JPS6045199B2 - Novel imidazobenzoxazines and pharmaceutical compositions containing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel imidazobenzoxazines and pharmaceutical compositions containing them.

According to one feature of the present invention, the following general formula 1 (wherein X represents a hydrogen atom, a nitro group, an amino group or a protected amino group, and Z represents the following formula [where R is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms or a group of the following formula (wherein n represents 1, 2 or 3) or a group of the following formula; and Their salts are provided.

When X represents a protected amino group, this is, for example, an alkanoylamino group containing 2 to 5 carbon atoms, such as an acetamido group or a group of the formula represents an alkyl group containing a carbon atom.

When x represents an amino group or a group of the formula where R'' is as defined above, z preferably represents a group of the formula COOR where R is as defined above for R''. represents the group of

In the compounds of general formula 1, when R'' represents an alkyl group containing 1 to 5 carbon atoms, they can represent, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl.

Compounds of general formula 1 and their salts generally have interesting pharmacological properties, in particular antiallergic and bronchodilatory activity.

The compound of general formula 1 can be an acid, such as hydrochloric acid, hydrobromic acid,
Such as hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, methanesulfonic acid Acid addition salts can be formed with arylsulfonic acids such as alkanesulfonic acids and benzenesulfonic acids.

Also, z represents a carboxyl group and/or X is a group containing a free carboxyl group, such as a group of the formula -NH-C
Compounds of general formula 1 representing the group O--COOH may form salts with bases, for example with metals or nitrogenous chlorine.

Metal salts can be formed, for example, with alkali metals such as sodium, potassium or lithium, alkaline earth metals such as calcium or magnesium, or metals such as aluminum. Base addition salts that may be formed include ammonium salts and salts formed with amines such as lysine, arginine, triethanolamine and tris(hydroxymethyl)aminomethane. For pharmaceutical use, the salts mentioned above are pharmacologically acceptable salts, but other salts may also be used as intermediates in the preparation of compounds of general formula 1 and their pharmaceutically acceptable salts. It can be understood that it can have.

Preferred compounds according to the invention are those in which X is a hydrogen atom, a nitro group, an amino group, an acetamido group or has the formula -NH-CO-C
OOR'' (wherein R'' represents a hydrogen atom, a methyl group or an ethyl group) and Z represents a group of the formula -COOR (wherein R is as defined above for R'' or a group of the formula or a group of the following formula and salts thereof.

More preferably, X is a hydrogen atom, a nitro group, an acetamido group, or has the formula -NH
-CO-COOR'' (where R5 represents a hydrogen atom, methyl group or ethyl group), and Z represents a group of the formula -COO
R (where R is as defined above for R'' or represents a morpholinoethyl group) or a 4-methylpiperazin-1-ylcarbonyl group and salts thereof. .

Particularly preferred among the above compounds are compounds of the general formula 1, in which X represents a hydrogen atom and Z represents a carboxyl, morpholinoethoxycarbonyl or 4-methylpiperazin-1-ylcarbonyl group, and salts thereof.

Particularly preferred compounds according to the invention are as follows.

Shinichi imidazo [2.1-c] [1.4] Benzoxazine-2-carboxylic acid and its salt core-imidazo [2.1-
c] [1.4] Benzoxazine-2-carboxylic acid 2-
Morpholinoethynole 8-nitro 4H-imidazo [21
-c]・[1.4] Benzoxazine-2-carboxylic acid and its salts 8-acetamido d-imidazo [2◆11c] [1●4] Benzoxazine-2-carboxylic acid and its salts General formula 1 The compounds can be prepared, for example, by the methods described below (which, of course, form a separate feature of the invention).

CA) Process for the preparation of compounds of the general formula 1, in which X represents a hydrogen atom and Z represents a group of the formula -COOR, in which R represents an alkyl group containing 1 to 5 carbon atoms, for example a methyl group .

Decarboxylation of compounds of the formula (1) in which R3 represents an alkyl group containing 1 to 5 carbon atoms, for example a methyl group.

