JPS61282385A - Tetrahydroimidazoquinazolinone cardiotonic agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention generally selectively increases myocardial contractile force without significantly increasing winning power. substituted 1,C
5-tetrahydroimidazo[s1-b)-quinazoline-
2-(IH)-one cardiotonic agents. The compounds are useful in the curative or prophylactic treatment of cardiac conditions, particularly in the treatment of cardiac dysfunction.

(Structure of the Invention) That is, according to the present invention, substituted La3,5-tetrahydroimidazo[su1
-b] quinashiri/-2-(xH)-ones and pharmaceutically acceptable salts thereof are provided. Here l He
tl is the above L:15-tetrahydroimidazo (a
x-b) Quinazolin-2-(IH)-one 6-. 7-
．． R is an optionally substituted 5- or 6-membered aromatic heterocyclic group when bonded to the 8-, t- or 9-position;
-,? −.

Bonded to the 8- or 9-position, hydrogen, C□-04
Alkyl group, C, -C4 alkoxy group, hydroxy group,
Hydroxymethyl group, halogen or CF3; and R1, R2, R3, R' and R5 are each H or C4 alkyl group.

Preferably 'Het' means LZ:C5-tetrahydroimidazo(s1
-b) Contains La3 or 4 nitrogen atoms in the aromatic ring bonded to the quinazolin-2-(IH)-one.

An example of the above group @He tI in formula (1) is 1, for example.

Pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazinyl group,
Pyrimidinyl group, pyridazinyl group.

oxazolyl, inxazolyl, thiazolyl/inthiazolyl, furyl, chenyl, oxadiazolyl, and their N-oxides when containing nitrogen, all of which may contain up to three ( preferably 1 or 2), each separately e.g.
-C4 alkyl group.

CneyC4fur=yoxy group, hydroxy group, halogen,
CF3. Cyano group, hydroxymethyl group, (C1-04
alkoxy) carbonyl group, -NO□ -NR6R7゜-CONR6Rζ -8o2NR'R7 and -8(0
)m(C,-04 alkyl), where R6 and R7 are each independently H or a C1-04 alkyl group, and m is 0.1 or 2. .

°Halogen 1 means F, C, Br or H. C3
and C4 alkyl and alkoxy groups can be straight chain or branched. A preferred alkyl group is a methyl group.

Although the compound of formula (1) is described as a La3,5-tetrahydroimidazo(21-b)ki+zo+):/-2-CLH)-off compound, when %R5 is H, the following equation It should be understood that variability will occur (la) (xb); however, as the keto form (la) is considered the most stable tautomer, those skilled in the art will Although it will be appreciated that all three tautomers may exist or that any particular compound so named may exist primarily as (lb) or (lc),
The final raw material herein will be named and illustrated as the L23.5-tetrahuman 10 imidazo(21-b)quinazolin-2-(IH)-one compound. and the following description should be construed to include all tautomeric forms. Similarly, compounds having a hydroxy substituent on I He tl are tautomeric with their oxo homologs, and such tautomers are also included.

R is preferably H or a C1-04 alkyl group,
More preferably H or CH3.

When R is a substituent, it is preferably at the 9-position.

R is most preferably 9-CH3.

R1 is preferably H or C1-C, an alkyl group, more preferably H or CH3.

R1 is most preferably H.

R2 is preferably H.

R3 is preferably H or CH3. Most preferably R3 is H.

R4 is preferably H or CH3. Most preferably R4 is H.

R5 is preferably H.

IHetl is preferably attached to the 7-position.

l He tl is preferably an imidazolyl, triazolyl or pyridyl group, optionally substituted as defined above. @He tl is more preferably imidazolyl (especially imidazol-1-yl),
Triazolyl (especially 1cLZ4-triazol-1-yl, 1,2.4-triazol-4-y/I/ or 1,
2.4-triazol-5-yl) or pyridyl (
In particular, the imidazolyl and triazolyl groups are optionally substituted by silyl or two C1-C, alkyl groups (in particular methyl groups). The pyridyl group mentioned above is optionally di-substituted by one or two Cni04 alkyl groups (particularly methyl groups) or one hydroxy group.

Most preferably, IH,tl is %a4-dimethylimidazol-1-yl, L2,4-)lyazole-1-
I/l'%1,2.4-triazol-4-yl, 1-
Methyl-1,2,4-triazol-5-yl, 26-
Dimethyl-pyrid-3-yl or 2-hydroxypyrid-5-yl group.

The most preferred individual compounds have the formula H3, where (a) 'Het' is a λ4-dimethylimidazol-1-yl group and R3 and R4 are H; fbl 'Het' is a 2,4-dimethylimidazol-1-yl group, R3 is CH3, R4 is H
or (cl 'Het' is L2.4-triazole-4-
yl group, R3 and R4 are H.

Particular preference is given to the compounds of fa) above.

Pharmaceutically acceptable salts of compounds of formula (1) are preferably hydrochlorides, hydrobromides, hydroiodides, sulfates or bisulfates, phosphates or hydrogen phosphates.

acetate, maleate, 7 malate, lactate, tartrate, citrate, gluconate, p-) Rue 7, (k
phon group, and methanesulfonic acid tJt.

Acid addition salts formed from acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions such as. Also included are metal salts, especially alkali metal and alkaline earth metal salts, preferably sodium and potassium salts.

The cardiotonic activity of the compound of formula (1) was determined by the first test = (a) 1 Starring (Sta) measured by left ventricular catheter.
rling) “increasing contractile force in canine heart-lung preparations; (b) increasing myocardial contractility (left ventricular dp/dt maximum) under anesthesia as measured by left ventricular catheter; (C) implantation. left ventricular transducer (a
p/d maximum) or externally transposed carotid loop (
Increasing contractility of the myocardium in conscious dogs with contraction time interval ``As measured in canine heart-lung specimens, selectivity for increasing the frequency of contractions of the test compound is obtained.''

In test [b), the positive inotropic effect after intravenous administration of the test compound is measured in the anesthesia hole. The magnitude and duration of this effect, as well as the selectivity of the test compound for increasing the frequency and strength of contractions, are obtained, as are the peripheral effects 1, for example on blood pressure.

In study (c), test compounds were administered intravenously or orally to conscious dogs with an implanted left ventricular transducer (maximum dp/a) or an externally displaced carotid artery loop (systolic time interval). The subsequent positive inotropy is measured. The magnitude of the inotropic effect of the test compound, the selectivity for increasing the frequency and strength of contractions, and the duration of the inotropic effect are all obtained.

Although the compounds of formula (1) and their carriers can be administered alone, they will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. There will be. For example, they may be in the form of tablets containing excipients such as starch or milk, or in capsules, alone or mixed with excipients, or in elixirs or suspensions containing flavorings or colorants. It can be administered orally in the form of a suspension. They may be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions that may contain other solutes, such as sufficient salt or glucose to make the solution isotonic.

