JPS6182A - Quinolone cardiac stimulant - 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 The present invention relates to substituted quinolone inotropes that generally selectively increase myocardial contractility without significantly increasing heart rate. The compounds of this invention are useful in the curative or prophylactic treatment of cardiac conditions, particularly cardiac dysfunction.

The compound of the present invention has the following formula: (wherein @Hat" contains at least one nitrogen atom in the aromatic ring ζ and is bonded to the 5-16-17- or 8-position of the quinolone through one nitrogen atom, May be optionally substituted 5
-represents a -membered monocyclic aromatic heterocyclic group, R is bonded at the 5-56-17'- or 8-position ζ, a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
C1-C4 alkoxy group, hydroxy group,
CF3 represents a halogen atom, a cyano group or a hydroxymethyl group, and the dotted line between the 8-position and the 4-position represents that it may be a double bond. ) Substituted 2-+1H)-quinoloni/ and pharmaceutically acceptable salts thereof.

"Hgt-" preferably contains 1, 2.8 or 4 nitrogen atoms in the aromatic ring and no other heteroatoms.

Examples of the radicals -Hat'' are pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups, which optionally contain e.g.
alkyl, carbon atoms 1 to 417), flukoxy, hydroxy, fluorocarbons, CFs, cyano, hydroxymethyl, (C1 to 4 alkoxy)carbonyl, nitro, -CONR1R2 and -NR'R'' (
In the group, R1 and R2 each independently represent 1H or an alkyl group having 1 to 4 carbon atoms. ) is substituted with up to 8 substituents, preferably 1 or 2, each independently selected from .

The halogen atoms are F, C11%Er or I. C3 and C4 alkyl and alkoxy groups are straight chain or branched. Preferred alkyl and alkoxy groups are methyl and methoxy groups. .

Although the compound of formula I is described as a 2-[LH)-quinolone, it should also be understood that the following tautomerism occurs: However, the keto form is the more stable tautomer. Although the final product is named and described herein as a quinolone because it is believed to be It will be appreciated that some particular compounds may exist as the predominant ζ-hydroxy tautomer, and the following description should be construed to include all of these isomeric forms. be.

Preferably, there is a double bond in the 3- and 4-positions.

Preferably, Htt t- is attached to the 6-position of the quinolone.

Preferably, R is bonded to the 8-position.

R is preferably H1 alkyl having 1 to 1 carbon atoms, C
F or halogen atom. More preferably R is H, CH8, CFs or Br. R is H or C
H, is the most preferable case.

"Hat" means imidazolyl, pyrazolyl, optionally substituted with up to 8 substituents selected from alkyl having 1 to 4 carbon atoms, CF, NO, NH, CN, and hydrogen atoms, and having a good temperature at °C; A triazolyl or tetrazolyl group is preferred.

Preferred substituents on @Hat' are CHs, CF
3, NO2, NH2, CN, Br or I. More preferably, ``Het'' is imidazol-1-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl,
yl, 1,2.41 lyazol-1-yl, 2,4-dimethylimidazol-1-yl, pyrazol-1-yl, 4-trifluoromethylimidazol-1-yl, tetrazol-1-yl, 3,5 -dimethyl-1,2,4
-triazol-1-yl, 8,5-dimethyl-1,2
, 4-triazol-4-yl, tetrazol-2-yl, 1,2.4-triazol-yl, 2゜4-dimethyl-5-nitroimidazol-1-yl, 5-nitro-4-methylimidazole -1-yl, 5-amino-
2,4-dimethylimidazol-1-yl, 5-bromo-2,4-dimethyl-imidazol-1-yl, 5-iodo-2,4-dimethylimidazol-1-yl or 5-cyano-2, It is a 4-dimethylimidazol-1-yl group.

Most preferably @Hat” is 2,4-dimethyl-5-
Nitroimidazol-1-yl, 2,4-dimethylimidazol-1-yl, tetrazol-1-yl or 1
, 2.4-triazol-4-yl group.

The most preferred individual compounds represented by formula 1 are as follows: (wherein Het is 2,4-dimethylimidazole-1
yl, 2,4-dimethyl-5-nitroimidazole-1
-yl, tetrazol-1-yl or 1,2.4-triazol-4-yl group. ).

Pharmaceutically acceptable salts of the compounds of Formula I are acid addition salts formed from acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, including salt salts. , hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconic acid salts, acid addition salts such as methanesulfonate and p-toluenesulfonate or metal salts, especially alkali metal and alkaline earth metal salts. Particularly preferred metal salts also include the sodium and potassium salts. All of these salts can be prepared according to conventional methods.

The cardiotonic activity of a compound of formula (I) is indicated by its efficacy in one or more of the following tests: (α
(b) Increased myocardial contractility in anesthetized dogs (Starling l 5 tarl ing l J canine heart-lung specimen) measured by left ventricular catheter; (left ventricular dp/dt maximum); (c) implanted left ventricular transducer 1 dp/dt maximum) myocardial contraction in a conscious dog with a carotid loop (cardiac contraction time interval) that is still transposed outside the body. Increased sexuality.

In test (α), the positive inotropic effect of the test compound following pill administration [Starli%g] is measured in canine heart-lung specimens. Selectivity for increasing the frequency of contractions and potency of the test compound is obtained.

In test (b), the positive inotropic effect of the test compound after intravenous administration is determined in anesthetized dogs. The magnitude and duration of this effect and the selectivity for increasing the force versus frequency of contractions of the test compound are obtained along with distal effects, such as effects on blood pressure.

In test (c), the test compound was administered intravenously or orally to conscious dogs implanted with a left ventricular transducer I d p/d (maximum value) or with a carotid artery loop (interval of cardiac contraction time) transposed outside the body. Measure the positive inotropic effect of magnitude of inotropy, selectivity relative to increase in force versus frequency of contractions;
and the duration of action of the inotropic effect of the test compound.

While the compounds of formula (1) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be in the form of tablets containing excipients such as starch or lactose, or as capsules alone or mixed with excipients, or in the form of elixirs or suspensions with flavoring or coloring agents. Can be administered orally. These can be administered parenterally, e.g. intravenously,
It can also be injected intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions, which may contain other solutes, such as sufficient salt or glucose to make the solution isotonic. .

When administered to humans for the curative or prophylactic treatment of cardiac conditions such as congestive circulatory failure, the oral dosage of the compounds of the invention may be 2 to 2 times a day for an average adult patient (70 kg). 10 to 1 g per day, taken in 4 divided doses
It is thought that it is within the range of . Doses for intravenous administration, for example in the treatment of acute cardiac insufficiency, will be within the range of 0.5 to 100 μm per single dose depending on the requirements. Therefore, for a typical adult patient,
An individual tablet or capsule can contain from 2.5 to 100 rv of the active compound in a suitable pharmaceutically acceptable excipient system or carrier. The amount used may vary according to the weight and condition of the patient being treated, as is known to the clinician.

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

The present invention also provides a method of stimulating the human heart, which method comprises administering a compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, in an amount sufficient to stimulate the human heart. (consisting of administering to said human a pharmaceutical composition as defined herein).

The present invention furthermore provides a compound of formula (1) or a pharmaceutically acceptable salt thereof for use in medicaments, particularly for stimulating the heart of humans suffering from congestive circulatory failure.

Compounds of formula ■ can be prepared by a number of routes, for example by the following reaction: Route A: This method is described as follows: (formerly
(IA) 'Q' is a leaving group such as an alkoxy group having 1 to 4 carbon atoms.

The cyclization is preferably carried out by treating the propenamide (in) with concentrated, preferably substantially anhydrous (98%) sulfuric acid at room temperature until the reaction is complete, generally from 6 to 48 hours. If it is necessary, the reaction can be accelerated by heating to 1 (JO℃).

The product is then isolated and purified using conventional methods. In propenamide+l), Q is preferably an ethoxy or methoxy group.

Propenamide (formerly in acid addition salt form (e.g. hydrochloride))
It can also be used in

Typical reactions are described below: Starting materials of the formula However, it is as follows.

CHs Pathway B: This path is generally designated as follows: The reaction is generally carried out by heating the molten reactants to 100-250° C. until the reaction is complete.

The general reaction is described below: Starting materials (prints) can be prepared according to conventional methods.

Representative routes to the starting materials are: Route C:
This route is generally depicted as follows: T IA) (IB) This reaction is generally carried out using a transition metal catalyst (for example, 5- 14% palladium or platinum oxide) at 1 to 880 atm.
This is carried out by hydrogenating the starting material (IA) at temperatures up to .degree.

A typical reaction is as follows (shown here: Route D): This route is generally shown as follows (shown here: Specifically, 5 M HCII aqueous solution or 48% H
In a Br aqueous solution, at a temperature up to the reflux temperature, the general f value is 0.
．． The product is then isolated and purified according to conventional methods.

