EP0639075A1 - Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet - Google Patents

Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet

Info

Publication number
EP0639075A1
EP0639075A1 EP92900837A EP92900837A EP0639075A1 EP 0639075 A1 EP0639075 A1 EP 0639075A1 EP 92900837 A EP92900837 A EP 92900837A EP 92900837 A EP92900837 A EP 92900837A EP 0639075 A1 EP0639075 A1 EP 0639075A1
Authority
EP
European Patent Office
Prior art keywords
pyrimidine
diamino
benzyl
methoxy
bromo
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.)
Ceased
Application number
EP92900837A
Other languages
German (de)
English (en)
Other versions
EP0639075A4 (fr
Inventor
Ivan Kompis
Jeffrey M. Blaney
Charles K. Marlow
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.)
Novartis Vaccines and Diagnostics Inc
Original Assignee
Chiron Corp
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 Chiron Corp filed Critical Chiron Corp
Publication of EP0639075A4 publication Critical patent/EP0639075A4/fr
Publication of EP0639075A1 publication Critical patent/EP0639075A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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

Definitions

  • This invention relates to pharmacology and the inhibition of enzymes specific to pathogens. More particularly, the invention relates to methods for spe ⁇ cifically inhibiting the enzyme dihydrofolate reductase in fungal pathogens, and compounds therefor.
  • PCP Pneumocystis carinii pneumonia
  • trimethoprim and pyrimethamine exhibit 50% inhibition concentrations (IC 50 ) of 8 and 2,500 nM for E. coli DHFR, while IC J QS for P. carinii DHFR are 39,600 and 2,400 nM, respectively.
  • R x is 3-R 3 -4-R 4 -5-R 5 -benzyl or (N-R ⁇ - ⁇ -azabicycloI ⁇ .lloct-S-yl;
  • R. and R 2 together form where R 3 .and Rj are
  • compositions for treating a fungal infection such as P. carin ⁇
  • a fungal infection such as P. carin ⁇
  • a mammal comprising an effective amount of a compound of formula I in combination with a pharmaceutically acceptable excipient.
  • Another aspect of the invention is the use of a compound of formula I to prepare a composition for treating a fungal infection (such as P. carin ⁇ ' ) in a mam ⁇ mal comprising an effective amount of a compound of formula I in combination with a pharmaceutically acceptable excipient
  • fungal infection and "fungal pathogen” refer to the infection of a mammal with an organism of the Kingdom Fungi, for example Pneumocystis carin ⁇ . Aspergillus, Candida, Fusarium, and the like.
  • the presently preferred method of the invention is the treatment of Pneumocystis carin ⁇ using the compounds of the invention.
  • pharmaceutically acceptable refers to compounds and compo ⁇ sitions which may be administered to mammals without undue toxicity.
  • Exem ⁇ plary pharmaceutically acceptable salts include mineral acid salts such as hydro- chlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • the term "effective .amount” refers to an amount of compound sufficient to exhibit a detectable therapeutic effect.
  • the therapeutic effect may include, for example, without ⁇ mitation, inhibiting the growth of pathogens, inhibiting or pre ⁇ venting the release of toxins by pathogens, killing pathogens, and preventing the estab ⁇ shment of infection (prophylaxis).
