glomerulonephritis, respiratory distress syndrome, septic shock, Crohn's disease, gout, pancreatis and similar illnesses.
Other characteristics and advantages of the invention can be better gathered from the following examples.
Examples 1 to 7.
These examples disclose the preparation of 3 N-aryl azetidinones of the invention according to the following reaction diagrams :
CH
osi ~ C (tN3) 3 f 0~ F 1l~
H2N ~ 0 ~1 \ tH3 f tH~ ~ tH3 f ~ r oSi_ t(CH~)3 f . H(compound 2~) ~ c~ _ r ~ r 20 (compound 3~) ( compound /f ~ t F ~ tl ~p r' ' ~ SO2~
( compOund 5b) (compound Se (compound 5a) ' ~ r~' /
( compound Sd) Example 1: PreParation of N-ttert-2,butYldlmethYlsilylox~meth~l-phen~l) 2,2-difluoro-3-bromopropionamide (comPound 2a).
For this synthesis use i9 made of tert butyl 2-dimethylsilyl-oxymethyl-aniline prepared according to the method described by G. Ju3t and R. Zamboni in Canad. J. Chem., 1978, 5b, p.2720 and 3-bromo-2,2-difluoropropanoyl chloride prepared by the proc-ess described by Joyeau et al in Journal of Medicinal Chemistr~, 1988, Vol. 319 No. 2, pp. 372-373.
Dropwise addition takes place at 4C to a solution of 3-bromo-2,2-difluoropropanoyl chloride (1.1 eq) in dry toluene (2 ml/
mmole) of an equimolar mixture of triethylamine and tert butyl-2-dimethylsilyloxymethyl aniline dissolved in toluene (1 ml/
mmole). The temperature is maintained at 15 to 20C for 35 minutes. The reaction mi~ture is taken up with ether, washed with a saturated aqueous Na~C03 solution and then by a 3aturated aqueous NaCl solution to neutrality. The organic phase is dried on MgS04 and i9 evaporated.
me residue obtained is purlfied by flash chromatography using an ether/pentane mixture with a ~olume ratio of 1:6. mis gi~es 560 mg of N-(tert-2,butyldimethylsilylo~ymethyl-phen~l) 2,2-difluoro-3-bromopropionamide, which corresponds to a 68% yield.
me prod~ct obtained has the following characteristics:
Melting point : 36.8C
Infrared analysis : IR(CH2C12~ : 3400 ; 1700 cm 1 '~005~59 Analysis by nuclear magnetlc resonance : lHMMR (CD3)2C0) :
0.17 ppm (6H, 8) ; 0.96 (9H, 8) ; 4.16 (2H, t, J~14.07Hz) ;
4.94 (2H, 8) ; 7.4 (3Harm, m) ; 8.07 (lH, NH).
~ 19FNMR S(CFC13) : - 105.6 ppm (2F, t, J~14.1Hz).
Elementary analysis :
foundcalculated C 47.28 47.06 H 5.94 5.92 N 3.37 3.43 10 m/z : 393-3g5 (M-14) ; (350-352) ; (230-228) ; 13~ ; 91 ; 77.
Example 2 : Preparation of N-(tert butyl-2-dimeth~lsil~loxymethyl phen~l)-3.3-difluoro-2-azetidinone (comPound 3a).
1.5 mmole of compound 2a obtained in example 1 are dissolYed in 9 El of a mixture of dimethyl formamide (DMF) and CH2C12 with a ~olume ratio of 1:6. The solution is then added over a period of 40 minutes and at -10C to a suspension of Na~
(60% dispersed in oil; 3.5 eq) in the same sol~ent ~i~ture of DMF and CH2C12 (9 ~1)-After stirring the reaction ~ixture for 35 to 45 d n., it is rapidl~ washed with an aqueous ~aturated a~monium chloride solu-tion to neutralit~. Drying takes place on MgS04 and evaporation takes place on the vane pump. The residue is then purified on a Florisil column using an ethane:pentane mixture (1:12).
Thic gi~es 303 mg of compound 3a in the form of a white solid corresponding to a 53% yield.
The product obtained has the following characteristics:
s9 melting point : 30.2C
Infrared analysis : IR(CH2C12) : 1775 cm 1 ~ Analysiq by nuclear magnetlc resonance : 1HNMR (CD3)2CO) :
0.13 ppm (6H, ~) 0.95 (9H, 8) ; 4.56 (2H, t, J-6.78Hz) ; 4.91 (2H, A); 7.46 (4H, arom, m).
FNMR - s(CFC13) : - 117 ppm (2F, t, J=6.50Hz).
m/z : 312 (M-15) ; 270 ; 162 ; 148 ; 117 ; 91 ; 77.
Example 3 : Preparation of N-(2-hYdroxYmethYl phenyl) 3.3-diflu-oro-2-azetidinone (compound 4a).
0.19 mmole of compound 3a is dissolved in 1 ml of acetonitrile and this ~olution i8 added dropwise to a 40~ H20/HF mixture corresponding to 3 eq. Stirring is maintained for 5 min. at ambient tempersture, followed by the neutralization of the excesQ
~F by a 5% aqueouq NaH003 solution.
The mixture iq then taken up in ether, the organic phase is rapidly washed with a ~aturated aqueous NaCl qolution, follo~ed by drying on MgS04 and e~aporation. Thi~ give~ compound 4a in the form of a colourles~ oil and having the following chara-cteristicq:
Infrared analysi~ : IR(CH2C12) : 3590-3490 (~ OH) ; 1768 (~CO) cm -Analysis by nuclear magnetic resonance : lHNMR (CD3)2GO) :
4.58 ppm (2H, t, J=6.84Hz) ; 4.76 (2H, m) ; 7.4 (2Harm, m) ;
7.62 (2 & rm, m) FNMR ~(CFC13) : - 112.66 (2F, t, J=6.7Hz).
Example 4 : Preparation of N-(2-chloromethyl phenyl)-3,3-diflu-oro-2-azetidinone (compound 5a).
;~n~
The rea8ent used in this case is the Vilsmaier re~ent and it is prepared by adding 200 yl of thion~l chloride ~JC12) to 1 ml of dr~ dimethyl formamide (DMF) at a temperature of 0 to 4C and whilst stirring for 5 min. This gives a SOC12/DMF
reagent. 53 ~1 of this reagent are then added dropwise to 0.11 mmole of compound 4a dissolved in the minimum of dr~ DMF. The mixture iq then stirred for 20 min. at ambient temperature and vacuum evaporation then takes place of the thionyl chloride.
This is followed by the elimination of the DMF with the vane pump. The residue obtained is purified on a silica gel prep-arative layer using an ether:pentane mixture with a volume ratio of 1:1.5. Thic gives 13 mg of compound 5a in the form of an oil corresponding to a 51% yield.
The characteristic~ of this compound are as follows:
IR(CH2C12) : 1780 cm (~ C0) HNMR (CD3)2C0) : 4.6 ppm (2H, t, J~6.88Hz) ; 4.97 (2H, 8) 7.63 (4Harm' m)-19FNMR - ~(CFC13) : - 112.8 (2F, t, J~6.7Hz).