This decarboxylation is preferably carried out by heating the compound of formula (1). (B) of the general formula 1, in which X represents a hydrogen atom, a nitro group or a protected amino group, such as a lower alkanoylamino group, and z represents a group of the following formula, where n is as defined above: Method of manufacturing compounds.

Compounds of the formula 1 (Z represents a group of the formula -COOH) or reactive derivatives thereof, as defined above, such as the following formula 1, where X represents a hydrogen atom, a nitro group or a protected amino group; 2. Reaction of a compound of the following formula (1) with a compound of the following formula (1) in which n is as previously defined.

(C) A process for producing a compound of general formula 1, where X represents a hydrogen atom, a nitro group or a protected amino group, for example an alkanoylamino group containing 2 to 5 carbon atoms, and z represents a group of the following formula: .

Reaction of a compound of formula 1, as defined above, in which Z represents a group of formula -COOH, or a reactive derivative thereof, such as a compound of formula 1, as defined above, with a compound of formula 1, as defined above.

The compound of formula (1) is preferably reacted with a compound of formula (2) in the presence of an anhydrous organic solvent, such as dichloromethane.

(2) x represents a nitro group, and Z is as defined above,
Process for the preparation of compounds of the general formula 1, for example a radical of the formula -COOR, where R is an alkyl group containing 1 to 5 carbon atoms, for example a methyl group.

Nitration of a compound of formula 1 (X represents a hydrogen atom) as defined above.

This nitration may conveniently be carried out with a mixture of nitric acid and concentrated sulfuric acid.

(E) X represents an amino group and Z represents a group of the formula -COOR, where R is as defined above, for example an alkyl group containing 1 to 5 carbon atoms, such as a methyl group; A method for producing a compound of general formula 1.

Reduction of a compound of formula 1 as defined above, where X represents a nitro group and Z represents a group of formula -COOR, where R is as defined above, provides the desired compound of formula 1. can get.

This reduction is conveniently carried out using a mild reducing agent, such as stannous chloride, preferably in an acidic medium.

(F) A process for producing a compound of general formula 1, wherein X represents a protected amino group and Z is as defined above other than a group of the following formula.

Reaction of a compound of formula 1, as defined above, in which X represents an amino group and Z is as defined above other than a group of the formula, with an amine protecting agent provides the desired compound of formula 1. .

Amine groups can be isolated, for example, by reaction with a suitable alkanoyl chloride, such as acetyl chloride, as an amine protecting agent.
It can be protected with an alkanoyl group containing ~5 carbon atoms, such as an acetyl group.

Alternatively, the amine group may be of the formula -CO-COO-R, for example
'' (where R'' is as defined above, for example an ethyl group). Suitable amine protecting agents in this case are, for example, compounds of the following formula, where R'' is as defined above.

This reaction is conveniently carried out in an organic solvent such as dimethylformamide.

2(G) A method for producing a compound of general formula 1, wherein Z represents a group of formula -COOR (where R represents a hydrogen atom). Compounds of formula 1 as defined above (where Z is of formula 1COOR
(wherein R represents a group other than a hydrogen atom as defined above, such as an alkyl group containing 1 to 5 carbon atoms, such as a methyl group) to produce the desired compound of formula 1. is obtained. This hydrolysis is preferably carried out by
In the presence of a base, such as an alkali (e.g. sodium hydroxide). It will be held in

As is clear, when X in the starting compound of formula 1 represents a protected amino group, the protecting group can be hydrolyzed under the reaction conditions described above.

For example, in the starting compound of formula 1 the protecting group is of the formula -CO-
COOR'' (where R'' represents an alkyl group containing 1 to 5 carbon atoms, e.g. an ethyl group), this group has the formula -CO-COOH under the reaction conditions.
It is hydrolyzed to (H) A process for producing a compound of general formula 1, wherein Z represents a group of the formula -COOR, where R is other than a hydrogen atom.

A compound of the formula 1 (where Z represents a group of the formula 1COOH) or a reactive derivative thereof, as defined above, of the following formula
'' is as defined above for R other than a hydrogen atom) or a reactive derivative thereof.