A typical reaction of this type is shown below: and the starting material of formula (1) can also be prepared in a conventional manner. Typical routes to these substances, many of which are shown in detail in the Preparation Examples below, are generally as follows: (cL) 6-bromo-2-methoxy-8-methylquinoline is equivalent to The 2-chloro compound is prepared by refluxing the 2-chloro compound in methanol with sodium methoxide for up to 24 hours.

(b) Route E: This route is generally designated as follows: The reaction is generally carried out using the starting material (V), preferably the methyl or ethyl ester! , 3;, 5M11 (J) in an aqueous solution by heating with a trowel at a temperature up to reflux temperature, generally for 0.5 to 4 hours. The product is isolated and purified according to conventional methods.

Typical reactions are shown below: Starting material (V) can be prepared according to conventional methods.

A typical route to the starting material may be as follows: An alternative route to the starting material (Vl is abbreviated as route J).

Path F: This path is generally designated as: IVI
) Ga (1B) This reaction is generally carried out in two steps. The first stage is
Starting materials (Vl, typically methyl or ethyl esters) are treated with transition metal catalysts (e.g. 5-
Hydrogenation over 10X palladium on activated carbon) at 1-4j atmospheres and temperatures up to 70°C. The hydrogenated intermediate (Vl) is then heated in a suitable organic solvent (e.g. xylene) at a temperature of up to 200°C (trowel approx.
Cook for up to 8 hours.

A typical reaction is as follows: Starting material (V) is prepared in a conventional manner as outlined in Route E).

Route G: This route to nitro-substituted heterocyclic groups is generally depicted as Generally, the temperature is 0.5 to 2 hours at a low temperature (-10° to +2
The product is then isolated and purified by conventional methods.

A representative reaction is shown below: Pathway H This route to a niaminosubstituted heterocyclic group is generally depicted as: (■) (■) This reduction is
This is typically done by selectively hydrogenating the starting material in a suitable organic solvent such as ethanol over a Raney nickel under 1 to 6 atmospheres and at temperatures up to about 70°C.

The product is then isolated and purified in a conventional manner.

Representative reactions are shown below: Route I: This route to a halo-substituted heterocyclic group is generally shown as an arrow (shown here: (mA) IIK). This is carried out by halogenating the compound in a suitable organic solvent according to a conventional method. Representative halogenating agents are N-chlorosuccinimide, N-bromosuccinimide and iodine monochloride. The product is then isolated and purified according to conventional methods.

A typical reaction is as follows: Pathway: This path is generally denoted as: Δ (Xl [1,4)(VA
) "M# is an alkali metal, preferably Nα.

This reaction is carried out by heating the starting aldehyde (IX) with Witschig's reagent in a suitable organic solvent such as ethanol with wet ash up to reflux temperature, generally for 1 to 8 hours. The product is then isolated and purified according to conventional methods.

Typical reactions are shown below: C.F.

Starting material IX) can be prepared according to conventional methods.

Typical routes to the starting material are shown as arrows: Route K:
This route to halo-substituted quinolones is generally depicted as follows: (1) (■) IHalJ=C1,,Br or I) This reaction is typically performed by converting starting material (1) into 98% sulfuric acid. This is carried out by halogenation in the presence of silver sulfate. The product is aged and purified using conventional methods.

A typical reaction is shown below: Route L: Compounds with a “Het” group
aN0. /CuCN (Sandmeyer reaction) or (b) the corresponding bromo- or iodo-substituted compound with a metal cyanide (even ffcucN or N
αCM), preferably with FiPd CPP/1.
) 4 or Pd(OAC) 2 in the presence of a catalyst.

When the compound of the present invention has one or more asymmetric centers,
The present invention includes separated optical antipodes and diastereomers or mixtures thereof. The isolated form can be obtained by conventional methods.

The invention is illustrated by the following examples (all temperatures are °C).
): Example 1゜6-(1-imidazolyl)-8-methyl-2-(IH)
- Preparation of quinolones trans-1-C4-(N-C3-ethoxypropenamide)13-methylphenyl]-1 midazole (2,7
F) is added dropwise to 98% W/W sulfuric acid (20i) at 0° with stirring. After 24 hours at room temperature (205 °C, the mixture is carefully poured onto ice (200 g) and the resulting solution is saturated with carbonic acid) and basified to pH 8 with IJum solution. The resulting suspension was extracted (7 x 200 cm'') with methanol:chloroform (1:4 by volume), the combined and dried (M2SO4) extracts were evaporated under reduced pressure to give a solid, which was purified on silica. (Merck “Ill,” 60
．． 9385'') and eluted with methanol:chloroform (1:19 by volume).

The appropriate fractions were collected and evaporated to give a white solid, which was recrystallized from ethyl acetate/methanol.
6-(1-imidazolyl)-8-methyl-2-CIH]
- 2m, p, 259-2626.1 from which quinolones are obtained
．． 71 g.

Analysis (%): Actual value: C, 692; H, 4,9; #, 13, 3; Calculated value CCtsHuNsO): C, 69, a; H, 4, 9; #, ts, 6° Example 2 ~
11. Using a method similar to Example 1, starting with appropriately substituted trans-3-ethoxypro-4-mide (or its hydrochloride salt in Examples 4 and 5) and 98% (W/W) sulfuric acid. , the following compound is obtained: Example 12゜6-(2,4-dimethylimidazol-1-yl)=8
-Preparation of methyl-2-(14)-quinolone trans-z
-(4-[#-(3-ethoxypropenamide)]-]
3-Methylphe=#-2° 4-dimethylimidazole (3.2 g) is added dropwise to 98% W/W sulfuric acid (15c&) at 0° C. with stirring. After 24 hours at room temperature (20° C.), the mixture is carefully poured onto ice (150 g) and the resulting solution is basified to pH 3 with saturated aqueous sodium bicarbonate solution. The mixture is then extracted (6 x 100 i) with methanol:chloroform (1:9 by volume), combined and dried (CMtS04) and the organic extracts are evaporated under reduced pressure to give a solid. This is recrystallized from ethyl acetate/methanol (!: 6-(2,4-dimethelimidazo-l-yl)-8-methyl-2-(lH)-quinolone is obtained: rn, 1°322-5 ~325', 1.
0g.

Analysis (%): Actual value C, 71,4; H, 6,1: #, 1
a7: Calculated value (c,, H, llN5O): C, 71,
1; H, 6, 0: N, 16.6° Examples 13-17.
.

Analogously to Example 12, the following compound is obtained from the appropriate trans-3-ethoxypropenamide and 98% W/W sulfuric acid: lf Example 18゜3.4-Dihydrocaga-8-methyl -6-(1°2.4
-triazol-1-yl)-2-(14)-quinolone? 6-(1,2,4-triazol-1-yl)-8-methyl-2-(IH)-quinolone (see Example 9) (1,7 g) was suspended in ethanol manufactured by A (450i). 60'' and 60 p, s, i (4,13X 10
'Pα) with 10% palladium on activated carbon (0.35 g
) for 72 hours. The cooled mixture is then filtered through a Solka-floc (a trade name for a cellulosic filter aid) and evaporated under reduced pressure to obtain a solid.
85” [trade name]),
Elute with chloroform:methanol (49:1),
Appropriate fractions are then collected and evaporated under reduced pressure to obtain a solid. When this was recrystallized from ethyl acetate/methanol, 3,4-dihydro-8-methyl-6-(
1,2,4-triazol-1-yl)-2-(14)
l-Nolone is obtained: yrL, 12258-259
@, 0.266#.

Analysis (%): Actual value C, 6Z9: H, 5, 2: N, 24
4; Calculated value CCItHIt) 10): Cr 6 & 1
:H+ 5.31N, 245゜Examples 19-23゜Similarly to Example 18, the following compounds are obtained by hydrogenating a suitable substituted quinolone in ethanol over palladium-supported charcoal. : Example 24 (instead of Example 15) Preparation of hydrate to 8-methyl-6-(1,2,4-triazol-4-yl)-2-(IH)-6-amino -8-Methyl-2-(IZf)-quinolone (
0,4851 and 1,2-diformylhydrazine (0,2
45 g) is melted and heated at 200° C. for 1 hour while stirring. The residue is then ground with a hot improvisation tool, cooled and filtered. The solid residue was recrystallized from chloroform-isopropanol to give 6-(1,
2,4-triazol-4-yl)-8-methyl-2-
(lH)-Kinokuchi/, 0.25 HvO is obtained: m
, p.

369-371', 0.112g.

Analysis (%): Actual value: C, 62,7; H, 4,3: #,
23.8° Calculated value (c12H1oN40・1/4HtQ): C, 62-5; H, 4, 6; A+
', 24.3゜Example 25゜6-[3,5-dimethyl-1,2,4-triazole-
4-ylo8-methyl-2-1:14)-quinolone,
0.66 Preparation of H,O Hs 5M hydrochloric acid (6-(3,5-dimethyl-1,
2.4-triazol-4-yl2=methoxy8
- Heat the stirred solution in which methylquinoline (0,24F) is dissolved under reflux for 1 hour.

