WO1997036895A1 - Process for the preparation of tenidap - Google Patents

Process for the preparation of tenidap Download PDF

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Publication number
WO1997036895A1
WO1997036895A1 PCT/HU1997/000013 HU9700013W WO9736895A1 WO 1997036895 A1 WO1997036895 A1 WO 1997036895A1 HU 9700013 W HU9700013 W HU 9700013W WO 9736895 A1 WO9736895 A1 WO 9736895A1
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Prior art keywords
general formula
compound
process according
chloro
formula
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PCT/HU1997/000013
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French (fr)
Inventor
Gábor BLASKÓ
Gyula LUKÁCS
Józsefné REITER
Endréné FLÓRIÁN
Márta PORCS-MAKKAY
Tibor Mezei
Gyula Simig
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EGIS Gyógyszergyár Rt.
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Priority to AU21735/97A priority Critical patent/AU2173597A/en
Publication of WO1997036895A1 publication Critical patent/WO1997036895A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the invention relates to the process for the preparation of teni ⁇ dap. More particularly it is concerned with a process for the preparation of 5-chloro-3-(2-thenoyl)-1-carboxamido-2-oxindole of the Formula
  • Tenidap is a known analgesic and spasmolytic therapeutical active ingredient described in prior art. The main indications are alleviation of post-operational and injury caused pains, but teni- dap is also readily applicable for the alleviation of strong pains occurring in connection with chronical diseases (e g rheuma ⁇ toid arthritis or ostenosynovitis)
  • chronical diseases e g rheuma ⁇ toid arthritis or ostenosynovitis
  • the compound of the Formula IV is finally acylated in an inert solvent with a chloride, ester or anhydride of th ⁇ ophen-2- carboxyhc acid to yield tenidap of the Formula I
  • Acylation is carried out in the presence of a catalyst and an acid binding agent (e g tertiary amines, such as t ⁇ ethyl amine, N,N- dimethyl-py ⁇ dine, N-methyl morpholine, etc )
  • a catalyst and an acid binding agent e g tertiary amines, such as t ⁇ ethyl amine, N,N- dimethyl-py ⁇ dine, N-methyl morpholine, etc
  • the tenidap of the Formula I or salts of the general Formula II thereof, present in enol form, are obtained with low yields
  • the starting material of the For ⁇ mula VII may be prepared as described in EPA Ns 155,828
  • the carboxamido group of 5-chloro-1-carboxam ⁇ do-2-ox ⁇ ndole of the Formula IV may be formed by two methods According to one route the urea derivative of the Formula III is used which contains said carboxamido group According to the other pro ⁇ cess the carboxamido group is subsequently introduced into the compound of the Formula V by reaction with chloro-sulfonyl isocyanate and hydrolysis The latter method is used for the preparation of the compound of the Formula VII containing a 2- thenoyl group in position 3
  • the best known process for the preparation of the compounds of the general Formula III starts from 5-chloro-2-ox ⁇ ndole of the Formula V (Hungarian patent specification Ns 196, 178)
  • the 5- chloro-1-carboxam ⁇ do-2-ox ⁇ ndole of the Formula IV can be pre ⁇ pared from the compound of the Formula V in one or two steps by using chloro-sulfonyl isocyanate and direct hydrolysis of the compound of the Formula VI
  • the disadvantage of this process is that highly poisonous and very expensive chlorosulfonyl iso ⁇ cyanate is to be used and the yield is rather low (20-40 %)
  • the present invention is based on the recognition that when treating the compounds of the general Formula IX with a weak base the carbalkoxy group in position 1 remains unchanged and a selective reaction takes place to yield the compounds of the general Formula X It could not be aforeseen that the alk ⁇ oxycarbonyl group in position 2 could be selectively removed while the alkoxycarbonyl group in position 1 does not partici ⁇ pate in the reaction, is neither amidated nor split off
  • the above recognition is so much the more surprising as at a later stage of the synthesis said alkoxycarbonyl group in position 1 is ami- dated to form a carboxamido group
  • the 5-chloro-2-oxindole of the Formula V used as starting ma ⁇ terial is a known compound which can be readily prepared by methods known from prior art [Gassman, Journal of Organic Chemistry 42, 1340 (1977), Wright, Journal of American Chemical Society 78 ⁇ 221 (1956), Walker, Journal of American Chemi-cal Society 77, 3844 (19
  • the com ⁇ pounds of the general Formulae X and XI can be isolated if de ⁇ sired
  • tenidap of the Formula I and salts thereof of the general Formula II can also be prepared without isolating the compounds of the general Formulae X and/or XI
  • lower used in the present specification relates to groups having 1-6, preferably 1-4 carbon atoms
  • lower alkyl relates to straight or branched chain saturated ali- cycilic hydrocarbon groups having 1-6, preferably 1-4 carbon atoms (e g methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, n-hexyl, etc )
  • the lower alkyl groups may be optionally substi ⁇ tuted by one or more halogeno atoms (e g chloro methyl, 2- chloro ethyl, 2,2,2-tr ⁇ chloro ethyl, etc )
  • aryl covers mono- or bicyclic aromatic groups (e.
  • aryl-lower alkyl relates to lower al ⁇ kyl groups substituted by one or more aryl groups - the alkyl and aryl groups are as defined above (e g benzyl, beta-phenyl- ethyl, etc )
  • the aralkyl groups may bear one or more substitu- ents on the aryl ring, whereby the substituents may be those defined in connection with the aryl groups.
  • halogen encompasses the fluorine, chlorine, bromine and io ⁇ dine atoms.
  • the compound of the Formula I is capable of enolization and may be present in one or more tautomeric (enol) forms.
  • the present invention encompasses all tautomeric (enolic) forms of the compounds of the Formulae I and XI.
  • salts relate to salts of the compound of the Formula I formed with pharmaceutically suitable bases.
  • the salts may be preferably alkali (e.g. sodium or potassium) salts but the ammonium salt is preferable as well, the latter salt can readily be prepared and advantageously used as therapeutical active ingredient.
  • the compounds of the general Formula IX are prepared by re ⁇ acting the compound of the Formula V with a halogeno formic acid ester, preferably a chloro formate of the general Formula XII or a reactive derivative thereof. It is preferred to use chloro formates of the general Formula XII, wherein R stands for methyl, ethyl, 2-chloroethyl, 2,2,2-trichloroethyl, n-butyl, tert. butyl, sec. butyl, phenyl, 4-nitro-phenyl or benzyl.
  • the com ⁇ pound of the general Formula IX, wherein R stands for tert. bu ⁇ tyl may be prepared by using di-tert. butyl dicarbonate as reac ⁇ tive chloro formic acid derivative.
  • reaction medium aprotic solvents or dipolar aprotic solvents may be used.
  • aprotic solvents preferably ethers (e.g. diethyl ether, dioxane, tetra-hydrofurane) aliphatic or aromatic hydrocarbons (e.g. hexane, benzene) or dipolar aprotic solvents (e.g. dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide) may be used.
  • ethers e.g. diethyl ether, dioxane, tetra-hydrofurane
  • aromatic hydrocarbons e.g. hexane, benzene
  • dipolar aprotic solvents e.g. dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide
  • One may work preferably in tetrahydrofurane as medium.
  • the reaction may be performed in the presence of an acid binding agent.
  • trimethyl amine, pyridine, N-methyl-piperidine or preferably triethyl amine) or alkali carbonates e.g. sodium carbonate or potas ⁇ sium carbonate
  • the acid binding agent may be used in equimolar amount or in a small excess.
  • the reaction may be accomplished at a temperature of 10-50 °C, preferably at room temperature. The reaction time is some hours.
  • the compound of the general Formula IX thus obtained may be isolated in a known manner by direct crystallization or precipita ⁇ tion in aqueous medium with a solvent and subsequent filtration or centrifuging.
  • a solvent etha ⁇ nol, acetone or ethyl acetate may be used.
  • the compound of the general Formula IX thus obtained is con ⁇ verted into a 5-chloro-1-alkoxycarbonyl-2-oxindole derivative of the general Formula X by treatment with a weak base.
  • a weak base ammonium salts, alkali carbonates (e.g. sodium carbon ⁇ ate or potassium carbonate) or alkali hydrogen carbonates (e.g. sodium hydrogen carbonate or potassium hydrogen carbonate) may be used.
  • the compound of the general Formula IX is re ⁇ acted with an ammonium salt, preferably ammonium carbonate, ammonium acetate or ammonium formate.
  • the above ammo ⁇ nium salts formed with weak acids are advantageously used in equimolar amount.
  • the reaction may be carried out at a tem ⁇ perature of 0-80 °C. The reaction is completed within some hours.
  • the compound of the general Formula X thus obtained may be isolated by known methods e.g. by pouring the reaction mixture on water and subsequent filtration or centrifuging. One may also proceed by using the reaction mixture directly to the next step of the synthesis, without isolating the compound of the general Formula X.
  • the compound of the general Formula X thus obtained is acy ⁇ lated with t ⁇ ophen-2-carboxylic acid or an activated derivative thereof with or without isolation.
  • the compounds of the general Formula XI are prepared by known acylation methods.