This esterification can be carried out, for example, in compounds of formula 1 (Z is of formula -C
(representing an OOH group) with a compound of formula (1).

As understood herein, in the starting compound of formula 1 x
When represents a protected amino group, this protecting group may also undergo reaction with a compound of formula (1).

Thus, for example, if the protecting group consists of -CO-COOH, this group will still undergo reaction with a compound of formula (i) to form the formula -CO-COOR'', where R'' is as defined above. can form a group of

The compound of general formula 1 can also be converted, if desired, into its acid addition salt by reaction with a suitable acid, such as those exemplified above, preferably in substantially equimolar amounts. I can do it.

Furthermore, compounds of general formula I in which Z represents a carboxyl group can, if desired, be converted into their base addition salts by reaction with a suitable organic or inorganic base. General formula 1
The compound of general formula (1) used as a starting material in the production of the compound (2) is itself a novel compound and constitutes yet another feature of the present invention.

Compounds of general formula (1) can be prepared, for example, by combining compounds of formula (1) (wherein R3 is as defined above and Hal represents a halogen atom, such as bromine, iodine or more preferably a chlorine atom) with a base, e.g. It can be prepared by treatment with a weak base such as sodium carbonate followed by treatment with an acid such as concentrated hydrochloric acid.

Furthermore, the compound of general formula (1) is novel and constitutes yet another feature of the present invention. A compound of the general formula (2) can be obtained, for example, by reaction of a compound of the following formula (1) (wherein R3 is as defined above) with a haloacetyl halide, such as chloroacetyl chloride.

Compounds of formula (3) in which R3 represents an ethyl group are described in the literature. However, the remaining compounds of general formula (1) have not been described and are therefore novel compounds that constitute yet another feature of the present invention. A compound of the general formula (2) can be produced, for example, by hydrogenation of a compound of the following formula (2) (wherein R3 is as defined above).

Compounds of formula (3) in which R3 represents an ethyl group are described in the literature. However, the remaining compounds of the general formula (1) have not been described, and are therefore novel compounds that constitute yet another feature of the present invention. Compounds of general formula (2) can also be produced, if desired, by reaction of a compound of formula be able to.

Furthermore, the compound of general formula (2) used as a starting material in the production of the compound of general formula (1) is also a new compound and constitutes yet another feature of the present invention.

They are, for example, compounds of formula 1 as defined above (
X represents a hydrogen atom, a nitro group or a protected amino group, Z represents a carboxyl group) and a halogenating agent,
For example, it can be obtained by reaction with thionyl chloride or phosphorus halides (eg phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride). As mentioned above, compounds of general formula 1 and their salts have interesting pharmacological properties.

The tested compounds showed antiallergic and bronchodilator activity as exemplified below. The compounds of general formula 1 and their physiologically acceptable salts can therefore be used in the treatment of humans, in particular in the treatment of asthma and allergic bronchial asthma.

Pharmacologically Active Passive Skin Hypersensitivity (PCA) in Rats Skin hypersensitivity can be induced by sensitizing rats intradermally (ID) with antiserum and then administering the antigen systemically 3 days later. can.

Evans blue dye, which is injected with the antigen, is used to assess the severity of the local response. Anti-allergic medicines suppress this reaction. This method uses 0VARY(19
62) by “PassiveCutaneOusAr
laphy-1axisinA11erg010gyJ
p. 358-367 (edited by BrOwn, PergamOn
Press).

Male rats weighing 180-220y are divided into 7 groups and used.

Preparation of Sensitizing Antigen (Alum Precipitated Ovalbumen) Wash 1120 y of Al(0H)3 gel in 140 mt of saline (use of macerator facilitates mixing).

Centrifuge at 23,000 rpm for about 1 minute.

3 Precipitate 300ml of Albumen powder (1.3m91m
Resuspend together with 1) in salt water and leave to stand for 3 minutes.

Centrifuge once at 43,000 rpm. 5 Weigh the wet precipitate and add 1 ml of brine for every 1 g of weight.

