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WO1992008461A1 - 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 Download PDF

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Publication number
WO1992008461A1
WO1992008461A1 PCT/US1991/008515 US9108515W WO9208461A1 WO 1992008461 A1 WO1992008461 A1 WO 1992008461A1 US 9108515 W US9108515 W US 9108515W WO 9208461 A1 WO9208461 A1 WO 9208461A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidine
diamino
benzyl
methoxy
bromo
Prior art date
Application number
PCT/US1991/008515
Other languages
English (en)
Inventor
Ivan Kompis
Jeffrey M. Blaney
Charles K. Marlow
Original Assignee
Protos Corporation
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 Protos Corporation filed Critical Protos Corporation
Priority to JP4502293A priority Critical patent/JPH07509215A/ja
Priority to EP92900837A priority patent/EP0639075A1/fr
Publication of WO1992008461A1 publication Critical patent/WO1992008461A1/fr

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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)
  • Nitrogen Condensed Heterocyclic Rings (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.
PCT/US1991/008515 1990-11-14 1991-11-14 Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet WO1992008461A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP4502293A JPH07509215A (ja) 1990-11-14 1991-11-14 ジヒドロ葉酸還元酵素の特異的阻害およびそのための化合物
EP92900837A EP0639075A1 (fr) 1990-11-14 1991-11-14 Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US61361990A 1990-11-14 1990-11-14
US613,619 1990-11-14
US73069191A 1991-07-16 1991-07-16
US730,691 1991-07-16

Publications (1)

Publication Number Publication Date
WO1992008461A1 true WO1992008461A1 (fr) 1992-05-29

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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)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0629403A1 (fr) * 1993-06-17 1994-12-21 F. Hoffmann-La Roche Ag Mélange d'antibiotiques
WO1996016046A3 (fr) * 1994-11-24 1996-07-25 Hoffmann La Roche Nouvelles benzylpyrimidines
WO1997043277A1 (fr) * 1996-05-15 1997-11-20 F. Hoffmann-La Roche Ag Derives de 2,4-diaminopyrimidine
WO1998037898A1 (fr) * 1997-02-24 1998-09-03 Barclay Barry J Agents antifongiques agissant en synergie, inhibiteurs du metabolisme du folate, plus specifiquement le methotrexate et le sulfamethoxazole
WO2000071160A1 (fr) * 1999-05-24 2000-11-30 Sankyo Company, Limited Compositions medicinales contenant un anticorps anti-fas
RU2173164C2 (ru) * 1996-10-14 2001-09-10 Корея Инститьют Оф Сайенс Энд Текнолоджи ЭКСТРАКТ ИЗ КОЖУРЫ ПЛОДОВ ЦИТРУСОВЫХ В КАЧЕСТВЕ ИНГИБИТОРА 3-ГИДРОКСИ-3-МЕТИЛГЛУТАРИЛ-СoА (ГМГ - СoА) -РЕДУКТАЗЫ

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8853228B2 (en) * 2007-06-04 2014-10-07 University Of Connecticut Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3577543A (en) * 1966-03-31 1971-05-04 Ici Ltd Insecticidal and fungicidal 2-aminopyrimidinyl-6-carbamate compositions
US3852450A (en) * 1971-12-23 1974-12-03 Lepetit Spa Antibacterial compositions containing rifampicin and a pyrimidine derivative
US4374136A (en) * 1980-10-27 1983-02-15 May & Baker Limited Pyrimidine derivatives
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
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
US4640923A (en) * 1984-05-10 1987-02-03 Bayer Aktiengesellschaft Methods of combatting fungi employing 2,4-diamino-6-halogeno-5-alkylthio-pyrimidines
US4954498A (en) * 1987-01-17 1990-09-04 Boehringer Mannheim Gmbh Tricyclic benzimidazole compounds, pharmaceutical compositions and methods of use
US4996198A (en) * 1988-07-11 1991-02-26 Hoffmann-La Roche Inc. Anticoccidial composition

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US3577543A (en) * 1966-03-31 1971-05-04 Ici Ltd Insecticidal and fungicidal 2-aminopyrimidinyl-6-carbamate compositions
US3852450A (en) * 1971-12-23 1974-12-03 Lepetit Spa Antibacterial compositions containing rifampicin and a pyrimidine derivative
US4374136A (en) * 1980-10-27 1983-02-15 May & Baker Limited Pyrimidine derivatives
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
US4640923A (en) * 1984-05-10 1987-02-03 Bayer Aktiengesellschaft Methods of combatting fungi employing 2,4-diamino-6-halogeno-5-alkylthio-pyrimidines
US4954498A (en) * 1987-01-17 1990-09-04 Boehringer Mannheim Gmbh Tricyclic benzimidazole compounds, pharmaceutical compositions and methods of use
US4996198A (en) * 1988-07-11 1991-02-26 Hoffmann-La Roche Inc. Anticoccidial composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0639075A4 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0629403A1 (fr) * 1993-06-17 1994-12-21 F. Hoffmann-La Roche Ag Mélange d'antibiotiques
AU685449B2 (en) * 1993-06-17 1998-01-22 F. Hoffmann-La Roche Ag Antibiotic combination
US5721242A (en) * 1993-06-17 1998-02-24 Hoffmann-La Roche Inc. Antibiotic combination
CN1054745C (zh) * 1993-06-17 2000-07-26 霍夫曼-拉罗奇有限公司 抗菌组合物
WO1996016046A3 (fr) * 1994-11-24 1996-07-25 Hoffmann La Roche Nouvelles benzylpyrimidines
WO1997043277A1 (fr) * 1996-05-15 1997-11-20 F. Hoffmann-La Roche Ag Derives de 2,4-diaminopyrimidine
US5866583A (en) * 1996-05-15 1999-02-02 Hoffmann-La Roche Inc. Substituted 2,4-diaminopyrimidines
RU2173164C2 (ru) * 1996-10-14 2001-09-10 Корея Инститьют Оф Сайенс Энд Текнолоджи ЭКСТРАКТ ИЗ КОЖУРЫ ПЛОДОВ ЦИТРУСОВЫХ В КАЧЕСТВЕ ИНГИБИТОРА 3-ГИДРОКСИ-3-МЕТИЛГЛУТАРИЛ-СoА (ГМГ - СoА) -РЕДУКТАЗЫ
WO1998037898A1 (fr) * 1997-02-24 1998-09-03 Barclay Barry J Agents antifongiques agissant en synergie, inhibiteurs du metabolisme du folate, plus specifiquement le methotrexate et le sulfamethoxazole
WO2000071160A1 (fr) * 1999-05-24 2000-11-30 Sankyo Company, Limited Compositions medicinales contenant un anticorps anti-fas
US6746673B2 (en) 1999-05-24 2004-06-08 Sankyo Company, Limited Pharmaceutical compositions containing anti-Fas antibody

Also Published As

Publication number Publication date
JPH07509215A (ja) 1995-10-12
CA2095518A1 (fr) 1992-05-15
EP0639075A4 (fr) 1993-09-29
PT99514B (pt) 1999-04-30
EP0639075A1 (fr) 1995-02-22
AU2202792A (en) 1994-04-28
AU657348B2 (en) 1995-03-09
IE913974A1 (en) 1992-05-20
PT99514A (pt) 1992-10-30

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