US3860636A - Substituted indenyl phosphonic acids having anti-inflammatory activity - Google Patents

Substituted indenyl phosphonic acids having anti-inflammatory activity Download PDF

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Publication number
US3860636A
US3860636A US312549A US31254972A US3860636A US 3860636 A US3860636 A US 3860636A US 312549 A US312549 A US 312549A US 31254972 A US31254972 A US 31254972A US 3860636 A US3860636 A US 3860636A
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Prior art keywords
indenyl
methyl
fluoro
mole
ethyl
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US312549A
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Tsung-Ying Shen
Howard Jones
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Merck and Co Inc
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Merck and Co Inc
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Priority to US312549A priority Critical patent/US3860636A/en
Priority to NL7316014A priority patent/NL7316014A/xx
Priority to GB5583273A priority patent/GB1418950A/en
Priority to FR7343196A priority patent/FR2209562B1/fr
Priority to DE2360550A priority patent/DE2360550A1/de
Priority to CH1711373A priority patent/CH613688A5/xx
Priority to JP48135794A priority patent/JPS4986353A/ja
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Publication of US3860636A publication Critical patent/US3860636A/en
Priority to US05/752,647 priority patent/US4087549A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/50—Halogenated unsaturated alcohols containing six-membered aromatic rings and other rings
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/383—Cycloaliphatic acids
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids

Definitions

  • ABSTRACT New substituted indenyl tetrazoles, sulfonic and phosphonic acids and derivatives thereof which have antiinflammatory, anti-pyretic and analgesic activity. Also included are methods of preparing said indenyl compounds, pharmaceutical compositions having said indenyl compounds as an active ingredient and methods of treating inflammation by administration of said indenyl compounds.
  • This invention relates to new substituted l@ alkylidene (or heteroalkylidene) indenyl tetraz e s, sulfonic and phosphoric acids and derivatives thereof to processes for producing the same.
  • This invention also relates to pharmaceutical compositions containing said indenyl compounds as an active ingredient and to methods of treating pain, fever or inflammation by administering these particular compounds to patients.
  • I R R5 2 R4 (if! 7 R maybe I 'u-mi c R may be CH H N41 g! SO M; a" 3 wherein M may be hydrogen, alkyl or a cation; and R and R each may be hydrogen, alkyl, aryl, alkylthio, hydroxy, alkoxy, halogen or to ether a carbonyl.
  • the aryl or heteroaryl substituent may include an aryl ring system such as benzene, naphthalene or biphenyl or a heteroaryl ring system such as a pyrrole, furan, thiophene, pyridine, imidazole, pyrazine, thiazole, pyrimidine, benzothiazole, pyrazole, oxazole, pyrane, pyridazine, indole, thionaphthene, benzofuran, benzimidazole, azaindole, benzoxyrane, quinoline, isoquinoline, quinoxaline, naphthyridine or benzoxazole and may be substituted with any of the aforementioned R and R substitutents.
  • aryl ring system such as benzene, naphthalene or biphenyl
  • a heteroaryl ring system such as a pyrrole, furan,
  • R is hydrogen, C loweralkyl or C chloro, bromo, or fluoro loweralkyl
  • R and R are each hydrogen, chloro, bromo, fluoro, C loweralkylthio, C, loweralkyl, trifluoromethyl, C loweralkyl-su
  • R is hydrogen or C loweralkyl
  • R R R and R are each hydrogen, chloro, bromo, fluoro, c loweralkyl, C loweralkoxy, nitro, amino C loweralkylamino, halo C loweralkyl, C diloweralkylamino, C loweralkanoylamino, hydroxy, C loweralkanoyloxy or trifluoromethyl, at most only 2 of R R R or R being other than hydrogen at any one time
  • R and R are each hydrogen, c loweralkyl, C loweralkoxy, C loweralkylsulfinyl, C loweralkylsulfonyl, chloro, bromo, fluoro, C loweralkysulfamyl, C, diloweralkylsulfamyl or nitro
  • X is C, alkylene, C alkenylene,
  • This invention also relates to a method of treating vpain, fever or inflammation in patients using a compound of Formula I, particularly and especially the preferred compounds as the active constituent.
  • the compounds of the instant invention can be used to treat inflammation by reducing inflammation and relieving pain in such diseases as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever.
  • the compounds of Formula I can also be used as an anti-py retic and would be administered and used in riers are lactose, corn starch, gelatin, talc, sterotix, stetaric acid, magnesium stearate, terra alba, sucrose, agar,
  • pectin cab-o-sil and acacia.
  • liquid carriers are peanut oil, olive oil, seasame oil and water.
  • the carrier or diluent may include a time delay material such as glyceryl monosterate or glyceryl distearate alone or with a wax.
  • compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques.
  • a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup, an aqueous solution or liquid suspension.
  • Suppositories may be prepared in a conventional manner by mixing the compounds of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature. Such materials are cocoa butter and polyethylene glycol. Gels and lotions for topical application may be prepared in conventional manners.
  • compositions of this invention are to be administered in an amount sufficient to treat inflammation, that is to reduce inflammation.
  • the compositions will contain the active ingredient; namely, the compounds of Formula I in an amount of from about 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to 3.5 mg. per patient per day), preferably from about 1 mg. to mg./kg. body weight per day (50 mg. to 1 g. per patinet per day).
  • the method of treatment of this invention comprises administering to a patient (animal or human), a compound of Formula I, particularly an especially preferred compound admixed with a non-toxic pharmaceutical carrier such as exemplified above.
  • a patient animal or human
  • the compounds of Formula I and particularly the especially preferred compounds will be administered in an amount of from 0.1 mg. to 50 mg./kg. body weight per day, preferably from about 1 mg. to about 15 mg. per kilogram body weight per day.
  • the most rapid and effective antiinflammatory effect is obtained from oral administration of a daily dosage of from about 1 to 15 mg./kg./day. It should be understood, however, that although preferred dosage ranges are given, the dose level for any particular patient depends upon the activity of the specific compound employed.
  • 3-indenyl methyl tetrazole compounds are known from U.S. Pat. No 3,631,167 issued Dec. 28, 1971. These compounds differ structurally from the 3-indenyl ethyl tetrazole compounds of this invention in that the 3-position of the indene contains a methyl group rather than an ethyl group, and are prepared by an overall different process.
  • the compounds of this invention may be prepared from their corresponding acids or esters.
  • a l-unsubstituted 3-indenyl acetic acid or ester may be first converted to its corresponding alcohol by methods well known in the art for reduction of an acid group or ester to an alcohol group (such as with complex hydrides, for example, lithium aluminum hydride or calcium borohydride, in such solvents as tetrahydrofuran ether and the like), halogenation of the alcohol to ethyl halide formation of the corresponding nitrile by methods well known to the art, followed by reactions with an alkali azide to form the tetrazole nucleus, and finally condensation and dehydration with the appropriate aldehyde in the l-position of the idene.
  • This latter reaction may readily be carried out by using a strong base such as alkali hydroxide or alkoxide and the like, as the catalyst, the reaction can be carried out in a solvent, if desired.