For administration to humans in the curative or prophylactic treatment of heart conditions such as congestive cardioplegia, the oral dose of a compound of formula (1) is 1 per day for an average adult patient (7okii).
or 10 to 19 times a day, used in 4 divided doses
It is considered that the range is up to For intravenous administration, the rounding dose is 1"! For example, in the treatment of acute cardiac insufficiency, a single administration may be required"! 0.5 to 10019
would be considered to be within the range of Thus, for a typical adult patient, one individual tablet or capsule may contain two tablets or capsules in a suitable pharmaceutically acceptable excipient or carrier.
It will contain from 5 to 250 μ of active compound.

As will be known to practitioners, various changes will occur depending on the weight and condition of the patient being treated.

The present invention therefore provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, as defined above, and a pharmaceutically acceptable diluent or carrier.

The present invention also includes: comprising administering to an animal a compound of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in an amount sufficient to stimulate the heart of the animal. Also provided are methods of stimulating the heart of animals, including humans.

The present invention furthermore provides. A compound of formula (1) or a pharmaceutically acceptable salt thereof is provided for use as a medicament, particularly for use in stimulating the heart in humans suffering from congestive heart palsy.

The present invention also encompasses all novel intermediates described herein, such as intermediates of formulas ([1), ([IO and (5)).

Compounds of formula (1) can be prepared by many routes,
Among them are the following routes: A: This route can generally be shown as: Q is a suitable leaving group, such as Br or E. Q
is preferably . It will therefore be seen that this reaction involves displacement of the leaving group Q by a heteroaryl lead chloride using tetrakis(triphenylphosphine)palladium(0) catalysis, ? The reaction is typically carried out in a suitable organic solvent such as detrahyfuran (THF) at 25-80°C, preferably id
It is carried out at reflux temperature.

Typical reactions are specifically exemplified as follows: magnesium chloride and magnesium chloride. Other suitable transition metal catalysts (e.g. nickel-based)
can be used in place of zinc chlorides.

The starting materials used in this process are known compounds or can be obtained computationally.

Heterobril lead chloride is prepared by reacting a suitable heterocycle at -70 to 100°C with two t-butyllithium or one n-butyllithium in THF to produce a lithium derivative. Then obtain anhydrous lead chloride in THF'
In certain cases, the -\teroaryllithium reagent is most conveniently obtained in situ by reaction with a solution of n-methyllithium in the parent complex buried THE'.
It can be produced by direct lithiation at 70 to -100°C. Heteroarylzinc chlorides can also be prepared from the corresponding Grignard A reagents by reacting them with TIP solutions of chloride chains.

The desired final product of formula (1) is then typically:

1 reaction with the addition of the appropriate L2.3.5-detrahydroimidazo(Zl-b)quinazolin-2-(IH)-one in THF' and tetrakis-(triphnynylphosphine)palladium(0). is obtained by heating to reflux temperature until completion (typically 1 to 748 hours).The product is then collected.

It can be purified by conventional methods.

The starting materials of the formula (river) can also be prepared by common methods. The sand casting routes to these materials are as follows, and many of these can be Illustrated in detail in an example: One route B This route to compounds where R5 is H involves starting materials (7
) with a bromated or chlorinated cyanodiene followed by cyclization of the resulting N-cyan intermediate. A preferred method is generally represented as follows: H(LA)
゜R3 and R4 are the same formula as defined for Il.

Accordingly, this preferred method involves the use of a suitable organic solvent, such as ethanol, typically at 25-80°C.

Reaction of benzylamine 9 conductor(s) with a halogenated cyanodiene, preferably a habrominated cyanodiene, preferably under reflux, followed by an aqueous base solution.

Treatment with an aqueous alkali metal base, such as sodium carbonate or sodium hydroxide, t-.

This in some cases leads to the next intermediate, 2-amino-quinazoline! However, usually an N-cyano intermediate is formed (see, eg, Example 10).

This N-cyan intermediate has the formula:
(as defined above). Then, although in some cases (e.g. in Examples 7-9) cyclization to the final product (A) may occur spontaneously without heating, the cyclization typically The reaction is completed by heating to reflux in ethanol or n-butanol for 1-72 hours. Compound(
1) is preferably used as methyl or ethyl ester.

This product can be isolated and purified by conventional methods.

A typical reaction is illustrated as follows.The starting materials for this route can be prepared by conventional methods. Typical routes to this material are listed below, many of which are illustrated in specific detail in the preparation examples below.

Salts of compounds of formula 1) can be prepared by conventional methods, for example by reacting a solution of the parent compound in an organic solvent with a solution of a suitable acid in an organic solvent to form an acid addition salt, or by forming an acid addition salt with a suitable base. 1, for example an alkali metal or alkaline earth metal hydroxide, preferably an aqueous solution of sodium or potassium hydroxide.

can be prepared by reacting with metal salts to form pharmaceutically acceptable metal salts.

When the compounds of the present invention contain one or more asymmetric centers, the present invention includes 5) separated individual enantiomers and diastereomers or mixtures thereof. This isolated form can be obtained by conventional means.

The following examples specifically illustrate the preparation of the compound of formula (1). All temperatures are in °C. Examples Example 1 A solution of 3-bromo-2,6-lutidine (131 g) in tetrahydrofuran (THF) (3 cm3).

A suspension of magnesium (0,1879) in stirred THF (433) was added at reflux temperature under nitrogen.

After about 20 hours of this addition, iodine crystals were introduced and the remaining 3-bromo-'2,6-lutidine was added. Reflux for an additional 0.5 hour.

After cooling, anhydrous zinc chloride (0,
959) was added. 7-iodo-L2:a5-tetrahydroimidazo(2,1-b)quinazoline-2(I
A mixture of H)-one (0,94 g) and tetrakis(triphenylphosphine)palladium(0) (0,039) was added and the mixture was heated to reflux for 2.5 hours.

The cooled solution was evaporated in vacuo and the residue was dissolved in a solution of ethylene/diaminetetraacetic acid disodium salt (5,29) in chloroform:methanol, 9:'1 (100 ctn3) and water (100 ctn3), distributed between.

The organic phase was discarded and the aqueous phase was further extracted with chloroform:methanol, 9:1 (2X5007!3). Discard the organic phase again.

The aqueous phase was basified to pH 91 with IJum solution (saturated carbonate) and purified with chloroform:methanol, 9:1 (4X
60cWL3). The combined organic extracts from this last extraction were dried (M9SO4) and evaporated in vacuo to give a solid. Add this to chloroform:methanol%
19:1. Silica [Merck
)'MK60-9385' (trademark)]. Appropriate fractions were combined and evaporated to give a solid (0,659). This was recrystallized from chloroform-impropanol to give the title compound, melting point 330-
332° (0,2511)) was obtained.

