EP0327590A1 - 7-deazaguanines ayant une activite d'immunomodulateurs - Google Patents

7-deazaguanines ayant une activite d'immunomodulateurs

Info

Publication number
EP0327590A1
EP0327590A1 EP87907864A EP87907864A EP0327590A1 EP 0327590 A1 EP0327590 A1 EP 0327590A1 EP 87907864 A EP87907864 A EP 87907864A EP 87907864 A EP87907864 A EP 87907864A EP 0327590 A1 EP0327590 A1 EP 0327590A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
treating
hydrogen
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP87907864A
Other languages
German (de)
English (en)
Inventor
Thomas C. Malone
Jagadish C. Sircar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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 Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP0327590A1 publication Critical patent/EP0327590A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • R is n-C 3 H 7
  • R is CH 2 C 6 H 5
  • R is cyclopentyl
  • hydroxy and mercapto analogs of the antibiotic sparsomycin A are pyrrolo[2,3-d]pyrimidin-4-one or thione having a sugar moiety in the seven (7) position are disclosed by Upjohn in Netherlands 6,407,785 (Derwent Abstract No. 15,466) and similarly by Warner Lambert in European publication 57,548 (Derwent Abstract No. 68572 E/33).
  • the present invention relates to a compound of the formula (I)
  • R 6 is OH or SH
  • R 2 is hydrogen or NH 2
  • R 7 and R 8 are independently hydrogen or NH 2 with the proviso that both canno be NH 2 at once
  • n is an integer of from one through four
  • Ar is (i) phenyl unsubstituted or substituted by halogen, trifluoromethyl, alkyl of one to four carbon atoms, hydroxy, or alkoxy of from one to four carbon atoms, (ii) 2- or 3-thienyl, or (iii) 2- or 3-furanyl with the proviso that when R 6 is OH, and R 2 is H 2 N, and R 7 and R 8 are both hydrogen then Ar cannot be unsubstituted phenyl; or a pharmaceutically acceptable base or acid addition salt thereof.
  • the present invention also includes methods of manufacturing and novel intermediates therein, and a pharmaceutical composition for treating autoimmune diseases such as arthritis, systemic lupus erythematosus, inflammatory bowel diseases, juvenile diabetes, myasthenia gravis, multiple sclerosis, gout and gouty arthritis, as well as psoriasis, viral infections and cancer, or rejection of transplantation, comprising an anti-psoriatic, immunomodulator or antirejection effective amount such as an advantageously cytotoxic to T-cell amount, of a compound of the formula (I)
  • R 6 is OH or SH
  • R 2 is hydrogen or NH 2
  • R 7 and R 8 are independently hydrogen and NH 2 with the proviso that both cannot be NH 2 at once
  • n is an integer of from one to four
  • Ar is (i) phenyl unsubstituted or substituted by halogen, trifluoromethyl, alkyl of one to four carbon atoms, hydroxy, alkoxy of from one to four carbon atoms, (ii) 2- or 3-thienyl, or (iii) 2- or 3-furanyl with a pharmaceutically acceptable carrier.
  • the invention is also a method of treating psoriasis, an autoimmune disease, such as is listed above, or rejection of transplantation comprising administering to a host, such as a mammal including a human, suffering from psoriasis, the autoimmune disease or rejection of transplantation comprising administering an effective amount; i.e. an amount advantageously affecting T-cells by toxicity thereto, of a pharmaceutical composition of the formula I as defined above in unit dosage form.
  • an ordinarily skilled physician would begin treatment with a less than effective amount and increase the dose until the desired effect is obtained exercising care to administer an amount less than the amount toxic to the host of the disease.
  • novel intermediates of the present invention are compounds of formula (X)
  • the method of manufacture of the present invention is a novel process for the preparation of a compound of the formula I as defined above; which comprises treating a compound of the formula (X) X
  • Suitable oxygen protecting groups are benzyl, t-butyldimethylsilyl, methyl, isopropyl, ethyl, tertiary butyl, ethoxyethyl, and the like. Protection of an N-H containing moiety is necessary for some of the processes described herein for the preparation of compounds of this invention.
  • Suitable nitrogen protecting groups are benzyl, triphenylmethyl, trialkylsilyl, trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, and the like. Under certain circumstances it is necessary to protect two different oxygens with dissimilar protecting groups such that one can be selectively removed while leaving the other in place.
  • benzyl and t-butyldimethylsilyl groups are used in this way; either is removable in the presence of the other, benzyl being removed by catalytic hydrogenolysis, and t-butyldimethylsilyl being removed by reaction with, for example, tetra-n-but ⁇ lammonium fluoride.
  • the compounds of formula I of the present invention exist in tautomeric forms as purines or guanines as illustrated below. Both forms are included as part of the invention and are indiscriminately described in the specification.
  • alkyl of one to four carbon atoms means a straight or branched hydrocarbon chain up to four carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, secondary butyl or tertiary butyl.
  • Alkoxy of one to four carbon atoms includes methoxy, ethoxy, propoxy, butoxy and isomers thereof.
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • the compounds of formula I are useful both in the free base form, in the form of base salts where possible, and in the form of acid addition salts. The three forms are within the scope of the invention.
