JPS60246377A - Composition containing novel heterocyclic compound - 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 novel compounds, processes for making the compounds, and compositions containing the compounds.

According to the present invention, there is provided the use of a compound of formula (1) or its chemical compound as a medicament.

d In the above formula, one of the radicals R and R3 has no significance and the other is hydrogen, phenyl or 01-6 alkyl optionally substituted by phenyl, and R3 is If it has no significance, R may further represent R1-6
can represent alkanoyl, one of the bonds is a double bond and the other is a single bond, at least one of R1 and R2, R4 and R5 are the same or different and pyridinyl, pyrimidinyl , thiazolyl, pyrazinyl, pyridazinyl, imidazolyl and phenyl, and optionally halogen, -00015, -00R5,
-ON, -CONH2, -8O2NR5R6, -NR
5R,! , -0R5 or C1,6 alkyl (the latter optionally substituted by a fluoride), and R5 and R6 are the same or different groups. and each hydrogen or I-i optionally substituted by a heptano or di-alkyl (c1-6) amine.
-6 alkyl, and the remaining p of R2, R4 and R5, in addition to the above meanings, are selected from hydrogen, hydroxy, 01-6 alkyl and 01-6 alkyl, or R1 and one of R4A- and R5 has the abovementioned meaning and the v4 linkages of R2, R4 and R5 can be trapped together to form a -CH-0H-OH-OH- chain.

Further, according to the present invention, R2 and R4 together form a chain -Ck3-OH-1jH-CH- as a novel compound.
Provided are compounds of formula (1) that do not form a compound and a chemically acceptable salt thereof.

According to the present invention, (a) a compound of the formula (Ill Rζ 4 (wherein R2, R4 and R5rt are as described above and 2 is a good removal group) is converted into a compound of the formula () % formula %() (wherein R%R1 and R3 are as described above), the compound fC is reacted with its salt. (b) Equivalent to formula (1) in which one of R and R5 is aqueous. The compound of formula (1) in which R is C1-6 alkanoyl is produced by alkanoylation of the compound, and (ω
R by alkylation or phenylalkylation of the corresponding compound of formula +1) in which one of R and R5 is aqueous.
and one of R5 is optionally t by phenyl.
Formula f1) which is 01-6 alkyl which may be -m
A compound of formula (1) having -COOH substitution is produced by calohydrolysis of a corresponding compound of formula (1) having 1cll -000 alkyl or 100kjH2 moiety, e) Removal of the alkyl group from the corresponding compound of formula (1) with an alkoxy substituent to produce a compound of formula (1) with an -OH[substituent; or (f) R2, R4 and R5. R2%R4v can be increased by reacting the corresponding compound of formula (1), in which at least one is hydroxy, with an alkylating agent which may optionally be mono- or di-alkylaminodirectly substituted. R5 (at least one Q optionally t by 7- or di-alkylamino)
If a compound r of formula (1) is formed with alkoxy which may be
) is provided, comprising converting the obtained compound of formula (11) into its pharmaceutically acceptable salt or vice versa. Ru.

Process (a) it can also be carried out in a base bath, for example pyridine, and at a temperature between 0°C and 11111°C, for example about 115°C, the reflux temperature of the reaction medium. Good removal groups 2 can be, for example, dialkylamino, hydroxy or alkoxy, such as ethoxy groups. When R4 in the compound of formula tUt is alkoxy, the group R4 in the product compound is -OH.

Process Furukaylation of fbl can be carried out in pyridine using a suitable alkanoylation process such as vinegar anhydride. The reaction is about O~50
It can be carried out at a temperature of °C.

The process (cl) can be carried out in a core agent which is inert under the reaction conditions F, for example diethyl ether, acetone or acetonitrile. The alkylating agent is, for example...alkyl rogenide, such as methyl iodide or phenyl alkylation. - Ride example Vf, bromide. If 1q in the R position a is required, the reaction can be carried out in the presence of a base such as aqueous sodium.

The hydrolysis of method (1) can be carried out using a base such as sodium hydroxide in a water-miscible solvent such as ethanol or glyme.

Process (e) is based on the American ethereal technology such as a mixture of acetic acid and hydrogen bromide or a suitable bath agent (e.g.) C-1dN-
It is carried out using sodium Me chloride in 1 methylpyrrolidone. The reaction is preferably carried out for example about 80
It is performed at an elevated temperature of ~100°C.

The alkylation of process if) can be carried out using American alkylation techniques, e.g. in the product compound; k
1. kj-Dimethylformamide'P (Cν and diazomethane (L'')*tta-cyru.-ma/
Alternatively, in the presence of a strong base, a compound of the formula (]) in which one of R2, R4 and R5 is hydroxy is added to an alkyl halide which is optionally substituted with hydroxy. can be made to react.

Compound 1 of formula (1) can be obtained by using the technology available in the United States.

The starting materials for the above process are known or can be prepared from known compounds using known American technology.

