WO1997022605A1 - Sels stables et a action prolongee de derives d'indole pour le traitement de maladies articulaires - Google Patents

Sels stables et a action prolongee de derives d'indole pour le traitement de maladies articulaires Download PDF

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Publication number
WO1997022605A1
WO1997022605A1 PCT/IB1996/001280 IB9601280W WO9722605A1 WO 1997022605 A1 WO1997022605 A1 WO 1997022605A1 IB 9601280 W IB9601280 W IB 9601280W WO 9722605 A1 WO9722605 A1 WO 9722605A1
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WIPO (PCT)
Prior art keywords
carbons
alkyl
salt
group
tenidap
Prior art date
Application number
PCT/IB1996/001280
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English (en)
Inventor
Imran Ahmed
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to AU75034/96A priority Critical patent/AU7503496A/en
Publication of WO1997022605A1 publication Critical patent/WO1997022605A1/fr

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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

Definitions

  • This invention provides stable, long acting salts of anti-inflammatory carboxamides, especially salts of (z)-5-chloro-2,3-dihydro-3-(hydroxy-2- thienylmethylene)-2-oxo-1-H-indole-1-carboxamide (tenidap) which are useful as analgesic or anti-inflammatory agents in the treatment of joint disease.
  • Tenidap and other 2-oxindole-1 -carboxamides are acute phase protein modulating anti-inflammatory drugs which are useful for the treatment of rheumatoid arthritis. Similar to the steroids, these compounds have been shown to cause rapid reduction in acute phase proteins in arthritic patients. Intra-articular administration of these compounds relieves joint pain and swelling while minimizing systemic drug exposure. Prolonged-acting formulations employing sparingly soluble salts are required for intra-articular administration.
  • This invention provides the magnesium, calcium, lidocaine and benzathine salts of 2-oxindole-1 -carboxamides of the formula
  • X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido and N,N- dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons and tri
  • R 1 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy )-alkyl having 1 to 3 carbons in said alkyl, naphthyl, b ⁇ cyclo[2 2 1]heptan- 2-yl, b ⁇ cyclo[2 2 1]hept-5-en-2-yl and -(CH 2 ) n -Q-R°, wherein the substituent on said substituted phenyl, said (sub
  • salts are sparingly soluble in water and are suitable for intra-articular injection to alleviate pain and swelling associated with joint disease.
  • Especially preferred compounds are the calcium and benzathine salts of 5- chloro-2,3-d ⁇ hydro-3-(hydroxy-2-th ⁇ enyl-methylene)-2-oxo-1-H- ⁇ ndole-1-carboxam ⁇ de and 5-fluoro-6-chloro-2,3-d ⁇ hydro-3-(hydroxy-2-th ⁇ enylmethylene)-2-oxo-1-H- ⁇ ndole-1- carboxamide
  • this invention provides a method for treating joint disease comprising intra-articular injection of a calcium, magnesium, lidocaine or benzathiene salt of a compound of formula I
  • this invention provides a pharmaceutical composition suitable for intra-articular injection of the calcium, magnesium, lidocaine or benzathine salt of a compound of formula I and a pharmaceutically acceptable earner
  • this invention compnses a salt selected from the group consisting of magnesium, calcium, benzothiene and lidocaine of a compound of the formula
  • X is H, F, Cl, Br, (C,-C 6 )a.kyl, (C 3 -C 8 )cycloalkyl, N0 2 , CF 3 , CN, SH, S(0) m R 3 , OR 4 , COR 4 or CONR R 5 ;
  • Y is H, F, Cl, Br, (C ⁇ -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, N0 2 , CF 3 , CN, SH, S ⁇ R 17 , OR 18 , or CONR 18 R 19 ;
  • R 1 is H
  • R 20 is COR 6 , CONR 7 R 8 , phenyl or mono- or disubstituted phenyl wherein the substituent or substituents are each Cl, F, Br, (C ⁇ -C 6 )alkyl, (d-C 6 )alkoxy, or, CF 3 ;
  • A is H, F, Cl, Br, I, CF 3 , OR 9 , S(0) p R 10 , COOR 11 , CONR 9 R 11 , CN, N0 2 , COR 10 , CH 2 OR 11 , OCOR 10 , NR 9 R 11 , N(R 9 )COR 11 , S0 2 NR 9 R 11 ,
  • B is H, F. Cl, Br, I, CF 3 , OR 13 , S(O), R 14 , COOR 15 , CONR 13 R 15 , CN, N0 2 , COR 14 , CH 2 OR 15 , OCOR 14 , NR 13 R 15 , N(R 13 )C0R 15 . or SO 2 NR 13 R 15 , provided that A and B cannot both be H, or A and B are taken together, bonded to the same ring carbon of Q 1 and equal oxo, or when A is not H, B is as defined above or (d-C 4 )alkyl;