  • acy ⁇ lating agent preferably a halide, anhydride or mixed anhydride of tiophen-2-carboxylic acid may be used.
  • acylation is per ⁇ formed by using tiophen-2-carbonyl chloride in the presence of an acid binding agent.
  • acid binding agent preferably tertiary amines (e.g.
  • trimethyl amine, triethyl amine, N-methyl ⁇ morpholine, N-methyl-piperidine or preferably 4-(N,N- d ⁇ methylamino)-p ⁇ peridine may be used.
  • the acylating agent may be applied in a 1 0-1.3 equivalent amount.
  • Acylation may be preferably carried out in an inert solvent.
  • reaction medium ethers (e.g. dioxane, tetrahydrofurane), halo- genated hydrocarbons (e.g. dichloro ethane, chloroform) or di ⁇ polar aprotic solvents (e g. dimethyl formamide, dimethyl acetamide, etc.) may be used.
  • the compound of the general Formula XI is converted into tenidap of the Formula I by amidation This reaction may be accomplished with or without isolating the compound of the ge ⁇ neral Formula XI. It is preferred to use as compound of the general Formula XI 5-chloro-1-phenoxycarbonyl-3-(2-thenoyl)- 2-ox ⁇ ndole, in which R is phenyl. Amidation may be carried out with the aid of ammonia or an ammonium salt As ammonium salt one may use ammonium salts formed with a weak acid, e.g. ammonium carbonate, ammonium formate or ammonium acetate.
  • a weak acid e.g. ammonium carbonate, ammonium formate or ammonium acetate.
  • the ammonium salt may be used in a 1.0-1.3 equiva ⁇ lent amount
  • the reaction may be performed at a temperature between 10 and 100 °C
  • the reaction time varies between some minutes and 24 hours, depending on the definiton of R If the compound of the general Formula XI is used, in which R is phenyl, the reaction is completed within some hours
  • Amidation may be preferably carried out in an inert solvent.
  • reaction medium alcohols (e.g methanol, ethanol), ethers (e.g diethyl ether, tetrahydrofurane) or dipolar aprotic solvents (e.g dimethyl formamide, dimethyl acetamide or N-methyl- pyrrolidone) may be used.
  • reaction mixture is worked up by methods known per se
  • a mineral acid e g hydrochloric acid, sul ⁇ phuric acid, phosphoric acid, etc
  • organic acid e g ace ⁇ tic acid, tartaric acid, citric acid, etc
  • the acylated derivatives of the general Formula XI may be iso ⁇ lated by methods known per se Thus one may proceed e g by acidifying the reaction mixture and precipitating the product by adding a solvent or water Acidification may be carried out by using inorganic acids (e g hydrochloric acid, sulphuric acid) or organic acids To the precipitation step any organic solvent may be used which is miscible with the reaction mixture, it is pre ⁇ ferred to use acetone, methanol, ethanol or ethyl acetate
  • the compounds of the general Formula XI may be converted into their salts, if desired as salts alkali salts (e g sodium or potassium salts), ammonium salts or organic salts (e g dime ⁇ thyl amine, pyridine salts) may be used Salt formation may be carried out by using the corresponding base (e g ammonia, alkali hydroxides or alcoholates) The salts may be precipitated from the reaction mixture by adding an organic solvent (e g acetone, ethyl ether, ethyl acetate, etc.) or the salts spontane ⁇ ously fall out after salt formation.
  • an organic solvent e g acetone, ethyl ether, ethyl acetate, etc.
  • Tenidap of the Formula I may be converted into a salt formed with a suitable therapeutically acceptable base if desired.
  • Salt formation may be carried out in a manner known per se.
  • a suitable organic solvent e.g. ethers such as tetrahydrofurane
  • the corresponding base e.g. ammonia, ammonium salts e.g. ammonium carbonate; or alkali hydroxides, or alkali alcoho- lates.
  • the reaction mixture is diluted preferably with a suitable organic solvent (e.g. acetone, ethyl acetate, diethyl ether) and the precipitated salt is isolated by filtration or centrifuging.
  • a suitable organic solvent e.g. acetone, ethyl acetate, diethyl ether
  • the precipitated salt is isolated by filtration or centrifuging.
  • the alkali salts e.g. sodium or potassium salt
  • the am ⁇ monium salts may
  • tenidap of the Formula I is prepared from the compounds of the general Formula IX in one step without isolat ⁇ ing the intermediates of the general Formulae X and XI.
  • the compound of the general Formula IX is reacted in a suitable solvent with a weak base, the compound of the general For ⁇ mula X formed is acylated with an activated derivative of tio- phen-2-carboxylic acid, whereupon the compound of the gen ⁇ eral Formula XI thus formed is amidated.
  • the solvents, weak bases and activated thiophen-2-carboxylic acid derivatives are those disclosed above in details. According to a particularly preferred embodiment of our invention dimethyl formamide is used as reaction medium.
  • the present in ⁇ vention tenidap of the Formula I is prepared from a compound of the general Formula X in one step without isolating the in ⁇ termediate of the general Formula XI.
  • Acylation of the com ⁇ pound of the general Formula X and amidation of the general Formula XI are carried out under the conditions described above.
  • a salt of the general Formula II is prepared.
  • Amidation may be carried out by using ammonia or a salt thereof (preferably ammonium car ⁇ bonate, ammonium formate or ammonium acetate, particularly ammonium carbonate) as described above. Amidation is per ⁇ formed under heating, preferably at 60-90 °C. The reaction is accomplished preferably in an ether (e.g. diethyl ether or tetra ⁇ hydrofurane) or alcohol (preferably methanol) as medium.
  • ether e.g. diethyl ether or tetra ⁇ hydrofurane
  • alcohol preferably methanol
  • reaction medium If ethers are used as reaction medium, the reaction mixture is evaporated, the residue is dissolved in methanol and salt for ⁇ mation is performed. Salt formation may preferably be carried out with an alkali methylate in methanol as medium. If methanol is used as solvent, the evaporation of the reaction mixture can be omitted and the salt can be directly formed by adding an alkali methylate.
  • Example 1 One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 65 6 g (0 31 mole) of 2,2,2- t ⁇ chloroethyl chloro formate, as solvent 200 ml of dioxane are used and triethyl amme is replaced by 21 2 g (0 2 mole) of powdered sodium carbonate The reaction is carried out at 5-10 °C for 30 minutes Thus 36 5 g of the title compound are ob ⁇ tained in the form of yellowish white crystals Yield 70 4 % Mp 90-90 5 °C (from ethanol)
  • Example 2 One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 34 4 g (0.22 mole) of phenyl chloro formate. Thus 39 96 g of the title compound are obtained in the form of white crystals. Yield- 98 0 % Mp 130-132 °C
  • Example 10 One proceeds as described in Example 10 except that as starting material 43 6 g (0 1 mole) of 1 -benzyloxycarbonyl-2- benzyloxycarbonyloxy-5-chloro- ⁇ ndole (Example 2) are used and ammonium carbonate is replaced by 2 5 g (0 15 mole) of ammonia in the form of an aqueous ammonium hydroxide solu ⁇ tion Thus 28 72 g of the title compound are obtained in the form of white crystals Yield 95 2 % Mp 130-131 °C (from a 1 1 mixture of ethyl acetate and hexane) Analysis for the formula C 16 H 12 CIN0 5 (301 73)
  • Example 10 One proceeds as described in Example 10 except that as starting material 36 78 g (0 1 mole) of 1-butoxycarbonyl-2- butoxycarbonyloxy-5-chloro-indole (Example 4) are used. Thus 23.9 g of the title compound are obtained in the form of white crystals. Yield: 89.4 %. Mp. 67-68.5. °C (from a 1 :1 mixture of ethyl acetate and hexane)
  • Example 10 One proceeds as described in Example 10 except that as starting material 31 17 g (0 1 mole) of 1-ethoxycarbonyl-2- ethoxycarbonyloxy-5-chloro- ⁇ ndole (Example 1) and as solvent tetrahydrofurane are used Thus 12 3 g of the title compound are obtained in the form of white crystals Yield- 51 5 % Mp 101-102 5 °C (from hexane) Analysis for the formula CnH 10 CINO 3 (239.66)
  • Example 10 One proceeds as described in Example 10 except that as starting material 28 4 g (0.1 mole) of 5-chloro-1- methoxycarbonyl-2-methoxycarbonyloxy-indole (Example 9) and as solvent dimethyl acetamide are used Thus 15.2 g of the title compound are obtained in the form of white crystals Yield 69 9 % Mp 129 5-130 °C (from ethyl acetate)
  • Example 15 One proceeds as described in Example 15 except that as starting material 23.97 g (0 1 mole) of 5-chloro-1- ethoxycarbonyl-2-ox ⁇ ndole (Example 13) are used and 4- (d ⁇ methylamino)-pyr ⁇ d ⁇ ne is replaced by 30 0 g (0.3 mole) of N- methyl-pipe ⁇ dine Thus 11 16 g of the title compound are ob ⁇ tained in the form of white crystals Yield 32 0 % Mp 118,5- 120 °C
  • Example 15 One proceeds as described in Example 15 except hat as start ⁇ ing material 30 17 g (0 1 mole) of 1-benzyloxycarbonyl-5- chloro-2-ox ⁇ ndole (Example 11) and as solvent dimethyl ⁇ acetamide are used The product is precipitated with ethyl acetate in the place of water Thus 37 8 of the title compound are obtained in the form of yellow crystals Yield 92 0 % Mp 130-131 °C
  • Example 15 One proceeds as described in Example 15 except that as starting material 26 71 g (0 1 mole) of 1-butoxycarbonyl-5- chloro-2-ox ⁇ ndole (Example 12) are used The addition of thio- phen-2-carbonyl chloride having been completed the reaction mixture is stirred at 60-65 °C for 2 hours Thus 15 86 of the de ⁇ sired compound are obtained in the form of yellow crys ⁇ tals Yield 42,0 % Mp 73-74 °C Analysis for the formula C ⁇ 8 H 16 CINS0 4 (377 85)
  • Example 14 One proceeds as described in Example 15 except that as starting material 22 5 g (0 1 mole) of 5-chloro-1- methoxycarbonyl-2-ox ⁇ ndole (Example 14) are used Thus 32 9 g of the title compound are obtained in the form of a yellow powder Yield 98,2 % Mp 156-158 °C (from acetoni ⁇ trile)
  • Example 7 One proceeds as described in Example 10 except that as starting material 36 78 g (0 1 mole) of 5-chloro-1 -(2-methyl- propyloxycarbonyl)-2-(2-methyl-propyloxycarbonyloxy)- ⁇ ndole (Example 7) are used Thus 24 3 g of the desired compound are obtained in the form of white crystals Yield 90 9 % Mp 99 0-100 0 °C Analysis for the formula C ⁇ 3 H ⁇ CI N0 3 (267 71)
  • Example 15 One proceeds as described in Example 15 except that as starting material 26 8 (0 1 mole) of 5-chloro-1-(2-methyl- propyloxycarbonyl)-2-ox ⁇ ndole (Example 25) are used Thus 26 4 g of the title compound are obtained in the form of yellow crystals Yield 69 8 % Mp 116 5-118 °C
  • Example 29 One proceeds as described in Example 29 except that metha ⁇ nol is used as solvent.