Molecular ~eight for CloH8ClF2N0 fouDd : 231.0263 calculated : 231.02625.
m/z : 231-233 (M+-- isotopes Cl) ; 165-167 ; 132, 118, 92, 77.
EYample 5 : Preparation of N-(2-fluorometh~l phen~l)-3,3-diflu-oro-2-azetidinone (compound 5b).
An equimolar quantity of diethylamino sulphur trifluoride (DAST) i9 added to a solution of compound 4a in dry meth~lene chloride, at -78C and under a dry atmosphere. The reaction mixture is kept at -40C for 40 to 50 min. The end of the reaction i9 monitored on a silica film. After evaporating the solvent, the residue obtained is purified on a preparative layer using _ 19_ an ether:pentane mixture in a ratio of 1:1.5. This gives 11mg of compound 5b in the form of a colourless oil corresponding to a 41% yield.
The characteristics of this compound are as follovs:
IR (CH2C12) : (1780m (~C0) lHNMR (CD3)2C0) : 4.59 (2H, t, J~7.05Hz) ; 5.64 (2H, d, JHF-47.51 Hz) ; 7.59 (4~, m).
19FNMR - ~(CFC13) : - 112.6 ppm (2F, t, J~6.8 Hz) ; -205(1F, t, J~47.5H~) Molecular weight :
found : 215.0562 calculated : 215.05580 m/z : 215 (M+-) ; 151 ; 109.
ExamPle 6 : PreParation of N-(2-methane sulPhon~lo~ymethyl Phen~1)-3,3-difluoro-2-azetidinone (compound 5c).
0.17 mmole of compound 4a i9 dissol~ed ~n 0.8 ml of 2,6-1utidine at 0C, followed by the sddition of 0.18 m~ole of sulphonyl methane chloride to ~aid solution. After stirrin8 the reaction mixture for 90 min. at a temperature of 4 to 10C, the solution is taken up in 1 ml of ether and then washed twice with 0.5 ml of saturated aqueous NaCl ~olution.
The organic pha~e is dried on MgS04 and then evaporated. The oil obtained is purified on a silica preparati~e la~er using an ether:pentane mixture in a ratio of 1:1. This gi~es 19 mg of compound 5c corresponding to ~ 39% yield.
The compound has the following characteristic~:
IR (CH2C12) : 1780cm 1 (~C0) ; 1350 cm 1 HNMR (tCD3)2C0) : 3.95 (3H, 9) ; 4.6 (2H, t, J-6.31Hz) 4.95 (2H, 9); 7.6 (4N, m).
19FNMR (CFC13) : - 118 ppm (2F, t, J-6.4Hz).
Example 7 : Preparation of N-(2-bromometh~l phen~ 3.3-difluoro-2-szetidinone (comPound 5d).
60mg (0.28 mmole) of compound 4a are treated with 4 equi~slents (0.15 ml) of trimethylsilylbromide at ambient temperature for 35 min. The compound obtained is purified by silica gel plate chromatography using an ether:pentane mixture (1:6). Thi~ gi~es 16mg of compound 5d corresponding to a 25% yield.
This compound has the following characteristics:
IR : (CH2C12) : 1775 cm 1 IH NMR (CD3)2C0 : 7.37 ppm (4H, m) ; 4.72 (2H, 8); 4.47 (2H, t, J-6.7Hz).
19FNMR (/CFC13) : -115.6 ppm (t, J=6.6 Hz).
Precise ~eight: (obser~ed/calculated : 274.9760/274.97579).
m/z : 275-277 (M+ isotopes Br) ; 196(M-Br) ; 132 ; 91 ; 77.
Examp1es 8 to 12.
mese examples correspond to the following reaction diagrams:
'~VOS~59 tH3 ~ osi ~ C~CH3)3 f Br H2N ~ \ CH3 8r ~
0 8r.
F Br 8r ~
O ~ NH O ~ C(CH3)~
(compound 2b) f CH~
8r _ os1 _ CtCN3)3 F
( compound 3b) tcompound 4b) F F
8 r~ r c l B r ~1 ~ F
( compound S~) ( compound ~b) a. 9942 MDT
2005'759 - 22 ~
Example 8 : Preparation of N-(tert but~l 2-dimethylsil~loxy-methYl phenvl)-2,3-dibromo-2-fluoro pro~anamide (compound 2b~.
The same operating procedure as in example 1 i9 adopted for preparing compound 2b, except that 1.1 eq of 2,3-dibromo-2-fluoro S propanoyl bromide i8 u~ed in place of 1.1 eq of 3-bromo-2,2-difluoropropanoyl chloride. This gives 882mg of compound 2b corresponding to a yield of 63%.
The product has the following characteristics:
Melting point : 58.2C
10 IR(CH2C12) : 3290 ; 1695 cm 1 1HNMR (CD3)2CO) : 0.08 (6H, s) ; 0.87 (9H, s) ; 4.40 (lH, dd, J=11.49 ; 9.01Hz); 4.63 (lH, dd, J=11.52 ; 31.06 Hz) ; 7.3 (4H, m) ; 9.2 (lH, NH).
19FNMR ~(CFC13) : -118.6 ppm (ddd ; 30 ; 8Hz) Analysis :
ObservedCslculated C 41.20 40.95 H 5.08 5.16 N 2.98 2.98 20 m/z : 410-412-414 (M-57) ; 252 (M 2Br)130, 91, 77.
..
Example 9 : Preparation of N-(tert butyl-2-dimeth~lsil~loxy-methyl phenyl)-3-bromo-3-fluoro-2-azetidinone (compound 3b).
The operating procedure of example 2 is adopted for preparing compound 3b using 1.5 mmole of compound 2b in place of 1.5 mmole of compound 2a. Following purification on the ~ilica gel prep-arative layer using a mixture of ethylene acetate:pentane in a ratio of 1:10, 93 mg of compound 3b sre obtained in the form 2005~59 of an oil corresponding to a 41% yield.
The product obtained has the following characteristics:
IR(CH2C12) : 1770 cm 1 ;
lHNMR (CD3)2CO) : 0.14 ppm (6H, 9) : 0.95 (9H, s) ; 4-6 (1H~
dd ; J=7.21 (x2)Hz) ; 4.8 (lH, dd, J=7.36 ; 9.29Hz) ; 4.9 (2H;
sys (AB) ; J=13.93Hz) ; 7.35 (2Ham ; m) ; 7.6 (2Ha~ ; m).
19FNMR ~(CFC13) : - 120 ppm (dd ; J=7.52 (x2) Hz) Molecular weight for C16H23BrFN02Si found : 387.0640 calculated : 387.0666 m/z : 388 (M+- low) ; (373-375) (332-335) ; 132 ; 91.
Fxam~le 10 : Preparation of N-(2-hydrox~meth~l phen~l)-3-bromo-3-fluoro-2-azetidinone (comPound 4b).
