JPS63216885A - Compound and medicinally acceptable salt, medicine, manufacture and remedy for proliferative disease - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2,4-diaminopyrido[2,3-d]pyrimidines, pharmaceutical formulations containing said compounds and their use in medicine.

British Patent No. 1084 103 (and corresponding US Pat. No. 3,322,765) describes the general formula: where R is hydrogen or ar4, and Rb is inter alia an unsubstituted benzyl group or one or more 2,4-diaminopyrido[2,3-d]pyrimidine which is a benzyl group substituted by the above halogen atoms, alkyl or alkoxy groups is disclosed.

British Patent No. 970583! No. 1llIl discloses compounds similar to those of formula (I) above, but in which R is hydrogen and Rb is inter alia phenylalkyl, optionally with one or more substituents. There is.

Compounds of formula (I) have been described as having high in vivo and in vitro activity against bacteria or bacterial infections in experimental animals.

Subsequently, the compounds of formula (I) specifically disclosed in British Patent No. 1084 103 exhibit certain inhibitory activity against mammalian dihydrofolate reductase (D HF R'), and by this activity It has now been found that the compounds have become potentially useful in the treatment of conditions in which inhibition of DHFR in mammals is desirable.

Furthermore, many of these compounds have been found to be effective inhibitors of histamine N-methyl transerapepi (HMT), an enzyme involved in the metabolism of histamine. Thus, inhibitors often cause undesirable accumulation of histamine in organs and tissues. The effects of histamine are known, and any potential further benefits of these compounds are limited by the strong I-I M
was substantially reduced by T inhibition.

Further studies showed that a number of other compounds of formula (I) also had DHFR inhibitory activity, but these compounds were also effective inhibitors of HMT. HMT
Other compounds with acceptably low levels of inhibition include D
It was found to have insufficient activity as an inhibitor of HFR.

European Patent No. 0021292 and US Patent No. 4372957 discloses that formula (II) [wherein,
The compounds of 1 and pharmaceutically acceptable acid addition salts thereof, wherein Ar is and R and Rd are lower (C 1-6) alkyl, are highly effective inhibitors of o H+:R in mammals. Not only does HMT have an acceptable low alcohol rosacea, but it is also effective against various forms of cancer, including xerostomia, basal cell carcinoma and squamous cell carcinoma of the skin, and leukemia, lymphoma, sarcoma, and solid tumors. are disclosed to be useful in the treatment of proliferative diseases such as. - Salt cloudy salts are preferred.

2.4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-d]pyrimidine is -
Confirmed as a preferred compound.

The present invention provides 2,4-diamino-5-methyl-6-(2,
The desmethyl analogue of 5-dimethoxybenzyl)pyrido[2<3-d]pyrimidine has effective inhibitory activity against dihydrofolate reductase and is useful in the treatment of bacterial infections and proliferative diseases, e.g. 2゜4-diamino-5-mebru-6-(5-humanOxy-2-methoxybenzyl)pyrido [2,3-d
]Pyrimidine and 2,4-diamino-5-methyl-6
-(2-hydroxy-5-methoxybenzyl)pyrido [
2,3-d]pyrimidine.

Accordingly, the present invention provides compounds of general formula (III) (wherein R1 is hydrogen when R2 is methyl or R1 is methyl when R2 is hydrogen) and their pharmaceutically acceptable Provide salt.

Therefore, the present invention provides 2,4-diamino-5-methyl-6
-(2-hydroxy-5-methoxybenzyl)pyrido [
2,3-d]pyrimidine and pharmaceutically acceptable salts of 2,4-diamino-5-methyl-6-(3-hydroxy-2-methoxybenzyl)pyrido[2,3-d
pyrimidine and its pharmaceutically acceptable salts.

