JPH0710876A - Pyrrolo(2,3-d)pyrimidine having cyclic amino group at 4-position - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a preventing and a therapeutic agents for hypoxemia due to diseases in respiratory organs. CONSTITUTION:This compound is expressed by formula I [R<1> is H, alkyl, alkenyl or aralkyl ; R'' is alkyl, alkenyl or aralkyl; Y is cyclic amino (G<1> and G<2> are each 1-6C alkyl) such as formula II bound through N to the pyrimidine ring], e.g. 2-allylamino-4-(2,6-dimethylpiperidino)-7-methyl-7H-pyrrlo[2,3- d]pyrimidine. The compound expressed by formula I is obtained by reacting a compound expressed by formula III (X is halogen) with an amine expressed by the formula Y-H under alkaline conditions. The compound expressed by formula I is capable of enhancing the respiratory function in the lungs. Some thereof are capable of raising only the partial pressure of oxygen mainly in arterial blood and some have action on reduction in the partial pressure of gaseous carbon dioxide in the arterial blood together with a rise in the partial pressure of oxygen in the arterial blood.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrrolo [2,3-d] pyrimidine having a cyclic amino group at the 4-position.

More specifically, a 4 at the 2-position of the pyrimidine ring.
A new pyrrolo [2,3-d] having a cyclic amino group at the 4-position having an optionally substituted amino group
The present invention relates to a pyrimidine derivative and a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical preparation containing the same, and particularly to a pharmaceutical preparation effective for the treatment (prevention and treatment) of hypoxemia associated with various respiratory diseases.

[0003]

BACKGROUND OF THE INVENTION Pyrrolo [2,3-d] pyrimidine skeleton:

[0004]

[Chemical 5]

Compounds having are known to exhibit various interesting pharmacological actions. For example, 2 of the skeleton
A compound having antibacterial activity in which both the 4-position and the 4-position are substituted with amino groups and a method for producing the same are known [Reference: British Patent No. 812,336, Townsend LB et al., Journal of Medicinal Chemistry (J. . Me
d.Chem.) Vol. 31 , 1501 (1988), etc.], and compounds in which their amino substituents are primary amino groups are also known as herbicides and antibiotics, respectively [Okuda et al., Japan Pesticide Chemistry. Journal Vol. 6 , 9 (1981), Pede
rsen EB et al., Chemica Scripta
Vol. 28 , 201 (1988), etc.]. Further, compounds having an amino group at the 2- and 4-positions of the skeleton and a sugar residue at the 7-position and exhibiting antiviral activity are also known [for example, European Patent Publication No. 57548].

In particular, a pyrrolo [2 having an alkyl group or an alkenyl group at the 7-position, an alkyl- or alkenyl-substituted amino group at the 2-position, and a cyclic amino group or a chain-substituted amino group at the 4-position. , 3-d] pyrimidine derivatives are disclosed by Sakuma et al. As a prophylactic and therapeutic agent for hypoxemia associated with respiratory diseases [International Publication WO 91/04254]. However, 2
Substituted piperidine ring and pyrrolidine ring; unsubstituted, 1-substituted or 2-substituted pyrrole ring; a pyrrolo [2,3-d] pyrimidine derivative having a tetrazole ring substituted at the 4-position via a nitrogen atom has not been disclosed in the prior art documents. It is listed.

As a result of diligent studies on the pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position, the present inventors have found that among the compounds not listed in the above-mentioned document, the compound represented by the following formula [I]: What is shown is the same as the pyrrolo [2,3-d] pyrimidine derivative disclosed in the above-mentioned application by Sakuma et al. [International Publication No. WO 91/04254] for the prevention of hypoxemia associated with respiratory diseases and The present inventors have completed the present invention by finding that they are effective for treatment and have distinctly superior characteristics in terms of toxicity and physical properties.

[0008]

That is, the present invention provides the following formula [I]:

[0009]

[Chemical 6]

[In the above formula, R ¹ is a hydrogen atom, an alkyl group,
Represents an alkenyl group or an aralkyl group, R ² represents an alkyl group, an alkenyl group, or an aralkyl group, and Y represents a group bonded to a pyrimidine ring via a nitrogen atom.

