JPH06329675A - 4-substituted alkylamino-pyrrolo(2,3-d)pyrimidine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound effective in preventing and treating hypoxemia accompanied by respiratory diseased. CONSTITUTION:A 4-substituted alkylamino-pyrrolo[2,3-d]pyrimidine derivative of formula I [R1 is H, alkyl, alkenyl, etc.; R2 is alkyl, alkenyl, etc.; R3 is H or 1-3C alkyl; R4 is 1-6C alkylene; R5 is 2-6C alkylene or 6-10c arylene; R6 is H or 1-3C alkyl; A and B are O, S, H or 1-3C alkyl-substituted N; (n) is 1 when R5 is 2-6C alkylene and (n) is 1-3 when R5 is 6-10C arylene] and its acid addition salt, e.g. 2-allylamino-4-(trans-4-ethoxyethoxycyclohexyl)amino-7- methyl-7H-pyrrolo[2,3-d]pyrimidine. The compound of formula I is obtained by silylating a compound of formula II (X is halogen) synthesized from acetal and cyanoacetic acid ester and reacting the resultant compound of formula III with an amine of formula IV.

Description

Detailed Description of the Invention

[0001]

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

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

[0003]

[Prior Art and Problems to be Solved by 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 the 4-position are substituted with amino groups and a method for producing the same are known [British Patent No. 81.
2,336; Townsend, LB et al., Journal
Of Medicinal Chemistry (J. Med. Chem.) V
ol. 31, 1501 (1988), etc.], and more their amino substituents primary amino group, compounds as each herbicide and antibiotic agents are also known [Okuda et al., Pesticide Science Journal of the Chemical Society Vol. 6, 9 (1981); Pedersen, EB
Chemica Scripta Vol. 2
8 , 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, a pyrrolo [2,3-d] pyrimidine having at the 4-position an alkylamino group in which an alkylene group or an arylene group substituted with a hydrogen atom or an alkyl group through a hetero atom is further substituted through a hetero atom. Derivatives are not listed in the prior art literature.

As a result of diligent studies on 4-substituted alkylmino-pyrrolo [2,3-d] pyrimidine derivatives, the present inventors have found that among the compounds not listed in the above literature, those represented by the following formula [I] Was found to have distinctly superior characteristics in terms of drug efficacy, toxicity and physical properties, as compared with the pyrrolo [2,3-d] pyrimidine derivative exemplified in the above-mentioned application by Sakuma et al. Was completed.

[0008]

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

[0009]

[Chemical 3]

(Where R is¹Is a hydrogen atom, alkyl group,
Represents a alkenyl group or an aralkyl group, R²Is alkyl
Represents a group, an alkenyl group or an aralkyl group, and R³Is water
Elementary atom or C₁~ C₃Represents an alkyl group of R,^FourIs C
₁~ C₆Represents an alkylene group of R^FiveIs C₂~ C₆A
Ruylene group or C₆~ C_TenRepresents an arylene group of
⁶Is a hydrogen atom or C₁~ C₃Represents an alkyl group of
And B are independently of each other an oxygen atom; a sulfur atom; or
Is a hydrogen atom or C₁~ C₃Substituted with an alkyl group of
Represents a nitrogen atom, n is R^FiveIs C₂~ C₆Alkylene group
Is 1, then R^FiveIs C₆~ C_TenArylene group
In the case of, it represents an integer of 1-3. ) 4-substitution
Alkylamino-pyrrolo [2,3-d] pyrimidine derivative
The body and pharmaceutically acceptable acid addition salts thereof, and
Of the derivative or a pharmaceutically acceptable acid addition salt thereof
It is a pharmaceutical preparation containing 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 cycloaliphatic hydrocarbon group, or a chain-cyclic aliphatic hydrocarbon group. , For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include cyclohexyl, cyclopropylmethyl and cyclobutylmethyl groups. Of these, preferred is a C ₁ -C ₆ alkyl group.

