IE45338B1 - Composition for treating leukemia and ascites tumour - Google Patents
Composition for treating leukemia and ascites tumourInfo
- Publication number
- IE45338B1 IE45338B1 IE485/77A IE48577A IE45338B1 IE 45338 B1 IE45338 B1 IE 45338B1 IE 485/77 A IE485/77 A IE 485/77A IE 48577 A IE48577 A IE 48577A IE 45338 B1 IE45338 B1 IE 45338B1
- Authority
- IE
- Ireland
- Prior art keywords
- deazaminopterin
- composition
- dosage
- ils
- tumour
- Prior art date
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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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)
- Epidemiology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
1534238 Treatment of malignancies with 10-deazaminopterin SRI INTERNATIONAL 4 March 1977 [5 March 1976] 09255/77 Heading A5B Leukemia, ascites tumour and other malignancies may be treated 10-deazaminopterin of formula: in the form of tablets, capsules, suppositories, cachets or a sterile aqueous solution.
Description
Leukemia is an acute or chronic disease of unknown cause in man and other warm-blooded animals. It is characterized by an abnormal increase in the number of immature leukocytes in the tissues of the body and in the circulating blood. The disease apparently affects the blood-forming organs, and is classified according to the type of leukocyte that is being proliferated abnormally. The disease is one of a number of forms of neoplastic disease, and the development of drugs for amelioration or curing the disease has occupied the attention of research organizations for many years, and until most recently without appreciable success. Today, many forms of leukemia can be effectively treated with drugs. In the case of combination chemotherapy with acute lymphocytic leukemia in children a large percentage (50 - 60%) of five-year survivals are obtained, and the disease is now classified as curable.
The present invention is based on the discovery that leukemia, as well as other malignancies, including ascitic tumours, can be ameliorated in warm-blooded lower animals by the administration of 10-deazaminopterin, a nontrival analogue of methotrexate, the current drug of choice for the treatment ; Of these malignancies ih the clinic, and it is expected that
-deazaminopterin will· have a similar effect in humans.
45333
OCNHCH CH2
I
COOH
COOH
CI-I„
The relationship between this compound and the N-1O methyl derivative of aminopterin, methotrexate, is apparent from the followings
4-A.fflino-4-deoxy-l'.>“deazapteroic acid, a key intermediate for synthesis of lC-deazaminopterin, was first prepared by DeGraw, Brown, KrsliuK and Gaumont, Journal of Medicinal
Chemistry 14 866 (1971', OeGra Tsakotellis, Kisliuk, and Gaumont, Journal of Heterocyclic Chemistry 8. 105 (1971) had reported the potent growth-inhibitory activity of 10-deazapteroic acid and its tefcranydro derivative against Streptococcus faecinm, a folate-dependent organism. Activity was greatly enhanced by reduction to the tetrahydro compound. Accordingly, it was thought that the 2,4-diamino-pteridines should be investigated, because they would be expected to be more capable of cell penetration, and among the 2,4-diamino-pteridines prepared was 4~5m3.no-4-deoxy-l0-deazapteroic acid, the com433.33
- 4 pound shown under the Scheme I, Series d, at' page 867 of the article.
In the Journal of Medicinal Chemistry 17 552 (1974) DeGraw Kisliuk, Gaumont, Baugh and Nair reported on the synthesis and antifolate activity of 10-deazaminopterin. The antimicrobial and antitumour activities of the powerful dihydrofolic reductase inhibitors aminopterin and its N-10 methyl derivative, methotrexate, are well known, and numerous analogues have been made to further improve the potency, cell penetration and toxicity properties of these compounds. As part of a continuing programme to investigate structure-activity relationships in folic acid analogues, DeGraw et al. were interested in the effects of replacement of the nitrogen atom in the side chain of aminopterin, and reported on the synthesis and biological activity of 10-deazaminopterin in this paper. Continuing work with 10-deazaminopterin has now led to the discovery of its antileukemic activity and to its efficacy in treating various ascites tumour systems.