The biological activity of the compounds of the invention resides in the free base, so the nature of the salt is not critical. Suitable acid addition salts include, for example, hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, p
-Toluenesulfonic acid, methanesulfonic acid, maleic acid, lactic acid, citric acid, tartaric acid, succinic acid, oxalic acid, p-
These include those derived from chlorobenzenesulfonic acid, isethionic acid, glucuronic acid, pantothenic acid and lactobionic acid. Suitable basic salts include those formed with alkali metals such as sodium or potassium.

The compound of formula (III) is a compound of similar structure IIIJ,
It can be manufactured by any manufacturing method known in the art.

Thus, for example, a compound of formula (III) may be a compound of formula (IV) (
(wherein R3 is benzyl when R4 is methyl or R3 is methyl when R4 is benzyl) can be prepared by debenzylation of the corresponding benzyloxy compound or a salt thereof.

Debenzylation is carried out by any suitable method known to those skilled in the art, for example catalytic hydrogenation, ie hydrogen in the presence of a transition metal catalyst such as palladium on carbon. The reaction is carried out in an inert solvent, suitably an alcohol such as the methyl ether of ethylene glycol (2-methoxyethanol), at non-extreme temperatures, e.g.
Suitably it is usually carried out at room temperature.

Compounds of formula (IV) can be prepared by methods known to those skilled in the art. In particular, these compounds can be prepared by reduction of the corresponding 7-substituted compounds of formula (V) in which R and R4 are as defined above and R is a detm base which can be removed by hydrogenolysis. Can be made into 3 by cleavage. Such groups include, for example, mercapto or halogeno (eg chloro) radicals.

When R5 is SH, dethiolation can suitably be carried out by reaction with a desulphurizing agent such as Raney nickel or Raney cobalt, or by catalytic hydrogenation utilizing hydrogen in the presence of a catalyst such as palladium on charcoal. .

When R5 is a hydrogen atom, compounds of formula (IV) can be suitably obtained, for example, by catalytic hydrogenation. Alternatively, the hydrogen atom R5 can be removed, for example by using zinc in aqueous ammonia.

If λ8R5 is removed by catalytic hydrogenation, the debenzylation can suitably be carried out simultaneously with the cleavage of the R5 group, giving formula (V)
It can be seen that the compound of formula (III) can be obtained directly from the compound of formula (III). That is, a further process for producing a compound of formula (I[I) is characterized by catalytic hydrogenation of a compound of formula (V) (wherein R5 is a group that can be removed by catalytic hydrogenation).

Compound 1 of formula (V) (wherein R5 is a mercapto group) can be converted into the corresponding 7-chloro compound (R5=Cj or by treating the corresponding 7-hydroxy compound with phosphorus pentasulfide.

Compounds of formula (V) in which R5 is a halogen atom, e.g. chlorine, can be prepared from compatible 7-oxo compounds by halogenation with a Vilsmeier reagent prepared from e.g. oxalyl chloride or thionyl chloride. The 7-oxo compound is 2. /1.6-Triaminopyridine can be prepared by reacting with a compound of formula (Vl) 1-4 where Afk is C alkyl.

Compounds of formula (IV) contain 2,4,6-triaminopyrimidine of formula (■), where R3 and R4 are as defined above, and A is and R6 is, for example tertiary amino, alkoxy,
It can also be prepared directly by reaction with a compound that is a leaving group such as an alkylthio, halogeno, sulfonate or tosylate group.

A compound of formula (IV) is a compound of formula (■) where R3 and R4 are as defined above, and Y and Z are the same or different, and are sycamohalokene (e.g. Br, CI) OH, 5t- 1 or NH2, provided that at least one of Y and Z is a halogen, O
It can be further prepared by converting the halogen atoms, hydroxy and/or mercapto groups in the compounds (H or 8N) into amino groups by methods known per se in pyrimidine chemistry. This type of reaction is called “hetero-cytocombinous”.
clic C01pOtlndS) J Volume 16, (Wiley Interscience, 1962).

Compounds of formula (■) can be prepared (7) by methods known in the art for the preparation of such compounds.