A pharmaceutically acceptable bottle containing compound 14IIJ of formula (1) is:
Togically acceptable organic or j! If the anion ions chloride, sulfate, maleate form acid addition salts with the meterate 13 ion.

The compound of formula (1) and its scientifically acceptable salt is 1
In particular, these compounds are useful because they have immunological activity in animals, e.g. in the tests described in Example AVC. Thus, novel compounds Treatments such as cytotoxic drugs, immunosuppression, etc. are used to raise immune responses that have been reduced by associated or radiotherapy or surgery.In this way, the combination of 1. (θpi
Immunosuppression (1), such as hypomedullary hypofunction (1)
Make sure that it does not get easily damaged during production. The compound may prove useful as an adjunct to existing treatments.

The compounds are also used in the elevation of depressed immune responses associated with secondary immune deficiency diseases (AIDS, neoplastic diseases) and in infectious diseases mediated by viruses, bacteria, fungi or metazoan parasites. Such compounds can be applied alone or together with anti-infective agents. Historically, the compound has been associated with thermal damage, surgery (post-surgical stress),
Used in wound therapy and age-related immune deficiencies.

Compounds are also used to modulate aberrant immunoregulatory pathways such as those seen in rheumatoid arthritis and systemic erythema lupus.

For the aforementioned uses, the administered use: Ijt will, of course, vary depending on the compound used, the mode of administration, the treatment desired (e.g. topical, topical, or oral) and the disease being treated. . However, in general? # The results show that the compound was tested on animals in a test with 6 subjects on NA. - Obtained when administered at a dosage of between 90.1 and 200 R9.

For humans, the total daily dosage used is in the range 1-1000, preferably 10-5001 g. These lines should be used twice a week or once per day.
It can be administered in six divided doses or in sustained release form. Thus, unit dosage forms suitable for administration, e.g., esophageally, contain 2 to 500 mg of the compound, preferably solid or liquid, mixed with a pharmaceutically acceptable diluent, carrier, or adjuvant. It is preferably 1 to 500 my.

It is preferred that R1 and R2, R4 and R5 have different JJs. Further, it is preferable that at least one of R1 and R2 is substituted.

In this way, when R2, R4 or R5 is a benzene term, it is preferable that the alkalinity has a filtering term at a position para to pyrimidine 4. When R1 is insane, it is preferred that the radical is unsubstituted or has a substituent at the para position to the group -NR-9. benzene(
Specific substituents on the substituents (or individual compounds) include halogen, e.g., salt, hydroxy, 01-6 alkoxy, 7 e.g.
5, -ON, -000H, -0000H5, -CO
OH3, -5o2N(aH3)2, -N(OH5>2.
-0H3 or 100H2CH2N(02H5)2 b
Ru.

It is preferred that R3 has no significance. A specific example for RK is Hs -0H5, -C! 2H5s'
0H2CH2CH5, -0H(OH5)2 *Metal with acetyl, 2-methylpropanoyl, phenyl or benzyl. It is preferred that R4 is hydrogen.

Especially when R2 is used, for example, rose alkoxy (
methoxy)it-substituted benzene ring, R4 and R5 are hydrogen, R3 has no significance, and R is 0
It is preferred that 1-4 alkyl is eg methyl or 02-4 alkanoyl eg acetyl and R1 is phenyl, preferably unsubstituted phenyl.

According to the invention, a compound of formula (1) or a pharmaceutically acceptable salt thereof, preferably less than 80% by weight, in combination with a pharmaceutically acceptable auxiliary, diluent or carrier, more preferably (up to 50% by weight) is provided. Examples of suitable auxiliaries, diluents or carriers for tablets, capsules and dragees are microcrystalline cellulose, calcium phosphate, diatomaceous earth, sugars such as lactose, dextrose or mannitol, talc, stearic acid, starch, chacarbonate. Sodium and/or gelatin, natural or hardened oils or waxes for layering agents and coarse lactose for inhalation compositions. The compound of formula (1) is in the form of a pharmaceutically acceptable salt thereof having a median diameter of 0.01 to 10 microns. The composition may contain preservatives, stabilizing and wetting agents, solubilizing agents, sweetening agents, coloring agents and flavoring agents.The composition may be formulated in a connected release form. Preferred are compositions designed to be administered at a specific time such that their contents are released during treatment.

Compounds of formula (1) in which R2, R4 or R5 are hydroxy can also exist in the keto form. This is also encompassed within the scope of the present invention.

The present invention will be further explained by the following example. However, the present invention is not limited to the following examples.

Example 1 5-(4-methoxyphenyl)-N-phenylpyrimidin-2-amine 2-(4-methoxyphenyl)-3-dimethylaminoacrolein (1[1,Or) and enylguanidine picarbonate (10, Of), pyridine (100
Heating under reflux for 17 hours in

The solvent is removed in vacuo and the resulting residue is suspended in chloroform and washed with 2N sodium hydroxide solution and then with water. The suspended solid (9?) is collected by p-filtration and replanted from ethyl acetate to give the title compound (5,4F) as a white solid, mp 216-9°C.

