JPS60237086A - Pyrimidoisoquinoline derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, halogen or lower alkyl; R<2> is amino, nitro or acylamino; R<3> is (protected) carboxyl] and its salt. EXAMPLE:1-( 2,3-Dimethylpentanoylamino )-7-methyl-4-oxo-4H-pyrimido[2,1-n]-isoquinoline-3-carboxylic acid. USE:Antiallergic agent. PREPARATION:The compound of formula I (R<3> is protected carboxyl) can be pre pared by reacting the compound of formula II (e.g. 1-amino-4-methyl-7-nitroisoquinoline, etc.) or its salt with the compound of formula III (Ra<3> and Rb<3> are protected carboxyl; R<4> is alkoxy) (e.g. diethyl ethoxymethylenemalonate, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION INDUSTRIAL APPLICATION This invention relates to novel pyrimidoisoquinoline derivatives. More specifically, the present invention relates to salts thereof, methods for producing them, and pharmaceutical compositions containing them.

Problems to be Solved by the Prior Art and the Invention - Vehicle Weight Compounds that have anti-allergic effects have been known so far, but these compounds have
These compounds are not necessarily satisfactory in terms of side effects, stability, etc., and there has been a desire to create new compounds with antiallergic effects.

Means for Solving the Constituent Problems of the Invention The novel pyrimidoisoquinoline derivative of the present invention is represented by the following general formula.

(In the formula, R1 is hydrogen, halogen or lower alkyl group,
R2f71 means a diamino group, a nitro group or an acylamino group, R18 means a levoxy group or a protected carboxy group, respectively).

Examples of pharmaceutically acceptable salts of the pyrimidoisoquinoline derivative (1) include suium salt, potassium salt, ethanolamine salt, and tris(hydroxymethyl) salt.
Salts with inorganic or organic bases such as methylammonium salts,
and acid salts such as hydrochloride.

The novel pyrimidoisoquinoline derivative (I) of this invention and its pharmaceutically acceptable salts can be produced, for example, by the following production method.

Production method 1 (I) (H) (Ia) or a salt thereof or a salt thereof Production method 2 (Ib) (Ic) or a salt thereof or a salt thereof Production method 3 (Ie) (Id) or an amino group thereof or a salt thereof Process for producing a reactive derivative or a salt thereof 4 (Ia) (Is) or a salt thereof Process for producing a salt thereof 5 (Ie) (If) or a carboxy or salt thereof Process for producing a reactive derivative or a salt thereof in the cy group 6 (Ie ) (Ig) or a reactive derivative at the carboxy group or a salt thereof (wherein ml, R2 and R8 have the same meanings as before,
R2 is an acylamino group, R2 and R1) are each protected carboxy group, R
5 is an amidated carboxy group, rice is Nute! (R' means an alkoxy group).

The starting compound (It) or a salt thereof is a novel (Is compound), and can be produced, for example, in the production example described later or in a similar manner thereto.

Preferred examples and explanations of the various definitions in this specification will be described in detail below.

"Lower" shall mean 1 to 6 carbon atoms unless otherwise specified.

"Higher" shall mean 7 or more carbon atoms.

"Halogen" includes fluorine, chlorine, bromine and iodine.

Suitable lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzene, hexyl, and the like.

Suitable acyl moieties of the "acylamino group" include residues of organic acids such as organic carbonic acids, organic sulfonic acids, organic acetic acids, and the like.

Suitable "acyl" groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl n', 8.
8') Methylbutyryl, valeryl, isovale II t
and lower alkanoyl groups such as pivaloyl, or higher alkanoyl groups such as heptanoyl, 2,3-dimethylpentanoyl, lauroyl, myristoyl, valmitoyl, stearoyl, such as cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptyl. Lower cycloalkyl carbonyl group having 4 to 8 carbon atoms such as carbonyl, lower alkoxycalefonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, PI having 3 to 9 carbon atoms such as methoxalyl, ethoxalyl, propoxalyl, etc. Examples include lower alkanoyl groups having the following, lower alkanesulfonyl groups such as ethanesulfonyl and propanesulfonyl, arylcarbamoyl groups such as -yenylcarbamoyl and tolylcarbamoyl.

The acyl groups exemplified above may have one or more suitable substituents such as a hydroxy group, for example, an acyloxy group such as lower alkanoyloxy, or a heterocyclic carbonylamino group such as t-nicotinoylamino. .

Suitable "protected carboxy" groups include esterified carboxy groups and amidated carboxy groups;
Examples of 1 include methoxycarbonyl, ethoxycarbonyl, propoquinecarbonyl, improboxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 2- Examples include lower alecoxycarbonyl groups which may have a heterocyclic carboxamide such as nicotinamide, such as nicotinamide ethoxycarbonyl.

Suitable "amidated carboxy groups" include carbamoyl groups which may have suitable substituents on the nitrogen atom, such as heterocyclic groups, heterocyclic (lower) argyl groups, etc. can be mentioned.

” - “heterocyclic carboxamide”, “heterocyclic group-1” and “heterocyclic (lower) alkyl group”, more specifically, refers to It means a saturated or unsaturated heteromonocyclic or polycyclic group containing at least one heteroatom. Especially nail-shaped [heterocycle 1 is unsaturated 3 containing 1 to 4 nitrogen atoms]
~8-membered, and further nail-shaped 5- to 6-membered heteromonocyclic groups, examples of which include pyrrolyl, pyrrolinyl, pyrrolidinyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, Pyrimidyl, pyrazinyl, pyridazinyl, e.g. 4H-1
, 2,4-1-riazolyl, 1H-1,2,3-1-riazolyl, 2T(-1,,2,a-triazolyl, etc.), e.g., IH-tetrazolyl, 2H-tetrazolyl, etc. Can be mentioned.

The "heterocycle" exemplified above may have one or more suitable substituents, such as alkyl (lower) alkyl such as diphenylmethyl and benzyl.

Preferred amidated carboxyl groups include, for example, N-1) 1-tetrazolylcarbamoyl, N-2
-N-tetrazolycarbamoyl group such as -tetrazolylcarbamoyl, 4-alI group such as N-(4-diphenylmethylpiperazin-1-yl)ethylcarbamoyl, etc.
'(ItM) Alki lrepiberanno] - Itshikui Mr. R) Alreki! A lecarbamoyl group is mentioned.

Suitable examples include Metkin, Engineering 1, etc.
-oxy, propoxy, impropoxy, but-1-oxy, isobutoxy, tertiary-butoxy, pentyloxy, hexyloxy and the like.

The manufacturing method will be explained in more detail below.

Manufacturing method The target compound (Ia,) Takeso salt is compound (II)
It can be produced by reacting its salt with compound (III).

The salt of compound (It) is, for example, an acid addition salt such as a hydrochloride or a sulfate.

This reaction is usually carried out under heat in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, propatool, isobutyl alcohol, diphenyl ether, trichloride, xylene, and the like.

Production method 2 Compound (IC)t or a salt thereof can be produced by reducing compound (ll))i or a salt thereof.

The reduction is carried out by conventional methods such as reduction using a reducing agent such as a combination of iron and ammonium chloride, catalytic reduction, etc.

it original 1d iM constant, water, efnor, propano-
7, and is carried out in a solvent that does not adversely affect the reaction, such as isobutyl alcohol, N,N-dimethylformamide, tetrahydrofuran, chloroform, etc., under cooling or heating.

Production method 3 Compound (rd) or a salt thereof can be produced by reacting a reactive derivative at the amino group of compound (rd) or a salt thereof with an acylating agent.

Suitable reactive derivatives at the amine group of compound (IC) include Schiff's base-type imino-makaseno-enamine-type tautomers produced by the reaction of compound (IC) with carbonyl compounds such as aldehydes, ketones, etc. Examples include silyl rust conductors produced by the compound (re) and binu(trimethylsilyl)acetamide and trimethylsilylacetamide; derivatives produced by the reaction of the compound (IC) and phosphorous trichloride or honugen, and the like.

and its reactive derivatives.

Suitable reactive derivatives of the v compound (←) include, for example, acid halides such as acid chlorides and acid bromides, and conductors.

Delicious.