  • the reaction mixture is heated to boiling for 30 minutes, then cooled to 40 °C and 1.0 g of sodium methylate is added.
  • the mixture is stirred at 10 ° for 4 hours and filtered.
  • Yield 81.4 %.
  • the product can be purified as described in Example 22. Mp.: 215-220 °C. Purity: 94.6 % (based on HPLC).

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Abstract

The invention relates to new processes for the preparation of 5-chloro-3-(2-thenoyl)-1-carboxamido-2-oxindole (tenidap) of Formula (I) and salts thereof which are known analgesic and spasmolytic therapeutical active substances.

Description

Process for the preparation of tenidap
The invention relates to the process for the preparation of teni¬ dap. More particularly it is concerned with a process for the preparation of 5-chloro-3-(2-thenoyl)-1-carboxamido-2-oxindole of the Formula
Figure imgf000003_0001
(referred to furtheron as '"tenidap") and salts of the general Formula
Figure imgf000003_0002
thereof (wherein B stands for a pharmaceutically acceptable cation).
Tenidap is a known analgesic and spasmolytic therapeutical active ingredient described in prior art. The main indications are alleviation of post-operational and injury caused pains, but teni- dap is also readily applicable for the alleviation of strong pains occurring in connection with chronical diseases (e g rheuma¬ toid arthritis or ostenosynovitis)
In Hungarian patent specifications NQS 196,178 and 194,825 two basic procedures are disclosed for the preparation of teni¬ dap According to one process 5-chloro-1-carboxamιdo-2- oxindole of the Formula
Figure imgf000004_0001
is prepared by subjecting 2-(5-chloro-2-ureιdo)-phenyl-acetιc acid of the general Formula
Figure imgf000004_0002
(wherein R is alkyl or aryl) to cyclization in tπfluoro acetic anhy¬ dride, or reacting 5-chloro-2-oxιndole of the Formula
V
Figure imgf000004_0003
with chlorosulfonyl isocyanate and thereafter hydrolizing the intermediate of the Formula
Figure imgf000005_0001
The compound of the Formula IV is finally acylated in an inert solvent with a chloride, ester or anhydride of thιophen-2- carboxyhc acid to yield tenidap of the Formula I
Acylation is carried out in the presence of a catalyst and an acid binding agent (e g tertiary amines, such as tπethyl amine, N,N- dimethyl-pyπdine, N-methyl morpholine, etc )
According to EPA Ns 153,818 5-chloro-3-(2-thenoyl)-oxιndole of the Formula
Figure imgf000005_0002
is reacted in toluene with chlorosulfonyl isocyanate, whereupon the 5-chloro-3-(2-thenoyl)-N-chlorosulfonyl-2-oxιndole of the Formula
Figure imgf000006_0001
thus obtained is hydrolized The tenidap of the Formula I or salts of the general Formula II thereof, present in enol form, are obtained with low yields The starting material of the For¬ mula VII may be prepared as described in EPA Ns 155,828
The carboxamido group of 5-chloro-1-carboxamιdo-2-oxιndole of the Formula IV may be formed by two methods According to one route the urea derivative of the Formula III is used which contains said carboxamido group According to the other pro¬ cess the carboxamido group is subsequently introduced into the compound of the Formula V by reaction with chloro-sulfonyl isocyanate and hydrolysis The latter method is used for the preparation of the compound of the Formula VII containing a 2- thenoyl group in position 3
The known methods are accompanied by several drawbacks The conversion of the 2-(5-chloro-2-ureιdo)-phenyl-acetιc acid derivatives of the general Formula III into the compound of the Formula IV is carried out in tnfluoro acetic anhydride which is a very toxical, poisonous and expensive reagent Moreover by this method 5-chloro-1-carboxamιdo-2-oxιndole of the Formula IV of suitable purity can be obtained but with moderate yields
The best known process for the preparation of the compounds of the general Formula III starts from 5-chloro-2-oxιndole of the Formula V (Hungarian patent specification Ns 196, 178) The 5- chloro-1-carboxamιdo-2-oxιndole of the Formula IV can be pre¬ pared from the compound of the Formula V in one or two steps by using chloro-sulfonyl isocyanate and direct hydrolysis of the compound of the Formula VI The disadvantage of this process is that highly poisonous and very expensive chlorosulfonyl iso¬ cyanate is to be used and the yield is rather low (20-40 %)
The process disclosed in Hungarian patent Ne 194,825 necessi¬ tates the use of chlorosulfonyl isocyanate which is a very toxical and expensive reagent and can be used on industrial scale production only under special safety measures
According to Hungarian patent Ne 196,178 the introduction of the thenoyi group into position 3 of 5-chloro-2-oxmdole can be performed only with low yields (30-40 %) This process is prac¬ tically unsuitable for industrial scale manufacture of tenidap because of the low yields and the impurities derived from nu¬ merous side reactions Tenidap of the Formula I prepared by said method is suitable for the preparation of salts of the gen¬ eral Formula II to be used as active ingredient in pharmaceuti¬ cal compositions only after purification which is accompanied by substantial losses
It is the object of the present invention to eliminate the above drawbacks of the known procedures and to provide a process for the preparation of tenidap which uses inexpensive readily available and nontoxical starting materials, is suitable for indus¬ trial scale manufacture, can be carried out with high yields and gives highly pure product
The above object is achieved by the new process of the present invention by using 5-chloro-2-oxιndole of the general Formula V as starting material
According to the present invention there is provided a process for the preparation of 5-chloro-3-(2-thenoyl)-1-carboxamιdo-2- oxindole of the Formula I and pharmaceutically acceptable salts thereof which comprises a ) amidating a compound of the general Formula
XI
Figure imgf000008_0001
(wherein R stands for optionally halogenosubstituted lower alkyl or optionally substituted aryl or aryl-lower alkyl); or b ) acylating a compound of the general Formula
Figure imgf000009_0001
(wherein R is as stated above) with tιophen-2-carboxylic acid or an activated derivative thereof, if desired converting the compound of the general Formula XI thus obtained into a salt, and amidating the compound of the general Formula XI, or c ) reacting a compound of the general Formula
Figure imgf000009_0002
(wherein R is as stated above) with a weak base, acylating the compound of the general Formula X thus obtained with tiophen-2-carboxilyc acid or an activated derivative thereof and amidating the compound of the general Formula XI thus obtained; or d ) reacting 5-chloro-2-oxιndole of the Formula V with a halo- geno formic acid ester, preferably with a chloro formate of
the general Formula
CI-COOR xu
(wherein R is as stated above), reacting the compound of the general Formula IX thus obtained with a weak base acylating the compound of the general Formula X thus ob¬ tained with tιophen-2-carboxylιc acid or an activated deriva¬ tive thereof and amidating the compound of the general Formula XI thus obtained, and if desired converting the compound of the Formula I thus obtained into a pharmaceutically acceptable salt thereof
The present invention is based on the recognition that when treating the compounds of the general Formula IX with a weak base the carbalkoxy group in position 1 remains unchanged and a selective reaction takes place to yield the compounds of the general Formula X It could not be aforeseen that the alk¬ oxycarbonyl group in position 2 could be selectively removed while the alkoxycarbonyl group in position 1 does not partici¬ pate in the reaction, is neither amidated nor split off The above recognition is so much the more surprising as at a later stage of the synthesis said alkoxycarbonyl group in position 1 is ami- dated to form a carboxamido group The 5-chloro-2-oxindole of the Formula V used as starting ma¬ terial is a known compound which can be readily prepared by methods known from prior art [Gassman, Journal of Organic Chemistry 42, 1340 (1977), Wright, Journal of American Chemical Society 78^ 221 (1956), Walker, Journal of American Chemi-cal Society 77, 3844 (1955)]
According to the process of the present invention the com¬ pounds of the general Formulae X and XI can be isolated if de¬ sired However, tenidap of the Formula I and salts thereof of the general Formula II can also be prepared without isolating the compounds of the general Formulae X and/or XI
The term "lower" used in the present specification relates to groups having 1-6, preferably 1-4 carbon atoms The term "lower alkyl" relates to straight or branched chain saturated ali- cycilic hydrocarbon groups having 1-6, preferably 1-4 carbon atoms (e g methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, n-hexyl, etc ) The lower alkyl groups may be optionally substi¬ tuted by one or more halogeno atoms (e g chloro methyl, 2- chloro ethyl, 2,2,2-trιchloro ethyl, etc ) The term "aryl" covers mono- or bicyclic aromatic groups (e. g phenyl or naphtyl) op¬ tionally bearing one or more substituents (e g halogen such as chlorine or fluorine, lower alkyl, lower alkoxy e g methoxy, ethoxy, or nitro) The term "aryl-lower alkyl" relates to lower al¬ kyl groups substituted by one or more aryl groups - the alkyl and aryl groups are as defined above (e g benzyl, beta-phenyl- ethyl, etc ) The aralkyl groups may bear one or more substitu- ents on the aryl ring, whereby the substituents may be those defined in connection with the aryl groups. The term "halogen" encompasses the fluorine, chlorine, bromine and io¬ dine atoms.