The invention accordingly provides a pharmaceutical composition, in dosage unit form comprising from 0.1 to 500 mg of 10-deazaminopterin or a pharmaceutically acceptable acidaddition or quaternary ammonium salt thereof, per dosage unit, together with a pharmaceutically acceptable nontoxic inert carrier or diluent.
The composition may be, for example, in the form of a tablet, capsule, suppository, cachet or sterile aqueous liquid. The term pharmaceutically acceptable means that the carrier (as well as the resulting composition) is sterile and nontoxic.
The salts are-formed with one or more free NH2 groups of 10-deazaminopterin. The acid-addition salts are the pharmaceuti4S333 cally acceptable nontoxic addition salts with suitable acids, such as those with inorganic acids, fcr example, hydrochloric, hydrobromic, nitric, sulphuric and phosphoric acids, and with organic acids, such as organic carboxylic acids, for example, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicyclic, o-acetyloxyhenzoie, nicotinic and isonicotinic acid, and organic sulphonic acids, for example, methanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, toluene-p-sulphonio, and naphthalene-2-aulphonic acid.
An acid-addition salt can be converted into the free compound according to known methods, for example, by treating it with a base, such as with a mstai hydroxide or alkoxide, for example, an alkali metal or alkaline-eart’·! metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline-earth metal carbonate or hydrogen carbonate, for example sodium, potassium or calcium carbonate or hydrogen carbonate; with, ammonia; or with a hydroxyl ionexchange resin, or with any other suitable reagent.
?0 An acid-addition salt may also be converted into another acid-addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt, of an acid in a suitable diluent in which a resulting inorganic salt is in25 soluble and is thus removed ftm the reaction medium. An acid-addition salt may also be converted into another acidaddition salt by treatment with an anion-exchange preparation.
’O-Ceazaminoptsi-in or salt unereof can be administered tc f-he animal by any available route, including oral and ?0 parenteral (intravenous, intraperitonea 1, subcutaneous, and
- 6 intramuscular) administration. The amount administered is sufficient to ameliorate the leukemia or the ascitic tumour and will depend upon the type of malignancy, the species of animal, and the weight of the animal. For example, in human administration, a dosage of 10-deazaminopterin within the range from 0.1 mg/kg to 500 mg/kg per day should be sufficient. Dosages in the higher· part of the range, approaching 500 mg/kg, are normally administered in conjunction with leucovoran (dl-5formyl tetrahydrofolate) to avoid toxicity. In the treatment of lower test animals, a similar dosage range is therapeutic.
The upper limit of dosage is that imposed by toxic side effects, and can be determined by trial and error for the animal to be treated, including humans.
To facilitate administration, 10-deazaminopterin or salt thereof.is preferably provided in dosage unit form.
The carrier or diluent can be solid, semisolid, or liquid, and can serve as a vehicle, excipient, or medium for 10-deazaminopterin. Examples of diluents and carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, methyl and propyl- .
hydroxybenzoate, talc and magnesium stearate.
For convenience in handling, the 10-deazaminopterin and carrier or diluent can be enclosed or encapsulated in a capsule, sachet, cachet, gelatin, paper or other container, especially when intended for use in dosage units. The dosage units can for example take the form of tablets, capsules, suppositories or cachets.
The following Examples illustrate various forms of
-3333 dosage units in which the 10-deazaminopterin or salts thereof can be prepared:
EXAMPLE 1
Tablet formulation Mg/tablet
-deazaminopterin 15
Lactose 86
Corn starch (drie:1) 45.5
Gelatin 2.5
Magnesium stearate 1.0
The 10-deazaminopterin is powdered and passed through a mesh sieve and well mixed with the lactose and 30 mg of the corn starch, both passed through a sieve.
The mixed powders are massed with a warm gelatin solution, prepared by stirring the gelatin in water and heating to form a 10% w/w solution. The is granulated by passing through a sieve, and the moist. granules dried at 40°C.