The reaction usually involves N,N-dimethylformamide, dimethylnulphoxide, tetrahydrofuran, dichloromethane,
It is carried out in a solvent that does not adversely affect the reaction, such as chloroform, pyridine, or a mixture thereof.

This acylation reaction can be carried out using, for example, atvr.
Alkaline earth metals such as gold m, fallen wood ff calcium, alkali metal hydrides such as sulfur hydride, calcium hydride, or alkaline earth metal hydrides such as sulfur hydroxide, potassium hydroxide, Alkali metal hydroxides such as calcium hydroxide or alkali metal hydroxides, such as sodium carbonate, potassium carbonate, ←←Silium carbonate, etc. Alkali metal carbonates or carbonic acid such as hydrogen carbonate and II-ium Hydrogen salts or alkaline earth metal bicarbonates, such as alkali metal alkoxides or alkaline earth metal alkoxides such as sodium ethoxide, lithium methoxide, magnesium methoxide, trialkylamines such as triethylamine, pyridine, e.g.
,5-diazabicyclo-(3,4, go]nonene-5
, 1,5-diazabicyclo-[5.

The reaction can also be carried out in the presence of an organic base such as a hycyclodiaza compound such as 4,0') undensen-5 or an inorganic base.

This reaction may be carried out in a well-cooled trench or at room temperature.

Manufacturing method 4 Compound (IC)? ! The salt of bamboo shoots can be produced by subjecting compound (Ia)t or a salt thereof to an elimination reaction of the carboxy protecting group.

This elimination reaction of the carboxy protecting group and (-) include hydrolysis, reduction, etc.

Hydrolysis can be carried out using inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc., as well as sodium hydroxide.
It is preferable to carry out the reaction in the presence of an inorganic base such as aluminum or an organic base.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as water, methanol, ethanol, propatool, acetic acid, etc., under cooling or heating.

When the starting compound (Ia) has an acylamino group substituted with an acyloxy group as 1 (2), along with the elimination of the carboxy protecting group in this reaction, the acyl group of the acyloxy group may be eliminated and converted to hydrogen. This case is also included within the scope of the present invention.

Production method 5 Compound (I f ) or a salt thereof is a compound (ru
It can be prepared by reacting a reactive derivative thereof or a salt thereof in the t- or sulfoxy group with an amidating agent.

As an amidating agent, amine, ie, thiR2NH2 (■
) [wherein R represents a suitable substituent such as a heterocyclic group, an alk(lower)alkylheterocyclic(lower)alkyl group], and reactive derivatives thereof or salts thereof.

Suitable reactive derivatives of compound (10) include acid halides, acid anhydrides, activated esters, and the like.

Suitable reactive derivatives of compound (V) include compound (
The same reactive derivatives as IC) can be mentioned.

This reaction is usually carried out in solvents that may adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dichloromethane, and the like.

This reaction is carried out under cooling or heating.

This reaction is preferably carried out in the presence of a condensing agent such as, for example, 1.1-levonyldiimidazole.

Production method 6 Compound (Ig)i Takeso salt can be produced by reacting Compound (IC)t or its reactive derivative in a carboxyne group or its salt with an esterifying agent.

Alcohols, i.e. 1(,7,
OH(V l ) (wherein R,, Ij represents a suitable substituent such as a lower alkyl group optionally having a heterocyclic carboxamide) and its reactive derivatives or salts thereof.

Suitable reactive derivatives of compound (IC) include acid halides, acid anhydrides, activated esters, and the like.

Suitable reactive derivatives of the compound (Vl) include the corresponding halides such as alkyl halides, diazo compounds such as diazoalkanes, esters of sulfonic acids, alkyl sulfonic acid esters, sulfates or alkaline earth metals. Examples include salts such as

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethylnulphoxide, pyridine, dichloromethane, and the like.

This reaction may be carried out under cooling or heating.

The target compounds of the above production methods 1 to 6 are purified by conventional methods,
It can lead to the desired salt.

The pyrimidoisoquinoline derivative (1) ld of the present invention is used as an antiallergic agent in its free form, as a salt with an inorganic acid or a salt with an organic acid, a salt with an inorganic base or an organic base, and a salt with an amino acid. It can be used in the form of pharmaceutically acceptable salts such as.

The target compound (I) or a pharmaceutically acceptable salt thereof can be generally administered to mammals including humans in the form of capsules, microcapsules, tablets, granules, powders, troches, and medical compresses.

The pharmaceutical composition of the present invention includes excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, l-calcium, cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, and gelatin. , gum arabic,
Binders such as polyethylene glycol, sucrose, starch, etc., such as starch, carboxymethyl! Disintegrants such as rerose, calcium salts of carboxymethyl cellulose, hydroxypropyl starch, sodium starch glycolate, sodium bicarbonate, calcium phosphate, calcium citrate, MA such as magnesium stearate, talc, sodium lauryl sulfate, etc. Lubricants, such as citric acid. acid,
Flavoring agents such as menthol, glycine, orange powder, etc., preservatives such as sulfur benzoate, sodium bisulfite, methylparaben, propylparaben, stabilizers such as citric acid, sulfur citrate, acetic acid, etc., such as methyl cellulose, Suspending and dispersing agents such as polyvinylpyrrolidone and aluminum stearate, aqueous diluents such as water, cocoa butter, polyethylene glycol, base waxes such as white petrolatum, and various organic or It may also contain an inorganic phase.

The dosage of this preferred ingredient will vary depending on various factors such as the weight and/or age of the patient and/or the stage of the allergic disease and also the type of administration route.

In general, the effective dosage is approximately 2 ml per day for oral administration.
0 to 2000 to approximately 2.5 to 25 ON per day for intramuscular injection or intravenous injection, approximately 1 per day for subcutaneous injection
O~1000■ and about 120 per day for rectal administration
~20011F. The total daily dose may be divided and administered to the patient at intervals of 6 to 12 hours per day. Preferred 1 indentation ff-! of this active ingredient! The amount is, for example, about 1 (1 to 5) per 11 tablets or capsules.
ff1y, approximately 1.25 per vial or ampoule
~25 ()■, or about 60-50 (l p
Examples of preparations of raw material compounds used in the preparation of ointments, solutions, or emulsions, for example, in the case of external medical dosage forms, are shown below.

Production Example 1 (1) Concentrated sulfuric acid (50 liters) of potassium nitrate (lllf)
The solution was stirred and a solution of 3,4-dihydro-4-methylisoquinoline (1219) in concentrated sulfuric acid (50 liters) was added to it.
It was added gradually over 1 hour at 20 to -111°C. The reaction mixture was stirred at room temperature for 3 hours, heated at 60° C. for 1.5 hours, poured onto ice, and made alkaline with 28% ammonium hydroxide while cooling. Count the resulting brown solid,
It was washed with water and dried under reduced pressure to obtain 3,4-dihydro-4-methyl-7-nitroisoquinoline (14,6:In).

IR (Nujol)・1628.1504. +842.
772,744 Ken - 1 time MR (ODO + 8.δ) + 1
．． 88 (8H, d, , I = 8.0Hz), 8.02 (I
H, m).

8.80 (2H, m), 7.46 (IH, d,, 1=
8J(I(z).

8.17 (IH, d, J = 2.1 HIz), 8.29 (
II(,dd,,I=8.8 and2.81(z),
8.46 (ITT, s) Mass spectrometry: 19ij (M
) 148,115(2) 3,4-dihydro-4-methyl-7-nitroisoquinoline (14,63g), palladium black (4g) and decalhydronaphthalene (170m
The mixture consisting of 1) was refluxed for 6 hours with stirring.

The reaction solution was left overnight at room temperature and then filtered, and the residue on the filter was washed with chloroform. P solution was diluted with 2N hydrochloric acid (70*
/X3). Combined water and dry ice
While cooling with acetone, an aqueous sodium hydroxide solution was gradually added. A light brown solid was collected, washed with water, and dried.

The crude product was purified by silica gel chromatography and eluted with chloroform to yield 4-methyl-7-nitroisoquinoline (6.06 fl).

IR (Nushor): +620.1460. +840,
795cM'.

NMR (CDOl, , δ): 2.70 (8Tl, s
), 8. +8(+1(,d,J=9.1lil(z).

8.49(IT(, dd, J=9.6, 2.4I(z)
, 8.59 (IH, s).