  • a 1 is F, Cl. Br, I, CF 3 , OR 9 , S(O) p R 10 , COOR 11 , CONR 9 R 11 , CN, N0 2 , COR 10 CH 2 OR 11 , OCOR 10 , NR R 11 , N(R 9 )COR 11 , or S0 2 NR 9 R 11 ;
  • n, p, q and t are each zero, one or two; W and Z are each O, S or NR 11 ;
  • W 1 and W 2 are each O, S or NR 10 , provided that when one of W 1 and W 2 is O, S or the other is O or S;
  • R 3 , R 6 , R 10 , R 14 and R 17 are each (C C 6 )alkyl or phenyl;
  • R 5 , R 8 , R 11 , R 15 and R 19 are each H, (C ⁇ -C 6 )alkyl or phenyl;
  • R 4 , R 7 , R 9 , R 13 and are each H or (d-C 6 )alkyl;
  • R 12 is H, F, Cl, Br, CF 3 or (C,-C 6 )alkyl.
  • Tenidap an oxindole
  • Tenidap is an acute phase protein modulating anti-inflammatory drug intended for use in the treatment of rheumatoid arthritis. Similar to the steroids, the oxindoles have been shown to cause rapid reduction in acute phase proteins in arthritic patients and in in vitro studies have been shown to inhibit production of IL-6 and IL-1. These properties suggested the use of tenidap and other oxindoles for intra-articular treatment for arthritis. B.H. Littman, et al. Arthritis and Rheumatism 35/9 Suppl., S341, 1992. An intra-articular suspension dosage form of tenidap free acid was developed as a two-vial product.
  • One vial contained sterile tenidap free acid that was aseptically synthesized and aseptically jet milled.
  • the second vial consisted of a sterile, aqueous, buffered constituting vehicle containing a surfactant.
  • Upon constituting the drug substance with the vehicle the product needed to be vortexed to provide uniform dispersibility of the drug as well as to insure delivery of the required dose.
  • a placebo controlled, double-blind clinical study was conducted in patients with rheumatoid-arthritis or osteo-arthritis. The drug or placebo was administered by intra-articular injection. All patients receiving 120 mg of tenidap free acid or placebo had knee effusions.
  • 2-Oxindole-1 -carboxamides are prepared by procedures described in U.S. Patent 4,556,672, the disclosure of which is hereby inco ⁇ orated by reference.
  • Compounds of formula II are prepared by the procedure described in U.S.
  • Patent 5,047,554 the disclosure of which is hereby inco ⁇ orated by reference.
  • Calcium, magnesium, ⁇ -diethylamino-2,6-dimethylacetanilide (lidocaine), and N,N-dibenzylethylenediamine (benzathine) salts of 2-oxindole-1 -carboxamides are readily prepared by dissolving or suspending the 2-oxindole-1 -carboxamide in a suitable liquid such as glycerine, ethanol, isopropanol or dimethylacetamide and adding equivalent amounts of calcium oxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, lidocaine or benzathine either neat or in the same or different liquid at room temperature or warmed to about 50°C to 100°C.
  • the salt may precipitate or may be precipitated by addition of a second liquid such as water or aqueous alcohol.
  • the salts so obtained may be purified by recrystallization from a suitable solvent.
  • In vitro release rates of 2-oxindole-1 -carboxamide from the salts are shown in table 3 below.
  • Preferred salts are tenidap calcium and tenidap benzathine.
  • a single intra-articular dose of 0.5 ml of a tenidap free acid suspension that contained 30 or 60 mg of tenidap (free acid) activity/ml was shown to be non-irritating.
  • the assay results indicated that in excess of 50% of the single 30 mg dose was cleared from the knee joint at 2 hours post dose and that practically all of the compound was cleared from the joint by 24 hours post dose.
  • the calcium and the benzathine salts of tenidap were selected to develop a long-acting dosage form. In in vitro studies, these salts were found to have substantially slower dissolution rates when compared with tenidap free acid. Formulations were prepared by suspending the appropriate amount of the calcium salt or benzathine salt form of the compound in the clinical vehicle (Tenidap Suspension Vehicle; See Table 1) to obtain a concentration of 120 mg of the active moiety (tenidap free acid)/ml.
  • Suspensions of tenidap salts were wet-milled for 12 hours to reduce the particle size to approximately 10 ⁇ .
  • the test suspensions were maintained at room temperature until they were used for dosing.
  • the tenidap calcium suspension was bright yellow, opaque, and somewhat viscous, while the tenidap benzathine suspension was pale yellow and opaque.
  • the vial containing the appropriate test suspension was agitated vigorously to ensure homogeneity.