Store in the refrigerator. Preparation of antiserum (i.e., anti-ovalbumen) (sufficient for a 3-day training program for 60 rats)
Rats aged 0-200y are injected subcutaneously on days O, 2 and 4.

Blood is collected from rats on day 214 by visceral puncture or via the dorsal abdominal aorta.

3. Collect an equal amount of serum from each animal and mix thoroughly.

A quantity of 42 ml is stored at -20°C in a plastic test tube.

Serum dilution sensitizing antiserum for PCA was added to control animals in 0.1 mL (7) ID.
2.0 to 3.5 injections per site using a 4-score system
diluted to give an average score between.

Method (4) Sensitized rats were treated with Nembutal (40-60 mg 1k91.p.
) and then sensitized by administering four D injections (0.1 ml each) on the shaved back.

The animals are then left for 3 days to allow sensitization to develop. (B)
Administration of 1 mt antigen/Evans blue mixture (a) to sensitized animals. The drug is administered orally or intravenously immediately before administering 5 mt of saline and 0.5 TfLt of 1% Evans blue plus 1 m9 of albumen egg powder intravenously through the superficial vein of the penis.

Injections are accelerated using an automatic 1 ml self-filling glass syringe. The "dosed" rats are sacrificed 30 minutes later (usually by puncture through the brain) and the skin on the dorsal surface is excised. The extent and area of bluing, which is proportional to the sensitivity phenomenon reaction, is evaluated using a 4-point system. Calculation 1 Total score for locations 1, 2, 3 and 4 = X2 Mean value of X for each group = X3 Older brother = Y for test group Amount of drug given The ED5O values for the compounds tested in the passive skin hypersensitivity screen in rats are as follows:

Acute Toxicity Examples of Compounds of the Invention Compounds of 1, 2, 4 and 5 were administered to a group of mice at 100 m
The g1k9 dose did not result in the death of any animal.

According to yet another feature of the invention, there is provided a pharmaceutical composition comprising at least one compound of formula 1 or a physiologically acceptable salt thereof, as defined above, together with a pharmaceutical carrier or adjuvant.

For pharmaceutical use, the compounds of general formula 1 and their physiologically acceptable salts can be incorporated as solids or liquids, optionally together with other active ingredients, into customary pharmaceutical formulations. . These compositions can be provided in a form suitable for oral, rectal, topical or parenteral administration, for example. Preferred forms include tablets, coated tablets, gelatin capsules, granules, suppositories, syrups, aerosols, creams, ointments and solutions, such as for injection. The active ingredients include auxiliaries commonly used in these pharmaceutical compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, It can be incorporated into paraffin derivatives, glycols, various wetting, dispersing or floating agents and/or preservatives.
Advantageously, these compositions may be formulated as dosage units, each unit being adapted to provide a fixed amount of active ingredient. A suitable dose for adults is 2 units of 0.5-100
m9, preferably 2 to 50 m9 of active ingredient.
The daily oral dosage may vary depending on the compound used, the patient being treated and the disease, but for example, 0.5 mg per day for adults.
It can be ~100 mg. The following examples illustrate the invention and do not limit it in any way. Example 1? -Imidazo [2.1-c] [1.4] Benzoxazine-2-methyl carboxylate α-oximinor 2-oxo? -1,4-benzoxazine-3-methyl acetate 82 da (0.375 mol) of 2-oxo? -1●4-
Benzoxazine-Δ3(4H)αmethyl monoacetate (Bu
ll. Chem. Sec. Japanl97l, 44(
5), P. 13ll~3) in 1f glacial acetic acid,
To this was added 15.0y (0.09 mol) of trichloroacetic acid, and then 48 da (0.38 mol) of amyl nitrite (
AnTlalen196&P. 83-104) were added.

The solution became warm (approximately 60° C.) and all of the starting material dissolved. After 2 hours, thin layer chromatography showed only a small amount of starting material remained.

