JP3221406B2 - Novel pyrimidine nucleus-containing compound, medicament containing the same for improving blood oxygen partial pressure, and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a thienopyrimidine derivative effective for improving arterial oxygen partial pressure (PaO ₂ ) of patients with hypoxemia or patients receiving acute oxygen inhalation due to acute respiratory failure by drug therapy. And pyrimidine nucleus containing compounds such as quinazoline derivatives.

[0002]

2. Description of the Related Art
For respiratory failure, bronchodilators, anti-inflammatory drugs, heart failure drugs, antitussives, etc. have been used as symptomatic treatments. Chronic obstructive pulmonary diseas
e: No drug is effective for hypoxemia patients like COPD).

[0003] Therefore, there has been a demand for a drug which raises and improves PaO ₂ lowered by these respiratory diseases. In these diseases, it is often observed that the arterial blood carbon dioxide partial pressure (PaCO ₂ ) is increased together with the decrease in PaO ₂ , and in such a case, the PaCO ₂ lowering effect is exhibited in addition to the PaO ₂ increasing effect. There is a need for a drug that combines.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies with the aim of searching for a drug for improving blood oxygen partial pressure in hypoxemia, and as a result, pyrimidine nuclei such as thienopyrimidine derivatives and quinazoline derivatives described below. It has been found that the compound contained is effective for the prevention and treatment of hypoxemia caused by various respiratory diseases.

The compounds of the present invention enhance respiratory function in the lungs, increase PaO ₂ mainly by redistribution of blood flow due to hypoxic pulmonary vasoconstriction (HPV) enhancing action, or increase ventilation and respiratory rate, It has the effect of decreasing PaCO ₂ with increasing PaO ₂ .

The present compound has the formula (I):

[0007]

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Wherein ring A is a group represented by the formula (a):

[0009]

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Wherein R ¹ is a nitro group, an amino group, a substituted amino group, a halogen atom, or a ring represented by the formula (b):

[0011]

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Wherein R ^{1 '} is an alkyl group, an alkenyl group, a phenyl group, a nitro group, an amino group, a substituted amino group or a halogen atom; and R ² and R ⁴ are R ³ and R ⁵ are each an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a cycloalkyl group, an adamantyl group, a pyridylmethyl group, a furylmethyl group, a thienylmethyl group; A cinnamyl group, an acyl group, an alkoxycarbonyl group, a substituted alkyl group, a substituted carbamoyl group or a substituted amino group; or one of R ² and R ³ or R ⁴ and R ⁵ is a nitrogen atom to which they are bonded. Together form a 4- to 7-membered optionally substituted heterocyclic monocyclic ring; provided that at least one of R ^{2 to} R ⁵ is
Are alkenyl groups] or an acid addition salt thereof.

That is, the pyrimidine nucleus-containing compound of the present invention has the formula (II):

[0014]

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A quinazoline derivative represented by the formula or an acid addition salt thereof, or a compound represented by the formula (III):

[0016]

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A thienopyrimidine derivative or an acid addition salt thereof.

The alkyl group to be substituted on the ring A (R ^{1 '} ) is preferably a C ₁ -C ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl. Butyl, n-pentyl,
Neopentyl and n-hexyl. Particularly preferred R ^{1 '} is methyl, ethyl or propyl substituted at the 7-position of the thienopyrimidine ring.

The alkenyl group substituted on ring A (R ^{1 '} ) is preferably a C ₃ -C ₆ alkenyl group such as allyl, cis-2-butenyl, trans-2-butenyl,
3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyl, 3-
Methyl-3-butenyl, 4-pentenyl, cis-2-pentenyl, trans-2-pentenyl, cis-2-hexenyl, trans-2-hexenyl, 1,4-pentadien-3-yl.

Examples of the substituted amino group which is substituted in the ring ^{A (R 1, R 1 '} ), preferably mono- or di C _{1 - 3} alkylamino groups, for example methylamino, ethylamino, propylamino, dimethylamino, diethylamino Or mono- or diallylamino.

Examples of the halogen atom substituted on the ring A (R ¹ , R ^{1 ′} ) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the alkyl groups for R ² to R ^5, preferably C ₁ -C _{2 0} alkyl, for example methyl, ethyl,
Propyl, isopropyl, n-butyl, isobutyl, se
c-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl.

The alkenyl group for R ^{2 to} R ⁵ includes
Preferably C ₃ -C ₆ alkenyl group such as allyl, cis-2-butenyl, trans-2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2 -Butenyl, 3-methyl-3
-Butenyl, 4-pentenyl, cis-2-pentenyl,
Trans-2-pentenyl, cis-2-hexenyl, trans-2-hexenyl, 1,4-pentadiene-3-
Ill.

Alkynyl groups for R ³ and R ⁵ include, for example, 2-propynyl, 2-butynyl, 2-pentynyl, 2-peptinyl; aralkyl groups include, for example, benzyl, phenethyl, 1-naphthylmethyl, - naphthylmethyl and the like, preferably benzyl,; the cycloalkyl group is preferably a C ₃
Cycloalkyl, such as cyclopropyl -C _6, cyclobutyl, cyclopentyl, cyclohexyl can be mentioned; as the adamantyl group, such as 1-adamantyl, 2-adamantyl can be mentioned; as the pyridylmethyl group include 2-pyridylmethyl, 3 A furylmethyl group includes, for example, furfuryl and 3-furylmethyl; a thienylmethyl group includes, for example, 2-thenyl, 3-thienylmethyl; an acyl group preferably includes C.I. ₁ -C ₆ aliphatic acyl group, such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl like; alkoxycarbonyl group, preferably a C ₁ -C ₆ alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, prop Oxycarbonyl, 2-methylpropyloxycarbonyl, t-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; substituted alkyl groups include, for example, alkoxy-, amino-, carbamoyl-, hydroxy- or halo-substituted alkyl Groups such as methoxymethyl, 2-
Methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2-aminoethyl, 3-aminopropyl, 4-
Aminobutyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2- (N-methylcarbamoyl) ethyl, 3- (N-ethylcarbamoyl) propyl, 2-
(N-allylcarbamoyl) ethyl, 2- (piperazinocarbonyl) ethyl, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl; substituted carbamoyl groups include Preferably C ₁ -C ₉ straight chain alkyl- or alkenyl-carbamoyl, C ₃ -C ₈ cycloalkyl- or cycloalkenyl-carbamoyl, arylcarbamoyl or heterocyclic monocyclic-containing carbamoyl groups, for example methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl ,
t-butylcarbamoyl, n-butylcarbamoyl, nonylcarbamoyl, cyclohexylcarbamoyl, allylcarbamoyl, 1-pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-thiomorpholinocarbonyl; and the substituted amino group is preferably a substituted amino group. A mono- or di-C ₁ -C ₆ alkylamino group or a heterocyclic saturated monocyclic group-containing amino group such as methylamino,
Ethylamino, propylamino, t-butylamino, pentylamino, heptylamino, dimethylamino, diethylamino, dipropylamino, 1-pyrrolidino, piperidino, morpholino, 1-thiomorpholinyl.

R ² and R ³ or R ⁴ and R ⁵ may have a substituent together with the nitrogen atom to which they are bonded.
Examples of forming a 7- to 7-membered saturated monocyclic ring include, for example, 1
-Aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, piperazino, morpholino, 1-thiomorpholinyl, and lower alkyl such as methyl, ethyl, propyl, benzyl, naphthylmethyl, benzhydryl. , 4,4'-
Difluorobenzhydryl may be substituted.

Examples of the acid addition salts include salts of inorganic acids such as hydrochloric acid and sulfuric acid, and salts of organic acids such as acetic acid, propionic acid, citric acid, maleic acid, tartaric acid, methanesulfonic acid and paratoluenesulfonic acid. Can be

The pyrimidine nucleus-containing compound of formula (I) is prepared by the following steps: a) Formula:

[0028]

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(Wherein ring A is as defined above) and a halogenating reagent are reacted in the presence of a base to obtain a compound represented by the formula:

[0030]

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Obtaining a 2,4-dihalo compound represented by the formula: wherein X is a halogen atom; b) converting the 2,4-dihalo compound into a compound represented by the formula:

[0032]

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Wherein R ² and R ³ are as defined above, and reacted with an amine derivative represented by the formula:

[0034]

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Obtaining a 2-halo-4-amino compound represented by the formula: and c) converting the 2-halo-4-amino compound into a compound of the formula:

[0036]

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Wherein R ⁴ and R ⁵ are as defined above,
It can be produced by a method comprising a step of obtaining a compound of the formula (I).

In particular, the quinazoline derivative of the formula (II) is synthesized by the method shown in the following reaction formula.

[0039]

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In the first step, the quinazolinedione derivative (I
This is a step of producing a 2,4-dihaloquinazoline derivative (IV) by reacting I) with a halogenating reagent (III) in the presence of a base. Raw materials of quinazolinedione derivatives (II)
Can be easily produced by reacting a substituted or unsubstituted 2-aminobenzoic acid with urea (J. Med. Chem.,
1995, 38, 2763-2773). As the halogenating reagent, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride is used,
As the base, an organic base such as N, N-dimethylaniline, N, N-diethylaniline, triethylamine, pyridine or collidine is used. The reaction can be carried out without a solvent or in the presence of an inert solvent at 50 to 200 ° C.

The second step is a step of reacting the 2,4-dihaloquinazoline derivative (IV) with the amine derivative (V) to produce a 2-halo-4-aminoquinazoline derivative (VI). The reaction was performed using N, N-dimethylformamide (DM
F), tetrahydrofuran (THF), dioxane, dimethylsulfoxide (DMSO), and an inert solvent such as chloroform at −78 to 100 ° C. The reaction is preferably performed in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium methoxide, and potassium t-butoxide in addition to the organic base.

The third step is a step of producing the quinazoline derivative (I) by reacting the 2-halo-4-aminoquinazoline derivative (VI) with the amine derivative (VII). The reaction can be carried out at 0 to 250 ° C. without a solvent or in the presence of the above-mentioned inert solvent. It is preferable to add the above-mentioned organic base or inorganic base to the reaction in order to increase the reaction efficiency.

The thienopyrimidine derivative of the formula (III) is synthesized according to the following reaction formula.

[0044]

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In the first step, the 3-aminothiophene derivative (II) is reacted with urea to give thienopyrimidine-2,
This is a step of producing a 4-dione derivative (III). The reaction can be carried out without solvent or in an inert organic solvent such as DMF or DMSO at 0 to 250 ° C.

In the second step, thienopyrimidine-2,4-
In this step, the dione derivative (III) and the halogenating reagent (IV) are reacted in the presence of a base to produce a 2,4-dihalothienopyrimidine derivative (V). Phosphorus oxychloride, phosphorus pentachloride, and thionyl chloride are used as the halogenating reagent, and N, N-dimethylaniline,
Organic bases such as N, N-diethylaniline, triethylamine, pyridine and collidine are used. The reaction can be carried out at 0 to 200 ° C. without solvent or in the presence of an inert solvent.

In the third step, the 2,4-dihalothienopyrimidine derivative (V) is reacted with the amine derivative (VI) to form a 2-halo-4-aminothienopyrimidine derivative (VI
This is the step of manufacturing I). The reaction is performed in an inert solvent such as DMF, THF, dioxane, DMSO, chloroform at a reaction temperature of -78C to 100C. Further, in addition to the above-mentioned organic bases, inorganic bases such as sodium carbonate, potassium carbonate, sodium methoxide and potassium t-butoxide can also be used.

The fourth step is a step of reacting the 2-halo-4-aminothienopyrimidine derivative (VII) with the amine derivative (VIII) to produce a thienopyrimidine derivative (I). The reaction is carried out in the absence of a solvent or in
It can be performed at 50 ° C. It is preferable to add the above-mentioned organic base or inorganic base to the reaction in order to efficiently perform the reaction.

The novel pyrimidine nucleus-containing compound of the present invention exhibits an excellent arterial blood oxygen partial pressure increasing effect and has no toxicity, and thus is useful as an agent for preventing and treating hypoxemia.

The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more pharmaceutically acceptable excipients. Pharmaceutical compositions of the present invention include those particularly suitable for oral, nasal, transdermal, rectal, sublingual, ocular, or respiratory administration, especially tablets, dragees, sublingual tablets, sachets, packets , Gelatin capsules, gross set,
Lozenges, suppositories, creams, ointments, skin gels,
And ampoules for drinking or injection.

Dosages will vary from 0.01 mg to 1 g per 24 hours depending on the gender, age and weight of the patient, the route of administration, the nature of the therapeutic application, or the potential treatment involved.
Administer the drug more than once.

[0052]

The present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples. Reference Example 1 4-allylamino-2,6-dichloroquinazoline

[0053]

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6-chloroquinazoline-2,4 (1H, 3
To 2.00 g (10.17 mmol) of H) -dione were added 8.88 g (57.93 mmol) of phosphorus oxychloride and 822 mg (6.81 mmol) of N, N-dimethylaniline to give 16
Heated to reflux for an hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, and 2,4,6-trichloroquinazoline 1.9 was obtained.
8 g were obtained as crude crystals. This was dissolved in 5 ml of DMF,
1.16 g (20.34 mmol) of allylamine was added, and the mixture was stirred for 1 hour under ice cooling and then for 1 hour at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 1.11 g (yield: 43.0%) of the title compound. NMR (δ, CDCl ₃ ): 4.29-4.35 (2H, m), 5.29 (1H, d with
fine couple, J = 10Hz), 5.35 (1H, d with fine couple,
J = 17Hz), 5.82 (1H, br), 5.96-6.09 (1H, m), 7.67-7.76
(3H, m) EI-Mass (m / z,%): 257 (M ⁺ +4, 4), 255 (M ⁺ +2, 24), 253
(M ⁺ , 38), 238 (100)

Example 1 2,4-diallylamino-6-chloroquinazoline

[0056]

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300 mg (1.18 mmol) of 4-allylamino-2,6-dichloroquinazoline was added to 1,3-dimethyl-
Dissolve in 1 ml of 2-imidazolidinone and add allylamine 11
After adding 0 mg (1.87 mmol), the mixture was stirred at 100 ° C. in a sealed tube for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to give the title compound 2
83 mg (87.3% yield) were obtained. Melting point: 78-79 ° C NMR (δ, CDCl ₃ ): 4.11-4.16 (2H, m), 4.20-4.25 (2H,
m), 5.04 (1H, br), 5.11-5.33 (4H, m), 5.46 (1H, br),
5.93-6.07 (2H, m), 7.37-7.48 (3H, m) EI-Mass (m / z,%): 276 (M ⁺ +2, 12), 274 (M ⁺ , 36), 259 (1
00), 233 (14) IR (ν, cm ^{- 1} ), KBr: 3476, 2920, 1572, 1482, 1408, 8
30

Reference Example 2 4-allylamino-2-chloro-6-methylaminoquinazoline

[0059]

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100 mg (0.438 mmol) of 2,4-dichloro-6-methylaminoquinazoline was dissolved in 1 ml of DMF, 50 mg (0.88 mmol) of allylamine was added, and the mixture was stirred for 30 minutes under ice-cooling and then for 30 minutes at room temperature. did. The reaction solution was poured into water, and the precipitated crystals were collected by filtration, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 100 mg (yield: 91.8%) of the title compound. NMR (δ, CDCl ₃ ): 2.94 (3H, s), 4.11 (1H, br), 4.30-4.
34 (2H, m), 5.25 (1H, d with fine couple, J = 10Hz), 5.
34 (1H, d with fine couple, J = 17Hz), 5.61 (1H, br),
5.99-6.12 (1H, m), 6.41 (1H, d, J = 3Hz), 7.09 (1H, dd,
J = 9Hz, 3Hz), 7.60 (1H, d, J = 9Hz) EI-Mass (m / z,%): 250 (M ⁺ 2, 27), 248 (M ⁺ , 82), 233 (1
00)

Example 2 2,4-diallylamino-6-methylaminoquinazoline hydrochloride

[0062]

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100 mg (0.40 mmol) of 4-allylamino-2-chloro-6-methylaminoquinazoline and 761 mg (13.33 mmol) of allylamine were added in a sealed tube to 140 mg.
Stirred at C for 22 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 100 mg (yield: 92.4%) of the free base compound of the title compound. NMR (δ, CDCl ₃ ): 2.89 (3H, s), 3.70 (1H, br), 4.13 (2
H, t, J = 6Hz), 4.25 (2H, t, J = 6Hz), 4.82 (1H, br), 5.
09-5.33 (4H, m), 5.39 (1H, br), 5.95-6.11 (2H, m), 6.4
4 (1H, d, J = 3Hz), 6.99 (1H, dd, J = 9Hz, 3Hz), 7.36 (1
(H, d, J = 9Hz)

Then, under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added to 90 mg (0.33 mmol) of the free base compound of the title compound.
Was added dropwise to an ethyl acetate solution. The precipitated crystals are collected by filtration,
85 mg (84.5%) of the title compound were obtained. Melting point: 155 to 158 ° C NMR (δ, DMSO-d ₆ , 55 ° C): 2.79 (3H, s), 4.06-4.09 (2H,
m), 4.21-4.24 (2H, m), 4.76 (1H, br), 5.13-5.28 (4H,
m), 5.88-6.03 (2H, m), 7.23 (1H, dd, J = 9Hz, 2Hz), 7.
29 (1H, d, J = 2Hz), 7.36 (1H, d, J = 9Hz), 8.00 (1H, b
r), 9.52 (1H, br ), 12.47 (1H, br) EI-Mass (m / z,%): 269 (M +, 85), 254 (100), 228 (14) IR (ν, cm - ¹ ), KBr: 3064, 1652, 1612, 1580, 1416, 1
340, 992

Reference Example 3 4-Allylamino-2-chloro-6-nitroquinazoline

[0066]

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6-nitroquinazoline-2,4 (1H, 3
To 2.00 g (9.66 mmol) of H) -dione, 82.30 g (0.54 mol) of phosphorus oxychloride was added, and the mixture was heated under reflux for 4 days. After removing phosphorus oxychloride by atmospheric distillation, crystallization was performed from diethyl ether-hexane to obtain 3.10 g of 2,4-dichloro-6-nitroquinazoline as crude crystals. This was dissolved in 15 ml of DMF, and 1.10 g (19.32 mmol) of allylamine was added dropwise under ice cooling, followed by stirring for 2 hours under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 1.77 g (yield: 69.1%) of the title compound.
I got NMR (δ, CDCl ₃ ): 4.38 (2H, t, J = 6Hz), 5.34 (1H, d wit
h fine couple, J = 10Hz), 5.39 (1H, d with fine coupl
e, J = 17Hz), 5.98-6.11 (1H, m), 6.33 (1H, br), 7.88 (1
H, d, J = 9Hz), 8.53 (1H, dd, J = 9Hz, 2Hz), 8.73 (1H,
d, J = 2Hz) EI-Mass (m / z,%): 266 (M ⁺ +2, 16), 264 (M ⁺ , 49), 249 (1
00)

Example 3 2,4-Diallylamino-6-nitroquinazoline

[0069]

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265 mg (1.00 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.52 g (26.65 mmol) of allylamine were stirred at room temperature for 2.5 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 230 mg (yield: 80.6%) of the title compound. Melting point: 198-200 ° C (dec.) NMR (δ, CDCl ₃ , 55 ° C): 4.16-4.19 (2H, m), 4.25 (2H,
t, J = 6Hz), 5.14-5.36 (5H, m), 5.75 (1H, br), 5.93-6.
06 (2H, m), 7.41 (1H, d, J = 9Hz), 8.29 (1H, dd, J = 9Hz,
3Hz), 8.50 (1H, d, J = 3Hz) EI-Mass (m / z,%): 285 (M ⁺ , 65), 270 (100), 224 (26), 1
98 (11) IR (ν, cm ^{- 1} ), KBr: 3400, 3260, 3084, 1612, 1554, 1
484, 1308, 1166, 832

Example 4 4-allylamino-6-nitro-2-propylaminoquinazoline

[0072]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 719 mg (12.16 mmol) of propylamine were stirred at room temperature for 2.5 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 211 mg (yield: 77.7%) of the title compound. Melting point: 197-198 ° C NMR (δ, CDCl ₃ , 45 ° C): 1.00 (3H, t, J = 7Hz), 1.61-1.7
3 (2H, m), 3.49 (2H, td, J = 7Hz, 7Hz), 4.26 (2H, t, J =
5Hz), 5.25-5.36 (3H, m), 5.80 (1H, br), 5.95-6.09 (1
H, m), 7.40 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9Hz, 2H
z), 8.50 (1H, d, J = 2Hz) EI-Mass (m / z,%): 287 (M ⁺ , 86), 272 (56), 258 (83), 24
5 (100), 230 (73), 212 (62) IR (ν, cm ^{− 1} ), KBr: 3420, 32
60, 1588, 1556, 1482, 130
2, 1170, 832

Example 5 4-Allylamino-2-neopentylamino-6-nitroquinazoline

[0075]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 740 mg (8.49 mmol) of neopentylamine were dissolved in 0.5 ml of acetonitrile and stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to give the title compound 2
15 mg (72.2% yield) were obtained. Mp: 167~168 ℃ NMR (δ, CDCl 3, 45 ℃): 0.99 (9H, s), 3.38 (2H, d, J = 7
Hz), 4.26 (2H, t, J = 6Hz), 5.26 (1H, d with fine coup
le, J = 10Hz), 5.34 (1H, d with fine couple, J = 17Hz),
5.82 (2H, br), 5.96-6.10 (1H, m), 7.38 (1H, d, J = 9H
z), 8.27 (1H, dd, J = 9Hz, 2Hz), 8.50 (1H, d, J = 2Hz) EI-Mass (m / z,%): 315 (M ⁺ , 25), 258 (100), 212 (30) IR (ν, cm ^{- 1} ), KBr: 3416, 3240, 2960, 1588, 1540, 1
484, 1306, 922

Example 6 4-Allylamino-2-benzylamino-6-nitroquinazoline

[0078]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 981 mg (9.15 mmol) of benzylamine were dissolved in 1 ml of DMF.
The mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 243 mg of the title compound (yield: 76.
7%). Melting point: 216-217 ° C NMR (δ, DMSO-d ₆ , 55 ° C): 4.11-4.15 (2H, m), 4.58 (2H,
d, J = 6Hz), 5.10 (1H, d, J = 10Hz), 5.21 (1H, d, J = 17H
z), 5.88-6.02 (1H, m), 7.17-7.36 (6H, m), 7.66 (1H, b
r), 8.20 (1H, dd, J = 9Hz, 2Hz), 8.67 (1H, br), 9.09 (1
H, d, J = 2Hz) EI-Mass (m / z,%): 335 (M ⁺ , 100), 294 (28), 248 (19), 9
1 (32) IR (ν, cm ^{- 1} ), KBr: 3424, 3260, 1612, 1556, 1482, 1
304, 832

Example 7 4-Allylamino-2-cyclohexylamino-6-nitroquinazoline

[0081]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 867 mg (8.74 mmol) of cyclohexylamine were stirred at room temperature for 5 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 237 mg (yield: 76.6%) of the title compound. Melting point: 183-184 ° C NMR (δ, CDCl ₃ , 45 ° C): 1.20-1.81 (8H, m), 2.04-2.09
(2H, m), 3.94-4.04 (1H, m), 4.24 (2H, t, J = 6Hz), 5.1
5 (1H, br), 5.23-5.36 (2H, m), 5.72 (1H, br), 5.95-6.0
8 (1H, m), 7.37 (1H, d, J = 9Hz), 8.27 (1H, dd, J = 9Hz,
2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%): 327 (M ⁺ , 49), 286 (13), 245 (100), 2
30 (42) IR (ν, cm ^{- 1} ), KBr: 3420, 2932, 1588, 1546, 1302, 1
168, 836

Example 8 4-Allylamino-2- (2-methoxyethylamino)
-6-nitroquinazoline

[0084]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 864 mg (11.50 mmol) of 2-methoxyethylamine were stirred at room temperature for 2.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give the title compound (214 mg, yield 74.7).
%). Mp: 164~165 ℃ NMR (δ, CDCl 3, 45 ℃): 3.40 (3H, s), 3.59 (2H, t, J = 5
Hz), 3.72 (2H, td, J = 5Hz, 5Hz), 4.25 (2H, t, J = 6Hz),
5.24 (1H, d with fine couple, J = 10Hz), 5.32 (1H, d
with fine couple, J = 17Hz), 5.85 (1H, br), 5.92-6.0
8 (2H, m), 7.40 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9Hz,
2Hz), 8.53 (1H, d, J = 2Hz) EI-Mass (m / z,%): 303 (M ⁺ , 41), 288 (52), 258 (100), 2
12 (80) IR (ν, cm ^{- 1} ), KBr: 3424, 3256, 1586, 1558, 1480, 1
308, 1126, 830

