JPH0710877A - 4-heteroalicyclic-pyrrolo(2,3-d)pyrimidine - Google Patents

Abstract

PURPOSE:To obtain a new compound useful for preventing and treating hypoxemia due to diseases in respiratory organs. CONSTITUTION:This compound is expressed by formula I [R<1> is H, alkyl, alkenyl, etc.; R<2> is an alkyl, alkenyl or aralkyl; R<2> is H or a 1-3C alkyl; Z is 4-to 7-membered heteroalicyclic group), e.g. 2-al lylamino-4-(4- tetrahydropyranyl)-amino-7-methyl-7H--pyrrolo[2,3-d]pyrimidine. The compound expressed by formula I is obtained by reacting a compound expressed by formula II (X is halogen) with an amine expressed by formula III 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]

FIELD OF THE INVENTION The present invention relates to a novel 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine.

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

[0003]

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

[0004]

[Chemical 2]

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 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. . Med.
Chem.) Vol. 31 , 1501 (1988)], and compounds whose amino substituents are primary amino groups are also known as herbicides and antibiotics, respectively [Okuda et al., Journal of Japan Society of Pesticides Chemistry Vol. . 6, 9 (1981), Peders
en EB et al., Chemica Scripta Vo
l. 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 derivative is disclosed by Sakuma et al. As a prophylactic and therapeutic agent for hypoxemia associated with respiratory disease [International Publication WO91 / 04254]. However, a pyrrolo [2,3-d] pyrimidine derivative having a heteroalicyclic group-substituted amino group at the 4-position has not been described in the prior art document.

As a result of diligent research on 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivatives, the present inventors have shown, among the compounds not listed in the above-mentioned document, especially those represented by the following formula [I]. 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], the prevention and treatment of hypoxemia associated with respiratory diseases. The present invention has been completed by finding out that it is effective for.

[0008]

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

[0009]

[Chemical 3]

[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, R ³ represents a hydrogen atom or a C _{1 to} C ₃ alkyl group, and Z represents ₁ to ₃ oxygen atoms. , A 4- to 7-membered heteroalicyclic group containing a nitrogen atom or a sulfur atom. However, when Z contains a nitrogen atom and this nitrogen atom is not bonded to the nitrogen atom substituted at the 4-position of the pyrrolo [2,3-d] pyrimidine ring, this nitrogen atom is a heteroalicyclic group. And C ₁
It may be substituted with a C ₃ alkyl group. ] 4-heteroalicyclic-pyrrolo [2,3-
d] A pharmaceutical preparation comprising a pyrimidine derivative or a pharmaceutically acceptable acid addition salt thereof and a derivative thereof or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

In the present invention, unless otherwise defined, the alkyl group means a C _{1 to} C ₁₀ linear or branched 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 refers to an aromatic hydrocarbon ring group or 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-pyrrolylmethyl, 2-furfuryl, 2-thienylmethyl and the like.

The heterocyclic group means a 4- to 7-membered saturated heteromonocyclic group containing 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms, for example, 3-oxetanyl, 1
-Methyl-3-pyrrolidinyl, 1-ethyl-3-pyrrolidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl, 1-ethyl-4-piperidinyl, 3-piperidinyl, 1-methyl-3-piperidinyl, 1-ethyl ―3―
It means piperidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-tetrahydropyranyl 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.

R ³ in the general formula [I] represents a hydrogen atom or a C ₁ -C ₃ alkyl group. Particularly preferably, it represents a hydrogen atom, a methyl group or an ethyl group.

Z in the general formula [I] represents a 4- to 7-membered heteroalicyclic group containing 1 to 3 oxygen atoms, nitrogen atoms, or sulfur atoms. However, Z contains a nitrogen atom, and this nitrogen atom is pyrrolo [2,3-
d] When not bonded to the nitrogen atom substituted at the 4-position of the pyrimidine ring, this nitrogen atom constitutes a heteroalicyclic group and may be further substituted with a C _{1 to} C ₃ alkyl group. A preferred specific example is 1-
Examples thereof include a methyl-3-pyrrolidinyl group, a 1-methyl-4-piperidinyl group, a 1-methyl-3-piperidinyl group, a 4-methyl-1-piperazinyl group and a 4-tetrahydropyranyl group.