8.91(IT(,d,J =2.4I(z),9.8
2(H(,s) mass spectrometry: 188(M), 142.
115(3) 4-Methyl-7-nitroisoquinoline (4
A solution of 00 My) and 30% hydrogen peroxide (+1.65 kg) in acetic acid (2 ttl) was refluxed for 3.5 hours. After removing the solvent, stirring the residue in ether (50 liters) gives
A yellow powder formed. The powder was collected, washed with ether, and dried to give 4-methyl-7-nitroisoquinoline N-oxide (360 Wg).

IR (Nujol): 8060. +602.1524
, 1461.1844°1179-1 NMR, (DM80-d6.δ): 2.60 (8H,
s), 8.0-8.5 (8H, m).

8.88 (1) r, s), 9.10 (IH, s) mass spectrometry 204 (M) (4) 4-Methyl-7-nitroisoquinoline N-oxide ((1,8FM) of pyridine (20+++ /') While cooling the suspension, 1.82 g of tol chloride was added three times to it. After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethanol at room temperature. Amine (18m
7) was added and stirred for 45 hours. Pour this into ice water, ■-amino-4-methyl-7-nitroisoquinoline (
0,51Q Lr? 4*.

IR (Nu1os-le):8460.18]0,8860
．． 8100.16+2°1329τ-1 NMR (DM80-d6.δ): 2.84C81r, s
>, 7.20 (2TI, s).

7.90(11(,s), 7.96(IH,d,,I=
IO, 01fz).

8.89(IT(,dd,,I=10.0 and 2
．． 0T(z).

9.27 (IFT, d, J=2.11Hz) Mass spectrometry:
20B(M) Production Example 2 The following compound was obtained in the same manner as in Production Example 1 (4).

l-Amino-7-nitroisoquinoline IR (Nun*',k): 8460,8820,80
9011500.1825°339m-' NMR (DM80-d, , δ) near, 01 (ITT,
d, J=6.0Hz), 7.87 (2H.

brs), 7.85(11(,d,J-9,0
)1z) , 8.01 (Itf, d, J=
6.01 Tz).

8.81 (IH, dd,, I=9.0 and 2.2
Hz), 9.27 (IH, d.

J-2, 2nz) w amount analysis: 189 (M), 148, 116 Production Example 3 The following compound was obtained in the same manner as in Production Example 1 (4).

1-Amino-5-nitroisoquinoline I R, (Nujol) + 8480.8800.81
05. +640.1510°1332.790n' NMR, (DMSO-d6.δ) near, 27(2T(,
s), 7.34(11(,d,.

, l=6+Tz), 7.65(ITT, d,, ■==8
．． +ITz), 8.05 (ITJ, d.

J=6.0Hz), 8.44 (IT(,d,
J=8. N■z), 8.67(1■■, d
.

J=8.1 ITz) Mass spectrometry 189 (M) Production example 4 The following compound was obtained in the same manner as in Production Example 1 (4).

1-Amino-5-promo 8-nitroisoquinoline IR (Nunyol): F1475.3810. +64
8.1597.1095°865.840,740nR
'NMR(r)M2O-d6. , I): 635(21(
, s), 7.33 (ITT, d.

J=6.0Hz), 7.87(IHld, J
=8.011z), 8.19 (Hl, d.

J=8[II[z), 8.21 (+1-1.
d, ,I =6. +lHz) Mass spectrometry 269
(M +2), 268,267 (M), 250,22
1,142 Next, the present invention will be explained with reference to examples.

Example 1 1-amino-4-methyl-7-diI leusoquinoline (
3,87g), diethyl xymethylene malonate (
4,53 g) and N,N-dimethylformamide (2
Heat the mixture at 20°C for 4 hours while stirring. Diethyl ethoxymethylenemalonate (1g
) was added and the reaction mixture was then refluxed for 18 hours.
A precipitate formed upon cooling. The obtained crystals were separated and washed with cold ethanol to give 7-methyl-10-nitro-4-oxo-4H-pyrimyl'(2,1-a)isoquinoline-3.
-Ethyl ester of carbonic acid (4,21,&) was obtained.

I R, (Nujol): 1780. +480.13
36.1181m'Mass Spectrometry・827(M), 28
2,255.227 Example 2 7-Methyl-1+1-nitro-4-oxo-4H-pyrimido(2,1,-a)isoquinoline-3-carboxylic acid 6
ter (260~) with acetic acid (6πt) and 36% hydrochloric acid (8*
t) and refluxed for 50 minutes. 0 mixture
Upon cooling to °C, a yellow solid formed. The yellow solid was collected, dried and 7-methyl-1O-nitro-4
-Oxo-4H-pyrimido(2,1-a)isoquinolino-3-carphonic acid (180πg) was obtained.

Melting point 801-808°C I R (5+n, -r): 1748.1498.18
48ffi' mass spectrometry: 299 (M), 255,
227 Example 3 7-Methy7le-10-nitro-4-oxo-4-pyrimide (ethyl ester of 2,1-al isoquinoline-3-carboxylic acid (1401#y), iron powder (9077g),
Water (0,5*t) and ethanol (137〃/')
A solution of ammonium chloride (90 gg) in water (0.5 ml) was added to the stirred mixture under reflux. After refluxing for 1 hour and 50 minutes, ammonium chloride (28)Wl
) in water (0.5πl) and iron (50 gg) were added, and the reaction solution was stirred for 1 hour. Next, the reaction solution was filtered,
The residue on the second filter was washed with hot ethanol. The p-liquid was concentrated under reduced pressure and then titrated with a 1-lium oxyhydrogen solution to yield a crude product.

Silica alk 11 using chloroform-methanol:
Pure 10-amino-7
-Methyl-4-oxo-411-pyrimide [2゜l-a
) Ethyl ester of isoquinoline-3-carboxylic acid (
10 (1+17) was obtained.

Melting point 245-248℃ (0TICIsMeOH
).

IR (Nujol): 8440, 8850, 8280
．． +698. -1111678, +290,
I 186gM=NMR(DMSO-d6.δ): 1
．． 84 (811,t, J=6,4TTz).

2.49(3I(,s), 4.82(2H,q,
, I=6.4Hz), 6.05 (2H,s)
.

7.28 (IH, dd,, I=8.2 and 2.2
Hz).

7.72 (If (, d, J = 8.2 Hz),
8.04 (IH, d, J = 2.211z)
.

833 (]) T, s), 8.78 (1 T, s) Mass spectrometry: 297 (M ), 252.225, 197.15
7 Example 4 IO-amino-7-methyl-4-oxo-4■-pyrimido(2,1'-a')isoquinoline-3-carboxylic acid ethyl ester (40(1) e acetic acid (6 shoulders e) and 36
% hydrochloric acid (3 t) and refluxed for 55 minutes. The reaction mixture was then cooled and diluted with water. The resulting solid precipitate was collected and diluted with IN aqueous solution of 1-11% of hydroxide (6y
ne). 6 g of this solution is filtered to remove insoluble matter. The axilla was cooled, adjusted to pH 6 with IN hydrochloric acid, neutralized with acetic acid, and prepared with 10-amino-7-methyl-4-oxo-4)]-pyrimiI.(2,]-a) inquinoline. -3
-carboxylic acid (270m9) was obtained.

Melting point>300℃ r r< (Nureyol): 8455,8340.3
200. +726.1613°145 Nail 1 NMR (1) 20 Na (for, δ): 1.62 (31
1, s), 6.8-6.6 (8TT, m).

7.10 (+11.s), 8.07 (LII, s) Mass spectrometry 269 (M), 225,197,157 Example 5 10-amino-7-methyl-4-oxo-Apripyrimide' (2 , 1-a) In A pyridino (110πf) solution of ethyl ester of quinoline-3-carphonic acid (1,5F) was cooled with water and 2,3-dimethylbentainol chloride (1,4F) was added.
) was added. After stirring for 2 hours at room temperature, the reaction mixture was reduced in vacuo for 7 hours. The residue was dissolved in chloroform (1 (10yve)
), washed sequentially with water, IN cold hydrochloric acid and water, and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on silica gel, eluting with 1O-(2,3-dimethylpentanoylamino)
-7-methyl-4-oxo-4I(-pyrimido[2,l
-a] Ethyl ente of inquinoline-3-carphonic acid)
v(1,94y) was obtained.