The cooled solution is basified to pH 8 with 10% aqueous sodium carbonate and extracted with chloroform (5×50d). The combined and dried (MfSO,) organic layer was evaporated under reduced pressure and the residue was purified with silica (Merck "MK60.9385").
Chromatography using dichloromethane:methanol (20:1) yielded 6-
[3,5-dimethyl-1,2,4-triazole-4-
yl]-8-methyl-2-CIM)-quinolone, 0.6
6H,0 is obtained; m, p, 308-310°40
．． 17g.

Analysis (%): Actual value: c, 63.4: H, 5,
4:N, 21.2° Example 26 (instead of Examples 15 and 24) 8-Methyl-6-(1,2,4-triazol-4-yl)-2-(IH)-quinolone hydrochloride 2-methoxy-8-methyl-6-(1,
2,4-triazol-4-yl)-quinoline and 5M
Using HCl, as in the previous example, but after refluxing the methoxy starting material and 5M HCl, cooling, the hydrochloride i-hydrate crystallizes from the solution, shavings and drying give the following compound: Cm-p->350") is obtained: Analysis (%): Observed value: C, 54,1; H, 4,4; N,
21.2; Example 27゜8-methyl-6-(tetrazol-2-yl)-2-(
14) - Preparation of quinolone hydrate in 5M hydrochloric acid (20 cIr
f') was added to trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-2-yl]phenyl)fluor'-2-enoate (0.45 g) and the mixture was heated in a steam bath for 1 hour. The mixture is then cooled and adjusted to pH 7 with an aqueous solution of IJ and dichloromethane:
Extract with methanol 20:1 (3X50i).

The combined organic extracts are dried (MtSO4), filtered and evaporated to dryness. The residue was treated with silica (Merck “MK60.938
5” (trade name) and eluted with ethyl acetate/methanol (10:1).

When appropriate fractions are collected and evaporated, 8-methyl-
6-(tetrazol-2-yl)-2-(lH)-quinolone, O,'25H20 is obtained: rn, p.

264-266°, o, osg.

Analysis (%): Actual value: C, 57, 0: II, 4J: N,
30.2: Example 28 Preparation of 8-trifluoromethyl-6-(1,2,4-triazol-4-yl)-2-(IH)-quinolone trans-ethyl 3-(2-amino-3 -trifluoromethyl-5-[1,2,4-triazol-4-yl]
Starting from phenyl)furobu-2-enoate and 5M HCl, the following compounds (m,
Example 29゜3.4-dihydro-8-methyl-6-(tetrazole-
Preparation of trans-ethyl-2-(IH)-quinolone in ethanol (250 cm')
-(2-amino-3-methyl-5-[tetrazole-i
-yl]phenyl) furo'7''-2-enoe-) (2,
5 g) was suspended on 10% palladium-supported activated carbon (1y) at 60'' for 100 hours at 15 p, s, dead (1
,04X 10')'α).

The cooled mixture is filtered through "Turkafloc" (trade name) and evaporated under reduced pressure to give a solid. A suspension of this solid in xylene (100 CIn3) is heated under reflux for 7 hours. The mixture was then cooled and the product was filtered and washed with dichloromethane:methanol (5:1) to yield 3,4-dihydro-8-methyl-6-(tetrazol-1-yl)-2-CIH). - Quinolones are obtained:
m,,p.

271-272', 1.37.90 Analysis (%): Actual value: C, 57,4", H, 50:N,
30.2: Calculation direct CCHIIuN*O): C, 57,
6; H, 4, 8: A', 30.6° Examples 30-3
2° Suitably substituted trans-ether 3- as starting material
A method similar to Example 29 is carried out using a phenylproa"-2-enoate derivative, hydrogen 2 and palladium-supported activated carbon, followed by ring closure of the resulting intermediate in xylene under reflux to yield the following compound: Obtained: E Example 33 Preparation of 8-methyl-6-(2,4-dimethyl-5-nitroimidazol-1-yl)-2-(Br)-quinolone in concentrated sulfuric acid (4d) at θ'' 8-methyl-6-(2゜4-
Concentrated nitric acid (1d) is added to the stirred solution in which dimethylimidazol-1-yl)-2-(IH)-quinolone (0,5,51) is dissolved. The mixture is stirred for 1 hour, poured carefully onto ice (100 g), and the solution is basified to pH 13 with solid sodium carbonate. The resulting suspension is extracted with dichloromethane (3 x 100 iL), the combined organic layers are dried (WySO), filtered and evaporated to give a foam. When this is triturated with ethyl acetate/ether, 8-
Methyl-6-(2,4-dimethyl-5-nitro-imidazol-1-yl)-2-(14)-quinolone is obtained: m, p, 244-247', 0.52 g.

Analysis (%): Actual value c, 6o, o; g, 4 swords; #, 19
．． 3; calculation direct CC,, n3, y, to): C, 60, 4;
H,4,7:N, 13,8° Example 34° 3.4 in a similar manner to Example 33 by nitration of the corresponding 3,4-dihydroquinolone as starting material
-dihydro-8-methyl-6-(2゜4-dimethyl-5
-Nitroimidazol-1-yl)-2-CIH)-quinolone-hydrate is obtained: m, pA 98-20.
1~ Analysis (%): Actual value: c, 5a5; H, 5, 2; N,
xs, 1; Calculated value 'CrJIaN40s.

H, O): C, 5613; H, 5A:N, 17.7
゜Example 35゜Preparation of hydrate in 8-methyl-6-(5-amino-2,4-dimethylimidazol-1-yl)-2-(IH)-quino a dihydrochloride Ethanol (50 cm') 8-methyl-6-(2゜4-dimethyl-5-nitroimidazol-1-yl)-
A suspension of 2-(LH)-quinolone (2,26 g) was heated with hydrogen over Raney nickel (0,2 g) for 3 hours at 60°C and 60 p, s, i, (4,13x 105Pα). Added. The cooled mixture is filtered through a 1-neck filter and evaporated under reduced pressure to give a dark oil. This is triturated with Improper Tool/ethyl acetate to solidify to a solid (2 g). A small amount of the solid is dissolved in ethanol, triturated with ethereal hydrogen chloride and filtered to give 8-methyl-6-(5-amino)-2°4-dimethylimidazol-1-yl)-2-.
(IH)-2m, which gives a hydrate to quinolone dihydrochloride;
p, 223°.

Analysis (%): Actual value: C, 523: H, 5, 2: N, 1
6.1; Example 36 Preparation of 8-methyl-6-(5-bromo-2,4-dimethylimidazol-1-yl)-2-(IH)-quinolone H3B Chloroform (10 cm”) i8- Methyl-6-(2
゜4-dimethylimidazol-1-yl)-2-(IH
)-To the stirred solution in which the quinolone (0.5 g) is suspended, N-promosuccinimide (NBE) C0.37 is added at room temperature.
Add 4fl). After 5 minutes, the reaction mixture was evaporated to dryness and
The residue is chromatographed on silica (Merck "MK60.9385" (trade name)) and eluted with ethyl acetate:methanol (10:1). Collection and evaporation of appropriate fractions yielded a solid, which was recrystallized from ethyl acetate/methanol to yield 8-methyl-6-(5
-bromo-2,4-dimethylimidazol-1-yl)
-2-(14)-quinolones are obtained: m, p.

273': 0.277g.

Analysis (%): Actual value: C, 54, 2; H, 44; N,
12.7: Calculated value (c, J, 4#30Br): C,
54,2; H, 4,3:N, 12.7° Example 37° Preparation of 8-trifluoromethyl-6-(2,4-dimethylimidazol-1-yl)-2-(IH)-quinolone Triethyl phosphonoacetate (0,376g) Sodium hydride (0,076g) in ethanol (4Crn')
Add g) to the stirred solution in which it is suspended. After 30 minutes, add 1 to (-4-amino-3-formyl-5-)-2-2゜4 to ethanol (6cmII?).
A solution of -dimethylimidazole (0,375,1) is added and the mixture is heated under reflux for 1 i hour.

Cool the mixture and add water (100 c) and chloroform (10
0cIr? ) and the aqueous layer is further re-extracted with chloroform (100 cf). The combined organic extracts are dried (CM7S04), filtered and evaporated to give a yellow solid. This solid substance is silica (Merck "MK60.
9385” (trade name) and eluted with ethyl acetate:methanol (100:8). The trans-ethyl 3-(amino-
3-Trifluoromethyl-5-(2,4-dimethylimidazole-1-(l)phenyl)fluor'-2-enoate: mp 181-2° (8 0.268 g, R
F=0.36 (ethyl acetate:methanol 20:1).