  • the precise effective amount for a sub ⁇ ject will depend upon the subject's size and health, the nature of the pathogen, the severity of the infection, and the like. Thus, it is not possible to specify an exact effective amount in advance. However, the effective amount for a given situation can be determined by routine experimentation based on the information provided herein.
  • lower alkyl refers to saturated straight or branched-chain rad ⁇ icals consisting of carbon and hydrogen having from 1 to 6 carbon atoms, inclu ⁇ sive, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-hexyl, and the like.
  • Lower alkoxy refers to a radical of the form R-O-, where "R" is lower .alkyl as defined above. Suitable examples include methoxy, ethoxy, prop- oxy, butoxy, .and the like.
  • lower alkylthio refers to radicals of the form R-S-
  • lower alkylsulfinyl refers to groups of the form R-S(-O)-.
  • methylthio ethylthio, methylsuhlnyl, t-butylsulfinyl, and the like.
  • alkenyl refers to straight or branched-chain radicals consist- ing of carbon and hydrogen having 2-6 carbon atoms and at least one double bond between a pair of carbon atoms, such as ethenyl (vinyl), 2-propenyl, 1-methyl- ethenyl, 2-butenyl, 3-butenyl, and the like.
  • carboxy-lower alkyl refers to radicals having the form -(CH 2 ) n -COOH, where n is an integer from 1 to 6 inclusive. "Dicarboxy-lower alkyl” indicates lower allcyl chains having two COOH groups attached.
  • Aryl denotes cyc ⁇ c hydrocarbon radicals of 6-10 carbon atoms which exhibit aromatic character, for example phenyl and napthyl.
  • halo refers to fluoro, chloro, bromo, and iodo.
  • amino acid refers to any of the 20 or so commonly occurring amino acids, for example, glycine, alanine, arginine, phenylalanine, glutamic acid, va ⁇ ne, histidine, proline, ornithine, norleucine. and the like.
  • R 8 When attached as R 8 in a radical of the form -O(CH 2 ) n -COR 8 , the amino acid will preferably be attached via a peptide bond, e ⁇ by a bond between the amino group of the amino acid and the acyl car ⁇ bon of the radical.
  • coadministering means administration of a compound of the invention in combination with a second therapeutic agent.
  • the second therapeutic agent is a dihydropteroate synthase inhibitor, preferably dapsone or a sulfa drug.
  • Suitable sulfa drugs include, without limitation, sulfadiame, sulfamethoxazole, and the like.
  • Coadministration may be simultaneous, for example by administer ⁇ ing a mixture of the therapeutic agents, or may be accomplished by administration of the agents separately within a short time period.
  • the compounds of the invention are structurally related to the compound trimethoprim (2,4-diam o-5-(3,4,5-trimemoxybenzyl)pyrimidine), the synthesis for which is known in the ait. See for example U.S. Pat No. 2,909,522, which des- cribes the synthesis of trimethoprim and related compounds.
  • Compounds of for ⁇ mula I may simflarly be synthesized by those of ordinary skill in the art. Syntheses of such compounds are described in the following U.S. patents: Hitchings ___ (2,658,897); Hitchings et_al.
  • Presently preferred compounds of the invention are: ,4-diamino-5-[3,5-dimemoxy-4-(2-hydroxyprop-2-yl)benzyl]pyrimidine; 2,4-diamino-5-(3 ,5-dimethoxy-4-N-pyrrolylbenzyl)pyrimidine; 2,4-diamino-5-(3,5-diethoxy-4-N-pyrrolylbenzyl)pyrimidine; 2,4-diar no-5-(3,5-dipropoxy-4-N-py ⁇ olylben ⁇ l)pyrimidine; 2,4-diammo-5-(3,5-dibutoxy-4-N-pyrrolylbenzyl)pyrimidine; 2,4-diammo-5-(3,5-diethoxy-4-carboethoxyber ⁇ zyl)pyrimidine; 2,4-diammo-5-(3,5-divinyl-4-vinyloxybenzyl)pyrimidine;