Analysis value (for 0+ 7H15N30 K) total, value =
Experimental value for C7 65, N5, 42, N15.16: C!
73.61, N5.45, N15.00% Example 2 L2-uhydro-5-(4-methoxyphenyl)-1-
Methyl-2-phenyliminopyrimidine methyl iodide (1
9,2j') to N,N-dimethylformamide (150
m) of 5-(4-nodoxyphenyl)-2-phenylaminohylyne (1,52) in m) and the mixture is stirred at 100° C. for 22 hours. After evaporation, the remaining 9 parts were dissolved in chloroform, and the bath solution was washed with a 6-hydrochloride potassium bath solution. It was dried over reduced magnesium oxide and evaporated as an orange solid to give the image 6 compound (1
, 42F) are obtained. Melting point 124-125°.

Analysis value (for 018”17N30K) Calculation value: C7
1,46, H5,37, N13.16 Experiment jli: C
71,55, H5,49,N 13.23 Example 3 60 hydrogen in 5-(4-methoxyphenyl)-N-methyl-N-phenylpyrimidin-2-amine N,N-dimethylformamide (5-) Sodium (87M9) I) Suction P3iilHwo, N
, 5-(4-methoxyphenyl)-N-phenylpyrimidin-2-amine (100-9) in N-dimethylformamide (8-) is added to the solution and the mixture is stirred for 15 minutes at 08. Add methyl iodide (51yly) and stir the solution at 0° for 60 minutes.

The urea agent is removed by evaporation and the ethanol remains 111f Vf
Add to fl. The resulting precipitate was purified by heating to obtain the title compound (66'49) as a white solid.

Melting point 149-1506° Example 4 N-acetyl-5-(4-nodoxyphenyl)-N-phenylpyrimidin-2-amine 5-(4-nodoxyphenyl)-N-phenylpyrimidin-2-amine (1, O
r) in acetic anhydride (50 yd) and the mixture is stirred at 90° for about 5 hours. The resulting clear bath liquid is completely condensed. The residue was dissolved in chloroform (150d) and the bath was diluted with 5% sodium chloride and washed with water. Dry over magnesium sulfate and evaporate to an oily residue. This is applied to a silica gel column and triturated with a mixture of chloroform and methanol to give the title compound (0,9El) as a white solid. Melting point 90~
91″.

Analysis value (019) (for 7NSO2) Calculation value: o
7t46, H5,37, N13.16 Experimental value: 071.
55, H5, 49, N13.23 The following compounds were prepared using the method of this example.

5-(4-Methoxyphenyl)-N-(2-methylpropanoyl)-N-phenylpyrimidin-2-amine (melting point 11a5-120°) Example 5 4-(5-(4-methoxyphenyl)pyrimidine-2 −
yl]amine methyl benzoate 4-(5-(4-methoxyphenylcupyrimidin-2-yl)aminobenzenate (2, Or)
Add a mixture of 00° dioxa/(150d)% water (60ml) and 1N sodium hydroxide bath solution (18ml) and stir to +6 liquid at 18:00 llfJ at water temperature. lN
4i (18)·-) is added to the reaction mixture. The resulting precipitate is collected by filtration and washed successively with water and methanol and dried over phosphorous oxide under reduced pressure to yield the title compound (1.65t). Melting point > 300@. Actually i m/
z 321 (M+).

Example 6 5-(4-hydroxyphenyl)-N-(4-hydroxyphenyl)pyrimidine-2-amine 5-(4-methoxyphenyl)-N-(4-methoxyphenyl)pyrimidine-2-7s, , Or) is heated under reflux for 6 hours in a mixture of acetic acid (80d) and hydrogen bromide (80d). The solvent is evaporated off and the resulting residue is washed with water! Cloudy and neutralized with sodium bicarbonate -5
Make it. The suspended solids are separated by P filtration and dissolved in ethyl acetate. The solution was subjected to silica gel column chromatography and eluted with ethyl acetate to give a yellow solid.

This solid is washed with a small amount of acetone to obtain the title compound (0,5F) as pale yellow crystals. Melting point 246-247
．． 5°. +X amount ny'z 279 CM").

Example 7 5-(4-hydroxyphenyl)-N-phenylpyrimidin-2-amine 5-(4-methoxyphenyl)-N-phenylpyrimidin-2-amine (2,Or) and sodium sulfide (
2,81F) to N-methyl-2-pyrrolidone (10+,
d) Heat at 140° for 24 hours in a tube. After cooling - the mixture is acidified with 0.1N hydrochloric acid.

The resulting precipitate is collected by filtration to obtain a yellow solid.

The solid is washed with carbon billionide to obtain 411 compound (0,91') as a white solid. Melting point 205-206@. Buy 1m m/z 265 (M).