As the alkenyl group, at least one alkenyl group
C containing double bond₂~ C₆Straight chain or branched chain fat
Aliphatic hydrocarbon group, such as vinyl, allyl, 1-me
Cylallyl, 2-methylallyl, 2-butenyl, 2-me
Cyl-2-butenyl, 3-methyl-2-butenyl, 3-
Butenyl, 2-pentenyl, 3-methyl-2-pentenyl
2-hexenyl, 3-cyclopropylallyl, 3-
Cyclopentenyl, 3-cyclohexenyl group and the like are mentioned.
be able to. Preferably among these, C ₃~ C_Four
Means an alkenyl group.

The aryl group is an aromatic hydrocarbon ring group consisting of a 5- or 6-membered monocyclic or condensed ring (or 1-2 selected from oxygen atom, sulfur atom and nitrogen atom).
5 or 6-membered aromatic heterocyclic group having 4 heteroatoms), phenyl, 1-naphthyl, 2-naphthyl,
It means 2-pyrrolyl, 2-furyl, 2-thienyl, 2-pyridyl and the like.

The aralkyl group is a group consisting of the above alkyl group and aryl group having 7 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 group and the like can be mentioned. Preferably a C ₇ -C ₁₀ aralkyl group such as benzyl,
It means 1-phenyl ether, 1-methyl-1-phenylethyl, 2-phenylethyl and 3-phenylpropyl groups.

The alkylene group means a divalent C _{1 to} C ₁₀ linear or branched aliphatic hydrocarbon group, a cyclic aliphatic hydrocarbon group or a chain aliphatic hydrocarbon group, for example, methylene,
Ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, trans-
1,3-cyclopentylene, cis-1,3-cyclopentylene, trans-1,4-cyclohexylene, c
is-1,4-cyclohexylene, trans-1,2
- means cyclohexylene, alkylene group of C ₁ -C _10, such as cis-1,2-cyclohexylene.

The arylene group means an aromatic hydrocarbon ring group or aromatic heterocyclic group consisting of a divalent to tetravalent 5- or 6-membered monocyclic or condensed ring, for example, 1,4-phenylene, 1, 3-phenylene, 1,2-phenylene,
1,3,5-phenylene, 1,2,4-phenylene,
1,2,3,5-phenylene, 1,2,4,5-phenylene, 1,2-naphthylene, 1,4-naphthylene, 1,
6-naphthylene, 1,7-naphthylene, 2,3,6-naphthylene, 2,3,7-naphthylene, 2,5-pyrrolylene, 3,4-pyrrolylene, 2,3,4-pyrrolylene,
2,3,5-pyrrolylene, 2,5-furylene, 3,4-
Furylene, 2,3,4-furylene, 2,3,5-furylene, 2,5-thienylene, 3,4-thienylene, 2,
3,4-thienylene, 2,3,5-thienylene, 2,6
-Pyridylene, 3,5-pyridylene, 2,3,5-pyridylene, 2,4,6-pyridylene, 2,3,5,6-pyridylene group and the like are meant.

Based on this definition, the general formula [I] is
K R¹Is a hydrogen atom, an alkyl group, an alkenyl group
Rui represents an aralkyl group. Preferably hydrogen atom, C₁
~ C ₆Alkyl group of C₃~ C_FourThe alkenyl group
Is C₇~ C₂₀Represents an aralkyl group of
Is a methyl group, an allyl group, a cyclopropylmethyl group, 2-
Methylallyl group or benzyl group, particularly preferably methyl
Represents a radical.

R ² in the general formula [I] represents an alkyl group, an alkenyl group or an aralkyl group. It is preferably the same as R ¹ , particularly preferably allyl group, 2-methylallyl group or cyclopropylmethyl group, particularly preferably allyl group.

R ³ in the general formula [I] represents a hydrogen atom or a C ₁ -C ₃ alkyl group. Of these, a hydrogen atom, a methyl group or an ethyl group is preferable, and a hydrogen atom or a methyl group is particularly preferable.