Example 9 4-allylamino-2-diallylamino-6-nitroquinazoline

[0087]

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300 mg (1.13 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.18 g (12.15 mmol) of diallylamine were added at room temperature for 2 hours.
Then, the mixture was stirred at 60 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 325 mg (yield: 88.5%) of the title compound. Melting point: 167-168 ° C NMR (δ, CDCl ₃ , 50 ° C): 4.24 (2H, t, J = 6Hz), 4.34 (4H,
d, J = 5Hz), 5.14-5.35 (6H, m), 5.72 (1H, br), 5.84-
6.08 (3H, m), 7.44 (1H, br), 8.26 (1H, dd, J = 9Hz, 2H
z), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%): 325 (M ⁺ , 26), 284 (100), 271 (37), 2
38 (69) IR (ν, cm ^{- 1} ), KBr: 3416, 1622, 1586, 1518, 1316, 9
20

Example 10 2-allylamino-6-nitro-4-propylaminoquinazoline

[0090]

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6-nitroquinazoline-2,4 (1H, 3
15.13 g (98.70 mmol) of phosphorus oxychloride was added to 367 mg (1.77 mmol) of H) -dione, and the mixture was heated under reflux for 4 days. After removing phosphorus oxychloride by atmospheric distillation, crystallization was performed from diethyl ether-hexane to obtain 550 mg of 2,4-dichloro-6-nitroquinazoline as crude crystals. This was dissolved in 5 ml of DMF, 209 mg (3.54 mmol) of propylamine was added dropwise under ice-cooling, and the solution was added under ice-cooling.
Stirred for hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 2-chloro-6-nitro-4-propylaminoquinazoline. 1.52 g of allylamine
(26.65 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column,
231 mg (yield 45.4%) of the title compound were obtained. Melting point: 211-212 ° C NMR (δ, CDCl ₃ , 45 ° C): 1.04 (3H, t, J = 7Hz), 1.70-1.8
2 (2H, m), 3.59 (2H, td, J = 7Hz, 7Hz), 4.18 (2H, t, J =
6Hz), 5.16 (1H, d with fine couple, J = 10Hz), 5.28 (1
H, d with fine couple, J = 17Hz), 5.47 (1H, br), 5.79
(1H, br), 5.92-6.05 (1H, m), 7.42 (1H, d, J = 9Hz), 8.
29 (1H, dd, J = 9Hz, 2Hz), 8.49 (1H, d, J = 2Hz) EI-Mass (m / z,%): 287 (M ⁺ , 43), 272 (100), 226 (30 ) IR (ν, cm ^{- 1} ), KBr: 3412, 3256, 1588, 1556, 1484, 1
316, 1168, 832

Example 11 2-Allylamino-4-neopentylamino-6-nitroquinazoline

[0093]

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6-nitroquinazoline-2,4 (1H, 3
Example 10 was added to 15.3 g (98.70 mmol) of phosphorus oxychloride to 367 mg (1.77 mmol) of H) -dione.
Then, 309 mg (3.54 mmol) of neopentylamine was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 2-chloro-4-neopentylamino-6-nitroquinazoline. This was dissolved in 2 ml of DMF, 1.52 g (26.65 mmol) of allylamine was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to give 210 mg of the title compound (yield 37.
6%). Melting point: 216-217 ° C NMR (δ, CDCl ₃ , 45 ° C): 1.05 (9H, s), 3.50 (2H, d, J = 6)
Hz), 4.18 (2H, t, J = 6Hz), 5.17 (1H, d with fine coup
le, J = 10Hz), 5.29 (1H, d with fine couple, J = 17Hz),
5.39 (1H, br), 5.79 (1H, br), 5.93-6.05 (1H, m), 7.43
(1H, d, J = 9Hz), 8.31 (1H, dd, J = 9Hz, 2Hz), 8.49 (1H,
d, J = 2Hz) EI-Mass (m / z,%): 315 (M ⁺ , 40), 300 (100), 285 (26), 2
70 (48), 258 (16), 228 (8), 212 (17) IR (ν, cm ^{- 1} ), KBr: 3436, 3252, 2964, 1602, 1562, 1
484, 1294, 1164, 834

Example 12 2-allylamino-4-benzylamino-6-nitroquinazoline

[0096]

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6-nitroquinazoline-2,4 (1H, 3
Example 10 was added to 15.3 g (98.70 mmol) of phosphorus oxychloride to 367 mg (1.77 mmol) of H) -dione.
The reaction was carried out in the same manner as Next, benzylamine 37 was added under ice cooling.
9 mg (3.54 mmol) was added dropwise, and the mixture was stirred under ice cooling for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration.
-Chloro-4-benzylamino-6-nitroquinazoline was obtained. 761 mg of allylamine (13.33)
mmol) and stirred at room temperature for 2.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 224 mg (yield: 56.8%) of the title compound. Melting point: 235-236 ° C NMR (δ, DMSO-d ₆ , 55 ° C): 3.95-4.01 (2H, m), 4.72 (2H,
d, J = 6Hz), 5.02 (1H, d, J = 10Hz), 5.14 (1H, d, J = 17H
z), 5.83-5.96 (1H, m), 7.24-7.41 (7H, m), 8.20 (1H, d
d, J = 9Hz, 3Hz), 8.99 (1H, br), 9.12 (1H, d, J = 3Hz) Mass (m / z,%): 335 (M ⁺ , 70), 320 (100), 274 ( 16), 244
(11), 198 (15), 91 (65) IR (ν, cm ^{- 1} ), KBr: 3420, 3256, 1584, 1558, 1480, 1
306, 1250, 832

Example 13 2-allylamino-6-nitro-4-piperidinoquinazoline

[0099]

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6-nitroquinazoline-2,4 (1H, 3
Example 10 was added to 15.3 g (98.70 mmol) of phosphorus oxychloride to 367 mg (1.77 mmol) of H) -dione.
The reaction was carried out in the same manner as Next, piperidine 301 mg under ice cooling
(3.54 mmol) was added dropwise, and the mixture was stirred under ice cooling for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration.
Chloro-6-nitro-4-piperidinoquinazoline was obtained. This was dissolved in 1 ml of DMF, and allylamine.
52 g (26.65 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 213 mg (38.4%) of the title compound. 123-124 ° C NMR (δ, CDCl ₃ , 45 ° C): 1.79 (6H, br), 3.74 (4H, br),
4.13-4.18 (2H, m), 5.15 (1H, d with fine couple, J = 1
0Hz), 5.27 (1H, d with fine couple, J = 17Hz), 5.33 (1
H, br), 5.91-6.04 (1H, m), 7.43 (1H, d, J = 9Hz), 8.25
(1H, dd, J = 9Hz, 3Hz), 8.66 (1H, d, J = 3Hz) Mass (m / z,%): 313 (M ⁺ , 49), 298 (100), 283 (27), 268
(41), 252 (15) IR (ν, cm ^{− 1} ), KBr: 3260, 29
44, 1580, 1484, 1322, 112
0,838

Example 14 2,4-Diallylamino-6-amino-quinazoline hydrochloride

[0102]

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3.32 g (14.73 m) of tin chloride dihydrate
mol) and 1.40 g (4.91 mm) of concentrated hydrochloric acid and 2,4-diallylamino-6-nitroquinazoline under ice-cooling.
ol) and stirred overnight at room temperature. The reaction solution was neutralized by adding an aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 1.61 g of the free base compound of the title compound.
(92.5% yield). NMR (δ, CDCl ₃ ): 3.65 (2H, br), 4.12 (2H, t, J = 6Hz),
4.22 (2H, t, J = 6Hz), 4.89 (1H, br), 5.09-5.32 (4H,
m), 5.43 (1H, br), 5.93-6.08 (2H, m), 6.73 (1H, d, J = 3
Hz), 7.02 (1H, dd, J = 9Hz, 3Hz), 7.34 (1H, d, J = 9Hz) EI-Mass (m / z,%): 255 (M ⁺ , 73), 240 (100), 214 (14) IR (ν, cm ^{- 1} ), KBr: 3256, 1578, 1548, 1494, 1414, 1
252, 840

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (650 mg, 2.55 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to give 615 mg (82.8%) of the title compound. Melting point: 212-215 ° C NMR (δ, DMSO-d ₆ , 55 ° C): 4.05-4.07 (2H, m), 4.18 (2H,
t, J = 6Hz), 5.12-5.27 (4H, m), 5.32 (2H, br), 5.88-
6.01 (2H, m), 7.15 (1H, dd, J = 9Hz, 2Hz), 7.24 (1H, d,
J = 2Hz), 7.30 (1H, d, J = 9Hz), 7.93 (1H, br), 9.31 (1
H, br), 12.27 (1H, br) EI-Mass (m / z,%): 255 (M ⁺ , 64), 240 (100), 214 (15) IR (ν, cm ^{- 1} ), KBr: 3268, 1648, 1580, 1416, 1338, 9
twenty two

Example 15 4-allylamino-2-diallylamino-6-chloroquinazoline

[0106]

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268 mg (1.06 mmol) of 4-allylamino-2,6-dichloroquinazoline and diallylamine 7
87 mg (8.10 mmol) were stirred in a sealed tube at 120 ° C. for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 284 mg (yield: 85.1%) of the title compound. Melting point: 73-74 ° C NMR (δ, CDCl ₃ ): 4.18-4.23 (2H, m), 4.30 (4H, d, J = 6H
z), 5.11-5.32 (6H, m), 5.40 (1H, br), 5.83-6.07 (3H,
m), 7.37-7.44 (3H, m) EI-Mass (m / z,%): 314 (M ⁺ , 34), 273 (100), 260 (42) IR (ν, cm ^-1 ), KBr: 3288, 1572, 1502, 1414, 1248, 9
twenty four

Example 16 4-Allylamino-2-methylamino-6-nitroquinazoline

[0109]

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230 mg (0.87 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 902 mg (12.88 mmol) of a 40% aqueous solution of methylamine were added at room temperature for 3 hours.
Stirred for 0 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give the title compound (190 mg, yield 84.2%).
I got Melting point: 238-239 ° C NMR (δ, DMSO-d ₆ , 55 ° C): 2.88 (3H, d, J = 4Hz), 4.11-
4.17 (2H, m), 5.13 (1H, d with fine couple, J = 10Hz),
5.24 (1H, d, J = 17Hz), 5.94-6.04 (1H, m), 7.07 (1H, b
r), 7.28 (1H, d, J = 9Hz), 8.20 (1H, dd, J = 9Hz, 2Hz),
8.57 (1H, br), 9.10 (1H, d, J = 2Hz) EI-Mass (m / z,%): 259 (M ⁺ , 100), 244 (71), 198 (16) IR (ν, cm ^{- 1), KBr: 3412,} 3264, 1614, 1552, 1484, 1
310, 1178, 836

Example 17 4-Allylamino-2-ethylamino-6-nitroquinazoline

[0112]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 796 mg (15.52 mmol) of a 70% aqueous solution of ethylamine were added to the solution at room temperature.
Stirred for hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 234 mg (yield 90.6%) of the title compound. Melting point: 227-228 ° C NMR (δ, CDCl ₃ , 55 ° C): 1.27 (3H, t, J = 7Hz), 3.53-3.5
9 (2H, m), 4.25 (2H, t, J = 6Hz), 5.20 (1H, br), 5.25 (1
H, d with fine couple, J = 10Hz), 5.33 (1H, dwith fin
e couple, J = 17Hz), 5.74 (1H, br), 5.97-6.07 (1H, m),
7.39 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9Hz, 2Hz), 8.49
(1H, d, J = 2Hz) EI-Mass (m / z,%): 273 (M ⁺ , 100), 258 (65), 230 (64), 2
12 (24) IR (ν, cm ^-1 ), KBr: 3420, 3260, 1594, 1560, 1486, 1
300, 1172, 834

Example 18 4-Allylamino-2-isopropylamino-6-nitroquinazoline

[0115]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 694 mg (11.74 mmol) of isopropylamine were stirred at room temperature for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 270 mg (yield 99.4%) of the title compound. Melting point: 150-151 ° C NMR (δ, CDCl ₃ , 55 ° C): 1.27 (6H, d, J = 6Hz), 4.25-4.3
3 (3H, m), 5.09 (1H, br), 5.25 (1H, d with fine coupl
e, J = 10Hz), 5.33 (1H, d with fine couple, J = 17Hz),
5.77 (1H, br), 5.97-6.07 (1H, m), 7.37 (1H, d, J = 8H
z), 8.27 (1H, dd, J = 8Hz, 2Hz), 8.50 (1H, d, J = 2Hz) EI-Mass (m / z,%): 287 (M ⁺ , 89), 272 (100), 245 (37), 2
30 (55), 226 (39) IR (ν, cm ^{- 1} ), KBr: 3436, 2976, 1588, 1546, 1480, 1
306, 1176, 838

Example 19 4-Allylamino-2-t-butylamino-6-nitroquinazoline

[0118]

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225 mg (0.85 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 696 mg (9.52 mmol) of t-butylamine were stirred at 80 ° C. overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was purified by a silica gel column to give 240 mg (yield 93.7%) of the title compound. Mp: 139~140 ℃ NMR (δ, CDCl 3, 55 ℃): 1.51 (9H, s), 4.26 (2H, t, J = 6
Hz), 5.26 (1H, d withfine couple, J = 10Hz), 5.33 (1H,
d with fine couple, J = 17Hz), 5.35 (1H, br), 5.73 (1
H, br), 5.97-6.07 (1H, m), 7.35 (1H, d, J = 9Hz), 8.27
(1H, dd, J = 9Hz, 2Hz), 8.50 (1H, d, J = 2Hz) EI-Mass (m / z,%): 301 (M ⁺ , 44), 286 (100), 245 (90) , 2
30 (49) IR (ν, cm ^-1 ), KBr: 3424, 2976, 1582, 1548, 1504, 1
320, 842

Example 20 4-Allylamino-2- (2-aminoethylamino)-
6-nitroquinazoline

[0121]

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230 mg (0.87 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 899 mg (14.96 mmol) of ethylenediamine were stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 200 mg (yield: 79.9%) of the title compound. Melting point: 126-128 ° C NMR (δ, DMSO-d ₆ , 55 ° C): 1.36 (2H, br), 2.70-2.74 (2
H, m), 3.34-3.38 (2H, m), 4.14 (2H, t, J = 5Hz), 5.11-
5.27 (2H, m), 5.94-6.04 (1H, m), 7.06 (1H, br), 7.25
(1H, br), 8.19 (1H, dd, J = 9Hz, 3Hz), 8.60 (1H, br),
9.09 (1H, d, J = 3Hz) EI-Mass (m / z,%): 288 (M ⁺ , 10), 258 (57), 246 (100), 2
12 (44) IR (ν, cm ^{- 1} ), KBr: 3420, 3260, 1590, 1554, 1488, 1
306, 1166, 924

Example 21 2-Allylamino-4-methylamino-6-nitroquinazoline

[0124]

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6-nitroquinazoline-2,4 (1H, 3
Example 10 was added with 12.83 g (83.47 mmol) of phosphorus oxychloride to 311 mg (1.50 mmol) of H) -dione.
The reaction was carried out in the same manner as Next, 208 mg (3.00 mmol) of a 40% aqueous solution of methylamine was added dropwise under ice cooling, and the mixture was stirred for 2 hours under ice cooling. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, drying over anhydrous sodium sulfate, the solvent was distilled off, and 2-chloro-4-methylamino-6 was removed.
-Nitroquinazoline was obtained. 761 mg (13.33 mmol) of allylamine was added to the obtained compound, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 158 mg (yield 40.7%) of the title compound. Melting point: 211-212 ° C NMR (δ, CDCl ₃ , 55 ° C): 3.16 (3H, d, J = 5Hz), 4.18-4.2
1 (2H, m), 5.14-5.31 (3H, m), 5.77 (1H, br), 5.94-6.0
4 (1H, m), 7.41 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9Hz, 2
Hz), 8.49 (1H, d, J = 2Hz) EI-Mass (m / z,%): 259 (M ⁺ , 67), 244 (100), 198 (41) IR (ν, cm ^{- 1} ), KBr: 3444, 3252, 1588, 1562, 1480, 1
312, 1100, 834

Example 22 2-Allylamino-4-ethylamino-6-nitroquinazoline

[0127]

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6-nitroquinazoline-2,4 (1H, 3
Example 10 was added with 12.80 g (83.47 mmol) of phosphorus oxychloride to 311 mg (1.50 mmol) of H) -dione.
The reaction was carried out in the same manner as Next, 151 mg (3.00 mmol) of a 70% ethylamine aqueous solution was added dropwise under ice cooling, and the mixture was stirred for 2 hours under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2-chloro-4-ethylamino-6.
-Nitroquinazoline was obtained. 761 mg (13.33 mmol) of allylamine was added to the obtained compound, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 180 mg (yield 44.1%) of the title compound. Mp: 215~216 ℃ NMR (δ, CDCl 3, 55 ℃): 1.35 (3H, t, J = 7Hz), 3.62-3.6
9 (2H, m), 4.16-4.20 (2H, m), 5.14-5.30 (3H, m), 5.68
(1H, br), 5.94-6.03 (1H, m), 7.40 (1H, d, J = 9Hz), 8.
28 (1H, dd, J = 9Hz, 2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%): 273 (M ⁺ , 61), 258 (100), 212 (30 ) IR (ν, cm ^{- 1} ), KBr: 3416, 3264, 1590, 1554, 1486, 1
306, 1102, 834

Reference Example 4 2-chloro-4-trans-cinnamylamino-6-
Nitroquinazoline

[0130]

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6-nitroquinazoline-2,4 (1H, 3
H) -dione (400 mg, 1.93 mmol), 1,3-dimethyl-2-imidazolidinone (1 ml), phosphorus oxychloride (2.
96 g (19.3 mmol) was added, and the mixture was heated under reflux for 3 hours.
After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 3 ml of acetonitrile, and 5.94 ml of triethylamine (42.
46 mmol), trans-cinnamylamine hydrochloride 51
4 mg (3.86 mmol) was added, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
After evaporating the solvent, the residue was purified by a silica gel column to obtain 85 mg (13.0%) of the title compound. NMR (δ, CDCl ₃ ); 4.43-4.46 (2H, m), 6.35-6.42 (1H,
m), 6.67 (1H, d, J = 16Hz), 7.24-7.42 (5H, m), 7.77 (1
H, d, J = 9Hz), 8.45 (1H, dd, J = 9Hz, 2Hz), 9.11 (1H, b
r), 9.44 (1H, d, J = 2Hz)

Example 23 2-Allylamino-4-trans-cinnamylamino-6-nitroquinazoline hydrochloride

[0133]

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2-chloro-4-trans-cinnamylamino-6-nitroquinazoline 75 mg (0.22 mmol)
To this was added 761 mg (13.33 mmol) of allylamine, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by a silica gel column. A 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain 57 mg (65.1%) of the title compound. NMR (δ, DMSO-d ₆ , 55 ° C); 4.16 (2H, t, J = 6 Hz), 4.40 (2
H, t, J = 5Hz), 5.15 (1H, d, J = 10Hz), 5.30 (1H, d, J = 1
7Hz), 5.91-6.00 (1H, m), 6.37-6.44 (1H, m), 6.69 (1H,
d, J = 16Hz), 7.23-7.65 (6H, m), 8.50 (1H, br), 8.52 (1
H, d, J = 9Hz), 9.34 (1H, s), 10.22 (1H, br), 13.11 (1H,
br) EI-Mass (m / z,%); 361 (M ⁺ , 100), 346 (53), 117 (59) IR (ν, cm ^{- 1} ), KBr; 3386, 2595, 1655, 1594, 1491 , 1
335, 845 Melting point: 206-208 ° C

Reference Example 5 4-butylamino-2-chloro-6-nitroquinazoline

[0136]

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6-nitroquinazoline-2,4 (1H, 3
(H) -dione (500 mg, 2.41 mmol), 1,3-dimethyl-2-imidazolidinone (2 ml), phosphorus oxychloride (8).
23 g (53.64 mmol) was added, and the mixture was heated under reflux for 3 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, and 5.9 ml of butylamine (60 mmol
l) was added and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give the title compound 43.
0 mg (63.6%) were obtained. NMR (δ, CDCl ₃ ); 1.02 (3H, t), 1.45-1.55 (2H, m), 1.
73-1.81 (2H, m), 3.72-3.77 (2H, m), 6.30 (1H, br), 7.
86 (1H, d, J = 9Hz), 8.51 (1H, dd, J = 9Hz, 2Hz), 8.72 (1
(H, d, J = 2Hz)

Example 24 2-Allylamino-4-butylamino-6-nitroquinazoline

[0139]

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To 170 mg (0.67 mmol) of 4-butylamino-2-chloro-6-nitroquinazoline was added 1.52 g (26.66 mmol) of allylamine, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was purified by a silica gel column to give 166 mg (82.1%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 1.00 (3H, t, J = 7Hz), 1.44-1.5
1 (2H, m), 1.68-1.73 (2H, m), 3.59-3.64 (2H, m), 4.16
-4.19 (2H, m), 5.14-5.30 (3H, m), 5.70 (1H, br), 5.94
-6.03 (1H, m), 7.39 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9
Hz, 2Hz), 8.47 (1H, d, J = 2Hz) EI-Mass (m / z,%); 301 (M ⁺ , 49), 286 (100) IR (ν, cm ^{- 1} ), KBr; 3392 , 2935, 1606, 1558, 1481, 1
302, 831 Melting point: 214-215 ° C

Reference Example 6 2-chloro-6-nitro-4-pentylaminoquinazoline

[0142]

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6-nitroquinazoline-2,4 (1H, 3
H) -dione (400 mg, 1.93 mmol), 1,3-dimethyl-2-imidazolidinone (1 ml), phosphorus oxychloride (6)
58 g (42.91 mmol) was added, and the mixture was heated under reflux for 3 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 4 ml of acetonitrile, and 5.60 ml of propylamine (4.
(8.25 mmol), and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 342 mg (70.1%) of the title compound. NMR (δ, CDCl ₃ ); 0.94-0.97 (3H, m), 1.41-1.47 (4H,
m), 1.75-1.81 (2H, m), 3.71-3.76 (2H, m), 6.25 (1H, b
r), 7.86 (1H, d, J = 9Hz), 8.51 (1H, dd, J = 9Hz, 2Hz),
8.70 (1H, d, J = 2Hz)

Example 25 2-Allylamino-6-nitro-4-pentylaminoquinazoline hydrochloride

[0145]

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To 170 mg (0.61 mmol) of 2-chloro-6-nitro-4-pentylaminoquinazoline was added 1.52 g (26.66 mmol) of allylamine, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 160 mg of the free base compound of the title compound (83.6).
%). NMR (δ, CDCl ₃ , 55 ° C.); 0.93-0.96 (3H, m), 1.39-1.46
(4H, m), 1.69-1.76 (2H, m), 3.58-3.63 (2H, m), 4.16-
4.19 (2H, m), 5.14-5.30 (3H, m), 5.72 (1H, br), 5.94-
6.03 (1H, m), 7.39 (1H, d, J = 9Hz), 8.27 (1H, dd, J = 9H
z, 2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%); 315 (M ⁺ , 42), 300 (100)

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the free base compound of the title compound (120 mg, 0.38 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 112 mg (83.8%) of the title compound. NMR (δ, CDCl ₃ ); 0.91-0.95 (3H, m), 1.35-1.46 (4H,
m), 1.80-1.87 (2H, m), 3.74-3.79 (2H, m), 4.20 (2H, t,
J = 6Hz), 5.19-5.36 (2H, m), 5.86-5.96 (1H, m), 7.58
(1H, d, J = 9Hz), 8.36 (1H, t, J = 6Hz), 8.38 (1H, dd, J
= 9Hz, 2Hz), 9.06 (1H, t, J = 5Hz), 9.45 (1H, d, J = 2H
z), 13.87 (1H, br) IR (ν, cm ^{- 1} ), KBr; 3435, 2931, 1655, 1610, 1425, 1
338, 746 Melting point: 190-192 ° C

Reference Example 7 2-chloro-4-heptylamino-6-nitroquinazoline

[0149]

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6-nitroquinazoline-2,4 (1H, 3
(H) -dione (300 mg, 1.45 mmol), 1,3-dimethyl-2-imidazolidinone (1 ml), phosphorus oxychloride
22 g (14.48 mmol) was added, and the mixture was heated under reflux for 3 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 3 ml of acetonitrile, and 5.38 ml of heptylamine (3.
6.25 mmol) and stirred under ice cooling for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 247 mg (52.8%) of the title compound. NMR (δ, CDCl ₃ ); 0.89-0.92 (3H, m), 1.30-1.48 (8H,
m), 1.74-1.81 (2H, m), 3.71-3.76 (2H, m), 6.20 (1H, b
r), 7.86 (1H, d, J = 9Hz), 8.51 (1H, dd, J = 9Hz, 2Hz),
8.69 (1H, d, J = 2Hz)