Furthermore, Y is OH or NH2 and Z is OH or SH, e.g. urea, guanidine or thiourea of the formula (IX), where R and R4 are -CON as defined above.
+-12 or CN, and R is N+-1, C
jl! or E3r) with a suitable compound.

2.4-diamino-5-methyl-6-(2-hydroxy-5-methoxybenzyl)pyrido2<3-d]pyrimidine or 2.4-diamino-5-methyl-6-(3-
Hydroxy-2-methoxybenzyl)pyrido[2,3-
Although dl pyrimidine or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active compound") can be administered as a drug substance, it is preferably provided in the form of a pharmaceutical formulation.

Accordingly, the present invention further provides pharmaceutical formulations comprising an active compound together with a pharmaceutically acceptable carrier thereof. The carrier is "acceptable" in the sense that it is compatible with the other ingredients of the formulation.
and should not be harmful to its receptors.

Pharmaceutical formulations can be manufactured by a method characterized by combining an active compound and its pharmaceutically acceptable carrier.

Topical application is particularly suitable when the active compounds are used for the treatment of proliferative skin diseases.

The term "topical" as applied in Honkawa Ill relates to the use of active ingredients formulated in suitable pharmaceutical carriers and applied to the affected area to exert local action.

Pharmaceutical formulations suitable for topical administration include ointments, lotions, pastes, jellies, sprays, 1. It can be provided in anhydrous forms such as L-rosol and σ bath. The term ointment includes preparations (including creams) with oily, absorbent, water-soluble and emulsion-type bases, such as petrolatum, lanolin, polyethylene glycols and mixtures thereof.

Topical formulations have concentrations of 0.05% W/W to 10% W/W1, preferably 0.1% W/W to 2% W,'w, most preferably 0.2% W/W to 1% It may contain W/W active ingredients.

Other pharmaceutical formulations include oral, rectal and parenteral.

Although some are suitable for oral administration, oral formulations are preferred. The formulation may suitably be presented in discrete dosage units, if appropriate, and may be prepared by any method known to the pharmaceutical art.
You can build J. A suitable unit dose formulation contains 1 kg of active compound.
~1 g, preferably 2Il! g to 500j+9, most preferably about 10q to 30019, 1 day per day.
taken once or several times.

All methods of preparing such formulations include the step of bringing into association the active compound with liquid carriers and/or finely divided solid carriers and then, if necessary, shaping the product into the desired formulation.

Pharmaceutical formulations suitable for oral administration in which the carrier is a solid are most preferably presented in unit ml units, such as bolus, capsules, cachets, or tablets, each containing a predetermined amount of the active compound. Tablets can be made by compression or molding, optionally with one or more 01 ingredients.

Compressed tablets are compressed in a suitable machine the active compound in free-flowing form, such as a powder or granules, optionally mixed with binders, lubricants, inert diluents, lubricating surfactants or dispersants. It can be manufactured by Molded tablets can be made by molding an inert liquid diluent. The tablets can be optionally coated, and if uncoated, they can be optionally scored. Capsules can be made by filling a capsule case with the active compound, either alone or in admixture with one or more accessory ingredients, and then encapsulating the capsule case in conventional manner. Cachets are similar to capsules in which the active ingredient is enclosed in a rice paper envelope along with any accessory ingredients.

Pharmaceutical formulations suitable for oral administration in which the carrier is a liquid can be presented as aqueous liquid solutions or suspensions, or as oil-in-water or water-in-oil liquid emulsions.

Pharmaceutical formulations suitable for rectal administration in which the carrier is a solid are most preferably presented as unit dosage forms.

Suitable carriers include cocoa butter, which is commonly used in the art, and the scientific rule is that the active compound is mixed with the softened or molten carrier, then cooled and shaped in a mold to achieve the desired shape. can be formed into

Pharmaceutical preparations suitable for parenteral administration include aqueous or oily sterile solutions or suspensions of the active compounds. Suitably, such formulations are presented in unit-dose or multi-dose containers in which the formulation is introduced and enclosed until required for use.