Analysis Chi21 actual value: C, 67,9; H, 5,5; N, 1
8.9C17H16"40. Calculated value as 0.5H20: C,67,8; H,5,7;N, 18.6 appropriately substituted 7-yo1-"-L 2.3.5- Tetrahydroimidazo(2,1-b)quinazoline-2-(I
The following compound was prepared analogously to Example 1 starting from H)-one, a6-dimethylpyridol-3-ylzinc chloride and tetrakis(triphenylphosphine/)-palladium(0).

Example 4 7-(1-Methyl-Ls4-triazole-5-n-methyllithium (1.6M solution in n-hexane 6.6c
1n3) in THF (2
1-methyl-1,2,4-)lyazole (0i) in
, 839). After stirring at -70' for 1 hour, the white suspension was treated with a solution of anhydrous zinc chloride (4,19) in THF (20 crrr3) and the mixture was allowed to warm to room temperature. 7-iodo”-1,2,3,5-tetrahydroimidazo(2,1-b)quinazoline-2-(
IH)-one (1,339) and tetrakis(triphenylphosphine)palladium(0) (0,059) were added and mixture 1 was heated to reflux for 6 hours. Evaporate the cooled solution in vacuo and dissolve the residue in dichloromethane:methanol.

s:tlooi) and a solution of ethylenediaminetetraacetic acid disodium salt (10g) in water (200i). The aqueous phase was further extracted with dichloromethane:methanol, 9:1 (2X150-) and the combined dried (MgSO,) organic phases were evaporated in vacuo to give a solid, which was extracted with chloroform:methanol:ammonia. Water (S, G.

0,. Silica [Merck's MK 60.0%] eluting with 90:10:1. 9385
' (Trademark)]. The appropriate fractions were combined and evaporated to give a solid (0,369) which was recrystallized from chloroform-methanol to give the title compound, mp 340-343° (0,16II)).
,was gotten.

Analysis: - Actual value: C, 54.7; Be 4.3;
N, 28.9; C13)1. Calculated values for N, O, H2O: C, 54,5; H, 4,9; 1-b) Quinazolin-2-(IH)-one, 1-methyl-L2.4-triazol-5-ylzinc chloride and tetrakis(triphenylphosphine)palladium(0) Starting from this, The following compounds were produced in the same manner.

Example 7 H N-(2-amino-5-Cz4-dimethylimidazol-1-yl]-!ndyl)glycine methyl ester (0
, 419) and cyanodiene bromide (09159 g) was heated to reflux in ethanol (5bi3) for 72 hours. Upon cooling to room temperature, a precipitate formed and the resulting suspension was treated with a solution of sodium hydroxide (0.06 g) in water (3 x 3). The solid material dissolved and after 2 hours at room temperature a solid precipitated which was filtered off and washed with ethanol (5 cm3) to give the title compound, mp 324-328° (0,199).

Analysis: - Actual value: C, 57,6; H, 5,0
;N, 224: C15H engineering, N50, calculated value as 1.75H20: C, 57,6; H, 6,0; N, 22
．． 4 An appropriately substituted 9N-benzylglycine methyl ester derivative (Example 8) or N-benzylglycine methyl ester derivative (Example 8) in refluxing ethanol
-Benzylglycine ethyl ester derivative (Example 9)
The following compounds were prepared analogously to the previous examples by treatment with an aqueous IJ solution starting from cyanodiene bromide followed by hydroxylation at room temperature: Example 10 CH3(21Na2) 3//ri2su α3 CH3 N-(2-amino-3-methyl-5-C2,4-dimethylimidazol-1-yl]benzyl)glycine ethyl ester (0,75 g) and cyanodiene bromide (0,
265g) in ethanol (5crn3)
I stirred for hours. This mixture was mixed with dichloromethane (25
cWL3) and 10% sodium carbonate aqueous solution (10c1r
L3) and the aqueous phase was further extracted with dichloromethane (2 x 10 crn3).

The combined dried (M%04) organic extracts were evaporated in vacuo and the residue was coated on silica (Merck ”M
K60.9385'' (trademark) and eluted with dichloromethane:methanol, 19:1. Appropriate fractions were combined and evaporated to give a solid (0.69
), a small portion of which was recrystallized from ethyl acetate-methanol to give N-cyano-N-(2-amino-3-methyl-s -C24-dimethylimidazol-1-yl]benzyl)glycine ethyl ester. , melting point 135-1
40° was obtained. Pour the remaining substance into ethanol (5 m3
) for 24 hours at reflux and the solvent removed in vacuo.

The residue was treated with silica [Merck's MK
60.

9385™] and eluted with dichloromethane:methanol, 19:1. Combining and evaporating the appropriate fractions gave a solid which was recrystallized from ethyl acetate-methanol to give the title compound, 1.
A melting point of 310-312°C (0,289') was obtained.

Analysis: - Actual value: C, 64,8; H, 5,8
; N, 23.6; Calculated as C16H17N50: C,65,1; H,5,8;゜13 and 14) or N
-Benzylglycine methyl ester derivative (Example 12)
) and cyanodiene bromide, the following compounds were prepared analogously to the previous examples. [In all cases the intermediate N-cyanide derivative was isolated in crude form.

Directly cyclized without purification or characterization. ]H3 The following Preparative Examples illustrate the synthesis of the novel starting materials used in the examples above.

Knee preparation example 1 (7) N-( in stirred acetic acid (loOcWL3)
2-aminobenzyl)chrysin ethyl ester (4,1
69) (see U.S. Pat. No. 3,983,120) and in a solution of sodium acetate (1,8049).

Iodine monochloride (3,249) was added at room temperature. After 1 hour the volatiles were removed in vacuo and the residue was dissolved in chloroform (20
0 m”) and saturated aqueous sodium carbonate solution (50 cm3
) was distributed between The aqueous phase was further purified with chloroform (2
X50cW13) and the combined organic extracts were washed with a 10% aqueous solution of sodium thiosulfate (50oys3). The dried (M9SO4) organic extracts were evaporated in vacuo and the oily residue was purified on silica (Merck @MK 60,9385') eluting with chloroform.
Trademark)] was subjected to the above chromatograph. When appropriate fractions are combined and evaporated, a solid (4,'l) is obtained, so
A small portion of this was recrystallized from ethyl hexacetate to give the title compound, melting point 58-61°. Analytical values: - Observed values: C, 39,5; H, 4,5
; N, 8.4; Calculated value as C□1H, lN2O□: C, 39,5; H, 4,5; ) glycine ethyl ester, sodium acetate, acetic acid.

and - Starting from iodine chloride, the following compounds were prepared analogously to Preparation 1. The starting materials used in Preparation Example 3 are known compounds (see US Pat. No. 3,932,407).

The starting materials used in Preparation Example 2 were prepared using the method of Preparation Example 11 by using 2-amino-3-methylinduldehyde and glycine ethyl ester and then hydrogenating over P (1/C). Manufactured in the same way.

Production example 4 (2,1-1 quinazolin-2-(IH)-one N-(2
-Amino-5-iodobenzyl)glycine ethyl ester (3,34g) Cyanodiene bromide (1,119g)
) in ethanol (20 m3) for 18 h.
Heat to reflux.