Melting point 216-218℃ (CIIO+3-Et(Ml)
I R, (Nunyol): 3250.8+00. +7
55.1742. +6Ll.

1490.1122α-1 NMR ((1!Do+3.δ): 0.7-2.5(+
611. m), 2.57 (3H, s).

4.48 (211,q, J =7.211z)
, 7.79 (IH, d, J=8.2T]z)
.

8.00(Ill,s), 8.50(IH,dd,,I
=8.2 and 2.2TTz).

8.66 (IH, s), 8.90 (II-1, d, , I
=2.2Hz).

8.97 (ITI, s) Example 6 IO-(2,3-dimethylpentanoylamine)(-7
-Methyl-4-oxo-4■-pyrimide [2゜1-a]
Ethyl ester of isoginoline-3-carboxylic acid (50
0If/ ), 1. A mixture of N sodium hydroxide (3,6 t) and methanol (20 ml) was stirred at room temperature for 40 minutes. The reaction mixture was then diluted with water (30 m
1) and filtered. The fP solution was made acidic with hydrochloric acid, and the resulting precipitate was collected and dried to give 1O-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4-pyrimide [2゜1- a] Isoquinoline-3-carboxylic acid (320 mg) was obtained.

IR: 8B20. +? 4L] 690.
+5+5.1500°1433-1 NMR(r)MF30-d6. δ): 0.7-2.4C
IBT4. m), 2.62 (BIT, s).

8.02 (III, d, , I=8.411z), 8.
26 (IH, dd, , 1 = 8.4 and 2.4H
z), 8.59(IH,s), 8.97(11(,
s).

9.38 (IH, d, , I=2.411z), 10
．． 87(11(,s).

12.8-13.0 (IH, m) '16m1 analysis: 381 (M), 337,809,
269,251,197.85 Example 7 The following compound was obtained in the same manner as in Example 5.

10-L: “haloylamino-7-methyl-4-oxo-4■-pyrimido(2,1-a,)isoquinoline-3
-Calsifonic acid noethyl ester IR (Nujol) +
3410.8370.1740. +288.1322
゜11QQz' NMR (ODO+3.δ): 1.42 (911,s)
, 1.45 (811,1,,1=7.011z).

2.56 (811, s), 4.44 (2TI, q, J
=7.0ITz).

7.79 (IT-T, d, 1=9.OI]z), 8.
00 (III, broads).

8.48 (IT-1, dd, , I=9.0 and
2.2Hz).

8.65(11-1,s), 8.85(IT(,
d, J=2.2T(z), 8.94(II-
T, s) Example 8 10-pinochroylamino-7-methyl-4-oxo-
4H-pyrimido(2,1,-a,)inquinoline-3-
Ethyl ester of levonic acid (40011y), IN
A mixture of sumum hydroxide (B, 1 ml) and aqueous methanol (19 ff/) was stirred at room temperature for 2 days. Aqueous methanol was added to the reaction mixture and then heated on a water bath until almost all the precipitate had dissolved. The solution was filtered and the furnace solution was made acidic with 1N hydrochloric acid. The resulting precipitate was collected, washed successively with water and methanol, and dried. Recrystallize from a mixture of N,N-dimethylformamide and water to obtain pure 1
0-pivaloy 7 raremino-7-methyl-4-oxo-4
(1)-Pyrimido (2,1-a) isoquinoline-3-carboxylic acid (0,31F) was obtained.

rR (Nushor): 8850. +780.1687
．． 149B, +480°1292.853,805z
'Mass spectrometry: 85B(M), 309.281.251
, 224, 197.157.57 Example 9 The following compound was obtained in the same manner as in Example 5.

10-cyclohexylcarbonylamino-7-methyl-
Ethyl ester of 4-oxo-4■-pyrimido(2,1-a)isoquinoline-3-carboxylic acid IR
): 3340. +707.1690.1679. +4
80°797cm' NMR, (T)M2O-d6. δ): 1.1-2.8
(1111, m).

1.85 (311,t, J=7.4TTz), 2.58
(31T, s).

4.88 (2H,q, J=7.4Hz),
7.87 (ITI, d, , I=8.8Hz)
.

8.18(IT(,dd,,I=8.8 and 2.
0Hz), 8.5] (IH,s).

8.80 (IT-r, s), 9.21 (In, d
, J=2.0TIz), 10.30(11(
, s) Example 10 The following compound was obtained in the same manner as in Example 5.

10-isobutyrylamino-7-methyl-4-oxo-
41-i-pyrimido(2,1-a)isoquinoline-3-
Ethyl ester of levonic acid NMR (1) 8480-
66, δ)+1.17(6I(,d,,I=6.6Hz
).

+32 (8H, t, , I =7.21(z), 2.3
−2.9 (IT-f, m).

2.52 (8H,s), 4.80 (2H,q
, J=7.21'+z).

7.87NI(,d, ,I=8.2T(z),8.2
1(IH, dd, , I=8.2and 2.211z
), 8.49 (IH, s), 8.79 (II (, s).

9.18 (ITJ, d, J=2.2Hz), 10.
81 (IT(,s) Example 11 10-(2,3-dimethy7leventanoylamino)-7
-Methyl-4-oxo-4■-pyrimide [2゜1-a)
Add isoquinoline-3-carboxylic acid (257tf1g) and luponylciimidazole (1421ffg), and heat at 100°
It was heated to C. To this mixture was added 5-amino-Il,-tetrazo-I (7511fj), heated at the same temperature for 1 hour, and then cooled.

The resulting precipitate was collected in an oven, washed sequentially with N,N-dimethylformamide and methanol-I, dried, and converted to N-(llf-tetrazol-5-yl)-10-(2,8-dimethyl-I). noylamino)-7-methyl-4-,l-2so 41t(-pyrimido(2,1-a)isoquinoline-3
-carboxamide co, 16F) was obtained.

Movement: >aOO℃ IR, (Nujol): 8500,8290.81
00. +682,1597°1470, 800aR' Mass spectrometry: 448(M), 420.864.887
．． 266.251. +97°157.118.85.4
3 Example 12 The following compound was obtained in the same manner as in Example 8.

1()-isobutyrylamino-7-methyl-4-oxo-4H-pyrimido(2,1-a,)isoquinoline-3-
Carboxylic acid melting point 〉300℃ IR (Nushor): 8B10, 1748.1550
．． 1466.1440011-'Mass spectrometry + 889(
M), 295,269,251,225,197,1
57°142.115.7+, 48.27 Example 13 The following compound was obtained in the same manner as in Example 8.

10-Cyclohexy7 Shiruponi! Leamino-7-methyl-4-oxo-4,8-pyrimido (2,1-a) isoquinoline-3-carboxylic acid Melting point: ) 300°C IR (Nujol): 8810.1748.1698
．． +496.1436°1073α-1 Mass spectrometry: 879 (M+), 839. ao7.269
．． 251,225,197.88.55 Example 14 7-Methyl-10-nitro-4-oxo-4■-pyrimido(2,1-a)inquinoline-3-carphonic acid (3
00πy) of N,N-dimethylformamide (40
) solution was added to an aqueous sodium bicarbonate solution (60++/). After stirring for 1 hour, the reaction solution was left in a refrigerator, and the resulting precipitate was collected.

To this solid was added aqueous methanol, stirred at room temperature and collected under suction to give 7-methyl-IO-nitro-4-.

Melting point:) 800°C IR, (Nujol): 8870 (hr), 1707
．． 1497.1842.811m' Example 15 10-(2,3-dimethylpentanoylamino)-7-
Methyl-4-oxo-411-pyrimide [2゜i -a
) Ethyl ester of isoquinoline-3-carboxylic acid (
520m! fI>, IN sodium hydroxide aqueous solution (g (
A mixture of 3.6M/), aqueous methanol (25+yl) was stirred at room temperature for 2 days.More methanol was added until almost all the precipitate was dissolved.

This solution was concentrated to half its volume under reduced pressure and filtered.