In addition to the carrier ingredients, the pharmaceutical formulations may optionally contain diluents, buffers, fragrances, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). It is to be understood that one or more additional carrier ingredients may be included, such as, and substances included to render the formulation isotonic with the blood of the intended recipient.

As mentioned above, the active compounds of the invention are useful in the treatment of proliferative diseases. This active compound can therefore be used in a method for the treatment of proliferative diseases in humans and other animals, characterized in that an effective amount of the active compound is administered orally or applied topically once or several times a day. .

The compounds of the invention can also be used for the manufacture of medicaments for the treatment of proliferative conditions.

The present invention also provides pharmaceutically acceptable salts of the active compounds as defined above for use in medicine.

Furthermore, the present invention also provides an active compound as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of proliferative conditions.

Proliferative conditions for which the active compounds of the invention can be used include:
There are various forms of cancer including psoriasis of the skin, basal and squamous cell carcinomas and leukemias, lymphomas, sarcomas and solid tumors and rheumatoid or proliferative arthritis.

The amount of active compound required for therapeutic effect as an antiproliferative agent will, of course, vary depending on such factors as the nature and severity of the disease, the age and weight of the patient, the route of administration and, if the compound is used in salt form, the nature of the salt.

Generally, doses suitable for the treatment of mammals (including humans) are within the range of 0.1 #iF/phantom body weight/day to 150 Mg/phantom body weight/day, preferably 0.311! J/Ny weight/1”
It is within the range of ˜50 ttty/Ky body weight/day, more preferably within the range of 0.5 ttty/Ky body weight/day to 20 i*/9 body weight/day.

The development of toxicity due to active compounds is typically in combination with folate deficiency, such as bone marrow depression, megaloblastic changes, and gastric 11M ulceration. Administration of calcium leucovorin (5-formyl-5,6,7°8-tetrahydro mM calcium salt) can reverse or prevent these toxic episodes. Administration of calcium leucovorin can be carried out simultaneously with treatment or at any stage thereof, as soon as toxic symptoms appear.

Therefore, the hematological activity of the active compound can be prevented or reduced by co-administration of leucovorin.

Therefore, the concentration of active compounds can be safely increased by increasing the use of the compounds with co-administration of leucovorin.

The following examples illustrate the invention without limiting it. In Examples 1 to 4, the active ingredient is 2,4-diamino-5-methyl-6-(2-hydroxy-5-methoxybenzyl)pyrido [2,3-dlpyrimidine or 2°4-diamino-5 -methyl-6-(
3-hydroxy-2-methoxybenzyl)pyrido [2,
It can be either a 3-dl pyrimidine or a salt thereof.

Example 1 Water-soluble ointment active ingredient 0.5 Polyethylene glycol 300 20.0 Polyethylene glycol 1500 79.5 Total
100.0 Example 2 Skin Cream Active Ingredients 0.5 Glycerin Monostearate 20.0 Methylparaben
0.3 Vaseline light liquid
4,0 propylene glycol
5.0 Span 60
2.0 Tween 61 4
．． 0 water
64.2 total
"100.0F Span" and "RT-Vienna" are trademarks.

Example 3 Tablet formulation active ingredients 100IFj starch 50q lactose
50#y stearic acid
3q Zeradin
151tj total
218I1g Example 4 Injectable preparation active ingredient 5Rg/d [ ]
Pyrene glycol 40d ethanol
11d water
9m Example 5 Synthesis of 2.4-diamino-5-medyl-6-(2-hydroxy-5-methoxybenzyl)pyrido2゜3-d]pyrimidine 2-benzyloxy-5-methoxybenzaldehyde [
Helvetica Simica Fist Acta (IIOIV.