4 of the general formula [I] according to the present invention
Preferable specific examples of the heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative include compounds containing each substituent shown in the following table. When the compound structural formula of the present invention has an asymmetric carbon, it includes all optical isomers thereof. Furthermore, when a functional group which gives rise to a geometrical isomer is contained in the structural formula of the compound of the present invention,
It also includes all geometric isomers thereof.

[0021]

[Table 1]

The 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative of the present invention may be an acid addition salt, and examples of such an acid include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Inorganic acids such as nitric acid, boric acid, carbonic acid, formic acid, acetic acid, propionic acid, citric acid, succinic acid, malic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid and other organic carboxylic acids, methanesulfonic acid, ethanesulfonic acid ,
Organic sulfonic acids such as benzene sulfonic acid, p-toluene sulfonic acid, camphor sulfonic acid and the like can be mentioned.
Of these, hydrochloric acid, sulfuric acid, tartaric acid, maleic acid, fumaric acid, and methanesulfonic acid are preferable.

The 4-heteroalicyclic-pyrrolo [2,3-d] represented by the above formula [I] according to the present invention.
The pyrimidine derivative and a pharmaceutically acceptable acid addition salt thereof may be produced by any method, but the whole reaction process scheme including general production steps can be represented as follows.

[0024]

[Chemical 4]

In the above formulas, R ¹ , R ² , R ³ and Z are as defined above, and X is independently 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 the formula ( 4 ) from the compounds of the above formulas ( 1 ) and ( 2 ), see [J. Davall., Journal of Chemical Society (J. Chem. Soc. ) 131 (1960), F. See
la et al, Liebig Analen Chemie (Liebigs. An
n. 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 under alkaline conditions with R ¹ X (X is a halogen atom) 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.

[0034]

[Chemical 5] [In the above formula, R ³ and Z are the same as defined in the above formula [I]. ]

The compound of the present invention has 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 ameliorates PaO ₂ which has been lowered by the 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 to enhance the respiratory function of the lung, which is intended primarily PaO ₂ only increases the, while others have the effect of lowering the PaCO ₂ with increasing PaO _2, such 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 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative and its acid adduct of the present invention are orally or parenterally such as intravenous, subcutaneous, intramuscular, transdermal, and rectal. Can be administered locally.

Examples of the dosage form for oral administration include 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 carboxymethylcellulose, methylcellulose 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 method 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, usual suppositories such as gelatin soft capsules are used.

The dose of the 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative of the present invention varies depending on the kind of disease, administration route, age of patient, sex, degree of disease, etc. 1-500mg per adult
/ Day.

[0048]

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

[0049]

[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 value 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

[0053]

Example 1 2-allylamino-4- (4-tetrahydropyranyl)
Amino-7-methyl-7H-pyrrolo [2,3-d] pyri
Synthesis of Midine and Hydrochloride (No. 101) 4-aminotetrahydropyran hydrochloride (500 mg, 3.65 mmol) was added to an autoclave equipped with a stirrer.
-Dissolve in 6 ml of butyl alcohol and add to it 2-allylamino-4-chloro-7-
Methyl-7H-pyrrolo [2,3-d] pyrimidine ( 6 )
700 mg (3.14 mmol) and potassium carbonate 1.
77 g (12.8 mmol) was added, and under nitrogen atmosphere, 1
The mixture was heated to 60 ° C. and reacted for 16 hours. After returning the reaction solution to room temperature, 5 ml of water was added, and ethyl acetate (30 ml x 2
2 times). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained oily residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1 to 1 /
2) and by high performance liquid chromatography (ODS, acetonitrile / 0.1% TFA aqueous solution = 1/3) to give 2-allylamino-4- (4-tetrahydropyranyl) amino-7-methyl as a pale yellow oil. -7H-pyrrolo [2,3-d] pyrimidine [No. 101, free base]
Was obtained (270 mg, yield 30%). This free base 2
Dissolve 70 mg (0.94 mmol) in 3 ml of ethanol, and add 6 N hydrochloric acid / ethanol solution to this solution for 1 m.
1 to give the hydrochloride. Ethanol and excess hydrochloric acid were distilled off, and the resulting residue was lyophilized to give 2-allylamino-
4- (4-Tetrahydropyranyl) amino-7-methyl-7H-pyrrolo [2,3-d] pyrimidine hydrochloride [N
o. 101, hydrochloride] was obtained as white powder (270 mg, 89% yield from the free base).