Example 8 N-phenyl-4-(4-methoxyphenyl)pyrimidin-2-amine p-methoxyacetophenone (5,65F) and N,
N-dimethylformamide dimethylatal (8d)
Heat for 2 days. After evaporation, the residue was washed with ether to give 1-(N,N-dinothylamino)-3-(4-
methoxyphenyl)-propenone (5,81F) is obtained. The propenone (4,C1) and phenylguanidine carbonate C5,89y) are heated to reflux in pyridine (50m) for 12 hours. The millings were removed in a steam bath and the remaining '1121 was treated with chloroform and water. The filtrate layer was collected and the bath was evaporated to give a yellow solid, which was subjected to silica gel column chromatography and eluted with chloroform to give the title compound (
2,45F). Melting point 145-146'. quality, +t
m/z 277 CM+).

Analysis value (for 017H151J3o) Calculation value: 07
3.66, H5,45, N15.15 Experimental value: C73,
74, H5,59, N15.24 Example 9 N-722-5-(4-pyridyl)-pyrimidine-2
-Amine literature ((!o11.0zech, Ohem, Oon++
3-hydroxy-2-(
4-Pyridyl) propenal (3,(1)) and phenylguanidine carbonate (30d) are heated under reflux for 12 hours at 7+11. The mixture is evaporated off and the resulting residue is dissolved in hydrochloric acid.

The solution is washed with chloroform and neutralized with 50% potassium hydroxide. The resulting precipitate is collected to obtain a white solid. This solid was recrystallized from methanol to give the title compound as white crystals <0.96? ). Melting point 244~2
45.5@.

Example 10 5-(4-methoxyphenyl)-2-phenylamino-
4(1H)-pyrimidinone ether 6-hydroxy-2-(4-methoxyphenyl)
Acrylate (14,0 or) and phenylguanidine carbonate (10,47 F) are heated in pyridine (280 or) for 17 hours with 4 streams.

After cooling the reaction mixture, the mixture was removed. The crude product was suspended in hot ethyl acetate, and after washing, the compound (10,8f') was obtained as white crystals. Melting point 250”.

Analysis value (for 0+7H1sN302) Calculation value: 06
9.61, H5,15, N14.33 Experimental value: 0 7
0.02. H5, 27, N14.58 Example 11 4-Methoxy-5-(4-methoxyphenyl)-N-phenylpyrimidine-2-Fumi 2 Literature (Org, Syn,
0o11.4 volume 2550 Sada (1963)] K Yotsu” (
A solution of diazomethane in ether prepared from p-toluene-sulfonylmethyl nidrosamide and potassium hydroxide was dissolved in N,N-';
Add the 5-(4-methoxyphenyl 2-phenylamino-4(1H)-pyrimidinone (ioP)) in d) to the bath solution.

The reaction mixture is stirred overnight and acetic acid is added to destroy the diazomethane. The bath is evaporated and the residue is dissolved in chloroform and diluted with a water bath of molten sodium bicarbonate and seed water. Dry bed over magnesium and evaporation give the crude product which is then subjected to silica gel column chromatography using a mixture of chloroform and methanol as a releasing agent to give the title compound as white crystals. *u, sr) is obtained. Melting point 208-209°M8
mz7z 307 (M+).

Example 12 5-(4-Methoxyphenyl)-N-(2-pyrimidyl)pyrimidin-2-amine N, 2-chloropyrimidine (3,5j) and guanidine carbonate (2,5j) in N-r methylformamide (50m) 73F) mixed low at 56:11 J1 heating il
Flow. Steam the solvent and remove the residue with methanol (151n
t) and a 28% solution of sodium methoxide in methanol (6.5d) is added. The resulting precipitate was removed by filtration and the P solution was condensed to give a brownish residual oil, which was dissolved in pyridine <50d) and 2-(4-methoxyphenyl)-6-dimethylaminoacrolein. After adding (6,28F), heat the mixture overnight. Evaporate the solvent and add methanol. The resulting precipitate is dissolved in salt water and mixed with potassium carbonate to yield 4111 U. The precipitated solid is separated, washed with α1N sodium hydroxide and dissolved in chloroform. After treatment with activated charcoal, the chloroform is evaporated and the lAw product is washed with methanol to obtain the compound (0,91r) as white crystals. Melting point 200-2026 Example 13 5-[4-(2-diethylamino) etoxy7) phenyl)
-N-Methyl-N-phenylpyrimicin-2-amine 5-(4- in N-methyl-2-pyrrolidone (10d)
methoxyphenyl)-N-methyl6phenylpyrimidin-2-amine (1, Of) and sodium sulfide (1,
Heat 34f of the mixture at 140° for 22 hours. Once drunk, the mixture is acidified with 0.1N hydrochloric acid and the resulting precipitate is collected by filtration. The solid is washed with chloroform to obtain 5-(4-hydroxyphenyl)-N-methyl-N-phenylpyrimidin-2-amine (0,61F) as a white solid. This compound was dissolved in N,N-dimethylformamide (10m) and hydrogenated.
Add 0.22r) to 0. Addition of a bath solution of 2-diethylamine ethyl chloride (0,4522) in 0'' N,N-dimethylformamide (IQ+d) and stirred the mixture at 40°C for 4 hours. ?The steamer's brother has a mouthful of chloroform and 7 degrees of residual proboscis.He has M modesty and has 1.+2 million yen of magnesium soil.
．． I feel hazy. Evaporate the "Hemorrhoid" to obtain a yellow solid (α84?). This was dissolved in chloroform and the solution was subjected to silica gel column chromatography. Bathing with chloroform gives the title compound "l'1Jc0.69F) as a pale yellow isomer. Melting point 67.
~6a5°.