Sodium hydroxide in water (5cWL3) < 0.429
) was added to the cooled (room temperature) solution and the mixture was stirred for an additional 2 hours. This mixture is then filtered and
The solid was washed with water (10m3) and dried under vacuum. A small portion of this material was removed from silica gel [Merck
)'MK' 60. 9385” (trademark)] chloroform:methanol,
19:1. It was eluted with Combine appropriate fractions and evaporate to obtain a solid, which is triturated with an impropat tool to obtain 1
The title compound, melting point 323-324°, was obtained.

Analysis: - Actual value: C, 38.3; Milk 2.7;
N, 13.2; calculated as C1oH8DJ30: C,38,4; H,2,6;
Production Example 7 The following compound was produced using 5-iodovanzyl) chrysine ethyl ester and cyanodiene bromide in the same manner as in the previous production example. Iodine monochloride (28,99) was added over 0.5 hours. hand.

2-Amino-3 in stirred acetic acid (250cz3)
-Methylbenzoic acid (24,1) (Aldrich Chemical Co., L
t, d, )). After 24 hours, ether (250 x 3) was added and the mixture was filtered. The solid material was dried in vacuo to give the title compound, melting point 214° (38,
6g) was obtained.

Analysis: - Actual value: C, 35.1; 2.9
．． S N, 5.2; Calculated value as C8H8 Go02: C, 34,7p He 2.9; N, 5.1 Production Example 8 A THE' solution of borane (1M solution 270cWL3),
For 0.5 hours, stir Oo's THF (400
It was added to the suspension of 2-amino-5-iodo-3-methylbenzoic acid (18,489) in Tan 3).

After stirring at Oo for 0.5 h, the reaction mixture was warmed to 50° for an additional 3 h. After cooling in a water bath, water (25 cWL3) was carefully added in portions with stirring and the resulting mixture was dissolved in a 10% aqueous solution of sodium hydroxide (
100cWL3) and continued stirring for an additional 24 hours. The volatiles were then removed in vacuo and the residue was dissolved in water (LoocWL) and chloroform (200 cm3).
It was distributed between. The aqueous phase was dissolved in chloroform (2X20
0cWL3) and combined and dried (M9S
O,) The organic extract was evaporated in vacuo to give an oil. Add this to silica [Merck's MK 6]
0. 9385” (trademark) and eluted with chloroform. Appropriate fractions were combined and evaporated to give the title compound.

A melting point of 101-103° (14,229) was obtained.

Analysis: - Actual value: C, 36,7; H, 4,0
;N, 5.4;C8H□. Calculated value as NO: C,3as:H,3,8;N, 5.3 Preparation Example 9 2-Amino-5-iodo-3-methylbenzyl alcohol C' in dichloromethane (50 cm3) under dehyde nitrogen
1. Freshly dried manganese dioxide (3,39) t- was added to the solution of 3F3. I stirred for a while. The mixture was filtered, the filtrate was evaporated to dryness, and the solid residue was washed with silica (Merck'MK 60.
9385'' (Trade Mark)] and eluted with dichloromethane. The appropriate fractions were combined and evaporated to give the title compound, mp 134° (1,69).

Analysis % knee actual value: C, 37,2; H, 3,2
; N, 5.4; Calculated value as C8H8 engineering NO: C, 36,8;
E tOH freshly prepared glycine ethyl ester (258 g),
A mixture of 2-amino-5-iodo-3-methylbenzaldehyde (4,039) and a 3-person molecular sieve (1/2 Fluka A, G, Product No. 69828) was Chloroform (50w3)
The mixture was heated to reflux temperature for 4 hours with stirring. Filter the cooled solution.

After evaporation in vacuo, the residue was dissolved in ethanol (30 m3) and sodium cyanoborohydride (1,43 g).
Processed with. After stirring for 72 hours, the ethanol was removed in vacuo and the residue was dissolved in chloroform (50crI@3).
and ammonia water (50c1n3°S, G, 0.88
) was distributed between The aqueous phase was further purified with chloroform (2
x100cm3).

The combined organic extracts were dried (MgSO4) and evaporated to give the title compound as a crude oil, (2,59).

Production example 11 Tyl ester H3 Glycine ethyl ester (0,389), 1-(4-amino-3-formyl-5-methylphenyl)-H24-
Triazole (0,5g> and 3Ae small sieve (1,0g
; “Full power (Fluka)” (m mark) Product number 6
9828) and chloroform (10
cm3) for 4 hours to reflux. Filter the cooled mixture and evaporate in vacuo.

The residue was dissolved in ethanol (30m3). This solution was then poured over 100% palladium on charcoal (0,29) at 60%
pressure of p, s, i, (4,13X I 05Pa),
Hydrogenation was carried out for 16 hours at room temperature (20°). Then add one ounce of catalyst to Solkafloc® (trademark).
The solution was evaporated in vacuo to give an oil, which was removed by filtration through silica (Merck @MK 60. 9385”
(Trademark)] on the chromatograph. Appropriate fractions were combined and evaporated to give the title compound as an oil (0.379).

A mixture of chrysin ethyl ester-hydrochloride (4,189) and triethylamine (5,6 cm3) in synethyl ester x l'/-k (40 cm3) was heated until all solid material was consumed. Next, ethanol (20cWL3)
3-fluoro-6-nitrobenzyl bromide (2,34
The solution of g) was added dropwise over 0.5 hours at reflux temperature and then heated for a further 1 hour. The cooled mixture was evaporated in vacuo and the residue was partitioned between dichloromethane (100an3) and saturated aqueous sodium carbonate (50cIFL3). The aqueous phase was further treated with dichloromethane (2X 50c
IR3) and combined and dried (MgSO4)
Evaporation of the organic extracts in vacuo gave an oil. Add this to silica [Merck "MK60,9385' (
Trademark) and eluted with chloroform. Appropriate fractions were combined and evaporated to give the title compound as an oil (1,159) which was used directly.

3-Fluoro-6-nitrobromide is a known compound.

Production Example 13 Trifluoroacetic anhydride (3,0 cna) was added to -
70', stirred dichloromethane (40an3
) was added dropwise to a solution of N-(ay/l/-5-di)obenzyl)glycine ethyl ester (5,109) and triethylamine (3,0 m3).

The mixture was warmed to room temperature and dichloromethane (60c1
n3) and a 10% solution of sodium carbonate (50 cm3
) was distributed between Dry the organic phase (M9SO4)
, evaporated in vacuo to remove the oily residue from silica [Me
rck)' MK60. 9385' (Trademark)
] Ethyl acetate:hexane, 1
:eluted at 9. Combining and evaporating the appropriate fractions gave an oil (6,279) which crystallized on standing for several days to give the title compound, mp 60-63°.

Analysis %: Actual value: C, 44.2; Milk 3.4
; H, s, t; Calculated value as C□3H1□F4N205: C, 44,3; Milk 3.4; N, 8.0N-)
Rifluoroacetyl N-(2-nitro-DMF.