The operating procedure of example 3 is adopted for preparing compound 4b using 0.19 mmole of compound 3b in place of 0.19 mmole of compound 3a. This gives 32mg of compound 4b in the form of a colourless oil and with a ~ield of 80~.
The product obtained has the following characteristics:
IR(CH2C12) : 3570 - 3460 (~OH) : 1765 (~CO)Cm 1 lHNMR (CD3)2CO) : 4.32 ppm (2H, t, J=5.26Hz) 4.47 (lH, dd, J=7.29 7.24Hz) ; 4.64 (lH, dd, J=7.27 ; 9.34Hz) 19FNMR- ~(CFC13) : - 122.33 (dd, J=7.7 ; 9.4 Hz) m/z : 273-275 (M+~(isotopes Br) : 216-194, 176, 149, 105, 118, 93, 77, 65.
- 24 ~
.
Example 11 : Preparation of N-(2-chlorometh~l phen~ 3-fluoro-3-bromo-2-azetidinone (comPound 5'a).
The operating procedure of example 4 is sdopted for preparing ~ compound 5'a using 0.11 mmole of compound 4b in place of 0.11 mmole of compound 4a. This gi~es 32mg of compound 5'a in the form of a colourless oil corresponding to a 75% yield.
The characteristics of the product obtained are as follows:
IR (CH2C12) : 1770 cm (~C0) lHNMR (CD3)2C0) : 4.47 ppm (lH, dd, J=7.32 ; 6.93Hz) 4.73 (lH, dd, J=7.23 ; 9.37Hz) ; 4.85 (2H, dd, sys (AB) ; J=12Hz) ; 7.4 (4Harm' m) 19FNMR - ~(CFC13) - 118.7 ppm / dd, J=7 : 9.2Hz) Molecular weight for ClOH8FClBrN0 found : 290.9411 calculated : 290.94624 m/z : 290 - 293 - 295 (M~ isotope Cl, Br) ; 216.167 ; 132.148.
Example 12 : Preparation of N-(2-fluoromethyl phen~l)-3-bromo-3-fluoro-2-azetidinone (compound 5'b).
The operating procedure of example 5 is used for preparing comp-ound 5'b using compound 4b in place of compound 4a. This giYes 12mg of compound 5'b in the form of a colourless oil and with a 64% yield.
The product obtained has the following characteristics:
IR (CH2C12) : 1770 cm 1 (~ C0) lHNMR (CD3)2C0) : 4.55 ppm (lH, dd; JAB=7.3 ; 7.17Hz) 4.76 (lH, dd, JAB = 7.3 ; 9.06Hz) ; 5.5 (2H, d, J=47.55Hz).
19FNMR ~(CFC13) : - 204.4 (lF, t, J=47.5Hz) ; - 118.4 (lF~ t, J=7.1 ; 9.23Hz).
2005~59 ~ 25 -Molecular weight:
found : 274.9763 calculated : 274.97579 m/z : (275-277) (M~-) ; 151 ; 123 ; 109 ; 96.
-Examples 13 to 18.
These examples relate to the preparation of N-ar~l-azetidinones according to the invention using the following reaction diagram:
200~759 F llr t H 3 f H2N --~ OSi / C~tH3)3 + ~_ S (compound 6) f llr fl--NH
7 ) ~ t H 3 ~compound F
osl ~ t(CH3)3 --~ tH3 (Compound 8 ) F
oD~ ~) O H ~/
2 5 ~ (compound 10a) (compound 9) `~ f 0/~ f compound 10b) . 9942 MDT
Example 13 : Preparation of tert but~l 4-dimethylsil~loxymethYl aniline (com~ound 6).
123mg (1 mmole) of 4-aminobenzyl alcohol are dissolved in 2ml of dry DMF and to the solution are added 180 mg (1.2 mmole) of tert butyl dimethylsilyl chloride, followed by 170 mg (2.5 mmole) of imidazole.
Stirring takes place for 40 min. at ambient temperature and then the DMF is evaporated with the vane pump. The residue is taken up in 10 ml of ether and the ethereal phase washed with 4x4 ml of water, followed by drying on MgS04 and evapora-tion. The oil obtained is purified by flash chromatog}aphy using an ether:pentane mixture in a volume ratio of 3:2. This gives 173 mg of compound 6 corresponding to a 73% yield.
The product obtained has the follo~ing characteristics:
IR (CH2C12) : 3430-3380 ; 2800 ; I610 ; 1510 ; 1100 cm 1 HNMR (CD3)2C0) : 0.05 pp~ (6H, s) ; 0.85 (9H, 9); 4-4 (2H, NH2 9 wide) ; 4.55 (2H, s) ; 6.35 (2H, d, J=8.8Hz) ; 6.95 (2H, d, Js8.7Hz).
Example 14 : Preparation of N-(tert but~l-4-dimeth~lsil~lox~-methYl phen~l)-2,2-difluoro-3-propionamide (compound 7).
The same operating procedure as in example 1 is used employing compound 6 is place of tert butyl-2-dimethyl3ilyloxymethyl aniline. This gives 230 mg of compound 7 corresponding to a 70% yield.
The characteristics of the product obtained are as follows:
Melting point : 57.3C
IR(CH2C12) 3400 ; 1700 cm 1 _28 _ lHNMR (CD3)C0) : 0.17 ppm (6H, s) ; 1 (9H, 9); 4.16 (2H, t, J~14.3Hz) ; 4,82 (2H, 9); 7.43 (2Ham; d ; J~8.58Hz) ; 7.8 (2H, d, J~8.53Hz).
19FNMR - ~(CFC13) : - 120.8 ppm (t; J314Hz) Molecular weight for C16H24F2BrN02Si :
found : 407.0729 calculated : 407.07283 Elementary analysis :
found calculated C 47.76 47.06 H 5.99 5.92 N 3.33 3.43 m/z : 407 (M+~) weak ; (352-350) isotopes Br ; (230-228) ; 106, 90.
Example 15 : Preparation of N-(tert butyl-4-dimethylsilyloxy-meth~l phen~l)-3,3-difluoro-2-azetidinone (compound 8).
The operating procedure of example 2 is adopted for preparing compound 8 using 1.5 mmole of compound 7 in place of 1.5 mmole of compound 2a. Following purification on a Florisil column using an ether:pentane mixture with a ~olume ratio of 1:6, 72mg of compound 8 are obtained corresponding to a 51~ yield. This compound is a white solid melting at 48C.
The product obtained has the following characteristics:
IR (CH2C12) : 1770 cm 1 lHNMR (CD3)2C0) : 0.2 ppm (6H, s) ; 1(9H, s) ; 4.49 (2H, t, J=6.42Hz) ; 4.87 (2H, s) ; 7.55 (4H, m).
19FNMR i(CFC13) : - 111.6 ppm (2F, t, J-6.4Hz).
200~759 Molecular weight :
found : 327.1471 calculated : 327.14661 m/z : 327 tM+-) : 312 ; 270 ; 196 ; 168.