R ⁴ in the general formula [I] is C _{2 to} C ₆
Represents an alkylene group. Among them, ethylene group, trimethylene group, trans-1,4-cyclohexylene group, cis-1,4-cyclohexylene group, tr are preferable.
ans-1,2-cyclohexylene group, or cis-
1,2-cyclohexylene group, particularly preferably ethylene group, trans-1,4-cyclohexylene group or c
It represents an is-1,4-cyclohexylene group.

R ⁵ in the general formula [I] is C _{2 to} C ₆
Represents an alkylene group or a C _{6 to} C ₁₀ arylene group. Among them, ethylene group, trimethylene group, trans
-1,4-Cyclohexylene group, cis-1,4-cyclohexylene group, trans-1,2-cyclohexylene group, cis-1,2-cyclohexylene group, 1,4-
Phenylene group, 1,3-phenylene group, 1,2-phenylene group, 1,3,5-phenylene group, 1,2,4-phenylene group, 1,2,3,5-phenylene group, 2,5- Pyrrolylene group, 3,4-pyrrolylene group, 2,3,4-pyrrolylene group, 2,3,5-pyrrolylene group, 2,5-furylene group, 3,4-furylene group, 2,3,4-furylene group ,
2,3,5-furylene group, 2,5-thienylene group, 3,
4-thienylene group, 2,3,4-thienylene group, 2,
3,5-thienylene group, 2,6-pyridylene group, 3,5
-Pyridylene group, 2,3,5-pyridylene group, 2,4
A 6-pyridylene group or a 2,3,5,6-pyridylene group is preferable, and an ethylene group, a trimethylene group, a trans-1,4-cyclohexylene group, and ci are particularly preferable.
s-1,4-cyclohexylene group, trans-1,2
-Cyclohexylene group, cis-1,2-cyclohexylene group, 1,4-phenylene group, 1,3-phenylene group, 1,2-phenylene group, 1,3,5-phenylene group, 1,2,4 A phenylene group, a 1,2,3,5-phenylene group or a 1,2,4,5-phenylene group, particularly preferably an ethylene group, a 1,4-phenylene group or a 1,3,5-phenylene group Can be mentioned.

R ⁶ in the general formula [I] represents a hydrogen atom or a C ₁ -C ₃ alkyl group. Of these, a methyl group, an ethyl group, an n-propyl group or an isopropyl group is preferable, and a methyl group or an ethyl group is particularly preferable.

A and B in the general formula [I] each independently represent an oxygen atom; a sulfur atom; or a hydrogen atom or a nitrogen atom substituted with a C ₁ -C ₃ alkyl group. Among them, A and B independently include an oxygen atom; a sulfur atom; and a nitrogen atom substituted with a hydrogen atom, and particularly preferably an oxygen atom.

Specific preferred examples of the 4-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative represented by the formula [I] according to the present invention include compounds having a substituent shown in the following Table 1. Can be 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.

[0025]

[Chemical 4]

[0026]

[Table 1]

The 4-substituted alkylamino-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, 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, organic carboxylic acids such as fumaric acid, methanesulfonic acid, ethanesulfonic acid, Organic sulfonic acids such as benzene sulfonic acid, p-toluene sulfonic acid, camphor sulfonic acid, etc. Of these, hydrochloric acid, sulfuric acid, tartaric acid, maleic acid, fumaric acid, and methanesulfonic acid are preferable.

The 4-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative represented by the above formula [I] and its pharmaceutically acceptable acid addition salt according to the present invention can be prepared by any method. Although it does not matter, the whole reaction process scheme including general manufacturing processes can be represented as follows.

[0029]

[Chemical 5]

In the above formulas, R ¹ , R ² , R ³ , R
⁴ , R ⁵ , A, B and n are as defined above, and X
Represents a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, 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 formula ( 3 ) is obtained by treating acetal ( 1 ) and 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). .