'' This intermediate is used in the method of Example 31.

Analysis (%): Actual value: C, 57.4; H, 5.1;
N, 11.7; Calculated value (c,, H,, F, situation): G,
57.8; H, 5,1; N, 11.9 The next eluate gave 8-trifluoromethyl-6-(2,4-
dimethyl-imidazol-1-yl)-2-(14)-
The quinolone is obtained and crystallized from ether; m, p
, 230~3°, 0.057. RF=0.1 (ethyl acetate:methanol 20:1).

Analysis (%): Actual temperature: c, ss, 2; H,
4, z; N, 13.3; Calculated value (c85 genus 2FsNsO
): C, 58,6:H, 3,9:N, 13.7 Example 38゜8-bromo-6-(2,4-dimethylimidazole-1
-yl)-3,4-dihydro-2-(IH)-quinolone Concentrated sulfuric acid (6-(2,4-dimethylimidazol-1-yl)-3,4-dihydro-2-(IH) )-bromine (0,2F) is added to the stirred solution in which quinolone (0,2F) is dissolved.
045c1! ? ) and silver sulfate (0,186,9). The mixture is stirred at room temperature for 16 hours and poured onto ice (20 g). The mixture was brought to pHLo with 5M hydroxide) and extracted with dichloromethane (100c). The organic extract is dried (MySO4), filtered and evaporated under reduced pressure to give a white solid.

When this solid was recrystallized from ethyl acetate, 8-bromo-6-(2,4-dimethylimidazol-1-yl)-
3,4-dihydro-2-(14)-quinolone (0,15
'l is obtained: m, p-242@.

Analysis (%): Actual value C, 52, 3: H, 4, 4; N,
12.8: Calculated value (c14 butt - general 0): C, 52,5
:H, 4,4:N, 13.1° Example 39° 8-Methyl-6-(4-methylimidazol-1-yl)-2-(Of)-quino y (see Example 6) In the same manner as in Example 33 by nitration, 8-
Methyl-6-(5-nitro-4-methylimidazole-
1,-yl)-2-CIH)-quinolone 3/4H2
0,m,,p,306-309' are prepared.

Analysis (%): Actual value: C, 58,3; H, 4,4;
N, 19.8; Example 40°8-Methyl-6-(5-iodo-2,4-dimethylimidazol-1-yl)-2-(IH)-quinolone, 0.
Preparation of 5H,O Iodine monochloride (0,406g) was mixed with acetic acid (10c
8-Methyl-6-(2,4-dimethylimidazol-1-yl)-2-CIH)-quinolone (0
, 506, +9) and sodium acetate (0,328 g) are dissolved in the stirred solution. After 16 hours, the volatiles are removed under reduced pressure and the residue is partitioned between 2M aqueous sodium carbonate (50c++r') and dichloromethane (50i). The aqueous layer is further extracted with dichloromethane (2
The combined and dried CMySO4) organic extracts are filtered and evaporated under reduced pressure. The residue is chromatographed on silica (Merck "MK 60.9385" (trade name)) and eluted with ethyl acetate. The appropriate fractions are collected and evaporated to give a solid, which is
ff Recrystallization from ethyl acetate/methanol gives the title compound: m, 9.242-245°, ci, 3
8g.

Analysis (%): Actual value: C, 46.4; H, 3-7;
N, 11.0; Example 41゜8-methyl-6-(2,4-dimethylimidazole-1
Preparation of -2-(IH)-quinolone methanesulfonate in methanol (914c++r') at 60°
Methanesulfonic acid (141
, 9g). Add ethyl acetate (3,41),
The solution is cooled to room temperature over 1 hour, followed by cooling in a water bath for 2 hours. Count the solids and add ethyl acetate (450cm
1) and drying at 50° under vacuum, the title compound is obtained: m, p.

282-284°.

Analysis (%): Actual value: c', 55.0; H, 5,6
; #, 12.2; Calculated value (c, 6H 5-cyano-2,4-dimethylimidazol-1-yl)-2-(14)-quinolone, 5
Preparation of 4H20 8-Methyl-6-(2,4-dimethyl-5-iodoimidazol-1-yl)-2-(14)-quinolone (0,1 ,!i
'), cupric cyanide (0,047 g), and palladium acetate (0,01,!i') were heated and stirred at 175° for 3 hours. The cooled mixture was diluted with aqueous ammonia solution (10i; S, G.

0.880) and dichloromethane (50cy?), and the aqueous layer was further extracted with dichloromethane (2X506I
n3) Do. The combined and dried CMySo,) organic extracts were filtered and evaporated under reduced pressure, and the residue was purified on silica (Merck's
Chromatography using dichloromethane:methanol 19:1
Elutes with Collecting and evaporating the appropriate fractions gives a 4 oil which, when triturated with ether, gives the title compound: ? 71~2°334~337'', 0.
03g.

Analysis (%): Actual value: c, 63,0; H, 5
, 1; N, 20.1; The following Preparative Examples illustrate the synthesis of the new starting materials used in the previous examples. All temperatures are in °C.

Preparation Example 1゜trans-1-(4-1#-(3-ethoxyproynamide))-3-methylphenylcoimidazole trans-3-ethoxyproynyl chloride (3,68
5 g) of 1-(4-amino-3-me,tylphenyl)imidazole (4,325 g) in anhydrous pyridine (30♂)
Add dropwise to the stirred solution in which g) is dissolved at O@. After stirring for 4 hours at room temperature, the pyridine was removed under reduced pressure and the residue was dissolved in chloroform (150 c) and saturated sodium carbonate solution (2
0cIrIs). The aqueous layer was further extracted with chloroform (2X50crI?), collected and dried with CM
f; o, ) (, When the extract is evaporated, an oily substance is obtained.
) and eluted with methanol:chloroform (3:97 by volume). Collection and evaporation of the appropriate fractions gives an oil which is triturated with ethyl acetate/ether and crystallized to give the title compound, 2.75 g.
.

Analysis (%): Actual value; c, 69.0:H, 6A:y
, 24.0; Calculated value (ni, scrap, Ns□,): C, 6
9,3:H, 6,4;N, 24.3° Preparation Examples 2 to 11
The following compounds were obtained in the same manner as in the above Preparation Examples using suitably substituted anilines as starting materials, U The anilines used in Preparation Examples 2.3.8 and 11 are known compounds. Preparation of the remaining anilines is described in later Preparation Examples herein.

The rice intermediate is directly purified by evaporation of the pyridine solvent under reduced pressure followed by chromatography of the crude hydrochloride on silica.

Preparation Example 12 1-(4-Amino-3-methylphenyl)imidazole stannous chloride dihydrate (s5.oIi) was dissolved as 1-(3-methyl-4-nitrophenyl) in absolute ethanol (100i). ) Add imidazole (10,0, li') dropwise to the stirred solution in which it is suspended. After heating under reflux for 4 hours, the cooled mixture is basified to pH 8 with a 2.5M aqueous solution of IJ hydroxide and filtered. Liquid F was evaporated under reduced pressure, partitioned between chloroform (100i) and water (50d), and the aqueous layer was further extracted with chloroform (3x 50cm").
)do. The combined and dried (My S04) extracts are concentrated under reduced pressure to give a solid, which is recrystallized from ethyl acetate to give 1-(4-amino-3-methylphenyl)imidazole: rn,p , 131-13
4@, 4.7 fi.

Analysis (%): Actual value: C, 69,0:H, 6,4:N
, 24.0; Calculated value (c, oH,, N3): C
, 69,3:H, 6,4:N, 24.3° Preparation Example 13~
18° The following compound is obtained analogously to the previous Preparation Example using a suitably substituted nitrobenzene derivative and stannous chloride dihydrate as starting materials: Nitrobenzene starting material used in Preparation Example 14 is a known compound. The preparation of the remaining nitrobenzenes is described in the Preparative Examples later herein.

Rice This compound is obtained as a mixture with the intermediate of Preparation Example 15. The mixture is made of silica (Merck "MK60.9"
385'') and eluted with chloroform:methanol (49:1 by volume).

The appropriate fractions are collected and evaporated under reduced pressure followed by recrystallization to obtain the pure product.

Preparation Example 19゜trans-N-(4-amino-2-methylphenyl)-
6-Amino-8-methyl-2-CIH)-quinolone is prepared analogously to the method of Example 1 by ring closure of 3-ethoxypropenamide with concentrated sulfuric acid: m, p,
290 @ (disassembly).

Analysis (%): Actual value: C', 56.7; H, 5,3
;#, 13.3; Calculated value (c, oH, .N, O):
C,57,0:H,5,2:N, 13.3° The pro-4-amide is alternatively prepared by stannous chloride dihydrate reduction of the corresponding 4-nitro derivative according to the method of Preparation Example 12. m, p, 140-2°.