The compound of the Formula I is capable of enolization and may be present in one or more tautomeric (enol) forms. The present invention encompasses all tautomeric (enolic) forms of the compounds of the Formulae I and XI.
The term "pharmaceutically acceptable salts" relates to salts of the compound of the Formula I formed with pharmaceutically suitable bases. The salts may be preferably alkali (e.g. sodium or potassium) salts but the ammonium salt is preferable as well, the latter salt can readily be prepared and advantageously used as therapeutical active ingredient.
The compounds of the general Formula IX are prepared by re¬ acting the compound of the Formula V with a halogeno formic acid ester, preferably a chloro formate of the general Formula XII or a reactive derivative thereof. It is preferred to use chloro formates of the general Formula XII, wherein R stands for methyl, ethyl, 2-chloroethyl, 2,2,2-trichloroethyl, n-butyl, tert. butyl, sec. butyl, phenyl, 4-nitro-phenyl or benzyl. The com¬ pound of the general Formula IX, wherein R stands for tert. bu¬ tyl, may be prepared by using di-tert. butyl dicarbonate as reac¬ tive chloro formic acid derivative. I I
The reaction is carried out in an organic solvent. As reaction medium aprotic solvents or dipolar aprotic solvents may be used. As aprotic solvents preferably ethers (e.g. diethyl ether, dioxane, tetra-hydrofurane) aliphatic or aromatic hydrocarbons (e.g. hexane, benzene) or dipolar aprotic solvents (e.g. dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide) may be used. One may work preferably in tetrahydrofurane as medium. The reaction may be performed in the presence of an acid binding agent. For this purpose tertiary amines (e.g. trimethyl amine, pyridine, N-methyl-piperidine or preferably triethyl amine) or alkali carbonates (e.g. sodium carbonate or potas¬ sium carbonate) may be used. The acid binding agent may be used in equimolar amount or in a small excess. The reaction may be accomplished at a temperature of 10-50 °C, preferably at room temperature. The reaction time is some hours.
The compound of the general Formula IX thus obtained may be isolated in a known manner by direct crystallization or precipita¬ tion in aqueous medium with a solvent and subsequent filtration or centrifuging. To the precipitation as solvent methanol, etha¬ nol, acetone or ethyl acetate may be used.
The compound of the general Formula IX thus obtained is con¬ verted into a 5-chloro-1-alkoxycarbonyl-2-oxindole derivative of the general Formula X by treatment with a weak base. As weak base ammonium salts, alkali carbonates (e.g. sodium carbon¬ ate or potassium carbonate) or alkali hydrogen carbonates (e.g. sodium hydrogen carbonate or potassium hydrogen carbonate) may be used. According to a preferred embodiment of the pre¬ sent invention the compound of the general Formula IX is re¬ acted with an ammonium salt, preferably ammonium carbonate, ammonium acetate or ammonium formate. The above ammo¬ nium salts formed with weak acids are advantageously used in equimolar amount. The reaction may be carried out at a tem¬ perature of 0-80 °C. The reaction is completed within some hours.
The compound of the general Formula X thus obtained may be isolated by known methods e.g. by pouring the reaction mixture on water and subsequent filtration or centrifuging. One may also proceed by using the reaction mixture directly to the next step of the synthesis, without isolating the compound of the general Formula X.
The compound of the general Formula X thus obtained is acy¬ lated with tιophen-2-carboxylic acid or an activated derivative thereof with or without isolation. The compounds of the general Formula XI are prepared by known acylation methods. As acy¬ lating agent preferably a halide, anhydride or mixed anhydride of tiophen-2-carboxylic acid may be used. According to a pre¬ ferred embodiment of the present invention acylation is per¬ formed by using tiophen-2-carbonyl chloride in the presence of an acid binding agent. As acid binding agent preferably tertiary amines (e.g. trimethyl amine, triethyl amine, N-methyl¬ morpholine, N-methyl-piperidine or preferably 4-(N,N- dιmethylamino)-pιperidine may be used. The acylating agent may be applied in a 1 0-1.3 equivalent amount.
Acylation may be preferably carried out in an inert solvent. As reaction medium ethers (e.g. dioxane, tetrahydrofurane), halo- genated hydrocarbons (e.g. dichloro ethane, chloroform) or di¬ polar aprotic solvents (e g. dimethyl formamide, dimethyl acetamide, etc.) may be used.
The compound of the general Formula XI is converted into tenidap of the Formula I by amidation This reaction may be accomplished with or without isolating the compound of the ge¬ neral Formula XI. It is preferred to use as compound of the general Formula XI 5-chloro-1-phenoxycarbonyl-3-(2-thenoyl)- 2-oxιndole, in which R is phenyl. Amidation may be carried out with the aid of ammonia or an ammonium salt As ammonium salt one may use ammonium salts formed with a weak acid, e.g. ammonium carbonate, ammonium formate or ammonium acetate. The ammonium salt may be used in a 1.0-1.3 equiva¬ lent amount The reaction may be performed at a temperature between 10 and 100 °C The reaction time varies between some minutes and 24 hours, depending on the definiton of R If the compound of the general Formula XI is used, in which R is phenyl, the reaction is completed within some hours
Amidation may be preferably carried out in an inert solvent. As reaction medium alcohols (e.g methanol, ethanol), ethers (e.g diethyl ether, tetrahydrofurane) or dipolar aprotic solvents (e.g dimethyl formamide, dimethyl acetamide or N-methyl- pyrrolidone) may be used
The reaction having been completed the reaction mixture is worked up by methods known per se Thus one may proceed e g by removing the solvent completely or partially in vacuo, suspending the residue in water, precipitating tenidap of the Formula I by adding a mineral acid (e g hydrochloric acid, sul¬ phuric acid, phosphoric acid, etc ) or an organic acid (e g ace¬ tic acid, tartaric acid, citric acid, etc ) and isolating the product by filtrating or centrifuging
The acylated derivatives of the general Formula XI may be iso¬ lated by methods known per se Thus one may proceed e g by acidifying the reaction mixture and precipitating the product by adding a solvent or water Acidification may be carried out by using inorganic acids (e g hydrochloric acid, sulphuric acid) or organic acids To the precipitation step any organic solvent may be used which is miscible with the reaction mixture, it is pre¬ ferred to use acetone, methanol, ethanol or ethyl acetate
The compounds of the general Formula XI may be converted into their salts, if desired As salts alkali salts (e g sodium or potassium salts), ammonium salts or organic salts (e g dime¬ thyl amine, pyridine salts) may be used Salt formation may be carried out by using the corresponding base (e g ammonia, alkali hydroxides or alcoholates) The salts may be precipitated from the reaction mixture by adding an organic solvent (e g acetone, ethyl ether, ethyl acetate, etc.) or the salts spontane¬ ously fall out after salt formation.