  • 2,2-dime yl-5-(2,4-dia ⁇ ninopyri ⁇ nidin-5-ylmethyl)-7-methoxybenz[b]dioxolane The most preferred compounds at present are 2,4-diamino-5-(3,5-diethoxy-4-N- pvrrolylbenzyl)pyrimidine and 2,4-diamino-5-[3 ⁇ -dimethoxy-4-(2-hydroxyprop-2- yl)benzyl]pyrimidine.
  • compositions of the invention for administration will generaUy include an effective amount of a compound of formula I in addition to a pharmaceutically acceptable excipient.
  • Suitable excipients include most carriers approved for oral or parenteral adininistration, including water, saline, Ringer's solution, H-ank's solution, and solutions of glucose, lactose, dextrose, ethanol, glycerol, albumin, and the like.
  • These compositions may optionally include stabilizers, antioxidants, antimicrobials, preservatives, buffering agents, surfactants, and other accessory additives.
  • a presently preferred vehicle comprises about 1 mg/mL serum albumin in phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • an effective dose of compound of formula I will range from about 10 ⁇ g/Kg to about 50 mg Kg.
  • Suitable ai ⁇ mal models include the mouse model illustrated in the Examples below. Rats and other rodents have DHFR very sim ⁇ ar to the human enzyme, and thus make suitable animal models.
  • a group of experimental animals is inoculated with 10-100 LD so s of Pneumocystis carin ⁇ , foUowed by treatment with a solution of test compound.
  • a negative con ⁇ trol group is left untreated, wh ⁇ e a positive control group is treated with a stan ⁇ dard therapy, such as trimethoprim.
  • Administration of the compounds is prefer- ably per os (e.g.. using a gavage), but may be parenteral, for example by subcu ⁇ taneous or intramuscular injection, or by inhalation of an aerosol.
  • the animals are monitored during treatment, and are sacrificed and examined after 60 days for presence of infection.
  • Buffers were prepared as follows: 4xDHFR buffe ⁇ 200 mM Tes, 300 mM BME, 4 mM EDTA, pH 7.0. +DHF buffe ⁇ 2.5 mg mL BSA, 0.25 mM NADPH, 62.5 uM dihydrofolate, 2.5x DHFR buffer. -DHF buffer: 2.5 mg/mL BSA, 0.25 mM NADPH, 2.5x DHFR buffer. Enzyme buffe ⁇ 50 mM Tes, 5 mM DTT, 1 mM EDTA, 20% glycerol, 1 mg/mL BSA, pH 7.0.
  • D ⁇ ution buffer 50 mM Tes, 5 mM DTT, 1 mM EDTA, 1 mg/mL BSA, pH 7.0.
  • PcDHFR 5 ⁇ g/mL P. carin ⁇ DHFR in enzyme buffer.
  • crude hDHFR crude recombinant human DHFR (obtained from Hoffmann-LaRoche) in enzyme buffer (9.9 mg mL total protein).
  • purified hDHFR purified recombinant human DHFR (obtained from Hoffmann- LaRoche) in enzyme buffer (3.5 mg/mL total protein).
  • Test compounds were prepared and provided by Hoffmann-L.aRoche. Stock solutions were prepared by dissolving 2-8 mg in dimethylsulfoxide (DMSO) to prepare 50 mM solutions. Compounds which did not dissolve at 50 mM were d ⁇ uted serially to 25, 16.6, or 12.5 mM.
  • DMSO dimethylsulfoxide
  • KK 2,4-dian_ ⁇ mo-5-(4,5,6-trimethoxy-2,3-dihydromd ⁇ n-l-yl)pyri ⁇ mdine; LL) 2,2-dimethyl-5-(2,4-diammopyrir din-5-ylmethyl)-7-methoxybenz[b]di- oxolane; MM) 2,4-diammcH5-(3,5-diethoxy-4-carboethoxybenzyl)pyrimidine; and NN) 2,4-diamino-5-(2,7-dimethylbenzpyrazol-5-y ethyl)pyrimidine. TABLE ⁇ :