The p solution was diluted with water and left in the refrigerator. The resulting eye wash was collected, washed with water, and dried to give 1O-(2,3dimethylpentanoylamino)-7-methyl-4-oxo-4-pyrimide(2,1-a]isoquinoli/-3-carvone. The sodium salt of the acid (210+Iy) was obtained.

Melting point:) 800°C IR (Nureyol): 8420. B270,1700
, 1690. +662°1880.817 equipment-1 Example 16 10-Amino-7-methyl-4-oxo-4H-pyrimide (2,1,-a) isoquinolino-3-carboxylic acid ethyl ester (800IIIg) in pyridine (6 Mesyl chloride (11,28f/Ie) was added to the solution at water bath temperature.
) was added. Reaction # was stirred at room temperature overnight then concentrated under reduced pressure. Collect the residue, 0. Wash sequentially with INt3 acid and water,
Recrystallized from N,N-dimethylformamide, 10-
Ethyl ester of mesylamino-7-methyl-4-oxo-411-pyrimido(2,1-a) isoquinoline-3-carboxylic acid (0,761) was obtained.

IR (Nushor): 8240.17+0.1660
, 1488.1142°962.802n' Mass spectrometry: 875(M), 'a60. B30.29
6.268,251,224゜196.157,128
．． 1+5.79,5L29 Example 171 The following compound was obtained in the same manner as in Example 16.

10-Ethoxy power! Levonylamino-7-methyl-4-
Oxo-411-pyrimido(2,]-a) ethyl ester of isoquinoline-3-carboxylic acid Melting point: 289-2
92°C IR (Nureyol): 8820.1728. +476
．． 1292.1222°1+48. l060.8Llα
-1 Mass spectrometry: 869 (M), 823, 297, 278
, 251.228.188°155.140. +14.
78,58.29 Example 18 The following compound was obtained in the same manner as in Example 8.

IO-Mesylamino-7-methyl-4-oxo-4H-
Pyrimido(2,]-a)inquinoline-3-carboxylic acid Melting point 〉300℃ IR (Nunyol): 8260.8+80.1728
,1512.1+62°+142,802n-' Mass spectrometry: 847(M), 308,275.285
,224,196,169°128.115.82,5
8.15 Example 19 The following compound was obtained in the same manner as in Example 16.

10-ethogyzarylamino-7-methyl-4-oxo-
Ethyl ester of 4-pyrimido(2,1-a)isoquinoline-3-carboxylic acid Melting point: 27B-275°C IR (Nujol): 8820.1740.1707
．． 1480. ++18°800α-1 Mass spectrometry: 397 (M), 852,825,296
,278,251.228°188,+57.140,
115.77.58.29 Example 20 10-Amino-7-methyl-4-oxo-4H-pyrimide (2,1,-a) Ethyl ester of isoquinoline-3-carboxylic acid (600~) in pyridine (60 ml) Phenyl isocyanate (0.22 t) was added to the solution at water bath temperature. The reaction was stirred at room temperature overnight. The precipitate was collected and
Wash with methanol and dry. Recrystallized from dimethyl sulfoxide to give 10-(3-phenylureido)-7-
Ethyl ester of methyl-4-oxo-4H-pyrimido (2,1-a) isoquinoline-3-carboxylic acid (0,5
8g) was obtained.

Melting point: >SOO℃ IR, (Nureyol) + 8350. +727. +70
4. +482. +2]6゜1+38.798/7x' Mass spectrometry: 416 (M), 828,297,252
, 197. +57.119°64.39 Example 21 The following compound was obtained in the same manner as in Example 1.

10-nitro-4-oxo-41(-pyrimido(2,)
=a,) Ethyl ester of inquinoline-3-carboxylic acid IR (Nureyol) 3060,1733. +488.
1350.1140.803NMR, (CI) CI3.
δ): 148 (8H, t, J=7.5Hz).

4.47 (2+1.q, , I=7.5Hz)
, 7.54 (IN, d, , I=7.95TI
z).

8.02 (IH, d, J = 9.01Tz),
8.72 (III, dd, , I=9.0 a
nd3.0Tlz), 9.13 (II(,d
, ,I=7.950z), 9.14(IT(,s).

10.0 (In, d, , I=8.0Hz) Mass spectrometry, 318 (M), 268,241. HL]27,29
Example 22 Actual) X5 The following compound was obtained in the same manner as in Example 3.

10-Amino-4-oxo-4H-pyrimide (2,1,
-8] Isoquinoline-3-carboxylic acid ethyl ester IR, (Nunyol)・3450.33+0.8200
．． :j+00. +728°1665.1118,830
,803.780(7)-1HMR(I)M2O-d6
．． δ): 1.32 (8H1t, I=6.8Hz)
, 4.30 (2IT.

q,,I =6.8Hz),6.09(2T(,br
s).

7.30 (In, dd, , 1 = 8.4 and
2. QI-1z), 7.55(IT(,d.

, I=7.2TTz ), 7.75 (IH,d
, ,I=8.4T(z).

8.03 (ITj d, J = 2.01Tz)
, 8.53 (IN, d, , I=7.2Hz)
.

8.86(11(,s) Example 23 The following compound was obtained in the same manner as in Example 5.

1O-(2,8-dimethylpentanoylamino)-4-
Oxo-4■-pyrimido(2,1-a)inquinoline-
Ethyl ester of 3-carphonic acid IR (Nujol):
3350. +720.1680.1488. +305
．． 1++8°34m-1 NMR (CDCl2.δ): 0.6-2.7N6TI
, m), 4.44 (21(, q.

J = 7.4■z), 7.38 (III, d
, ,I=7.8Hz)7.72(+i1.d,
J=9.0Hz), 8.88(IH,s).

8.47 (IIl, dd, , I=9.0 and 2
．． 0T-Tz), 8.8+(ITI, d.

J=7.8Hz), 8.95(In,d,,1=2.0
Hz), 9.00 (]H, s) Example 24 The following compound was obtained in the same manner as in Example 8.

1O-(2,3-dimethylpentanoylamino)-4-
Ogiso 4 l-1-pyrimide (2,1-a)isogynoline-3-carphonic acid Melting point ・＞aOO℃ TR (nu*, -ru): 3820.+740.1492
．． 1+22.840cIR'γT Month 1 analysis: 367 (hey), 255.21+, +83.85.43 Example 2
5 The following compound was obtained in the same manner as in Example 1.

8-nitro 4-oxo-4H-pyrimide [2゜l-a
] Ethyl ester of inginoline-3-carboxylic acid
Melting point: 202°C IR (51 mm): 1710. +690. +49
0. II40.790a 'NMR, (CDCl3.δ
): 1.44 (811,t, ,I=6.6H
z).

4.47 (2TI, q, J = 6.6tTz
).

7.87 (IIl, + , , I=8.0TIz
), 8.22(In, d, J=8.2rlz
).

8.62 (III, d, , 1 = 8.0TTz
) , 9.06 (III, d , , T = 8.2
Hz).

9.07(IIl,s), 9.50(IT(,d,,1
=8.01(z) Example 26 8-nitro-4-oxo-41]-pyrimide [2°1,
- a) Ethyl ester of isoquinoline-3-carboxylic acid (400 mf/) was suspended in a mixture of acetic acid (2+1 ml and 36% hydrochloric acid (4 ml), heated with go'c* for 5 hours, then cooled and diluted with water. The precipitated solids were collected and dried to give 8-nitro-4-oxo-4H-pyrimido(2,1-a)isoquinoline-3-carboxylic acid (32
(17?) was obtained, m point d>aoo°C (recrystallized from N,N'-dimethylformamide) IR (Nujol): 1720.1640. +250
, 880.770a++ 'Mass spectrometry: 285 (M
), 24+, 127.58.18 Example 27 The following compound was obtained in the same manner as in Example 3.

8-Amino-4-oxo-4■-pyrimide [2゜1-a
) Ethyl ester of isoquinoline-3-carboxylic acid Melting point 225℃ 11 ((Nunyol) + 3450.8360.+73
5.1490.1+80cm 'NMR, (CD) C1
0, δ)+1.44(IT(,+,,I=7.81T
z), 4.47 (Irr.

q, J-7,3TTz), 7.20(III
, d, J = 7.8T(Z), 7.48(
IH.

d, , I=7.811z), 7.61 (IT
T, t, , I=7.8TTz).