Chil, ^cta), 1964, Toyu, 1996)
] (42,65ay), ethyl acetoacetate (26,5g
) and cyclohexane (300Itl), toluene (
75 m), piperidine (0,87-) and vinegar 1! ! (
The mixture of 2,53d) was fast flow heated for 3 hours in an apparatus equipped with a Disi-Stark trap to collect the azeotropically distilled water. The solvent was removed and the intermediate was then subjected to E
tol+ (480d), then 5% Pd/C2
, 69 under 2 Ops of hydrogen for 3.5 hours in a Parr hydrogenator. The product was purified on a silica gel column eluting with hexane:ethyl acetate 9:1 to yield 51 g (81%) of ethyl 2-(2-benzyloxy-5-methoxybenzyl)-3-oxobutyrate.

Year @ C21H240s Ic Z l/' T measurement value C170,77,1'', 6.09° Actual '311 value
C,70,63,1'', 6.71゜The above product (21,
819), 2,4,6-triaminopyrimidine (7,5
1! ? ) and 1-methyl-2-bi1]lidinone (50
ml of the mixture was heated to 190° C. for 2 hours in an apparatus equipped with a Diesi-Stark trap. Metal (80-) was added to the cooled reaction mixture and the resulting solid was collected by filtration and then treated with boiling water to 2,4-diamino-6-(2-benzyloxy- 5-methoxybenzyl)-5-methylpyride [2,
3-dl pyrimidin-7(31'')-one (9,799
, 39%), melting point 283℃~287℃"L rise C2
Calculated for 3H23N503 (Direct C166, 17,
H2S, 55, N, 16.78. Actual value C, 66, 3
0, H, 5, 59, N, 16.53).

No. 4,372 except that oxalyl chloride was used in place of thionyl chloride in the Vilsmeier reagent.
．． This product was chlorinated as in Example 1 of the '957 specification (referenced herein). The Vilsmeier reagent consists of adding oxalyl chloride (13,4m) slowly to a mixture of dimethylformamide (12,5ae) and chloroform (80Ml) with stirring at 0°C, then warming to room temperature with stirring, and then adding to this temperature. It was produced by leaving it for 14 hours. 2゜4-diamino-6
-(2-benzyloxy-5-methoxybenzyl)-5
-Methyl pyridine 2.3-dl pyrimidine-7 (8H)
-one (6.74 g) was added to the Vilsmeier reagent and the mixture was then heated with rapid flow for 3 hours and then cooled to 0<0>C.

After chlorination, n-butylamine (37) was slowly added to the cold MI reacted (below 30° C.) and then fast-flowed for 1.5 hours. The resulting solid was filtered, washed with chloroform,
then washed with E t OH, then heated in hot water,
2.4-Diamino-6-(2-benzyloxy-5-methoxybenzyl)-7-chloro-5-methylpyride [2
, 3-dl pyrimidine, melting point 260°C-261°C 2.4
7g (35%) was obtained. Fort fr C23H22CI
Calculated value for N 50□, C, 63, 37, H, 5,
09, N, 16.07, CI, 8.13° Actual value, C
,63,10,H2S,16,N,15.96,C1,
8,04° The chloro product from above (3,0 g - portion from the second batch) was refluxed in 2-methoxy-ethanol (350d) and then added in portions with sodium formate (2,8
(29) and 5% Pd/G (1.4 g) for 4 h to dechlorinate and debenzylate. The product was purified with a silica gel column and CHCj3:MeOH/6
: eluted with 1, 2,4-diamino-5-medyru6
-(2-hydro4-cy5-methoxybenzyl)pyrido[2,3-dl pyrimidine, mp 284°C-286°C
0.34g (18%) was obtained. 91C16H17N50
□Autopsy value for H20, C158,35, H,5,8
1, N, 21.26゜Real 11ifi, C, 5B, 6
0, H, 5,60, N, 21.19° Example 6 Synthesis of 2.4-diamino-5-methyl-6-<5-hydroxy-2-methoxybenzyl)pyrido[2°3-d]pyrimidine 5 -Benzyloxy-2-m-1-xybenzaldehyde [Chew.