[0011]

[Chemical 7]

Represents a cyclic amino group represented by Where G
¹And G²Are C independent of each other₁~ C₆Alkyl group of
Represents G³And G^FourAre independently of each other a hydrogen atom, C
₁~ C _TenAlkyl group, alkenyl group, aryl group,
Or an aralkyl group, or two together form a cyclic alkyl group
It represents a kill group or an aryl group. ] To the 4th place
Pyrrolo [2,3-d] pyrimidines having cyclic amino groups
Derivatives or pharmaceutically acceptable acid addition salts thereof and
Its derivative or its pharmaceutically acceptable acid addition salt
A pharmaceutical preparation comprising an active ingredient.

In the present invention, unless otherwise defined, the alkyl group means a C _{1 to} C ₁₀ straight or branched chain aliphatic hydrocarbon group, a cyclic aliphatic hydrocarbon group, or a chain-cyclic aliphatic hydrocarbon group. , For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
It means butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl and the like.

The alkenyl group means a C _{2 to} C ₆ straight or branched chain aliphatic hydrocarbon group containing one double bond, for example, vinyl, allyl, 1-methylallyl, 2
-Methylallyl, 2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 3-butenyl, 2-
It means a lower alkenyl group such as pentenyl, 3-methyl-2-pentenyl, 2-hexenyl, 3-cyclopropylallyl, 3-cyclopentenyl, 3-cyclohexenyl.

The aryl group means an aromatic hydrocarbon ring group or an aromatic heterocyclic group consisting of a 5- or 6-membered monocyclic ring or condensed ring, and is phenyl, 1-naphthyl, 2-naphthyl, 2-pyrrolyl, 2 -Means furyl, 2-thienyl, 2-pyridyl and the like.

The aralkyl group is a group consisting of the above alkyl group and aryl group having 6 to 20 constituent atoms, for example, benzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenyl. Ethyl, 3-phenylpropyl, diphenylmethyl (benzhydryl),
Triphenylmethyl, 1-naphthylmethyl, 1- (1-
Naphthyl) ethyl, 1,2,3,4-tetrahydronaphthalen-1-yl, 2-pyrrolimethyl, 2-furfuryl, 2-thienylmethyl and the like.

Based on this definition, R ¹ in formula [I] represents a hydrogen atom, an alkyl group, an alkenyl group or an aralkyl group. Particularly preferably a methyl group,
It represents an allyl group, a cyclopropylmethyl group, a 2-methylallyl group, or a benzyl group.

R ² in the general formula [I] represents an alkyl group, an alkenyl group or an aralkyl group. Particularly preferably, it represents an allyl group, a 2-methylallyl group or a cyclopropylmethyl group.

Y in the general formula [I] is bonded to the pyrimidine ring via a nitrogen atom,

[0020]

[Chemical 8]

Represents a cyclic amino group represented by Where G
¹And G²Are C independent of each other₁~ C₆Alkyl group of
Represents G³And G^FourAre independently of each other a hydrogen atom, C
₁~ C _TenAlkyl group, alkenyl group, aryl group,
Or an aralkyl group, or two together form a cyclic alkyl group
It represents a kill group or an aryl group. Suitable examples of Y and
, 2,5-dimethylpyrrolidine, 3,4-dimethyl
Lupyrrolidine, 2,2-dimethylpiperidine, 2,6-
Dimethylpiperidine, 3,3-dimethylpiperidine,
3,5-dimethylpiperidine, pyrrole, 2-methylpyridine
Roll, 2-ethylpyrrole, 2-octylpyrrole,
2-benzylpyrrole, 3-methylpyrrole, 3-ben
Zirpyrrole, 2,5-dimethylpyrrole, 3,4-di
Methylpyrrole, 4,5,6,7-tetrahydropyrrole
Le, indole, 1-tetrazole, 2-tetrazole
And so on.