Example 26 2-Allylamino-4-heptylamino-6-nitroquinazoline hydrochloride

[0152]

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To 150 mg (0.46 mmol) of 2-chloro-4-heptylamino-6-nitroquinazoline was added 1.14 g (20.00 mmol) of allylamine, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 140 mg (88.6) of the free base compound of the title compound.
%). NMR (δ, CDCl ₃ , 55 ° C); 0.88-0.92 (3H, m), 1.26-1.47
(8H, m), 1.69-1.76 (2H, m), 3.58-3.63 (2H, m), 4.16-
4.19 (2H, m), 5.14-5.30 (3H, m), 5.68 (1H, br), 5.94-
6.03 (1H, m), 7.39 (1H, d, J = 9Hz), 8,28 (1H, dd, J = 9H
z, 3Hz), 8.47 (1H, d, J = 3Hz) EI-Mass (m / z,%); 343 (M ⁺ , 40), 328 (100)

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (120 mg, 0.35 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 100 mg (75.2%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C.); 0.89 (3H, t, J = 7 Hz), 1.26-1.5
1 (8H, m), 1.79-1.86 (2H, m), 3.73-3.78 (2H, m), 4.19
(2H, br), 5.20-5.37 (2H, m), 5.86-5.96 (1H, m), 7.63
(1H, d, J = 9Hz), 8.37-8.40 (2H, m), 8.51 (1H, br), 9.
19 (1H, s), 14.19 (1H, br) IR (ν, cm ^{- 1} ), KBr; 3367, 2927, 1651, 1612, 1425, 1
336, 748 Melting point: 186-188 ° C

Reference Example 8 2-chloro-4-cyclopentylamino-6-nitroquinazoline

[0156]

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6-nitroquinazoline-2,4 (1H, 3
1,3-Dimethyl-2-imidazolidinone (1 ml) and phosphorus oxychloride (1) were added to 300 mg (1.45 mmol) of H) -dione.
23 g (8.05 mmol) was added, and the mixture was heated under reflux for 3 hours.
After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 3 ml of acetonitrile, and 4.05 ml of triethylamine (29.
00 mmol), 0.89 ml of cyclopentylamine (8.7)
0 mmol) and stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to give the title compound 15
2 mg (35.9%) were obtained. NMR (δ, CDCl ₃ ); 1.58-1.90 (6H, m), 2.23-2.31 (2H,
m), 4.66-4.74 (1H, m), 6.18 (1H, d, J = 7Hz), 7.85 (1H,
d, J = 9Hz), 8.50 (1H, dd, J = 9Hz, 2Hz), 8.68 (1H, d, J
= 2Hz)

Example 27 2-Allylamino-4-cyclopentylamino-6-nitroquinazoline hydrochloride

[0159]

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2-chloro-4-cyclopentylamino-
To 128 mg (0.44 mmol) of 6-nitroquinazoline was added 913 mg (16.00 mmol) of allylamine, and the mixture was added at room temperature.
Stirred for hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 129 mg of the free base compound of the title compound (93.
6%). NMR (δ, CDCl ₃ , 55 ° C); 1.54-1.86 (6H, m), 2.14-2.22
(2H, m), 4.16-4.19 (2H, m), 4.50-4.56 (1H, m), 5.14-
5.30 (3H, m), 5.62 (1H, br), 5.94-6.04 (1H, m), 7.38
(1H, d, J = 9Hz), 8.27 (1H, dd, J = 9Hz, 3Hz), 8.45 (1H,
d, J = 3Hz) EI-Mass (m / z,%); 313 (M ⁺ , 49), 298 (100)

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (92 mg, 0.29 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to give 87 mg (85.8%) of the title compound. NMR (δ, CDCl ₃ ); 1.72-1.94 (6H, m), 2.17-2.24 (2H,
m), 4.20 (2H, t, J = 6Hz), 4.64-4.71 (1H, m), 5.20-5.3
6 (2H, m), 5.86-5.96 (1H, m), 7.61 (1H, d, J = 9Hz), 8.
21 (1H, d, J = 7Hz), 8.41 (1H, dd, J = 9Hz, 2Hz), 8.49 (1
H, t, J = 6Hz), 9.32 (1H, d, J = 2Hz), 14.13 (1H, br) IR (ν, cm ^{- 1} ), KBr; 3224, 2956, 1641, 1610, 1579, 1
446, 1338, 748 Melting point: 208-210 ° C

Reference Example 9 2-chloro-4-isopropylamino-6-nitroquinazoline

[0163]

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6-nitroquinazoline-2,4 (1H, 3
To 1.00 g (4.83 mmol) of H) -dione, 32.90 g (0.22 mol) of phosphorus oxychloride and 0.70 ml (4.83 mmol) of diisopropylformamide were added.
Heated to reflux for an hour. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 15 ml of acetonitrile, 2.49 ml (29.11 mmol) of isopropylamine was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 870 mg (67.5%) of the title compound. NMR (δ, CDCl ₃ ); 1.42 (6H, d, J = 6 Hz), 4.62-4.70 (1H,
m), 6.11 (1H, d, J = 7Hz), 7.85 (1H, d, J = 9Hz), 8.50 (1H
H, dd, J = 9Hz, 2Hz), 8.71 (1H, d, J = 2Hz)

Example 28 2-Allylamino-4-isopropylamino-6-nitroquinazoline hydrochloride

[0166]

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2-chloro-4-isopropylamino-6
-To 870 mg (3.26 mmol) of nitroquinazoline was added 3.81 g (66.64 mmol) of allylamine, and the mixture was added at room temperature.
Stirred for hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 895 mg of the free base compound of the title compound (95.
7%). NMR (δ, CDCl ₃ , 55 ° C.); 1.35 (6H, d, J = 7 Hz), 4.15-4.1
9 (2H, m), 4.44-4.52 (1H, m), 5.14-5.30 (3H, m), 5.48
(1H, br), 5.94-6.03 (1H, m), 7.39 (1H, d, J = 9Hz), 8.
27 (1H, dd, J = 9Hz, 2Hz), 8.46 (1H, d, J = 2Hz) EI-Mass (m / z,%); 287 (M ⁺ , 43), 272 (100), 230 (15 ), 2
26 (18) IR (ν, cm ^{- 1} ), KBr; 3256, 3096, 1590, 1588, 1488, 1
306, 1166, 924

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (510 mg, 1.78 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 536 mg (93.0%) of the title compound. NMR (δ, CDCl ₃ ); 1.50 (6H, d, J = 7 Hz), 4.18-4.21 (2H,
m), 4.62-4.71 (1H, m), 5.19-5.36 (2H, m), 5.86-5.95
(1H, m), 7.60 (1H, d, J = 9Hz), 8.40 (1H, dd, J = 9Hz, 2
Hz), 8.43 (1H, t, J = 6Hz), 8.59 (1H, d, J = 8Hz), 9.50
(1H, d, J = 2Hz), 13.97 (1H, br s) IR (ν, cm ^{- 1} ), KBr; 3244, 1649, 1583, 1527, 1342, 8
39 Melting point: 211-213 ° C

Example 29 4-Allylamino-6-nitro-2- (2-propynylamino) quinazoline

[0170]

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To 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was added 1.61 g (29.16 mmol) of 2-propynylamine, and the mixture was added at room temperature.
Stirred for hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 143 mg (88.6%) of the title compound. NMR (δ, DMSO-d ₆ , 55 ° C); 2.94 (1H, t, J = 2Hz), 4.14-
4.16 (4H, m), 5.12-5.28 (2H, m), 5.96-6.05 (1H, m),
7.32 (1H, d, J = 9Hz), 7.46 (1H, br), 8.23 (1H, dd, J = 9
Hz, 3Hz), 8.74 (1H, br), 9.13 (1H, d, J = 3Hz) EI-Mass (m / z,%); 283 (M ⁺ , 98), 282 (100), 236 (34) , 1
96 (53) IR (ν, cm ^{- 1} ), KBr; 3394, 3296, 1610, 1560, 1477, 1
317, 837 Melting point: 192-193 ° C

Example 30 4-Allylamino-2- (trans-2-butenylamino) -6-nitroquinazoline

[0173]

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150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 2 ml of acetonitrile, and 305 mg (2.83 mmol) of trans-2-butenylamine hydrochloride and 0.1 ml of triethylamine were dissolved.
39 ml (2.83 mmol) was added, and the mixture was stirred at 50 ° C. for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was purified by a silica gel column to give 138 mg (80.9%) of the title compound. NMR (δ, CDCl ₃ ); 1.71 (2H, d, J = 6Hz), 1.75 (1H, d, J =
7Hz), 4.09 (1.3H, t, J = 6Hz), 4.18 (0.7H, t, J = 6Hz),
4.26 (2H, br), 5.15-5.36 (3H, m), 5.47-6.06 (4H, m),
7.43 (1H, br), 8.30 (1H, dd, J = 9Hz, 2Hz), 8.51 (1H, br)
d, J = 2Hz) EI-Mass (m / z,%); 299 (M ⁺ , 54), 284 (34), 270 (100) IR (ν, cm ^{- 1} ), KBr; 3386, 3263, 1606 , 1551, 1481, 1
308, 833 Melting point: 188-189 ° C

Example 31 4-Allylamino-2-butylamino-6-nitroquinazoline hydrochloride

[0176]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 740 mg (10.02 mmol) of butylamine were stirred at room temperature for 3 hours.
Water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to obtain 249 mg (87.4%) of the free base compound of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 0.97 (3H, t, J = 7Hz), 1.40-1.4
9 (2H, m), 1.59-1.66 (2H, m), 3.50-3.55 (2H, m), 4.25
(2H, t, J = 6Hz), 5.20 (1H, br), 5.23-5.36 (2H, m), 5.
73 (1H, br), 5.97-6.07 (1H, m), 7.39 (1H, d, J = 9Hz),
8.27 (1H, dd, J = 9Hz, 2Hz), 8.49 (1H, d, J = 2Hz) EI-Mass (m / z,%); 301 (M ⁺ , 84), 272 (65), 259 (100 ), 2
58 (88), 245 (66), 230 (58), 212 (53) IR (ν, cm ^{- 1} ), KBr; 3428, 3256, 1586, 1556, 1482, 1
306, 1172

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (124 mg, 0.41 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 120 mg (86.6%) of the title compound. NMR (δ, CDCl ₃ ); 0.94 (3H, t, J = 7Hz), 1.39-1.48 (2H,
m), 1.62-1.71 (2H, m), 3.55-3.60 (2H, m), 4.39 (2H,
t, J = 6Hz), 5.25-5.39 (2H, m), 5.99-6.09 (1H, m), 7.54
(1H, d, J = 9Hz), 8.25 (1H, t, J = 6Hz), 8.37 (1H, dd, J
= 9Hz, 2Hz), 9.54 (1H, t, J = 6Hz), 9.57 (1H, d, J = 2H
z), 13.59 (1H, br s) IR (ν, cm ^{- 1} ), KBr; 3437, 3078, 1612, 1585, 1425, 1
338, 744 Melting point: 210-212 ° C

Example 32 4-Allylamino-6-nitro-2- (2-enylamino) quinazoline hydrochloride

[0180]

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200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 2.20 g (19.44 mmol) of 2-thenylamine were stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with chloroform, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was recrystallized from ethyl acetate-hexane to give 241 mg of the free base compound of the title compound (93.
4%). NMR (δ, DMSO-d ₆ , 55 ° C); 4.16 (2H, br), 4.72 (2H, d,
J = 6Hz), 5.10-5.26 (2H, m), 5.93-6.03 (1H, m), 6.93 (1
H, dd, J = 5Hz, 3Hz), 7.01 (1H, d, J = 3Hz), 7.25-7.35
(2H, m), 7.75 (1H, br), 8.22 (1H, dd, J = 9Hz, 2Hz),
8.69 (1H, br), 9.12 (1H, d, J = 2Hz) EI-Mass (m / z,%); 341 (M ⁺ , 100), 311 (58), 300 (33), 2
54 (20), 97 (52)

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (100 mg, 0.29 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 87 mg (79.4%) of the title compound. NMR (δ, DMSO-d ₆ , 55 ° C); 4.30 (2H, br), 4.89 (2H, b
r), 5.19-5.33 (2H, m), 5.94-6.04 (1H, m), 6.99 (1H, d
d, J = 5Hz, 4Hz), 7.12 (1H, br), 7.42 (1H, d, J = 5Hz),
7.68 (1H, d, J = 9Hz), 8.52 (1H, d, J = 9Hz), 8.88 (1H, b
r), 9.36 (1H, s), 10.24 (1H, br), 13.59 (1H, br) IR (ν, cm ^{- 1} ), KBr; 3246, 2723, 1651, 1589, 1525, 1
335, 845 Melting point: 228-233 ° C (decomp)

Example 33 4-Allylamino-2-furfurylamino-6-nitroquinazoline hydrochloride

[0184]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.10 g (11.33 mmol) of furfurylamine were stirred at room temperature for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 234 mg (95.1%) of the free base compound of the title compound. NMR (δ, CDCl ₃ , 55 ° C.); 4.26 (2H, t, J = 6 Hz), 4.73 (2H,
d, J = 6Hz), 5.25-5.33 (2H, m), 5.48 (1H, br), 5.77 (1
H, br), 5.96-6.04 (1H, m), 6.26 (1H, d, J = 3Hz), 6.32
(1H, dd, J = 3Hz, 2Hz), 7.36 (1H, d, J = 2Hz), 7.44 (1H,
d, J = 9Hz), 8.30 (1H, dd, J = 9Hz, 3Hz), 8.51 (1H, d,
J = 3Hz) EI-Mass (m / z,%); 325 (M ⁺ , 100), 295 (16), 284 (12), 2
38 (13), 81 (20) IR (ν, cm ^{- 1} ), KBr; 3428, 3252, 1586, 1560, 1480, 1
306, 1102, 748 Melting point: 217-218 ° C

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (100 mg, 0.31 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to give 90 mg (80.3%) of the title compound. NMR (δ, DMSO-d ₆ , 55 ° C); 4.27 (2H, br), 4.73 (2H, b
r), 5.19-5.34 (2H, m), 5.94-6.04 (1H, m), 6.40 (1H, b
r), 6.42 (1H, dd, J = 3Hz, 2Hz), 7.60 (1H, d, J = 2Hz),
7.68 (1H, d, J = 9Hz), 8.54 (1H, d, J = 9Hz), 8.81 (1H, b
r), 9.38 (1H, s), 10.30 (1H, br), 13.72 (1H, br) IR (ν, cm ^{− 1} ), KBr; 3350, 27
25, 1651, 1587, 1527, 145
0, 1335, 845 Melting point: 222-226 ° C (decomp)

Example 34 4-Allylamino-2-cyclopentylamino-6-nitroquinazoline hydrochloride

[0188]

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250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.73 g (20.32 mmol) of cyclopentylamine were stirred at room temperature for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and 232 mg (97.9%) of the free base compound of the title compound
I got NMR (δ, CDCl ₃ , 55 ° C); 1.49-1.80 (6H, m), 2.05-2.12
(2H, m), 4.25 (2H, t, J = 5Hz), 4.41-4.46 (1H, m), 5.22
(1H, br), 5.24-5.36 (2H, m), 5.72 (1H, br), 5.97-6.07
(1H, m), 7.38 (1H, d, J = 8Hz), 8.27 (1H, dd, J = 8Hz, 2
Hz), 8.48 (1H, d, J = 2Hz) Mass (m / z,%); 313 (M ⁺ , 48), 272 (37), 245 (100), 230
(55)

Under ice-cooling, a 4N solution of hydrochloric acid in ethyl acetate was added dropwise to a solution of the free base compound of the title compound in 100 mg (0.32 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 102 mg (91.2%) of the title compound. NMR (δ, CDCl ₃ ); 1.63-1.86 (6H, m), 2.02-2.10 (2H,
m), 4.36-4.44 (3H, m), 5.28-5.41 (2H, m), 6.00-6.09 (1
H, m), 7.53 (1H, d, J = 9Hz), 8.37 (1H, dd, J = 9Hz, 2H
z), 8.48 (1H, d, J = 7Hz), 8.99 (1H, t, J = 5Hz), 9.36 (1
H, d, J = 2 Hz), 13.65 (1H, brs) IR (ν, cm ^{− 1} ), KBr; 3238, 29
58, 1651, 1610, 1583, 133
8,746 Melting point: 230-232 ° C

Example 35 4-Allylamino-6-nitro-2-pentylaminoquinazoline hydrochloride

[0192]

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200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.50 g (17.25 mmol) of pentylamine were stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 219 mg (91.9 mg) of the free base compound of the title compound.
%). NMR (δ, CDCl ₃ , 55 ° C); 0.90-0.94 (3H, m), 1.38-1.43
(4H, m), 1.61-1.68 (2H, m), 3.52 (2H, m), 4.25 (2H,
t, J = 5Hz), 5.21 (1H, br), 5.25-5.33 (2H, m), 5.70 (1
H, br), 5.97-6.07 (1H, m), 7.39 (1H, d, J = 9Hz), 8.28
(1H, dd, J = 9Hz, 2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%); 315 (M ⁺ , 76), 286 (55), 272 (67) , twenty five
9 (100), 258 (97), 245 (65), 212 (72)

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the title compound (92 mg, 0.29 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to give 98 mg (96.1%) of the title compound. NMR (δ, CDCl ₃ ); 0.89 (3H, t, J = 7Hz), 1.29-1.42 (4H,
m), 1.64-1.71 (2H, m), 3.53-3.58 (2H, m), 4.39 (2H,
t, J = 6Hz), 5.24-5.38 (2H, m), 5.99-6.09 (1H, m), 7.55
(1H, d, J = 9Hz), 8.22 (1H, t, J = 6Hz), 8.37 (1H, dd, J
= 9Hz, 2Hz), 9.62 (1H, d, J = 2Hz), 9.68 (1H, t, J = 6H
z), 13.53 (1H, br s) IR (ν, cm ^{- 1} ), KBr; 3080, 2926, 1651, 1612, 1583, 1
448, 1335, 844 Melting point: 207-209 ° C

Example 36 4-Allylamino-2-heptylamino-6-nitroquinazoline

[0196]

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200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.55 g (13.49 mmol) of heptylamine were stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was purified by a silica gel column to give 228 mg (87.8%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 0.89 (3H, t, J = 7Hz), 1.26-1.4
4 (8H, m), 1.60-1.67 (2H, m), 3.51 (2H, m), 4.25 (2H, m
t, J = 5Hz), 5.20 (1H, br), 5.25-5.33 (2H, m), 5.70 (1H,
br), 5.97-6.07 (1H, m), 7.39 (1H, d, J = 8Hz), 8.28 (1H
H, dd, J = 8Hz, 3Hz), 8.48 (1H, d, J = 3Hz) EI-Mass (m / z,%); 343 (M ⁺ , 79), 300 (56), 272 (64), twenty five
9 (100), 258 (95), 245 (57), 212 (57) IR (ν, cm ^{- 1} ), KBr; 3394, 2927, 1612, 1556, 1481, 1
306,829 melting point: 173-174 ° C

Example 37 4-Allylamino-6-nitro-2-piperidinoaminoquinazoline

[0199]

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200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.86 g (18.53 mmol) of 1-aminopiperidine were stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 100 mg (40.3%) of the title compound. NMR (δ, CDCl ₃ ); 1.42-1.49 (2H, m), 1.73-1.78 (4H,
m), 2.86 (4H, br), 4.26 (2H, t, J = 6Hz), 5.24-5.36 (2
H, m), 5.93-6.06 (3H, m), 7.58 (1H, d, J = 9Hz), 8.30 (1
H, dd, J = 9Hz, 3Hz), 8.59 (1H, d, J = 3Hz) EI-Mass (m / z,%); 328 (M ⁺ , 8), 245 (64), 230 (100), 84
(29) IR (ν, cm ^{- 1} ), KBr; 3400, 2927, 1595, 1477, 1306, 8
47 Melting point: 221-222 ° C

Example 38 4-Allylamino-6-nitro-2- (2-propoxyethylamino) -6-nitroquinazoline

[0202]

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100 mg (0.38 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 1.5 ml of acetonitrile, and 124 mg (0.76 mmol) of 2-propoxyethylamine hydrochloride and triethylamine 19
6 mg (1.94 mmol) was added, and the mixture was stirred at 80 ° C. for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was purified by a silica gel column to give 91 mg (72.3%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 0.92-0.96 (3H, m), 1.57-1.64
(2H, m), 3.42-3.46 (2H, m), 3.62 (2H, t, J = 5Hz), 3.7
0-3.74 (2H, m), 4.24-4.27 (2H, m), 5.23-5.35 (2H, m),
5.61 (1H, br), 5.73 (1H, br), 5.97-6.06 (1H, m), 7.4
0 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9Hz, 3Hz), 8.48 (1
H, d, J = 3Hz) EI-Mass (m / z,%); 331 (M ⁺ , 29), 301 (9), 288 (100), 25
8 (92) 212 (43) IR (ν, cm ^{- 1} ), KBr; 3397, 3255, 1608, 1554, 1477, 1
303, 1102, 837 Melting point: 169-170 ° C

Example 39 2-Allylamino-6-nitro-4- (2-propoxyethylamino) quinazoline

[0205]

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6-nitroquinazoline-2,4 (1H, 3
H) -dione (450 mg, 2.17 mmol), phosphorus oxychloride (4.50 ml, 48.28 mmol) and collidine (658 mg).
(5.43 mmol) was added and the mixture was heated under reflux for 24 hours. After removing phosphorus oxychloride by distillation under reduced pressure, acetonitrile 1
0-ml, 2-propoxyethylamine hydrochloride (320 mg, 2.29 mmol), triethylamine 3.51 under ice-cooling.
ml (25.18 mmol) was added and the mixture was stirred under ice cooling for 30 minutes. Water was added to the reaction solution, and the precipitated crystals were collected by filtration. 2-Chloro-6-nitro-4- (2-propoxyethylamino)
Quinazoline was obtained. 5.00 ml of allylamine
(66.64 mmol) was added and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 346 mg (48.1%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 0.97 (3H, t, J = 7Hz), 1.61-1.7
0 (2H, m), 3.49 (2H, t, J = 7Hz), 3.69 (2H, t, J = 5Hz),
3.78-3.82 (2H, m), 4.17 (2H, t, J = 6Hz), 5.14-5.30 (3
H, m), 5.93-6.03 (1H, m), 6.12 (1H, br), 7.39 (1H, d,
J = 9Hz), 8.27 (1H, dd, J = 9Hz, 3Hz), 8.48 (1H, d, J = 3
Hz) EI-Mass (m / z,%); 331 (M ⁺ , 63), 316 (100), 258 (13), 2
12 (12) IR (ν, cm ^{- 1} ), KBr; 3388, 2924, 1587, 1535, 1493, 1
311, 1117, 746 Melting point: 156-157 ° C

Reference Example 10 2-Allylamino-4-amino-6-nitroquinazoline

[0208]

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6-nitroquinazoline-2,4 (1H, 3
25.60 g (0.17 mol) of phosphorus oxychloride was added to 622 mg (3.00 mmol) of H) -dione, and the mixture was heated under reflux for 4 days. After phosphorus oxychloride was removed by atmospheric distillation, crystallization was performed from ether-hexane to obtain a dichloride as crude crystals. The obtained dichloride was dissolved in 5 ml of DMF, 0.73 ml (12.00 mmol) of a 28% aqueous ammonia solution was added, and the mixture was stirred for 2 hours under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 4-amino-2-chloro-6-nitroquinazoline. To this, 5 ml of allylamine was added and stirred at room temperature overnight. After adding water to the reaction solution and extracting with chloroform and washing with saturated saline,
It was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 342 mg of the title compound.
(46.5%). NMR (δ, DMSO-d ₆ , 55 ° C); 3.99-4.02 (2H, m), 5.03-5.2
0 (2H, m), 5.88-5.93 (1H, m), 7.17 (1H, br), 7.25 (1H,
d, J = 9Hz), 7.71 (2H, br), 8.20 (1H, dd, J = 9Hz, 3H
z), 9.05 (1H, d, J = 3Hz)

Example 40 2-Allylamino-4- (t-butylcarbamoyl) amino-6-nitroquinazoline

[0211]