The following compounds were prepared in a similar manner.

1,N,5-di(4-methoxyphenyl)pyrimidin-2-amine (melting point 179-1806) 2,5-(4
-Methoxyphenyl)-N-(4-methylphenyl)pyrimidin-2-amine (melting point 186-76) AN-(3,4-dichlorophenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine (melting point 195
~7″) 4, N*5-′) Phenylpyrimidin-2-amine (melting point 171~2@) 5.5-(4-methylphenyl)-N-phenylpyrimidin-2-amine (melting point 180~1°) )6.5-<5.
4-dichlorophenyl)-N-phenylpyrimidine-2
-Amine (melting point 206-77, N-methyl-N-phenyl-5-(3-trifluoromethylphenyl)pyrimidi/-2-amine (melting point 167-96) aN-acenal-5-(4-methyl phenyl)-N-phenylpyrimidine-2-amine CM point 74-5°) 9.14-Methyl-5-(4-methylphenyl)-N-
Phenylpyrimidine-2-7mi/(one point 118 to so0) 10.5-(4-methoxyphenyl)-h-phenyl-
N-7'Robirch'): ';N-2-7min (#l
! It point 72-4'') 11.5-(4-dimethylaminophenyl)-N-methyl-N-phenylpyrimidi/-2-amine (melting point 140
~1'1) 12, N-(4-cyanophenyl)-5-(4-methoxyphenyl)-pyrimidin-2-amine (melting point 185~
66] 15, N, N-diphenyl-5-(4-nodoxyphenyl)-pyrimidin-2-amine (melting point 141-5″) 14, Methyl 4-(5-(4-methoxyphenyl)pyrimido-2- yl]aminobenzoate (melting point 188-9
0”) 15, N-benzyl-5-(4-nodoxyphenyl)-
N-phenylhyrimidine-2-ymine (melting point 116-8
″) 16,) J-(4-1 cetyl phenyl)-5-(4-methoxyphenyl)-pyrimidin-2-amine (melting point 18
5-7°) 17.4-[5-(4-methoxyphenyl)pyrimide-
2-yl]aminobenzamide (melting point 263-5°) 18,N,N-dimethyl-4-[2-(N-methyl-N
-phenyl)aminopyrimidin-5-yl]benzenesulfonamide (melting point 190-192°) +9. N-Methyl-N-phenyl-4-phenylpyrimidine-2-amine (melting point 88-90°) 20.4-(4-methoxyphenyl)-N-methyl-N-phenylpyrimidine-2-
Amine (melting point 104-106') 21.4-methyl-1(-phenyl-5-(4-pyridyl)pyrimidi/-2-amine (melting point 116-117.5
”) 22, N-phenyl-5-(pyrimidin-4-yl)pyrimidin-2-amine (melting point 238-99) 23.1.
2-dihydro-5-(4-nodoxyphenyl)-2-phenylimino-1-propylbyrimidine (4111 points 7
3-74.5')24. N-methyl-N-phenyl-5
-(pyrimidin-4-yl)pyrimidin-2-amine (
Melting point 127.5-a5@) 25.5-(4-methoxyphenyl)-2-(11-methyl-N-phenylamino)-4(IH)-pyrimidone (melting point 205-207'') 26.4-methoxy -5-(4-methoxyphenyl)-
N-Methyl-N-phenylpyrimidin-2-amine (melting point 116-114") 27.5-(2-methylphenyl)-N-phenylpyrimidin-2-amine (melting point 129-131°) 2a N
-Methyl-5-(2-methylphenyl)-N-phenylpyrimidine-2-amineC88-9') 29,5-(4-methoxyphenyl)-N-methyl-N
-(2-methylphenyl)pyrimidine-2-amine (melting point 116-117.5') 50,5-(4-methoxyphenyl)-N-(2-methylphenyl)pyrimidine-2
-Amine (melting point 104-6″) 31,5-(4-methoxyphenyl)-4-methyl-N
-phenylpyrimidine-2-amine (melting point 165-56
) 32,5-(4-methoxyphenyl)-4,N-dimethyl-N-phenylpyrimidin-2-amine (melting point 1
02-4'') 33,4.6-dimethoxy7-5-(4-methoxyphenyl)-N-phenyl? −! J Mi”C 2-Amine (
Melting point 160-2'') 34, 4.6-Simethoxy5-(4-methoxyphenyl)-N-methyl-N-phenylhy'J Mi';
-Amine (melting point 112-15') 35,5-(4-methoxyphenyl)-N-(4-methylthiazol-2-yl)pyrimidin-2-amine (melting point 240-2@) 56,5-C4-methoxy phenyl)-N-methyl-N
-(4-methylthiazol-2-yl)pyrimidine-2
-Amine (melting point 169-41°) 37,5-(4-methoxyphenyl)-N-methyl-N-(pyrimidine-2-
yl)pyrimidin-2-amine (melting point 96-8″) 3a N-7-r-nyl-5-(pyrazin-2-yl)
Pyrimidine-2-amine (melting point 207-8″) 39, N
-Methyl-N-phenyl-5-(pyrazin-2-yl)
Pyrimidine-2-amine (melting point 129, 5-130.5
0") 4α 3-(2-phenylaminopyrimidin-5-yl)pyridazine (melting point 196-7°) 41, 3-(2-(
N-methyl-N-phenylamino)pyrimidin-5-yl]pyridazine (melting point 146-7.5') 42, N-ethyl-5-(4-methoxyphenyl)-N
-phenylpyrimidine-2-amine (melting point 99, 5-1
00.5') 43, 1,2-dihydro-1-ethyl-5-(4-methoxyphenyl)-2-phenyliminopyrimidine (melting point 86-4'') 44, N-phenyl-4-(4-pyridyl ) Pyrimidine-2-amine (melting point 149-50'') 45, N-methyl-N-phenyl-4-(4-pyridyl)pyrimidine-
2-Amine (#a point 109-11°) 46,5-(3-methoxyphenyl)-N-methyl-N
-phenylpyrimidine-2-amine (melting point 102-6°
] 47,'5(2-methoxyphenyl)-N-methyl-N
-Phenylpyrimidine-2-amine (melting point 76-75'
) 4a 1,2-dihydro-2-phenylimino-1-propyl-5-(pyrimidin-4-yl)pyrimidine hydroiodide (melting point 265-267°) 49.5-(1-methylimidazole-2 -yl)-N-phenylpyrimidin-2-amine (melting point 160-161.5°) 50, N-methyl-5-(1-methyl-1H-iotasol-2-yl)-N-phenylpyrimidine-2- Amine (melting point 187.5-188.5°) 51.5-(4-
methquinphenyl)-N-(1-methylethyl)-N-
Phenylpyrimidine-2-amine (melting point 112-115
@) Example A It has been found that animals bearing tumors often have acutely depressed immune responses. This reduction is currently thought to be a result of tumor-released immunosuppressive factors. In H), this immunosuppression is further exacerbated by tumor treatments such as surgery, chemotherapy and radiotherapy, all of which are known to cause immunosuppression.