  • the animals were manually restrained in a supine position during the brief dosing procedure and were not anesthetized. Each injection was made through the patellar ligament into the intra-articular space using a sterile, 1 ml plastic, disposable syringe equipped with a sterile, disposable, 5/8-inch, 25 gauge hypodermic needle. All animals were returned to their respective cages after dosing. The rabbits were observed intermittently throughout the day of dosing and daily thereafter for clinical signs of discomfort and/or systemic toxicity and for gross changes at the injection site. Each day, the animals' food consumption was evaluated, and individual body weights were recorded. Plasma and both knee joints were obtained from the undosed animal and from two rabbits/treatment group each at 2, 24, 48 and 120 hours after dosing.
  • the knee was placed in a plastic bag and frozen until use.
  • the knee was partially thawed ( ⁇ 15 minutes).
  • the tissue was excised from the joint using a scalpel and scissors, and placed into three heavy-walled Nalgene (100 ml) centrifuge tubes.
  • the remaining bone material was separated into three portions, cut into small pieces with a bone cutter, and combined with the tissue portions in the tubes (i.e., each knee was cut into three segments for extraction).
  • TSA triethylamine
  • the solvent was removed under vacuum (Buchi RE 121 Rotavap, at 40° - 50°C, at 80kPa).
  • the residue was reconstituted with a 10 ml portion of the solvent by vigorously vortexing to disperse the film.
  • a 5 ml portion of the above solution was pipetted into a 10 ml volumetric flask and brought to volume with 0.1 M TRIS buffer (24.2 g TRIS, 4.6 ml H 3 PO 4 , 2 L H 2 0).
  • Tenidap was added to the sample as an internal standard at approximately 2 ⁇ g/ml in the sample).
  • Intact tenidap levels were then quantitated using a high performance liquid chromatography procedure.
  • the chromatographic conditions were as follows: Waters Novapak C-18 column (39 mm x 150 mm: 5 ⁇ particle size); 55% methanol, 45% 0.025M TRIS buffer mobile phase (pH 6.3 with H 3 PO 4 ); flow rate 1 ml/min; detection at 276 nm).
  • the yield was 99% as the crystalline bis salt.
  • the product purity was 72% activity which is correct for the bis salt.
  • the product can be recrystallized by dissolution in warm N,N-dimethylacetamide and reprecipitation by the addition of 4 or more volumes of isopropyl alcohol.
  • Example 2 Tenidap Calcium Salt Dihydrate A 64.15 gram (200 mmol) portion of tenidap was combined with 7.94 gram (105mmol) of 98% calcium hydroxide in 160 milliliters of dimethylacetamide. The resulting thick slurry was heated to 65°C for 15 minutes yielding a hazy solution. The reaction was cooled to 25°C and filtered to sparkle the solution. Precipitation was accomplished by the addition of 480 milliliters of a 50/50 mixture of isopropanol and water. The thick slurry was granulated at ambient temperature for one hour. The partially crystalline product was collected by filtration.
  • This product was charged to 1240 milliliters of a 9/1 mixture of isopropanol and water. The slurry was heated to reflux for one hour. During this reflux period the slurry changed in color from yellow to a deep orange as the dihydrate was formed. The slurry was cooled to 60°C and filtered at that temperature. The collected crystalline product was dried in vacuo at 45°C. A yield of 83% was obtained using this procedure.
  • the product is the bis salt (5.6% calcium) and the dihydrate (5.03% water). Micro analysis was correct for this product and crystallinity was confirmed by both microscopy and X-ray powder diffraction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Des sels de calcium, de magnésium, de lidocaïne et de benzathine de 2-oxyindole-1-carboxamides répondant aux formules (I) ou (II) se révèlent efficaces pour le traitement de maladies articulaires et ce, par administration intra-articulaire. Dans ces formules, X, Y, R1, R20, Q et n sont tels que présentés dans la description.
PCT/IB1996/001280 1995-12-19 1996-11-21 Sels stables et a action prolongee de derives d'indole pour le traitement de maladies articulaires WO1997022605A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75034/96A AU7503496A (en) 1995-12-19 1996-11-21 Stable, long acting salts of indole derivatives for the treatment of joint diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US884495P 1995-12-19 1995-12-19
US60/008,844 1995-12-19