Tenidap of the Formula I may be converted into a salt formed with a suitable therapeutically acceptable base if desired. Salt formation may be carried out in a manner known per se. One may proceed by dissolving tenidap of the Formula I in a suitable organic solvent (e.g. ethers such as tetrahydrofurane), adding the corresponding base (e.g. ammonia, ammonium salts e.g. ammonium carbonate; or alkali hydroxides, or alkali alcoho- lates). The reaction mixture is diluted preferably with a suitable organic solvent (e.g. acetone, ethyl acetate, diethyl ether) and the precipitated salt is isolated by filtration or centrifuging. As therapeutically and pharmaceutically acceptable salts prefera¬ bly the alkali salts (e.g. sodium or potassium salt) or the am¬ monium salts may be mentioned.
According to a preferred embodiment of the process of the pre¬ sent invention tenidap of the Formula I is prepared from the compounds of the general Formula IX in one step without isolat¬ ing the intermediates of the general Formulae X and XI. The compound of the general Formula IX is reacted in a suitable solvent with a weak base, the compound of the general For¬ mula X formed is acylated with an activated derivative of tio- phen-2-carboxylic acid, whereupon the compound of the gen¬ eral Formula XI thus formed is amidated. The solvents, weak bases and activated thiophen-2-carboxylic acid derivatives are those disclosed above in details. According to a particularly preferred embodiment of our invention dimethyl formamide is used as reaction medium.
According to a further preferred embodiment of the present in¬ vention tenidap of the Formula I is prepared from a compound of the general Formula X in one step without isolating the in¬ termediate of the general Formula XI. Acylation of the com¬ pound of the general Formula X and amidation of the general Formula XI are carried out under the conditions described above. One may work particularly preferably in dimethyl for¬ mamide as medium.
According to a particularly preferable embodiment of the pre¬ sent invention from a compound of the general Formula XI di¬ rectly a salt of the general Formula II is prepared. One may ad¬ vantageously use a compound of the general Formula XI, wherein R stands for phenyl. Amidation may be carried out by using ammonia or a salt thereof (preferably ammonium car¬ bonate, ammonium formate or ammonium acetate, particularly ammonium carbonate) as described above. Amidation is per¬ formed under heating, preferably at 60-90 °C. The reaction is accomplished preferably in an ether (e.g. diethyl ether or tetra¬ hydrofurane) or alcohol (preferably methanol) as medium. If ethers are used as reaction medium, the reaction mixture is evaporated, the residue is dissolved in methanol and salt for¬ mation is performed. Salt formation may preferably be carried out with an alkali methylate in methanol as medium. If methanol is used as solvent, the evaporation of the reaction mixture can be omitted and the salt can be directly formed by adding an alkali methylate.
The advantages of the process of the present invention can be summarized as follows:
- inexpensive, readily available starting materials are used;
- the toxical, poisonous reagents are eliminated;
- the process is readily feasible with good yields on industrial scale too;
- high yield;
- pure product is obtained.
Further details of the present invention are to be found in the Examples without limiting the scope of protection to said Examples.
Example 1
1 -ethox ycarbon yl-2-ethox ycarbon yloxy-5-chloro-ιndole
A mixture of 16 7 g (0 10 mole) of 5-chloro-oxιndole, 22 2 g (0 22 mole) of triethyl amme, 23,8 g (0 22 mole) of ethyl chloro formate and 360 ml of tetrahydrofurane is stirred at 20 °C for an hour The solvent is distilled off in vacuo, the residue is poured into water and the precipitated crystals are filtered Thus 28 6 g of the title compound are obtained in the form of white crystals Yield 91 8 % Mp 76 0-77 5 °C (from hexane)
Analysis for the formula C14H14CIN05 (311 72)
C % H % Cl % N %
Calc. 53 94 4 53 11 37 4 50
Found 53 72 4,54 11 12 4 38
Example 2
1-benzyloxycarbonyl-2-benzyloxycarbonyloxy-5-chloro-ιndole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 37 4 g (0 22 mole) of benzyl chloro formate and tetrahydrofurane is replaced by an identical volume of diethyl ether Thus 38 5 g of the desired compound are obtained in the form of white crystals Yield 88 3 % Mp 109-1 11 5 °C (from a 1 1 mixture of ethyl acetate and hexane) Analysis for the formula C24Hi8CIN05 (435,87)
C % H % Cl % N %
Calc. 66 14 4 16 8 13 3 21
Found 66 22 4,09 8 08 3 21
Example 3
5-chloro-1-ϊ(2.2.2-tπchloroethoxy)-carbonyll- 2-U2 2 2-trιchloroethoxy)-carbonyloxy]-ιndole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 65 6 g (0 31 mole) of 2,2,2- tπchloroethyl chloro formate, as solvent 200 ml of dioxane are used and triethyl amme is replaced by 21 2 g (0 2 mole) of powdered sodium carbonate The reaction is carried out at 5-10 °C for 30 minutes Thus 36 5 g of the title compound are ob¬ tained in the form of yellowish white crystals Yield 70 4 % Mp 90-90 5 °C (from ethanol)
Analysis for the formula C14H8CI7N05 (518 40)
C % H % Cl % N %
Calc. 32 44 1 56 47 87 2 70
Found 32 15 1 60 47 52 2 65 Example 4
5-chloro-1-butoxycarbonvf-2-butoxycarbonyloxy-ιndole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 42 35 g (0 31 mole) of butyl chloro formate and benzene is used as solvent Thus 33 8 g of the title compound are obtained in the form of white crystals Yield 92 1 % Mp 57-58 5 °C
Analysis for the formula Cι8H22CIN05 (367 83)
C % H % Cl % N %
Calc. 58 78 6 03 9 64 3 81
Found 58 61 5,90 9 59 3 76
Example 5
5-chloro-1-(2-chloro-ethoxycarbonyl)-2-(2-chloro- ethoxycarbonyloxy)-ιndole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 65 73 g (046 mole) of 2- chloroethyl chloroformate Thus 29 3 g of the desired com¬ pound are obtained in the form of light violet crystals Yield 77 2 % Mp 70-72 °C (from ethanol) Analysis for the formula Cι4Hi2CI3N05 (380 16)
C % H % Cl % N %
Calc. 44 18 3 18 27 94 3 68
Found 44 23 3,22 27 58 3 58 Example 6
5-chloro-1-tert. butoxycarbonyl-2-tert. butoxycarbonyloxy-indole
A mixture of 5.01 g (30 millimoles) of 5-chloro-oxindole, 13.08 g (60 millimoles) of di-tert. butyl-dicarbonate, 7.5 g (75 millimoles) of triethyl amine and 100 ml of anhydrous tetrahydrofurane is stirred at 50-60 °C for 48 hours. The solvent is distilled in vacuo, the residue is poured into water and the product is ex¬ tracted with n-hexane. The organic layer is cooled to -5 °C and the precipitated crystals are filtered. Thus 2.53 g of the desired compound are obtained in the form of white crystals. Yield: 22.9 %. Mp.: 94-95.5 °C.
Analysis for the formula C18H22CIN05 (367.83)
C % H % Cl % N %
Calc. 58.78 6.03 9.64 3.81
Found 58.33 6,09 9.55 3.92
Example 7
5-chloro-1-{2-methyl-DroDyloxycarbonyl)- 2-(2-methyl-propyloxycarbonyloxy)-indole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 37.54 g (0.274 mole) of isobutyl ~>
chloro formate. The reaction mixture is poured into water, the product is extracted with hexane, the organic layer is clarified with charcoal and evaporated. Thus 30.8 g of the desired com¬ pound are obtained in the form of faint yellow crystals Yield 83.7 % n25 D: 1.502.