E~ample 16 : PreParation of N-(4-hvdroxYmethYl phen~l)-3,3-difluoro-2-azetidinone (compound 9).
The operating procedure of example 3 iQ adopted for preparing compound 9 from compound 8 using 0.19 mmole of compound 8 in place of 0.19 mmole of compound 3a. 1`his gives 42mg of compound 9 in the form of a solid, which corresponds to an 82% yield.
The product obtained has the following characteristics:
Melting point : 124C
IR (CH2C12) : 3580-3490 (~OH) : 1768 (~CO) cml lHNMR (CD3)2CO) : 4.68 ppm (2H, d, J=5.7Hz) ; 4.45 (2H, t, J=6.32 Hz) ; 4.35 (lH, t, J=5.76Hz) ; 7.5 (4Ham ; 8) 19FNMR - ~(CFC13) : - 111.6 ppm (2F, t, J=6.4Hz) Molecular weight for CloHgF2N02 ; found : 213.0604 calculated : 213.06014 m/z : 213(M~-) ; 149 ; 106.
Example 17 : Preparation of N-(4-chlorometh~l phen~l)-3,3-difluoro-2-azetidinone (compound lOa).
The operating procedure of example 4 is followed for the prep-aration of compound 10a from compound 9 using 0.11 mmole of compound 9 in place of 0.11 mmole of compound 4a. This gi~eQ
16mg of compound lOa in the form of a white solid corresponding to a ~5~ yield.
ZO()5~59 The compound obtained has the following characteristics:
Melting point : 93C
IR (CH2C12) : 1770 cm 1 ( C0) lHNMR (CD3)2C0) : 4.48 (2H, t, J-6.53Hz) ; 4.79(2H, 9); 7.57 (4Harm, d ; J-8.6Hz).
19FNMR - (CFCl3) : - 111.5 ppm (2F, t, J=6.6Hz) Molecular weight for CloH8F2ClN0 found : 231.0260 calculated : 231.02625 m/z : 231-233 (M+~ isotope Cl) : 196 ; 167 ; 169 ; 168 ; 132 118 ; 90 ; 77.
Example 18 : Preparation of N-(4-fluorometh~l phenyl)-3.3-difluoro-2-azetidinone (compound lOb).
The operating procedure of example 5 i~ used for preparing comp-ound lOb from compound 9, the latter being used instead of com-pound 4a. This gives 16mg of compound lOb in the form of a solid corresponding to a 38% yield.
The product obtained has the following characteristics:
Melting point : 104C
IR (CH2C12) : 1770 cm 1 ( C0) lHNMR - (CD3)C0) : 4.49 ppm (2H, t, J=6.49Hz) ; 5.46 ~2H, d, J=48Hz) ; 7.58 (4H, s) l9FNMR (CFCl3) : - 111.5 ppm (2F, t, J=6.6Hz) ; - 200.39 (lF, t, J=48Hz) Molecular weight found : 215.0559 calculated : 215.05580 m/z : 215 (M+~) ; 151 ; 106 ; 109 B 9 9~ MDT
2005'~59 Examples 19 to 22.
These examples ;llustrate the preparation of N-aryl-azetidinones according to the in~ention using the following reaction diagram :
CH3 ~ ~
H2N ~ CH3 0 Cl Cl CH3 ' C p CH, ~ c~ ¦ c~ r Os~_ C~tH3)3 o\ r~ CtCH3)3 ~ H ~ ~ CN3 ~ ~ ~ tN3 ( Compound 2e) t compound 3e tl Cl.
~ ~~ 0~ ~
tCompound 4e) (compound 5e) ~. 9942 MDT
2005'7~9 Example 19 : Preparation of N(tert butYl-2-dimethYlsil~lox~-meth~l phenyl)-2,2,3-trichloro propionamide (comPound 2e).
For this synthesis, use iq made of tert butyl-2-dimethylsilyl-- oxymethyl aniline prepared according to the method describedby ~. Just and R. Zamboni in Canad. J. Chem. 1978, 5b, p.2720 and trichloropropanoyl chloride prepared in the following way.
Firstly 2,2,3-trichloropropionitrile is prepared by adding chlor-ine to ~ -chloroacrylonitrile, as described by H. Brintzinger et al in Angew. Chemie, 1948, 60, p.311 and then the 2,2,3-tri-chloropropionitrile undergoes acid hydrolysis with 60% H2S04 at 125C and for 5 hours in order to obtain the corresponding acid, as described by H. Laato in Suomen Kemistilehti, 1968, 41B, p.266. The acid is then treated by SOC12 in the presence of a catalytic quantity of DMF at 40 to 50C and for 1 hour, which gives 2,2,3-trichloropropanoyl chloride, which is distilled at 50C under 2700 Pa (20 mm of Hg), the yield being 66%.
This compuund has the following characteristics:
IR (CH2C12) : 1800 1770 cm 1 (intense band) lHNMR (CDC13) : 4.4 ppm (2H, s).
The same operating procedure as in example 1 is used for prep-aring N-(tert butyl-2-dimethylsilyloxymethyl phenyl)-2,2,3-trichloropropionamide from tert butyl-2-dimethylsilyloxymethyl aniline and 2,2,3-trichloropropanoyl chloride. This gi~es 814 mg of compound 2e corresponding to a 70% yield.
The compound has the following characteristics:
White solid : m.p. 41C ;
IR(CH2Cl2) ; 3300 ; 1690 ; 1585 cm 1 lHNMR : 10.25(1H,NH) ; 8,25(1H,d) ; 7.35(2H,m) ; 4.8(2H,s) ;
4.2(2H,s) ; 0.95(9H,s) ; 0.15(6H,s).
200S7~:;9 m/z : 382-384 (M-14) ; 338-340 ; 268 ; 200 ; 192 ; 164 ; 132 93 ; 75 ; 29.
Micro analysis :
found /calculated %
C 48.32 / 48.43 H 6.32 / 6.10 N 3.6 / 3,53 Example 20 : Preparation of N-(tert butvl-2-dimethvlsilYloxy-methyl Phenyl)-3,3-dichloro-2-azetidinone (compound 3e).
The same operating procedure as in example 2 is adopted for preparing compound 3e from compound 2e. The product obtained is purified by flaih chromatography using an ether:pentane mixt-ure (1:10). This gives compound 3e in the form of a white solid with a 59% yield.
This compound has the following characteristics:
IR(CH2Cl2) : 1770 cm 1 (~ co ~o lactame).
lHNMR (CDCl3) ; 7.5(4H, m) ; 4.8(2H,s) ; 4.5(2H,s) ; 0.95(9H,s);
0.15(6H,s).
Precise weight : (observed/calculated 359.087 / 359.0875).
20 m/z : 344-346 ; 302-304 ; 206 ; 192 ; 132 ; 93 ; 73 ; 29 ;
Micro analysis :
found /calculated %
C 53.24 / 53.33 H 6.62 / 6.43 25 N 3.67 / 3.89 Example 21 : Preparation of N-(2-hydrox~methyl phen~l) 3,3-dichloro-2-azetidinone (comPound 4e).