The dried gr v ul.as are regranulated by passing through a sieve and the b-;.ar.ctj of the starch and the magnesium stearate is added and ir.oroughly mixed.
The granules are compressed to produce tablets ea< weighing 150 mg. EXAMPLE 2 Tablet, formulation Mg/tablet 10-deazaminopteriu 100 25 Lactose 39 Corn starch (dried) 80 Gelatin 4.0 Magnesium stearate 2.0
43333
- 8 The method of preparation is identical with that of Example 1 except that 60 mg of starch is tion process and 20 mg during tableting.
EXAMPLE 3
Capsule formulation
-deazaminopterin Lactose
The 10-deazaminopterin and lactose sieve and the powders well mixed together before filling into 10 hard gelatin capsules of suitable size, so that each capsule contains 400 mg of mixed powders.
used in the granulaMg/capsule
250
150 are passed through a
EXAMPLE 4 Suppositories
Mg/suppositorv
950
-deazaminopterin 15 Oil of Theobroma
The 10-deazaminopterin is powdered and passed through a sieve and triturated with molten oil of theobroma at 45°C to form a smooth suspension.
The mixture is Well stirred and poured into moulds, each 20 of nominal lg capacity, to produce suppositories.
EXAMPLE 5
Cachets
-deazaminopterin Lactose
The 10-deazaminopterin is passed through a mesh sieve, mixed with previously sieved lactose, and fitted into cachets of suitable size so that each contains 500 mg.
Mg/cachet
100
400
53 3a
- 9 EXAMPLE 6
Intramuscular injection (sterile suspension in aqueous vehicle) Mg
-deazaminopterin 10
Sodium citrate 5.7
Sodium carboxymethylcellulose (low viscosity grade) 2.0
Methyl para-bydroxybenzoate 1.5
Propyl para-hydroxybenzoate 0.2
Water for injection to 1.0 ml
Inbraperitoneal intraveneons or subcutaneous injection (sterile solution in aqueous carrier system) Mg
-deazaminopterin, hydrochloric acid-addition salt 15 Sodium citrate 5.7
Sodium carboxymethylcellulose (low viscosity grade) 2.0
Methyl para-hydroxyben?cate 1.5
Propyl para-hydroxybenzoate 0.2
Water for injection to 1.0 ml
The following Example illustrates administration cf 10deazaminopterin using a standardized test procedure:
ΕΧΉΡΙΕ £
Sodium hydroxide (0.2 ml of ο.1 N) was added to 5 mg of 10-deazaminopterin. Distilled water was then added, the pH adjusted tc 7.0, and the solution then diluted with distilled water to 10 ml. The resulting solution and dilutions thereof were administered in aliquot portions of 0.1 ml by intraperitonea 1 injection into L12J.0 leukemic BD (2) p female mice (A.S. -Schmid, Madison, Wis). Injections were given once per uay, three times per week (Monday, Wednesday, Friday) starting one day after tumour transplantation (10^ cells/mouse).
Therapy was continued until death of the animals.
45333
- 10 For comparison purposes, and as' a control, a parallel series of tests was carried out simultaneously using L1210 leukemic BD (2) F£- female mice, under exactly the same test conditions, administering methotrexate instead of 10-deazamino pterin.
The procedure for testing, and the maintenance and transplantation of the L1210 leukemia, is in accordance with the method of Hutchison, D.J., Robinson, D.C., Martin, D., Ittensohn, O.L. and Dillenberg, Journal Cancer Res. 22 57-72 (1962). The antileukemic activity of lO-deazaminopterin was evaluated against methotrexate in terms of the increase in median life span obtained at various dosages, up to the maximum tolerated level, when compared to untreated controls. Toxicity of various dosages was evaluated by the extent of weight loss and eventual death, with.no evidence of tumour.