An additional 3y of amyl nitrite was added and the mixture was then allowed to cool in an ice bath for an additional 2 hours. The solid product thus obtained was separated and thoroughly washed with ether until the liquid was colorless. Yield 74.4q, P2O. Dry with. The mother liquor was evaporated in a rotary evaporator to 70%
Concentration at °C to a volume of approximately 200 ml gave a secondary yield of 2.3y. Total yield 76.7 g (83%), pale yellow needles. Alcohol = 169-70℃. IR (KBr disc):
771, 979, 1022, 1250112 birds, 175
4, 3310c7r1-1(B) α-amino-2-oxo? -1,4-benzoxazine-Δ3(4H)α-monoacetate methyl 42.5y (0.17 mol) obtained in the previous step, α-oximinor 2-oxo? Methyl -1,4-benzoxazine-3monoacetate was suspended in 500 ml of tetrahydrofuran (dried with KOH pellets) and to this was added 0.7 g of platinum oxide.

The resulting mixture was hydrogenated under pressure up to 4 atmospheres.
Hydrogen absorption was fast and steady and ended after 1.5 hours.
The resulting dark red solution was filtered through Celite and the filter pad was thoroughly washed with chloroform. The suspension was then evaporated to dryness in a rotary evaporator at 45°C. 100 mt of cold absolute ethanol was added to the residue from Part 4 while grinding. The dark red crystalline product thus obtained was separated, washed with a small amount of cold ethanol and ether and finally dried. Yield 35.5f. 88% yield. MP=122-5°C. IR (KBr disc): 750
11218, 1241, 1280, 1302, 1510
, 1556, 1695, 1728, 3300, 3470 cm to 336:C) 2-Chloracetamide 2-
α of 50.2y (0.214 mol) obtained in the above step of (2-oxo?-1,4-benzoxazin-3-yl)methyl acetate
-Amino-2-oxo? -1,4-benzoxazine-Δ3(4H)α methyl monoacetate in glacial acetic acid (400ml)
30y (0.266 mol) of chloroacetyl chloride was added thereto.

A yellow precipitate formed, but redissolved upon heating. 50℃
After 3 hours, thin layer chromatography showed no starting material remained.

The glacial acetic acid was then removed in a rotary evaporator and 150 ml of absolute ethanol were added to the residue while cooling and trituring. The product was then separated and washed thoroughly with ether to give yellow needles after drying. Yield 52.6y179%
. Raccoon = 129-31℃. IR (KBr disc): 765,
1226, 1533, 1670, 174 length 1767, 3
295C7F! -1)) 4H-2-methoxycarbonylimidazo[2,1-c][1,4]benzoxazine-1-carboxylic acid
mol) of 2-chloroacetamido-2-(2-oxo?-1.4-benzoxazin-3-yl)methyl acetate was suspended in a mixture of 400 ml of water and 500 ml of acetone.

Add 40y (0.38 mol) to the solution thus obtained.
of anhydrous sodium carbonate was added. The resulting mixture was then warmed on a water bath for approximately 1 hour until a clear yellow solution was obtained.
Next, add concentrated hydrochloric acid to this hot solution while stirring until the pH is 2~2.
It was dripped slowly until it reached 3. A solid product crystallized immediately. After cooling this in an ice bath, it was taken separately, thoroughly washed with water, and finally dried with P2O5 to obtain the desired compound of 43.5y (off-white needles). 69% yield, ■=160~
2°C (decarboxylation).

IR (KBr disc): 75011243, 1276, 1
508, 15 Open, 1722 (1-1()4H-imidazo[2.1-c](1.4)benzoxazine-2-carboxylic acid methyl 20y (0.073 mol) obtained in the above step) 4H-2-methoxycarbonylimidazo [2●1
1c] [1.4] Benzoxazine-1-carboxylic acid was placed in a flask equipped with a magnetic stirrer.