The operating procedure of example 3 is used for preparing comp-ound 4e from compound 3e. This gives compound 4e in the form of a colourless oil with a 70% yield.
This compound has the following characteristics:
IR ( CH2C12 ) : 3580-3480 (~ OH cm 1 ; 1765 (~ co lactame) cm~
lH NMR (CDC13) : 7.45 ppm (4H,m) ; 4.75(2H,s) ; 4.5(2H,s) ;
3(1H,s).
Example 22 : Preparation of N-(2-chloromethyl phenYl)-3,3-di-chloro-2-azetidinone (compound 5e).
The operating procedure of example 4 is used for preparing comp-ound 5e from compound 4e. The product obtained is purified by silica gel chromatography using an ether:pentane mixture (1:5). This gives compound 5e in the form of a white solid with a yield of 67%.
This compound has the following characteristics:
F : 79C
IR : (CH2C12) : 1770 cm 1 lH NMR (CDC13) : 7.5 (4H,s) ; 4.8(2H,s) ; 4.5(2H,s) ;
Precise weight : (found : calculated : 262.9675 / 262.96715).
m/z : 263-261 (isotopes Cl) ; 169-167 ; 132 ; 91 ; 77 ; 40 ;
29.
Micro analysis :
found / calculated %
C : 45.67 / 45.4 H : 3.12 / 3.05 N : 5.06 / 5.3 ExamPle 23 : PreParation of N-(2-bromomethyl phenYl)-3,3-di-fluoro-2-azetidinone (comPound 5d).
This example uses another process for preparing compound 5d of example 7. This process corresponds to the following reaction diagram:
__ _ . _ _ _ O f ~1i3~B r- t~ F ~ ~ B
(compound n11 ) ( compound n 5d) >~
Hl~
O
The starting compound 11 is prepared from 3-bromo-2,2-difluoro propanoyl chloride used in example 1 and ortho-toluidine by cyclization following the operating procedure of examples 1 and 2 for preparing compound 3a.
24mg (0.12 mmole) of compound 11 are dissolved in 20 ml of CC14 and 21 mg (0.12mmole) of N-bromosuccinimide and a catalytic quantity of benzoyl peroxide are added. After refluxing (78C) for 1 hour and illuminating with a 150 watt lamp, hot filtering takes place of the succinimide formed. The filtrate is then cooled and evaporated in vacuo, which gives a solid product, 200S~59 purified by silica gel chromatography. This gives 20mg of com-pound 5d corresponding to a 62% yield.
Example 24, The properties of the N-aryl-azetidinones obtained in examples 4,5,6,7,11,17,22 and 23 are checked and in particular their deactivation capacity for porcine pancreatic elastase (PPE) and human leucocytic elastase (HLE) using the methods of Kitz and Wilson for HLE in the case of compounds 5a,5c,5d,5e,5a' and lOa, the method of Kitz and Wilson for PPE in the case of compounds 5a,5c,5e and lOa and the method of Hart and O'Brian for PPE in the case of compounds 5a and 5'a. All the kinetic measurements are carried out at 37C and at a pH of 8 with a O.lM tris buffer (PPE) or a O.lM tris buffer, Brij 0.01%, NaN3 0.02% (HLE) (pH 7.5 for compound 5d).
The method of Hart and O'Brian was published in 1973 in Bioch-emistry, Vol. 12~ pp.2940-2945 and that of Kitz and Wilson in 1962 in J. Biol. Chem., Vol. 237, pp.3245-3249.
In this way the first order constant ki is determined for the formation of the deactivated enzyme and the dissociation constant ~i of the enzyme-inhibitor complex. The ki:~i ratio is the apparent second order constant characterizing the deactivation.
The results obtained are given in the following table.
On the basis of these results, it can be seen that compounds 5a,5c,5'a,5e and lOa deactivate PPE and HLE.
On testing compounds 5a,5c,5'a and lOa under identical conditions as chymotrypsin or trypsin inhibitors, it can be seen that they have no action on these enzymes.
x~ 9 Example 25 This example used for testing the properties of compounds 5b and lOb with respect to elastase and it can be seen that these compounds are elastase substrates, but that the~ are not inhib-itors. mus, the nature of the R3 substituent has a significantinfluence on the properties of the product obtained.
Example 26.
The effect of compound 5a on the degradation of elastin, the natural substrate of elastase in the human organism was tested.
The elastase, previously treated by compound 5a, lost its capa-city to degrade elastin. Compounds 5a,5c and S'a remain capable of deactivating elastase previously incubated for 30 min. in the presence of an elastin excess (2mg).
me acute toxicity of compound 5a researched on male and female mice exceeds 200 mg/kg.
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~ O ~ ~
~1 ~ .. u~ o o o l_ ~ ~s o U~ ~
~_ O O O O O
~n O O O o O
. _ ~
1~ _ N -- _ _ , N ~L IL ID LL ~ IL
_ ` .
_ ~ ~0 ~
~ . 9942 MDT
200S7~:;9 m/z : 382-384 (M-14) ; 338-340 ; 268 ; 200 ; 192 ; 164 ; 132 93 ; 75 ; 29.
Micro analysis :
found /calculated %
C 48.32 / 48.43 H 6.32 / 6.10 N 3.6 / 3,53 Example 20 : Preparation of N-(tert butvl-2-dimethvlsilYloxy-methyl Phenyl)-3,3-dichloro-2-azetidinone (compound 3e).
The same operating procedure as in example 2 is adopted for preparing compound 3e from compound 2e. The product obtained is purified by flaih chromatography using an ether:pentane mixt-ure (1:10). This gives compound 3e in the form of a white solid with a 59% yield.
This compound has the following characteristics:
IR(CH2Cl2) : 1770 cm 1 (~ co ~o lactame).
lHNMR (CDCl3) ; 7.5(4H, m) ; 4.8(2H,s) ; 4.5(2H,s) ; 0.95(9H,s);
0.15(6H,s).
Precise weight : (observed/calculated 359.087 / 359.0875).
20 m/z : 344-346 ; 302-304 ; 206 ; 192 ; 132 ; 93 ; 73 ; 29 ;
Micro analysis :
found /calculated %
C 53.24 / 53.33 H 6.62 / 6.43 25 N 3.67 / 3.89 Example 21 : Preparation of N-(2-hydrox~methyl phen~l) 3,3-dichloro-2-azetidinone (comPound 4e).
The operating procedure of example 3 is used for preparing comp-ound 4e from compound 3e. This gives compound 4e in the form of a colourless oil with a 70% yield.
This compound has the following characteristics:
IR ( CH2C12 ) : 3580-3480 (~ OH cm 1 ; 1765 (~ co lactame) cm~
lH NMR (CDC13) : 7.45 ppm (4H,m) ; 4.75(2H,s) ; 4.5(2H,s) ;
3(1H,s).