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

Abstract

L'invention décrit des composés dérivés de pyrimidines, qui possèdent une activité accrue contre les champignons tels que le Pneumocystis carinii, ainsi qu'une sélectivité plus grande pour la dihydrofolate réductase du P. carinii par rapport à la dihydrofolate réducase humaine. La pneumonie à Pneumocystis carinii est traitée avantageusement au moyen de ces composés.
EP92900837A 1990-11-14 1991-11-14 Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet Ceased EP0639075A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US730691 1985-05-02
US61361990A 1990-11-14 1990-11-14
US613619 1990-11-14
US73069191A 1991-07-16 1991-07-16
PCT/US1991/008515 WO1992008461A1 (fr) 1990-11-14 1991-11-14 Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet

Publications (2)

Publication Number Publication Date
EP0639075A4 EP0639075A4 (fr) 1993-09-29
EP0639075A1 true EP0639075A1 (fr) 1995-02-22

Family

ID=27087063

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92900837A Ceased EP0639075A1 (fr) 1990-11-14 1991-11-14 Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet

Country Status (7)

Country Link
EP (1) EP0639075A1 (fr)
JP (1) JPH07509215A (fr)
AU (1) AU657348B2 (fr)
CA (1) CA2095518A1 (fr)
IE (1) IE913974A1 (fr)
PT (1) PT99514B (fr)
WO (1) WO1992008461A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721242A (en) * 1993-06-17 1998-02-24 Hoffmann-La Roche Inc. Antibiotic combination
AU704911B2 (en) * 1994-11-24 1999-05-06 Basilea Pharmaceutica Ag Novel benzyl pyrimidines
TW438796B (en) * 1996-05-15 2001-06-07 Hoffmann La Roche 2,4-diaminopyrimidine derivatives, the manufacture process thereof, and the antibiotically-active pharmaceutical composition containing the same
AU6203098A (en) * 1997-02-24 1998-09-18 Barry J. Barclay Synergistically acting anti-fungal agents that are inhibitors of folate metabolism, especially methotrexate and sulfamethoxazole
CN1191861C (zh) 1999-05-24 2005-03-09 三共株式会社 含有抗Fas抗体的药物组合物
US8853228B2 (en) * 2007-06-04 2014-10-07 University Of Connecticut Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase

Citations (16)

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Publication number Priority date Publication date Assignee Title
US2658897A (en) * 1951-06-27 1953-11-10 Burroughs Wellcome Co 2, 4-diamino-5-benzyl pyrimidines
FR1090394A (fr) * 1953-03-11 1955-03-30 Wellcome Found Dérivés de pyrimidine et leur fabrication
FR1292920A (fr) * 1959-04-18 1962-05-11 Wellcome Found Dérivés de la pyrimidine et leur préparation
US3671564A (en) * 1965-10-28 1972-06-20 Burroughs Wellcome Co Benzylidene cyano-acetals
DE1720031A1 (de) * 1966-02-19 1972-08-03 Wellcome Found Biologisch wirksame 5-Benzylpyrimidin-Derivate und Verfahren zu ihrer Herstellung
US4024145A (en) * 1973-11-08 1977-05-17 Hoffmann-La Roche Inc. Benzylpyrimidine derivatives
DE2617967A1 (de) * 1976-04-24 1977-11-03 Nordmark Werke Gmbh Verfahren zur herstellung von 2,4-diamino-5-benzylpyrimidinen
FR2357563A1 (fr) * 1976-07-09 1978-02-03 American Home Prod Nouvelles 7h-pyrrolo(3,2-f) quinazoline-1,3-diamines substituees en position 7, leur procede de preparation et medicament les contenant
LU77268A1 (fr) * 1977-05-05 1979-01-18
LU77269A1 (fr) * 1977-05-05 1979-01-18
EP0003212A1 (fr) * 1977-11-10 1979-08-08 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft 2.4-Diamino-5-benzylpyrimidines, compositions pharmaceutiques les contenant et leur préparation
US4233445A (en) * 1979-07-05 1980-11-11 American Home Products Corporation 7-(Substituted)-7H-pyrrolo[3.2-F]-quinazoline-1,3-diamines
US4258045A (en) * 1979-11-30 1981-03-24 Merck & Co., Inc. Inhibitor of dihydrofolate reductase
EP0054756A2 (fr) * 1980-11-27 1982-06-30 The Wellcome Foundation Limited Benzylpyrimidines antibactériennes
US4451466A (en) * 1982-07-02 1984-05-29 Shell Oil Company Use of pyrroloquinazolinediamines as pesticides
EP0122580A1 (fr) * 1983-04-14 1984-10-24 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Derivés de la pyrimidine, leur préparation et compositions pharmaceutiques