The flask was placed in an oil bath at 175-180°C. Stirring was continued for about 20 minutes until boiling stopped. The decarboxylated product so produced was dissolved in chloroform and the resulting solution was run down a short silica column to remove remaining low Rf impurities. ■-Imidazo [2.1
1c] [1●4] The combined fractions containing methyl benzoxazine-2-carboxylate were dried and ether was added with stirring. The off-white product was separated, washed with a little ether and dried. Yield 14.0y18
3%, MP=133-4°C. IR (KBr disc): 74
5, 1259, 1562, 1715, 31a G-1 Example 2 4H-imidazo[2.1-c][1.4]benzoxazine-2-carboxylic acid 10.0' (4). 0435 mol) of 4H-imidazo[2.11c][1●4]methyl benzoxazine-2-carboxylate (e.g. prepared according to Example 1) in a mixture of 100 ml of methanol and 50 ml of water. suspended in.

A NaO solution was added to the resulting mixture until the pH became 11. The mixture was warmed until the starting material was completely dissolved. Thin layer chromatography showed no starting material remaining. The solution was then acidified to pH 2-3 using concentrated hydrochloric acid. Since the desired compound crystallized, the mixture was separated from each other after cooling and thoroughly washed with water. The white product was dried over P2O5. Yield 8.5', 91%,
? =256-8°C (decarboxylation). IR (KBr disc): 7
55, 1191, 1218, 1275, 1512, 15
5λ1695s2300-350 31ad-1 Example 3 1 Imidazo[2.1-c][1.4] Formation of THAM salt 6.0f (0.028 mol) of benzoxazine-2-carboxylic acid-imidazo[ 2.11c] [1●4] Benzoxazine-2-carboxylic acid (e.g. prepared according to Example 2) is suspended in methanol and charged at 3.5V (0
．． 029 mol) of tris(hydroxymethyl)aminomethane (THAM) was added.

A clear solution was obtained upon warming. Upon cooling and stirring, the desired salt formed as a white crystalline product. Yield 8.1
y185%, MP=203-5°C. IR (KBr disk)
:7501104011222, 1277, 1349s
136gs140λ1510~1602300~35
000 Example 4-N-(N''-methylpiperazinyl)imidazo[2.1-c][1.4]benzoxazine-2-
Carboxamide CA). 4H-imidazo [2.1-c]
[1.4] 4H-imidazo[2.1-c] of benzoxazine-2-carbonyl chloride 5f (0.023 mol)
] [1●4] Benzoxazine-2-carboxylic acid (e.g. prepared according to Example 2) was suspended in 15 ml of thionyl chloride and the resulting mixture was refluxed for 2 hours, during which time the solid material was completely dissolved.

Excess thionyl chloride was removed by azeotroping with benzene on a rotary evaporator. The product was triturated with ether, filtered and dried. Yield 4.5g, 83%. M.P.
=240°C (decomposition). IR (KBr disc): 84λ1 (
) &1764, 3110α-1(B)4H-N-(N
″-methylpiperazinyl)imidazo[2.1-c][1
・4] Benzoxazine-2-carboxamide 1.0f (0.0043 mol) of the acid chloride obtained in the above step was suspended in dry dichloromethane, and 1.0f (0.01 mol) of the acid chloride obtained in the above step was suspended in dry dichloromethane.
mol) of N-methylpiperazine was added.

After 3 hours at room temperature, thin layer chromatography showed no starting material remaining. The solution was then washed with water, dried and evaporated. Trituration of the residue with ether gave the desired compound. Yield 0.9y171%. M
P=215-7°C. IR (KBr disc): 740.12
53s1630s3130d-1 Example 5? -Imidazo [2
・1-c] [1.4] 2-morpholinoethyl benzoxazine-2-carboxylate 1.0f (0.0043 mol)
A monoimidazo[2.1-c][1.4]benzoxazine-2-carbonyl chloride (for example, prepared according to Example 4, A) is suspended in dry dichloromethane and mixed with 1. 31y (0.01 mol) of N-(2-hydroxyethyl)morpholine was added.