Example 22 : Preparation of N-(2-chloromethyl phenYl)-3,3-di-chloro-2-azetidinone (compound 5e).
The operating procedure of example 4 is used for preparing comp-ound 5e from compound 4e. The product obtained is purified by silica gel chromatography using an ether:pentane mixture (1:5). This gives compound 5e in the form of a white solid with a yield of 67%.
This compound has the following characteristics:
F : 79C
IR : (CH2C12) : 1770 cm 1 lH NMR (CDC13) : 7.5 (4H,s) ; 4.8(2H,s) ; 4.5(2H,s) ;
Precise weight : (found : calculated : 262.9675 / 262.96715).
m/z : 263-261 (isotopes Cl) ; 169-167 ; 132 ; 91 ; 77 ; 40 ;
29.
Micro analysis :
found / calculated %
C : 45.67 / 45.4 H : 3.12 / 3.05 N : 5.06 / 5.3 ExamPle 23 : PreParation of N-(2-bromomethyl phenYl)-3,3-di-fluoro-2-azetidinone (comPound 5d).
This example uses another process for preparing compound 5d of example 7. This process corresponds to the following reaction diagram:
__ _ . _ _ _ O f ~1i3~B r- t~ F ~ ~ B
(compound n11 ) ( compound n 5d) >~
Hl~
O
The starting compound 11 is prepared from 3-bromo-2,2-difluoro propanoyl chloride used in example 1 and ortho-toluidine by cyclization following the operating procedure of examples 1 and 2 for preparing compound 3a.
24mg (0.12 mmole) of compound 11 are dissolved in 20 ml of CC14 and 21 mg (0.12mmole) of N-bromosuccinimide and a catalytic quantity of benzoyl peroxide are added. After refluxing (78C) for 1 hour and illuminating with a 150 watt lamp, hot filtering takes place of the succinimide formed. The filtrate is then cooled and evaporated in vacuo, which gives a solid product, 200S~59 purified by silica gel chromatography. This gives 20mg of com-pound 5d corresponding to a 62% yield.
Example 24, The properties of the N-aryl-azetidinones obtained in examples 4,5,6,7,11,17,22 and 23 are checked and in particular their deactivation capacity for porcine pancreatic elastase (PPE) and human leucocytic elastase (HLE) using the methods of Kitz and Wilson for HLE in the case of compounds 5a,5c,5d,5e,5a' and lOa, the method of Kitz and Wilson for PPE in the case of compounds 5a,5c,5e and lOa and the method of Hart and O'Brian for PPE in the case of compounds 5a and 5'a. All the kinetic measurements are carried out at 37C and at a pH of 8 with a O.lM tris buffer (PPE) or a O.lM tris buffer, Brij 0.01%, NaN3 0.02% (HLE) (pH 7.5 for compound 5d).
The method of Hart and O'Brian was published in 1973 in Bioch-emistry, Vol. 12~ pp.2940-2945 and that of Kitz and Wilson in 1962 in J. Biol. Chem., Vol. 237, pp.3245-3249.
In this way the first order constant ki is determined for the formation of the deactivated enzyme and the dissociation constant ~i of the enzyme-inhibitor complex. The ki:~i ratio is the apparent second order constant characterizing the deactivation.
The results obtained are given in the following table.
On the basis of these results, it can be seen that compounds 5a,5c,5'a,5e and lOa deactivate PPE and HLE.
On testing compounds 5a,5c,5'a and lOa under identical conditions as chymotrypsin or trypsin inhibitors, it can be seen that they have no action on these enzymes.
x~ 9 Example 25 This example used for testing the properties of compounds 5b and lOb with respect to elastase and it can be seen that these compounds are elastase substrates, but that the~ are not inhib-itors. mus, the nature of the R3 substituent has a significantinfluence on the properties of the product obtained.
Example 26.
The effect of compound 5a on the degradation of elastin, the natural substrate of elastase in the human organism was tested.
The elastase, previously treated by compound 5a, lost its capa-city to degrade elastin. Compounds 5a,5c and S'a remain capable of deactivating elastase previously incubated for 30 min. in the presence of an elastin excess (2mg).
me acute toxicity of compound 5a researched on male and female mice exceeds 200 mg/kg.
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~_ O O O O O
~n O O O o O
. _ ~
1~ _ N -- _ _ , N ~L IL ID LL ~ IL
_ ` .
_ ~ ~0 ~
~ . 9942 MDT
Claims (19)
1. N-aryl-azetidinones according to the formula:
(I) in which R1 and R2, which can be the same or different, repre-sent an atom of F, Br, C1 or I, or a radical of formula CF3, COOR5, CN, CONHR5 or COR5 with R5 rep-resenting an alkyl or aryl radical, R3 represents a fluorine, chlorine, bromine or iodine atom, or a radical of formula OC(O)R6, OSO2R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoro-alkyl or aryl radical and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula COOR7, CONHR7, NO2, CF3, CN, SO2R7, (CH2)nOR7 and OR7 with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18.
(I) in which R1 and R2, which can be the same or different, repre-sent an atom of F, Br, C1 or I, or a radical of formula CF3, COOR5, CN, CONHR5 or COR5 with R5 rep-resenting an alkyl or aryl radical, R3 represents a fluorine, chlorine, bromine or iodine atom, or a radical of formula OC(O)R6, OSO2R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoro-alkyl or aryl radical and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula COOR7, CONHR7, NO2, CF3, CN, SO2R7, (CH2)nOR7 and OR7 with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18.
2. N-aryl-azetidinone according to claim 1, characterized in that -CH2R3 is in the ortho or para position relative to N.
3. N-aryl-azetidinone according to claim 2, characterized in that -CH2R3 is in the ortho position relative to N.
4. N-aryl-azetidinone according to any one of the claims 1 to 3, characterized in that R4 is a hydrogen atom.
5. N-aryl-azetidinone according to any one of the claims 1 to 4, characterized in that R3 represents F, Cl, Br or OSO2CH3.
6. N-aryl-azetidinone according to claim 5, characterized in that R1 and R2 represent F.
7. N-aryl-azetidinone according to claim 5, characterized in that R1 represents F and R2 represents Br.
8. N-aryl-azetidinone according to claim 5, characterized in that R1 and R2 represent Cl.
9. Process for the preparation of a N-aryl-azetidinones accor-ding to the formula:
(I) in which R1 and R2, which can be the same or different, repre-sent an atom of F, Br, Cl or I, or a radical of formula CF3, COOR5, CN, CONHR5 or COR5 with R5 representing an alkyl or aryl radical.
R3 represents a fluorine, chlorine, bromine or iodine atom, or a radical of formula OC(O)R6, OSO2R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoro-alkyl or aryl radical and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula COOR7, CONHR7, NO2, CF3, CN, SO2R7, (CH2)nOR7 and OR7 with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18, characterized in that it comprises the foll-owing successive stages:
1) preparing a N-aryl-azetidinone of formula:
(II) in which R1, R2 and R4 have the meanings given herein-before and 2) transforming the N-aryl-azetidinone of formula (II) into N-aryl-azetidinone of formula (I) by reaction with a reagent chosen as a function of R3.