A specific method for synthesizing ( 4 ) from compounds ( 1 ) and ( 2 ) is, for example, J. Davall, J. C.
hem. Soc., 1960 , 131; F. Seela et. al., Liebi.
gs.Ann. Chem., 1983 , 137; F. Seela et. al.,
Liebigs. Ann. Chem., 1986 , 15 etc.

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, then R ¹ X (X is a halogen atom) under alkaline conditions and then R under strong alkaline conditions. The compound of formula ( 6 ) can be obtained by reacting ² X (where X is a halogen atom) and finally by de-methoxytritylation 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.

[0039]

[Chemical 6]

(Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , A, B
And n are the same as defined in the above formula [I]. The compound of the present invention has an excellent pharmacological action against hypoxemia associated with various respiratory diseases.

In general, in various lung diseases such as emphysema, bronchitis, bronchial asthma, interstitial pneumonia and pulmonary tuberculosis, the arterial oxygen partial pressure (PaO ₂ ) decreases as the condition worsens or becomes chronic. Is known, and symptoms such as dyspnea, cyanosis, and consciousness disorder are exhibited in severe cases including fatigue, shortness of breath, and difficulty in breathing.

Therefore, there has been a demand for a drug which increases and ameliorates PaO ₂ which has been lowered by these respiratory diseases. 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 enhance the respiratory function in the lung, some of them mainly increase PaO ₂ only, and some of them have the effect of lowering PaCO ₂ with increase of PaO _2. It can be used to treat hypoxemia associated with various diseases of the nervous system.

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. [Reference: Munekata et al., The 35th Annual Meeting of the Japanese Society of Anesthesia, p. 179 (1988)]. Also, by administering transmucosally acetic acid or crotonic acid, which has mucosal inflammatory properties, in the same manner as PaO. _{It is possible} to create 2 models of acute hypoxemia with reduced hypoxia. 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 4-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative of the present invention and its pharmaceutically acceptable acid adduct are orally or intravenously, subcutaneously,
It can be administered parenterally, such as intramuscularly, transdermally, and rectally.

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.

Similarly, pills, powders and granules can 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,
Creams and the like can be mentioned. 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-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative of the present invention varies depending on the type of disease, administration route, age of patient, sex, degree of disease, etc. 1 to 500 mg / day per person.

[0053]

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

[0054]

[Reference example] 2-allylamino-4-chloro-7-methyl-7H-pi
Synthesis of loro [2,3-d] pyrimidine <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 1 liter of methylene chloride. 300 ml of a 1N NaOH aqueous solution was added to the obtained oily substance, and the mixture was extracted with hexane (500 ml × 4 times). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate,
The solvent was distilled off. The obtained crystals are recrystallized from hexane to give 2-tert-butyldimethylsilylamino-4.
35.27 g of -chloro-7H-pyrrolo [2,3-d] pyrimidine as light brown plate crystals (mp114 ° C)
(Yield 78.2%) 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 methyl iodide 13.56 ml (1.4 eq) were added. DMF 150 ml
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).

Then, the obtained 2-tert-butyldimethylsilylamino-4-chloro-7-methyl-7H-
Pyrrolo [2,3-d] pyrimidine ( 5 ) together with allyl iodide 21.19 ml (1.5 eq) DMF 300 ml
Was dissolved in the solution, 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

[0059]