24-dimethylimidazole (6,259), N-trifluoroacetyl-N-(5-fluoro-2-nitro-
A mixture of benzyl) chrysine ethyl ester C22,09) and sodium carbonate (6,629) was stirred and heated to 130° for 2 hours. The volatiles were removed from this cooled mixture in vacuo and the residue was dissolved in ethyl acetate (200 m”
) and water (100ml). The organic phase was washed with water (2X25cWL3), dried (MgSO
), and evaporated in vacuo to give an oil. This was chromatographed on silica (Merck "MK60.9385"™) eluting with ethyl acetate:methanol, 1:19. The appropriate swatches were combined and evaporated to give an oil which crystallized upon trituration with ether to give the title compound, mp 172.5-176° (3.1 g).
,was gotten.

Analysis knee actual measurement value: C, 50, 7; H, 4, 8
;N,,IZ7;Calculated value as C engineering JIH19'3N405:C,50,5;H,4,5;N, 13.1
Production Example 15 N-trifluoroacetyl-N-(5-
With fluoro-2-nitrobenzyl)-chrysine ester and 124-) lyazole.

N-) IJ Fluoroacetyl-N-(2-nitro-5-(L2.4-triazol-1-yl)benzyl)chrysine ethyl ester, melting point 99-102°, tube preparation as in the previous preparation example. did.

Analysis: - Actual value: C, 44,7; H, 3,5
;N, 17.4: Calculated value as C15'□4F3"5015: C, 44,9; 8 3.5; N, 17.
Solution of N-)lifluoroacetyl-N-(2-nitro-5-(2,4-dimethylimidazol-1-yl)benzyl)glycine ethyl ester (1,5 g) in 4 ethanol (60 cIIL3) 11 at room temperature. 20p, s, i
, (1,38×105 Pa) hydrogen pressure over Raney nickel (0,159) for 3 hours. the mixture,
Filtration through “Solkafloc”™ and evaporation in vacuo gave an oil (1,49). This was triturated with ether and crystallized to give the title compound, mp 163-166°.

Analysis % knee actual value: C, 53,4; H, 5,1
;N, 13.7;Cl8H2□F'3N403.0
．． Calculated value as 25 H2O: C, 53,7; H, 5
,4;N, 13.9 Production Example 17 N-)lifluoroacetyl-N-(2-
Using nitro-5-[Lλ4-triazol-1-yltuindyl)chrysine ethyl ester, N-)! J fluoroacetyl N-(2
-Amino-5-024-triazol-1-yl]benzyl)glycine ethyl ester, crude oil, prepared in tubes.

Preparation Example 18 N-trifluoroacetyl-N-(2-amino-5-(24-dimethylimidazol-1-ylcoindyl)glycine ethyl ester (1) in sternmethanol (20 m3)
, 49) and anhydrous sodium carbonate (0,749) was heated to reflux for 3 hours. The cooled solution was evaporated to dryness in vacuo and the residue was dissolved in chloroform (50 ml).
and water (10 cm3). The aqueous phase was re-extracted with chloroform (2X25m3) and the combined and dried (Mgso4) organic extracts were evaporated to give an oil. This is silica [Merck (Merck) MK
60. 9385™] and eluted with 9:1 ethyl acetate:methanol. The appropriate fractions were combined and evaporated to give the title compound as an oil (0,419) which was used directly.

Preparation Example 19 Using N-)lifluoroacetyl-N-(2-ami/-5-(L24-triazol-1-yl)benzyl]glycine ethyl ester and sodium carbonate in methanol as starting materials, the procedure was as in the previous Preparation Example. Similarly, N
-(2-amino-5-[LZ4-)lyazol-1-ylcoindyl)glycine methyl ester, crude oil, was produced.

Production example 20 H3 methylphenyl)-LZ4-triazole (1.5 g)
A stirred suspension of diisobutylaluminum hydride (a 1.5 M solution in toluene, 11.1
cm3) T-merchant ship. The solution was stirred at room temperature for 0.5 h, heated to reflux for 2 h, and methanol (1 m
) and water (100 cWL3). The solid material was filtered off and washed with methanol (50 cm3) and the filtrate was evaporated in vacuo. The residue was dissolved in 2M hydrochloric acid (20 cm3) and heated at 100 cm for 10 min. The solution was warmed to 50° and cooled. The solution was neutralized with saturated sodium carbonate solution and extracted with chloroform (4×50m3). The combined organic extracts were dried (M9SO4λ) to give an oil upon evaporation.

This is coated with silica (Merck) MK 60.
9385'' (trademark) and eluted with ethyl acetate. The appropriate fractions were combined and evaporated, followed by recrystallization from ethyl acetate/hexane to give the title compound, mp 209-211° (1,279 ), which was characterized by n, m, r, and infrared spectroscopy.

Production Example 21 A mixture of 1-(4-amino-3-iodo-5-methyl-phenyl)-L2.4-triazole (14,23 g) and cupric cyanide (5,949) was added to N-methylpyrrolidone. (32 m3) for 2.5 hours.

Heated to 120°. Pour the cooled mixture into ammonia solution (100 cWL3; S, G, 0.880).

The resulting solution was diluted with chloroform:methanol.

Extracted with 19:1 (3 x 150 cm3). The combined dried (M9SO4) organic extracts were filtered and evaporated in vacuo (0,5m) to give an oil. This is silica (Merck) MK 60.9385
” (trademark), eluting with ethyl acetate:methanol, 19:1. The appropriate fractions were combined and evaporated to give an oil, which was triturated with ether and crystallized. The title compound, melting point 231-3°
(2-89)1! jr: Got it.

Analysis: - Actual value: C, 59,8; H, 4,6
:N, 35.6;C□3H14N4 'Calculated value as Akira H20:C,60,3:戊4.6;N, 35.2
a(3) (7) 1-( in stirred acetic acid (100 cW #3)
4-amino-3-methylphenyl)-1,2,4-triazole (5,229) and sodium acetate (2-5
-Iodine chloride (5,103 min) was added to a solution of 83 g). After 16 hours, all volatiles were removed in vacuo and the residue was partitioned between dichloromethane (100 ml) and sodium carbonate solution (50 ml). The organic phase was diluted with thiosulfate) IJum solution (109% in 5Q cm3 of water)
), dried (M9SO4) and evaporated to give a solid. This is silica [Merck (Merck) MK
60. 9385°(TM)] and eluted with ethyl acetate.

The solid obtained by combining and evaporating the appropriate fractions is recrystallized from ethyl acetate-ether to give the title compound, mp 15
1-154° (3,19) was obtained.