8.58 (IH, d, , 1 = 7.8Hz),
8.96 (II(,d, ,I=7.8Hz)
.

9.11 (11(,s) Example 28 The following compound was obtained in the same manner as in Example 4.

8-Ami/-4-oxo-414-pyrimide [2゜1-
a, :]]isoquinoline-3-carboxylic acid melting point>3
00'C In (Nushor): 3450,8350. ]735
．． +680. +140°787(7)-1 Mass spectrometry: 255(M), 188. +43. +8 Example 29 The following compound was obtained in the same manner as in Example 5.

812.3-Dimethylpentanoylamino)-4-oxo-4H-pyrimido(2,1-a)isoquinoline-3-
Melting point of ethyl ester of carbonic acid・209-2+0℃ In, (Nushor)+3250.8100. +
789. +650.1290°1118.798rrn
'NM'R (CDCl2.δ): 0.7-2.9 (+61
1. +η), 4.47(2+1.Q.

, I=7.4+1z), 7.36 (IIT,
d, , I=7.811z), 7.59 (I
n.

+ , , I=8.0T)z) , 8.01 (Il
l, d, J =8. OI]z), 8.26(
III.

l+r s), 8.70 (11-1, d,, I=8.0
11z), 8.76 (III, d.

J=7.8tlz), 8.99(In,s) Mass spectrometry:
895 (M), 350.283, 287, 142.
85.43 Example 3 (1) The following compound was obtained in the same manner as in Example 6.

8-(2,3-dimethylpentanoylamino-4-oxo-4)-pyrimido(2.1-a')isoquinoline-3-carboxylic acid fMI point: 290-291°C IR (5t di.-l): 8280.+?2fl,16
54.1250.800ffi'NMR(DM80-
d6, δ): [1.8-8.0 (14] 1, m), 78
3 (IIl.d, J=8.4112), 7.86 (IT
(, t,, r ==8.411z).

815 (group, d,, I = 8.41Tz'), 8.92 (
l11. d,, I=8.4]1z) , (9,0+(
IN, d, J = 8.411z), 9.06(II(,
s).

10, 16 (10, s) Mass spectrometry: 867 (M), 287, 85.43 Example 31 The following compound was obtained in the same manner as in Example 5.

1, (1-(2-acetoxypropionylamino)-7-methyl-4-oxo-4B-pyrimide [2.

1-a''1. Ethyl ester of quinoline-3-force I levonic acid IT(, (Nunyol): L9+5.1738.
1700.1680. +480.

1292, +288.1130.803 ('I11'
NMR (CDCl2.6 1.45 (8h, I-,
J=6.8JIz), 1.64 (811.

d, J=6.8Hz), 2.28 (BIT, s), 2.
60 (8 guns (, s).

4, 46 (2T1.q, J=6.9Hz)
, 5.46 (IT(, q , , I=6.8T
(z).

7, 86 (In, d, J = 9.27-1z
), 8.58 (IH, dd, , T =
9.2 and2, 2Tlz), 8.54 (ITJ,s
), 8.72(II-T,s), 8.94(IT(,d
).

8, 99 (In.s) Example 32 The following compound was obtained in the same manner as in Example 6.

10-(2-acetoxypropionylamino)
-7-Methyl-4-oxo-4 B-pyrimide [2.

i-a]]ethyl ester of isosonoline-3-carvone, fi] (1-(2-hydroxypropiodanylamino)-7-methyl-4-oxo-4
I-1-pyrimido[2,■-a]inquinoline-3-carboxylic acid was obtained.

Melting point: 300°C IR ('l*gr): 8300. +71
0. +692. +498. +840,806℃1M'N
MR. (DM80-d6, δ): 1.89(81(,
d, J=7.4TIz) 8, 50 (IH, m), 4.2
7(H(,m), 7.8-8.7(41T,m).

8, 97 (IIi.s), 9.56 (IH, l+r s
), 10.25 (In, br s) Mass spectrometry: 841 (
M) Example 33 The following compound was obtained in the same manner as in Example 5.

Ethyl ester of 1(1-(8.8-cynotylgutyrylamino)-7-methyl-4-oxo-4H-pyrimyl'(2.1-a)inquinoline-3-carphonic acid Melting point: 259- 260.5℃ IR (Nujol): 3340.+705.1692
．． +676, +481.

+142,797o++'NMR(1)MF'IO-d6,δ): 1.08(
9JI, s), 1.36 (817, +.

, I=6.8T(z), 2. :11(2TI,s),
8.80 (8T1.s), 4.88 (2IT, q,
J=6.8ITz), 7.97(IT-I, d
, J=8.211z).

8.26 (1 piece (, dd, J = 8.2 and 2.0Hz
), 8.60 (] ■ T, s).

8.89(IT(,s), 9.81(ITT, d, J=
2. O■Nz).

10.36 (ITI, s) Example 34 The following compound was obtained in the same manner as in Example 6.

1O-(3,3-dimethylbutyrylamino)-7-methyl-4-oxo-4-pyrimido[2,1-a]inquinoline-3-carboxylic acid Melting point: 〉300℃ IR (Nujol): 3800. +780.1686
,1500.1425°1143.860,807m-
'Mass spectrometry: 867 (M), 828, 295.269
, 251. +97.57 Example 35 The following compound was obtained in the same manner as in Example 1.

8-7-Roti-11-nitro-4-oxo-4■-pyrimido (2,1-a) Ethyl ester of isoquinoline-3-carboxylic acid M midpoint: 256-256.5°C IR (nui;i -ru)': 1748.1688. ]2
295.1138.0080cm'NMR(DMSO-
d6. δ): 1.83(811,I, , ]=7
．． 5Hz).

4.88 (2H,q,,1=7.5Hz), 7.95
(In, (+, J=8.IT(z,l.

8.10 (In, d, , 1 = 9.011z)
, 8.52 (+11.d, J = 9.0Tlz
).

8.79 (111, s), 9.04 (III, d, 1
=8.111z) Mass spectrometry a9a (M +2), 3
92.89L (M), 348,319 Example 36 The following compound was obtained in the same manner as in Example 26.

8-Zolomo 11-nitro-4-oxo-4Ii-pyrimido (2,1-a) isoquinoline-3-carboxylic acid Melting point: ) 287-289°C I R, (5t di,-l): 1727. +642. ]
085.818,785n'NMR (DMSO-d6
．． δ)+7.86 (III, d,, I=8.011z)
.

8.00 (IH, d, , 1 = 8.0Hz),
843 (Ill, d, J=8.0Hz).

8.68 (IH, s), 8.98 (IH, d, ,!
=8.0ITz).

10.50 (IH, br　s) Example 37 The following compound was obtained in the same manner as in Example 3.

11-Amino-8-bromo 4-oxo-April-pyrimido (2,1,-a) Ethyl ester of isoquinoline-3-carboxylic acid Melting point: 278-280°C JR (Nushor): 8880.1?20,1586
．． 1810.1280°839m' Mass spectrometry 863 (M +2), 36] (M) Example 38 11-amino-8-bromo4-oxo-4■-pyrimido[2,1-a]isoquinoline-3-carboxylic acid Ethyl ester (50 () ml) of acetic acid (25 ml) and 3
It was suspended in a mixture with 6% hydrochloric acid (5*f) and heated at 80°C for 3 hours. The reaction was then cooled and diluted with water.

Collect the precipitated solid and wash with N.

Dissolved in N-dimethylformamide (30ml).

Add this solution to sodium bicarbonate 11 Uno aqueous solution (15m/)
added to. The resulting precipitate was collected and then dissolved in N,N-dimethylformamide (13(lπl)).

The solution was filtered to remove insoluble materials. The obtained Fr liquid acid was acidified with acetic acid, and 11-amino-8-bromo-4-oxo-4f(-pyrimido(:2.1-a)isoquinoline-
3-carboxylic acid (180πV)e? 8*.

Melting point: 28B-284°C IR (Nungyol): 8400, 1780. +638
．． +200.800,780 bacteria-1HMR (DMS0-
d6. δ): 8.80 (2T(,I+rs)
.

6.92 (IH, d, J=9.4Hz), 7.
57 (ITI, d, J=8.0ITz).