Specific preferred examples of the pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position represented by the general formula [I] according to the present invention include the substituents shown in the following table. The compound which does is mentioned. When the compound structural formula of the present invention has an asymmetric carbon, it includes all optical isomers thereof. Further, when a functional group which gives rise to a geometrical isomer is included in the structural formula of the compound of the present invention, all geometrical isomers thereof are also included.

[0023]

[Table 1]

The pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position of the present invention may be an acid addition salt, and examples of such an acid include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, boric acid, carbonic acid, formic acid,
Acetic acid, propionic acid, citric acid, succinic acid, malic acid,
Examples thereof include organic carboxylic acids such as oxalic acid, tartaric acid, maleic acid and fumaric acid, and organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid. Of these, hydrochloric acid, sulfuric acid, tartaric acid, maleic acid, fumaric acid, and methanesulfonic acid are preferable.

The pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position represented by the above formula [I] and the pharmaceutically acceptable acid addition salt thereof according to the present invention can be produced by any method. Although it does not matter, a whole reaction process scheme including a general manufacturing process can be represented as follows.

[0026]

[Chemical 9]

In the above formulas, R ¹ , R ² , and Y
Is the same as the above definition, X's each independently represent a halogen atom (eg, chlorine atom, bromine atom, iodine atom, etc.), and TBDMSOTf represents tert-butyldimethylsilyl trifluoromethanesulfonate.

The reaction steps leading to the compound of the above formula [I] are summarized as follows.

The compound of the formula ( 3 ) is obtained by treating the acetal ( 1 ) and the cyanoacetic acid ester ( 2 ) under alkaline conditions,
It can then be obtained by ring closure with guanidine in the presence of a strong alkali.

The compound of formula ( 4 ) can be obtained by subjecting the compound of formula ( 3 ) obtained above to ring closure in the presence of hydrochloric acid, and then halogenating by a conventional method (for example, phosphorus oxychloride). .

Regarding the method for producing the compound of formula ( 4 ) from the compounds of formula ( 1 ) and formula ( 2 ) above,
Reference [J. Davall., Journal of Chemical Society (J. Chem. Soc.) 131 (1960), F.S.
eela et al., Liebig Annalen Chemie (Liebigs. A
nn. Chem.) 137 (1983), 15 (1986)].

The compound of formula ( 5 ) is obtained by silylating the compound of formula ( 4 ) obtained above with TBDMSOTf,
Then, it can be obtained by reacting R ¹ X (X is a halogen atom) under alkaline conditions.

The compound of formula ( 6 ) is obtained by reacting the compound of formula ( 5 ) obtained above with R ² X (X is a halogen atom) in the presence of a strong alkali, and then desilylating with hydrochloric acid. be able to.

Alternatively, the compound of formula ( 4 ) is 4-methoxytritylated with p-anisylchlorodiphenylmethane and then R ¹ X (X is a halogen atom) under alkaline conditions and then in the presence of a strong alkali. The compound of the formula ( 6 ) can also be obtained by reacting R ² X (where X is a halogen atom) with, and finally by dehydromethoxylation with hydrochloric acid.

Finally, the compound of the above formula (I) can be obtained by reacting the compound of the above formula ( 6 ) with an amine of the following formula [II] under alkaline conditions.

Y-H ... [II] [wherein Y is the same as defined in the above formula [I]. ]

The compounds of the present invention have an excellent pharmacological action on hypoxemia associated with various respiratory diseases.

Generally, in various lung diseases such as emphysema, bronchitis, bronchial asthma, interstitial pneumonia, and pulmonary tuberculosis, the oxygen partial pressure (PaO ₂ ) in arterial blood decreases as the condition worsens or becomes chronic. It is known to cause fatigue, shortness of breath, difficulty in breathing, and in severe cases, symptoms such as dyspnea, cyanosis, and consciousness disorder.

Therefore, there has been a demand for a drug which increases and improves the PaO ₂ which has been lowered by various diseases of the respiratory system. In addition, in these diseases, it is often recognized that the arterial blood carbon dioxide partial pressure (PaCO ₂ ) is increased together with the decrease of PaO _{2. In} such a case, Pa
There has also been a need for a drug that has the effect of lowering PaCO ₂ in addition to the effect of increasing O ₂ .