  • salt form amounts to use of the base form.
  • Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, benzenesulfoni ⁇ acid, p-toluenesulfonate, and the like, respectively, or those derived from bases such as suitable organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds of this invention include the hydroxides of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like.
  • Salts may also be formed with suitable organic bases.
  • Bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form such salts. These organic bases form a class whose limits are readily understood by those skilled in the art.
  • the class may be said to include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine; amino acids such as arginine, and lysine; guanidine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tri (hydroxymethyl) aminomethane; and the like.
  • mono-, di-, and trialkylamines such as methylamine, dimethylamine, and triethylamine
  • mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine
  • amino acids such as arginine, and lysine
  • guanidine N-methylglucamine
  • L-glutamine L-glutamine
  • N-methylpiperazine N-methylpiperaz
  • the acid addition salts of said basic compounds are prepared either by dissolving the free base of compound I in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid or base and isolating the salt by evaporating the solution, or by reacting the free base of compound I with an acid as well as reacting compound I having an acid group thereon with a base such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • a preferred embodiment of the present invention is a compound of formula I wherein R 6 is OH or SH; R 2 and R 8 are NH 2 , n is one, and Ar is 2- or 3-thienyl.
  • a more preferred embodiment is 2-amino-7-(2-thienylmethyl)-4-pyrrolo[2,3-d)] pyrimidone.
  • the compositions having compounds of the formula I of the present invention are shown to exhibit significant enzyme inhibition activity and cytotoxicity activity.
  • PNP-4 activity for the compound of formula I is measured radiochemically by measuring the formation of [ 14 -Cjhypoxanthine from [ 14 -C]inosine
  • HPLC-1 purine nucleoside phosphorylase
  • PNP inhibition and removal of T-cells or modulation of T-cells are known to be characteristics of compounds beneficial in the treatment of psoriasis, rejection phenomenon in transplantation, and autoimmune diseases
  • the present invention compositions of compounds being selectively cytotoxic to T-cells and being PNP inhibitors will, therefore, also be useful in such treatment.
  • 8-Aminoguanosine a known PNP-inhibitor, has been shown to be efficacious for inhibiting rejection of skin graft in dogs [J. B. Benear, et al. Transplantation, 1986, 41:274].
  • Cyclosporin A a T-cell modulator, showed beneficial effects in the treatment of juvenile diabetes. (A. Assan, et al. The Lancet, January 12, p. 67 (1985).) Additionally, cyclosporin A is presently the drug of choice for the prevention of transplant rejection, (R. M. Merion, et al. New Eng. J. Med., (1984) 148). More recently, cyclosporin A is shown to be useful to treat psoriasis.
  • cyclosporin therapy is shown to markedly reduce activated T-cells in psoriatic lesions. Therefore, it is reasonable to believe the basis of the successful treatment of psoriasis is modulation of T-cell activity as shown by compounds in the present invention composition. (See C. N. Ellis, et al, JAMA, V-256, No. 22, Dec. 12, 1986, pp. 3110-3116.) Finally, cyclosporin A is shown to be efficacious in rheumatoid arthritis. (M. E. Weinblatt, et al. Arthritis and Rheumatism, V-30, No. 1, pp. 11-17 (January, 1987); O. Forre, et al.
  • T-cells play a central role in immune response
  • use of the compounds of the invention is contemplated for the immunoregulation to prevent rejection in transplantation or in the treatment of psoriasis and in the treatment of autoimmune disease such as rheumatoid arthritis, systemic lupus erythrematosus, inflammatory bowel disease, multiple sclerosis, myasthemia gravis, gout or gouty arthritis, juvenile diabetes, cancer, and viral diseases.
  • the present invention thus includes compositions containing a compound of formula I in treating rejection of transplantation or disease such as psoriasis in humans or autoimmune disease characterized by abnormal immune response in primates or humans.
  • the properties of the compounds of the invention are utilized by administering to a warmblooded animal an effective amount of a pharmaceutical composition containing as the active ingredient at least about 0.1 percent by weight, based on the total weight of the composition of at least one such compound of the invention.
  • compositions of the invention can be formulated in any suitable way, preferably with an inert carrier for administration orally, parenterally, ophthalmically, topically, or by suppository.
  • the compounds of the present invention are formulated into dosage forms such as tablets or syrups by blending with an inert pharmaceutical carrier such as lactose or simple syrup by methods well-known in the art.
  • an inert pharmaceutical carrier such as lactose or simple syrup by methods well-known in the art.
  • injectable dosage forms they are formulated with vehicles such as water, propylene glycol, peanut oil, sesame oil, and the like.
  • the active ingredient is from about 0.05 grams to 0.5 grams per dosage unit.
  • Priority Country US (European patent), NO, RO, SD, SE (European patent) (OAPI patent), SU, TD (OAPI patent), TG (OAPI pat