Representative results obtained against the L1210 leukemia are as follows:
3 3 8
TABLE I
Mice (Exp. ’s x No. Dosage ) (mg/kg) Median life span (days) Increased span {%) life Weight change 10-deazaminopter in: 5 2 x 10 None (control) 6.8 + 0.5 + 15 2x5 0.1875 7.2 + 0.6 3.0 + 10 2x5 0.375 8.9 + 1.0 29.7 + 7 3x5 0.75 10.7 + 1.4 58.3 + 15 10 3x5 1.5 14.7 + 1.8 116.5 + 11 2x5 3.0 1S.0 £ 1.9 164.8 + 5 2x5 6.0^ 21,8 + 1.5 210.0 -3 Methotrexate (control): 2 x 5 0. 75 9,9 + 1.0 46.0 + 11 15 2x5 1.5 12.7 + 1.8 86.5 + 13 3x 5 3.0 17.5 + 2.9 152.8 + 8 3x5 6.0 18.3 + 3.5 169.0 + 3
~ Slight toxicity
Examples 9 - 12, which follow, deal with the treatment 20 of ascites tumours of one species or another. The nature of the tumour, the condition of its treatment in the mice host animals, and the results obtained from the treatment are indicated by the data of the several tabl'S and the notes appended to each. The results of these treatments are summarized at the conclusion of Example 12.
45333
- 12 EXAMPLE' 9 S180-J ascites
Dosage* Methotrexate_ 10-Deazaminopterin
mg/kg x 5 MST ILS Toxic MST ILS Toxic 5 s.c. (days) Deaths (days) (%) Deaths — 12.1 + 1.1 — 0/15 12.1 + 1.1 -- 0/15 3 11.7 + 1.7 0 0/10 13.0 + 1.1 8.7 0/10 6 15.2 + 0.9 24.9 0/15 21.2 + 1.7 74.8 0/15 9 18.3 + 2.0 51.3 0/15 26.3 + 0.7 117.3 0/15 10 12 19.8 + 1.8 64.0 0/15 > 31.4 + 2.5 > 159.6X 0/15 18 19.4 + 2.7 60.6 6/10 18.6 + 2.4 54.0 7/10 * One dose (s.c.) every 2 days for a . total of 5 doses. + Toxic animals weigh 13-15 g at death (orig. wt. 20 g) •
x two 60-day survivors.
MST = Medium survival time + standard deviation. ILS = increased life span.
Each dose tested 2-3 times.
I ίί ο 3 3 8
- 13 EXAMPLE 10
Ρ815 ascites
Dosage * mg/kg x 5 S.C. Methotrexate 10-Deazaminopterin MST (days) ILS (%) Toxic+ Deaths MST (days) ILS (%) Toxic Deaths __ 8.8 + 0.9 0/10 8.8 + 0.9 0/10 3 — — 6 15-4 + 1.1 75.0 0/10 18.2 + 1.3 107.5 0/10 9 17.6 + 1.6 100.3 0/10 19.0 + 0.9 116.3 0/10 10 12 18.4 + 1.3 109.1 0/10 19.2 + 1.2 118.4 0/10 18 — -.-
* One dose (s.c.) every 2 days for a total of 5 doses.
+ Toxic animals weight 13-15 g at death (orig. wt. 20 g). MST = Medium survival time + standard deviation.
ILS = Increased life span.
Each dosage tested twice.
- 14 43338
EXAMPLE 11
L1210 ascites
Dosage* Methotrexate
mg/kg x 5 s.c· Route MST (days) ILS (%) — 6.6 + 0.7 — 3 S.C. 11.5 + 1.1 74 6 14.4 + 0.8 118 9 15.8 + 0.9 139 12 16.7 + 1.1 148 3 Oral 9.4 + 1.1 42 4.5 9.6 + 0.8 45 S.O 10.4 + 0.7 58
_ 10-Deazaminopterin
Toxic+ MST ILS Toxic
Deaths (days) (%) Deaths
0/20 o/lo 6.6 + 0.7 108 0/20 0/10 13.8 + 0.7 0/10 15.2 + 1.5 131 0/10 0/15 17.8 + 0.8 168 0/15 0/15 18.2 + 1.3 176 1/15 0/15 11.7 + 1.0 77 0/15 0/20 13.3 + 0.9 101 0/20 0/15 14.7 + 1.3 122 0/15
*0ne dose every 2 days for a total of 5 doses.