Analysis (%): Actual value: C, 64.8; H, 7.4;
#, I Z2 ; 4-nitro derivative is i.e. trans-N-(4-=)O-2-methylphenyl)-3-
Ethoxyproinamide (m-p, 171~3) is prepared by the method of Preparation Example 1 (thus by reacting trans-3-ethoxypro4noyl chloride with 2-methyl-4-nitroaniline). .

Analysis (%): Actual value: C, 57.9; H, 5.8;
#, 11.3: Calculated value (c□H,, N, 04): ni'
, 57.6: H15,6; N, 11.2° Preparation Example 20° 1-(3-methyl-4-nitrophenyl)imidazole 7113 4-fluoro-2-methylnitrobenzene (15.5 g
), imidazole (6,8 g) and sodium carbonate (
11.1 g) of dimethylformamide (DM
Heat in F) for 24 hours at 100@. The mixture was then concentrated under reduced pressure, the residue was acidified with 4M hydrochloric acid; z:'pg 1, and the resulting solution was extracted with chloroform (2
♂) Do. pH the aqueous layer with 2.5M sodium hydroxide solution.
10 and extracted the mixture with chloroform (3X
1002). Evaporation of the dried (MfSO4) organic extract gives a solid that is recrystallized from ethyl acetate to give 1~(3-methyl-4-nitrophenyl)imidazole: rn, p, x 12~ 115"
, 10.0g.

Analysis (%): Actual value: c, 53,9; H, 4
, 4; N, 20.7: Fu Hyunzhi CC, oHoN, Ox
): C, 59, 1", II, 4.5: N, 2
0.7° Preparation Examples 21-25° The following compounds are prepared in analogy to the previous Preparation Examples using appropriately substituted fluoronitrobenzene, the appropriate heterocycle and sodium carbonate as starting materials: Preparation Example 26゜trans-1~(4-(#-(3-ethoxypro'7
7mido)) -3-methylphenyl)-2,4-dimethylimidazole trans-3-ethoxypropenoyl chloride (4,5
6 g) in 4 od of anhydrous pyridine at 0°C.
-Amino-3-methylphenyl)-2,4-dimethylimidazole (6,5,l) is added dropwise to the stirred solution in which it is dissolved. After stirring at room temperature for 2 hours, the pyridine is removed under reduced pressure.
The residue is partitioned between chloroporum (150c&) and saturated aqueous sodium carbonate (30ams). The aqueous layer was further extracted with chloroform (2xt00cm), collected and dried (CMfSO4), and the organic extract was evaporated to give an oil.
60.9385” (trade name)) methanol:chloroform (volume ratio 1:19).
Elutes with The appropriate fractions are collected and evaporated to give an oil. This was triturated with ether and crystallized to give the title compound (6.3 g). When this small amount is recrystallized from ethyl acetate, fine crystals are obtained.p
m-'I)-]42.5"~144.5':.

Analysis (%): Actual value: C, 68, 6:H, 7 with N,
13.9; Calculated value (c mouth H2 □ situation Q,): C, 68,
2", H, 7, 1:N, 14.0° Preparations 27-31° Starting materials suitably substituted aniline (as hydrochloride in Preparations 27 and 28) and trans-3-ethoxybroynoyl chloride The following compounds are prepared in analogy to the previous Preparation Example:
Dimethylimidazole B3 Stannous chloride dihydrate (40,7,1) was dissolved in absolute ethanol (100c) to 1-(3-methyl-4-nitrophenyl)-2,4-dimethylimidazole (8,3 #)
Add dropwise to the stirred solution in which is suspended. After heating at reflux for 4 hours, the cooled mixture is basified to pH 8 with 2.5M aqueous sodium hydroxide and filtered.

The F solution was evaporated under reduced pressure, partitioned between chloroform (200♂) and water (50 mL), and the aqueous layer was further extracted with chloroform (2 x 100C1rI').Collected and dried, CMySO<)L, and the organic The extract was concentrated under reduced pressure to obtain a solid (6,8,9), which was recrystallized from ethyl acetate to give 1 to (4-amino-3-methylphenyl).
-2,4-dimethylimidazole is obtained: yyi
, p, 92-966° Preparation Examples 33-36° The following compounds were prepared in the same manner as in the previous Preparation Examples using an appropriately substituted nitrobenzene derivative and stannous chloride dihydrate as starting materials. Ru.

In Preparation Example 33, the 2 free base is converted to the hydrochloride salt by reaction with hydrogen chloride in ether. The hydrochloride salt is used in the next step (Preparation Example 28).

Preparation Example 37゜4-(4-amino-3-methylphenyl)-1゜2.4
-) Riazole CH.

A solution of 4-(3-methyl-4-nitrophenyl)-1,2,4-triazole (1.0 g) in acetic acid (25♂) was heated with Raney nickel (0.2 g) for 2 hours. 25" on top and 60 p, s, i, c 4.13X10'
Hydrogenate with PtL). The mixture was then filtered through “Tulkafloc” (cellulose filter aid), the solvent was evaporated under reduced pressure and the residue was dissolved in chloroform (100 c
II? ) and an aqueous sodium carbonate solution (20σ). The aqueous layer was further extracted with chloroform (3X 5
0ci) The combined and dried (MySQ4) organic extracts are concentrated to give an oil. This was subjected to chromatography using silica (Merck "MK60.9385" (trade name)), and methanol:ethyl acetate (1:9
). Collection and evaporation of the appropriate fractions gave a solid that was recrystallized from ethyl acetate/hexane to give 4-(4-amino-3-methylphenyl)-
1,2,4-) lyazole is obtained, h: m, p, 1
52-154°, 0.67 g.

Analysis (%): Actual value: c, 62. o; H, s, 6;
N, al, s; Calculated value (c, H,.N,): C,
62,1; H,5,7; 7V, 32.2° Preparation Example 38° As described above using 1-(3-methyl-4-nitrophenyl)-4-trifluoromethylimidazole and Raney nickel/yt as starting materials The following compounds (rn, 2.230) are prepared in the same manner as in the preparation example, except that ethanol was used instead of acetic acid as the solvent. The product was converted to the hydrochloride salt by reaction with hydrogen chloride in ether. Transform.

This hydrochloride is used in the next step (Preparation Example 27).

Analysis (%); Actual value: C, 47.5 near f, 4.1
; #, 15.2; Calculated value (cII scrap J8, CI): C, 47,6; ff, 4.0; #, 15.
1゜Preparation example 39゜1-(3-methyl-4-nitrophenyl)-2゜4-dimethylimidazole 5-fluoro-2-nitrotoluene (10.3g), 2
．． A mixture of 4-dimethylimidazole (6,36 g) and sodium carbonate (7,5 g) is heated and stirred in dimethylformamide (40i) at 1306 for 40 hours. The cooled mixture was then concentrated under reduced pressure and the residue
Acidify to pH 1 with M hydrochloric acid and extract the resulting solution with chloroform (2X 25 crn') to remove any neutrals. 2.5M hydroxide of the collected aqueous layer) IJ
The mixture is basified to pH 10 with um solution and the mixture is extracted with chloroform (3×250cIIP). Collect and dry (My
S O4) The organic extract was concentrated under reduced pressure to obtain a solid, which was purified by distillation.
9385" (Sho 4i1)) and eluted with methanol:ethyl acetate (1:19). Appropriate fractions were collected and evaporated to give a solid (8,
4#) is obtained, which is recrystallized from ethyl acetate to obtain 1-(3-methyl-4-nitrophenyl)-2,4-dimethylimidazole: m, p, 135.5
"-138"0 Analysis (%): Actual value: C, 62, 0: H, 5, 7:
N, 17.9; Calculated value (c!zH+sA'5Qt):
C* 62,3; H+ 5.7; N* 13,2
Preparation Examples 40-44 The following compounds are obtained analogously to the previous Preparations using suitably substituted fluorobenzenes, suitable heterocycles and sodium carbonate as starting materials: Preparation Examples 45゜4-(3-methyl-4-nitrophenyl)-1゜2.4
-) lyazole 5-amino-2-nitrotoluene (2,0,p) and 1.
A mixture of 2-diformylhydrazine (1,3J)
Heat under nitrogen for 1 hour at 000C. The residue is then cooled and
Silica (Merck “AfK60.9385” (trade name))
Chromatography was carried out using methanol:dichloromethane (1:19) and elution was carried out. Appropriate fractions were collected and evaporated to give a solid (1.03 g), which was recrystallized from ethanol to give 4-(3-methyl-4
-nitrophenyl)-1,2,4-) lyazole is obtained, 2m, p, 208-210@.

Analysis (%): Actual value: C, 52.8; B, 4.0;
#, 27.3; Calculated value CCQIIsN401):
C, 52,9; H, 3,9; #, 27.4° Preparation Example 4
6゜4-(4-nitro-3-)fluoromethylphenyl)
The following compound (m, pA 00°)
is obtained.

C.F.