Analysis: - Actual value: C, 36, 6: 3.1
; N, 19.0 ; Calculated value as C9H8 engineering N4: C, 3s, o; H, 3,0; N, 18.7 Manufacturing example
23 GE (1 in stirred absolute ethanol (500 cm3)
To a suspension of -(3-methyl-4-nitrophenyl)-144-triazole (42 g) was added stannous chloride, dihydrate (2259) in several portions. After heating to reflux temperature for 4 hours, the cooled mixture was basified to pH 3 with a 2.5M aqueous solution of hydroxide and filtered. Evaporate solution a in vacuo and add chloroform (200c
frL3) and water (5oc1n3),
The aqueous phase was further extracted with chloroform (2X100 crn3). The combined dried (MgSO4) organic extracts were concentrated in vacuo to give a solid <309%, which was recrystallized from total ethyl acetate to give -(4-amino-3-methylphenyl)-12,4- ) Riazole, melting point 122
-5°. I got it.

Analysis % knee actual value: C, 61,9: H, 5,9
:N, 32.1: Calculated value as C9H1oN4: C,62,1;H,5,8;N, 32.2 Production example 2
4 H3 H3 3-fluoro-6-nitrotoluene (50,09).

1.2.4-) A mixture of lyazole (22,29) and sodium carbonate (34, Og) was heated to 130° with stirring in dimethylformamide (300 m3) for 16 hours. The cooled mixture was then concentrated in vacuo and the residue was acidified to pH 1 using 4M hydrochloric acid.
The resulting solution was extracted with chloroform (2X 25 cm3) to remove all neutral materials. The combined aqueous phases were basified to pH 10 using 2.5M sodium hydroxide solution.

The mixture was extracted with total chloroform (3X250m3).

The combined and dried (Mgso) organic extracts were concentrated in vacuo to give a solid, which was recrystallized from toluene to give 1-(3-methyl-4-nitrophenyl).
-L'2.4-) riazole, melting point 116-7°, was obtained.

Analysis % knee actual value: C, 52,9; H, 3,9
;N, 27.6; Calculated value as COH8N,02: C,52,9;H,3,9;N, 27.5Methylimidazol-1-yl]benzyl)glyH3 Glycine ethyl ester (2,29 ) and 1-(4-
Amino-3-formyl-5-methylphenyl)-2,4
- a mixture of dimethylimidazole (0,647 g),
Dean and Siark
) toluene (
30 m3) for 3 hours to reflux. Vacuum removal of volatiles converts the intermediate imine to the crude oil (0,8
49). This material was dissolved directly without purification in absolute ethanol (25 m3) over 10% palladium on charcoal (0.1 g).

Hydrogenation was carried out for 2.5 hours at 25° and a pressure of 5 Q p,s,i.

Add the mixture to 'SolkafloC'
” (TM) and the ethanol was removed in vacuo to give the title compound as an oil (0,759).

Production Examples 26 and 27 As a starting material, racemic alanine ethyl ester (Production Example 26)'! or methyl 2-aminoinbutyrate (Production Example 27), 1-(4-amino-3-formyl-5-methylphenyl>-2,4-:)methylimidazole, and hydrogen on Pd/C, f: used The following compound was prepared in the same manner as in Preparation Example 25. did.

Production example 28 43 CH3 glycine ethyl ester (5,79) and 4-(4-
amino-3-formyl-5-methylphenyl)-L2.
4-) A mixture of lyazole (1,62 g) was poured into toluene (120 g) with constant removal of water using a Dean and Stark apparatus.
cm3) for 45 hours. Vacuum removal of the volatiles yields the intermediate imine as a crude solid (2,359)
obtained as. This material was dissolved directly in absolute ethanol (200 cm3) without purification and treated with sodium cyanoborohydride (5,09). After heating to reflux for 10 hours, the cooled solution was evaporated in vacuo to a volume t of approximately 50-3, and diluted with aqueous sodium carbonate solution (10
0cWL3). The mixture was extracted with dichloromethane (3 x 200 m3) and the mixture was dried (M
gso4) The organic extract was evaporated in vacuo to give an oil.

This is f'/Lika [Merck] MK 60
．． 9385'(TM)] and eluted with dichloromethane:ethanol, 19:1.

Appropriate fractions were combined and evaporated to give 1 title compound to an oil (1
, 14 minutes).

Preparation Example 29 CH3 1-(4-Amino-3-cyano-5-methyl- in stirred tetrahydrofuran (THF) (30 parts)
phenyl)-2,4-dimethylimidazole (2,26
The suspension of g) was cooled to fto°.

A solution of diisobutylaluminum hydride (17 cm3 of 1.5 M toluene solution) was added for treatment. next.

The mixture was warmed to 55° for 1 hour, cooled to 0° and treated carefully with methanol (5c1n3).

After dilution with water (20CrIL3), the precipitated aluminum salts were removed by filtration, and the filtrate was diluted with 2M hydrochloric acid (20cm
3). Thereafter, the aqueous solution 1ffl' was basified with saturated aqueous sodium carbonate solution (pH 9), and the mixture was extracted with dichloromethane (4X 20c!n3). The combined and dried (Mgso4) organic extracts were evaporated in vacuo to give an oil, which was fused onto silica (Merck
)'MK60,9385'(TM)] dichloromethane:methanol.

Eluted at 19:1. Combining and evaporating the appropriate fractions gave a solid which was recrystallized from ethyl acetate to give the title compound, mp 203-207° (1.2 g).

Analysis % knee actual value: C, 65, 3; Vero, 4;
N, 18.2; C13H15N30, 0.5 H2
Calculated value as O: C, 65, 2; H, 6, 8; N,
17.6 Preparation Example 30 4-(4-Amino-3-cyano-5-methylphenyl)-L2.4-triazole and diisobutylaluminum hydride were used as starting materials and 4- (4-amino-3-formyl-5-methylphenyl)-1,Z 4-triazole, melting point 250
-252°, all produced.

Analysis % knee actual value: CH59-3: 戊5.1
; N, 28. OCo. Calculated value as H1oN40: C,59,4;
4-amino-3-iodo-5-methylphenyl)-1,
2,4-) lyazole (3,0 g) and tetrakis (
triphenylphosphine)palladium(0)(1,1?
) was deoxygenated for 0.5 h using a stream of nitrogen.

The mixture is then placed under carbon monoxide (approximately 2 atmospheres) and heated at 50°
A solution of tri-n-butyltin hydride (3.2 g) in THF (200 m3) was added in portions to warm the mixture for 4 hours. After a further 0.5 hour, the mixture was diluted with water (200 c
The mixture was extracted with dichloromethane (5X200m3). The combined and dried (M9SO4) materials were evaporated in vacuo and the residue was purified with silica (Merck's M9SO4).
Dichloromethane:methanol% 9:1
It was eluted with The solid obtained by combining and evaporating the appropriate fractions was recrystallized from ethyl acetate-methanol to give the title compound, mp 250-252° (1,879).

As a result of characterizing this product by spectroscopic analysis, Production Example 3
The product was identical to that of 0.

Production example 32 1-(4-amino-3-bromo-5-methylphenyl)
-Z4-Dimethylimidazole (17,3 g) and cupric cyanide (17,99) were heated in a mixture of N-methylpyrrolidone (50 m3).