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To a solution of 165 mg (0.67 mmol) of 2-allylamino-4-amino-6-nitroquinazoline in 5 ml of THF was added 24 mg (0.70 mmol) of 70% sodium hydride.
After stirring for 0.5 hour under ice cooling, 76 mg (0.77 mmol) of t-butyl isocyanate was added, and the mixture was returned to room temperature.
Stir for 5 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with chloroform (10 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (79 mg, yield 34.2%). Melting point: 200-201 ° C NMR (δ, CDCl ₃ ); 1.41 (9H, s), 4.04 (2H, br), 5.12 (1
H, dd, J = 9Hz, 2Hz), 5.21 (1H, d, J = 17Hz), 5.92-6.02
(1H, m), 7.39 (2H, d, J = 8Hz), 7.67 (1H, br), 8.29 (1H,
dd, J = 8Hz, 2Hz), 9.14 (1H, br), 9.46 (1H, d, J = 2H
z), 10.14 (1H, br) .IR (ν, cm ^{- 1} ), KBr; 1685, 1597, 1323 EI-Mass (m / z,%); 344 (M ⁺ , 13), 271 (35), 256 (80), 23
0 (100)

Example 41 2- [N-allyl-N- (t-butylcarbamoyl) amino] -4- (t-butylcarbamoyl) amino-6
Nitroquinazoline

[0214]

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To a solution of 123 mg (0.50 mmol) of 2-allylamino-4-amino-6-nitroquinazoline in 5 ml of DMF were added 56 mg (0.55 mmol) of t-butoxycali,
50 mg (0.50 mmol) of butyl isocyanate were added,
Heated at 150 ° C. for 0.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (80 mg, yield 36.0%). Melting point: 105-106 ° C NMR (δ, CDCl ₃ ); 1.44 (9H, s), 1.49 (9H, s), 4.82 (2H,
d, J = 5Hz), 5.16-5.20 (2H, m), 5.92-6.00 (1H, m), 7.
60 (1H, d, J = 9Hz), 8.51-8.54 (2H, m), 9.09 (2H, br),
10.87 (1H, br s) IR (ν, cm ^{- 1} ), KBr; 1693, 1550, 1365,763 EI-Mass (m / z,%); 443 (M ⁺ , 2), 344 (15), 271 (43), 256
(97), 230 (100)

Example 42 4-Acetylamino-2-allylamino-6-nitroquinazoline

[0217]

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300 mg (1.22 mmol) of 2-allylamino-4-amino-6-nitroquinazoline was dissolved in 5 ml of THF, and 5.0 g (29.38 mmol) of acetic anhydride and 30 mg (0.37 mmol) of sodium acetate were added. Lower 12
Stirred for hours. The reaction solution was neutralized with a 1N aqueous sodium hydroxide solution, and the precipitated crystals were filtered, washed with water and dried to obtain 150 mg (42.7%) of the title compound. NMR (δ, DMSO-d ₆ , 55 ° C); 2.39 (3H, s), 4.04-4.07 (2H,
m), 5.07-5.23 (2H, m), 5.91-6.01 (1H, m), 7.47 (1H,
d, J = 9Hz), 7.92 (1H, br), 8.32 (1H, d, J = 9Hz), 9.10
(1H, br), 10.79 (1H, br) EI-Mass (m / z,%); 287 (M ⁺ , 51), 272 (76), 244 (20), 230
(100) IR (ν, cm ^{- 1} ), KBr; 3257, 3085, 1685, 1618, 1504, 1
333, 1302 Melting point: 253-254 ° C

Example 43 2-Allylamino-4- (2-methylpropoxycarbonyl) amino-6-nitroquinazoline

[0220]

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500 mg (2.04 mmol) of 2-allylamino-4-amino-6-nitroquinazoline was dissolved in 5 ml of dimethylformamide, and 80 mg (2.33 mmol) of 70% sodium hydride and 2-methylpropoxycarbonyl were added under ice-cooling. 280 mg (2.05 mmol) of chloride are added,
Stir for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 131 mg (19.1%) of the title compound. NMR (δ, CDCl ₃ ); 1.01 (6H, d, J = 7Hz), 2.01-2.11 (1H,
m), 4.08 (2H, d, J = 7Hz), 4.21-4.23 (2H, m), 5.18-5.3
3 (2H, m), 5.70 (1H, br), 5.93-6.03 (1H, m), 7.58 (1H,
br), 7.75 (1H, br), 8.39 (1H, d, J = 9Hz), 8.72 (1H, b
r) EI-Mass (m / z,%); 345 (M ⁺ , 25), 330 (34), 271 (40), 25
6 (100), 230 (42), 210 (36) IR (ν, cm ^{- 1} ), KBr; 3325, 3257, 2960, 1732, 1622, 1
514, 1329 Melting point: 148-149 ° C

Reference Example 11 4-Allylamino-2-amino-6-nitroquinazoline

[0223]

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After dissolving 10 ml of ammonia gas in 50 ml of ethanol at -78 ° C., 2.40 g (9.07 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved.
15 ml of the THF solution of l) was added and stirred in a sealed tube at 70 ° C. overnight. 150 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to obtain 1.88 g (84.6%) of the title compound. NMR (δ, DMSO-d ₆ ); 4.13-4.17 (2H, m), 5.11-5.27 (2H,
m), 5.94-6.02 (1H, m), 6.84 (2H, br), 7.23 (1H, d, J =
9Hz), 8.22 (1H, dd, J = 9Hz, 3Hz), 8.72 (1H, t, J = 6H
z), 9.14 (1H, d, J = 3Hz)

Example 44 2-acetylamino-4-allylamino-6-nitroquinazoline

[0226]

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100 mg (0.41 mmol) of 4-allylamino-2-amino-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and 84 mg (0.82 mmol) of acetic anhydride and 0.06 ml (0.45 mmol) of triethylamine were added thereto. Heated to reflux overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was recrystallized from ethyl acetate-hexane to obtain 95 mg (80.7%) of the title compound. NMR (δ,
DMSO-d ₆ ); 2.33 (3H, s), 4.20-4.22 (2H, m), 5.14-5.30
(2H, m), 5.97-6.07 (1H, m), 7.59 (1H, d, J = 9Hz), 8.4
0 (1H, dd, J = 9Hz, 3Hz), 9.21 (1H, t, J = 5Hz), 9.31 (1H,
d, J = 3Hz), 10.19 (1H, s) EI-Mass (m / z,%); 287 (M ⁺ , 100), 272 (67), 244 (29), 2
30 (98), 198 (45), 184 (37) IR (ν, cm ^{- 1} ), KBr; 3367, 1671, 1596, 1471, 1313, 1
020, 748 Melting point: 239-240 ° C

Example 45 4-Allylamino-6-nitro-2- (propylcarbamoyl) aminoquinazoline

[0229]

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200 mg (0.82 mmol) of 4-allylamino-2-amino-6-nitroquinazoline was added to 10 ml of THF.
And 153 mg (1.80) of propyl isocyanate.
mmol) and 0.13 ml of triethylamine (0.90 mmol)
l) was added and the mixture was refluxed overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 218 mg of the title compound (8 mg).
0.5%). NMR (δ, DMSO-d ₆ ); 0.94 (3H, t, J = 7Hz), 1.51-1.60 (2
H, m), 3.19-3.24 (2H, m), 4.17 (2H, t, J = 5Hz), 5.15-
5.32 (2H, m), 5.95-6.04 (1H, m), 7.59 (1H, d, J = 9Hz),
8.40 (1H, dd, J = 9Hz, 3Hz), 9.24 (1H, t, J = 5Hz), 9.28
(1H, d, J = 3Hz), 9.38 (1H, s), 9.52 (1H, t, J = 6Hz) EI-Mass (m / z,%); 330 (M ⁺ , 14), 301 (100) , 272 (54), 2
26 (10) IR (ν, cm ^{- 1} ), KBr; 3237, 1675, 1598, 1531, 1469, 1
326, 1238, 638 Melting point: 254-255 ° C

Example 46 2-Allylamino-4- (2,2-dimethylhydrazino) -6-nitroquinazoline

[0232]

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6-nitroquinazoline-2,4 (1H, 3
(H) -dione (300 mg, 1.45 mmol), 1,3-dimethyl-2-imidazolidinone (1 ml), phosphorus oxychloride (1).
23 g (8.05 mmol) was added, and the mixture was heated under reflux for 3 hours.
After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 3 ml of acetonitrile, and 520 mg of 1,1-dimethylhydrazine was dissolved.
(8.69 mmol) and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2-chloro-4- (2,2-dimethylhydrazino) -6-nitroquinazoline. To this was added 2.00 ml (26.65 mmol) of allylamine, and the mixture was added at room temperature for 3 hours.
After stirring for an hour, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 73 mg (17.5%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C.); 2.75 (6H, s), 4.15-4.18 (2H,
m), 5.14-5.30 (2H, m), 5.36 (1H, br), 5.92-6.01 (1H,
m), 6.22 (1H, br), 7.43 (1H, d, J = 9Hz), 8.29 (1H, dd,
J = 9Hz, 3Hz), 9.12 (1H, br) EI-Mass (m / z,%); 288 (M ⁺ , 51), 273 (8), 245 (88), 230
(100), 198 (23), 184 (54) IR (ν, cm ^{- 1} ), KBr; 3307, 3257, 3101, 1587, 1552, 1
296 melting point: 145-146 ° C

Reference Example 12 2-chloro-4-dodecylamino-6-nitroquinazoline

[0235]

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6-nitroquinazoline-2,4 (1H, 3
To 250 mg (1.21 mmol) of H) -dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the mixture was refluxed for 24 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, 2.80 ml (12.10 mmol) of dodecylamine was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 310 mg (67.0%) of the title compound. NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 1.27-1.49 (18H,
m), 1.74-1.81 (2H, m), 3.70-3.75 (2H, m), 6.21 (1H,
br), 7.86 (1H, d, J = 9Hz), 8.51 (1H, dd, J = 9Hz, 2Hz),
8.69 (1H, d, J = 2Hz)

Example 47 2-Allylamino-4-dodecylamino-6-nitroquinazoline

[0238]

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To 170 mg (0.44 mmol) of 2-chloro-4-dodecylamino-6-nitroquinazoline was added 1.70 ml (22.66 mmol) of allylamine, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 170 mg (93.4%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 0.88 (3H, t, J = 7Hz), 1.27-1.4
8 (18H, m), 1.68-1.75 (2H, m), 3.58-3.63 (2H, m), 4.1
6-4.19 (2H, m), 5.14-5.30 (3H, m), 5.68 (1H, br), 5.94
-6.03 (1H, m), 7.39 (1H, d, J = 9Hz), 8.28 (1H, dd, J = 9
Hz, 2Hz), 8.46 (1H, d, J = 2Hz) EI-Mass (m / z,%); 413 (M ⁺ , 21), 398 (100), 384 (18), 3
70 (20), 356 (14), 272 (14) IR (ν, cm ^{- 1} ), KBr; 3397, 2923, 1612, 1563, 1479, 1
301, 1103, 746 Melting point: 154 to 155 ° C

Example 48 4-Allylamino-2-dodecylamino-6-nitroquinazoline

[0241]

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150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and 158 mg (0.86 mmol) of dodecylamine was dissolved.
mmol) and 0.40 ml (2.85 mmol) of triethylamine.
l) was added and the mixture was heated under reflux overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 223 mg of the title compound (9 mg).
4.7%). NMR (δ, CDCl ₃ , 55 ° C); 0.88 (3H, t, J = 7Hz), 1.22-1.4
2 (18H, m), 1.60-1.67 (2H, m), 3.49-3.54 (2H, m), 4.2
4-4.26 (2H, m), 5.21 (1H, br), 5.23-5.35 (2H, m), 5.71
(1H, br), 5.97-6.07 (1H, m), 7.39 (1H, d, J = 9Hz), 8.
27 (1H, dd, J = 9Hz, 2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%); 413 (M ⁺ , 84), 384 (24), 370 (25 ), 35
6 (22), 272 (55), 259 (100), 258 (69), 212 (32) IR (ν, cm ^{- 1} ), KBr; 3394, 2921, 1614, 1558, 1481, 1
303, 1105, 829 Melting point: 148-155 ° C

Reference Example 13 2-chloro-4- (1-methylpropylamino) -6
Nitroquinazoline

[0244]

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6-nitroquinazoline-2,4 (1H, 3
To 250 mg (1.21 mmol) of H) -dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the mixture was refluxed for 24 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, 1.23 ml (12.10 mmol) of 1-methylpropylamine was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 234 mg (68.9%) of the title compound.
I got NMR (δ, CDCl ₃ ); 1.03 (3H, t, J = 8Hz), 1.38 (3H, d, J =
7Hz), 1.69-1.81 (2H, m), 4.47-4.56 (1H, m), 6.15 (1H,
d, J = 8Hz), 7.84 (1H, d, J = 9Hz), 8.50 (1H, dd, J = 9Hz,
2Hz), 8.75 (1H, d, J = 2Hz)

Example 49 2-Allylamino-4- (1-methylpropylamino)
-6-nitroquinazoline hydrochloride

[0247]

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2-chloro-4- (1-methylpropylamino) -6-nitroquinazoline 150 mg (0.53 mmol)
1.50 ml (20.00 mmol) of allylamine was added to l), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give the free base compound 15 of the title compound.
6 mg (98.0%) were obtained. NMR (δ, CDCl ₃ , 55 ° C.); 1.00 (3H, t, J = 8 Hz), 1.31 (3H,
d, J = 7Hz), 1.61-1.77 (2H, m), 4.15-4.18 (2H, m), 4.
29-4.39 (1H, m), 5.13-5.29 (3H, m), 5.46 (1H, br), 5.9
3-6.03 (1H, m), 7.39 (1H, d, J = 9Hz), 8.27 (1H, dd, J =
9 Hz, 3 Hz), 8.46 (1 H, d, J = 3 Hz) Under ice cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of the free base compound of the title compound (100 mg, 0.33 mmol) in ethyl acetate. The precipitated crystals were collected by filtration to give the title compound 105
mg (94.2%). NMR (δ, CDCl ₃ ); 1.02 (3H, t, J = 7Hz), 1.46 (3H, d, J =
7Hz), 1.74-2.00 (2H, m), 4.17-4.20 (2H, m), 4.46-4.53
(1H, m), 5.18-5.35 (2H, m), 5.85-5.95 (1H, m), 7.61 (1
H, d, J = 9Hz), 8.38-8.41 (2H, m), 8.75 (1H, d, J = 8H
z), 9.59 (1H, d, J = 2Hz), 13.84 (1H, s) EI-Mass (m / z,%); 301 (M ⁺ , 60), 286 (100), 272 (10), 2
26 (7) IR (ν, cm ^{- 1} ), KBr; 3214, 1668, 1610, 1556, 1502, 1
342, 926 Melting point: 176-177 ° C

Example 50 4-Allylamino-2- (1-methylpropylamino)
-6-nitroquinazoline hydrochloride

[0250]

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160 mg (0.61 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.60 ml (15.84 mmol) of 1-methylpropylamine were stirred overnight at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 180 mg of the free base compound of the title compound (9 mg).
8.4%). NMR (δ, CDCl ₃ , 55 ° C.); 0.98 (3H, t,
J = 8 Hz), 1.24 (3H, d, J = 6H)
z), 1.54-1.66 (2H, m), 4.1.
2-4.19 (1H, m), 4.25 (2H,
t, J = 6 Hz), 5.08 (1H, br),
5.24-5.35 (2H, m), 5.73 (1
H, br), 5.97-6.07 (1H, m),
7.37 (1H, d, J = 8 Hz), 8.27
(1H, dd, J = 8Hz, 2Hz), 8.48
(1H, d, J = 2 Hz) Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of 100 mg (0.33 mmol) of the free base compound of the title compound in ethyl acetate. The precipitated crystals were collected by filtration, and the title compound 100
mg (90.9%). NMR (δ, CDCl ₃ ); 0.99 (3H, t, J = 8Hz), 1.31 (3H, d, J =
7Hz), 1.61-1.74 (2H, m), 4.10-4.20 (1H, m), 4.37-4.40
(2H, m), 5.24-5.38 (2H, m), 5.99-6.08 (1H, m), 7.50 (1
H, d, J = 9Hz), 8.13 (1H, d, J = 8Hz), 8.34 (1H, dd, J = 9
Hz, 2Hz), 9.57-9.61 (2H, m), 13.52 (1H, s) EI-Mass (m / z,%); 301 (M ⁺ , 44), 286 (27), 272 (100), 2
26 (37) IR (ν, cm ^{- 1} ), KBr; 3215, 1651, 1610, 1587, 1340, 7
44 Melting point: 219-220 ° C

Reference Example 14 4-t-butylamino-2-chloro-6-nitroquinazoline

[0253]

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6-nitroquinazoline-2,4 (1H, 3
To 250 mg (1.21 mmol) of H) -dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the mixture was refluxed for 24 hours. After phosphorus oxychloride was removed by distillation under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, and 1.26 ml (12.10 mmol) of t-butylamine was added under ice-cooling.
Stirred for minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 218 mg (64.2%) of the title compound. NMR (δ, CDCl ₃ ); 1.65 (9H, s), 6.07 (1H, br), 7.83 (1
H, d, J = 9Hz), 8.48 (1H, dd, J = 9Hz, 2Hz), 8.64 (1H,
d, J = 2Hz)

Example 51 2-Allylamino-4-t-butylamino-6-nitroquinazoline hydrochloride

[0256]

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4-tert-butylamino-2-chloro-6-
1.60 ml (21.32 mmol) of allylamine was added to 150 mg (0.55 mmol) of nitroquinazoline, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 165 mg of the free base compound of the title compound (98.2).
%). NMR (δ, CDCl ₃ ); 1.59 (9H, s), 4.16-4.19 (2H, m), 5.1
5-5.30 (2H, m), 5.42 (1H, br), 5.63 (1H, br), 5.94-6.
03 (1H, m), 7.36 (1H, br), 8.28 (1H, dd, J = 9Hz, 2Hz),
8.44 (1H, d, J = 2 Hz) Under ice cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to a solution of 102 mg (0.34 mmol) of the free base compound of the title compound in ethyl acetate. The precipitated crystals were collected by filtration, and the title compound 100
mg (88.2%). NMR (δ, CDCl ₃ ); 1.67 (9H, s), 4.18-4.21 (2H, m), 5.2
2-5.37 (2H, m), 5.86-5.95 (1H, m), 7.00 (1H, s), 7.68
(1H, d, J = 9Hz), 8.46 (1H, dd, J = 9Hz, 2Hz), 8.70 (1H,
t, J = 6Hz), 8.85 (1H, d, J = 2Hz), 14.54 (1H, s) EI-Mass (m / z,%); 301 (M ⁺ , 61), 286 (56), 244 ( 18), 23
0 (100) IR (ν, cm ^{- 1} ), KBr; 3222, 3084, 1653, 1608, 1574, 1
444, 1338, 1207, 744 Melting point: 208-209 ° C

Reference Example 15 4- (1-adamantylamino) -2-chloro-6-nitroquinazoline

[0259]

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6-nitroquinazoline-2,4 (1H, 3
To 250 mg (1.21 mmol) of H) -dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the mixture was refluxed for 24 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, 183 mg (1.21 mmol) of 1-adamantylamine and 0.84 ml (6.05 mmol) of triethylamine were added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 90 mg (20.7%) of the title compound. NMR (δ, CDCl ₃ ); 1.75-1.82 (6H, m), 2.22 (3H, br), 2.
28-2.32 (6H, m), 5.83 (1H, br s), 7.82 (1H, d, J = 9H
z), 8.48 (1H, dd, J = 9Hz, 2Hz), 8.60 (1H, d, J = 2Hz)

Example 52 4- (1-Adamantylamino) -2-allylamino-
6-nitroquinazoline

[0262]

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To 82 mg (0.25 mmol) of 4- (1-adamantylamino) -2-chloro-6-nitroquinazoline was added 1.00 ml (13.33 mmol) of allylamine, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 77 mg (88.7%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 1.76-1.77 (6H, m), 2.18 (3H, b
r), 2.27-2.28 (6H, m), 4.14-4.18 (2H, m), 5.14-5.30
(3H, m), 5.42 (1H, br), 5.94-6.04 (1H, m), 7.35 (1H,
d, J = 9Hz), 8.26 (1H, dd, J = 9Hz, 2Hz), 8.41 (1H, d, J
= 2Hz) EI-Mass (m / z,%); 379 (M ⁺ , 65), 364 (100), 135 (44) IR (ν, cm ^{- 1} ), KBr; 3401, 2908, 1587, 1485, 1309, 1
107, 839 Melting point: 224 to 225 ° C

Example 53 4-Allylamino-6-nitro-2- [2- (piperidinocarbonyl) ethylamino] quinazoline

[0265]

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150 mg (0.57 mmol) of 4-allylamino-2-chloro-nitroquinazoline was added to acetonitrile 1
The mixture was dissolved in 0 ml, and 2-piperidinocarbonylethylamine hydrochloride (220 mg, 1.14 mmol) and triethylamine (0.40 ml, 2.85 mmol) were added, followed by heating under reflux overnight.
Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain 191 mg (87.7%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C.); 1.51-1.67 (6H, m), 2.67 (2H,
t, J = 6Hz), 3.40 (2H, br), 3.56 (2H, br), 3.87 (2H, t
d, J = 6Hz, 6Hz), 4.24 (2H, br), 5.24 (1H, d, J = 10Hz),
5.32 (1H, d, J = 17Hz), 5.95-6.05 (2H, m), 6.90 (1H, b
r), 7.44 (1H, d, J = 9Hz), 8.29 (1H, dd, J = 9Hz, 2Hz),
8.62 (1H, br) EI-Mass (m / z,%); 384 (M ⁺ , 17), 300 (2), 272 (100), 25
8 (10), 226 (15) IR (ν, cm ^{- 1} ), KBr; 3265, 2937, 1620, 1589, 1535, 1
484, 1311, 839 Melting point: 178-179 ° C

Example 54 4-Allylamino-6-nitro-2- (2-pyridylmethylamino) quinazoline

[0268]

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150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and 2-pyridylmethylamine hydrochloride 1 was dissolved.
65 mg (1.14 mmol) and triethylamine 0.40
ml (2.85 mmol) was added and the mixture was refluxed overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give the title compound 1.
80 mg (93.9%) were obtained. NMR (δ, DMSO-d ₆ , 55 ° C); 3.96-4.20 (2H, m), 4.67 (2H,
d, J = 6Hz), 4.96-5.29 (2H, m), 5.72-6.08 (1H, m), 7.
20-7.34 (3H, m), 7.60 (1H, br), 7.68-7.72 (1H, m), 8.
20 (1H, dd, J = 9Hz, 2Hz), 8.49 (1H, d, J = 5Hz), 8.68 (1
H, br), 9.10 (1H, d, J = 2Hz) EI-Mass (m / z,%); 336 (M ⁺ , 100), 244 (7), 212 (11) IR (ν, cm ^{- 1} ), KBr; 3401, 1587, 1552, 1477, 1304, 1
167, 746 Melting point: 202-203 ° C

Example 55 2-Allylamino-4- (2,2,2-trifluoroethylamino) -6-nitroquinazoline

[0271]

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6-nitroquinazoline-2,4 (1H, 3
H) To 250 mg (1.21 mmol) of dione, 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide were added, and the mixture was heated under reflux for 24 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, and cooled under ice-cooling to 2,2,2-.
328 mg of trifluoroethylamine hydrochloride (2.42 mm
ol) and 1.69 ml (12.10 mmol) of triethylamine.
l) was added and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, 1.50 ml (20.00 mmol) of allylamine was added, and the mixture was stirred overnight. After adding water, the reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. . After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (12.6%) of the title compound. NMR (δ, CDCl ₃ , 55 ° C); 3.99-4.02 (2H, m), 4.34-4.43
(2H, m), 5.04-5.20 (2H, m), 5.88-5.98 (1H, m), 7.33
(1H, d, J = 9Hz), 7.51 (1H, br), 8.25 (1H, dd, J = 9Hz,
3Hz), 8.93 (1H, br), 9.15 (1H, d, J = 3Hz) EI-Mass (m / z,%); 327 (M ⁺ , 65), 312 (100), 266 (60) IR ( ν, cm ^{- 1} ), KBr; 3379, 1612, 1556, 1483, 1313, 1
250, 1157, 835 Melting point: 215 to 216 ° C

Example 56 4-Allylamino-2- (2,2,2-trifluoroethylamino) -6-nitroquinazoline

[0274]

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4-Allylamino-2-chloro-6-nitroquinazoline 150 mg (0.57 mmol), 2,2,2-
772 mg (5.70 mmol) of trifluoroethylamine and 1.15 g (11.4 mmol) of triethylamine were stirred at room temperature for 16 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with chloroform (10 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 57 mg (yield: 30.8%) of the title compound. Melting point: 221-222 ° C NMR (δ, CDCl ₃ , 55 ° C); 4.21-4.29 (4H, m), 5.26-5.37
(3H, m), 5.85 (1H, br), 5.97-6.06 (1H, m), 7.49 (1H,
d, J = 8Hz), 8.34 (1H, dd, J = 8Hz, 2Hz), 8.53 (1H, d, J
= 2Hz) IR (ν, cm ^{- 1} ), KBr; 3396, 1562, 1313, 1160 EI-Mass (m / z,%); 327 (M ⁺ , 100), 312 (86), 258 (28)