The compounds of the present invention have the effect of enhancing respiratory function in the lungs, some of which mainly increase PaO ₂ only, and some of which decrease PaCO ₂ with increase of PaO ₂ . It can be used for treating hypoxemia associated with respiratory diseases.

The pharmacological action of the compound of the present invention can be clarified by an acute or chronic hypoxemia pathological model using experimental animals. For example, by injecting charcoal powder, silica gel, glass beads, and fine powder such as dental impression material into the lungs of small animals such as rats through the respiratory tract, an acute hypoxemia pathological model with reduced PaO ₂ is created. Yes [Reference: Munakata et al., The 35th Annual Meeting of the Japanese Society of Anesthesia, 179 (1988)]. In addition, by similarly administrating acetic acid or crotonic acid having mucosal inflammatory properties through the respiratory tract, it is possible to prepare an acute hypoxemia pathological model in which PaO ₂ is similarly reduced. Alternatively, a chronic hypoxemia pathological model in which PaO ₂ is lowered can be prepared by transbronchially administering bleomycin hydrochloride having a lung fibrosis effect. The compound of the present invention was orally or parenterally administered to such model animals, and after a certain period of time, arterial blood was collected and PaO ₂ (or PaCO ₂ ) was measured by a blood gas analyzer. A significant PaO ₂ increasing effect (or PaCO ₂ decreasing effect) was observed.

The pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position of the present invention and its acid adduct are orally or intravenously, subcutaneously, intramuscularly, transdermally, intrarectally and the like. It can be administered orally.

The dosage form for oral administration includes, for example, tablets, pills, granules, powders, solutions, suspensions and capsules.

In the form of tablets, for example, excipients such as lactose, starch and crystalline cellulose; binders such as carboxymethyl cellulose, methyl cellulose and polyvinylpyrrolidone; disintegrants such as sodium alginate, sodium hydrogen carbonate and sodium lauryl sulfate. And the like can be used for molding by an ordinary method.

Pills, powders and granules can also be formed by the usual methods using the above-mentioned excipients and the like.
Liquids and suspensions are formed by a usual method using, for example, glycerin esters such as tricaprylin and triacetin, alcohols such as ethanol and the like. Capsules are formed by filling granules, powders or liquids into capsules such as gelatin.

The subcutaneous, intramuscular, and intravenous administration forms include injections in the form of aqueous or non-aqueous solutions. As the aqueous solution, for example, physiological saline is used. As the non-aqueous solution, for example, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and if necessary, a preservative, a stabilizer and the like are added. The injection is sterilized by appropriately performing treatments such as filtration through a bacteria-retaining filter and addition of a germicide.

As the dosage form for transdermal administration, for example, ointment,
Examples include creams and the like. Ointments are oils and fats such as castor oil and olive oil; petroleum jelly and the like are used, creams are fatty oils; It

For rectal administration, conventional suppositories such as gelatin soft capsules are used.

The dose of the pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position of the present invention varies depending on the type of disease, administration route, age of patient, sex, degree of disease, etc. 1-500mg / per adult
Is the day.

[0050]

EXAMPLES The present invention will be described more specifically below with reference to examples and reference examples.

[0051]

[Reference example] 2-allylamino-4-chloro-7-methyl-7H-pi
Synthesis of loro [2,3-d] pyrimidine (6) <Method A> 5.00 g (29.6) of 2-amino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine ( 4 )
mmol), 4.96 ml of triethylamine (1.2e)
q), p-anisylchlorodiphenylmethane 10.08
g (1.1 eq) with dimethylformamide (DMF) 6
The reaction was carried out for 30 minutes with stirring at room temperature using 5 ml of the solvent. After cooling to 0 ° C, methyl iodide 4.50 ml
(2.44 eq), 3.00 g of sodium hydride (2.4.
53 eq) were added sequentially and the reaction was carried out for 1 hour. Further, 5.36 ml (1.5 eq) of allyl iodide and 2.00 g (1.7 eq) of sodium hydride were sequentially added and the reaction was carried out for 1 hour. 2N hydrochloric acid 200ml, diethyl ether 100
ml was added and the mixture was further stirred at room temperature for 1 hour. After neutralizing with sodium hydrogen carbonate, ethyl acetate (100 ml x 3
Times). Wash the organic layer sequentially with water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off.
The obtained oily substance was subjected to silica gel chromatography and eluted with a mixed solvent of hexane / ethyl acetate (8/1) to give the desired 2-allylamino-4-chloro-7.
3.51 g (yield 53.1%) of -methyl-7H-pyrrolo [2,3-d] pyrimidine ( 6 ) was obtained.