Ber,) 1974.107.686] (10,
19), a mixture of ethyl acetoacetate (6,4y) and cyclohexane (80 Ml), toluene (20d), piperidine (0,2m> and acetic acid (0,6d)) for 3 h in HM equipped with a Disi-Stark trap. The azeotropically distilled water was collected by heating in a stream. The solvent was removed and the intermediate was dissolved in E tOH (110 m Reduced in a Parr hydrogenator for .5 hours. The product was purified on a silica gel column and purified with hexane:ethyl acetate/9
:12.4 g of 2-(5-benzyloxy-2-methoxybenzyl)-3-oxoFIFW ethyl
(85%). Analysis value, calculated value for C21H2405, C170,77, H16,79, actual value, C
,70,88,H,6,74° The mixture of the above product (12,(1), 2.4.6-triaminopyrimidine (4,09) and 1-methyl-2-pyrrolidinone (30se), Heated at 190° C. for 2 hours in an apparatus equipped with a Disi-Stark trap. Methanol (40 ad) was added to the cooled reaction mixture and the resulting solid was collected by filtration and then treated with boiling water. and 2,4-diamino-6-(3-benzyloxy-2-meth4nidibenzyl)-5-methylpyrido[2,3-d]pyrimidin-7(3H)-one (6
, 02g, 45%), melting point 338°C-342°C.

Calculated value for C23H23N503, C,66,
17,1], 5.55, N, 16.78, actual value, C1
66,08,H2S,59,N,16. No. 4.372 except that oxalyl chloride was used instead of thionyl chloride in the 70° Vilsmeier reagent.
This product was chlorinated as in Example 1 of the '957 specification. Oxalyl chloride (12,1d) was dissolved in dimethylformamide (10,89) and chloroform (70m
) into the mixture at 0°C with stirring,
Then warm up to room temperature with stirring, then heat to 14FR at room temperature.
Vilsmeier reagent was prepared by standing for a while. 2.4-diamino-6-(3-benzyloxy-2-
methoxybenzyl)-5-methylpyride [2,3-dl
Pyrimidin-7(8H)-one (5,72g) was added to the Vilsmeier reagent and the mixture was then heated at reflux for 3 hours, then cooled to 0<0>C. Chlorinated, n-butylamine (
29 l1) was slowly added to the cold 7 J] reaction mixture and then refluxed for 1.5 hours. Filter the resulting solid,
Washing with EtOl-1 and then heating in hot water,
2゜4-Diamino-6-(3-benzyloxy-2-methoxybenzyl)-7-chloro-5-methylpyrid [2
,3-d]pyrimidine, melting point 249°C to 251°C 4.
92g (82%) was obtained. Analysis C23H22C1N5
Calculated value for 02・H2O, C160,86, H,5
,33,N,15.43,CI,7.81,Actual value,
C, 60, 90, H, 5, 31, N, 15.43, CI
, 7.80° chloro product from above <1.09rJ>
was centrifuged in 2-methoxyethanol (200d) and then added in portions to GiPIibutrium (1,02d).
Dechlorination and debenzylation using 9,6 eq.) and 5% l) d/C (0.8 g) over 4 hours. The product was purified on a silica gel column with CHCl:MeOH
/3:1 to give 2.4-diamino-5-medylene-6-(5-hydroxy-2-methoxybenzyl)pyrido [2,3-dl pyrimidine, mp 266°C to 270°C.
0.62g (83%) was obtained. Analysis CH No. 1.2H20 calculated value, C157
,72,H,5,87,N,21.03,actual value,C1
57,72, H, 5,51, N, 20.97° Example 7 (c) 2,4-diamino-5-medyru-6-(2-hydroxy-5-methoxybenzyl)pyrido [2,3-d
) pyrimidine (to) 2,4-diamino-5-methyl-6-(3-human[1x-2-methoxybenzyl)pyrido[2,3-
d] Pyrimidine^, isolated from bacterial and mammalian sources with in vitro DHFR binding affinity D)l F R
Inhibition by the title compound of
et al., Journal of Medicinal Chemistry (
J, Hed, Ches, ) 241.933 (
1981)].