Analysis for the formula Cι8H22CINO5 (367.83)
C % H % Cl % N %
Calc. 58.78 6.03 9.64 3.81
Found 58.73 6.11 9 72 3.68
Example 8
1 -phenox ycarbon yl-2-phenox ycarbon ylox y-5-chloro-ιndole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 34 4 g (0.22 mole) of phenyl chloro formate. Thus 39 96 g of the title compound are obtained in the form of white crystals. Yield- 98 0 % Mp 130-132 °C
Analysis for the formula C22H14CIN05 (407.81 )
C % H % Cl % N %
Calc. 64,80 3.46 8.69 3.43
Found 64.75 3,38 8.60 3.42 Example 9
1 -methoxycarbon yl-2-methox ycarbon ylox y-5-chloro-ιndole
One proceeds as described in Example 1 except that ethyl chloro formate is replaced by 20 8 g (0 22 mole) of methyl chloro formate and 17 4 g (0 22 mole) of pyridine are used as acid binding agent Thus 12 6 g of the title compound are ob¬ tained Yield 44 5 % Mp 97 5-98 °C (from ethyl acetate)
Analysis for the formula Cι2H10CINO5 (283 67)
C H % Cl % N %
Calc. 50,81 3 55 12 50 4 94
Found 50 67 3,52 12 31 4 89
Example 10
1-phenoxycarbonyl-5-chloro-2-oxιndole
40 78 g (0 1 mole) of 1-phenoxycarbonyl-2-phenoxy- carbonyloxy-5-chloro-ιndole (prepared according to Example 8) are dissolved in 200 ml of dimethyl formamide To the solution at 0-5 °C 7 8 g (0 08 mole) of ammonium carbonate are added The reaction mixture is stirred until no starting material can be detected, not even in traces The reaction time is to 5-8 hours The reaction mixture is poured on a fivefold volume of water The precipitated product is filtered and washed with ethanol Thus 27 08 g of the title compound are obtained in the form of almost white crystals Yield 94 0 % Mp 175-176 5 °C (from ethyl acetate)
Analysis for the formula C15H10CINO3 (287 70)
C % H % Cl % N %
Calc. 62 62 3 50 12 32 4 87
Found 62 79 3,57 12 35 4 79
Example 11 1-benzyloxycarbonyl-5-chloro-2-oxιndole
One proceeds as described in Example 10 except that as starting material 43 6 g (0 1 mole) of 1 -benzyloxycarbonyl-2- benzyloxycarbonyloxy-5-chloro-ιndole (Example 2) are used and ammonium carbonate is replaced by 2 5 g (0 15 mole) of ammonia in the form of an aqueous ammonium hydroxide solu¬ tion Thus 28 72 g of the title compound are obtained in the form of white crystals Yield 95 2 % Mp 130-131 °C (from a 1 1 mixture of ethyl acetate and hexane) Analysis for the formula C16H12 CIN05 (301 73)
C % H % cι % N %
Calc. 63 69 4 01 , 11 75 4 64
Found 63 81 4,05 1 1 57 4 61
Example 12 1-butoxycarbonyl-5-chloro-2-oxιndole
One proceeds as described in Example 10 except that as starting material 36 78 g (0 1 mole) of 1-butoxycarbonyl-2- butoxycarbonyloxy-5-chloro-indole (Example 4) are used. Thus 23.9 g of the title compound are obtained in the form of white crystals. Yield: 89.4 %. Mp. 67-68.5. °C (from a 1 :1 mixture of ethyl acetate and hexane)
Analysis for the formula C13H14CIN03 (267,71)
C % H % Cl % N %
Calc. 58.33 5.27 13,24 5.23
Found 58.48 5,25 13 1 1 5 18
Example 13 1 -ethox ycarbon yl- 5-chloro-2-oxindole
One proceeds as described in Example 10 except that as starting material 31 17 g (0 1 mole) of 1-ethoxycarbonyl-2- ethoxycarbonyloxy-5-chloro-ιndole (Example 1) and as solvent tetrahydrofurane are used Thus 12 3 g of the title compound are obtained in the form of white crystals Yield- 51 5 % Mp 101-102 5 °C (from hexane) Analysis for the formula CnH10CINO3 (239.66)
C % H % Cl % N %
Calc. 55.13 4.21 14.79 5 84
Found 55.22 4,20 14 68 5.82 Example 14
5-chloro- 1 -methox ycarbon yl-2-oxιndole
One proceeds as described in Example 10 except that as starting material 28 4 g (0.1 mole) of 5-chloro-1- methoxycarbonyl-2-methoxycarbonyloxy-indole (Example 9) and as solvent dimethyl acetamide are used Thus 15.2 g of the title compound are obtained in the form of white crystals Yield 69 9 % Mp 129 5-130 °C (from ethyl acetate)
Analysis for the formula Cι0H8CINO3 (225 63)
C % H % Cl % N %
Calc. 53.23 3 57 15 71 6.21
Found 53 13 3,53 15 64 6 24
Example 15
1-phenoxycarbonyl-5-chloro-3-(2-thenoyl)-2-oxιndole
A mixture of 28 77 g (0 1 mole) of 1-phenoxycarbonyl-5-chloro- 2-oxιndole (Example 10), 16 13 g (0 11 mole) of thιophen-2- carbonyl chloride, 26 9 g (0 22 mole) of 4-dιmethylamιno- pyndine and 200 ml of dimethyl formamide is stirred at 6-12 °C for 30 minutes To the reaction mixture a mixture of 400 ml water and 17 ml of 37 % hydrochloric acid is added The mix¬ ture is stirred for 2 hours, whereupon the precipitated product is filtered Thus 39 7 g of the title compound are obtained in the form of yellowish white crystals. Yield 99.8 %. Mp.. 140.5- 142 5 °C (from acetonitrile)
Analysis for the formula C2oH12CIN04S (367.83)
C % H % Cl % N % S %
Calc. 60.38 3.04 8.91 3.52 8.06
Found 59.84 3,19 8.79 3.63 7.93
Example 16
1-ethoxycarbonyl-5-chloro-3-(2-thenoyl)-2-oxindole
One proceeds as described in Example 15 except that as starting material 23.97 g (0 1 mole) of 5-chloro-1- ethoxycarbonyl-2-oxιndole (Example 13) are used and 4- (dιmethylamino)-pyrιdιne is replaced by 30 0 g (0.3 mole) of N- methyl-pipeπdine Thus 11 16 g of the title compound are ob¬ tained in the form of white crystals Yield 32 0 % Mp 118,5- 120 °C
Analysis for the formula Cι6H12CIN04S (349.80)
C % H % Cl % N % S %
Calc. 54 94 3.46 10 14 4.00 9 17
Found 55.06 3,33 10.02 3.95 9.07 Example 17
1-benzyloxycarbonyl-5-chloro-3-(2-thenoyl)-2-oxιndole
One proceeds as described in Example 15 except hat as start¬ ing material 30 17 g (0 1 mole) of 1-benzyloxycarbonyl-5- chloro-2-oxιndole (Example 11) and as solvent dimethyl¬ acetamide are used The product is precipitated with ethyl acetate in the place of water Thus 37 8 of the title compound are obtained in the form of yellow crystals Yield 92 0 % Mp 130-131 °C
Analysis for the formula C21H1 CINO4S (411 87)
C % H % Cl % N % S %
Calc. 61 24 3 43 8 61 3 40 7 79
Found 61 05 3 45 8 65 3 37 7 75
Example 18
1-butoxycarbonyl-5-chloro-3-(2-thenoyl)-2-oxιndole
One proceeds as described in Example 15 except that as starting material 26 71 g (0 1 mole) of 1-butoxycarbonyl-5- chloro-2-oxιndole (Example 12) are used The addition of thio- phen-2-carbonyl chloride having been completed the reaction mixture is stirred at 60-65 °C for 2 hours Thus 15 86 of the de¬ sired compound are obtained in the form of yellow crys¬ tals Yield 42,0 % Mp 73-74 °C Analysis for the formula Cι8H16CINS04 (377 85)
C H % Cl % N % S %
Calc. 57.22 4 27 9 38 3 71 8 49
Found 57 31 4 29 9.38 3 72 8 48
Example 19
5-chloro-1-methoxycarbonyl-3-(2-thenoyl)-2-oxιndole
One proceeds as described in Example 15 except that as starting material 22 5 g (0 1 mole) of 5-chloro-1- methoxycarbonyl-2-oxιndole (Example 14) are used Thus 32 9 g of the title compound are obtained in the form of a yellow powder Yield 98,2 % Mp 156-158 °C (from acetoni¬ trile)
Analysis for the formula C15H10CINO4S (335,77)
C % H % Cl % N % S %
Calc. 53 66 3 00 10 56 4 17 9 55
Found 53 70 2 97 10 45 4 12 9 58
Example 20
1-carboxamιdo-5-chloro-3-(2-thenoyl)-2-oxιndole
A mixture of 39 78 g (0 1 mole) of 1-phenoxycarbonyl-5-chloro- 3-(2-thenoyl)-2-oxιndole (Example 10), 15 37 g (0 16 mole) of ammonium carbonate and 250 ml of dimethyl formamide is stirred at 75-80 °C for 5 hours The reaction mixture is added to a mixture of 500 ml of water and 25 ml of 37 % hydrochloric acid under stirring The precipitated crystals are filtered Thus 32.26 g of the crude title compound are obtained. Yield: 100 % Mp.. 221-224 °C
The crude product (32.6 g) is dissolved in 635 ml of hot metha¬ nol To the solution 6.35 g of 2-amιno-ethanol are added, the solution is clarified with activated charcoal, filtered and to the filtrate 18 75 ml of 37 % hydrochloric acid are added at 40-50 °C dropwise The crystal suspension is stirred at 20-30 °C for 2 hours and dried Thus 25 83 g of the title compound are ob¬ tained Yield. 80 53 % Mp. 229 5-230.5 °C.
Analysis for the formula C14H9CIN2O3S (320.69)
C % H % Cl % N % S %
Calc. 52.42 2.83 11.05 8.73 10.00
Found 52 80 2.90 10 99 8.59 9 90
Example 21 1-carboxamido-5-chloro-3-(2-thenoyl)-2-oxιndole
A mixture of 40 7 g (0 1 mole) of 5-chloro-1-phenoxycarbonyl-2- phenoxycarbonyloxy- dole, 7.8 g (0 8 mole) of ammonium car¬ bonate and 200 ml of dimethyl formamide is stirred at 0-5 °C for 5 hours. To the reaction mixture 26.9 g (0.22 mole) of 4- dimethylamino-pyridine and at 6-12 °C a solution of 26.9 g (0 22 mole) of thιophen-2-carbonyl chloride in 50 ml of dimethyl formamamide are added dropwise After 30 minutes 45 6 g (0.16 mole) of ammonium carbonate are added and the mixture is stirred at 75-80 °C for 5 hours The suspension is poured into a mixture of 500 ml of water and 25 ml of 37 % hydrochloric acid under stirring Thus 25 4 g of the crude title compound are obtained Yield: 79.2 %. Mp.. 212-221 °C.