  • the l-substituent may be placed in the indene moiety at any stage of the process, for example the l-substituent may be placed on the 3-indenyl acetic acid or ester followed by the subsequent reactions to result in the final 3-indenyl ethyl tetrazole compounds of this invention.
  • the starting material i.e., l-unsubstituted-3-indenyl acetic acids or esters are known compounds as indicated by such U.S. Patents as U.S. Pat. No. 3,654,349, 3,312,730, and others.
  • the l-substituted derivatives thereof may be readily prepared by condensation and dehydration of the 1-unsubstituted-3-indenyl acetic acids or esters.
  • methyl 5-allyloxy-2-methyl-3-indenyl acetate and methyl 5-methoxy-6-fluoro-2-methyl-3-indenyl acetate are used in place of methyl 5-fluoro-2-methylindenyl- 3-acetate in an equivalent amount, in step 1A above, and the product therefrom carried out through step lB-l E, there is obtained the corresponding substituted indenyl-3-ethyl-5tetrazoles.
  • EXAMPLE 2 5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)- indenyl-3-methanesulfonic acid A. 5-Fluoro-2-methylindenyl-3-methylamine 5-Fluoro-Z-methylindenyl-3-acetic acid (0.12 mole) is dissolved in acetone (dry 270 ml.) and triethylamine (0.0124 mole) is added with stirring i-butyl chloroformate is then added (0.12 mole). The precipitate is collected after 10 minutes and the triethylamine hydrochloride rinsed out with acetone (50 ml.).
  • EXAMPLE 3 5-Fluoro-2-methyll p-methylsulfinylbenzylidene indenyl-3-methylphosphoric acid
  • 5-Fluoro-2-methylindenyl-3-methyl chloride (see Example 2C) (0.5 mole) is heated in isopropylphosphite (300 ml.) at 180 for 2 days while removing isopropanol. At the end of this time all the excess isopropylphosphite is removed by distillation at 40 and 2 mm. and the crude ester is chromatographed on Baker analyzed silica gel (2 ft. X 3 in.) using mixtures of benzene petroleum benzene as eluants. In this way, pure isopropylphosphonate ester is obtained by evaporation of pure fractions.
  • the ester is heated to reflux in 5N hydrochloric acid (200 ml.) with strong stirring for 8 hrs. At the end of this time the solution is evaporated to dryness and the crude phosphonic acid recrystallized from ethyl alcohol.
  • Example 3A 5-Fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-indenyl-3- methylphosphonic acid
  • the product of Example 3A is reacted with p-methylsulfinylbenzaldehyde in accordance with the procedure of Example IE to obtain the desired product.
  • EXAMPLE 4 cisand trans-5-Fluoro-2-methyl-l-(4- methylsulfinylcinnamylidenyl)-indeny-3-ethyl-5- tetrazole
  • To a solution of 0.02 mole of 5-fluoro-2-methylindenyl-B-ethyl-S-tetrazole in methanol (60 ml.) is added sodium methoxide (2.16 g., 0.04 mole) and after solution p-methylsulfinylcinnamaldehyde (0.02 mole).
  • the mixture is extracted with chloroform (3 X 1.5 liter), the combined chloroform extracts washed with water (3 X 660 ml.) and dried (Na SO The chloroform is distilled and the residue fractionated in vacuo to obtain 1,ldimethoxy-(3-chloro-4-methylthiophenyl)-2-propyne.
  • This compound (1.0 mole) is added to water (1 liter) containing concentrated sulfuric acid ml.) and the mixture is heated on the steam bath for 30 minuteswith occasional mixing.
  • the mixture is extracted with'ether (3 X 750 ml. the ether extract washed with .water and saturated salt solution,
  • Example 2 when the other .tetrazole compounds obtained from Example 1 are used in place of 5-fluoro-2- methyl-indenyl-3-ethyl-5-tetrazole in the above Example, there is obtained the corresponding 1-(3'-chloro- 4'-methyl-thiophenylpropargylidene substituted indenyl tetrazole compounds.
  • EXAMPLE 6 A. t-Butyl 5-fluoro-2-methyl-3-indenyl acetate Ethyl 5-fluoro-2-methyl-3-indenyl acetate (1.0 mole), t-butyl acetate (700 g., 6.0 mole) and sodium methoxide (108 g., 2 mole) under nitrogen are stirred and refluxed at 10:1 ratio through a 1.5 column packed with glass one-eighth inch helices. The mixture is distilled for 18 hours and 250 ml. of distillate is collected. The excess of t-butylacetate is distilled in vacuo and the residue is taken up in methylene chloride, filtered through diatomaceous earth then through acidwashed alumina. The methylene chloride is removed and the residue crystallized from acetone-n-hexane to yield t-butyl -fluoro-2-methyl-3-indenyl acetate.
  • Example 6A when an equivalent amount of any one of the methyl or ethyl acetate compounds from Example 1 is used in place of ethyl-5-fluoro-2-methyl-3-indenyl acetate in Example 6A above and the resulting product used in Example 6B-D, there is obtained the corresponding 3-indenyl-5-tetrazole compound.
  • step 6C when the product of step 6C is reacted in accordance with Example 2 A-F, or (Example 2 A-C and 3A), there is obtained the corresponding 3-methylsulfonic acid or 3-methylphosphonic acid respectively.
  • EXAMPLE 9 A mixture of 260 parts of 5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-indenyl-3-ethyl-5-tetrazole and 25 parts of lactose is granulated with suitable water and to this is added parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a temperature belwo 60C. The dry granules are passed through a 16 mesh screen and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets sutiable for oral administration.
  • tablets are prepared by employing an equivalent amount of 5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-indenyl-3-methylsulfonic acid or 5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-indenyl-3- methylphosphonic acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)
US312549A 1972-12-06 1972-12-06 Substituted indenyl phosphonic acids having anti-inflammatory activity Expired - Lifetime US3860636A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US312549A US3860636A (en) 1972-12-06 1972-12-06 Substituted indenyl phosphonic acids having anti-inflammatory activity
NL7316014A NL7316014A (enrdf_load_stackoverflow) 1972-12-06 1973-11-22
GB5583273A GB1418950A (en) 1972-12-06 1973-12-03 1-aryl-alkylidene-indenyl derivatives of tetrazoles and sulphonic and phosphonic acids
FR7343196A FR2209562B1 (enrdf_load_stackoverflow) 1972-12-06 1973-12-04
DE2360550A DE2360550A1 (de) 1972-12-06 1973-12-05 Indenylaethyltetrazole, -sulfonsaeuren und -phosphorsaeuren
CH1711373A CH613688A5 (enrdf_load_stackoverflow) 1972-12-06 1973-12-06
JP48135794A JPS4986353A (enrdf_load_stackoverflow) 1972-12-06 1973-12-06
US05/752,647 US4087549A (en) 1972-12-06 1976-12-20 Sulphonic acid containing indenyl derivatives