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GB1181657A (en) * 1966-03-31 1970-02-18 Ici Ltd Pyrimidine Derivatives and Compositions Containing them
BE793253A (fr) * 1971-12-23 1973-04-16 Lepetit Spa Nouvelles compositions bactericides et leur utilisation
OA07362A (fr) * 1980-10-27 1984-06-30 May & Baker Ltd Dérivés de la pyrimidine, leur procédé de préparation et les compositions les contenant.
EP0139613A1 (fr) * 1983-08-29 1985-05-02 Ciba-Geigy Ag Dérivés de la N-(nitro-2 phényl) amino-4 pyrimidine, leur préparation et leur application
US4501890A (en) * 1983-09-26 1985-02-26 Eli Lilly And Company Trans-(±)-2,4,6-substituted-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinolines
DE3417264A1 (de) * 1984-05-10 1985-11-14 Bayer Ag, 5090 Leverkusen Neue 2,4-diamino-6-halogen-5-alkylthio-pyrimidine
DE3701277A1 (de) * 1987-01-17 1988-07-28 Boehringer Mannheim Gmbh Neue tricyclische benzimidazole, verfahren zu ihrer herstellung und verwendung als arzneimittel
US4996198A (en) * 1988-07-11 1991-02-26 Hoffmann-La Roche Inc. Anticoccidial composition

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2658897A (en) * 1951-06-27 1953-11-10 Burroughs Wellcome Co 2, 4-diamino-5-benzyl pyrimidines
FR1090394A (fr) * 1953-03-11 1955-03-30 Wellcome Found Dérivés de pyrimidine et leur fabrication
FR1292920A (fr) * 1959-04-18 1962-05-11 Wellcome Found Dérivés de la pyrimidine et leur préparation
US3671564A (en) * 1965-10-28 1972-06-20 Burroughs Wellcome Co Benzylidene cyano-acetals
DE1720031A1 (de) * 1966-02-19 1972-08-03 Wellcome Found Biologisch wirksame 5-Benzylpyrimidin-Derivate und Verfahren zu ihrer Herstellung
US4024145A (en) * 1973-11-08 1977-05-17 Hoffmann-La Roche Inc. Benzylpyrimidine derivatives
DE2617967A1 (de) * 1976-04-24 1977-11-03 Nordmark Werke Gmbh Verfahren zur herstellung von 2,4-diamino-5-benzylpyrimidinen
FR2357563A1 (fr) * 1976-07-09 1978-02-03 American Home Prod Nouvelles 7h-pyrrolo(3,2-f) quinazoline-1,3-diamines substituees en position 7, leur procede de preparation et medicament les contenant
LU77268A1 (fr) * 1977-05-05 1979-01-18
LU77269A1 (fr) * 1977-05-05 1979-01-18
EP0003212A1 (fr) * 1977-11-10 1979-08-08 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft 2.4-Diamino-5-benzylpyrimidines, compositions pharmaceutiques les contenant et leur préparation
US4233445A (en) * 1979-07-05 1980-11-11 American Home Products Corporation 7-(Substituted)-7H-pyrrolo[3.2-F]-quinazoline-1,3-diamines
US4258045A (en) * 1979-11-30 1981-03-24 Merck & Co., Inc. Inhibitor of dihydrofolate reductase
EP0054756A2 (fr) * 1980-11-27 1982-06-30 The Wellcome Foundation Limited Benzylpyrimidines antibactériennes
US4451466A (en) * 1982-07-02 1984-05-29 Shell Oil Company Use of pyrroloquinazolinediamines as pesticides
EP0122580A1 (fr) * 1983-04-14 1984-10-24 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Derivés de la pyrimidine, leur préparation et compositions pharmaceutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9208461A1 *

Also Published As

Publication number Publication date
WO1992008461A1 (fr) 1992-05-29
PT99514B (pt) 1999-04-30
AU2202792A (en) 1994-04-28
EP0639075A4 (fr) 1993-09-29
PT99514A (pt) 1992-10-30
IE913974A1 (en) 1992-05-20
CA2095518A1 (fr) 1992-05-15
AU657348B2 (en) 1995-03-09
JPH07509215A (ja) 1995-10-12

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