The crude product is purified as described in Example 20. Thus 19 15 g of the purified title compound are obtained Yield- 75 4 % Mp 229 5-230 5 °C
Analysis for the formula C14H9CIN2O3S (320.69)
C % H % Cl % N % S %
Calc. 52 42 2.83 11 05 8.73 10.00
Found 52 64 2.72 11.01 8 68 9.85
Example 22
1-carboxamιdo-5-chloro-3-(2-thenoyl)-2-oxιndole
A mixture of 28 7 g (0 1 mole) of 1-phenoxycarbonyl-5-chloro-2- oxmdole, 16 1 g (0 11 mole) of tιophen-2-carbonyl chloride, 26.9 g (0.22 mole) of 4-dimethylamιno-pyrιdιne and 200 ml of dimethyl formamide is stirred for half an hour The reaction mixture is heated to 80 °C, stirred at this temperature for 6 hours and poured into a mixture of 500 ml of water and 25 ml of concentrated hydrochloric acid Thus 31 0 g of the crude title compound are obtained Yield: 96 6 % Mp . 215-220 °C The crude product is purified as described in Example 20. Thus 24.3 g of the purified title compound are obtained. Yield: 78.5 % Mp.: 229.9-230.5 °C.
Analysis for the formula Cι4H9CIN2O3S (320.69)
C % H % Cl % N % S %
Calc. 52.42 2.83 11.05 8.73 10.00
Found 53.10 2.90 11.12 8.37 10.09
Example 23 Ammonium salt of 1-ethoxycarbonyl-5-chloro-3-(2-thenoyl)-2- oxindole
0.70 g (2 millimols) of 1-ethoxycarbonyl-5-chloro-3-(2-thenoyl)- 2-oxindole (Example 16) is dissolved in 4 ml of dimethyl for¬ mamide and 0.16 g (1.7 millimoles) of ammonium carbonate are added. The reaction mixture is stirred for half an hour, whereupon it is poured on 20 g of ice. The precipitated product is filtered. Thus 0.61 g of the title compound is obtained in the form of yellow crystals. Yield: 80 %. Mp.: 194-197 ° C.
Analysis for the formula Cι6H15CIN204S (366,84)
C % H % Cl % N % S %
Calc. 52.39 4.12 9.67 7.64 8.74
Found 52.48 4.18 9.65 7.59 8.68 Example 24
Sodium salt of 1-carboxamιdo-5-chloro-3-(2-thenoyl)-2-oxιndole
A mixture of 4 0 g (10 millimoles) of 1-phenoxycarbonyl-5- chloro-3-(2-thenoyl)-2-oxιndole (Example 15), 1 54 g (15 milli¬ moles) of ammonium carbonate and 25 ml of tetrahydrofurane is stirred at 75 °C for 8 hours The clear yellow solution is evaporated in vacuo, the residue is dissolved in 20 ml of ace¬ tonitrile and 0 54 g (10 millimoles) of sodium methylate are added The product is crystallized at 0 °C for 4 hours and dried Thus 3 23 of the title compound are obtained in the form of yellow crystals Yield 94 2 % Mp 237-238 °C
Analysis for the formula C14H9CIN2θ3SNa (343 69)
C % H % Cl % N % S %
Calc. 48 91 2 64 10 31 8 14 9 33
Found 48 85 2 60 10 33 8 25 9 28
Example 25
5-chloro-1 '-(2-meth yl-propyloxycarbonyl)-2-oxιndole
One proceeds as described in Example 10 except that as starting material 36 78 g (0 1 mole) of 5-chloro-1 -(2-methyl- propyloxycarbonyl)-2-(2-methyl-propyloxycarbonyloxy)-ιndole (Example 7) are used Thus 24 3 g of the desired compound are obtained in the form of white crystals Yield 90 9 % Mp 99 0-100 0 °C Analysis for the formula Cι3Hι CI N03 (267 71)
C % H % Cl % N %
Calc. 58.33 5.27 13 24 5.23
Found 58 10 5.28 13.20 5.19
Example 26 5-chloro-1-(2-methyl-orOoyloxycarbonyl)-3-(2-thenoyl)-2- oxindole
One proceeds as described in Example 15 except that as starting material 26 8 (0 1 mole) of 5-chloro-1-(2-methyl- propyloxycarbonyl)-2-oxιndole (Example 25) are used Thus 26 4 g of the title compound are obtained in the form of yellow crystals Yield 69 8 % Mp 116 5-118 °C
Analysis for the formula Cι8H16CIN04S (377,85)
C % H % Cl % N % S %
Calc. 57.22 4.27 9 38 3 71 8 49
Found 57 41 4 30 9 31 3 65 8 51
Example 27
5-chloro-3-(2-thenoyl)-1-f(2, 2, 2-tπchloroethoxy)carbonyll-2- oxmdole
To a solution of 2 6 g (5 millimoles) of 5-chloro-1 -[(2,2,2- trιchloro-ethoxy)-carbonyl]-2-[(2,2,2-trichloroethoxy)-carbonyl- 35
oxy]-indole (Example 3) in 10 ml of dimethyl formamide at 5 °C 0.4 g (4.1 millimole) of ammonium carbonate is added and the reaction mixture is stirred at 20 °C for 3 hours. The mixture is cooled to 10 °C whereupon 1.4 g (12 millimoles) of 4- dimethylamino-pyridine and a solution of 0.8 g (5 millimoles) of thiophen-2-carbonyl chloride in 3 ml of dimethyl formamide are added. The reaction mixture is stirred at 5 °C for 3 hours, then poured into a mixture of 100 g of ice and 2 ml of concentrated hydrochloric acid. The product is filtered and crystallized from a fivefold volume of acetonitrile. Thus 1.0 g of the desired com¬ pound are obtained in the form of yellow crystals. Yield: 44.2 %. Mp.: 117-119 °C.
Analysis for the formula Ci6H9CI.,N04S (453.13)
C % H % Cl % N %
Calc. 44.22 2.00 31.30 3.09
Found 42.88 2.02 31.13 3.02
Example 28
5-chloro- 1 -(2-chloro-ethox ycarbon yl)-3-(2-thenoyl) -2-oxindole
A mixture of 5.75 g (15 millimoles) of 5-chloro-1-(2-chloro- ethoxy-carbonyl)-2-(2-chloro-ethoxycarbonyloxy)-2-indole (Example 5), 1.2 g (12 millimoles) of ammonium carbonate and 20 ml of dimethyl formamide is stirred at 20 °C for 3 hours. To the mixture at 5 °C 4.2 g (36 millimoles) of 4-dimethylamino- pyridine and a solution of 2.4 g (15 millimoles) of thiophen-2- carbonyl chloride in 10 ml of dimethylformamide are added. The reaction mixture is stirred for 3 hours and poured into a mixture of 100 g of ice and 5 ml of concentrated hydrochloric acid. The precipitated crystals are filtered and washed with hexane. Thus 1.4 g of the desired compound are obtained. Yield: 24.3 %. Mp.:138-140 °C.
Analysis for the formula C16H11CI2NO4S (384,24)
C % H % Cl % N % S %
Calc. 50.02 2.89 18.45 3.65 8.34
Found 49.86 2.89 18.27 3.57 8.28
Example 29 Sodium salt of 1-carboxamido-5-chloro-3-(2-thenoyl)-2-oxindole
A mixture of 1.99 g (5 millimoles) of 1-phenoxycarbonyl-3-(2- thenoyl)-2-oxindole, 1.27 g (7.5 millimole) of ammonium carbo¬ nate and 70 ml of tetrahydrofurane is stirred at 70-80 °C for 9 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in 40 ml of methanol and 1 g of sodium methylate is added. The precipitation of the product begins after some mi¬ nutes. The mixture is stirred at 10 °C for 20 hours and dried. Thus 1.1 g of the desired compound are obtained. Yield: 64.0%. Mp.: 237-238 °C. Analysis for the formula Cι4H9CIN203 SNa (343,69)
C % H % Cl % N % S %
Calc. 48.91 2.64 10.31 8.14 9.33
Found 48.97 2.72 10.15 8.32 9.35 Example 30
Sodium salt of 1-carboxamido-5-chloro-3-(2-thenoyl)-2-oxindole
One proceeds as described in Example 29 except that metha¬ nol is used as solvent. The reaction mixture is heated to boiling for 30 minutes, then cooled to 40 °C and 1.0 g of sodium methylate is added. The mixture is stirred at 10 ° for 4 hours and filtered. Thus 1.4 g of the desired title compound are ob¬ tained. Yield: 81.4 %. Mp.: 237-238 °C Purity: 99.8 % (based on sodium content).