It was stirred at 1500 for 6 hours. The cooled mixture was diluted with ammonia solution (200ml; S, G, O, 5SO).
and chloroform (200cWL3). The aqueous phase was further treated with chloroform (2X 1.0011
The combined and dried (M9SO4) organic phases were evaporated in vacuo to give an oil. This is silica [Merck (Merck) MK 60. 9385" (trademark) and eluted with dichloromethane:methanol, 19:1. The appropriate fractions were combined and evaporated, and the resulting oil was triturated with ether to give a solid (10,
05g) was obtained. A small portion of this material was dissolved in ethyl acetate.
Recrystallization from methanol gives the title compound, mp 214.
−217° was obtained.

Analysis fi Knee actual value: C, 69,0; H, 6,5
; N, 24.7; Calculated value as C13H14N4: C, 69,0; H, 6,2; N, 24.8 Production example 3
3. 4-(4-
Amino-3-cyano-5-methylphenyl)-L2.4
-triazole, 0.25H20, melting point 283-28
6° was produced.

Analysis Chi21 actual value: C, 58,9; H, 4,5
:N, 34.4; Calculated value as C10H9N5°0.25H20: C,59,0;H,4,7;N, 34
．． 4 Preparation Example 34 H3 Bromine (5,6cII #3) in Glacial Acetic Acid (50cfn3)
solution of gold.

Glacial acetic acid (200cn) stirred for 0.5 hours.
1-(4-amino-3-methylphenyl)-2 in 3)
, 4-dimethylimidazole (20,39) and sodium acetate (9,02 g).

After a further 0.5 hours, volatiles were removed in full vacuum.

The residue was partitioned between chloroform (200m3) and 10% aqueous sodium hydroxide (to pH 10).

The aqueous phase was further extracted with chloroform (2X100m3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to yield solid gold. This is silica [Merck (Me)
rck) 'MK 60. 9385' (trademark)
] and eluted with dichloromethane:methanol, 19:1. Combining and evaporating the appropriate fractions gave an oil which was triturated with ether to give the title compound 5, mp 176-180. s': was obtained.

The mother ff1k was evaporated and the residue was again chromatographed on silica as before, giving a further crop (total yield 17.3 g).

Analysis: - Actual value: C, 49,5; H, 5,0
;N, 14.4;C□2H,N3Br, Q,5H
Calculated value as 2o: C, 49,8; H, 5,2; N,
14.5 4-(4-amino-3-methylphenyl)-L2.4-triazole in glacial acetic acid as starting material,
- 4-(4-amino-3-iodo-5-methylphenyl)-L2,4-triazole, melting point 211, analogously to the previous preparation using iodine chloride and sodium acetate.
-214°, all produced.

Analysis: - Actual value: C, 35,8; H, 3,1
;N, 18.4;Calculated value as C9H8 engineering N4: C,36,0;Toki 3.0;N, 18.7Manufacturing example
36 H3 H3 Stannous chloride dihydrate (40,7 g) was dissolved in 1-(3-methyl-4-nitrophenyl)-44-dimethylimidazole (8,39) in stirred absolute ethanol (lOocrn3). It was added to the suspension in several portions. After heating to reflux for 4 hours, the cooled mixture was basified to pH 8 using a 2.5M aqueous solution of hydroxide and filtered. The filtrate was evaporated in vacuo and diluted with chloroform (2
00crn3) and water (50crrL3) and the aqueous phase was further extracted with chloroform (2X100cWL3). The combined dried (MgSO4) organic extracts were concentrated in vacuo to give a solid (6.8 g);
This was recrystallized from ethyl acetate to give 1-(4-amino-3-methylphenyl)-2,4-dimethylimidazole, melting point 92-96°.

Preparation Example 37 A solution of 4-(3-methyl-4-nitrophenyl)-L24-triazole (t, og) in acetic acid (25 cWL') was heated over Raney nickel (0,29) at 25°.

Pressure 60 p, s, i, (4,13X 105Pa)
The mixture was hydrogenated for 2 hours. The mixture was then filtered through 1 Solkafloc' (a trademark for cellulose-based filter agents), the solvent was evaporated in vacuo, and the residue was dissolved in chloroform (Looctn 3).
and an aqueous sodium carbonate solution (20m3). The aqueous phase was further diluted with chloroform (3X 50cWL3
) and the combined dried (JSO4) organic extracts were concentrated to give an oil. Add this to silica [Merck
methanol:ethyl acetate.

Eluted at a ratio of 1:9. Combining and evaporating the appropriate fractions gave a solid, which was recrystallized from ethyl acetate/hexane to give 4-(4-amino-3-methylphenyl)-
LZ4-) lyazole, melting point 152-154° (0,
67g) was obtained.

Analysis: - Actual value: C, 62, o; H, 5, 6
; N, 31.8; Calculated value as C9H1ON4: C, 62,1; Rui 5.7; M, 32.2 Production example 3
8 H3 3-Fluoro-6-nitrotoluene (10.3 g).

A mixture of 2.4-dimethylimidazole (6,36 g) and sodium carbonate (7,5 g) was stirred in :) methylformamide (40 cm3).

Heated at 130° for 40 hours. The cooled mixture was then concentrated in vacuo and the residue 't-acidified with 4M hydrochloric acid to pH
1, the resulting solution was diluted with chloroform (2X25c1
n3) to remove all neutral substances. Combined aqueous phase '1'2. ．． pH with 5M sodium hydroxide solution
The mixture was basified to 10% in chloroform (3X25
0 m3). The mixture was dried (M2SO4
Vacuum concentration of the Sui extract yielded a solid, which was coated with silica (Marck "MK 60.9385'").
(Trade Mark)] and eluted with methanol:ethyl acetate, 1:19. The appropriate fractions were combined and evaporated to give a solid (8,49). This was recrystallized from ethyl acetate to give 1-(3-methyl-4-nitrophenyl)-44-dimethylimidazole.

A melting point of 135.5-138% was obtained.

Analysis % knee actual value: C, 62,0; H, 5,7
”, N, 17.9; Calculated value as C□2H□3N30□: C,62,3; H,5,7; ) and L
A mixture of 2-diformyl-hydrazine (1,3!J) was heated to 200° under nitrogen for 1 hour.

The residue is then cooled and silica [Merck
)'MK 60.9385' (trademark)] in methanol:dichloromethane, 1:19.
It was eluted with When appropriate fractions are combined and evaporated, a solid (
1,039) was obtained, which was recrystallized from ethanol to give 4-(3-methyl-4-nitrophenyl)-L
2.4-trif/-r, melting point 208-210°, was obtained.