<Method B> 2-Amino-4-chloro-7H
-Pyrrolo [2,3-d] pyrimidine ( 4 ) 26.9 g
(159.5 mmol) and triethylamine 111 m
1 (5 eq) was added to 300 ml of methylene chloride, and -30
Stir at ℃. 36.7 ml of tert-butyldimethylsilyl trifluoromethanesulfonate (1.1
eq) was slowly added dropwise, and then the mixture was returned to room temperature and reacted for 1.5 hours. The crystals were completely dissolved into a light brown solution. The reaction solution was filtered through a glass filter lined with 200 g of silica gel, and the solvent was distilled off together with that eluted with methylene chloride 11. 1N in the obtained oily substance
Add 300 ml of aqueous NaOH and add hexane (500
(ml x 4 times). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. When the obtained crystals were recrystallized from hexane, 2
35.27 g of (-tert-butyldimethylsilylamino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine as light brown plate crystals (mp 114 ° C.) (yield 7
8.2%) was obtained.

Physical property values ¹ H-NMR (CDCl ₃ ) δ: 0.30 (s, 6
H), 0.98 (s, 9H), 4.5 (br-s, 1
H), 6.4 (m, 1H), 6.9 (m, 1H), 8.
3 (br-s, 1H). 2-tert-Butyldimethylsilylamino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine 43.7 g (154.5 mmol) thus obtained and 13.56 ml (1.4 eq) of iodomethane were added to 150 ml of DMF.
34.40 g (1.6 eq) of potassium carbonate was added and the mixture was reacted at room temperature for 15 hours with vigorous stirring. Add 300 ml of water to the reaction mixture and add hexane (200 ml x 4
Times). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 2-t.
ert-Butyldimethylsilylamino-4-chloro-7
-Methyl-7H-pyrrolo [2,3-d] pyrimidine ( 5 ) as light yellow crystals, 45.87 g (154.5 m)
mol) (quantitative). Allyl iodide 2
DMF (300 ml) was added and dissolved together with 1.19 ml (1.5 eq), and the mixture was cooled to 0 ° C. under a nitrogen stream and vigorously stirred. To this, 9.27 g (1.5 eq) of sodium hydride (60%) thoroughly washed with hexane was added little by little as a hexane suspension. After reacting for 10 minutes while stirring, 300 ml of water was slowly added to stop the reaction. It was extracted with hexane (300 ml × 4 times), and the organic layer was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 53.
5 g was obtained. This was dissolved in 30 ml of diethyl ether, and 50 ml of concentrated hydrochloric acid was added with stirring at 0 ° C. to react for 10 minutes. After completion of the reaction, diethyl ether (100 ml
(× 2) was added and the organic layer was separated. 200m ice water layer
It was diluted with 1 then neutralized with 5N aqueous NaOH and the resulting precipitate was extracted with ethyl acetate (250 ml x 3). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 2-allylamino-4-chloro-7-methyl-7H-pyrrolo [2,2].
3-d] pyrimidine ( 6 ) is 33.5 as pale yellow crystals.
7 g (yield 97.6%) was obtained. When recrystallized from ethyl alcohol, a slightly yellow plate crystal (mp113-
32.57 g (yield 9 as 114 ° C.)
4.0%) was obtained.