7.78 (1fT, d,,!=9.41■z), 8.5
5 (IHLbr s).

8.67(IT(,d,,I=8.0T(z),8.9
2(IT(,s) mass spectrometry: 885(M +21.8
Ll(M) Example 39 The following compound was obtained in the same manner as in Example 5.

8-Bromo11. -(2,3-dimethylpentanoylamino)-4-oxo-4■-pyrimide (2,1-a)
Ethyl ester of isoquinoline-3-carboxylic acid NMR (DMS 0-d6.δ): 0.5-2.0(
16H, m), 4.84 (211゜q, J=7.0II
z), 7.74 (IIT, d,, 1 = 8.0 Hz).

8.15(11-(,d, ,1 =9.4l-Tz
), 8.88(I)T, d, J=9.4H
z).

8.89(IT(,s), 8.92(IT(,d,,1
=8.0r(z) mass spectrometry: 475(M++2),
474.478 (M ), 890,888 Example 40 The following compound was obtained in the same manner as in Example 6.

8-Promo 11. -(2,3-dimethylpentanoylamino)-4-oxo-4II-pyrimido(2,1,-
a) Isoquinoline-3-carboxylic acid Melting point: 288-2
89℃ IR (Nujol): 1740.1660,1480
．． 1197,805°780α-1 Mass spectrometry: +147 (M +2), 445 (M) Example 41 1, (1-(2,3-dimethylpentanoylamino)-
7-Methyl-4-oxo-4H-pyrimide [2゜1-a
] A mixture containing inquinoline-3-carboxylic acid (455 Mg), triethylamine ((1,174?) and dry dichloromethane (7 (l ml)) was stirred,
This was added to ethylulamine chloroformate (35 gMf) in dry dichloromethane (1 () ml) under an inert atmosphere at 0°C.
) The solution was added to the reaction solution at 5°C. After continued stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography using chloroform-methanol. Concentrate the eluate under reduced pressure,
The residue was crystallized from chlorophorem~ether,
N-(2-(4-diphenylmethylpiperazin-1-yl)ethyl)-7-)f-jL'-1(1-(2,3-
Dimethylpentanoylamino)-4-oxo-4■-pyrimide (2,1,-a-1 isoquinoline-3-carboxamide ((1,5!l) was obtained.

Melting point: 226-280°C IR (nu;s J'): 3B70.1660. +4
80.1290,114811005.800m' NMR (CDCl, , δ): 0.5-2.1 (18
H, m), 2.1-2.9 (511゜m), 8.1 (2
TI, m), 4.25 (IH, s), ? , Q-7.6(
10TI.

m), 7.81 (IT (, d, J=9.4Hz), 8.
64 (IH, s).

8.77 (ITI, dd, J=9.4 and 2.4
1rz), 9.08 (In.

d, J=2.411z), 9.17(IH,s), 9.
50 (11 (, m).

9.70 (IH, s)! Bacterial quantity analysis: 658 (M), 486,864.265
, 167 Example 42 1(1-(2,8-dimethylpentanoylamino)-7
-MethiI-4-oxo-4H-pyrimide [2゜1-a
] A mixture of isoquinoline-3-carboxylic acid (250 capes) and thionyl chloride (4 ttl) was stirred at 10°C for 30 minutes. The reaction solution was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure to obtain the acid chloride. Acid chloride, pyridine ((1
, 1 m/), dry dichloromethane (60 fft) was cooled to 5°C. N-(2-hydroxyethyl)
A solution of nicotinamide (H18jV) in dry dichloromethane was added to the mixture.

The reaction was stirred at 5°C for 1 hour and left at room temperature overnight.

The solution was then diluted with chloroform-methanol, washed with water and brine, dried over magnesium sulfate,
Evaporated under reduced pressure. The residue was dissolved in chloroform-methanol-1
The product was subjected to silica gel column chromatography using silica gel. The eluate was concentrated under reduced pressure, and the residue was dissolved in chloroform-
Recrystallization from ether gave 7-methyl 1(1-(2
,8-dimethylpentanoylamino)-4-oxo-4
■-pyrimido (2,1-a) isoquinoline-3-carvone M (D2-C nicotinamide) ethyl ester (0,
261) was obtained.

Melting point: 204-210℃ IR (Nujol): 8250, 1780, 1650
．． +680.1226°1120.1060.800f
fi' NMR (DMSO-d, , δ): 0.5-
2.0 (18H, m), 8.27 (811, s).

8.70 (2H, m), 4.42 (2TI, m), 7.
8-9.4 (IOH, m).

10.82 (IH, s) Example 43 The following compound was obtained in the same manner as in Example 42.

10-42.3-dimethylpentanoylamino)-4-
Oxo-411-pyrimide (2,1-a) isoquinoline-3-carboxylic acid 2-nicotinamide) ethyl ester Melting point: 200-207°C IR (Nujol): 8450% 12+10.173
5.1660.1280°1142.1115,850
,810QII=NMR(CDC1,,δ): 1.6
-2.7 (18H, m), 8.90 [2TI, m).

4.45(j)H,m), 7.0-9.8(12H,m
) Example 44 The following compound was obtained in the same manner as in Example 42.

10-pinocroylamino-7-methyl-4-ogiso41(-pyrimido(2,1-a')isoquinoline-3-
1 point of 2-cotinamito)ethyl ester of carbonic acid: 205-210°C In, (Nujol) 3400.8300. +7
25. +650.1290°1128.8QQcy-' NIJR (CDCl2.δ): 1.43 (911,s
), 2.45(:11(,s).

8.95 (2H, m), 4.50 (21-Lm), 7
．． 1-9.4(IIIT, m) ethylamine (1,6
πt), N, N-dimethylformamide (2+10
ml) of ethyl chloroformate (1,1y+t) at water bath temperature. After stirring this at room temperature for 1 hour, ethyl ester of 10-amino-7-methyl-4-oxo-4fT-pyrimido(2,1-a:]]isosonorin-3-carvone (3 g) was added and heated at 60°C. Heat for 3 hours. The reaction mixture is stirred at room temperature overnight and then concentrated under reduced pressure.

The residue was washed with water and methanol and recrystallized from N,N-dimethylformamide to give l(1-(8-cotinoylamino)propionylamino)-7-methyl-4-
Ethyl ester of oxo-4H-pyrimido[2゜1,-a)]isoquinoline-3-repon (3,50
g) was obtained.

Melting point: 274-278°C IR (Nujol): 8B40.8290°+700
．． 1672.1295°1144.860.800' Mass spectrometry: 478 (M) Example 46 The following compound was obtained in the same manner as in Example 6.

1,0-[8-cotynoylamino)propionylamino]-7-methyl-4-ogiso4](-pyrimido[2,1-a]isoquinoline-3-carboxylic acid Melting point: >aOO℃ IR (Nujol) : 8820.3+60.3050
．． +7+8.1680°1490, I+42.800f
fi 'Example 47 (Preparation of granules or fine granules!! Ri 1
(1-(2,8-dimethylpentanoylamino)-7-
Methyl-4-oxo-4I-1-pyrimide (2,1-a
':]]Isoquinoline-3-carphonic acid 5 (1+1
(Sucrose 925 (1) Hydroxypropylcellulose 200 Starch 50) The two ingredients were mixed in a conventional manner and made into granules or fine granules to make granules or fine granules.

Example 48 (Preparation of capsules) lfl-(2,3-dimethylpentanoylamino)-4
-Oxo-4H-pyrimido (2,1,-a) isoquinoline-3-carboxylic acid [10C1/) Starch 1987 Magnesium stearate 13'' The two ingredients were mixed in a conventional manner and filled into hard gelatin capsules. 1 capsule containing 10 μ of active ingredient
0. (100 pieces were manufactured.

Effects of the Invention The object compound (r) of the present invention, a salt thereof which is acceptable as a paralysis drug, has strong anti-allergic activity.

That is, the object compound of this invention can be used to treat allergic asthma, allergic rhinitis, hives, hay fever, allergic rhinitis, atopic dermatitis, ulcerative colitis, dietary allergies such as milk allergy, and avian allergies. It is useful in the treatment of symptoms associated with allergic diseases such as feeder disease, aphthous stomatitis, and the like. To explain this, the antiallergic activities of some representative compounds of the target compound (1) are shown below.