Example 57 4-Allylamino-2- (2-chloroethylamino)-
6-nitroquinazoline

[0277]

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50 mg of 4-allylamino-2- (2-hydroxyethylamino) -6-nitroquinazoline (0.1
7 mmol) in dichloromethane solution.
g (13.7 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After heating and refluxing for another 1 hour, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 25 mg (yield: 46.8%) of the title compound. NMR (δ, CDCl ₃ ); 3.65-3.79 (2H, m), 3.88-3.93 (2H,
m), 4.26-4.28 (2H, m), 5.26-5.38 (2H, m), 5.57 (1H, b
r), 5.83 (1H, br), 5.98-6.08 (1H, m), 7.44 (1H, d, J =
7Hz), 8.32 (1H, dd, J = 7Hz, 2Hz), 8.53 (1H, d, J = 2Hz) IR (ν, cm ^{- 1} ), KBr; 3392, 1610, 1308 EI-Mass (m / z, %); 309 (M ⁺ +2, 7), 307 (M ⁺ , 23) 272 (10
0), 258 (38)

Example 58 4-Allylamino-2- (3-methyl-2-butenylamino) -6-nitroquinazoline

[0280]

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To a solution of 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline in 10 ml of acetonitrile was added 137 mg (1.13 mmol) of 3-methyl-2-butenylamine hydrochloride and 288 of triethylamine.
mg (2.85 mmol) was added, and the mixture was heated under reflux for 4.5 hours.
After completion of the reaction, ice water was added, and the mixture was extracted three times with chloroform (10 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give the title compound 13
3 mg (75.1% yield) was obtained. Mp: 194~195 ℃ NMR (δ, CDCl 3, 50 ℃); 1.75 (6H, s), 4.10 (2H, t, J = 6
Hz), 4.25 (2H, br), 5.15 (1H, br), 5.24-5.35 (3H, m),
5.73 (1H, br), 5.97-6.06 (1H, m), 7.41 (1H, d, J = 8H
z), 8.28 (1H, dd, J = 8Hz, 2Hz), 8.49 (1H, d, J = 2Hz) IR (ν, cm ^{- 1} ), KBr; 1597, 1296 EI-Mass (m / z,%) ; 313 (M ⁺ , 83), 270 (100)

Example 59 2-Allylamino-4- (3-methyl-2-butenylamino) -6-nitroquinazoline

[0283]

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6-nitroquinazoline-2,4 (1H, 3
To 278 mg (1.45 mmol) of H) -dione, 0.71 ml of 1,3-dimethyl-2-imidazolidinone and 5.48 g (35.76 mmol) of phosphorus oxychloride were added, and the mixture was heated under reflux for 3 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 3 ml of acetonitrile, and 2.81 ml of triethylamine was dissolved.
(20.07 mmol) and 267 mg (2.19 mmol) of 3-methyl-2-butenylamine hydrochloride were added, and the mixture was stirred under ice cooling for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2-chloro-4- (3-methyl-2-butenylamino) -6-nitroquinazoline. 1.00 ml of allylamine (13.33 mm
ol), and the mixture was stirred at room temperature for 3 hours, water was added to the reaction solution, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give the title compound (70 mg, 1
6.7%). NMR (δ, CDCl ₃ ); 1.78 (3H, s), 1.82 (3H, s), 4.18-4.2
1 (4H, m), 5.15-5.31 (3H, m), 5.38-5.42 (1H, m), 5.57
(1H, br), 5.94-6.04 (1H, m), 7.40 (1H, br), 8.29 (1H,
dd, J = 9Hz, 2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%); 313 (M ⁺ , 100), 298 (97), 270 (21), 24
4 (29) IR (ν, cm ^{- 1} ), KBr; 3400, 3253, 3086, 1608, 1560, 1
306 melting point: 209-210 ° C

Example 60 2-butylamino-4- (3-methyl-2-butenylamino) -6-nitroquinazoline

[0286]

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6-nitroquinazoline-2,4 (1H, 3
Example 59 from 278 mg (1.45 mmol) of H) -dione
2-chloro-4- (3-methyl-2-butenylamino) -6-nitroquinazoline was obtained in the same manner as described above. To this solution, butylamine (1.00 ml, 10.12 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. . After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (11.9%) of the title compound. NMR (δ, CDCl ₃ ); 0.97 (3H, t, J = 7Hz), 1.40-1.49 (2H,
m), 1.57-1.66 (2H, m), 1.78 (3H, s), 1.82 (3H, s), 3.
51-3.56 (2H, m), 4.15 (2H, br), 5.21 (1H, br), 5.40 (1
H, t, J = 7Hz), 5.56 (1H, br), 7.42 (1H, br), 8.28 (1H,
dd, J = 9Hz, 2Hz), 8.47 (1H, d, J = 2Hz) EI-Mass (m / z,%); 329 (M ⁺ , 100), 314 (15), 286 (33), 2
60 (27) IR (ν, cm ^{- 1} ), KBr; 3396, 3259, 2956, 1593, 1300 Melting point: 171-172 ° C

Example 61 2,4-bis (3-methyl-2-butenylamino) -6
-Nitroquinazoline

[0289]

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6-nitroquinazoline-2,4 (1H, 3
Example 59 from 278 mg (1.45 mmol) of H) -dione
2-chloro-4- (3-methyl-2-butenylamino) -6-nitroquinazoline was obtained in the same manner as described above. 0.30 ml (2.14 mmol) of triethylamine and 3
-Methyl-2-butenylamine hydrochloride 87 mg (0.72
mmol), and the mixture was stirred at 80 ° C. for 12 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to give the title compound 6
5 mg (14.2%) were obtained. NMR (δ, CDCl ₃ ); 1.75 (6H, br), 1.77 (3H, s), 1.81 (3
H, s), 4.06-4.13 (4H, m), 5.13 (1H, br), 5.30-5.40 (2
H, m), 5.53 (1H, m), 7.40 (1H, br), 8.23 (1H, dd, J = 9H
z, 2Hz), 8.48 (1H, d, J = 2Hz) EI-Mass (m / z,%); 341 (M ⁺ , 100), 326 (13), 298 (78), 2
72 (32) IR (ν, cm ^{- 1} ), KBr; 3390, 3248, 3093, 1610, 1583, 1
304 melting point: 168-172 ° C

Example 62 2-butylamino-4- (1-methyl-2-propenylamino) -6-nitroquinazoline

[0292]

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6-nitroquinazoline-2,4 (1H, 3
To 278 mg (1.45 mmol) of H) -dione, 0.71 ml of 1,3-dimethyl-2-imidazolidinone and 5.48 g (35.76 mmol) of phosphorus oxychloride were added, and the mixture was heated under reflux for 3 hours. After removing phosphorus oxychloride by distillation under reduced pressure, the residue was dissolved in 3 ml of acetonitrile, and 2.81 ml of triethylamine was dissolved.
(20.07 mmol) and 281 mg (2.61 mmol) of 1-methyl-2-propenylamine hydrochloride, and the mixture was added under ice-cooling.
Stirred for hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2-chloro-4- (1-methyl-2-propenylamino) -6-nitroquinazoline. Add 1.00 ml of butylamine (10.12 mm
ol), and the mixture was stirred at room temperature for 3 hours, water was added to the reaction solution, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 73 mg (1%) of the title compound.
7.3%). NMR (δ, CDCl ₃ ); 0.97 (3H, t, J = 8Hz), 1.44 (5H, br),
1.60 (2H, br), 3.49-3.54 (2H, m), 5.01 (1H, br), 5.18
-5.30 (2H, m), 5.51 (1H, br), 5.66 (1H, br), 5.95-6.03
(1H, m), 7.43 (1H, br), 8.29 (1H, dd, J = 9Hz, 2Hz),
8.49 (1H, d, J = 2Hz) EI-Mass (m / z,%); 315 (M ⁺ , 98), 300 (60), 272 (85), 25
8 (100), 246 (34) IR (ν, cm ^{− 1} ), KBr; 3408, 32
55, 2958, 1606, 1540, 130
4 Melting point: 156-158 ° C

Example 63 2-Allylamino-4- (1-methyl-2-propenylamino) -6-nitroquinazoline

[0295]

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6-nitroquinazoline-2,4 (1H, 3
Example 6 from 278 mg (1.45 mmol) of H) -dione
In the same manner as in 2, 2-chloro-4- (1-methyl-2-propenylamino) -6-nitroquinazoline was obtained. After adding 1.00 ml (13.33 mmol) of allylamine thereto at room temperature and stirring for 3 hours at room temperature, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. . After the solvent was distilled off, the residue was purified by a silica gel column to give the title compound (75 mg, 18.7).
%). NMR (δ, CDCl ₃ ); 1.34 (3H, d, J = 7 Hz), 4.17 (2H, br),
5.01 (1H, q, J = 7Hz), 5.15-5.30 (5H, m), 5.65 (1H, br),
5.94-6.03 (2H, m), 7.40 (1H, br), 7.79 (1H, dd, J = 9H
z, 2Hz), 8.51 (1H, d, J = 2Hz) EI-Mass (m / z,%); 299 (M ⁺ , 53), 284 (100), 244 (15), 23
0 (23) IR (ν, cm ^{- 1} ), KBr; 3404, 3246, 3080, 1587, 1535, 1
302 melting point: 172-173 ° C

Example 64 2,4-Bis (1-methyl-2-propenylamino)-
6-nitroquinazoline

[0298]

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6-nitroquinazoline-2,4 (1H, 3
Example 62 from 278 mg (1.45 mmol) of H) -dione
As above, 2-chloro-4- (1-methyl-2-propenylamino) -6-nitroquinazoline was obtained. To this were added 0.30 ml (2.14 mmol) of triethylamine and 87 mg (0.1 mg) of 1-methyl-2-propenylamine hydrochloride.
81 mmol), and the mixture was stirred at 80 ° C. for 12 hours, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (11.9%) of the title compound. NMR (δ, CDCl ₃ ); 1.34-1.36 (3H, m), 1.42-1.46 (3H,
m), 4.82 (1H, br), 4.98-5.30 (5H, m), 5.40 (1H, br),
5.80 (1H, br), 5.91-6.04 (2H, m), 7.34 (1H, br), 8.28
(1H, dd, J = 9Hz, 2Hz), 8.56 (1H, d, J = 2Hz) EI-Mass (m / z,%); 313 (M ⁺ , 56), 298 (100), 258 (16) , 2
44 (35) IR (ν, cm ^{- 1} ), KBr; 3408, 3081, 2975, 1620, 1585, 1
317 Melting point: 122-125 ° C

Example 65 4-Allylamino-2- (1-methyl-2-propenylamino) -6-nitroquinazoline

[0301]

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150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline are dissolved in 2 ml of acetonitrile, and 120 mg (1.12 mmol) of 1-methyl-2-propenylamine hydrochloride and 0.40 ml of triethylamine ( 2.86 mmol) and stirred at 80 ° C. for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate,
After washing with saturated saline, it was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 100 mg (58.9%) of the title compound. NMR (δ, CDCl ₃ ); 1.36 (3H, d, J = 7Hz), 4.26 (2H, br),
4.84 (1H, br), 5.08-5.36 (2H, m), 5.80 (1H, br), 5.91
-6.07 (2H, m), 7.39 (1H, br), 8.30 (1H, dd, J = 9Hz, 2H
z), 8.52 (1H, d, J = 2Hz) EI-Mass (m / z,%); 299 (M ⁺ , 46), 284 (100), 252 (7), 23
8 (36) IR (ν, cm ^{- 1} ), KBr; 3402, 3226, 3082, 1620, 1587, 1
311 Melting point: 123-124 ° C

Test Example Measurement of Oxygen Partial Pressure Elevation Effect The elevation effect of arterial blood oxygen partial pressure by the quinazoline derivative of the present invention was measured by the following method. Spra weighing about 250g
Male gue-Dawley rats were anesthetized with urethane (ip) and cannulated into the respiratory tract, femoral artery and femoral vein. 0.8 ml / kg of olive oil-charcoal powder suspension (10 mg / ml) was injected into the lungs from the tracheal cannula into the hypoxemia state P.
aO ₂ 75 mmHg or less). The quinazoline derivative described in Table 1 was added to the hypoxemia model animal at 0.1 mg / kg /
The solution was continuously administered intravenously for 10 minutes at min and the arterial blood oxygen partial pressure (PaO ₂ ) 10 minutes after the administration was measured by a blood gas analyzer (Ciba Corning 800 series). From the measurement results of PaO ₂ before and after administration of the test compound, the increase value (ΔPaO ₂ ) was determined. Table 1 shows the results.

[0304]

[Table 1]

Reference Example 16 7-Methylthieno [3,2-d] pyrimidine-2,4
(1H, 3H) -dione

[0306]

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To 25.0 g (146 mmol) of methyl 3-amino-4-methylthiophene-2-carboxylate was added 43.5 g (730 mmol) of urea.
Heat for 5 hours. After returning to room temperature, DMF (400 ml) was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration to give 23.0 g of the title compound (yield 9).
3.7%). NMR (δ, DMSO-d ₆ ): 2.20 (3H, s), 7.69 (1H, s), 11.24
(2H, br)

Reference Example 17 2,4-Dichloro-7-methylthieno [3,2-d] pyrimidine

[0309]

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18.0 g of 7-methylthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione (107 g)
163.0 g (1068 mmol) of phosphorus oxychloride
And N, N-dimethylaniline 12.9 g (107 mmol)
Was added and heated under reflux for 3 hours. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration to obtain 16.4 g (yield: 74.8%) of the title compound. NMR (δ, CDCl ₃ ): 2.51 (3H, s),
7.75 (1H, s)

Reference Example 18 4-Allylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine

[0312]

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1.50 g (6.8 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine
l) was dissolved in DMF, and 917 mg of allylamine was added under ice-cooling.
(16.1 mmol) was added dropwise over 5 minutes. Reaction solution at 0 ° C
After stirring for 1 hour, the mixture was returned to room temperature and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and saturated saline in this order,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 8)] to obtain 1.25 g (yield: 76.2%) of the title compound. NMR (δ, CDCl ₃ ): 2.43 (3H, s), 4.28-4.33 (2H, m), 5.0
9 (1H, br), 5.22-5.35 (2H, m), 5.94-6.07 (1H, m), 7.3
6 (1H, s)

Example 66 2,4-Diallylamino-7-methylthieno [3,2-
d] pyrimidine

[0315]

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4-Allylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine 250 mg (1.1 mm
ol) was suspended in 2.28 g (40.0 mmol) of allylamine and heated in a sealed tube at 140 ° C. for 24 hours. 50 ml of water after cooling
And extracted with 50 ml of ethyl acetate × 3. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (4: 1)) to obtain 233 mg (yield: 85.7%) of the title compound. Melting point: 77-80 ° C NMR (δ, CDCl ₃ ): 2.32 (3H, s), 4.09-4.16 (2H, m), 4.2
0-4.25 (2H, m), 4.67 (1H, br), 4.89 (1H, br), 5.08-5.
30 (4H, m), 5.93-6.06 (2H, m), 7.17 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3460, 3072, 1564, 1518, 1494 EI-Mass (m / z, %): 261 (M ⁺ +1, 10), 260 (M ⁺ , 57), 245 (8
Five)

Reference Example 19 2-Chloro-7-methyl-4-neopentylaminothieno [3,2-d] pyrimidine

[0318]

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300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
Dissolve in 3 ml of MF and 179 mg of neopentylamine (2.
1 mmol) and stirred for 3 hours. Add water to the reaction solution,
The precipitated crystals were collected by filtration and 355 mg of the title compound (yield 9).
6.1%). NMR (δ, CDCl ₃ ): 1.02 (H, s), 2.43 (3H, s), 3.51 (2H,
d, J = 6Hz), 7.36 (1H, s)

Reference Example 20 4-t-butylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine

[0321]

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300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
Dissolve in 3 ml of MF and add 150 mg of t-butylamine (2.1
mmol) and stirred for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to give 327 mg of the title compound (yield 93.
4%). NMR (δ, CDCl ₃ ): 1.57 (9H, s), 2.41 (3H, s), 4.72 (1H,
br), 7.29 (1H, s)

Reference Example 21 4-benzylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine

[0324]

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300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
Dissolved in 3 ml of MF, 220 mg of benzylamine (2.1 mm
ol) and stirred for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to give 375 mg of the title compound (yield 94.5).
%). NMR (δ, CDCl ₃ ): 2.43 (3H, s), 4.86 (2H, d, J = 6Hz),
5.21 (1H, br), 7.33-7.41 (5H, m)

Reference Example 22 2-chloro-4-cyclohexylamino-7-methylthieno [3,2-d] pyrimidine

[0327]

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300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
Dissolve in 3 ml of MF and add cyclohexylamine 204 mg
(2.1 mmol) and stirred for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 379 mg (yield 98.2%) of the title compound. NMR (δ, CDCl ₃ ): 1.20-2.14 (10H, m), 2.42 (3H, s), 4.
13-4.22 (1H, m), 4.88 (1H, br), 7.34 (1H, s)

Example 67 2-Allylamino-7-methyl-4-neopentylaminothieno [3,2-d] pyrimidine

[0330]

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2-Chloro-7-methyl-4-neopentylaminothieno [3,2-d] pyrimidine 250 mg
(0.9 mmol) in 2.28 g of allylamine (40.0 mm
ol) and heated in a sealed tube at 140 ° C. for 24 hours. After cooling, water (100 ml) was added, and the mixture was extracted with ethyl acetate (20 ml × 3). The organic layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 165 mg (yield 61.3%) of the title compound. Melting point: 90-92 ° C NMR (δ, CDCl ₃ ): 0.98 (9H, s), 2.32 (3H, s), 3.44 (2H,
d, J = 6Hz), 4.09-4.14 (2H, m), 4.63 (1H, br), 4.87 (1
H, br), 5.09-5.13 (1H, m), 5.24-5.30 (1H, m), 5.96-
6.05 (1H, m), 7.17 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3440, 2960, 1564, 1530, 1466, 7
94 EI-Mass (m / z,%): 291 (M ⁺ +1, 11), 290 (M ⁺ , 58), 275 (1
00)

Example 68 2-Allylamino-4-t-butylamino-7-methylthieno [3,2-d] pyrimidine

[0333]

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4-tert-butylamino-2-chloro-7-
250 mg of methylthieno [3,2-d] pyrimidine (1.
0 mmol) was dissolved in 2.28 g (40.0 mmol) of allylamine and heated in a sealed tube at 140 ° C. for 24 hours. Water 1 after cooling
After adding 00 ml, the mixture was extracted with 20 ml of ethyl acetate × 3. The organic layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography [developing solvent: ethyl acetate-hexane (1:
4)] to give 247 mg of the title compound (yield 91.
5%). Melting point: 89-90 ° C NMR (δ, CDCl ₃ ): 1.54 (9H, s), 2.30 (3H, s), 4.09-4.1
4 (2H, m), 4.40 (1H, br), 4.90 (1H, br), 5.08-5.12 (1
H, m), 5.22-5.30 (1H, m), 5.94-6.07 (1H, m), 7.12 (1H,
s) IR (ν, cm ^{- 1} ), KBr: 3448, 3236, 2976, 1588, 1514, 1
484, 1456, 796 EI-Mass (m / z,%): 277 (M ⁺ +1, 16), 276 (M ⁺ , 75), 261 (6
7), 219 (36), 205 (100)

Example 69 2-Allylamino-4-benzylamino-7-methylthieno [3,2-d] pyrimidine

[0336]

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4-Benzylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine 250 mg (0.9 mg)
mmol) was dissolved in 2.28 g (40.0 mmol) of allylamine and heated in a sealed tube at 140 ° C. for 24 hours. Water 10 after cooling
After adding 0 ml, the mixture was extracted with 20 ml of ethyl acetate × 3. The organic layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography [developing solvent: ethyl acetate-hexane (1:
4)] to give 217 mg of the title compound (yield 81.
3%). Melting point: 97-98 ° C NMR (δ, CDCl ₃ ); 2.33 (3H, s), 4.09-4.14 (2H, m), 4.8
0 (2H, d, J = 6Hz), 4.89-4.91 (2H, m), 5.07-5.11 (1H,
m), 5.22-5.29 (1H, m), 5.92-6.03 (1H, m), 7.17 (1H,
s), 7.27-7.40 (5H, m) IR (ν, cm ^{- 1} ), KBr: 3456, 1580, 1518, 1452, 704 EI-Mass (m / z,%): 311 (M ⁺ +1, 17 ), 310 (M ⁺ , 81), 296 (1
00)

Example 70 2-Allylamino-4-cyclohexylamino-7-methylthieno [3,2-d] pyrimidine hydrochloride

[0339]

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2-Chloro-4-cyclohexylamino-
7-methylthieno [3,2-d] pyrimidine 250 mg
(0.9 mmol) in 2.28 g of allylamine (40.0 mm
ol) and heated in a sealed tube at 140 ° C. for 24 hours. After cooling, water (100 ml) was added, and the mixture was extracted with ethyl acetate (20 ml × 3). The organic layer was washed with 20 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and hexane: ethyl acetate =
The 4: 1 eluate was concentrated, and 4N hydrochloric acid in ethyl acetate solution (1 m
l) was added, and the precipitated crystals were collected by filtration to give 200 m of the title compound.
g (66.7% yield). Melting point: 140-142 ° C NMR (δ, CDCl ₃ ); 1.21-2.11 (10H, m), 2.51 (3H, s), 4.
09-4.17 (3H, m), 5.17-5.20 (1H, m), 5.31-5.36 (1H,
m), 5.62-5.64 (1H, m), 5.84-5.97 (1H, m), 7.31 (1H,
s), 8.57 (1H, br), 14.08 (1H, br) IR (ν, cm ^{- 1} ), KBr: 2940, 1634, 1602, 1568, 1362, 7
86 EI-Mass (m / z,%): 303 (M ⁺ +1, 15), 302 (M ⁺ , 69), 287 (1
00)

Reference Example 23 4-Diallylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine

[0342]

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Dissolve 1.50 g (6.8 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in DMF and add 1.56 g of diallylamine under ice-cooling.
(16.1 mmol) was added dropwise over 5 minutes. Reaction solution at 0 ° C
After stirring for 1 hour, the mixture was returned to room temperature and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and saturated saline in this order,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:15)] to give 1.17 g (yield 61.1%) of the title compound. NMR (δ, CDCl ₃ ): 2.41 (3H, s), 4.38 (4H, d, J = 5 Hz),
5.19-5.26 (4H, m), 5.87-6.00 (2H, m), 7.38 (1H, s)

Example 71 2-Allylamino-4-diallylamino-7-methylthieno [3,2-d] pyrimidine hydrochloride

[0345]

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335 mg of 4-diallylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine (1.2 mg)
mmol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
277 mg of the free base compound of the title compound (yield 77.0)
%). NMR (δ, CDCl ₃ ): 2.31 (3H, s), 4.07-4.11 (2H, m), 4.3
2 (4H, d, J = 5Hz), 4.88 (1H, br), 5.08-5.28 (6H, m),
5.88-6.04 (3H, m), 7.20 (1H, d, J = 1Hz)

Under ice-cooling, 4N hydrochloric acid ethyl acetate solution (1 ml)
Was added dropwise to a solution of the above-mentioned free base compound (277 mg) in ethyl acetate. The precipitated crystals were collected by filtration to obtain 270 mg of the title compound. Melting point: 76-78 ° C (decomposition) NMR (δ, CDCl ₃ ): 2.53 (3H, s), 4.06-4.11 (2H, m), 4.3
8 (4H, d, J = 5Hz), 5.15-5.36 (6H, m), 5.84-5.97 (3H,
m), 7.40 (1H, s), 8.69 (1H, br), 14.22 (1H, br) IR (ν, cm ^{- 1} ), KBr: 2923, 2856, 1631, 1536, 926, 74
6 EI-Mass (m / z,%): 301 (M ⁺ +1, 14), 300 (M ⁺ , 66), 285 (3
6), 259 (100), 217 (41)

Example 72 4-Allylamino-2-diallylamino-7-methylthieno [3,2-d] pyrimidine hydrochloride

[0349]

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287 mg of 4-allylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine (1.2 mm
ol) and 1.87 g (19.2 mmol) of diallylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane 1: 4) to give 193 mg (yield 53.7%) of the free base compound of the title compound.
I got NMR (δ, CDCl ₃ ): 2.31 (3H, s), 4.18-4.23 (2H, m), 4.2
9 (4H, d, J = 6Hz), 4.59 (1H, br), 5.09-5.29 (6H, m),
5.86-6.06 (3H, m), 7.14 (1H, s)

Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution (1 m
l) was added dropwise to a solution of 193 mg of the above free base compound in ethyl acetate. The precipitated crystals were collected by filtration to give the title compound 193.
mg was obtained. Melting point: 136-138 ° C (decomposition) NMR (δ, CDCl ₃ ): 2.54 (3H, s), 4.12 (2H, br), 4.53 (4
H, br), 5.16-5.42 (6H, m), 5.81-6.02 (3H, m), 7.40 (1
H, br), 9.03 (1H, br), 11.48 (1H, br) IR (ν, cm ^{- 1} ), KBr: 3330, 3080, 1610, 1581, 1382, 9
95, 937 EI-Mass (m / z,%): 301 (M ⁺ +1, 13), 300 (M ⁺ , 63), 285 (3
3), 259 (100)

Reference Example 24 2-chloro-4- (1,3-dihydroxypropane-2)
-Yl) amino-7-methylthieno [3,2-d] pyrimidine

[0353]

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1.0 g (4.6 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
After dissolving in 8 ml of MF, 977 mg (10.7 mmol) of 2-amino-1,3-propanediol was added dropwise over 5 minutes under ice cooling. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 2)) to obtain 903 mg (yield: 72.3%) of the title compound. NMR (δ, DMSO-d ₆ ): 2.28 (3H, s), 3.52-3.61 (4H, m),
4.26-4.34 (1H, m), 4.73 (2H, t, J = 6Hz), 7.80 (1H, s),
7.90 (1H, d, J = 8Hz)

Example 73 2-Allylamino-4- (1,3-dihydroxypropan-2-yl) amino-7-methylthieno [3,2-
d] pyrimidine

[0356]

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2-Chloro-4- (1,3-dihydroxypropan-2-yl) amino-7-methylthieno [3,
328 mg (1.2 mmol) of 2-d] pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 1)] to give 293 mg of the title compound.
(83.2% yield). Melting point: 163-164 ° C NMR (δ, DMSO-d ₆ ): 2.18 (3H, s), 3.57 (4H, dd, J = 5 Hz,
5Hz), 3.93 (2H, br), 4.20-4.27 (1H, m), 4.63 (2H, dd,
J = 5Hz, 5Hz), 5.01 (1H, d, J = 10Hz), 5.17 (1H, d, J = 1
7Hz), 5.86-5.99 (1H, m), 6.48 (1H, br), 6.69 (1H, d,
J = 8Hz), 7.47 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3401, 1604, 1565, 1527, 1049, 7
87 EI-Mass (m / z,%): 295 (M ⁺ +1, 10), 294 (M ⁺ , 52), 279 (6
1), 263 (40), 205 (41), 66 (100)

Example 74 2-Diallylamino-4-cyclohexylamino-7-
Methylthieno [3,2-d] pyrimidine

[0359]

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2-chloro-4-cyclohexylamino-
338 mg of 7-methylthieno [3,2-d] pyrimidine
(1.2 mmol) and 1.87 g of diallylamine (19.2)
mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 2)] to give 298 mg (yield: 72.7%) of the title compound. NMR (δ, CDCl ₃ ): 1.19-1.47 (4H, m), 1.63-1.81 (4H,
m), 2.09-2.13 (2H, m), 2.30 (3H, s), 4.01-4.12 (1H,
m), 4.28 (4H, d, J = 6Hz), 4.38-4.41 (1H, m), 5.09-5.2
1 (4H, m), 5.86-5.99 (2H, m), 7.12 (1H, s) IR (ν, cm ^{- 1} ), film: 3425, 2931, 2854, 1574, 1527,
1496, 1265, 756 EI-Mass (m / z,%): 343 (M ⁺ +1, 13), 342 (M ⁺ , 56), 327 (3
1), 301 (100), 219 (58)

Reference Example 25 2-chloro-4- (4-methylpiperidino) -7-methylthieno [3,2-d] pyrimidine

[0362]

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To a solution of 1.0 g (4.6 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
After dissolving in 10 ml of MF, 1.06 g (10.7 mmol) of 4-methylpiperidine was added dropwise over 5 minutes under ice cooling. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 1.20 g (yield 93.3%) of the title compound. NMR (δ, CDCl ₃ ): 0.99 (3H, d, J = 6 Hz), 1.21-1.30 (2H,
m), 1.70-1.84 (3H, m), 2.41 (3H, s), 3.07-3.16 (2H,
m), 4.75-4.81 (2H, m), 7.36 (1H, s)

Example 75 2-Allylamino-4- (4-methylpiperidino) -7
-Methylthieno [3,2-d] pyrimidine

[0365]

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2-chloro-4- (4-methylpiperidino) -7-methylthieno [3,2-d] pyrimidine 42
2 mg (1.5 mmol) and 1.37 g of diallylamine (2
(4.0 mmol) was heated in a sealed tube at 160 ° C. for 16 hours.
After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 6)) to obtain 198 mg (yield 43.9%) of the title compound. NMR (δ, CDCl ₃ ): 0.96 (3H, d, J = 6 Hz), 1.18-1.31 (2H,
m), 1.62-1.77 (3H, m), 2.31 (3H, s), 2.97-3.06 (2H,
m), 4.08-4.12 (2H, m), 4.70-4.75 (2H, m), 4.81 (1H, b
r), 5.07-5.12 (1H, m), 5.22-5.29 (1H, m), 5.94-6.07
(1H, m), 7.19 (1H, s) IR (ν, cm ^{- 1} ), film: 2947, 2923, 1550, 1520, 1450,
756 EI-Mass (m / z,%): 303 (M ⁺ +1, 11), 302 (M ⁺ , 55), 287 (1
00)

Reference Example 26 2-Chloro-4-ethylamino-7-methylthieno [3,2-d] pyrimidine

[0368]

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700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
MF, and 338 mg (7.5 mg) of ethylamine under ice-cooling.
(mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and saturated saline in this order,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 6)] to obtain 524 mg (yield: 72.0%) of the title compound. NMR (δ, CDCl ₃ ): 1.34 (3H, t, J = 7 Hz), 2.42 (3H, s),
3.68-3.74 (2H, m), 4.97 (1H, br), 7.35 (1H, s)

Example 76 2-Allylamino-4-ethylamino-7-methylthieno [3,2-d] pyrimidine

[0371]

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273 mg (1.2 mm) of 2-chloro-4-ethylamino-7-methylthieno [3,2-d] pyrimidine
ol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 2)).
191 mg (yield 64.3%) of the title compound were obtained. Melting point: 96-97 ° C NMR (δ, CDCl ₃ ): 1.29 (3H, t, J = 7 Hz), 2.32 (3H, s),
3.58-3.65 (2H, m), 4.11-4.15 (2H, m), 4.57 (1H, br),
4.87 (1H, br), 5.09-5.12 (1H, m), 5.24-5.30 (1H, m),
5.96-6.06 (1H, m), 7.15 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3433, 2970, 1597, 1566, 1519, 1
349, 795 EI-Mass (m / z,%): 249 (M ⁺ +1, 9), 248 (M ⁺ , 52), 233 (10
0)

Reference Example 27 2-chloro-4-isopropylamino-7-methylthieno [3,2-d] pyrimidine

[0374]

Embedded image

700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
Dissolve in MF and add 443 mg of isopropylamine under ice-cooling
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 6)).
636 mg (82.4% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ): 1.33 (6H, d, J = 6 Hz), 2.42 (3H, s),
4.49-4.57 (1H, m), 4.81 (1H, br), 7.34 (1H, s)

Example 77 2-Allylamino-4-isopropylamino-7-methylthieno [3,2-d] pyrimidine

[0377]

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2-chloro-4-isopropylamino-7
-Methylthieno [3,2-d] pyrimidine 290 mg
(1.2 mmol) and allylamine 1.10 g (19.2 mm
ol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 244 mg (yield: 77.7%) of the title compound. Melting point: 106-107 ° C. NMR (δ, CDCl ₃ ): 1.29 (6H, d, J = 6 Hz), 2.32 (3H, s),
4.10-4.14 (2H, m), 4.40-4.48 (2H, m), 4.86-4.88 (1H,
m), 5.08-5.12 (1H, m), 5.24-5.29 (1H, m), 5.96-6.05
(1H, m), 7.15 (1H, s) IR (ν, cm ^-1 ), KBr: 3425, 3232, 2970, 1589, 1565, 1
519, 1465, 918, 795 EI-Mass (m / z,%): 263 (M ⁺ +1, 14), 262 (M ⁺ , 78), 247 (1
00), 205 (51)

Reference Example 28 2-Chloro-4-cyclopropylamino-7-methylthieno [3,2-d] pyrimidine

[0380]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and add 428 mg of cyclopropylamine under ice-cooling
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 6)).
780 mg (95.4% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ): 0.76-0.80 (2H, m), 0.95-1.04 (2H,
m), 2.42 (3H, s), 3.02-3.08 (1H, m), 5.68 (1H, br),
7.47 (1H, s)

Example 78 2-Allylamino-4-cyclopropylamino-7-methylthieno [3,2-d] pyrimidine

[0383]

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2-chloro-4-cyclopropylamino-
287 mg of 7-methylthieno [3,2-d] pyrimidine
(1.2 mmol) and allylamine 1.10 g (19.2 mm
ol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 265 mg (yield 84.9%) of the title compound. NMR (δ, CDCl ₃ ): 0.70-0.73 (2H, m), 0.88-0.92 (2H,
m), 2.32 (3H, s), 2.95-2.96 (1H, m), 4.10-4.13 (2H,
m), 4.82 (1H, br), 5.09-5.12 (2H, m), 5.24-5.29 (1H,
m), 5.94-6.05 (1H, m), 7.24 (1H, s) IR (ν, cm ^{- 1} ), film: 3263, 1565, 1511, 1349, 756 EI-Mass (m / z,%): 261 (M ⁺ +1, 14), 260 (M ⁺ , 77), 245 (1
00)

Reference Example 29 4- (1-Adamantylamino) -2-chloro-7-methylthieno [3,2-d] pyrimidine

[0386]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolved in MF and cooled to 1-adamantanamine 1.1 under ice-cooling.
An aqueous solution of 3 g (7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 1.10 g (yield 100%) of the title compound. NMR (δ, CDCl ₃ ): 1.67-1.78 (7H, m), 2.08-2.23 (8H,
m), 2.40 (3H, s), 4.61 (1H, br), 7.38 (1H, s)

Example 79 4- (1-adamantylamino) -2-allylamino-
7-methylthieno [3,2-d] pyrimidine

[0389]

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4- (1-adamantylamino) -2-chloro-7-methylthieno [3,2-d] pyrimidine 40
0 mg (1.2 mmol) and 1.10 g of allylamine (19.
(2 mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 292 mg (yield: 68.7%) of the title compound. Melting point: 107-109 ° C NMR (δ, CDCl ₃ ): 1.63 (2H, brs), 1.71-1.73 (5H, m),
2.13 (3H, br), 2.22-2.23 (5H, m), 2.30 (3H, s), 4.09-
4.13 (2H, m), 4.30 (1H, br), 4.88 (1H, br), 5.09-5.13
(1H, m), 5.23-5.29 (1H, m), 5.97-6.06 (1H, m), 7.11
(1H, s) IR (ν, cm ^{- 1} ), KBr: 3248, 2908, 2854, 1581, 1519, 1
450, 1357, 795 EI-Mass (m / z,%): 355 (M ⁺ +1, 15), 354 (M ⁺ , 58), 339 (1
00), 205 (16)

Reference Example 30 2-chloro-4-nonylamino-7-methylthieno [3,2-d] pyrimidine

[0392]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and add 1.07 g of n-nonylamine under ice-cooling
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 1.10 g (yield 100%) of the title compound. NMR (δ, CDCl ₃ ): 0.88 (3H, t, J = 7 Hz), 1.24-1.45 (12H,
m), 1.65-1.72 (2H, m), 2.42 (3H, s), 3.63-3.68 (2H,
m), 4.98 (1H, br), 7.35 (1H, s)

Example 80 2-Allylamino-4-nonylamino-7-methylthieno [3,2-d] pyrimidine

[0395]

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391 mg (1.2 mm) of 2-chloro-4-nonylamino-7-methylthieno [3,2-d] pyrimidine
ol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to obtain 238 mg (yield: 57.2%) of the title compound. Melting point: 65-66 ° C NMR (δ, CDCl ₃ ): 0.88 (3H, t, J = 7 Hz), 1.27-1.40 (12H,
m), 1.61-1.68 (2H, m), 2.32 (3H, s), 3.54-3.59 (2H,
m), 4.11-4.14 (2H, m), 4.59 (1H, br), 4.86 (1H, br),
5.08-5.12 (1H, m), 5.24-5.29 (1H, m), 5.96-6.05 (1H,
m), 7.15 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3421, 2924, 2856, 1597, 1571, 1
522, 1462, 791 EI-Mass (m / z,%): 347 (M ⁺ +1, 16), 346 (M ⁺ , 66), 331 (1
00), 205 (22)

Reference Example 31 4-butylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine

[0398]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
MF and 548 mg (7.5 mg) of butylamine under ice-cooling.
(mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and saturated saline in this order,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 698 mg (yield 85.4%) of the title compound. NMR (δ, CDCl ₃ ): 0.98 (3H, t, J = 7.3 Hz), 1.41-1.50 (2
H, m), 1.64-1.72 (2H, m), 2.42 (3H, s), 3.64-3.69 (2H,
m), 4.99 (1H, br), 7.35 (1H, s)

Example 81 2-Allylamino-4-butylamino-7-methylthieno [3,2-d] pyrimidine

[0401]

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307 mg (1.2 mm) of 4-butylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine
ol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 8)).
245 mg (73.8% yield) of the title compound were obtained. Melting point: 68-70 ° C NMR (δ, CDCl ₃ ): 0.96 (3H, t, J = 7.3 Hz), 1.38-1.47 (2
H, m), 1.60-1.72 (2H, m), 2.32 (3H, s), 3.55-3.60 (2H,
m), 4.11-4.14 (2H, m), 4.59 (1H, br), 4.85-4.87 (1H,
m), 5.09-5.12 (1H, m), 5.24-5.29 (1H, m), 5.96-6.05
(1H, m), 7.15 (1H, s) IR (ν, cm ^-1 ), KBr: 3448, 2928, 1594, 1564, 1528, 1
466, 1348, 1284, 790 EI-Mass (m / z,%): 277 (M ⁺ +1, 13), 276 (M ⁺ , 68), 261 (1
00), 205 (19)

Reference Example 32 2-Chloro-7-methyl-4-pentylaminothieno [3,2-d] pyrimidine

[0404]

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[0405] 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was dissolved in DMF, and 654 mg of pentylamine was dissolved under ice-cooling.
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 788 mg (yield 91.4%) of the title compound. NMR (δ, CDCl ₃ ): 0.91-0.95 (3H, m), 1.36-1.42 (4H, m),
1.66-1.73 (2H, m), 2.42 (3H, s), 3.63-3.68 (2H, m),
4.98 (1H, br), 7.35 (1H, s)

Example 82 2-Allylamino-7-methyl-4-pentylaminothieno [3,2-d] pyrimidine

[0407]

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391 mg of 2-chloro-7-methyl-4-pentylaminothieno [3,2-d] pyrimidine (1.2 mg)
mmol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 8)).
184 mg (yield 52.9%) of the title compound were obtained. Melting point: 64-65 ° C NMR (δ, CDCl ₃ ): 0.92 (3H, t, J = 7.1 Hz), 1.36-1.40 (4
H, m), 1.62-1.69 (2H, m), 2.32 (3H, s), 3.54-3.59 (2H,
m), 4.11-4.14 (2H, m), 4.60 (1H, br), 4.86 (1H, br),
5.09-5.12 (1H, m), 5. 24-5.29 (1H, m), 5.96-6.05 (1
H, m), 7.15 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3452, 2928, 1590, 1564, 1520, 1
464, 1382, 1284, 792 EI-Mass (m / z,%): 291 (M ⁺ +1, 12), 290 (M ⁺ , 64), 275 (1
00), 205 (17)

Reference Example 33 2-Chloro-4-heptylamino-7-methylthieno [3,2-d] pyrimidine

[0410]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and add 1.07 g of heptylamine under ice-cooling
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 8)).
1.00 g (100% yield) of the title compound was obtained. NMR (δ, CDCl ₃ ): 0.89 (3H, t, J = 6.8Hz), 1.28-1.45 (8
H, m), 1.65-1.73 (2H, m), 2.42 (3H, s), 3.63-3.68 (2H,
m), 5.01 (1H, br), 7.35 (1H, s)

Example 83 2-Allylamino-4-heptylamino-7-methylthieno [3,2-d] pyrimidine

[0413]

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2-Chloro-4-heptylamino-7-methylthieno [3,2-d] pyrimidine 82 mg (1.2 mm
ol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 261 mg (yield: 68.3%) of the title compound. Melting point: 56-57 ° C. NMR (δ, CDCl ₃ ): 0.89 (3H, t, J = 6.9 Hz), 1.28-1.42 (8
H, m), 1.61-1.68 (2H, m), 2.32 (3H, s), 3.54-3.59 (2H,
m), 4.11-4.14 (2H, m), 4.62 (1H, br), 4.87 (1H, br),
5.08-5.12 (1H, m), 5.24-5.29 (1H, m), 5.95-6.05 (1H,
m), 7.15 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3460, 2920, 1592, 1564, 1526, 1
468, 1354, 834 EI-Mass (m / z,%): 319 (M ⁺ +1, 14), 318 (M ⁺ , 67), 303 (1
00), 205 (17)

Reference Example 34 2-Chloro-7-methyl-4- (1-methylpropylamino) thieno [3,2-d] pyrimidine

[0416]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and add 1-methylpropylamine under ice-cooling.
An aqueous solution of 07 g (7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added and ethyl acetate 50 ml was added.
Extracted three times. The organic layer was washed with 1N hydrochloric acid, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 8)] to give 676 mg (yield: 82.7%) of the title compound. NMR (δ, CDCl ₃ ): 0.99 (3H, t, J = 7.4 Hz), 1.29 (3H, d,
J = 6.6Hz), 1.61-1.68 (2H, m), 2.42 (3H, s), 4.33-4.40
(1H, m), 4.77 (1H, br), 7.35 (1H, s)

Example 84 2-Allylamino-7-methyl-4- (1-methylpropylamino) thieno [3,2-d] pyrimidine

[0419]

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2-Chloro-7-methyl-4- (1-methylpropylamino) thieno [3,2-d] pyrimidine 3
07 mg (1.2 mmol) and allylamine 1.10 g (1
(9.2 mmol) was heated in a sealed tube at 160 ° C. for 16 hours.
After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel chromatography [developing solvent: ethyl acetate-hexane (1:10)].
266 mg (yield 80.1%) of the title compound
I got Melting point: 91-92 ° C NMR (δ, CDCl ₃ ): 0.96 (3H, t, J = 7.4 Hz), 1.25 (3H, d,
J = 6.4Hz), 1.54-1.68 (2H, m), 2.32 (3H, s), 4.09-4.13
(2H, m), 4.24-4.31 (1H, m), 4.36-4.38 (1H, m), 4.84-
4.86 (1H, m), 5.08-5.12 (1H, m), 5.23-5.29 (1H, m),
5.95-6.05 (1H, m), 7.15 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3448, 1588, 1564, 1514, 1466, 1
372, 1278, 840 EI-Mass (m / z,%): 277 (M ⁺ +1, 13), 276 (M ⁺ , 68), 261 (1
00), 247 (25), 219 (13), 205 (38)

Example 85 4-Allylamino-2- (2-methoxyethylamino)
-7-methylthieno [3,2-d] pyrimidine

[0422]

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287 mg of 4-allylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine (1.2 mm
ol) and 1.44 g of 2-methoxyethylamine (19.2).
mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 274 mg (yield: 82.3%) of the title compound. Melting point: 87-88 ° C NMR (δ, CDCl ₃ ); 2.32 (3H, s), 3.39 (3H, s), 3.57-3.6
0 (2H, m), 3.65-3.70 (2H, m), 4.20-4.24 (2H, m), 4.66
(1H, br), 5.15-5.30 (3H, m), 5.93-6.08 (1H, m), 7.16
(1H, s) IR (ν, cm ^{- 1} ), KBr; 3417, 2924, 1589, 1558, 1519, 1
457, 1342, 1103, 794 EI -Mass (m / z,%); 279 (M + +
1, 5), 278 (M ⁺ , 26), 263 (1
7), 2.33 (100), 220 (47), 2
05 (29)

Example 86 4-Allylamino-7-methyl-2-propylaminothieno [3,2-d] pyrimidine

[0425]

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288 mg of 4-allylamino-2-chloro-7-methylthieno [3,2-d] pyrimidine (1.2 mg)
mmol) and 1.13 g (19.2 mmol) of propylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 2)).
126 mg (40.0% yield) of the title compound were obtained. Melting point: 74-75 ° C NMR (δ, CDCl ₃ ); 0.99 (3H, t, J = 7.5 Hz), 1.59-1.68 (2
H, m), 2.32 (3H, s), 3.40-3.45 (2H, m), 4.21-4.25 (2
H, m), 4.65 (1H, br), 4.85 (1H, br), 5.15-5.19 (1H,
m), 5.25-5.30 (1H, m), 5.95-6.05 (1H, m), 7.16 (1H,
s) IR (ν, cm ^{- 1} ), KBr; 3448, 1596, 1566, 1528, 1464, 8
38 EI-Mass (m / z,%); 263 (M ⁺ +1, 14), 262 (M ⁺ , 85), 247 (4
3), 233 (100), 205 (71)

Reference Example 35 2-Chloro-7-methyl-4-piperidinoaminothieno [3,2-d] pyrimidine

[0428]

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To a solution of 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and cool under ice-cooling to 1-aminopiperidine 751 mg
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and ethyl acetate (50 ml) was added.
Extracted times. . The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 8)) to obtain 573 mg (yield: 59.4%) of the title compound. NMR (δ, CDCl ₃ ); 1.20-1.28 (1H, m), 1.76-1.91 (5H,
m), 2.41 (3H, s), 2.44-2.49 (2H, m), 3.17-3.20 (2H,
m), 6.46 (1H, s), 7.46 (1H, s)

Example 87 2-Allylamino-7-methyl-4-piperidinoaminothieno [3,2-d] pyrimidine

[0431]

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339 mg of 2-chloro-7-methyl-4-piperidinoaminothieno [3,2-d] pyrimidine (1.
2 mmol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 2)).
233 mg (64.0% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ); 1.20 (1H, br), 1.73-1.84 (5H, m), 2.
31 (3H, s), 2.37 (2H, br), 3.19 (2H, br), 4.08-4.11 (2
H, m), 4.74-4.76 (1H, m), 5.08-5.12 (1H, m), 5.23-5.2
9 (1H, m), 5.86 (1H, s), 5.94-6.04 (1H, m), 7.27 (1H,
s) IR (ν, cm ^{- 1} ), KBr; 3292, 2944, 1568, 1504, 1446, 7
98 EI-Mass (m / z,%); 304 (M ⁺ +1, 10), 303 (M ⁺ , 56), 220 (6
2), 205 (100)

Reference Example 36 2-Chloro-7-methyl-4- (2,2-dimethylhydrazino) thieno [3,2-d] pyrimidine

[0434]

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To a solution of 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and add 1,1-dimethylhydrazine 4 under ice-cooling.
An aqueous solution of 50 mg (7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added and ethyl acetate (50 m
Extracted three times in l). . The organic layer was washed with a 1N aqueous hydrochloric acid solution, water, and saturated saline in this order, dried over anhydrous sodium sulfate, and then dried.
The solvent was distilled off under reduced pressure. Silica gel chromatography of the residue [developing solvent: ethyl acetate-hexane (1: 4)]
173 mg (yield 20.9%) of the title compound
I got NMR (δ, CDCl ₃ ); 2.41 (3H, s), 2.68 (6H, s), 6.34 (1H,
br), 7.47 (1H, s)

Example 88 2-Allylamino-7-methyl-4- (2,2-dimethylhydrazino) thieno [3,2-d] pyrimidine

[0437]

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2-Chloro-7-methyl-4- (2,2-
Dimethylhydrazino) thieno [3,2-d] pyrimidine 150 mg (0.62 mmol) and allylamine 564 mg
(9.89 mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [eluent: ethyl acetate-hexane (1:
2)] to give 151 mg of the title compound (yield 92.0%).
6%). NMR (δ, CDCl ₃ ); 2.31 (3H, s), 2.64 (6H, s), 4.07-4.1
1 (2H, m), 4.78 (1H, br), 5.09-5.12 (1H, m), 5.23-5.2
9 (1H, m), 5.76 (1H, br), 5.94-6.03 (1H, m), 7.29 (1H,
s) IR (ν, cm ^{- 1} ), KBr; 3276, 1574, 1506, 1450, 800 EI-Mass (m / z,%); 264 (M ⁺ +1, 9), 263 (M ⁺ , 58) , 220 (3
6), 205 (100)