Compounds of the invention increase immune responses in normal animals. The following experiments were performed to determine whether expansion could be achieved in tumor-bearing or drug-treated animals.

(a) A small piece of Lswis lung 5arcoina is implanted subcutaneously just above the explanted paw of a C57/Bl mouse. 5 of the compound per day for the next 4 days.
Administer orally at a dose of 0 f/ky. 1 after 411
At appropriate times, mice were shaved and sensitized with 5% oxacillone and administered the test compound as described above for the next 2 days. 1% oxacillone was applied to the left ear and the increase in ear thickness (measurement of delayed contact cell-mediated immune response) was read rapidly over 24 hours. thwarted.

(b) Immune responses to oxacilone in 057/B1 mice are 2.
It is blocked by the alkylating agent cyclophos-7amide given by intraperitoneal method on the 8th day at a dose of 200,897 kl. A 64% inhibition of touch response is observed. 201197kl of the compound of the invention by subcutaneous method on the day before, during and after sensitization! 1 inhibition was reduced in mice treated with cyclophosphamide, thus indicating a significant a≠ from the inhibitory effect of cyclophosphamide.

Patent applicant: Faisons PLC Continuation from page 1 ■Int, CI,' Identification symbol: Office docket number 277:
00)7330-4C

Claims (1)

