EP0639075A1 - Specific inhibition of dihydrofolate reductase and compounds therefor - Google Patents
Specific inhibition of dihydrofolate reductase and compounds thereforInfo
- 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
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 ⁇ :
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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 (en) | 1990-11-14 | 1991-11-14 | Specific inhibition of dihydrofolate reductase and compounds therefor |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0639075A4 EP0639075A4 (en) | 1993-09-29 |
EP0639075A1 true EP0639075A1 (en) | 1995-02-22 |
Family
ID=27087063
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92900837A Ceased EP0639075A1 (en) | 1990-11-14 | 1991-11-14 | Specific inhibition of dihydrofolate reductase and compounds therefor |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0639075A1 (pt) |
JP (1) | JPH07509215A (pt) |
AU (1) | AU657348B2 (pt) |
CA (1) | CA2095518A1 (pt) |
IE (1) | IE913974A1 (pt) |
PT (1) | PT99514B (pt) |
WO (1) | WO1992008461A1 (pt) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5721242A (en) * | 1993-06-17 | 1998-02-24 | Hoffmann-La Roche Inc. | Antibiotic combination |
NZ296532A (en) * | 1994-11-24 | 2000-02-28 | F | Substituted 5-benzyl-2,4,-diaminopyrimidines |
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 |
WO1998037898A1 (en) * | 1997-02-24 | 1998-09-03 | Barclay Barry J | Synergistically acting anti-fungal agents that are inhibitors of folate metabolism, especially methotrexate and sulfamethoxazole |
KR20020008197A (ko) * | 1999-05-24 | 2002-01-29 | 가와무라 요시부미 | 항-Fas 항체를 함유하는 의약 조성물 |
US8853228B2 (en) * | 2007-06-04 | 2014-10-07 | University Of Connecticut | Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase |
Citations (16)
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 |
LU77269A1 (pt) * | 1977-05-05 | 1979-01-18 | ||
LU77268A1 (pt) * | 1977-05-05 | 1979-01-18 | ||
EP0003212A1 (de) * | 1977-11-10 | 1979-08-08 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | 2.4-Diamino-5-benzylpyrimidine und diese enthaltende pharmazeutische Präparate sowie deren Herstellung |
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 (en) * | 1980-11-27 | 1982-06-30 | The Wellcome Foundation Limited | Antibacterial benzylpyrimidines |
US4451466A (en) * | 1982-07-02 | 1984-05-29 | Shell Oil Company | Use of pyrroloquinazolinediamines as pesticides |
EP0122580A1 (de) * | 1983-04-14 | 1984-10-24 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrimidinderivate, deren Herstellung und pharmazeutische Präparate |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2852450A (en) * | 1954-06-10 | 1958-09-16 | Donnelley & Sons Co | Method of copper plating |
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. |
GR80171B (en) * | 1983-08-29 | 1985-01-02 | Ciba Geigy Ag | N-(2-nitrophenyl)-4-aminopyrimidine derivatives process for the preparation thereof and use |
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 |
-
1991
- 1991-11-14 CA CA002095518A patent/CA2095518A1/en not_active Abandoned
- 1991-11-14 PT PT99514A patent/PT99514B/pt not_active IP Right Cessation
- 1991-11-14 WO PCT/US1991/008515 patent/WO1992008461A1/en not_active Application Discontinuation
- 1991-11-14 EP EP92900837A patent/EP0639075A1/en not_active Ceased
- 1991-11-14 IE IE397491A patent/IE913974A1/en not_active Application Discontinuation
- 1991-11-14 JP JP4502293A patent/JPH07509215A/ja active Pending
-
1992
- 1992-08-31 AU AU22027/92A patent/AU657348B2/en not_active Ceased
Patent Citations (16)
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 |
LU77269A1 (pt) * | 1977-05-05 | 1979-01-18 | ||
LU77268A1 (pt) * | 1977-05-05 | 1979-01-18 | ||