Example 31
1-carboxamido-5-chloro-3-(2-thenoyl)-2-oxindole
A mixture of 0.99 g (2.5 millimoles) of 1-phenoxycarbonyl-5- chloro-3-(2-thenoyl)-2-oxindole, 0.7 ml of 25 % aqueous am¬ monium hydroxide solution and 6.2 ml of dimethyl formamide is stirred at 70-80 °C for 5 hours. The suspension is added to a mixture of 12.5 ml water and 0.6 ml of concentrated hydrochlo¬ ric acid. The precipitated product is filtered. Thus 0.75 g of the title compound is obtained. Yield: 93.5 %. Mp.: 215-220 °C.
The product can be purified as described in Example 22. Mp.: 215-220 °C. Purity: 94.6 % (based on HPLC).

Claims

What we claim is,
1 Process for the preparation of 5-chloro-3-(2-thenoyl)-1 carboxamido-2-oxindole of the Formula
Figure imgf000040_0001
and pharmaceutically acceptable salts thereof which comprises
a ) amidating a compound of the general Formula
Figure imgf000040_0002
(wherein R stands for optionally halogenosubstituted lower alkyl or optionally substituted aryl or aryl-lower alkyl), or b ) acylating a compound of the general Formula
Figure imgf000040_0003
(wherein R is as stated above) with tιophen-2-carboxylιc acid or an activated derivative thereof, if desired converting the compound of the general Formula XI thus obtained into a salt, and amidating the compound of the general Formula XI; or c.) reacting a compound of the general Formula
Figure imgf000041_0001
(wherein R is as stated above) with a weak base, acylating the compound of the general Formula X thus obtained with tiophen-2-carboxylic acid or an activated derivative thereof and amidating the compound of the general Formula XI thus obtained; or d.) reacting 5-chloro-2-oxindole of the Formula
Figure imgf000041_0002
with a halogeno formic acid ester, preferably with a chloro formate of the general Formula
CI-COOR xu
(wherein R is as stated above), reacting the compound of the general Formula IX thus obtained with a weak base, acylating the compound of the general Formula X thus ob¬ tained with tiophen-2-carboxylic acid or an activated deriva¬ tive thereof and amidating the compound of the general Formula XI thus obtained, and if desired converting the compound of the Formula I thus obtained into a pharmaceutically acceptable salt thereof.
2.) Process according to Claim 1 which comprises carrying out acylation of the compound of the general Formula X and amidation of the compound of the general Formula XI in one step ("Eintopfverfahren", "one-pot method") without isolating the compound of the general Formula XI.
3.) Process according to Claim 1 which comprises carrying out the reaction of the compound of the general Formula IX with a weak base, acylation of the compound of the general Formula X and amidation of the compound of the general For¬ mula XI in one step ("Eintopfverfahren", "one-pot method") without isolating the compounds of the general Formulae X and XI.
4.) Process according to Claim 1 which comprises reacting the compound of the Formula V and the chloro formate of the general Formula XII in an aprotic or dipolar aprotic solvent, in the presence of an acid binding agent.
5.) Process according to Claim 4 which comprises using as aprotic solvent an ether or aliphatic or aromatic hydrocarbon or as dipolar aprotic solvent dimethyl formamide, dimethyl sulfox¬ ide or dimethyl acetamide.
6.) Process according to Claim 4 or 5 which comprises using as acid binding agent a tertiary amine or an alkali carbonate, preferably triethyl amine. 41
7.) Process according to any of Claims 4-6 which comprises carrying out the reaction at 10-50 °C.
8.) Process according to Claim 1 which comprises react¬ ing a compound of the general Formula IX with an ammonium salt, an alkali carbonate or an alkali* hydrogen carbonate as weak base.
9.) Process according to Claim 8 which comprises using as weak base ammonium carbonate, ammonium formate or am¬ monium acetate.
10.) Process according to Claim 8 or 9 which comprises car¬ rying out the reaction at 0-80 °C.
11.) Process according to Claim 1 which comprises acylating a compound of the general Formula X with a halide, anhydride or mixed anhydride of tiophen-2-carboxylic acid.
12.) Process according to Claim 11 which comprises carrying out acylation with tiophen-2-carbonyl chloride in the presence of a tertiary amine.
13.) Process according to Claim 12 which comprises using as tertiary amine trimethyl amine, triethyl amine, N-methyl¬ morpholine, N-methyl-piperidine or preferably 4-(N,N- dimethylamino)-pyridine.
14 ) Process according to any of Claims 1 - 13 which com¬ prises carrying out acylation at 0-100 °C
15 ) Process according to Claim 1 which comprises using as compound of the general Formula XI 5-chloro-1- phenoxycarbonyl-3-(2-thenoyl)-2-oxιndole, in which R is phenyl
16 ) Process according to Claim 15 which comprises carrying out amidation with ammonium or an ammonium salt
17 ) Process according to Claim 16 which comprises using as ammonium salt ammonium carbonate, ammonium formate or ammonium acetate
18 ) Process according to Claim 16 or 17 which comprises using the amidating agent in an amount of 1 0 to 1 3 equivalent
19 ) Process according to any of Claims 16 - 18 which com¬ prises carrying out amidation at 10-100 °C
20 ) Process according to any of Claims 16 - 19 which com¬ prises carrying out amidation in a dipolar aprotic solvent
21 Process according to Claim 20 which comprises using as dipolar aprotic solvent dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide
22 ) Process according to Claim 1 which comprises forming the salt of the general Formula
Figure imgf000045_0001
after amidation of the compound of the general Formula XI without isolating the compound of the Formula I.
23.) Process according to Claim 22 which comprises amidat¬ ing a compound of the general Formula I in tetrahydrofurane or methanol as medium; whereby if tetrahydrofurane is used the reaction mixture is evaporated, the residue is taken up in methanol and salt formation is carried out by adding an alkali methylate in methanol as medium.
24.) Compounds of the general Formula IX (wherein R is as stated in Claim 1.
25.) Compounds of the general Formula X (wherein R is as stated in Claim 1.
26.) Compounds of the general Formula XI (wherein R is as stated in Claim 1 and salts thereof.
27. Process for the preparation of compounds of the general Formula IX which comprises reacting 5-chloro-2-oxindole of the Formula V with a halogeno formic acid ester or a reactive de¬ rivative thereof, preferably with a compound of the general Formula XII.
28. Process for the preparation of compounds of the general Formula X which comprises reacting a compound of the gen¬ eral Formula IX with a weak base.
29. Process for the preparation of compounds of the general Formula XI and salts thereof which comprises acylating a com¬ pound of the general Formula X with tiophen-2-carboxylic acid or an active derivative thereof and if desired converting the compound of the general Formula XI thus obtained into a salt thereof.
X -
PCT/HU1997/000013 1996-04-03 1997-04-03 Process for the preparation of tenidap WO1997036895A1 (en)

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US7799798B2 (en) 2005-04-11 2010-09-21 Xenon Pharmaceuticals Inc. Spiroheterocyclic compounds and their uses as therapeutic agents
US8101647B2 (en) 2008-10-17 2012-01-24 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8263606B2 (en) 2008-10-17 2012-09-11 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8445696B2 (en) 2009-10-14 2013-05-21 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US8450358B2 (en) 2009-06-29 2013-05-28 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
US9504671B2 (en) 2010-02-26 2016-11-29 Xenon Pharmaceuticals Inc. Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents
US9682033B2 (en) 2015-02-05 2017-06-20 Teva Pharmaceuticals International Gmbh Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound

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Publication number Priority date Publication date Assignee Title
US7700641B2 (en) 2005-04-11 2010-04-20 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US7799798B2 (en) 2005-04-11 2010-09-21 Xenon Pharmaceuticals Inc. Spiroheterocyclic compounds and their uses as therapeutic agents
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US8106087B2 (en) 2005-04-11 2012-01-31 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
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US8466188B2 (en) 2006-10-12 2013-06-18 Xenon Pharmaceuticals Inc. Use of spiro-oxindole compounds as therapeutic agents
US8916580B2 (en) 2008-10-17 2014-12-23 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8101647B2 (en) 2008-10-17 2012-01-24 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8263606B2 (en) 2008-10-17 2012-09-11 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8415370B2 (en) 2008-10-17 2013-04-09 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their uses as therapeutic agents
US9458178B2 (en) 2008-10-17 2016-10-04 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8450358B2 (en) 2009-06-29 2013-05-28 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US8883840B2 (en) 2009-06-29 2014-11-11 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US9480677B2 (en) 2009-06-29 2016-11-01 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
US8742109B2 (en) 2009-10-14 2014-06-03 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US9260446B2 (en) 2009-10-14 2016-02-16 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US8445696B2 (en) 2009-10-14 2013-05-21 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US9695185B2 (en) 2009-10-14 2017-07-04 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
US9504671B2 (en) 2010-02-26 2016-11-29 Xenon Pharmaceuticals Inc. Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents
US9682033B2 (en) 2015-02-05 2017-06-20 Teva Pharmaceuticals International Gmbh Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound

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HUP9600855A2 (en) 1998-03-30
HU9600855D0 (en) 1996-05-28
AU2173597A (en) 1997-10-22
HUP9600855A3 (en) 1998-04-28

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