+ Animals weigh 13-15 g. at death (orig. wt. 20 g).
MST = Medium survival time + standard deviation.
ILS = Increased life span.
Each dose tested 2-4 times.
ΰ' 3 3 3
-15EXAMPLE 12
Ehrlich ascites
Methotrexate lo-Deazaminopterin
Dosage* mg/kg x 5 s.c. MST (days) ILS (¾) Toxic Deathst MST (days) ILS (%) : Toxic Deaths! 3 17.2 2.1 — 0/10 17.2 + 2.1 — 0/10 6 19.8 2.3 15.1 0/10 23.2 + 1.8 34.8 0/10 10 9 20,8 + 3.0 20.9 0/10 27.2 + 2.2 58.1 0/10 12 18 20.2 + 1.9 17, C 0/10 28.2 + 2.9 64.0 0/10
*One dose (s.c) every 2 days for* a total of 5 doses. •(Toxic animals weigh 13—IS g at death (orig. wt. 20 g) .
MET - Medium survival time + standard deviation.
ILS = Increased life span.
Each dose tested twice.
3-3 3 τ-16In summarizing the data of Examples 9-12, it will be seen that 10-deazaminopterin (dAM) was more active than methotrexate (MIX) ih all of the ascites tumour systems examined. Optimum sc dosages for each agent were 6-12 mg/kg when given once q2d x 5. Maximum ILS (dAM/MTX) was +172%/+144% against L1210, +117%/+103% against P815, +61%/+19% against Ehrlich and > +160%/+64% against S180 with long-term survivors after dAM. Maximum ILS (dAM/MTX) at the same dosage and schedule against L1210 was +'2O3%/+182% by ip administration and +122%/+58% orally. The acute LDgQ ip or sc was 65 mg/kg (dAM) and 96 mg/kg (MTX). Plasma and tissue (tumour, small intestine and marrow) pharmacokinetics were similar for dAM and MTX.
The increase in efficacy of dAM over MTX at optimum dosages was associated with a greater persistence of exchangeable dAM in tumour, but similar persistence in drug-limiting normal tissue. Greater persistence of dAM versus MTX in tumour was accounted for by differences in membrane transport, specifically in regard to the saturability (K^) for influx, favouring greater accumulation of dAM. Both agents compete for the same carrier mechanism, but carrier in tumour exhibits a greater affinity for dAM.
Claims (7)
1. A pharmaceutical composition in dosage unit form comprising from O.i to 500 mg of 10-deazaminopterin or a pharmaceutically acceptable acid-addition or quaternary 5 ammonium salt thereof, per unit dosage, together with a pharmaceutically acceptable nontoxic inert carrier or diluent.
2. 2. A composition as claimed in Claim 1 in tablet form.