To DI-IFR source compound 8 18 Compound B 16 12 B, in vitro cytotoxicity test The cytotoxicity of the compound was found in the human T cell line CCRF/CE
M (ATCCCCCL119) and human chest pain II cell line MCF-7 [H, oral, 5 Oule et al.
of National Cancer Institute (
J, Mat, Cancer In5t,,51.1
409 (1973)] in cell culture.

Cell Lineage Compound A O,400,79 Compound B 0608 0.75 Example 8 2,4-Diamino-6-(2-benzyloxy-5 -methoxybenzyl)-7-chloro-5-
In a heated mixture of methylpyrid [2,3-dl pyrimidine <30 g) and zinc dust (309) (bath temperature 90 °C)
Then, ammonia was bubbled in for 22 hours while stirring.

The reaction mixture was filtered under heating, and the resulting residue was washed with Methyl Cellsolve (200a). The filtrate was collected, concentrated under reduced pressure, chromatographed on a silica gel (1.5 g) column, and methanol- Elution was with chloroform (methanol; 0-15%).

The fraction containing the target product was distilled to obtain 2,4-diamino-6-(2-benzyloxy-5-methoxybenzyl).
-5-methylpyrido[2,3-d]pyrimidine (9,1
g) was obtained as an off-white solid.

Melting point: 228-230°C (decomposition) Elemental analysis CI-I NO, 0,07CHC! 3゜0.5C
8308: Measured value: C, 66, 84: H, 5, 93: N, 16
．． 45: C1, 1, 75° Measured value: C, 66, 35: H, 5, 83; N, 16
．． 64: C11,59゜2,4-diamino-6-(2-benzyloxy-5-methoxybenzyl)-5-methylpyrido [2,3-dl pyrimidine (3,09), 5% P d / C-50 A solution of a mixture of % water (2,(1)) and sodium formate (8,0 g) in methyl pyride (200 m) was heated with stirring for 18 h (bax*; 9o C). The reaction mixture was filtered and reduced under reduced pressure. It was concentrated to the bottom and chromatographed twice using a silica gel column. Elution was carried out with methanol-chloroform (methanol: 0-30%). The fraction containing the target product was distilled and 2,4-diamino-5- Methyl-6-(2-hydroxy-5-methoxybenzyl)-
<0.30 g> of pyrido[2,3-dl pyrimidine] was obtained. This compound was the same as that of Example 5.

Claims (8)

[Claims] (1) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^1 is hydrogen when R^2 is methyl, or R^1 is hydrogen when R^2 is and pharmaceutically acceptable salts thereof. (2) 2,4-diamino-5-methyl-6-(2-hydroxy-5-methoxybenzyl)pyrido [2,3-d]
- Pyrimidine and its pharmaceutically acceptable salts. (3) 2,4-diamino-5-methyl-6-(5-hydroxy-2-methoxybenzyl)pyrido [2,3-d]
- Pyrimidine and its pharmaceutically acceptable salts. (4) A pharmaceutical formulation comprising a compound of formula (III) together with a pharmaceutically acceptable carrier thereof. (5) a) Formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, R^3 is benzyl when R^4 is methyl, or R^3 is R^4 is methyl when is benzyl) or b) Formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (where R^3 and R^4 is as defined above and R^5 is a leaving group that can be removed by catalytic hydrogenation).
III) Manufacturing method. (6) A method for treating proliferative diseases in mammals, which comprises administering an effective amount of the compound of formula (III) or a salt thereof. (7) Formula (III) in the manufacture of drugs for the treatment of proliferative conditions
) or its salts. (8) A compound of formula (III) or a salt thereof for the treatment of proliferative conditions.