Analysis (%): Actual value: c, 41.9; g, z, a;
y, 2x, r; Calculated value (caH 2 weeks false): c,
41.6; H, 2, 1; N, 222° Preparation Example 47
゜1~(3-Methyl-4-nitrophenyl)tetrazole HB 1~(3-methylphenyl)tetrazole (11,3I
), without stirring, to 0°C with fuming nitric acid (100cms).
and then warm the solution in a steam bath for 5 minutes.

Pour the cooled solution onto ice (200 g) and remove the solid, wash with water (100 crr?) and dry. Recrystallization from ethyl acetate gives 1-(3-mef-4-nitrophenyl)tetrazole: m, p, 166-
168°, 9.4g.

Analysis (%): Actual value: C, 47,0; H, a5; N
, 34.3; Calculated value: (c,, H7N, o2) :C
,46,8", H,3,4: N,34.2°1~(3
-methylphenyl)tetrazole is a known compound.

Preparation example 48° 6-Amino-2-methoxy-8-methylquinoline CH.

Rubutyl lithium (1,6M n-hexane solution 13.
75 cx') is added dropwise under nitrogen to a stirred solution in which 6-bromo-2-methoxy-8-methylquinoline (5,04 g) is dissolved in tetrahydrofuran (THF) (50 i). . After 15 minutes, the image suspension is introduced via cannula into a stirred solution in which diphenylphosphoryl azide (5.5 g) is dissolved in 50 cm of THF at -70° under nitrogen.

-70°ζ Stir the dark solution for 2 hours with a trowel, warm to 120' over 1 hour, then recool to 170'. 23.5 mL of sodium bis(2-methoxyethoxy)aluminum hydride (3,4 A/) toluene solution is slowly added and the solution is warmed to room temperature over 1.5 hours. The mixture was cooled in a 0" trench, ice (too much, l) was carefully added, the resulting suspension was filtered and the solids were washed with ethyl acetate. The aqueous F solution was further extracted with ethyl acetate (2 x 100 cm
The organic extracts were evaporated under reduced pressure to give a residue. This is chromatographed on silica (Merck "Mg20.9385" (trade name)). Elution with toluene followed by collection and evaporation of the appropriate fractions gives a solid which, upon recrystallization from hexane, gives 6-amino-2-methoxy-8-methylquinoline: m, pA 1
5~117°, LO7f! .

Analysis (%): Actual value: C, 69,8: H, 6,5;
N, 14.8; Calculated value (c+IHuNzO):
C+ 7o,z;H,6,4;N, 14.9゜Preparation Example 49゜6-acetamido-2-methquin-8-methylquinoline dichloromethane (20i) with acetic anhydride (0.55% dissolved) The solution was dichloromethane (30 d
) to 6-amino-2-methoxy-8-methylquinoline (
1.0 g) is dissolved in the stirring liquid. After 1 h, the solution was diluted with dichloromethane (50i), washed with saturated sodium carbonate solution (10i) and dried in CMfSO.
,)do. Evaporation of the solution under reduced pressure gives a solid which is recrystallized from dichloromethane/hexane to give 6-acetamido-2-methoxy-8-methylquinoline: m, pA 93-196', 1.143
Analysis (%): Actual value: C, 67, 6: H, 6, 2:
N, 12.2: Calculated value (cIsH++Nz negative): C,
67,8; H, 6,1; #, 12.2° Preparation Example 50° 6-C3,5-dimethyl-1,2,4-triazole-
4-yl2-methoxy-8-methylquinolinerX
H2Q CH.

CH3 Phosphorous pentachloride (1,0g) was added to a stirred bundle of 6-acetamido-2-methoxy-8-methylquinoline (1,0g) dissolved in toluene (50cms) and the mixture was stirred at 50° for 15 minutes. Stir. Acetylhydrazine (1.35 g) is then added and the mixture is stirred at 60' for 3 hours. Toluene was removed under reduced pressure and the residue was dissolved in ethanol and ammonia aqueous solution (S, G, 0.88)
Add (25i). Dichloromethane (100cTr?
) and separate the organic layer. The aqueous layer was further extracted with dichloromethane (2 x 25 sides), and the collected organic layer was dried (M
On evaporation, a solid is obtained. This is chromatographed on silica (Merck "Mg20.9385" (trade name)) and eluted with dichloromethane:methanol (19:1). Appropriate fractions were collected and evaporated to give 6-(3,5-dimethyl-1゜2.4-triazol-4-yl2-methoxy-8-methylquinoline (0,3069), which was purified by toluene) etc. When recrystallized, it becomes microcrystal; m, p, 211-213'
, 0.066 g.

Analysis (%): Actual value: C, 66.6; H, 5.9;
#, 20.6; Preparation Example 51゜2-methoxy-8-methyl-6-(1,2,4-triazol-4-yltuquinoline, 0.25% O CH.

1,2-diformylhydrazine (2,93g) and 6
-amino-2-methoxy-8-methylquinoline (5,4
, 9) is heated at 200' for 1 hour. The cooled residue is treated with silica (Merck=MK60.9385”)
Chromatograph using dichloromethane:methanol (50:1). Ry 0.44 (dichloromethane:methanol, 19:1) was collected and evaporated to produce 6-formamide-2 as a by-product.
-Methoxy-8-methylquinoline (1.35 g) was obtained and recrystallized from toluene to form white microcrystals: m,
p, 142-143.5', 0.67 g.

Analysis (%): Actual value: C, 66, 5: II, 5.6
;, V, 13.0: Calculated value (c,, H, 2N20.):
Further elution of the C,66-6:H,5,6;#, 13.0° column yielded a second fraction of RlrO,3 (dichloromethane:methanol, 19:1),
When this is evaporated, a solid (1,2 J) remains. When this solid is recrystallized from ethyl acetate, 2-methoxy-8-
Methyl-6-(1.

2.4-triazol-4-yltuquinoline, 0.2
5H20 is obtained: m, p, 157-159", 0
．． 73g.

Analysis (%): Actual value: c, 64.1; H, s
, 1; N, 22.6; Calculated value (c1, H,, N40
゜0.25H,0): C,63,8;H,5,1;#,
22.9゜Preparation Example 52゜6-Bromo-2-methoxy-8-methylquinoline Hs Hs A solution of 6-bromo-2-chloro-8-methylquinoline (10.7g) dissolved in methanol (80crI?) ,
Heat at reflux for 24 hours with a sodium methoxide solution (prepared from 2,761 ml of sodium methoxide in methanol) for 24 hours. The cooled solution is then evaporated under reduced pressure and the residue is dissolved in chloroform (100 cT?) and water (socrf?).
).

The aqueous layer was further extracted with chloroform (2x s Ocr/
? ), the combined dried (MfSO4) organic layer was evaporated under reduced pressure to give a solid, which was recrystallized from ethyl acetate:hexane, 1:9 to give 6-bromo-2-methoxy-8-methyl. 2m, p, 89 from which quinoline is obtained
~91', 3, 3.9° Analysis (%): Actual value: C, 52, 2: II, 3.9
:N, 5.7'.

Calculated value (c,, H, I, BrN0): C, 52,4
; , H+ 4. υ; N, 5.6° Preparation Example 53° 6-Bromo-2-chloro-8-methylquinoline 6-bromo-8-methyl-2-CIK)-quinolone (12, Og
) of phosphorus oxychloride (100d) is heated under reflux for 2 hours. The volatiles were removed under reduced pressure, the residue was dissolved in chloroform (200 crf?), and the resulting solution was placed on ice (200 crf?).
Inject into 0Jill.

The mixture is basified to pH 10 with aqueous ammonia (S, G, 0.88) and the aqueous layer is further extracted with chloroform (2xlOOc+++'). Collect and dry commercial
fSO4)L, the organic layer was concentrated under reduced pressure to obtain a solid (1
0.7 g) is obtained, which is recrystallized from ethanol to obtain 6-bromo-2-chloro-8-methylquinoline: m, pA 14-116°0 Analysis (%): Actual value: C, 47, 2:H, 2, 7;
N, 5.8; Calculated value (c, oH7BrCIN):
C, 46,8:H, 2,7:N, 5.5° Preparation Example 5
4゜6-Bromo-8-methyl-2-(LH)-trans-u-(4-bromo-2-methylphenyl)-3-ethoxyprozenami)' (2, (1) was dissolved in 98% sulfuric acid (1
5C7r? ) at room temperature without stirring. 16
After an hour, the solution is poured onto ice (100 cIr?) and the resulting precipitate is poured and dried (1.5, fi'
). When recrystallized from ethyl acetate/methanol 751, 6-
Bromo8-2thyl-2-(IH)-quinolone is obtained: rrL, p, 272-274°.