Analysis % knee actual value: C, 52,8: H, 4,0
:N, 27.3; Calculated value as C9H3N40□: C, 52,9; H, 3,9; N, 27.4 Production example 4
0 H3 Stirred tetrahydrofuran (THF') (70c
2-methoxy-5-bromopyridine (9
, 49) was added n-butyllithium (1.6 M solution in n-hex/33z3) at −70° under nitrogen. After stirring at −70° for 1 h, the mixture was
Anhydrous lead chloride (14,2g) in HF (70em3)
) and the mixture was warmed to room temperature. 2-
Amino-5-iodo-3-methylbenzyl alcohol (
3,! 1it-[Preparation Example 8 Minister] and tetrakis(triphenylphosphine)moradium(0)(0,49) were added and the mixture was heated to reflux for 3 hours. Saturated ammonium chloride solution ffL (50 CrI@3) was added to the cooled solution and the mixture was diluted with ethyl acetate/l/(300 an
3) and a solution of ethylenediaminetetraacetic acid disodium salt (20g) in water (300crn3). The aqueous phase was further extracted with ethyl acetate (300 cm3) and the combinations were dried (MgSO4). The organic phase was evaporated in total vacuum to give a brown oil. This costs 7 licas [Merck's MK 60. 9385
'(TM)] and eluted with dichloromethane:methanol, 49:1. Combining and evaporating the appropriate fractions yields the title compound as a waxy solid,
mp 80-82° (3,69), which was used directly without further purification.

H3 Freshly dried manganese dioxide (1,59)'k.

2-Amino-5-( in dichloromethane (20cn3)
A solution of 2-methoxypyrid-5-yl)-3-methylbenzyl alcohol (1,59) was added under nitrogen and the mixture was stirred at room temperature for 2 hours. Filter this mixture and
The filtrate was evaporated to dryness to leave a residue of silica [Merck
ck)' MK 60. 9385'(TM)] and eluted with dichloromethane. Combining and evaporating the appropriate fractions yields the title compound, mp 8
1-84° (0.98 g) was obtained.

Analysis: - Fluorometric value: C, 69,3; H, 5,6
;N, 11.6;C engineering. Calculated value as H□4N20□: C,69,4;H,5,8:N, 11.6H3 2-amino-5-(2-methoxypyrid-5-yl)-
3-methylinduldehy) (0.92 g) was stirred under nitrogen in anhydrous ethanol (100 cm3).
Hydrobromic acid (60tlbW/w aqueous solution 3cm3)
solution and the mixture was heated to reflux for 2 hours. The cooled solution was evaporated in vacuo and the residue was dissolved in 10% sodium carbonate solution (30m3) and dichloromethane (50cW
L3). Dry the organic phase (M9S0
The solid residue obtained by four-person vacuum evaporation was evaporated into silica [Merck (
Merck) MK 60°9385' (trade mark)] and eluted with chloromethane:methanol, 10:1. Appropriate fractions were combined, evaporated and recrystallized from ethyl acetate. 1 title compound, melting point 231-234° (0.26 g)% was obtained.

Analysis % Knee actual value: C, 66.9; 戊5.8;
N, ILI; C, 3H1□N2O2,0,25CH3C
Calculated value as o2Et: C, 67,2; H, 5,6;
About 11.2N-(2-amino-3-methyl-5-[2-
Human methyl ester glycine ethyl ester and 2-amino-5-(2-
The title compound was prepared as in Preparation Example 25 using hydroxypyrid-5-yl)-3-methyl-benzaldehyde followed by hydrogen on Pa/C. Isolated and used directly without further purification.

(5 other people)

Claims (17)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) [In the formula, "Het" is the above 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline-2 -(1H)-
R is an optionally substituted 5- or 6-membered aromatic heterocyclic group attached to the 6-, 7-, 8-, or 9-position of or bonded to the 9-position,
hydrogen, C_1-C_4 alkyl group, C_1-C_4 alkoxy group, hydroxy group, hydroxymethyl group, halogen or CF_3; and R^1, R^2, R^
3, R^4 and R^5 are each H or C_1-C_
4 alkyl group. ] or a pharmaceutically acceptable salt thereof. (2) "Het" is a pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group,
When containing an oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, furyl group, thienyl group, oxadiazolyl group, and nitrogen, these N-
oxide [all of these are each separately C_1-C_4
Alkyl group, C_1-C_4 alkoxy group, hydroxy group, halogen, CF_3, cyano group, hydroxymethyl group, (C_1-C_4 alkoxy)carbonyl group, -N
O_2, -NR^6R^7, -CONR^6R^7, -
SO_2NR^6R^7 and -S(O)_m(C_1
-C_4 alkyl), where R^6 and R^7 are each independently H or a C_1-C_4 alkyl group, and m is 0, 1 or 2. The compound according to claim 1, which is optionally substituted. (3) “Het” is (a) an imidazolyl or triazolyl group optionally substituted by one or two C_1-C_4 alkyl groups, or (b
) A compound according to claim 2, which is a pyridyl group optionally substituted by one or two C_1-C_4 alkyl groups or one hydroxy group. (4) "Het" is (a) an imidazolyl or triazolyl group optionally substituted with 1 or 2 methyl groups, or (b) optionally 1 or 2 methyl groups or 1 The compound according to claim 3, which is a pyridyl group substituted with a hydroxy group. (5) “Het” is 2,4-dimethylimidazole-1
-yl group, 1,2,4-triazol-1-yl group, 1
, 2,4-triazol-4-yl group, 1-methyl-1
, 2,4-triazol-5-yl group, 2,6-dimethylpyrid-3-yl group or 2-hydroxypyrid-5
-yl group, the compound according to claim 4. (6) “Het” is in the 7th position, the first claim
The compound according to any one of Items 1 to 5. (7) The compound according to any one of claims 1 to 6, wherein R is H or a C_1-C_4 alkyl group at the 9-position. (8) The compound according to claim 7, wherein R is H or CH_3 at the 9-position. (9) R^1, R^3 and R^4 are each H or CH
_3, and R^2 and R^5 are H, the compound according to any one of claims 1 to 8. (10) The compound according to claim 9, wherein R^1, R^3 and R^4 are H. (11) Formula: - ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula: - (a) “Het” is 2,4-dimethylimidazole-1
-yl group, and R^3 and R^4 are H; (b) "Het" is 2,4-dimethylimidazole-1
-yl group, R^3 is CH_3 and R^4 is H; or (c) "Het" is 1,2,4-triazol-4-yl group, and R^3 is CH_3 and R^4 is H; 3 and R^4 are H. ] or a pharmaceutically acceptable salt thereof according to claim 1. (12) The formula (
A pharmaceutical composition comprising a compound of I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. (13) A compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use as a medicament. (14) The formula (
Uses of the compound of I) or its pharmaceutically acceptable salt. (15) Formula: - ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (III) and (IV) (In the formula, “Het”, R, R^1, R^2, R^3 and R^ 4 is as defined in claim 1, and "Het" and R are 3-, 4-, and 5 of the benzene ring.
- or 6-position, and Y is H or CN). (16) Formula: - ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, Q is a leaving group, R, R^1, R^2, R^
3R^4 and R^5 are as defined in claim 1). (17) Claim 1, in which Q is Br or I
Compound according to item 6.