Physical Properties Free Base ¹ H-NMR (CDCl ₃ ) δ: 1.53 to 1.68
(M, 2H), 2.06 to 2.11 (m, 2H), 3.
52 to 3.60 (m, 2H), 3.65 (s, 3H),
4.00 to 4.11 (m, 4H), 4.29 (br, 1
H), 4.61 to 4.75 (m, 2H), 5.12 (d
d, 1H, J = 1.7, 10.2 Hz), 5.27 (d
d, 1H, J = 1.7, 17.2 Hz), 5.91-
6.03 (m, 1H), 6.18 (d, 1H, J = 3.
6 Hz), 6.62 (d, 1H, J = 3.6 Hz). Hydrochloride UV (EtOH) λmax, nm: 294, 232.

[0055]

Examples 2 to 5 In the following examples, the compound of the present invention was prepared according to the method of Example 1, and the corresponding starting materials ( 6 ) were used.
And the reactants (compounds of formula [II] above) and under the conditions using the reaction temperatures and times shown separately in Tables 2 and 3.

The physical properties of the compounds of the present invention (Nos. 102 to 105) thus obtained are also shown in Tables 2 and 3.

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

[Example 6] Effect on arterial blood gas partial pressure value (intravenous administration system) Wistar male rats weighing about 300 g were anesthetized with halothane, and then 2.0 ml of acetic acid 0.6 ml / kg was infused 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 4 below.

[0061]

[Table 4]

From Table 4, it is clear that the compound of the present invention has an action of increasing PaO _{2 in the} acute hypoxemia pathological model in comparison with the pre-administration value in the case of parenteral administration.

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.

[0064]

Example 7 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

[0065]

Example 8 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 Takashi Kadota 4-3, Asahigaoka, Hino-shi, Tokyo Inside Teijin Ltd. Tokyo Research Center (72) Hideki Horiuchi 4--3, Asahigaoka, Hino, 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 Teijin Limited Tokyo Research Center

Claims (7)

[Claims] 1. The following formula [I]: [In the above formula, R ¹ represents a hydrogen atom, an alkyl group, an alkenyl group, or an aralkyl group, R ² represents an alkyl group,
Represents an alkenyl group or an aralkyl group, R ³ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, and Z represents 1
It represents a 4- to 7-membered heteroalicyclic group containing 3 to 3 oxygen atoms, nitrogen atoms, or sulfur atoms. (However, when Z contains a nitrogen atom and this nitrogen atom is not bonded to the nitrogen atom substituted at the 4-position of the pyrrolo [2,3-d] pyrimidine ring, this nitrogen atom is a heteroalicyclic. Group which forms a group and may be further substituted with a C _{1 to} C ₃ alkyl group).
Heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivatives and pharmaceutically acceptable acid addition salts thereof. 2. The 4-heteroalicyclic 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 pyrrolo [2,3-d] pyrimidine derivative and a pharmaceutically acceptable acid addition salt thereof. 3. The 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative according to claim 1, wherein R ² is an allyl group, a cyclopropylmethyl group, or a 2-methylallyl group, and its pharmaceutically Acceptable acid addition salts. 4. The 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative and the pharmaceutically acceptable acid thereof according to claim 1, wherein R ³ is a hydrogen atom, a methyl group or an ethyl group. Addition salt. 5. R ¹ is a methyl group, R ² is an allyl group, R ³ is a hydrogen atom or a methyl group, Z is a 1-methyl-3-pyrrolidinyl group, 1-methyl-4-piperidinyl group. Group, 1-methyl-3-piperidinyl group, 4-
The 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, which is a methyl-1-piperazinyl group or a 4-tetrahydropyranyl group. 6. A pharmaceutical preparation comprising the 4-heteroalicyclic-pyrrolo [2,3-d] pyrimidine derivative according to claim 1 as an active ingredient. 7. The pharmaceutical preparation according to claim 6, which is effective in treating hypoxemia.