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

Diverses 7-déazaguanines de formule (I) dans laquelle R6 représente OH ou SH, R2 représente l'hydrogène ou NH2, R7 et R8 représentent l'hydrogène ou NH2, n est un nombre entier compris entre un et quatre, Ar représente (i) un phényl non substitué ou substitué par un halogène, un trifluorométhyl, un alkyl, un hydroxy ou un alcoxy, (ii) 2- ou 3-thiényle, ou (iii) 2- ou 3-furanyl; Ces composés ont une activité d'immunomodulateurs. Des compositions pharmaceutiques et des procédés utilisant ces compositions sont également décrits.
EP87907864A 1986-10-24 1987-10-19 7-deazaguanines ayant une activite d'immunomodulateurs Withdrawn EP0327590A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US92352186A 1986-10-24 1986-10-24
US923521 1986-10-24
US8623187A 1987-08-20 1987-08-20
US86231 1987-08-20

Publications (1)

Publication Number Publication Date
EP0327590A1 true EP0327590A1 (fr) 1989-08-16

Family

ID=26774505

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87907864A Withdrawn EP0327590A1 (fr) 1986-10-24 1987-10-19 7-deazaguanines ayant une activite d'immunomodulateurs

Country Status (9)

Country Link
EP (1) EP0327590A1 (fr)
JP (1) JPH02501306A (fr)
KR (1) KR880701721A (fr)
AU (1) AU614947B2 (fr)
CA (1) CA1294960C (fr)
ES (1) ES2008756A6 (fr)
FI (1) FI891870A0 (fr)
GR (1) GR871606B (fr)
WO (1) WO1988003142A2 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE60433B1 (en) * 1986-08-26 1994-07-13 Warner Lambert Co Novel 9-deazaguanines
US4968686A (en) * 1988-04-08 1990-11-06 The Regents Of The University Of Michigan Acyclic pyrrolo [2,3-d]pyrimidine analogs as antiviral agents
USRE36187E (en) * 1988-04-08 1999-04-06 The Regents Of The University Of Michigan Acyclic pyrrolo 2,3-d!pyrimidine analogs as antiviral agents
US5047407A (en) * 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
DK0460116T3 (da) * 1989-02-27 1998-03-30 Biocryst Pharm Inc 9-substitueret-8-usubstitueret-9-deazaguaniner
JP2866478B2 (ja) * 1989-10-31 1999-03-08 バイオクリスト・ファーマシューティカルズ・インコーポレイテッド プリンヌクレオシドホスホリラーゼの阻害剤
US5726311A (en) * 1989-11-29 1998-03-10 Biocryst Pharmaceuticals, Inc. 7-disubstituted-methyl-4-oxo-3H,5H-pyrrolo 3,2-d!pyrimidine and pharmaceutical uses and compositions containing the same
US5248672A (en) * 1990-11-01 1993-09-28 The Regents Of The University Of Michigan Polysubstituted benzimidazole nucleosides as antiviral agents
WO1995033752A1 (fr) * 1994-06-09 1995-12-14 Smithkline Beecham Corporation Antagonistes du recepteur de l'endotheline
GB201417163D0 (en) 2014-09-29 2014-11-12 Provost Fellows & Scholars College Of The Holy Undivided Trinity Of Queen Elizabeth Near Dublin Substituted pyrimidine derivatives useful in the treatment of autoimmune diseases
GB201417165D0 (en) 2014-09-29 2014-11-12 Provost Fellows & Scholars College Of The Holy Undivided Trinity Of Queen Elizabeth Near Dublin Treatments for Autoimmune Disease

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4748177A (en) * 1984-03-26 1988-05-31 Warner-Lambert Company Guanine derivatives
FR2574407B1 (fr) * 1984-12-12 1987-06-05 Rhone Poulenc Sante Nouveaux derives de la pyrrolo(2,3-d) pyrimidine, leur preparation et les compositions pharmaceutiques qui les contiennent
IE60433B1 (en) * 1986-08-26 1994-07-13 Warner Lambert Co Novel 9-deazaguanines
DE3739366A1 (de) * 1987-04-10 1988-10-27 Boehringer Mannheim Gmbh Desaza-purin-nucleosid-derivate, verfahren zu deren herstellung sowie deren verwendung bei der nucleinsaeure-sequenzierung sowie als antivirale mittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8803142A2 *

Also Published As

Publication number Publication date
FI891870A (fi) 1989-04-19
JPH02501306A (ja) 1990-05-10
CA1294960C (fr) 1992-01-28
GR871606B (en) 1988-02-23
KR880701721A (ko) 1988-11-04
ES2008756A6 (es) 1989-08-01
AU614947B2 (en) 1991-09-19
AU8328187A (en) 1988-05-25
FI891870A0 (fi) 1989-04-19
WO1988003142A3 (fr) 1988-05-19
WO1988003142A2 (fr) 1988-05-25

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