Reference Example 37 4- (2-t-butylhydrazino) -2-chloro-7-
Methylthieno [3,2-d] pyrimidine

[0440]

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Under ice cooling, t-butylhydrazine hydrochloride 24
9 mg (2.0 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine 438 mg (2.0 mmol)
And 445 mg (4.4 mmol) of triethylamine in DMF6
ml solution. After stirring at the same temperature for 1 hour, the temperature was returned to room temperature, and the mixture was further stirred for 16 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 2)] to give 314 mg (yield: 58.0%) of the title compound. NMR (δ, CDCl ₃ ); 1.18 (9H, s), 2.41 (3H, s), 3.62 (1H,
br), 7.00 (1H, br), 7.46 (1H, s)

Example 89 2-Allylamino-4- (2-t-butylhydrazino)
-7-methylthieno [3,2-d] pyrimidine

[0443]

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4- (2-t-butylhydrazino) -2-
Chloro-7-methylthieno [3,2-d] pyrimidine 2
70 mg (1.0 mmol) and allylamine 914 mg (16.
(0 mmol) was heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 92 mg (yield 31.6%) of the title compound. Melting point: 105-107 ° C NMR (δ, CDCl ₃ ); 1.17 (9H, s), 2.30 (3H, s) 3.52 (1H,
br), 4.09-4.13 (2H, m), 4.76 (1H, br), 5.09-5.13 (1H,
m), 5.24-5.29 (1H, m), 5.95-6.05 (1H, m), 6.39 (1H,
br), 7.27 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3232, 1577, 1539, 1385 EI-Mass (m / z,%); 292 (M ⁺ +1, 11), 291 ( M ⁺ , 48), 276 (1
00), 205 (30)

Example 90 2-Allylamino-7-methyl-4-pivaloylaminothieno [3,2-d] pyrimidine

[0446]

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2-Allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine 150 mg (0.68
mmol) and 83 mg (0.82 mmol) of triethylamine in a dichloromethane solution.
(68 mmol) and heated under reflux for 1 hour. After the reaction,
The solvent was distilled off under reduced pressure. Silica gel chromatography of the residue [developing solvent: ethyl acetate-hexane (1: 4)]
To give 90 mg (yield 43.5%) of the title compound. Melting point: 88-89 ° C NMR (δ, CDCl ₃ ); 1.36 (9H, s), 2.32 (3H, s), 4.12-4.1
5 (2H, m), 4.98 (1H, br), 5.12-5.16 (1H, m), 5.25-5.3
1 (1H, m), 5.94-6.04 (1H, m), 7.43 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3336, 2972, 1694, 1582, 1564, 1
480, 802 EI-Mass (m / z,%); 305 (M ⁺ +1, 17), 304 (M ⁺ , 92), 289 (1
00), 219 (27), 205 (53)

Example 91 2-Allylamino-4- (t-butylcarbamoyl) amino-7-methylthieno [3,2-d] pyrimidine

[0449]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile, and the mixture was stirred for 20 minutes. The reaction solution was added with 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine 220
mg (1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Further t
-Butylamine (102 mg, 1.4 mmol) was added, and the mixture was heated under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 2)] to give 161 mg (yield: 50.5%) of the title compound. NMR (δ, CDCl ₃ ); 1.47 (9H, s), 2.32 (3H, s), 4.07-4.1
1 (2H, m), 5.00 (1H, br), 5.16-5.20 (1H, m), 5.27-5.3
3 (1H, m), 5.95-6.05 (1H, m), 6.99 (1H, br), 7.33 (1H,
s), 9.24 (1H, br)

Example 92 2-Allylamino-4- (t-butylcarbamoyl) amino-7-methylthieno [3,2-d] pyrimidine hydrochloride

[0452]

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Under ice-cooling, add 4N hydrochloric acid-ethyl acetate solution to 2-
Allylamino-4- (t-butylcarbamoyl) amino-7-methylthieno [3,2-d] pyrimidine 398 mg
(1.3 mmol) in ethyl acetate. The precipitated crystals were collected by filtration and the title compound (400 mg, yield 90.3%)
I got Mp: 192~194 ℃ NMR (δ, CDCl 3); 1.50 (9H, s), 2.58 (3H, s), 4.10-4.1
4 (2H, m), 5.28-5.44 (2H, m), 5.88-5.97 (1H, m), 7.59
(1H, s), 8.78 (1H, br), 9.19-9.25 (2H, m), 15.12 (1H,
br) IR (ν, cm ^{- 1} ), KBr; 2971, 1662, 1502, 1280, 788 EI-Mass (m / z,%); 320 (M ⁺ +1, 8), 319 (M ⁺ , 40) , 220 (3
6), 205 (100)

Example 93 2-Allylamino-4- (cyclohexylcarbamoyl) amino-7-methylthieno [3,2-d] pyrimidine

[0455]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile, and the mixture was stirred for 20 minutes. The reaction solution was added with 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine 220
mg (1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Further, 139 mg (1.4 mmol) of cyclohexylamine was added, and 16
Heated to reflux for an hour. After completion of the reaction, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 172 mg (yield 49.9%) of the title compound. Melting point: 152-153 ° C NMR (δ, CDCl ₃ ); 1.19-1.32 (3H, m), 1.37-1.48 (2H,
m), 1.64-1.69 (1H, m), 1.74-1.79 (2H, m), 2.05-2.09 (2
H, m), 2.33 (3H, s), 3.75-3.82 (1H, m), 4.07-4.10 (2
H, m), 5.07 (1H, br), 5.17-5.21 (1H, m), 5.28-5.34 (1
H, m), 5.97-6.06 (1H, m), 6.88 (1H, br), 7.34 (1H,
s), 9.21-9.23 (1H, m) IR (ν, cm ^{- 1} ), KBr; 3208, 2932, 1678, 1600, 1494, 7
92 EI-Mass (m / z,%); 346 (M ⁺ +1, 11), 345 (M ⁺ , 51), 246 (2
6), 231 (60), 205 (100)

Example 94 2-Allylamino-4- (t-butyloxycarbonyl) amino-7-methylthieno [3,2-d] pyrimidine

[0458]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyl carbonate in acetonitrile to give a solution.
Stirred for 0 minutes. 220 mg of 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine was added to the reaction solution.
(1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Further t-
104 mg (1.4 mmol) of butanol was added, and the mixture was heated under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give the title compound 54
mg (16.9% yield). NMR (δ, CDCl ₃ ); 1.54 (9H, s), 2.32 (3H, s), 4.09-4.1
3 (2H, m), 5.10-5.15 (2H, m), 5.24-5.29 (1H, m), 5.93
-6.03 (1H, m), 7.41 (1H, s), 7.56 (1H, br) IR (ν, cm ^{- 1} ), KBr; 3448, 2980, 1582, 1516, 1488, 8
02 EI-Mass (m / z,%); 321 (M ⁺ +1, 7), 320 (M ⁺ , 38), 220 (7
5), 205 (100)

Example 95 2-Allylamino-7-methyl-4- (nonylcarbamoyl) aminothieno [3,2-d] pyrimidine hydrochloride

[0461]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyl carbonate in acetonitrile to give a solution.
Stirred for 0 minutes. 220 mg of 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine was added to the reaction solution.
(1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Further, 201 mg (1.4 mmol) of nonylamine was added, and the mixture was heated under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [developing solvent: ethyl acetate-
Hexane (1: 4)] to give 162 mg of the title compound as a free compound. Under ice-cooling, a 4N hydrochloric acid-ethyl acetate solution was added dropwise to the ethyl acetate solution of the free compound of the title compound. The precipitated crystals were collected by filtration to give the title compound (177 mg, yield 41.6%). Melting point: 181 to 184 ° C. NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 6.9 Hz), 1.27-1.39 (11
H, m), 1.60-1.67 (3H, m), 2.58 (3H, s), 3.41-3.46 (2H,
m), 4.09-4.12 (2H, m), 5.27-5.40 (2H, m), 5.88-5.97
(1H, m), 7.60 (1H, s), 8.89 (1H, br), 9.22 (1H, br),
9.97 (1H, br), 15.15 (1H, br) IR (ν, cm ^{- 1} ), KBr; 2924, 1705, 1639, 1498, 793 EI-Mass (m / z,%); 390 (M ⁺ +1) , 13), 389 (M ⁺ , 51), 374
(5), 231 (82), 205 (100)

Example 96 2-Allylamino-4- (allylcarbamoyl) amino-7-methylthieno [3,2-d] pyrimidine

[0464]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile, and the mixture was stirred for 20 minutes. The reaction solution was added with 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine 220
mg (1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Further, 80 mg (1.4 mmol) of allylamine was added, and the mixture was heated under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [developing solvent: ethyl acetate-
Hexane (1: 2)] to give 54 mg of the title compound.
(18.8% yield). Mp: 164~165 ℃ NMR (δ, CDCl 3); 2.34 (3H, s), 4.03-4.06 (4H, m), 5.1
1 (1H, br), 5.15-5.21 (2H, m), 5.26-5.33 (2H, m), 5.9
3-6.02 (2H, m), 6.94 (1H, br), 7.36 (1H, s), 9.44 (1H,
br) IR (ν, cm ^{- 1} ), KBr; 3375, 1697, 1585, 1493, 1327, 1
273 EI-Mass (m / z,%); 304 (M ⁺ +1, 9), 303 (M ⁺ , 48), 246 (1
8), 231 (45), 205 (100)

Example 97 2-Allylamino-4- (butylcarbamoyl) amino-7-methylthieno [3,2-d] pyrimidine

[0467]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyl dicarbonate in acetonitrile, and the mixture was stirred for 20 minutes. The reaction solution was added with 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine 220
mg (1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. And n
-Butylamine (102 mg, 1.4 mmol) was added, and the mixture was heated under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 2)] to give 140 mg (yield 43.9%) of the title compound. Melting point: 141 ° C. NMR (δ, CDCl ₃ ); 0.97 (3H, t, J = 7 Hz), 1.39-1.48 (2H,
m), 1.58-1.65 (2H, m), 2.33 (3H, s), 3.37-3.41 (2H,
m), 4.07-4.10 (2H, m), 5.08 (1H, br), 5.17-5.20 (1H,
m), 5.28-5.33 (1H, m), 5.95-6.05 (1H, m), 6.97 (1H, b
rs), 7.34 (1H, s), 9.27 (1H, br) IR (ν, cm ^{- 1} ), KBr; 3413, 2954, 1693, 1597, 1496, 1
269 EI-Mass (m / z,%); 320 (M ⁺ +1, 7), 319 (M ⁺ , 35), 231 (2
2), 205 (100)

Example 98 2-allylamino-7-methyl-4- (1-pyrrolidinylcarbonyl) aminothieno [3,2-d] pyrimidine

[0470]

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At room temperature, 122 mg (1.0 mmol) of N, N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyl carbonate in acetonitrile, and
Stirred for 0 minutes. 220 mg of 2-allylamino-4-amino-7-methylthieno [3,2-d] pyrimidine was added to the reaction solution.
(1.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. Further, 142 mg (2.0 mmol) of pyrrolidine was added and the mixture was refluxed for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 2)] to give 181 mg of the title compound.
(57.1% yield). Melting point: 98-101 ° C NMR (δ, CDCl ₃ ) 55 ° C; 1.98 (4H, br), 2.31 (3H, s), 3.
52 (4H, br), 4.11 (2H, br), 4.83 (1H, br), 5.10-5.28 (2
H, m), 5.94-6.02 (1H, m), 6.92 (1H, br), 7.38 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3263, 2866, 1628, 1554, 1416, 1
365 EI-Mass (m / z,%); 318 (M ⁺ +1, 4), 317 (M ⁺ , 19), 246 (3
8), 231 (100), 205 (17)

Reference Example 38 2-Chloro-7-methyl-4- (2-propynylamino) thieno [3,2-d] pyrimidine

[0473]

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700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine was added to D
Dissolve in MF and cool under ice-cooling, 2-propynylamine (413 mg)
(7.5 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and ethyl acetate (50 ml) was added.
Extracted times. . The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 620 mg (yield: 76.5%) of the title compound. NMR (δ, CDCl ₃ ); 2.33-2.34 (1H, m), 2.42 (3H, s), 4.4
6-4.48 (2H, m), 5.15 (1H, br), 7.39 (1H, s)

Example 99 2-Allylamino-7-methyl-4- (2-propynylamino) thieno [3,2-d] pyrimidine

[0476]

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2-Chloro-7-methyl-4- (2-propynylamino) thieno [3,2-d] pyrimidine 285
mg (1.2 mmol) and allylamine 1.14 g (19.2
mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 2)] to give 168 mg (yield: 54.2%) of the title compound. Mp: 95~96 ℃ NMR (δ, CDCl 3); 2.27 (1H, t, J = 2.6Hz), 2.32 (3H, s),
4.11-4.15 (2H, m), 4.38-4.40 (2H, m), 4.75 (1H, br),
4.94 (1H, br), 5.10-5.13 (1H, m), 5.24-5.30 (1H, m),
5.96-6.05 (1H, m), 7.19 (1H, s) IR (ν, cm ^{- 1} ), KBr: 3431, 2920, 1456, 675 EI-Mass (m / z,%); 259 (M ⁺ +1) , 13), 258 (M ⁺ , 71), 243
((100), 231 (7), 217 (9)

Reference Example 39 2-Chloro-7-methyl-4- (2-methyl-2-propenylamino) thieno [3,2-d] pyrimidine

[0479]

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To a solution of 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in MF and add 759 mg of triethylamine under ice-cooling
(7.5 mmol) and further 404 mg (3.8 mmol) of 2-methyl-2-propenylamine. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and ethyl acetate (50 ml) was added.
Extracted times. The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 687 mg (yield: 79.3%) of the title compound. NMR (δ, CDCl ₃ ); 1.83 (3H, s), 2.43 (3H, s), 4.24 (2H,
d, J = 6.0Hz), 4.92-4.95 (2H, m), 5.12 (1H, br), 7.37
(1H, s)

Example 100 2-Allylamino-7-methyl-4- (2-methyl-2
-Propenylamino) thieno [3,2-d] pyrimidine

[0482]

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305 mg (1.2 mmol) of 2-chloro-7-methyl-4- (2-methyl-2-propenylamino) thieno [3,2-d] pyrimidine and 1.14 of allylamine
g (19.2 mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml).
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [eluent: ethyl acetate-hexane (1:
4)] to give 108 mg of the title compound (yield 32.
7%). Melting point: 83 ° C NMR (δ, CDCl ₃ ); 1.80 (3H, s), 2.32 (3H, s), 4.09-4.1
3 (2H, m), 4.17 (2H, d, J = 6.0Hz), 4.69 (1H, br), 4.86
-4.93 (3H, m), 5.08-5.12 (1H, m), 5.23-5.29 (1H, m),
5.95-6.05 (1H, m), 7.17 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3421, 2918, 1524, 789 EI-Mass (m / z,%); 275 (M ⁺ +1 , 15), 274 (M ⁺ , 73), 259 (1
00), 233 (12), 219 (21)

Reference Example 40 2-Chloro-7-methyl-4- (3-methyl-2-butenylamino) thieno [3,2-d] pyrimidine

[0485]

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Under ice-cooling, 243 mg (2.0 mmol) of 3-methyl-2-butenylamine hydrochloride was added to 2,4-dichloro-7
438 mg of methylthieno [3,2-d] pyrimidine
(2.0 mmol) and 445 mg (4.4 mmol) of triethylamine.
l) in 10 ml of DMF. After stirring at the same temperature for 1 hour, the temperature was returned to room temperature, and the mixture was further stirred for 2 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give the title compound 3
96 mg (74.0% yield) was obtained. NMR (δ, CDCl ₃ ); 1.76 (3H, s), 1.78 (3H, s), 2.42 (3H,
s), 4.22 (2H, t, J = 6Hz), 4.87 (1H, br), 5.32-5.37 (1
H, m), 7.35 (1H, s)

Example 101 2-Allylamino-7-methyl-4- (3-methyl-2
-Butenylamino) thieno [3,2-d] pyrimidine

[0488]

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268 mg (1.0 mmol) of 2-chloro-7-methyl-4- (3-methyl-2-butenylamino) thieno [3,2-d] pyrimidine and 914 mg of allylamine
(16.0 mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [eluent: ethyl acetate-hexane (1:
4)] to give 201 mg of the title compound (yield 69.
8%). Melting point: 114-115 ° C NMR (δ, CDCl ₃ ); 1.74 (3H, s), 1.76 (3H, s), 2.32 (3H,
s), 4.12-4.17 (4H, m), 4.49 (1H, br), 4.87 (1H, br),
5.09-5.13 (1H, m), 5.24-5.30 (1H, m), 5.33-5.37 (1H, m
m), 5.96-6.06 (1H, m), 7.15 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3429, 1516, 1454, 1381, 1269 EI-Mass (m / z,%); 289 (M ⁺ +1, 19), 288 (M ⁺ , 90), 273 (1
00), 247 (18), 205 (95)

Reference Example 41 2-chloro-4- (trans-cinnamylamino)-
7-methylthieno [3,2-d] pyrimidine

[0490]

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Under ice-cooling, 339 mg (2.0 mmol) of trans-cinnamylamine hydrochloride was added to 2,4-dichloro-7-
438 mg of methylthieno [3,2-d] pyrimidine (2.
0 mmol) and 445 mg (4.4 mmol) of triethylamine in 10 ml of DMF. After stirring at the same temperature for 1 hour, the temperature was returned to room temperature, and the mixture was further stirred for 2 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 341 mg of the title compound.
(54.0% yield). NMR (δ, CDCl ₃ ); 2.44 (3H, s), 4.45-4.48 (2H, m), 5.1
3 (1H, br), 6.30-6.37 (1H, m), 6.65 (1H, d, J = 16Hz),
7.24-7.40 (6H, m)

Example 102 2-Allylamino-4- (trans-cinnamylamino) -7-methylthieno [3,2-d] pyrimidine

[0494]

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316 mg (1.0 mmol) of 2-chloro-4- (trans-cinnamylamino) -7-methylthieno [3,2-d] pyrimidine and 914 mg of allylamine (1
6.0 mmol) was heated in a sealed tube at 160 ° C. for 16 hours.
After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. Silica gel chromatography of the residue [developing solvent: ethyl acetate-hexane (1: 4)]
274 mg (81.5% yield) of the title compound
I got Mp: 82~84 ℃ NMR (δ, CDCl 3); 2.33 (3H, s), 4.12-4.16 (2H, m), 4.3
7-4.40 (2H, m), 4.73 (1H, br), 4.92 (1H, br), 5.09-5.
13 (1H, m), 5.24-5.30 (1H, m), 5.96-6.06 (1H, m), 6.32
-6.39 (1H, m), 6.61 (1H, d, J = 16Hz), 7.18-7.39 (6H,
m) IR (ν, cm ^{- 1} ), KBr; 3448, 1558, 1524, 1454, 1338 EI-Mass (m / z,%); 337 (M ⁺ +1, 23), 236 (M ⁺ , 100) , 321
(53), 295 (7), 245 (38), 91 (18)

Reference Example 42 2,4-Dichloro-7-ethylthieno [3,2-d] pyrimidine

[0497]

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To 1.21 g (6.5 mmol) of methyl 3-amino-4-ethylthiophene-2-carboxylate was added 1.95 g (32.5 mmol) of urea, and the mixture was heated at 200 ° C. for 1.5 hours. After returning to room temperature, 20 ml of DMF was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration, dried, and then treated with phosphorus oxychloride 8.67.
g (56.6 mmol) and N, N-dimethylaniline 685
mg (5.7 mmol) was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration to give the title compound 8
31 mg (64.7% yield) were obtained. NMR (δ, CDCl ₃ ); 1.37 (3H, t, J = 8Hz), 2.92-2.98 (2H,
m), 7.74 (1H, s)

Reference Example 43 4-Allylamino-2-chloro-7-ethylthieno [3,2-d] pyrimidine

[0500]

Embedded image

500 mg (2.1 mmol) of 2,4-dichloro-7-ethylthieno [3,2-d] pyrimidine was added to D
Dissolved in 6 ml of MF and cooled with ice to 269 mg of allylamine
(4.7 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to obtain 483 mg (yield: 88.8%) of the title compound. NMR (δ, CDCl ₃ ); 1.33 (3H, t, J = 8Hz), 2.86-2.91 (2H,
m), 4.29-4.32 (2H, m), 5.09 (1H, br), 5.22-5.26 (1H,
m), 5.29-5.34 (1H, m), 5.95-6.05 (1H, m), 7.37 (1H,
s)

Example 103 2,4-Diallylamino-7-ethylthieno [3,2-
d] pyrimidine

[0503]

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4-Allylamino-2-chloro-7-ethylthieno [3,2-d] pyrimidine 304 mg (1.2 mm
ol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
284 mg (86.3% yield) of the title compound were obtained. Melting point: 55 ° C IR (ν, cm ^{- 1} ), KBr; 3414, 2964, 1631, 1520, 1329, 8
39 NMR (δ, CDCl ₃ ); 1.31 (3H, t, J = 8 Hz), 2.74-2.80 (2H,
m), 4.09-4.13 (2H, m), 4.20-4.24 (2H, m), 4.66 (1H, b
r), 4.89 (1H, br), 5.08-5.12 (1H, m), 5.15-5.19 (1H,
m), 5.23-5.30 (2H, m) 5.95-6.05 (2H, m), 7.17 (1H, s) EI-Mass (m / z,%); 275 (M ⁺⁺ 1, 14), 274 (M ⁺ , 66), 259 (1
00), 246 (6), 233 (15), 218 (14)

Reference Example 44 4-t-butylamino-2-chloro-7-ethylthieno [3,2-d] pyrimidine

[0506]

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To a solution of 330 mg (1.4 mmol) of 2,4-dichloro-7-ethylthieno [3,2-d] pyrimidine in D
After dissolving in 5 ml of MF, under ice cooling, 228 mg of t-butylamine
(3.1 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 100)) to obtain 312 mg (yield: 81.7%) of the title compound. NMR (δ, CDCl ₃ ); 1.32 (3H, t, J = 8 Hz), 1.57 (9H, s),
2.84-2.90 (2H, m), 4.72 (1H, br), 7.29 (1H, s)

Example 104 2-Allylamino-4-t-butylamino-7-ethylthieno [3,2-d] pyrimidine

[0509]

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4-tert-butylamino-2-chloro-7-
269 mg of ethylthieno [3,2-d] pyrimidine (1.
(0 mmol) and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
241 mg (83.1% yield) of the title compound were obtained. IR (ν, cm ^{- 1} ), film; 3427, 2964, 1583, 1213, 793 NMR (δ, CDCl ₃ ); 1.30 (3H, t, J = 8Hz), 1.54 (9H, s),
2.72-2.78 (2H, m), 4.09-4.12 (2H, m), 4.40 (1H, br),
4.89 (1H, br), 5.09-5.12 (1H, m), 5.23-5.29 (1H, m),
5.96-6.06 (1H, m), 7.12 (1H, s) EI-Mass (m / z,%); 291 (M ⁺ +1, 14), 290 (M ⁺ , 74), 275
((11), 233 (39), 219 (100)

Reference Example 45 2,4-Dichloro-7-propylthieno [3,2-d]
Pyrimidine

[0512]

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1.15 g (5.8 mmol) of methyl 3-amino-4-propylthiophene-2-carboxylate
To the mixture was added 1.73 g (28.9 mmol) of urea, and the mixture was heated at 200 ° C. for 1.5 hours. After returning to room temperature, 50 ml of DMF was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration.
g (118.0 mmol) and N, N-dimethylaniline.
43 g (511.8 mmol) was added, and the mixture was heated under reflux for 3 hours.
After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration to obtain 886 mg (yield 62.1%) of the title compound. NMR (δ, CDCl ₃ ); 1.01 (3H, t, J = 7Hz), 1.74-1.83 (2H,
m), 2.88-2.92 (2H, m), 7.73 (1H, s)

Reference Example 46 4-Allylamino-2-chloro-7-propylthieno [3,2-d] pyrimidine

[0515]

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371 mg (1.5 mmol) of 2,4-dichloro-7-propylthieno [3,2-d] pyrimidine was added to D
Dissolve in 5 ml of MF, and cool with ice, 188 mg of allylamine
(3.3 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 244 mg (yield 60.7%) of the title compound. NMR (δ, CDCl ₃ ); 1.00 (3H, t, J = 7Hz), 1.71-1.81 (2H,
m), 2.81-2.85 (2H, m), 4.29-4.32 (2H, m), 5.08 (1H, b
r), 5.22-5.26 (1H, m), 5.29-5.34 (1H, m), 5.95-6.05
(1H, m), 7.36 (1H, s)