Analysis (%): Actual value: C, 50,4: H, 3,4;
N, 6.1; Calculated value (cIOHBNOBr): C
,50,4", If, 3.4', N, 5.9° Preparation Example 5
5゜trans-N-(4-bromo-2-methylphenyl)-
3-Ethoxyproinamide trans-3-ethoxyproinamide chloride (0,74
,9) into a stirred solution containing 4-bromo-2-methylaniline (,0,93g) dissolved in pyridine (10i).
Add at °. After 0.5 hours, water (40 crI?) is added and the solid is taken off, washed with water (30 i) and dried.

Recrystallization of the product from ethyl acetate yields trans-N-
(4-Bromo-2-methylphenyl)-3-ethoxy7probenamide is obtained: m, p, 163-16G1
．． 3g.

Analysis (%): Actual value: C, 50,'l: H, 5,0
;N, 5.1: Calculated value CC12CC12HJV: C
, 50,7+ H, 5,0:k, 4.9° Preparation Example 5
6゜1~(4-amino-3-trifluoromethylphenyl)
-2,4-dimethylimidazole F3 Ethanol (300c1r?) t-(4-=draw 3
- ) IJ fluoromethylphenyl)-2,4-dimethylimidazole (29,0 g) and the mixture was diluted with 16
50'' and 50 p,s,i,c 3.23 x 10jPcL on 5% palladium-supported activated carbon (2g)
). The mixture is then filtered through "Purkafloc" (trade name) and the solvent is evaporated under reduced pressure to give a pale yellow solid (25.8 g).

Recrystallizing the evening view of C from ethyl acetate/hexane yields 1~
(4-ami7-3-trifluoromethylphenyl)-2
,4-dimethylimidazole is obtained: m, p, 1
26-7°.

Analysis (%): Actual value: c, sas; H, 4, s: N
, i6.6; Calculated value (c12 2N3F: C, 5
6,5:, 11, 4.7 Near V, 16.5° Preparation Example 57° 4-(4-amino-3-trifluoromethylphenyl)
-1,2,4-) lyazole 4-(4-nitro-3-) IJ fluoromethylphenyl) -1,2,4-) IJ azole and 5% palladium on activated carbon/H2 as the starting material. In a similar manner to the examples, the following compounds are obtained:
m,, p, 196-8°.

C.F.

Analysis (%): Actual value: C, 47,7: H, 3,2;
N, 24.9; Calculated value CC, H, N, F, )
: C, 47,4:H, 3,1:N, 24.6° tone
Preparation Example 53, (instead of Preparation Example 32) 1-(4-amino-3-methylphenyl)-2゜4-dimethylimidazole Hs as starting material 1-(3-methyl-4-nitrophenyl)-2,4 The following compound is obtained in the same manner as in Preparation Example 56 using -dimethylimidazole and 5% palladium-supported activated carbon/Ht and ethanol as the solvent. The crude solids melt at 78-82°. 1-(4-amino-3-methylphenyl) by recrystallization from toluene
-2,4-dimethylimidazole is obtained: m, p,
118-120℃.

Analysis (%): Actual value: C,7LO:H,7,6;N
, 20.8; Calculated value (cII Masa, l also): C, 71
, 6; H, 7, 5; #, 20.9° Preparation example 59° trans-ethyl 3-(2-amino-3-trifluoromethyl-5-(1,2,4-triazol-4-yl)
phenyl) flob-2-enoate as starting material 4-
(3-formyl-4-ami/-5-)lifluoromethylphenyl) -1,2゜The following compound is obtained in the same manner as in Example 37 using 4-triazole, triethylphosphonoacetate and sodium hydride. : m, 2.2
25-7°0 [in this case, 8-trifluoromethyl-6
-(], , 2, 4-triazol-4-yl)-
2-(lH)-quinolone is formed only upon standing. ]Preparation example 0゜1~(4-amino-3-iodo-5-methylphenyl)
Tetrazole Hs Acetic acid (30cn?) - Iodine chloride (4,46,!i+)
4g of 2-methyl-4-(tetrazol-1-yl)anisoyC in acetic acid (30CIT?).
) is added dropwise to the stirred liquid in which it is dissolved. After 2 hours, the mixture is brought to pH 6 by adding aqueous sodium carbonate solution and extracted with dichloromethane (250i). Dry the organic layer C)l
tts O4) L, filtered and evaporated to give a dark brown solid. This solid substance is silica (Merck MK60
．． 9385'' (trade name) and eluted with dichloromethane, 1-(4-amino-
3-iodo-5-methylphenyl)tetrazole is obtained: rn, z+, 172-175', 6.2 g.

Analysis (%): Actual value: C, 32, 1: H, 2-, 7
;N, 23.4;Calculated value (c4H,N,I): C,
3L9:H, 2,7:N, 23.3° Preparation Example 61° 2-(4-amino-3-iodo-5-methylphenyl)
The following compound is obtained analogously to the preparation described in MiJ using 2-(4-amino-3-methylphenyl)tetrazole and iodine monochloride as starting materials: m, p, 196
~199°.

Analysis (%): Actual value; C, 31,9: H, 2,7:
N, 23.3: Calculated value (c, H, genus I): C, 3
1,9; H, 2,7; #, 23.3° Preparation Example 62° trans-ethyl 3-(2-amino-3-methyl-5-
[tetrazol-1-1l]phenyl) flob-2-enoate Hs 1-(4-amino-3) in acetonitrile (80 cT?)
-Iodo-5-methylphenyl)tetrasol (5g)
Add ethyl acrylate (2,!l') to the solution in which
) rietheramine (2I) and palladium arsenate (0
,1,! i'). The mixture is heated to reflux for 1-H hours, cooled and then partitioned between water (100 crr?) and dichloromethane (100 cm IT').

The aqueous layer was further extracted with dichloromethane (100i),
The organic layers are combined and dried (MfSO4), filtered and evaporated under reduced pressure. The residue was treated with silica (Merck “MK60.938
5" (trade name) and eluted with dichloromethane:methanol (20:1). Appropriate fractions were collected and evaporated to give a solid, which was paleocrystallized from ethyl acetate/methanol to give a yellow color. Acicular trans-ethyl 3-(2-amino-3-methyl-5-[tetrasol-1-yl]phenyl)furo-2-enoate is obtained: full, p, 210-211
6.3.459° Analysis (%): Actual value: C, 56,9; H, 5,6;
N+25.7; Calculated value CC+s11. Precept o, ): C,
57,1: H, 5,5; N, 25.6° Preparation Example 63° trans-ethyl 3-(2-amino-3-methyl-5
-Cte)ladaroo2-yl]phenyl)phrobou2-
Enoate, 0.16 H20 2- as starting material,
(4-amino-3-iodo.

-5-methylphenyl)tetrazole, ethyl acetate, palladium acetate and triethylamine,
Analogously to the previous example, the following compound is obtained: m
, p. 162-51″.

Analysis (%): Actual value: C, 56,5; H, 5, jx
;A', 25.7;”'”H,'l'6'A5')
: C, 5L5-, 5.7 :N, 25.4° Preparation Example 64° 4-nitro-3-)! J Fluoromethylaniline ammonia aqueous solution (100cTI, S, G, 0.88)
was added to 3-IJ fluoromethyl-4-nitrofluorobenzene (5 g) and the mixture was heated in a bomb for 2 hours at 150 ml.
Heat to °. Removal of the solvent under reduced pressure yields a yellow solid. Recrystallization of this solid from hexane/ethyl acetate gives yellow crystals of 4-nitro-3-trifluoromethylaniline: m, p, 134'', 3.5 g.

Analysis (%): Astronomical value: C, 4LO; H, 2,4; N
, 13.5; Calculated value (c, H,) <', F,):
C, 40,8; H, 2,4: N, 13.6°3-)!
J fluoromethyl-4-nitrofluorobenzene is a known compound.

Preparation Example 65゜1-(3-bromo-4-amino-5-trifluoromethylphenyl)-2,4-dimethylimidazole CF.

1-(4-amino-3-trifluoromethylphenyl)
-2,4-dimethylimidazole (10I) was added to glacial acetic acid (
Dissolve to 70 ml. Glacial acetic acid (45 ml of hydrogen bromide
Add the solution in which %W/W is dissolved. Then glacial acetic acid (3
0cII? ) is added dropwise to a solution in which bromine (2,1d) is dissolved. The mixture is heated to 70'' for 3 hours, cooled, concentrated and evaporated under reduced pressure to obtain a small portion and made basic to pH 8 by addition of aqueous sodium carbonate. The aqueous layer is extracted with chloroform (3X2oOcTr? ) and the combined organic extracts were dried with CMfSO, ) and evaporated under reduced pressure. The residue was purified on silica (Merck "MK60.9385").
(trade name)) and elute with ethyl acetate. Collection and evaporation of appropriate fractions yields 1-(3-bromo-4-amino-5-)-lifluoromethylphenyl)-2,4-dimethylimidazole (4
, 76 g), a small amount of which is recrystallized from ethyl acetate/hexane: yrLp, 149''.