Test 1: Passive cutaneous anawalaxy-PCA) Inhibitory effect on reaction (1) Test compound (a) Test compound of the following formula -71- (b) Test compound of the following formula 72- (2) Test method (a) Preparation of antiserum A solution of egg albumin (2 mg) in pertussis-diphtheria-tetanus combined vaccine (1ynl) was mixed with Freund's incomplete adjuvant (■πl) to obtain an emulsion. Spraggs are 8 weeks old and weigh approximately 300g each.
Emulsion 1 art was divided into four equal parts (0.25 ml) and administered once by subcutaneous injection to the foot gel of each of nine Doley strain (SD) rats.

Eight days after immunization, blood samples were collected from the femoral artery of the rats and kept under water cooling for 5 hours. The separated supernatant H was heated to 4°C.
,10,(1(1 hour centrifugation at l Or, p, m)]
~is. The antiserum thus obtained was heated at -80°C before use.
It was stored in

(+1) Suppressive effect of P, C0A, 8 weeks old, quadruplicate 250-30 (l g) DSD Itoo rats were used for PCA reaction with the uniformly sensitized antibody antiserum prepared in Section 2. A 32-fold dilution of the antiserum (1,1+n/) was injected subcutaneously into the dorsal septum of shaved Rano 1-, and 48 hours later, 5 μl each of ovalbumin and Vanne Blue were injected. The PCA reaction was induced by intravenous injection of an aqueous solution containing 11It.

Test compounds were administered intravenously to the animals 5 minutes prior to challenge.

The control group received carrier. Each treated animal group consisted of 4 animals. One hour after challenge administration, animals were sacrificed by stratification.
The skin was then peeled off. The size of spots stained with antiserum on the back of the skin was measured. The test results were expressed as a percentage inhibition value calculated from the average value of the longest and shortest diameters of each spot compared to the control group.

(3) Test results The test results are shown in the table below. The test compound dose was 1
my/kq.

As is clear from the above test examples, the pyrimidoisoquinoline derivative (I) of the present invention has an excellent antiallergic effect.

75- 83R-

Claims (1)

[Claims] (1) General formula: (wherein R1 is hydrogen, halogen or lower alkyl group, R2 is amino group, nitro group, or acylamino group, R
3 means a carboxyne group or a protected carboxy group, respectively) or a pharmaceutically acceptable salt thereof. (2) R2 is an amino group, a nitro group, a lower alkanoylamino group, a hydroxy (lower) alkanoylamino group,
Lower alkanoyloxy (lower) alkanoylamino group, pyridinecarbonylamino (lower) alkanoylamino group, higher alkanoylamino group, lower cycloalkylcarbonylamino group, lower alkoxycarbonylamino group, lower alkanoylamino group, lower alkanesulfonylamino group The pyrimidoisoquinoline derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the pyrimidoisoquinoline derivative or pharmaceutically acceptable salt thereof is an arylcarbamoyl group, and W is a carboxy group, an etherified carboxy group, or an amidated carboxy group. (81R" is a carboxy group, a lower alkoxycarbonyl group, a pyridine group, a diamino(lower) alkoxycarbonyl group, an N-tetrazolylcarbamoyl group, or an N-tetrazolylcarbamoyl group.
-1:4-al(lower)alkylpiperazin-1-yl(lower)a! 2. The pyrimidoisoquinoline derivative or pharmaceutically acceptable salt thereof according to claim 2, which is a pyrimidoisoquinoline derivative or a pharmaceutically acceptable salt thereof. (4) R' is hydrogen, methyl group or bromine, and a
2 is an amino group, a nitro group, a pivaloylamino group, an isobutyrylamino group, a 2-hydroginepropionylamino group, a 2-acetoxypropionylamino group, a 3,3-dimethylbutyrylamino group, a 2,3-dimethylpentanoylamino group group, cyclohexylcarbonylamino group, toxycarbonylamino group, 1-xarylamino group, mesylamino group, 3-cotinoylamino) propionylamino group type, and rt8 is a carboxyl group, ethoxycarbonyl group, 2- nicotinamide 1-oxylefonyl group, N-(J, i(-tetrazol-5-yl)carnobemoyl group or N-(2-
44=diphenylmethylpiperazin-1-yl)ethyl]carbamoyl group or a pharmaceutically acceptable salt thereof according to claim 3. (5) The pyrimidoisoquinoline derivative is 7-low-i alkyl tV (dissolved with water)-1,0-aryamino-4-
Oxo 4■-pyrimido(2,1-a)isoquinoline-
3-carphonic acid or its salts which are pharmaceutically acceptable as pyrimidoisoquinoline derivatives as described in item 1 of the patent scope. (6) The pyrimidoisoquinoline derivative is 10-(2.3-dimethylpentanoylamino)-7-methyl-4-
The pyrimidoisoquinoline-derived Kt or a pharmaceutically acceptable salt thereof according to claim 5, which is oxo-4■-pyrimido(2,1-8,)isoquinoline-3-carphonic acid. (7) Pyrimidoisoquinoline derivative is 1O-(2゜3
-dimethylpentanoylamino)-4-oxo-4H-
The pyrimidoisoquinoline derivative or pharmaceutically acceptable salt thereof according to claim 5, which is pyrimido(2,1,-a]isoquinoline-3-carboxylic acid. (8) The pyrimidoisoquinoline derivative (4) is 10-piparoylamino-7-methyl-4-oxo-414-pyrimido(2,1-a,)isoquinoline-3-carboxylic acid as claimed in claim 5; (9) The pyrimidoisoquinoline derivative is the ethyl ester of IO-isozotyrylamino-7-methyl-4-oxo-4H-pyrimido(2,1-a)isoquinoline-3-carboxylic acid. The pyrimidoisoquinoline derivative according to claim 5 or a pharmaceutically acceptable salt thereof. (10) The pyrimidoisoquinoline derivative 4K is 7-) f
71/ -10-(2,3-dimethylpentanoylamino)-4-oxo-4IT-pyrimido(2,1-a)isoquinoline-3-carboxylic acid 2-cotinamide) ethyl ester of Patent Claim 5 Pyrimidoisoquinoline conductor composition or pharmaceutically acceptable salts thereof as described in Section 2. (11) (a,) General formula: (In the formula, fart means hydrogen, halogen, lower alkyl group, a2v amino group, nitro group, or acylamino group, respectively) or a salt thereof represented by the general formula: (In the formula, R, R and U each mean a protected carboxy group, and R4 means an alkoxy group) to react with a compound represented by the general formula: (1)) general formula (wherein ul has the same meaning as before, n, "u carboxy group, ν two or protected group! Levoxyl) By reducing the compound represented by the general formula: or ((-) general formula: (wherein, R, l o and R, "id each have the same meaning as iT) or its amino group reactivity reading 1. The general formula: (wherein R1 and u8 each have the same meaning as before,
(The shield means an acylamino group) or its salt is obtained, or (Yama) General formula: (In the formula, R1, R2 and food each have the same meaning as before)
Power of the compound or its salt shown in! By subjecting the lephoxy protecting group to an elimination reaction, a compound represented by the general formula: (in formula 1, R1 and R2 have the same meanings as before) or a salt thereof is obtained, or (e) a compound represented by the general formula: (formula A compound represented by the formula (where R1 and R2 have the same meanings as before) or a reactive derivative or a salt thereof at the carboxy group is reacted with an amidating agent to form a compound of the general formula: (wherein R1 and R2 (each has the same meaning as before) and yang means an amidated carboxy group) or a salt thereof, or (f) general formula: (wherein R1 and R2 each have the same meaning as before) A compound having the same meaning as esterified carboxy group or its reactive derivative at the carboxy group or a salt thereof is reacted with an esterifying agent to form a compound having the general formula: The shield represents the esterified carboxy group. A method for producing a pyrimidoisoquinoline derivative or a pharmaceutically acceptable salt thereof represented by the general formula: (wherein rtl, R2 and R3 each have the same meaning as ml). (12) As an active ingredient, the general formula:
, a pyrimidoisoquinoline derivative (meaning a levoxy group or a protected carboxy group, respectively) or a pharmaceutically acceptable salt thereof.