Example 1 2-allylamino-4- (trans-4-ethoxy)
Toxycyclohexyl) amino-7-methyl-7H-pi
Lolo [2,3-d] pyrimidine and sulfate (No. 1
02) in an autoclave equipped with a stirrer for trans-4-ethoxycyclohexylamine 33.6 g (0.18 mo
1) was dissolved in 60 ml of n-butyl alcohol, and the mixture was added with 2-allylamino-4-chloro-7-methyl-7H-pyrrolo [2,3-
d] Pyrimidine ( 6 ) 20.0 g (89.8 mmo)
l), 31.0 g (0.22 mol) of potassium carbonate and 15.6 g (0.12 mol) of lithium iodide were added, and the mixture was heated to 160 ° C. in a nitrogen atmosphere and reacted for 65 hours (internal pressure: 2 to 3 kgf). / Cm ² ). After returning the reaction solution to room temperature, 200 ml of water was added, and ethyl acetate (200
(ml × 2 times). Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off.
The resulting oily residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 2 /
1-1 / 2), 2-allylamino-4- in the form of brown oil
(Trans-4-methoxycyclohexyl) amino-
7-Methyl-7H-pyrrolo [2,3-d] pyrimidine [No. 102, free base] 28.7 g (yield 86
%) Obtained. 28.7 g (76.8 mm) of this free base
ol) was dissolved in 150 ml of acetonitrile, and to this solution was added a solution of concentrated sulfuric acid (97%) 7.77 g (76.8 mmol) in acetonitrile (50 ml). The precipitated crystals are directly dissolved by heating and recrystallized to give 2-allylamino-4- (trans-4-ethoxyethoxycyclohexyl) amino-7-methyl-7H-pyrrolo [2,3
-D] pyrimidine sulfate [No. 102, sulfate] was obtained as blue crystals (19.4 g, yield 54% from the free base).

Physical Properties Free Base ¹ H-NMR (CDCl ₃ ) δ: 1.20 to 1.32
(M, 2H), 1.22 (t, 3H, J = 6.9H
z), 1.45 (dq, 2H, J = 3.0, 12.9H)
z), 2.08 to 2.22 (m, 4H), 3.32 (t
t, 1H, J = 4.0, 10.2 Hz), 3.54
(Q, 2H, J = 6.9 Hz), 3.58 to 3.68
(M, 4H), 3.62 (s, 3H), 3.95-4.
10 (m, 3H), 4.61 to 4.72 (m, 2H),
5.09 (dq, 1H, J = 1.3, 10.2Hz),
5.25 (dq, 1H, J = 1.7, 17.2Hz),
5.93 to 6.07 (m, 1H), 6.13 (d, 1)
H, J = 3.3 Hz), 6.57 (d, 1H, J = 3.
6 Hz). ¹³ C-NMR (CDCl ₃ ) δ: 15.13, 30.7
1,31.31,44.46,49.04,66.6
3,67.64, 70.14, 96.39, 97.3
1,115.04,121.60,136.48,15
2.72, 156.33, 159.34. Hydrochloride IR (neat) νmax, cm ⁻¹ : 3239, 310
0,2940,2865,1655,1628,156
8,1452,1233,1103,1061,88
5,856,729,592. UV (EtOH) λmax, nm: 293, 270, 2
30. FD-MS: m / z = 374 ([M + H] ⁺ ) detection Elemental analysis: C ₂₀ H ₃₃ N ₅ O ₆ S Calculated value: C, 50.94; H, 7.05; N, 14.8
5; S, 6.80 experimental value: C, 50.80; H, 7.00; N, 14.7.
8; S, 6.85.

[0061]

Examples 2-10 In the following examples, the compounds of the present invention are used according to the method of Example 1, using the corresponding starting materials ( 6 ) and reactants (amine [II]), and Table 2 It was prepared under the conditions using the reaction solvent, the additive, the reaction temperature, and the reaction time individually shown in ˜4. Thus obtained compound of the present invention (No. 101, 103 to 11)
The physical property values of 0) are also shown in Tables 2 to 4.

[0062]

[Table 2]

[0063]

[Table 3]

[0064]

[Table 4]

[0065]

[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 state of hypoxemia was stabilized (PaO ₂ : 60 to 70 mmHg), the compound synthesized in Example 1 [No. 102, sulfate] (Example 11) was continuously administered intravenously at 0.1 mg / kg / min for 10 minutes, and the arterial blood gas partial pressure values (PaO ₂ , Pa) immediately after the end of administration.
CO ₂ ) was measured.