[Scope of Claims] 1) Use of a compound of formula (11) or a pharmaceutically acceptable acid addition salt thereof as a medicament. In the above formula, one of the groups R and R3 has no significance. and the others are hydrogen, phenyl or optionally phenyl if-M 01-6 alkyl 6C and if R5 has no significance R further represents 01-6 alkanoyl , one of the bonds is a double bond and the other is a single bond, R+>Y, at least one of R2, R4 and R5 is the same or different, and pyridinyl is pyrimidinyl, selected from thiazolyl, hyrazinyl, pyridazinyl, imidazolyl and phenyl, and depending on the aVi combination, halogen, -000R5, -00
R5, -ON. -CONH2, -8O2Nf15R6, -Nl(5R6
, -0R5 or 01-6 alkyl (#, t' may be fluorine and δn depending on the case) 81-1
or more, the temperature may be changed to R5
and R6 is the same or different, and depending on the hydrogen or group, mono- or dialkyl (C, ~6
) denotes 01-6 alkyl which may be converted by an amine and the residues of R2, R4 and R5 are tl of the above meaning or further hydrogen, hydroxy, 01
-6 alkyl and 01-6 alkoxy, or R1 and one of R4 and R5 has the abovementioned meaning and R2, R4 and R5 are taken together - (-0H=OH-OH-OH- may form a chain. 2) R2 and R4 together form a chain -CI+=OH
The claims [! I] The compound of formula (1) as described in item 1 or a scientifically acceptable acid addition salt thereof. 6) The compound according to item 2, wherein R3 has no significance. 4) R2 is rosealkoxy-substituted benzene j, R4
and R5 are both hydrogen and 65. Paragraph 2 and fr of the above claim are compounds according to paragraph 3, wherein R is 01-4 alkyl or C2-4 alkanoyl, and R1 is unsubstituted phenyl. 5) R2 is a paramethquine-substituted benzene term and lyso
Claim 2, wherein is methyl or acetyl.
A compound based on any K of Section ~ Castle 4 We. 6) 5-(4-methoxyphenyl)-N-methyl-N-
Phenylpyrimidine-2-amine or N-acetyl-
5-(4-Methoxyphenyl)-N-phenylpyrimidi/-2 to amine with ◇6c% of the compound according to claim 2. 7) 5-(4-methoxyphenyl)-N-phenylpyrimidin-2-amine, 1,2-dihydro-5-(4-methoxyphenyl)-1
-Methyl-2-phenyliminopyrimidine, 5-(4-methoxy7enyl-N-(2-methylpropanoyl)-N-phenylpyrimidine-2-amine, 4-(5-(4-methoxyphenyl)pyrimidine) -2-
ylcoaminobenzoic acid, 5-(4-hydroxyphenyl)-N-(4-hydroxyphenyl)pyrimidine-2-amino, 5-(4-hydroxyphenyl)-N-phenylpyrimidin-2-amine, N-phenyl-4 -(4-methoxy7enyl)pyrimidine-2-amine, N-phenyl-5-(4-pyridyl)pyrimidine-2-
Amine, 5-(4-methoxyphenyl)-2-phenylamino-4(1)1)-pyrimidinone, 4-methoxy-5-(4
-methoxyphenyl) -N -71ylhyrimidine-
2-amine, 5-(4-methoxyphenyl)-N-(2
-pyrimidyl)pyrimidin-2-amine. 5-[4-(2-:, ;ethylaminoethoxy)phenyl]-N-methyl-N-phenylhyrimidin-2-amine, 5-(4-hydroxyphenyl)-N-methyl-N-phenylbi, rimidine-2 -Amine. N,5-di(4-methoxyphenyl)pyrimidine-2
-amine, 5-(4-methoxyphenyl)-N-(4-methylphenylumpyrimidin-2-amine, N-(3,4-dichlorophenyl)-5-(4-methoxyphenyl)pyrimidin-2-ami/ , N,5-diphenylpyrimidine-
2-7mino, 5-(4-methylphenyl)-N-phenylpyrimidin-2-amine, 5-(3,4-dichlorophenyl)-N-phenylh)mi';-2-amine, N-methyl-N -Phenyl-5-<5-trifluoromethylphenyl)pyrimidin-2-amine, N-7cetyl-5-(4-methylphenyl)-N-phenylpyrimidin-2-amine, N-methyl-5-(4-
methylphenyl)-N-phenylpyrimidin-2-amine, 5-(4-nodoquinphenyl)-N-phenyl-N
-Propylpyrimidine-2-amine, 5-(4-dinothylaminophenyl)-N-methyl-N-phenylpyrimidine-2-amine 1 N-(4-cyanophenyl)-5-(4-7toxyphenyl)pyrimidine -2-amine, N,N-diphenyl-
5-(4-methoxyphenyl)pyrimidine-2-7mi/
, methyl 4-(5-(4-methoxyphenyl)pyrimido-
2-ylcoaminobenzoate, N-benzyl-5-(
4-methquinphenyl)-N-phenylhyrimidine-2
-Amine, N-(4-acetylphenyl)-5-(4-
methoxyphenyl)pyrimidin-2-amine, 4-(5
-(4-methquinphenyl)pyrimid-2-yl]aminobenzamide, N,N-dimethyl-4-[2-(N-
methyl-N-phenyl)aminopyrimidin-5-yl]
Pencenesulfonamide, N-)f-N-phenyl-4-phenylpyrimidine-