Analysis (%): Actual value: C, 43,0:H, 3,5;
NA2.5: Calculated value CC,,H,,N,F,Dr):C
, 43,1:H, 3,3:N, 12.6° Preparation Example 6
6゜4-(4-amino-3-bromo-5-trifluoromethylphenyl)-1,2,4-toIJazole 4-(4-amino-3-trifluoromethylphenyl)-1,2 as starting material , 4-) Analogously to the previous preparation using IJ azole, bromine and sodium acetate (in place of hydrogen bromide and acetic acid) the following compound is obtained: m
, p. 202-3″.

C.F.

Analysis (%): Actual value: C, 35, 4; H, z, o;
N, xs, a; Calculated value (H6be F3 total): C, 35
, 2:H, 2,0:N, 1B, 3° Preparation Example 67° 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4-dimethylimidazole CH.

1-(4-
Add cupric cyanide (3,7,!?) to the stirred solution in which 7mi/-3-bromo-5-trifluoromethylphenyl)-2,4-dimethylimidazole (4,611) is dissolved, The mixture is heated to 150° for 2 days. The mixture is then cooled and the solvent is evaporated under reduced pressure. Aqueous ammonia solution (100♂, s, a, o, 8s) is added and the aqueous layer is dissolved in chloroform:methanol (20 :1)(3X100c
Extract with &).

The combined organic extracts are dried (My SO4), filtered and evaporated. The residue was treated with silica (Merck” Mg60.93
85” (trade name)) for chromatography.
Elute with chloroform:methanol (50:1). Appropriate fractions were collected and evaporated to give a solid, which was recrystallized from methanol/ethyl acetate to give microcrystalline 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4- Dimethyl imidal rule is obtained: rn, p, 208-210 s 1.1 p0 analysis (%): Actual value: C, 55, 7: H, 4, 0:
#, 19.7; Calculated value CCl5HIINIs): C
, 55,7:H, 4,0;#, 20.0° Preparation Example 6
8゜4-(4-amino-3-cyano-5-trifluoromethylphenyl)-1,2,4-)'J7:/-l As starting material, 4-C4-amino-3-bromo-5- )Vfluoroamer-y-phenyl)-1,2°4-triazole, cupric cyanide and 1-methyl-2-pyrrolidone, the following compound is obtained analogously to the previous preparation example: mp283 ”.

Cp.

Analysis (%): Actual value: C, 47.3; fi, 2.5
;N, 27.3; Calculated value CC1oHeNsFs):
C+ 4'Z4;H,2,4;N, 27.7° Preparation Example 69°1~(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazoletetrahydrofuran (10cm' ) to 1 to (4-amino-3-7ano-5-trifluoromethylphenyl)-2
, 4-dimethylimidazole (0,7,!i') is dissolved in the water-cooled stirred solution, and 3.52 mL of a 1.5 M solution of diisobutylaluminum hydride in toluene is added. The mixture was heated to 40' for 2 hours, cooled in water and diluted with methanol (
27) and evaporated under reduced pressure. Dilute the residue with water (25 c
m”) and 2M hydrochloric acid (5 pots and heated in a steam bath for 5 minutes; then cool and carbonate the solution), basify to pH 8 with an aqueous IJ solution, chloroform:methanol (
20:1) (3x30i). The combined organic extracts were dried (MfSO4), evaporated under reduced pressure, and the residue was chromatographed on silica (Merck "Mg20.9385" (trade name)) in ethyl acetate:methanol (
50:1) gives 1-(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazole: m, p, 200-20
2”, 0.391g.

Analysis (%): Actual value: C, 54, 6: H, 4, 3:
N, 14.4; Calculated value (c13HHJ'3#3Q):
C, 55-1; H, 43; N, 14.8° Preparation Example 70° 4-(4-amino-3-formyl-5-trifluoromethylphenyl)-1,2,4-triazole 4 as starting material -(4-amino-3-cyano-5-1
Analogously to the previous example using fluoromethylphenyl)-1,2°4-triazole and water-accumulated diisobutylaluminum, the following compounds are obtained: m, p, 2
34~6″.

Patent applicant: Pfizer Corporation (5 others)

Claims (13)

[Claims] (1) The following formula: ▲ Numerical formulas, chemical formulas, tables, etc. -, 6-, 7- or 8-position, optionally substituted 5
- represents a monocyclic aromatic heterocyclic group, R is bonded to the 5-, 6-, 7- or 8-position, and is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a carbon atom number 1 ~4
represents an alkoxy group, hydroxy group, CF_3, halogen atom, cyano group, or hydroxymethyl group, and the dotted line between the 3-position and the 4-position indicates that it may be a double bond. ) or a pharmaceutically acceptable salt thereof. (2) "Het" is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl group, and these groups may optionally be alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxy, or a halogen atom , CF_3, cyano, hydroxymethyl, (C1-C4 alkoxy)carbonyl, nitro, -CON
R^1R^2 and -NR^1R^2 (R^1 and R
^2 each independently represents H or an alkyl group having 1 to 4 carbon atoms) which may be optionally substituted with up to 3 substituents each independently selected from Compounds described. (3) R is H, an alkyl group having 1 to 4 carbon atoms, CF_
3 or a halogen atom. (4) (a) “Het” is bonded to the 6-position of the quinolone,
represents an imidazolyl, pyrazolyl, triazolyl or tetrazolyl group, and these groups contain up to three substituents each independently selected from an alkyl group having 1 to 4 carbon atoms, CF_3, NO_2, NH_2, CN and a halogen atom; 2. The compound according to claim 1, wherein (b) R is bonded to the 8-position of the quinolone and represents H, an alkyl group having 1 to 4 carbon atoms, CF_3 or a halogen atom. (5) (a) "Het" is imidazol-1-yl,
2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1,2,4-triazol-1-yl, 2,4-dimethylimidazol-1-yl, pyrazol-1-yl,
4-trifluoromethylimidazol-1-yl, tetrazol-1-yl, 3,5-dimethyl-1,2,4-
Triazol-1-yl, 3,5-dimethyl-1,2,
4-triazol-4-yl, tetrazol-2-yl, 1,2,4-triazol-4-yl, 2,4-dimethyl-5-nitroimidazol-1-yl, 5-nitro-4-methylimidazol- 1-yl, 5-amino-2
, 4-dimethylimidazol-1-yl, 5-bromo-
2,4-dimethyl-imidazol-1-yl, 5-iodo-2,4-dimethylimidazol-1-yl or 5
-cyano-2,4-dimethylimidazol-1-yl group, and (b) R is H, CH_3, CF_3 or Br
The compound according to claim 4, which is (6) The compound according to any one of claims 1 to 5, wherein a double bond is present at the 3- and 4-positions of the quinolone. (7) (a) “Het” is 2,4-dimethylimidazol-1-yl, 2,4-dimethyl-5-nitroimidazol-1-yl, tetrazol-1-yl or 1,2
,4-triazol-4-yl group, and (b) R is C
The compound according to claim 5, which is H_3 and has a double bond at the 3- and 4-positions of (c) the quinolone. (8) (a) "Het" is a pyrrolyl, imidazolyl, pyrazolyl, triazolyl or tetrazolyl group, and these groups may optionally be C1-C4 alkyl, C1-4 alkoxy, hydroxy, Halogen atom, CF_3, cyano, hydroxymethyl, (alkoxy having 1 to 4 carbon atoms) carbonyl, -CONR^
1R^2 and -NR^1R^2 (R^1 and R^2
each independently represents H or an alkyl group having 1 to 4 carbon atoms. ), each substituent 3 independently selected from
(b) R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Alkoxy group having 1 to 4 carbon atoms, hydroxy group, CF
The compound according to claim 1, which represents _3 or a halogen atom. (9) With a pharmaceutically acceptable diluent or carrier, the following formula: ▲Mathematical formula, chemical formula, table, etc.▼……(I) (where “Het” means at least one nitrogen in the aromatic ring) an optionally substituted 5-atom containing an optionally substituted
- represents a monocyclic aromatic heterocyclic group, R is bonded to the 5-, 6-, 7- or 8-position, and is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a carbon atom number 1 ~4
represents an alkoxy group, hydroxy group, CF_3, halogen atom, cyano group, or hydroxymethyl group, and the dotted line between the 3-position and the 4-position indicates that it may be a double bond. ) or a pharmaceutically acceptable salt thereof. (10) Claims 1 to 8 for use in medicine
A compound according to any one of paragraphs. (11) The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(IV) (In the formula, "Het" and R have the meanings given in claim 1.) Compound. (12) The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R and Het are 3-, 4-, 5- or 6-
these have the meaning given in claim 1, and Q represents a leaving group. ). (13) The compound according to claim 12, wherein Q is an alkoxy group having 1 to 4 carbon atoms.