The results are shown in Table 5 below.

[0067]

[Table 5]

[0068] active display ΔPaO ₂ = test compound (immediately after administration PaO ₂ - PaO before administration _{2) ΔPaCO 2} = test compound - from Table 5 (immediately after administration PaCO ₂ PaCO ₂ before administration), acute hypoxemia In the case of parenteral administration in the pathological model, the test compound No. 10
2 (sulfate) has remarkable PaO ₂ raising activity and PaCO
₂ It is found that it has a lowering activity.

[0069]

[Example 12] Effect on arterial blood gas partial pressure value (oral administration system) A subacute hypoxemia pathological model was prepared by the following method.

That is, the Wistar system having a weight of about 350 g
Male rats were anesthetized with halothane and then 2.0% acetic acid at 0.
Respiratory failure by injecting 6 ml / kg into the respiratory tract
I was in a state. From the 2nd day after acetic acid administration, fast overnight and 3rd day
Anesthetize rat with halothane and attach cannula to hip artery
did. After anesthesia awakened, hypoxemia (PaO₂:
60 to 80 mmHg), and the compound synthesized in Example 1
Compound [No. 102, sulfate] 10 mg / kg orally
I gave it. 60 minutes later, the arterial blood gas partial pressure value (PaO ₂, Pa
CO₂) Was measured.

The results are shown in Table 6 below.

[0072]

[Comparative Examples 1-2] Effects of conventional compounds on arterial blood gas partial pressure (oral administration)
Given system) The compound synthesized in Example 1 as a test compound [No. 1
02, sulfate], and Example 13 except that the compound A (Comparative Example 1) or B (Comparative Example 2) exemplified in the aforementioned application [International Publication WO91 / 04254] by Sakuma et al. Similarly to, the arterial blood gas partial pressure value ((Pa
O ₂ , PaCO ₂ ) was measured. The results are also shown in Table 6.

The comparative compounds A and B are represented by the following structural formulas.

Comparative compound A; 2-allylamino-4-cyclohexylamino-7-methyl-7H-pyrrolo [2,2]
3-d] pyrimidine hydrochloride

[0075]

[Chemical 7]

Comparative compound B; 2-allylamino-4-
(2- (N, N-dimethylamino) ethyl) amino-7
-Methyl-7H-pyrrolo [2,3-d] pyrimidine hydrochloride

[0077]

[Chemical 8]

[0078]

[Table 6]

Activity display ΔPaO ₂ = Test compound (PaO ₂ 60 minutes after administration−PaO ₂ before administration) ΔPaCO ₂ = Test compound (PaCO ₂ 60 minutes after administration)
-PaCO ₂ before administration) From Table 6, in the case of oral administration in the subacute hypoxemia model, the fructose of the present invention and the conventional compound have lower PaCO ₂ lowering activity than the pre-administration value. Almost equal,
It can be seen that the compound of the present invention has a remarkable activity in increasing PaO ₂ activity. In addition, the acute toxicity of the compound of the present invention (test compound) used in the above examples is LD
₅₀ was 2 g / kg or more (rat, PO). As for the cumulative toxicity, the intracellular cumulative toxicity was examined, and as a result, it was determined that the toxicity of the compound of the present invention (test compound) was extremely low.

[0080]

Example 14 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

[0081]

Example 15 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 the front page (72) Minor Furuya 4-3, Asahigaoka, Hino-shi, Tokyo 4-3 Teijin Research Center, Tokyo (72) 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 (12)