Physical property values ¹ H-NMR (CDCl ₃ ) δ: 3.67 (s, 1
H), 4.0-4.2 (m, 2H), 3.9-5.4.
(M, 3H), 5.75 to 6.25 (m, 1H), 6.
34 (d, 1H, J = 3.5 Hz), 6.77 (d, 1
H, J = 3.5 Hz). Elemental analysis: Calculated as C ₁₀ H ₁₁ N ₄ Cl: C, 53.94; H, 4.98; N, 25.1
6 Experimental value: C, 53.90; H, 4.98; N, 25.1
1

[0055]

Example 1 2-allylamino-4- (2,6-dimethylpiperidi
No) -7-methyl-7H-pyrrolo [2,3-d] pyrimy
Synthesis of gin and hydrochloride (No. 103) 2-allylamino-4-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine ( 6 ) 486 mg (2.18 mmol) 0.75 g (5.5 mmol) of potassium carbonate and 0.38 g (2.8 mmol) of lithium iodide were added to 1.51 g (13.4 mmol) of 2,6-dimethylpiperidine, and in a nitrogen atmosphere in an autoclave equipped with a stirrer. 160 ° C below
The mixture was heated to room temperature and reacted for 48 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate,
The solvent was distilled off. The residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3
1/1 to 1/1), the obtained colorless film-like substance is further fractionated and purified by high performance liquid chromatography (C ₁₈ column, elution solvent: acetonitrile / 0.1% trifluoroacetic acid aqueous solution = 37/63). , Colorless film-like 2-allylamino-4- (2,6-dimethylpiperidino) -7-methyl-7H-pyrrolo [2,3-d] pyrimidine [No. 103, free base] 36 mg (yield 6
%) Obtained. 36 mg (0.12 mmo of this free base
l) was dissolved in 5 ml of ethanol, and 2 ml of 7N hydrochloric acid / ethanol solution was added to this solution to give a hydrochloride. Ethanol and excess hydrochloric acid were distilled off, and the residue was dissolved in 10 ml of water and lyophilized to give 2-allylamino-4- (2,6
-Dimethylpiperidino) -7-methyl-7H-pyrrolo [2,3-d] pyrimidine hydrochloride [No. 103, hydrochloride] was obtained as a pale yellow powder in an amount of 23.2 mg (yield 57% from the free base).

Physical properties Free base ¹ H-NMR (CDCl ₃ ) δ: 1.30 (d, 6H,
J = 6.9 Hz), 1.51 to 2.04 (m, 6H),
3.62 (s, 3H), 4.07 (t, 2H, J = 5.
6 Hz), 4.77 (br, 1H), 5.05 (br,
2H), 5.07 (dd, 1H, J = 1.0, 10.2
Hz), 5.23 (dd, 1H, J = 1.2, 17.3)
Hz), 5.93 to 6.07 (m, 1H), 6.29
(D, 1H, J = 3.6 Hz), 6.57 (d, 1H,
J = 3.6 Hz). Hydrochloride EI-MS: m / z = 299 (M ⁺ ) detection

[0057]

Examples 2 to 10 In the following examples, the compound of the present invention was prepared according to the method of Example 1, and the corresponding starting material ( 6 ) and reactant (compound represented by the above formula [II])
Was used, and the reaction solvent, coexisting base, additives, and reaction temperature and reaction time separately shown in Tables 2 to 4 were used.

The physical properties of the compounds of the present invention (Nos. 101, 102, 104 to 110) thus obtained are shown in Tables 2 to 4 together.

[0059]

[Table 2]

[0060]

[Table 3]

[0061]

[Table 4]

[0062]

[Example 11] Effect on arterial blood gas partial pressure value (intravenous administration system) Male Wistar rats weighing about 300 g were anesthetized with halothane, and then 2.0 ml of 2.0% acetic acid was injected into the respiratory tract. It was made into the respiratory failure state by. Then, urethane-α-chloralose was anesthetized (ip) and the hip artery was cannulated. After the hypoxemia was stabilized (PaO ₂ : 60 to 70 mmHg), the compound provided by the present invention was continuously intravenously administered at 0.1 mg / kg / min for 10 minutes, and the arterial blood gas immediately after the administration was terminated. Partial pressure value (P
aO ₂ , PaCO ₂ ) was measured.