2-amine, 4-(4-methoxyphenyl)-N-methyl-N-phenylpyrimidin-2-amine, N-methyl-N-phenyl-5-(4-pyridyl)pyrimidin-2-amine, N- Phenyl-5-(pyrimidine-41)pyrimidin-2-amine, 1,2-dihydro-5-(4-methoxyphenyl)-2
-Phenylimino-1-propylpyrimidine 1 N-nonal-N-phenyl-5-(pyrimidin-4-yl)pyrimidin-2-amine, 5-(4-methoxyphenyl)-2-(N-nonal-N-phenylamino ) −
4(IH) -pyrimidone, 4-methoxy7-5-(4-metho-1-/phenyl)-N
-Methyl-N-phenylpyrimidino-2-amine, 5-(2-methylphenyl)-N-phenylpyrimidin-2-amine, N-methyl-5-(2-methylphenyl)-N-phenylpyrimidine-2 -Ami/%5-(4-methoxyphenyl)-N-methyl-N-(2-methylphenyl)pyrimidin-2-amine, 5-(4-methoxyphenyl)-N-(,2-methylphenyl) Birimicin-2-ami/, 5-(4-methquinphenyl)-4-7f-N-phenylbilimidin-2-humin, 5-(4-7methquinphenyl)-4,N
-dimethyl-N-phenylpyrimidine-2-amine, 4,6-dimethquine-5-(4-nodoquinphenyl)-
N-phenylhirimi//-2-7mine, 4,6-dimethquin-5-(4-methquinphenyl)-
N-nonal-N-phenylpyrimidin-2-amine, 5-(4-nodoquinphenyl)-N-(4-methylthiazol-2-yl)pyrimidin-2-amine, 5-(4-methoxyphenyl)-N -Methyl-N-(4
-methylteazol-2-yl)pyrimidin-2-amine, 5-(4-methoxyphenyl)-N-methyl-N-(pyrimidin-2-yl)pyrimidin-2-amine, N-phenyl-5-( Pyrazin-2-yl)pyrimidin-2-amine, N-methyl-N-phenyl-5-(pyrazin-2-yl)pyrimidin-2-amine, 5-(2-phenylaminepyrimidinol-5-yl)pyridazine , 3-(2-(N-methyl-N-phenylamino)pyrimidin-5-yl]hyridazine, N-ethyl-5-(4
-Me)-Pdiphenyl)-N-phenylpyrimidine-2
-Amine, 1,2-dihydro-1-ethyl-5-(4-
methoxyphenyl)-2-phenylimi/-pyrimidine, N-phenyl-4-(4-pyridyl)pyrimidine-2-
Amine, N-methyl-N-phenyl-4-(4-pyridyl)pyrimidin-2-amine, 5-(3-notoky/phenyl)-N-methyl-N-phenylpyrimidin-2-amine, 5-(2 -notki/phenyl)-N-methyl-N-phenylhy'J': '/
syn--amine, 1,2-dihydro-2-phenyl-1
-Propyl-5-(pyrimidin-4-yl)iminopyrimidine hydrogen iodide, 5-(1-methylimidazol-2-yl]-N-phenylpyrimidin-2-amine, N-methyl-5-(1-
% of which is methyl-111-imidazol-21l)-N-phenylpyrimidin-2-amine or 5-(4-methoxyphenyl)-N-(1-methylethyl)-N-phenylpyrimidin-2-amine A compound according to claim 2. 8) A compound according to any one of Claims 2j to 7 and a musically acceptable adjuvant, 8<h1
] or a carrier. 9) For the manufacture of medicines for the treatment of patients with decreased immune response @ec: Particular G'I-M9I Bo Range Item 2 ~
Item 8: 1'J it i) Use of h's compound θ. 10) fal Formula<II) 4 (wherein R2, R4 and R5 are as described above, and 2 is a convenient removal group), a compound of formula (Ill) R1-NRO(-Nk15) Elbow 12 (ml) (wherein R, Rj and R3 are the melons described above) compound m
'J/l is reacted with Dil to produce a compound of formula fl) in which R is 01-6 alkanoyl by alkanoylation of the corresponding compound in the formula in which tt+J R and R3) one is hydrogen; (c) By alkylation or phenyl alkylation of the corresponding compound of formula (1) in which one of R and R5 is hydrogen, [R$-Yohi R3's fliA is anastomosed and C is quenched by phenyl. (a) by hydrolysis of a corresponding compound of formula f1 with -COO alkyl or -(1!0NH2 substitution); A compound of formula (1) is prepared by producing a compound of formula (1) having a 000H substitution and commanding -OHi conversion by removal of the alkyl group from the corresponding compound of formula (1) having an (θ) alkoxy substitution. or (f) by reacting a corresponding compound of formula (1) in which at least one of R2, )C4 and R5 is hydroxy with an optionally mono- or di-alkylamino substituted fc alkylating agent. R2, R4 and R
At least one of 5 is optionally mono- or di-
A compound of formula (11) is formed which is an alkoxy optionally substituted by alkylamino, and if desired or if necessary the resulting compound of formula (1) can be used for pharmaceutical purposes. 2. A compound according to claim 2, which comprises converting the compound into a salt acceptable to the above or vice versa.