EP0003212A1 (de) * | 1977-11-10 | 1979-08-08 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | 2.4-Diamino-5-benzylpyrimidine und diese enthaltende pharmazeutische Präparate sowie deren Herstellung |
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 (en) * | 1980-11-27 | 1982-06-30 | The Wellcome Foundation Limited | Antibacterial benzylpyrimidines |
US4451466A (en) * | 1982-07-02 | 1984-05-29 | Shell Oil Company | Use of pyrroloquinazolinediamines as pesticides |
EP0122580A1 (de) * | 1983-04-14 | 1984-10-24 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrimidinderivate, deren Herstellung und pharmazeutische Präparate |
Non-Patent Citations (1)
Title |
---|
See also references of WO9208461A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU657348B2 (en) | 1995-03-09 |
EP0639075A4 (en) | 1993-09-29 |
IE913974A1 (en) | 1992-05-20 |
AU2202792A (en) | 1994-04-28 |
WO1992008461A1 (en) | 1992-05-29 |
PT99514B (pt) | 1999-04-30 |
CA2095518A1 (en) | 1992-05-15 |
JPH07509215A (ja) | 1995-10-12 |
PT99514A (pt) | 1992-10-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3718560A2 (en) | Cyclin dependent kinase inhibitors and methods of use | |
NZ539064A (en) | Novel adenine compound and use thereof | |
Walzer et al. | Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia | |
BRPI0613142A2 (pt) | uso de sangliferina em hcv | |
EP0639075A1 (en) | Specific inhibition of dihydrofolate reductase and compounds therefor | |
CN101820753A (zh) | 通过增量或减量调节哺乳动物细胞中的炎性介质的本地体内水平来治疗哺乳动物中的肺部疾病状态的方法 | |
US20090123389A1 (en) | Methods for modulating Th17 cell development in the treatment and prevention of cellulite | |
US20200022950A1 (en) | Composition containing artesunate | |
Nadel et al. | Synergistic inhibitory action of A-methopterin and a diaminopyrimidine upon leukemia L 1210 in mice | |
KR101519311B1 (ko) | 과호산구성 증후군을 위한 피리미딜아미노벤즈아미드 유도체 | |
Curtin et al. | Inhibition of the growth of human hepatocellular carcinoma in vitro and in athymic mice by a quinazoline inhibitor of thymidylate synthase, CB3717 | |
US20100028298A1 (en) | Interferon type i supporting compounds | |
EP0504290B1 (en) | Inhibitors of pneumocystis carinii dihydrofolate reductase | |
EP0885006B1 (en) | Pharmaceutical composition enabling to inhibit cancer metastasis formation containing n-acetyl-cysteine and doxorubicin | |
AU2001267553B2 (en) | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites | |
Kalghatgi et al. | Enhancement of Antitumor Activity of 2, 4-Diamino-5-(3′, 4′-dichlorophenyl)-6-methylpyrimidine and Baker's Antifol (Triazinate) with Carboxypeptidase G1 | |
JP2020532576A (ja) | 神経変性疾患の処置 | |
Rana et al. | Effect of rifamycin and tilorone derivatives on Friend virus leukemia in mice | |
BR0000011A (pt) | Composições injetáveis de alatrofloxacina pré-mistruadas | |
Miyauchi et al. | Oral Administration of BOF‐A2 to Rats with Lung Transplanted Tumors Results in Increased 5‐Fluorouracil Levels | |
Seydel et al. | Kinetics and Mechanisms of Action of ‘Folate Synthesis Inhibitors’, Alone or in Combination, on Escherichia coli: III. Pyrimethamine, Trimethoprim and Sulfamethoxazole | |
CA2457041A1 (en) | Novel combination | |
EP1744777B1 (en) | Use of il-6 in the preparation of pharmaceutical compositions for treating and preventing liver injury | |
Houghton et al. | ENHANCED CYTOTOXICITY OF 5-FLUOROURACIL COMBINED WITH [6RS] LEUCOVORIN AND RECOMBINANT HUMAN INTERFERON-a2a IN COLON CARCINOMA CELLS | |
Burchall | NH2 OCH3 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19930505 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
17Q | First examination report despatched |
Effective date: 19970605 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
18R | Application refused |
Effective date: 19980801 |