The results are shown in Table 5 below.

[0064]

[Table 5]

From Table 5, it is clear that the compound of the present invention has an effect of increasing PaO ₂ and an effect of decreasing PaCO _{2 in} parenteral administration compared to the pre-administration value in the acute hypoxemia pathological model. .

The acute toxicity of the compounds of the present invention is
₅₀ was 2 g / kg or more (rat, PO) in all cases. In addition, as a result of examination of intracellular accumulation toxicity, it was determined that the compound of the present invention had extremely low toxicity intensity.

[0067]

Example 12 Production of Tablet A tablet containing 30 mg of the compound of Example 1 was produced according to the following formulation. Example 1 Compound 30 mg Lactose 87 mg Starch 30 mg Magnesium stearate 3 mg

[0068]

Example 13 Preparation of Injection A solution for injection containing 0.3 mg of the compound of Example 1 in 1 ml was prepared according to the following formulation. Example 1 Compound 30 mg Salt 900 mg Injection-distilled water 100 ml

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Takahiro Takeuchi 4-3, Asahigaoka, Hino-shi, Tokyo Inside Teijin Ltd. Tokyo Research Center (72) Inventor Takashi Kadota 4--3, Asahigaoka, Hino-shi, Tokyo Teijin Limited Tokyo Research Center (72) Inventor Hideki Horiuchi 4-3 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center (72) Inventor Yoshihiro Yamanaka 4-3 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center (72) Inventor Keiji Komoritani 4-3 Asahigaoka, Hino City, Tokyo Inside Teijin Limited Tokyo Research Center

Claims (7)

[Claims] 1. The following formula [I]:[In the above formula, R¹Is a hydrogen atom, alkyl group, alkenyl
Represents a group or aralkyl group, R²Is an alkyl group,
Represents an alkenyl group or aralkyl group, Y is nitrogen
Attached to the pyrimidine ring via an atom of the formula:Represents a cyclic amino group represented by. Where G¹And G²
Are C independent of each other₁~ C₆Represents an alkyl group of³
And G^FourAre independently of each other a hydrogen atom, C₁~ C _TenA
Alkyl, alkenyl, aryl, or aralkyl
Group, or two together to form a cyclic alkyl group,
Represents an aryl group. ] Cyclic amino group at the 4-position
And a pyrrolo [2,3-d] pyrimidine derivative having
A pharmaceutically acceptable acid addition salt thereof. 2. A pyrrolo [2,3-d] having a cyclic amino group at the 4-position according to claim 1, wherein R ¹ is a methyl group, an allyl group, a cyclopropylmethyl group, a 2-methylallyl group or a benzyl group. A pyrimidine derivative and a pharmaceutically acceptable acid addition salt thereof. 3. A pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position according to claim 1, wherein R ² is an allyl group, a cyclopropylmethyl group, or a 2-methylallyl group, and a pharmaceutical thereof. Acid-acceptable acid addition salts. 4. R ¹ is a methyl group, R ² is an allyl group, and Y is of the formula: The pyrrolo [4] having a cyclic amino group at the 4-position according to claim 1, wherein G ¹ and G ² are each independently a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. 2,3-d] pyrimidine derivatives and pharmaceutically acceptable acid addition salts thereof. 5. R ¹ is a methyl group, R ² is an allyl group, and Y is of the formula: A cyclic amino group represented by, wherein G ³ and G ⁴ are each independently a hydrogen atom, a methyl group, an ethyl group, an n-octyl group, a phenyl group, a benzyl group, or two groups together are a phenyl group. The pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position according to claim 1, and a pharmaceutically acceptable acid addition salt thereof. 6. A pharmaceutical preparation comprising the pyrrolo [2,3-d] pyrimidine derivative having a cyclic amino group at the 4-position according to claim 1 as an active ingredient. 7. The pharmaceutical preparation according to claim 6, which is effective in treating hypoxemia.