[Claims] 1. The following formula [I]:(In the formula, R¹Is a hydrogen atom, alkyl group, alkenyl group
Or represents an aralkyl group, R²Is an alkyl group, alkeni
R group or aralkyl group, R³Is a hydrogen atom or
C₁~ C₃Represents an alkyl group of R,^FourIs C₁~ C₆A
Represents a alkylene group, R^FiveIs C₂~ C₆The alkylene group
Or C₆~ C_TenRepresents an arylene group of ⁶Is a hydrogen atom
Or C₁~ C₃Represents an alkyl group, and A and B are phases
Independently of each other, an oxygen atom; a sulfur atom; or a hydrogen atom
Or C₁~ C₃The nitrogen atom substituted with the alkyl group of
And n is R^FiveIs C₂~ C₆1 in the case of the alkylene group
And R^FiveIs C₆~ C_Ten1 for the arylene group of
Represents an integer of 3; ) 4-substituted alkylamido
No-pyrrolo [2,3-d] pyrimidine derivatives and
A pharmaceutically acceptable acid addition salt of. 2. R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, or a C ₇ -C ₁₀ aralkyl group, and R ² is C ₁ -C ₆ Alkyl group, C
Alkenyl group ₂ -C ₆ or C ₇ -C ₁₀ aralkyl group is claim 1 wherein the 4-substituted alkylamino, - pyrrolo [2,3-d] pyrimidine derivatives and pharmaceutically acceptable acid addition salt. 3. A 4-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative 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. And a pharmaceutically acceptable acid addition salt thereof. 4. The 4- according to claim 1, wherein R ² is an allyl group, a cyclopropylmethyl group or a 2-methylallyl group.
Substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivatives and pharmaceutically acceptable acid addition salts thereof. 5. The 4-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative according to claim 1, wherein R ³ is a hydrogen atom, a methyl group or an ethyl group, and a pharmaceutically acceptable acid addition salt thereof. . 6. R ⁴ is ethylene group, trimethylene group, t
trans-1,4-cyclohexylene group, cis-1,
The 4-substituted cyclohexylamino-pyrrolo [2,3-d] pyrimidine derivative according to claim 1, which is a 4-cyclohexylene group, a trans-1,2-cyclohexylene group or a cis-1,2-cyclohexylene group. A pharmaceutically acceptable acid addition salt thereof. 7. R ⁵ is ethylene group, trimethylene group, t
trans-1,4-cyclohexylene group, cis-1,
4-cyclohexylene group, trans-1,2-cyclohexylene group, cis-1,2-cyclohexylene group,
1,4-phenylene group, 1,3-phenylene group, 1,2
-Phenylene group, 1,3,5-phenylene group, 1,2,
The 4-substituted cyclohexylamino-pyrrolo [2,3-d] according to claim 1, which is a 4-phenylene group, a 1,2,3,5-phenylene group or a 1,2,4,5-phenylene group.
A pyrimidine derivative and a pharmaceutically acceptable acid addition salt thereof. 8. A 4-substituted cyclohexylamino-pyrrolo [2,3-d] pyrimidine derivative and a pharmaceutically acceptable derivative thereof according to claim 1, wherein R ⁶ is a methyl group, an ethyl group, an n-propyl group or an isopropyl group. Acid addition salts. 9. The method according to claim 1, wherein A and B are oxygen atoms.
9. The 4-substituted cyclohexylamino-pyrrolo [2,3-d] pyrimidine derivative according to any one of 8 above and a pharmaceutically acceptable acid addition salt thereof. 10. R ¹ is a methyl group, R ² is an allyl group, R ³ is a hydrogen atom or a methyl group, and R ^{4 is}
Is an ethylene group, a trans-1,4-cyclohexylene group or a cis-1,4-cyclohexylene group,
R ⁵ is an ethylene group, a 1,4-phenylene group or 1,
The 4-substituted cyclohexylamino-pyrrolo [2,3-group according to claim 1, which is a 3,5-phenylene group, R ⁶ is a methyl group or an ethyl group, and A and B are oxygen atoms.
d] Pyrimidine derivatives and pharmaceutically acceptable acid addition salts thereof. 11. A pharmaceutical preparation comprising the 4-substituted alkylamino-pyrrolo [2,3-d] pyrimidine derivative according to claim 1 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 12. The method according to claim 10, which is effective for treating hypoxemia.
The described pharmaceutical preparation.