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US312549A US3860636A (en) 1972-12-06 1972-12-06 Substituted indenyl phosphonic acids having anti-inflammatory activity

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US53937775A Continuation-In-Part 1972-12-06 1975-01-08

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JP (1) JPS4986353A (enrdf_load_stackoverflow)
CH (1) CH613688A5 (enrdf_load_stackoverflow)
DE (1) DE2360550A1 (enrdf_load_stackoverflow)
FR (1) FR2209562B1 (enrdf_load_stackoverflow)
GB (1) GB1418950A (enrdf_load_stackoverflow)
NL (1) NL7316014A (enrdf_load_stackoverflow)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047578A (en) * 1987-08-07 1991-09-10 The Dow Chemical Company Novel phosphonic acid compounds and method of preparation
US5371284A (en) * 1987-09-03 1994-12-06 Schering Corporation Phenyl acetylenic acetals
US5948779A (en) * 1997-12-12 1999-09-07 Cell Pathways, Inc. Substituted condensation products of n-benzyl-3-indenyl acetamides with heterocyclic aldehydes
US5965619A (en) * 1996-06-13 1999-10-12 Cell Pathways Inc. Method for treating patients having precancerous lesions with substituted indene derivatives
US5998477A (en) * 1996-06-13 1999-12-07 Cell Pathways Inc. Substituted methoxy benzylidene indenyl-acetic and propionic acids for treating patients with precancerous lesions
US6028116A (en) * 1998-04-03 2000-02-22 Cell Pathways, Inc. Substituted condensation products of 1H-indenyl-hydroxyalkanes with aldehydes for neoplasia
US6063818A (en) * 1996-06-13 2000-05-16 Cell Pathways Inc. Substituted benzylidene indenyl formamides, acetamides and propionamides
US6121321A (en) * 1996-06-13 2000-09-19 Cell Pathways, Inc. Substituted methoxy benzylidene indenyl acetic and propionic acids for treating patients with precancerous lesions
US6479493B1 (en) 2001-08-23 2002-11-12 Cell Pathways, Inc. Methods for treatment of type I diabetes