Example 105 2,4-Diallylamino-7-propylthieno [3,2
-D] pyrimidine

[0518]

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189 mg of 4-allylamino-2-chloro-7-propylthieno [3,2-d] pyrimidine (0.7 mg)
(1 mmol) and 644 mg (11.3 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
116 mg (56.9% yield) of the title compound were obtained. IR (ν, cm ^{- 1} ), KBr; 3427, 2958, 1587, 1516, 920, 79
3 NMR (δ, CDCl ₃ ); 0.99 (3H, t, J = 7 Hz), 1.61-1.80 (2H,
m), 2.70-2.74 (2H, m), 3.34-4.13 (2H, m), 4.20-4.24
(2H, m), 4.63 (1H, br), 4.86 (1H, br), 5.08-5.12 (1H,
m), 5.15-5.19 (1H, m), 5.23-5.30 (2H, m), 5.95-6.05
(2H, m), 7.16 (1H, s) EI-Mass (m / z,%); 289 (M ⁺⁺ 1, 8), 288 (M ⁺ , 37), 273 (1
1), 260 (27), 247 (20), 217 (19)

Reference Example 47 4-t-butylamino-2-chloro-7-propylthieno [3,2-d] pyrimidine

[0521]

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371 mg (1.5 mmol) of 2,4-dichloro-7-propylthieno [3,2-d] pyrimidine was added to D
Dissolved in 5 ml of MF, and cooled with ice to give 241 mg of t-butylamine.
(3.3 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 173 mg (yield 40.6%) of the title compound. NMR (δ, CDCl ₃ ); 0.99 (3H, t, J = 7Hz), 1.57 (9H, s),
1.70-1.80 (2H, m), 2.80-2.84 (2H, m), 4.72 (1H, br),
7.29 (1H, s)

Example 106 2-allylamino-4-t-butylamino-7-propylthieno [3,2-d] pyrimidine

[0524]

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4-tert-butylamino-2-chloro-7-
173 mg of propylthieno [3,2-d] pyrimidine
(0.61 mmol) and 557 mg (9.8 mmol) of allylamine
l) was heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 4)] to give 142 mg (yield: 76.3%) of the title compound. NMR (δ, CDCl ₃ ); 0.98 (3H, t, J = 7Hz), 1.53 (9H, s),
1.69-1.79 (2H, m), 2.68-2.72 (2H, m), 4.08-4.12 (2H, m
m), 4.39 (1H, br), 4.87 (1H, br), 5.08-5.12 (1H, m),
5.23-5.29 (1H, m), 5.96-6.06 (1H, m), 7.11 (1H, s) IR (ν, cm ^{- 1} ), film; 3427, 2960, 1581, 1516, 793 EI-Mass (m / z,%); 305 (M ⁺ +1, 15), 304 (M ⁺ , 75), 289 (1
00), 276 (28), 247 (27), 233 (80)

Reference Example 48 2-Chloro-4-methylamino-7-propylthieno [3,2-d] pyrimidine

[0527]

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Under ice-cooling, 28 mg (0.89 mmol) of a 40% methylamine methanol solution was treated with 100 mg of 2,4-dichloro-7-propylthieno [3,2-d] pyrimidine (0.1 mg).
(41 mmol) in 10 ml of DMF. After stirring at the same temperature for 1 hour, the temperature was returned to room temperature, and the mixture was further stirred for 2 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). . The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 2)).
50 mg (51.5% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ); 1.00 (3H, t, J = 7Hz), 1.71-1.81 (2H,
m), 2.81-2.85 (2H, m), 3.22 (3H, d, J = 5Hz), 5.01 (1H,
br), 7.34 (1H, s)

Example 107 2-allylamino-4-methylamino-7-propylthieno [3,2-d] pyrimidine

[0530]

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2-Chloro-4-methylamino-7-propylthieno [3,2-d] pyrimidine 50 mg (0.21
mmol) and 189 mg (3.31 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
37 mg (68.5% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ); 0.99 (3H, t, J = 7Hz), 1.70-1.80 (2H,
m), 2.70-2.74 (2H, m), 3.12 (3H, d, J = 5Hz), 4.11-4.1
5 (2H, m), 4.58 (1H, br), 4.86 (1H, br), 5.09-5.13 (1
H, m), 5.24-5.29 (1H, m), 5.97-6.06 (1H, m), 7.14 (1
H, s) IR (ν, cm ^{- 1} ), KBr; 2952, 1534, 1249, 906, 785 EI-Mass (m / z,%); 263 (M ^{+ +} 1, 8), 262 (M ⁺ , 48), 247 (10
0)

Reference Example 49 2,4-Dichloro-7-isopropylthieno [3,2-
d] pyrimidine

[0533]

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1.25 g (6.3 mm) of methyl 3-amino-4-isopropylthiophene-2-carboxylate
ol) was added with 1.88 g (31.4 mmol) of urea, and 200
Heated at 150C for 1.5 hours. After returning to room temperature, 50 ml of DMF was added, and the mixture was heated under reflux for 1 hour. After the reaction, add ice water,
The precipitated crystals are collected by filtration, dried, and then dried with phosphorus oxychloride 4.1.
6 g (27.2 mmol) and N, N-dimethylaniline 32
9 mg (2.7 mmol) was added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration to obtain 399 mg (yield: 28.8%) of the title compound. NMR (δ, CDCl ₃ ); 1.38 (6H, d, J = 7 Hz), 3.45-3.52 (1H,
m), 7.73 (1H, s)

Reference Example 50 4-Allylamino-2-chloro-7-isopropylthieno [3,2-d] pyrimidine

[0536]

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[0537] 2,4-Dichloro-7-isopropylthieno [3,2-d] pyrimidine (71 mg, 0.29 mmol) was dissolved in DMF (5 ml), and allylamine (36 mg) was dissolved under ice-cooling.
(0.63 mmol) was added dropwise over 5 minutes. Reaction solution at 0 ° C
After stirring for 1 hour, the mixture was returned to room temperature and further stirred for 1 hour. After the reaction was completed, ice water was added, and the mixture was extracted three times with ethyl acetate (30 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to give 73 mg (yield 94.8%) of the title compound. NMR (δ, CDCl ₃ ); 1.34 (6H, d, J = 7 Hz), 3.41-3.48 (1H,
m), 4.29-4.32 (2H, m), 5.01 (1H, br), 5.22-5.26 (1H,
m), 5.29-5.34 (1H, m), 5.95-6.05 (1H, m), 7.36 (1H,
s)

Example 108 2,4-Diallylamino-7-isopropylthieno [3,2-d] pyrimidine

[0539]

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70 mg of 4-allylamino-2-chloro-7-isopropylthieno [3,2-d] pyrimidine (0.
26 mmol) and 239 mg (4.2 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
67 mg (yield 89.3%) of the title compound were obtained. IR (ν, cm ^{- 1} ), KBr; 3429, 2958, 1587, 1514, 1454, 9
22, 793 NMR (δ, CDCl ₃ ); 1.33 (6H, d, J = 7Hz), 3.25-3.32 (1H,
m), 4.09-4.12 (2H, m), 4.20-4.24 (2H, m), 4.62 (1H, b
r), 4.87 (1H, br), 5.08-5.19 (2H, m), 5.23-5.30 (2H,
m), 5.94-6.06 (2H, m), 7.16 (1H, s) EI-Mass (m / z,%); 289 (M ⁺⁺ 1, 11), 288 (M ⁺ , 54), 273 (1
00), 260 (14), 247 (10)

Reference Example 51 2-chloro-7-isopropyl-4-methylaminothieno [3,2-d] pyrimidine

[0542]

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Under ice-cooling, 28 mg (0.89 mmol) of a 40% methylamine methanol solution was added to 100 mg of 2,4-dichloro-7-isopropylthieno [3,2-d] pyrimidine.
(0.41 mmol) in 10 ml of DMF. After stirring at the same temperature for 1 hour, the temperature was returned to room temperature, and the mixture was further stirred for 2 hours. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 2)).
90 mg (92.0% yield) of the title compound was obtained. NMR (δ, CDCl ₃ ); 1.34 (6H, d, J = 7 Hz), 3.22 (3H, d, J =
5Hz), 3.39-3.49 (1H, m), 5.03 (1H, br), 7.34 (1H, s)

Example 109 2-allylamino-7-isopropyl-4-methylaminothieno [3,2-d] pyrimidine

[0545]

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90 mg of 2-chloro-7-isopropyl-4-methylaminothieno [3,2-d] pyrimidine (0.
37 mmol) and 340 mg (5.96 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
89 mg (91.1% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ); 1.32 (6H, d, J = 7 Hz), 3.11 (3H, d, J =
5Hz), 3.25-3.32 (1H, m), 4.11-4.14 (2H, m), 4.57 (1H, m
br), 4.85 (1H, br), 5.09-5.12 (1H, m), 5.24-5.30 (1H,
m), 5.97-6.07 (1H, m), 7.14 (1H, s) IR (ν, cm ^{- 1} ), film; 2958, 1594, 1513, 792 EI-Mass (m / z,%); 263 (M ⁺ +1, 9), 262 (M ⁺ , 52), 247 (10
0)

Reference Example 52 2,4-Dichloro-7-phenylthieno [3,2-d]
Pyrimidine

[0548]

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Methyl 3-amino-4-phenylthiophene-2-carboxylate 2.04 g (8.7 mmol)
To the mixture was added 2.62 g (43.7 mmol) of urea, and the mixture was heated at 200 ° C. for 1.5 hours. After returning to room temperature, 50 ml of DMF was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration, dried, and dried to obtain a solution of phosphorus oxychloride (10.7%).
6 g (70.2 mmol) and N, N-dimethylaniline 85
1 mg (7.0 mmol) was added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration to obtain 341 mg (yield: 13.9%) of the title compound. NMR (δ, CDCl ₃ ); 7.42-7.46 (1H, m), 7.49-7.54 (2H,
m), 7.90-7.93 (2H, m), 8.17 (1H, s)

Reference Example 53 4-Allylamino-2-chloro-7-phenylthieno [3,2-d] pyrimidine

[0551]

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176 mg (0.63 mmol) of 2,4-dichloro-7-phenylthieno [3,2-d] pyrimidine was dissolved in 1 ml of DMF, and 79 mg of allylamine was added under ice-cooling.
(1.4 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After the reaction was completed, ice water was added, and the mixture was extracted three times with ethyl acetate (30 ml). . The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to obtain 168 mg (yield: 88.9%) of the title compound. NMR (δ, CDCl ₃ ); 4.32-4.36 (2H, m), 5.12 (1H, br), 5.
25-5.28 (1H, m), 5.32-5.37 (1H, m), 5.98-6.07 (1H, m
m), 7.36-7.40 (1H, m), 7.45-7.50 (2H, m), 7.80 (1H,
s), 7.89-7.92 (2H, m)

Example 110 2,4-Diallylamino-7-phenylthieno [3,2
-D] pyrimidine

[0554]

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168 mg of 4-allylamino-2-chloro-7-phenylthieno [3,2-d] pyrimidine (0.5 mg)
6 mmol) and 508 mg (8.9 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
154 mg (85.8% yield) of the title compound were obtained. Melting point: 98-100 ° C IR (ν, cm ^{- 1} ), KBr; 3429, 1593, 1545, 1495, 789, 69
6 NMR (δ, CDCl ₃ ); 4.12-4.16 (2H, m), 4.26-4.30 (2H,
m), 4.70-4.73 (1H, m), 4.95-4.97 (1H, m), 5.13-5.16 (1
H, m), 5.21-5.24 (1H, m), 5.27-5.35 (2H, m), 5.98-6.0
9 (2H, m), 7.29-7.38 (1H, m), 7.44-7.48 (2H, m), 7.67
(1H, s), 8.02-8.04 (2H, m) EI-Mass (m / z,%); 323 (M ⁺ +1, 14), 322 (M ⁺ , 49), 321 (7
5), 307 (100), 281 (19)

Reference Example 54 7-bromothieno [3,2-d] pyrimidine-2,4
(1H, 3H) -dione

[0557]

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At room temperature, 7.31 g (52.2) of thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
mmol) in an acetic acid solution (250 ml).
6 mmol) and heated at 80 ° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Ice water was added to the residue, and the precipitated crystals were collected by filtration to give 7.24 g of the title compound (yield 56.
2%). NMR (δ, DMSO-d ₆ ); 8.24 (1H, s), 11.44 (1H, br), 11.5
6 (1H, br)

Reference Example 55 7-bromo-2,4-dichlorothieno [3,2-d] pyrimidine

[0560]

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7-bromothieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione 3.00 g (12.
18.55 g (121.0 mm) of phosphorus oxychloride
ol) and 3.83 g (48.4 mmol) of pyridine were added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, ice water was added, and the precipitated crystals were collected by filtration, and 1.35 g (yield 39.1%) of the title compound was obtained.
I got NMR (δ, CDCl ₃ ); 8.11 (1H, s) EI-Mass (m / z,%); 288 (M ⁺⁺ 6, 8), 286 (M ⁺⁺ 4, 49), 284
(M ⁺ +2, 100), 282 (M ⁺ , 61)

Reference Example 56 4-Allylamino-7-bromo-2-chlorothieno [3,2-d] pyrimidine

[0563]

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Under ice cooling, 188 mg of allylamine (3.3 mm
ol) is converted to 7-bromo-2,4-dichlorothieno [3,2-
d] Pyrimidine (426 mg, 1.5 mmol) was added to a solution of DMF (5 ml). After stirring at the same temperature for 1 hour, return to room temperature, and
Stirred for hours. After completion of the reaction, ice water was added and ethyl acetate (5
0 ml). The organic layer was washed with 1N aqueous hydrochloric acid, water,
After washing with saturated saline in this order and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [eluent: ethyl acetate-hexane (1:
4)] to give 359 mg of the title compound (yield 78.
6%). NMR (δ, CDCl ₃ ); 4.30-4.34 (2H, m), 5.24-5.35 (3H,
m), 5.95-6.04 (1H, m), 7.74 (1H, s)

Example 111 2,4-Diallylamino-7-bromothieno [3,2-
d] pyrimidine

[0566]

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305 mg of 4-allylamino-7-bromo-2-chlorothieno [3,2-d] pyrimidine (1.0 mm
ol) and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
304 mg (93.3% yield) of the title compound were obtained. Melting point: 87-88 ° C NMR (δ, CDCl ₃ ); 4.11-4.15 (2H, m), 4.21-4.25 (2H,
m), 4.75 (1H, br), 5.10-5.31 (5H, m), 5.93-6.04 (2H,
m), 7.54 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3433, 3070, 1554, 1520, 1354, 1
292 EI-Mass (m / z,%); 326 (M ⁺ +2, 42), 324 (M ⁺ , 41), 311 (1
00), 309 (100), 285 (9), 283 (13)

Reference Example 57 2-chloro-4- (2-carbamoylethylamino)-
7-methylthieno [3,2-d] pyrimidine

[0569]

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To a solution of 1.0 g (4.9 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
MF (10 ml) and β-alanine amide hydrochloride (668 mg, 5.37 mmol) and triethylamine (1.0 ml) under ice-cooling.
9 g (10.7 mmol) were added. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml).
The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 8)).
1.05 g (yield 79.8%) of the desired product was obtained. NMR (δ, DMSO-d ₆ ); 2.28 (3H, s), 2.44 (2H, t, J = 7Hz),
3.64 (2H, dd, J = 6Hz, 7Hz), 6.87 (1H, br), 7.38 (1H, b
r), 7.79 (1H, s), 8.34 (1H, t, J = 6Hz)

Example 112 2-Allylamino-4- [2- (allylcarbamoyl)
Ethylamino] -7-methylthieno [3,2-d] pyrimidine

[0572]

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324 mg (1.2 mmol) of 2-chloro-4- (2-carbamoylethylamino) -7-methylthieno [3,2-d] pyrimidine and 1.096 g of allylamine
(19.2 mmol) was heated in a sealed tube at 160 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography [eluent: ethyl acetate-hexane (1:
1)] to give 248 mg of the title compound (yield 62.
5%). Melting point: 95-96 ° C NMR (δ, CDCl ₃ ); 2.31 (3H, s), 2.58 (2H, t, J = 6 Hz),
3.85-3.92 (4H, m), 4.08-4.13 (2H, m), 4.98 (1H, br),
5.08-5.16 (3H, m), 5.22-5.29 (1H, m), 5.42 (1H, br),
5.72-6.06 (3H, m), 7.17 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3440, 2293, 1666, 1589, 1566, 1
527, 918, 795 EI-Mass (m / z,%); 332 (M ⁺ +1, 17), 331 (M ⁺ , 81), 316 (1
00), 247 (60), 205 (51)

Reference Example 58 2-Chloro-4-dodecylamino-7-methylthieno [3,2-d] pyrimidine

[0575]

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To a solution of 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno [3,2-d] pyrimidine in D
Dissolve in 1 ml of MF, and under ice-cooling, 1.30 g of dodecylamine
(7.0 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at 0 ° C. for 1 hour, returned to room temperature, and further stirred for 1 hour. After completion of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layer was washed with a 1N aqueous hydrochloric acid solution, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1:10)] to obtain 745 mg (yield: 63.4%) of the title compound. NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 1.26-1.44 (18H,
m), 1.65-1.72 (2H, m), 2.42 (3H, s), 3.63-3.68 (2H,
m), 4.98 (1H, br), 7.35 (1H, s)

Example 113 2-Allylamino-4-dodecylamino-7-methylthieno [3,2-d] pyrimidine

[0578]

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442 mg of 2-chloro-4-dodecylamino-7-methylthieno [3,2-d] pyrimidine (1.2 mg)
mmol) and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140 ° C. for 16 hours. After the reaction was completed, the temperature was returned to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane (1: 4)).
209 mg (44.8% yield) of the title compound were obtained. NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 1.26-1.44 (18H,
m), 1.61-1.68 (2H, m), 2.32 (3H, s), 3.54-3.59 (2H,
m), 4.11-4.14 (2H, m), 4.58 (1H, br), 4.86 (1H, br),
5.09-5.12 (1H, m), 5.24-5.29 (1H, m), 5.96-6.05 (1H, m
m), 7.16 (1H, s) IR (ν, cm ^{- 1} ), KBr; 3429, 2922, 1560, 1522, 1462, 7
89 EI-Mass (m / z,%); 389 (M ⁺ +1, 13), 388 (M ⁺ , 49), 373 (1
00)

Example 114 2,4,7-Triallylaminothieno [3,2-d] pyrimidine

[0581]

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2,4-Diallylamino-7-bromothieno [3,2-d] pyrimidine 120 mg (0.37 mmol
l), 337 mg (5.9 mmol) of allylamine, 56 mg (0.41 mmol) of potassium carbonate and 1 mg of copper in a sealed tube,
Heated at ° C. for 5 hours. After completion of the reaction, the temperature was returned to room temperature, and excess allylamine was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent: ethyl acetate-hexane (1: 8)] to give 81 mg of the title compound (yield 7).
2.9%). NMR (δ, CDCl ₃ ); 3.83-3.86 (2H, m), 4.08-4.12 (2H,
m), 4.19-4.23 (2H, m), 4.63-4.65 (1H, m), 4.83-4.86 (1
H, m), 5.09-5.35 (6H, m), 5.93-6.05 (4H, m) IR (ν, cm ^{- 1} ), film; 1535, 1330, 782 EI-Mass (m / z,%); 302 (M ⁺ +1, 21), 301 (M ⁺ , 100), 272
(44)

Test Example Measurement of Oxygen Partial Pressure Elevation Effect The increase in arterial blood oxygen partial pressure by the thienopyrimidine derivative of the present invention was measured by the following method. Weighing about 250g
Male Sprague-Dawley rats were anesthetized with urethane (i.
p.), airways, femoral artery and femoral vein were cannulated. 0.8 ml / kg of an olive oil-charcoal powder suspension (10 mg / ml) was injected into the lungs from the tracheal cannula to obtain a hypoxemia (PaO ₂ 75 mmHg or less). The thienopyrimidine derivatives shown in Table 2 were continuously administered intravenously to the hypoxemia model animal at 0.1 mg / kg / min for 10 minutes, and the arterial blood oxygen partial pressure (PaO ₂ ) 10 minutes after the administration was completed. Was measured with a blood gas analyzer (Ciba Corning 800 series). An increase (ΔPaO ₂ ) was determined from the measurement results of PaO ₂ before and after administration of the test compound. Table 2 shows the results.

[0584]

[Table 2]

Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 405/12 C07D 405/12 409/12 409/12 495/04 105 495/04 105Z (72) Inventor Hiroshi Igawa Nihonbashi-hamacho, Chuo-ku, Tokyo 2-62-5 Inside Fuji Rebio Co., Ltd. (72) Inventor Toru Hiruma 2-62-5 Inside Nihonbashi Hamacho, Chuo-ku, Tokyo (58) Investigated field (Int.Cl. ⁷ , DB name) ) C07D 239/95 A61K 31/505 C07D 401/12 C07D 405/12 C07D 409/12 C07D 495/04 105 CA (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] 1. A compound of formula (I): [Wherein ring A is represented by the formula (a): Wherein R ¹ is a nitro group, an amino group, a substituted amino group or a halogen atom, or a ring represented by the formula (b): Wherein R ^{1 ′} is an alkyl group, an alkenyl group, a phenyl group, a nitro group, an amino group, a substituted amino group or a halogen atom; R ² and R ⁴ are each a hydrogen atom , an alkyl group or an alkenyl group; R ³
And R ⁵ are an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a cycloalkyl group, an adamantyl group, a pyridylmethyl group, a furylmethyl group, a thienylmethyl group, a cinnamyl group, an acyl group, an alkoxycarbonyl group, and a substituted alkyl group, respectively. Or a substituted carbamoyl group or a substituted amino group; or one of R ² and R ³ or R ⁴ and R ⁵ may have a substituent together with the nitrogen atom to which they are bonded. Which may form a 4- to 7-membered heterocyclic monocyclic ring; provided that at least one of R ^{2 to} R ⁵ is an alkenyl group] or an acid addition salt thereof. 2. The pyrimidine nucleus-containing compound or an acid addition salt thereof according to claim 1, wherein ring A is a ring of the formula (a) and R ¹ is a nitro group or an amino group. 3. The pyrimidine nucleus-containing compound or an acid addition salt thereof according to claim 1, wherein ring A is a ring of the formula (a), R ² is a hydrogen atom, and R ³ is an allyl group. 4. The pyrimidine nucleus-containing compound or an acid addition salt thereof according to claim 1, wherein ring A is a ring of formula (a), R ⁴ is a hydrogen atom, and R ⁵ is an allyl group. 5. The ring A is a ring of the formula (b), wherein R ^{1 ′} is
The pyrimidine nucleus-containing compound or an acid addition salt thereof according to claim 1, which is a methyl group, an ethyl group or a propyl group substituted at the 7-position of the thienopyrimidine ring. 6. The pyrimidine nucleus-containing compound or an acid addition salt thereof according to claim 1, wherein ring A is a ring of the formula (b), R ⁴ is a hydrogen atom, and R ⁵ is an allyl group. 7. Ring A is a ring of formula (b), R ² is a hydrogen atom or allyl group, R ³ is C ₁ -C _{2 0} alkyl group,
Allyl, cycloalkyl, aralkyl or 1,3
- or a dihydroxypropyl group, R ² and R ³ together with the nitrogen atom to which they are attached form a piperidino group, said group may be substituted by lower alkyl, pyrimidines according to claim 1, wherein A nucleus-containing compound or an acid addition salt thereof. 8. A process for preparing a pyrimidine nucleus-containing compound of formula (I) according to claim 1, comprising the following steps: a) Formula: (Wherein ring A is as defined in claim 1) and a halogenating reagent are reacted in the presence of a base to obtain a compound represented by the formula: (Wherein X is a halogen atom)
Obtaining a dihalo compound; b) converting the 2,4-dihalo compound to a compound represented by the formula: (Wherein R ² and R ³ are as defined in claim 1), and reacted with an amine derivative represented by the formula: Obtaining a 2-halo-4-amino compound represented by the formula: and c) converting the 2-halo-4-amino compound to a compound represented by the formula: Wherein R ⁴ and R ⁵ are as defined in claim 1, by reacting
A process comprising the step of obtaining a compound of formula (I). 9. A medicament comprising the pyrimidine nucleus-containing compound according to claim 1 or an acid addition salt thereof. 10. The method according to claim 9, which is an agent for improving blood oxygen partial pressure.
The medicament according to claim.