The resulting mixture was heated to 50°C for 2 hours. Thin layer chromatography showed that only a small amount of starting material remained. The mixture was then washed with water, dried and evaporated. The residue was chromatographed on a silica column using ethyl acetate as eluent. Finally, the product obtained was crystallized from ether. Yield 0.6y143%. Raccoon = 142~3℃. IR (KBr
Disc): 1255s1711, 314Scm-1 example 68
-Nitration-imidazo[2.1-c][1.4]methyl benzoxazine-2-carboxylate 8.0y (7).
Methyl 4FI-imidazo[2●1-c][14]benzoxazine-2-carboxylate (e.g. prepared according to Example 1) in a stirred mixture of 25 ml of concentrated magnetic acid and 25 ml of concentrated nitric acid. was added at 10°C.

The ester slowly became a solution, and the solution turned yellow. After 3 hours at room temperature, thin layer chromatography showed no starting material remaining. Then, 500 ml of water was added, and the resulting yellow product was separated, thoroughly washed with water, and then dried over P2O. Yield 7.5g, 79%. ■=
270-2℃. IR (KBr disc): 127den 134&
1541, 172 & 3150Crft-1 Example 7 8-Aminated-imidazo[21-c] [1.4] Methyl benzoxazine-2-carboxylate 5
．． 0y (0.018 mol) of methyl 8-nitro-imidazo[2◆1-c][1.4]benzoxazine-2-carboxylate (e.g. prepared according to Example 6) is
It was suspended in a mixture of 0ml acetic acid and 15ml concentrated hydrochloric acid.

15y (0.055 mol) of stannous chloride was added to the resulting solution. The resulting mixture was stirred and warmed to 40°C. After 1 hour crystalline product began to appear.

The mixture was then cooled in an ice bath for 2 hours. The product (sulfonate chloride) was separated and washed with ether. This salt was then dissolved in water and the pH of the resulting solution was adjusted to PH9 using dilute sodium hydroxide solution. Free amino compounds were extracted with chloroform. The combined chloroform extracts were dried, filtered and evaporated. The residue was triturated with ether to give brown crystals. Yield 2.7y1
61%. MP=213-4°C. IR (KBr disc): 1
740, 313 飄 3215. 3320, 3440 example 88
-acetamido-imidazo [2.11c] [1●4
] Methyl benzoxazine-2-carboxylate Follow the method of Step C of Example 1, except that 8-amino-imidazo[
2.1-c][1.4] The title compound was obtained using methyl benzoxazine-2-carboxylate (eg, prepared as shown in Example 7), acetyl chloride, and the solvent dimethylformamide.

Yield 72%, ■=216-9°C. IR (KBr disc):
To 151 To 170 To 175 3040 - 1 Example 98 - (Toxarylamino) 1 - Imidazo [2.1-c] [1
・4] Methyl benzoxazine-2-carboxylate Follow the method of Step C of Example 1, but with the exception of 8-amino-? using methyl -imidazo[2.1-c][1.4]benzoxazine-2-carboxylate (e.g. prepared as shown in Example 7) and ethyl chlorooxalate and dimethylformamide as the solvent. The title compound was obtained.

Yield 65%, MP=186-8°C. IR (KBr disk)
:156 to 1712, 173g. 3150, 3300 - 1 Example 10 8-Nitro-core-imidazo [21-c] [1.4] Benzoxazine-2-carboxylic acid The method of Example 2 is followed, except that 8-nitro-4H-imidazo [2.
The title compound was obtained using methyl 1-c][1.4]benzoxazine-2-carboxylate (eg, prepared as shown in Example 6).

Yield 83%, alcohol = 310-2°C. 1R (KBr disc):
127 to 1352, 153λ1571, 1690d-1
Example 11 8-acetamido? -Imidazo [2.11c] [1.
4] Benzoxazine-2-carboxylic acid Follow the method of Example 2, except that 8-acetamido-4-imidazo[2.1
-c][1.4]Methyl benzoxazine-2-carboxylate (prepared for example as shown in Example 8) was used to obtain the title compound.