(I) in which R1 and R2, which can be the same or different, repre-sent an atom of F, Br, Cl or I, or a radical of formula CF3, COOR5, CN, CONHR5 or COR5 with R5 representing an alkyl or aryl radical.
R3 represents a fluorine, chlorine, bromine or iodine atom, or a radical of formula OC(O)R6, OSO2R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoro-alkyl or aryl radical and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and the radicals of formula COOR7, CONHR7, NO2, CF3, CN, SO2R7, (CH2)nOR7 and OR7 with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18, characterized in that it comprises the foll-owing successive stages:
1) preparing a N-aryl-azetidinone of formula:
(II) in which R1, R2 and R4 have the meanings given herein-before and 2) transforming the N-aryl-azetidinone of formula (II) into N-aryl-azetidinone of formula (I) by reaction with a reagent chosen as a function of R3.
10. Process according to claim 9, characterized in that R3 represents C1 and in that the reagent is SOC12.
11. Process according to claim 9, characterized in that R3 represents F and in that the reagent is diethylaminosulphur trifluoride.
12. Process according to claim 9, characterized in that R3 represents Br and in that the reagent is (CH3)3SiBr.
13. Process according to claim 9, characterized in that R3 represents OSO2R6 and in that the reagent is ClSO2R6.
14. Process according to any one of the claims 9 to 13, char-acterized in that the N-aryl-azetidinone of formula (II):
(II) is prepared by a) reacting a .beta.-halogenopropanoyl halide of formula:
(III) in which X represents F, Cl, Br or I, x2 represents Cl, Br or I and R1 and R2 have the meanings given hereinbefore with a silyloxymethyl aniline of formula:
(IV) to obtain a halopropionanilide of formula:
(V) b) by forming a N-aryl-azetidinone of formula:
(VI) by cyclization of said halopropionanilide of formula (V) and c) transforming said N-aryl-azetidinone of formula (VI) into N-aryl-azetidinone of formula (II) by reaction with a mixture of hydrofluoric acid and water.
(II) is prepared by a) reacting a .beta.-halogenopropanoyl halide of formula:
(III) in which X represents F, Cl, Br or I, x2 represents Cl, Br or I and R1 and R2 have the meanings given hereinbefore with a silyloxymethyl aniline of formula:
(IV) to obtain a halopropionanilide of formula:
(V) b) by forming a N-aryl-azetidinone of formula:
(VI) by cyclization of said halopropionanilide of formula (V) and c) transforming said N-aryl-azetidinone of formula (VI) into N-aryl-azetidinone of formula (II) by reaction with a mixture of hydrofluoric acid and water.
15. Process for the preparation of a N-aryl-azetidinone of formula:
(I) in which:
R1 and R2, which can be the same or different, repre-sent an atom of F, Br, Cl or I, or a radical of formula CF3, COOR5 CN or CONHR5 with R5 representing an alkyl or aryl radical, R3 represents a bromine atom and R4 represents a hydrogen atom or a radical chosen from among radicals of formula COOR7 CONHR7 NO2, CF3, CN and SO2R7, with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18, characterized in that it consists of reacting a N-aryl-azetidinone of formula:
(VII) in which R1, R2 and R4 have the meanings given hereinbefore with N-bromosuccinimide.
(I) in which:
R1 and R2, which can be the same or different, repre-sent an atom of F, Br, Cl or I, or a radical of formula CF3, COOR5 CN or CONHR5 with R5 representing an alkyl or aryl radical, R3 represents a bromine atom and R4 represents a hydrogen atom or a radical chosen from among radicals of formula COOR7 CONHR7 NO2, CF3, CN and SO2R7, with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18, characterized in that it consists of reacting a N-aryl-azetidinone of formula:
(VII) in which R1, R2 and R4 have the meanings given hereinbefore with N-bromosuccinimide.
16. Pharmaceutical composition incorporating an elastase inhib-itor, characterized in that said elastase inhibitor is a N-aryl-azetidinone of formula:
(I) in which R1 and R2, which can be the same or different, stand for an atom of F, Br, Cl or I, or a radical of formula CF3, COOR5, CN, CONHR7 or COR5 with R5 representing an alkyl or aryl radical, R3 represents a chlorine, bromine or iodine atom, or a radical of formula OC(O)R6, OSO2R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoro-alkyl or aryl radical and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and radicals of formula COOR7 CONHR7 NO2, CF3, CN, SO2R7 (CH2)nOR7 and OR7 with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18.
(I) in which R1 and R2, which can be the same or different, stand for an atom of F, Br, Cl or I, or a radical of formula CF3, COOR5, CN, CONHR7 or COR5 with R5 representing an alkyl or aryl radical, R3 represents a chlorine, bromine or iodine atom, or a radical of formula OC(O)R6, OSO2R6, OP(O)R62 or S+R62 with R6 representing an alkyl, perfluoro-alkyl or aryl radical and R4 represents a hydrogen atom or a radical chosen from among the alkyl radicals and radicals of formula COOR7 CONHR7 NO2, CF3, CN, SO2R7 (CH2)nOR7 and OR7 with R7 representing a hydrogen atom or an alkyl or aryl radical and n being an integer between 1 and 18.
17. Pharmaceutical composition according to claim 16, charac-terized in that R4 is a a hydrogen atom and R3 is Cl, Br or OSO2CH3.
18. Pharmaceutical composition according to either of the claims 16 and 17, characterized in that R1 is F and R2 is F or Br.