Publications (1)

Publication Number Publication Date
WO1997022605A1 true WO1997022605A1 (fr) 1997-06-26

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AU (1) AU7503496A (fr)
GT (1) GT199600099A (fr)
MA (1) MA24045A1 (fr)
TN (1) TNSN96162A1 (fr)
WO (1) WO1997022605A1 (fr)
ZA (1) ZA9610582B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0826685A1 (fr) * 1996-08-21 1998-03-04 Pfizer Inc. Sels de carboxamides stables à effet prolongé destinés au traitement des maladies articulaires

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4556672A (en) * 1984-03-19 1985-12-03 Pfizer Inc. 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents
EP0337628A2 (fr) * 1988-04-13 1989-10-18 Pfizer Inc. Dérivés du 2-oxindole-1-carboxamide substitués en position 3, utilisés pour supprimer l'activité des cellules T
US5036099A (en) * 1987-02-02 1991-07-30 Pfizer Inc. Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
US5047554A (en) * 1989-04-18 1991-09-10 Pfizer Inc. 3-substituted-2-oxindole derivatives
EP0498588A1 (fr) * 1991-02-08 1992-08-12 Pfizer Inc. Utilisation du tenidap pour réduire le cholestérol total sérique, le cholesterol des lipoprotéine à faible densité (ldl) ainsi que les triglycerides
WO1994016694A1 (fr) * 1993-01-22 1994-08-04 Pfizer Inc. Sel de lysine de 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole-1-carboxamide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4556672A (en) * 1984-03-19 1985-12-03 Pfizer Inc. 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents
US5036099A (en) * 1987-02-02 1991-07-30 Pfizer Inc. Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
EP0337628A2 (fr) * 1988-04-13 1989-10-18 Pfizer Inc. Dérivés du 2-oxindole-1-carboxamide substitués en position 3, utilisés pour supprimer l'activité des cellules T
US5047554A (en) * 1989-04-18 1991-09-10 Pfizer Inc. 3-substituted-2-oxindole derivatives
EP0498588A1 (fr) * 1991-02-08 1992-08-12 Pfizer Inc. Utilisation du tenidap pour réduire le cholestérol total sérique, le cholesterol des lipoprotéine à faible densité (ldl) ainsi que les triglycerides
WO1994016694A1 (fr) * 1993-01-22 1994-08-04 Pfizer Inc. Sel de lysine de 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole-1-carboxamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0826685A1 (fr) * 1996-08-21 1998-03-04 Pfizer Inc. Sels de carboxamides stables à effet prolongé destinés au traitement des maladies articulaires

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GT199600099A (es) 1998-06-12
AU7503496A (en) 1997-07-14
ZA9610582B (en) 1998-06-17
TNSN96162A1 (fr) 2005-03-15
MA24045A1 (fr) 1997-07-01

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