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8204641L (sv) * 1981-08-14 1983-02-15 London Polytech Aminosyraderivat
US4477391A (en) * 1981-08-14 1984-10-16 Collins James F Amino acid isomers, their production and their medicinal use

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3622619A (en) * 1968-07-31 1971-11-23 Merck & Co Inc Biphenyl compounds
US3647858A (en) * 1970-05-01 1972-03-07 Merck & Co Inc Process for preparing 1-benzylidene-3-indenyl acetic acids
US3654349A (en) * 1970-05-01 1972-04-04 Merck & Co Inc Substituted indenyl acetic acids
US3671580A (en) * 1969-12-22 1972-06-20 Merck & Co Inc Substituted biphenyl acetic acids and ester derivatives thereof
US3714232A (en) * 1969-06-25 1973-01-30 Merck & Co Inc 5-arylphenyl sulfonic acids
US3732292A (en) * 1970-05-01 1973-05-08 Merck & Co Inc Indenyl compounds
US3754019A (en) * 1970-04-20 1973-08-21 Merck & Co Inc 5-arylphenylphosphonic and phosphonous acids

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3822310A (en) * 1971-01-21 1974-07-02 Merck & Co Inc Substituted indenyl acetic acids
NL7200060A (enrdf_load_stackoverflow) * 1971-01-21 1972-07-25

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3622619A (en) * 1968-07-31 1971-11-23 Merck & Co Inc Biphenyl compounds
US3714232A (en) * 1969-06-25 1973-01-30 Merck & Co Inc 5-arylphenyl sulfonic acids
US3671580A (en) * 1969-12-22 1972-06-20 Merck & Co Inc Substituted biphenyl acetic acids and ester derivatives thereof
US3754019A (en) * 1970-04-20 1973-08-21 Merck & Co Inc 5-arylphenylphosphonic and phosphonous acids
US3647858A (en) * 1970-05-01 1972-03-07 Merck & Co Inc Process for preparing 1-benzylidene-3-indenyl acetic acids
US3654349A (en) * 1970-05-01 1972-04-04 Merck & Co Inc Substituted indenyl acetic acids
US3732292A (en) * 1970-05-01 1973-05-08 Merck & Co Inc Indenyl compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047578A (en) * 1987-08-07 1991-09-10 The Dow Chemical Company Novel phosphonic acid compounds and method of preparation
US5371284A (en) * 1987-09-03 1994-12-06 Schering Corporation Phenyl acetylenic acetals
US5965619A (en) * 1996-06-13 1999-10-12 Cell Pathways Inc. Method for treating patients having precancerous lesions with substituted indene derivatives
US5998477A (en) * 1996-06-13 1999-12-07 Cell Pathways Inc. Substituted methoxy benzylidene indenyl-acetic and propionic acids for treating patients with precancerous lesions
US6063818A (en) * 1996-06-13 2000-05-16 Cell Pathways Inc. Substituted benzylidene indenyl formamides, acetamides and propionamides
US6121321A (en) * 1996-06-13 2000-09-19 Cell Pathways, Inc. Substituted methoxy benzylidene indenyl acetic and propionic acids for treating patients with precancerous lesions
US5948779A (en) * 1997-12-12 1999-09-07 Cell Pathways, Inc. Substituted condensation products of n-benzyl-3-indenyl acetamides with heterocyclic aldehydes
US6028116A (en) * 1998-04-03 2000-02-22 Cell Pathways, Inc. Substituted condensation products of 1H-indenyl-hydroxyalkanes with aldehydes for neoplasia
US6479493B1 (en) 2001-08-23 2002-11-12 Cell Pathways, Inc. Methods for treatment of type I diabetes

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Publication number Publication date
NL7316014A (enrdf_load_stackoverflow) 1974-06-10
FR2209562A1 (enrdf_load_stackoverflow) 1974-07-05
GB1418950A (en) 1975-12-24
CH613688A5 (enrdf_load_stackoverflow) 1979-10-15
JPS4986353A (enrdf_load_stackoverflow) 1974-08-19
DE2360550A1 (de) 1974-06-12
FR2209562B1 (enrdf_load_stackoverflow) 1978-11-10

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