3. A composition as claimed in Claiiti 1 in capsule form.
4. A composition as claimed in Claim 1 in suppository form,
5. A composition as claimed in Claim 1 in cachet form.
6. A composition as claimed in Claim 1 in sterile aqueous form.
7. A compos ition as in Claim 6 in the form of an aqueous solution. β. A composition as . in Claim 6 in the form of an aqueous dispersion. 9. A compos ition as claimed in Claim } substantially as here! nbefore described in any : >ne of Examples 1 to 7. ?. R. KELLY & CO.,
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66421376A | 1976-03-05 | 1976-03-05 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE45338L IE45338L (en) | 1977-09-05 |
IE45338B1 true IE45338B1 (en) | 1982-08-11 |
Family
ID=24665062
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE485/77A IE45338B1 (en) | 1976-03-05 | 1977-03-04 | Composition for treating leukemia and ascites tumour |
Country Status (10)
Country | Link |
---|---|
JP (1) | JPS52120134A (en) |
AU (1) | AU511856B2 (en) |
BE (1) | BE852095A (en) |
CA (1) | CA1085729A (en) |
DE (1) | DE2709506A1 (en) |
FR (1) | FR2342732A1 (en) |
GB (1) | GB1534238A (en) |
IE (1) | IE45338B1 (en) |
IL (1) | IL51593A (en) |
ZA (1) | ZA771315B (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4393064A (en) * | 1976-03-05 | 1983-07-12 | Sri International | Process and composition for treatment of leukemia and process for preparing the same |
US4460591A (en) * | 1982-08-26 | 1984-07-17 | Sri International | 8,10-Dideazaminopterins |
US4684653A (en) * | 1985-03-08 | 1987-08-04 | The Trustees Of Princeton University | Pyrido(2,3-d)pyrimidine derivatives |
US4927828A (en) * | 1985-03-08 | 1990-05-22 | The Trustees Of Princeton University | Diastereoisomeric tetrahydropyrido-(2,3,d) pyrimidine derivatives |
US5026851A (en) * | 1985-03-08 | 1991-06-25 | The Trustees Of Princeton University | Pyrido[2,3-]pyrimidine derivatives |
US4833145A (en) * | 1986-06-30 | 1989-05-23 | The Trustees Of Princeton University | 4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine derivatives |
US4818819A (en) * | 1986-10-20 | 1989-04-04 | The Trustees Of Princeton University | Process for the preparation of fused pyridine compounds |
US4902796A (en) * | 1986-10-20 | 1990-02-20 | The Trustees Of Princeton University | 6-alkenyl and ethynyl derivatives of 2-amino-4-hydroxypyrido[2,3-d]pyrimidines |
US5028608A (en) * | 1989-12-11 | 1991-07-02 | The Trustees Of Princeton University | N-(6-Amino-(pyrrolo(2,3-d)pyrimidin-3-ylacyl) )-glutamic acid derivatives |
WO2000023448A1 (en) * | 1998-10-22 | 2000-04-27 | Moheno Phillip B B | Novel pterin antineoplastic agents |
-
1977
- 1977-03-04 FR FR7706513A patent/FR2342732A1/en active Granted
- 1977-03-04 IE IE485/77A patent/IE45338B1/en not_active IP Right Cessation
- 1977-03-04 DE DE19772709506 patent/DE2709506A1/en active Granted
- 1977-03-04 CA CA273,253A patent/CA1085729A/en not_active Expired
- 1977-03-04 AU AU22926/77A patent/AU511856B2/en not_active Expired
- 1977-03-04 BE BE175475A patent/BE852095A/en not_active IP Right Cessation
- 1977-03-04 GB GB9255/77A patent/GB1534238A/en not_active Expired
- 1977-03-04 ZA ZA00771315A patent/ZA771315B/en unknown
- 1977-03-04 IL IL51593A patent/IL51593A/en unknown
- 1977-03-05 JP JP2333277A patent/JPS52120134A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS52120134A (en) | 1977-10-08 |
JPS613325B2 (en) | 1986-01-31 |
FR2342732A1 (en) | 1977-09-30 |
DE2709506A1 (en) | 1977-09-08 |
IL51593A0 (en) | 1977-05-31 |
AU511856B2 (en) | 1980-09-11 |
IE45338L (en) | 1977-09-05 |
IL51593A (en) | 1980-01-31 |
GB1534238A (en) | 1978-11-29 |
ZA771315B (en) | 1978-05-30 |
CA1085729A (en) | 1980-09-16 |
FR2342732B1 (en) | 1980-02-01 |
BE852095A (en) | 1977-07-01 |
DE2709506C2 (en) | 1987-03-26 |
AU2292677A (en) | 1978-09-07 |
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