Yield 75%, ■=295-6°C. IR (KBr disc):
3 to 152011555, 1667, 17401220
360 to 04-1 Example 12 8-Oxalamino? -Imidazo [2.11c] [1
・4] Benzoxazine-2-carboxylic acid Follow the method of Example 2, but with the exception that 8-(toxarylamino)-imidazo[2.1-c][1.4]benzoxazine-2-
Methyl carboxylate (eg, prepared as shown in Example 9) was used to obtain the title compound.

Yield 45%, MP=240°C (decomposition). IR (KBr disc): 156 to 1700 to 174 to 230 to 3700c
m″1 Example 13 Tablets containing the following ingredients were prepared.

THAM salt of imidazo[2.1-c][1.4]benzoxazine-2-carboxylic acid
・・5 da adjuvants (lactose, talc, starch, magnesium stearate)
...Amounts Sufficient to Make 1 Tablet 100 mg Example 1 A 4-dose meterable aerosol dispenser was filled with the following amounts of ingredients for one dose.

Heart-Imidazo[2.1-c][1.4]Benzo-xazine-2-carboxylic acid...5m9 Flotation agent...0.15m9 Propellant
...50m9

Claims (1)

[Claims] 1 The following general formula I ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) {Here, X is a hydrogen atom, a nitro group, an amino group, an alkanoyl containing 2 to 5 carbon atoms Represents an amino group or a group of the following formula ▲ Numerical formula, chemical formula, table, etc. [where R' represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms], and Z represents the following formula ▲ Numerical formula , chemical formulas, tables, etc. ▼ [Here, R is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, or the following formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (Here, n is 1, 2 or 3) represents a group] or Z represents a group of the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 2 X represents a hydrogen atom, a nitro group, an amino group, an acetamido group, or a group of the formula -NH-CO-COOR' (where R' represents a hydrogen atom, a methyl group or an ethyl group),
Z represents a group of the formula -COOR (where R represents hydrogen, a methyl group, an ethyl group, or a group of the following formula ▲ Numerical formula, chemical formula, table, etc.), or Z represents a group of the following formula ▲ Numerical formula, chemical formula, Compounds and salts thereof according to claim 1 representing the group ▼. 3 X is a hydrogen atom, a nitro group, an acetamido group, or a formula -
NH-CO-COOR' (where R' represents a hydrogen atom, a methyl group or an ethyl group), and Z is a group of the formula -C
OOR (where R represents a hydrogen atom, methyl group, ethyl group or morpholinoethyl group), or Z represents a 4-methylpiperazin-1-ylcarbonyl group, according to claim 2 Compounds and their salts. 4. Compounds and salts thereof according to claim 3, wherein X represents a hydrogen atom and Z represents a carboxyl group, a morpholinoethoxycarbonyl group or a 4-methylpiperazin-1-ylcarbonyl group. 5. The compound according to claim 1, which is 4H-imidazo[2.1-c][1.4]benzoxazine-2-carboxylic acid and a salt thereof. The compound according to claim 1, which is 2-morpholinoethyl 6 4H-imidazo[2.1-c][1.4]benzoxazine-2-carboxylate. 7 8-Nitro-4H-imidazo [2.1-c] [1.
4] The compound according to claim 1, which is benzoxazine-2-carboxylic acid and a salt thereof. 8 8-acetamido-4H-imidazo [2.1-c]
[1.4] The compound according to claim 1, which is benzoxazine-2-carboxylic acid and a salt thereof. 9 The following general formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {Here,
is a hydrogen atom, a nitro group, an alkanoylamino group containing 2 to 5 carbon atoms, or the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ [Here, R' is a hydrogen atom or an alkanoylamino group containing 1 to 5 carbon atoms [represents an alkyl group containing], Z represents the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Here, R is a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, or the following formula ▲ One or more of the compounds and salts thereof and a pharmaceutically acceptable carrier, including mathematical formulas, chemical formulas, tables, etc. or an antiallergic agent or bronchodilator composition comprising an adjuvant. 10. The composition according to claim 9, comprising 4H-imidazo[2.1-c][1.4]benzoxazine-2-carboxylic acid and its salt and a pharmaceutically acceptable carrier or adjuvant.