19. Pharmaceutical composition according to either of the claims 16 and 17, characterized in that R1, R2 and R3 represent Cl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8816732 | 1988-12-19 | ||
| FR8816732A FR2640621B1 (en) | 1988-12-19 | 1988-12-19 | N-ARYL-AZETIDINONES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ELASTASE INHIBITORS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2005759A1 true CA2005759A1 (en) | 1990-06-19 |
Family
ID=9373095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002005759A Abandoned CA2005759A1 (en) | 1988-12-19 | 1989-12-18 | N-aryl-azetidinones, their preparation process and their use as elastase inhibitors |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5030628A (en) |
| EP (1) | EP0375527A1 (en) |
| JP (1) | JPH0334966A (en) |
| AU (1) | AU628445B2 (en) |
| CA (1) | CA2005759A1 (en) |
| DK (1) | DK641589A (en) |
| FR (1) | FR2640621B1 (en) |
| NZ (1) | NZ231817A (en) |
| OA (1) | OA09432A (en) |
| PT (1) | PT92612A (en) |
| ZA (1) | ZA899725B (en) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5688787A (en) * | 1991-07-23 | 1997-11-18 | Schering Corporation | Substituted β-lactam compounds useful as hypochlesterolemic agents and processes for the preparation thereof |
| DE69222532T2 (en) * | 1991-07-23 | 1998-02-26 | Schering Corp | SUBSTITUTED BETA LACTAM COMPOUNDS AS HYPOCHOLESTEROLEMIC AGENTS AND METHOD FOR THE PRODUCTION THEREOF |
| US5688785A (en) * | 1991-07-23 | 1997-11-18 | Schering Corporation | Substituted azetidinone compounds useful as hypocholesterolemic agents |
| US5631365A (en) | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| FR2755015B1 (en) * | 1996-10-25 | 1998-12-24 | Sod Conseils Rech Applic | USE OF A FLAVONOID EXTRACT OF GINKGO BILOBA SUBSTANTIALLY FREE OF TERPENES, IN THE ORAL FIELD, AND COMPOSITION CONTAINING SUCH EXTRACT |
| WO1998050032A1 (en) * | 1997-05-09 | 1998-11-12 | Smithkline Beecham Corporation | BETA-LACTAM INHIBITORS OF CoA-IT |
| US6274597B1 (en) | 1998-06-01 | 2001-08-14 | Mount Sinai School Of Medicine Of New York University | Method of enhancing lysosomal α-Galactosidase A |
| AU4343500A (en) | 1999-04-16 | 2000-11-02 | Schering Corporation | Use of azetidinone compounds |
| US6982251B2 (en) * | 2000-12-20 | 2006-01-03 | Schering Corporation | Substituted 2-azetidinones useful as hypocholesterolemic agents |
| AU2002241956A1 (en) * | 2001-01-26 | 2002-08-06 | Schering Corporation | Combinations of bile acid sequestrant(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| JP2004517920A (en) * | 2001-01-26 | 2004-06-17 | シェーリング コーポレイション | Combination of sterol absorption inhibitors and blood conditioning agents to treat vascular conditions |
| PT1413331E (en) * | 2001-01-26 | 2007-12-18 | Schering Corp | Combinations of the peroxisome proliferator-activated receptor (ppar) activator fenofibrate with sterol absorption inhibitor ezetimibe for vascular indications |
| US7071181B2 (en) * | 2001-01-26 | 2006-07-04 | Schering Corporation | Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors |
| JP2004517916A (en) * | 2001-01-26 | 2004-06-17 | シェーリング コーポレイション | Combination of nicotinic acid and its derivatives and sterol absorption inhibitors, and treatment of vascular indications |
| BR0206644A (en) * | 2001-01-26 | 2004-02-25 | Schering Corp | Sterol absorption inhibitor (s) combinations with cardiovascular agent (s) for the treatment of vascular conditions |
| IL156422A0 (en) * | 2001-01-26 | 2004-01-04 | Schering Corp | The use of substituted azetidinone compounds for the treatment of sitosterolemia |
| DE60206365T2 (en) | 2001-03-28 | 2006-07-06 | Schering Corporation, Kenilworth | PROCESS FOR THE ENANTIOSELECTIVE SYNTHESIS OF AZETIDINONE INTERMEDIATE PRODUCTS |
| AU2002308778A1 (en) * | 2001-05-25 | 2002-12-09 | Schering Corporation | Use of azetidinone substituted derivatives in the treatment of alzheimer's disease |
| US7053080B2 (en) * | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| US20030119808A1 (en) * | 2001-09-21 | 2003-06-26 | Schering Corporation | Methods of treating or preventing cardiovascular conditions while preventing or minimizing muscular degeneration side effects |
| WO2003026644A1 (en) * | 2001-09-21 | 2003-04-03 | Schering Corporation | Methods for treating or preventing vascular inflammation using sterol absorption inhibitor(s) |
| US7056906B2 (en) | 2001-09-21 | 2006-06-06 | Schering Corporation | Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women |
| ATE345793T1 (en) * | 2001-09-21 | 2006-12-15 | Schering Corp | TREATMENT OF XANTHOMA USING AZETIDINONE DERIVATIVES AS STEROL ABSORPTION INHIBITORS |
| WO2004043456A1 (en) * | 2002-11-06 | 2004-05-27 | Schering Corporation | Cholesterol absorption inhibitors for the treatment of demyelination |
| EP1606287B1 (en) | 2003-03-07 | 2013-10-02 | Merck Sharp & Dohme Corp. | Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholesterolemia |
| US7235543B2 (en) | 2003-03-07 | 2007-06-26 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7208486B2 (en) | 2003-03-07 | 2007-04-24 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7459442B2 (en) | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| JP2007510659A (en) * | 2003-11-05 | 2007-04-26 | シェーリング コーポレイション | Combinations of lipid modulators and substituted azetidinones and treatment of vascular conditions |
| AR047658A1 (en) | 2004-02-03 | 2006-02-01 | Cargill Inc | CONCENTRATE OF PROTEINS AND WATER CURRENT WITH HYDROSOLUBBLE CARBOHYDRATES |
| EP2491794A1 (en) * | 2005-08-03 | 2012-08-29 | Cargill, Incorporated | Corn protein concentrates |
| WO2007019178A2 (en) * | 2005-08-03 | 2007-02-15 | Cargill, Incorporated | Corn protein concentrates |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4680391A (en) * | 1983-12-01 | 1987-07-14 | Merck & Co., Inc. | Substituted azetidinones as anti-inflammatory and antidegenerative agents |
| US4803266A (en) * | 1986-10-17 | 1989-02-07 | Taisho Pharmaceutical Co., Ltd. | 3-Oxoalkylidene-2-azetidinone derivatives |
-
1988
- 1988-12-19 FR FR8816732A patent/FR2640621B1/en not_active Expired - Fee Related
-
1989
- 1989-12-15 EP EP89403512A patent/EP0375527A1/en not_active Ceased
- 1989-12-18 PT PT92612A patent/PT92612A/en not_active Application Discontinuation
- 1989-12-18 NZ NZ231817A patent/NZ231817A/en unknown
- 1989-12-18 CA CA002005759A patent/CA2005759A1/en not_active Abandoned
- 1989-12-18 AU AU46917/89A patent/AU628445B2/en not_active Ceased
- 1989-12-18 DK DK641589A patent/DK641589A/en not_active Application Discontinuation
- 1989-12-19 JP JP1329376A patent/JPH0334966A/en active Pending
- 1989-12-19 ZA ZA899725A patent/ZA899725B/en unknown
- 1989-12-19 US US07/452,774 patent/US5030628A/en not_active Expired - Fee Related
- 1989-12-19 OA OA59703A patent/OA09432A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK641589D0 (en) | 1989-12-18 |
| OA09432A (en) | 1992-10-15 |
| JPH0334966A (en) | 1991-02-14 |
| FR2640621B1 (en) | 1992-10-30 |
| AU628445B2 (en) | 1992-09-17 |
| DK641589A (en) | 1990-06-20 |
| FR2640621A1 (en) | 1990-06-22 |
| PT92612A (en) | 1990-06-29 |
| AU4691789A (en) | 1990-06-21 |
| EP0375527A1 (en) | 1990-06-27 |
| NZ231817A (en) | 1992-03-26 |
| US5030628A (en) | 1991-07-09 |
| ZA899725B (en) | 1990-09-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |