DE2418498A1 - FUSED PYRIMIDINS AND THEIR PRODUCTION - Google Patents

Description

P 805

: Κ'ΛΕ

Pfizer Inc., Mew "fork 17, dew York, V. St. Α ..

Various pyrimidines and their preparation

The present invention relates to "fused heterocyclic ring systems in which an ohinoline, a naphthalene or a pyrimidine ring system with a 2-methyl-, 2-ethyl- or 2-acetylpyriaidin-4 (3H) -one or with a pyrimidin- 2-carboxylic acid-4 (3H) -one or a derivative thereof is fused, as well as their use as antiallergic agents. In particular, it relates to 2-alkylpyrimido Z ~ 4,5-b_7 quinolin-4 (3H) -one, 2-alkylpyrido [ _ 4> 5-b_7 pyrimidone-4 (3H) one in which alkyl is methyl or iithyl, and the corresponding 2-AeetyliJerivate, pyrimido £ ~ 4 _f 5-b_JT quinolin-4 (3H) -one-2-carboxylic acids, benzo / _ gj quinazolin-4 (3H) -one-2-carboxylic acids and pyrido l_ 2,3-d_7 * -4 (3H) -one-2-carboxylic acids as well as ßster, amides and pharmaceutically suitable salts thereof, which are used as inhibitors of allergic reactions and particularly useful for bronchial allergic asthma.

Allergic reactions resulting from an antigen-antibody effect The resulting symptoms show up in many different ways and in widely different organs and organs G-weaving. iione of the most debilitating and debilitating allergic reactions is asthma, a functional condition the bronchi, which is characterized by periodic

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and convulsive attacks of loss of breath, wheezing, coughing and slime ejection.

Much effort has been made to find medicinal agents that will alleviate the symptoms of this abnormal physiological condition. As early as lylO, Matthews reported in Brit.Med.J. 3., 441 (1910) on the bronchodilatory effect of epinephrine. Since then, Ohen and Schmidt have worked in J.Pharmacol.Bxper.'JJherap. 2Aj 539 (1924) reported the use of the alkaloid kphedrine as an orally active bronchodilator with the same spectrum of activity as epinephrine. In 1940, IConzett outlined in Arch.J & xp. Path.Pharmak. 197 » 27 (1940) the effect of the potent bronehodilatory agent isoproterenol in aerosol form, Cullum et al. Reported in Brit.J.Pharmacol, Exp. ! §., 141 (1969) on the pharmacology of solbutamol, a potent bronchodilator with extended duration of action, which is effective when administered orally as well as as an aerosol. Many bronehodilator preparations contain sheophylline. They are generally less potent than the sympathomimetic amines such as isoproterenol and solbutamol and ineffective when administered as an "aerosol".

Recently, Uox et al. In Adv. In Drug Res., J>, 115 (1970) have described the pharmacology of sodium chromogyycate [_ 1,3-bis- (2-carboxychromon ~ 5-yloxy) -2-hydroxypropane, Intal_ /, one agents useful in the treatment of bronchial asthma. Although BS is not a bronchodilator, it conveys the therapeutic effect of one through its unique mechanism of action. However, it suffers from a lack of oral efficacy and is administered by inhalation as a solid inhalant for optimal results.

A number of pyrimido quinolines (1,3-diazaacridines) are described in the literature - see J. Chem. Soc. 727 (1927) ι J. Hetero.Chem. 2, 99 (1970) | J.Am.Chem.Soc. 28,

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51Od (1956) and J.Üheia.Soc. 552 (1948). However, none of these compounds contains a üarboxygruppe or a functional derivative of a solcnen, that is an ester, amide, acid chloride, with the exception of 2,4-dihydroxy-pyrimido 4,5-j_ b_7 ehinolin-5-carboxylic acid ^ their Hethylester, amide, and Acid chloride; 1,3-i; iüiethyl-l, 2,3,4-tetrahydro-pyrimido ~ "4,5- & 7-quinoline-2,4-dione-5-carboxylic acid methyl ester and 10-methyl-2,3» 4 »10 Tetrahydropyrimido [_ 4,5-b_7 quinoline-2,4'-dione-5-carboxylic acid and its diethyl ester. These products have been investigated as potential antidotes against riboflavin, 'faylor et al. describe in J. Am. 28, 5106 (1956) 2-methylpyrimido Z ~ 4,5-b-7 quinolin-4 (3H) -one, but no 2-carboxy-substituted derivatives are described in the literature.

When tested with the PCA test described here (passive cutaneous anaphylaxis), the well-known pyrimido [_ 4 »5-b_7 quinolin-4 (3H) -one offers only 33% protection in rats with 3» 0 mg / kg when administered intravenously. Compared to the compounds according to the present invention, its value as an antiallergic is only marginal.

From the benzo /, g_7 quinazolin-4 (3H) -one series of compounds according to the formula. II, the literature does not seem to describe any analogous compounds in which a carboxy group (or an ester or amide thereof) sits directly on the core. Reid et al. Describe however in Ber. £ 6, 1218 (1963) 2-carbethoxymethylbenzo / _ g_7quinazolin-4 (3H) -one, without specifying a use for this compound. When administered intravenously at 3 mg / kg, it offers 49% protection in the POA-iDest. In the acid hydrolysis they decarboxylated readily at room temperature to '2-iiethylbenzo J_ g_7chinazolin-4 (3H) -one (Reid, inter alia, in ". 95, 3O42r 1962), which compound in turn, shows little or iceine activity in the PGA'I'est .

of Indian PS 74.146 (OA 60, 1773f, 1964) is benzo Z ~ g_7 ^c kinazolin-4 (3H) -one, a compound according to formula II,

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effective as a broncho-dilatory agent. In the PCA test like him below, was found for had at 3 »ο mg / kg and intravenous administration 31) 6 protection. The banks this connection is at best marginal for the treatment of bronchial allergies.

Fatutta describes in Gazz.ühim.Ital. £ 3_ (5), 576-84 (1963); OA 5ä, 6401 (1963) the preparation of pyrido / ~ 2,3-d_7 "pyrimidines with a 5-carboxy or 5-carbalkoxy group, but gives no use for the compound. Mulvey et al. Report in J. Org.Chem. £ 9_, 2903-7 (1964) on the synthesis of pyrido / 2,3-d_7pyrimidines with a 6-carboxy, 6- ^ arboxamido or 6-carbalkoxy group. No reports appear in the literature via pyrido [_ 2,3-d_7 "pyrimidin-4 (3H) -one-2-carboxylic acids, esters or amides according to the formula III. The preparation of 2-methylpyrido [_ 2,3-d_7pyrimidin-4 (3H) -one and its use as a saluretic and circulatory stimulant are described in the South African PS 6,902,561 ( approx. 72 _t 125o71s, 1970).

Although the compounds mentioned make a significant contribution to the treatment of asthma, many of them have undesirable side effect of cardiac stimulation. ßs has now found that fused pyrimidines according to the formulas

and

.III

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as well as the pharmaceutically acceptable cationic salts thereof a strong allergic effect in mammals including the jiensciien by virtue of an Intal-like mechanism. Unlike! Ntal, many of these compounds are intraperitoneal and oral administration and also effective for inhalation and intravenous administration.

In the above formulas is

H is selected from the group consisting of ethyl, ethyl, acetyl and GOR ⁰ , where R is selected from the group consisting of xiydroxy, alkoxy, hydroxyalkoxy, amino, hydroxyamines;

Y selected from the group consisting of Ca) hydrogen and (b) AIiEyI, carbalkoxyalkyl, carboxyalkyl, - (CH ₂ ) _m -0-GO-C ₆ H ₅ and CGH ₂ ) _m -0-alkanoyl,

where Y = H when R is amino or hydroxyamines.

. <ei "cerhin m is an integer from 2 up to and including 4» and R- is selected from the group consisting of hydrogen, alkyl and phenyl,

are Hp »Η · ζ, Ra and R, - selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, benzyloxy, methylthio and Lie thy 1 sulfynyl, and

R ₂ and R 1, R 1 and R 1, when taken together, are alkylenedioxy and are selected from the group consisting of liethylenedioxy and ethylenedioxy.

The terms "alkyl" and "alkoxy" as used herein capture alicyl and alkoxy groups from 1 to and including 4 β atoms, the term "hydroxyalkoxy" includes hydroxyalkoxy groups with 2 to 4 G atoms inclusive and the terms "alkanoyl" and "carbalkoxy" include alkanoyl and carbalkoxy groups, respectively with 2 up to and including 5 carbon atoms. The term "halogen" includes chlorine, bromine, fluorine and iodine. -

With the exception of those of the formula I for which Y is hydrogen and R is methyl and those of the formula III for which R is ethyl

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is, the compounds according to the above formulas are new.

The present invention teaches a method of manufacture fused pyrimidines of the IOraieln:

R ₂

R-

... II

... III

and pharmaceutically acceptable salts thereof, '

where R is selected from the group consisting of methyl, ethyl, acetyl, and COR ⁰ , and R ^{0 is} selected from the group consisting of hydroxy, alkoxy, hydroxyalkloxy, amino and hydroxyamino;

Y is selected from the groups consisting of (a) hydrogen and (b) alkyl, carbalkoxyalkyl, carboxyalkyl, - (CHg ^ -O-CO-CgH, - u & d ^ with the proviso that when R is methyl.

or ethyl, Ϊ is selected from group (b), and that when R »COR with R ⁰ » is amino or hydroxyamine, X = hydrogen j

wherein further m is an integer from 2 to 4;

R ^ is selected from the group consisting of hydrogen, alkyl and Phenyl consists of |

are each selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, ■ benzyloxy, Methylthio and Uethylsulfinylf

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and R

₅ ,

R ₅ and R.,

if taken together, from the group

are selected, which consists of methylenedioxy and ethylenedioxy, which is characterized in that a connection of the

formula

in the

elected is from the group that consists of

and

where R ₁ , R ₂ , R- *, R * and R, - correspond to the above definitions, reacts with a reactant AZ in such a way that,

U) if R ¹ = IH ₂ and R = GOR °, AZ

(a) a dialkyl oxalate,

(b) Mono acid halide (chloride, bromide) one Half-alkyloxalic acid ester,

(c) an alkyl cyanoformate,

(d) a dialkyl ester of uonoiminooxalic acid (a carbalkoxyformimidate),

(e) an alkyl ester of uxamic acid,

(f) 1-cyanoformamide,

(g) Cyan (Cyanogen) and

(h) 1-carbalkoxyformamidine .ist, or

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-Q-

(b) AZ is a 1-carbalkoxyformamidine if R ¹ is a ester part,

and, if jA in formula I or III is alkyl and at least one of the G groups R-,, R ₂ * R ·? » R * and R ₁ - is not hydrogen, AZ is an alkanoic anhydride or triethyl orthoacetate or uriethyl orthopropionate,

if R = acetyl, the compound in which R = ethyl, oxidized

and, when AZ contains a gyan group, hydrolyzes the cyan derivative so produced, and when R ⁰ = alkyoxy, reacts the ester with hydroxylamine to convert R to a hydroxyamine group, and when Y is not hydrogen, the compound in which Y = hydrogen is reacted with a suitable reactant.

The term "pharmaceutically acceptable cationic salt" is intended to Salts such as the alkali salts such as sodium and potassium, ürdalkali salts such as calcium and magnesium, the aluminum salts, Ammonium salts and salts with organic bases such as amines such as i'riäthylamine, l'ri-n-butylamine, piperidine, l'riäthanolamine, Diethylaminoethylamine, W, N'-dibenzylethylenediamine and denote pyrrolidines.

The following compounds are useful in the present invention of special interest:

formula R. ^R l R ₂ Si St. 5s I. CH ₃ , GOOH, H H H H H COalkoxy II COOH H H H H H III
I. COOH,
COalkoxy
CH ₅ , GOOH
GOalkoxy te te H
H H
OCH ₅ H
OCH ₅ H
H II COOH H H OCE ₃ OCH ₃ H III COOH,
UOalkoxy H H Supreme Court ₃ OCH ₃ H I. CH ₃ , GOOH
GOalkoxy H H UCH ₃ OC ₂ H ₅ H

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-S-

2418493

Compounds of jj'orueln I, II and III, in which H = carbalkoxy is, are also valuable intermediates for the adjustment of troubles in which R = carboxy or carbamyl. this applies especially for the connections according to j'or.uel II, since those where R = Garbalkoxy, seem to be of little interest as antiallergic drugs.

The anti-alienating property of the compounds according to the present invention Invention is through the PCA-iest (passive cutaneous Anaphylaxis; Ovary in J. Lamun. oil, 355, 195β) '. in the PüA-i'est normal i'iere receive an intradermal (i.d.) injection of antibodies in serum that were consumed by actively sensitized x'iers. The animals are then administered intravenous the antigen, mixed with a dye, e.g. .cjvan blue. The increased jiapillary permeability as a result of the Antigen-antibody reaction causes the dye to take place the antibody injection leaves. The animals are then asphyxiated, and the strength of the reaction is determined by the diameter and the depth of the blue color on the inner surface the iiaut the i'iere measures.

xde / erbindungen according to the present invention can Manufacture in different ways and ways. As the structures I, II and III have the fused pyrimidine ring in common, the same reaction can be used to make that part each Structure to complete. Correspondingly, the fused pyridine rings of structures I and III can be Achieve reaction of the same kind, provided that of course in everyone -b'all uses the appropriate precursor.

Compounds of the formula I (R = JOR ⁰ ) can be prepared by processes in which ..aan utilizes the intact carbocyclic ring and various ohinoline and pyrimidine systems with a structure. This process is the construction of the 2-aminocninolin-3-carboxamide or its 3- ^ arboxy acid or ester from the inxaicten carbocyclic ring and the subsequent use of the jhinoline system as a basis for building up the pyri.iii-

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- Io -

dinringes together. I / as general reaction scheme of these procedures is in the sequence set out below. summarized in the H '= hydroxy, alkoyxy and amino!

CN (./eg A)

COR '

^^ N0 ₂

... IV

. The basis aer Ausoeute and the quality of the final product of i'ormel I preferably used \ Terfaiiren is shown by, eg A, / urther method;. Vie for example, the "EC B, can also ..- to use. as explained below.

On each of those A and B, the condensation begins to form the carbocyclic aldenyd or ketone with an active ethylene-ukleopnile. Older Ausdi * ucic "aictives uethylen-iiukleophiles" denotes a compound with a relatively acidic methylene group, dn a LIethylengruppe, which with one and

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Preferably S7 / only two electron-dependent G groups are connected - such as -OH, -COCl, -J (IH) NH ₂ , COH ¹ , -0 (HH) -0-alkyl and -üO-alkyl

Condensation takes place in the presence of an inert solvent carried out, i.e. a solvent that as a result of the reaction does not change, although it is in hell one =! Catalyst or on the salt formation -minem reactant or product can participate.

Suitable solvents are alkanols such as methanol, ethanol, Isopropanol, n-butanol, and n-hexanol; chlorinated solvents vie methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; Pyridine; aromatic hydrocarbons such as benzene, toluene, xylene, hexane and H, N'-dimethylformamide. Other solvents can be found by simple experiments. Methanol is preferably used as the solvent, in particular if <;; used on piperidine as a catalyst, as it is too satisfactory Yield, easy 'separation and pure products. üin a solvent system of piperidine and pyridine is often useful too.

A catalyst is often used to promote the condensation facilitate, even if the nucleophiles have two activating groups - such as the derivatives of cyanoacetic acid. Suitable catalysts are ammonia, primary, secondary and tertiary amines such as n-butyiamine, diethylamine, triethylamine, Pyridine, piperidine, pyrrolidine, alkali alkoxides and fluorides, otannofluoride and basic ion exchange resins of the amine type such as Amberlite IR-45 (a weakly basic polystyrene with Polyamine groups available from Rohm & Haas Co.) and De-Acidite G (polystyrene resin with Mäthylaiainogruppen, available from the ifa. Permutit Co., Ltd., London).

The amount of catalyst used is not critical and can vary within a wide range - e.g. from about 0.1 up to about 100% by weight in relation to the carbocyclic aldehyde, Preferably about 10 to about 30 wt% become more carbocyclic

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Aldehyde used.

Reaction occurs at a leiaperatar of about 0 to about 5o ° C and generally carried out at ambient temperature and takes about 15 minutes to 5 hours. .Cut the products in general as pests from the reaction mixtures from and are obtained by filtration, those products which do not separate as pesticides, can be removed by evaporating the solvent or by pouring it into a Isolate a large volume of light solvent for the product.

i> The use of a jo-nitrobenzaldehyde or an R-. - (2-nitrophenyl) ketones as a reaction participant (; Veg A) results in an ÖC-üyan-ß- (2-nitrophenyl) acrylamide derivative, i.e. an amide, if fi 'of de, a active ethylene reaction participant NHp is that must subsequently be reduced and cyclized in order to obtain the desired 2-aminoquinoline-3-carboxylic acid derivative, uie reduction (the nitro to the amino group) happens to a number of Reagents. In short, any reaction agent can be used use the selectively or preferably the iiitrozu an alaino group, typical of such reactants are metal-acid combinations such as iron-acetic acid, iron hydrochloric acid, tin or stannous chloride hydrochloric acid, citric hydrochloric acid, Zinc dust-alkali and catalytic hydrogenation with catalysts like platinum, palladium and Raney nickel.

xia's reduced product appears instantly or almost instantly the ring to the 2-aminoquinoline-3-carboxylic acid derivative to conclude.

If ο, -aminobenzaldehyde is used as the reactant OVeg b), the cyanoacetic acid derivative closes the ring to the 2-aminoquinoline-3-carboxylic acid derivative very quickly, as above for the reaction product des «eges A is given.

Let formation of the fused pyrimidine ring with his

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2-jax * bonsäurederivat (.rister- or Aiaid-) - substituents leaves You can reach them in a variety of ways. For a more convenient presentation These processes are considered on the basis of the structure of the reaction participant Y-Z, which the fragment with one Xi.oh.1 ens toff atom contributes to the pyrimidine ring system To complete with a suitable 2-aminoquinoline-3-carboxylic acid derivative:

(1) Reaction of a 2-aminoquinoline-3-carboxamide (Formula V, Ji ¹ = HH ₂ ) with

Ca) a malcylocalate,

(b) a konosäurehalogenid (chloride, bromide) one xial alkyloxy esters,

(c) an Al & ylcyanforaiait,

(d) an M-alkyl ester of., lonoiminoxalic acid (a Carbalkoxyformimidate),

(e) an alkyl ester of oxamic acid,

(f) 1-Oyanoformamide,

(g) Cyan (Cyanogen) and

(h) l-v; arbalkoxyformaiaidin, or

(2) Reaction of a 2-aminoquinoline-3-carboxylic acid alkyl ester with

(a) a 1-carbalkoxyformamidine.

j) he ÄeaKtionteilenen-aer ϊ-Ζ (an oxalic acid derivative) of the step common to the goats α and ß provides the fragment with a carbon atom, which is required to complete the fused pyrimidine ring. Depending on the number of action participants, he can also deliver the -iJH-G group. Br represents cyano and Y-OOR ⁰ , v where Ϊ = -COCl, -CN, -COR ⁰ , -üü-alKyl, -o (lüi) HH ₂ and -C (NH) O-alkyl. If YZ is an alkyl ester of oxamic acid, e.g. H ₅ C ₂ OOG-UONH ₂ , the ring formation reaction results in the amide (R = GONHp) of the formula I.

ofi'ensicxitlich must be one of the two rieaiction participants in the The last step is where A and B deliver the -HH residue. Contains the iteaiction participant who has the fused pyrimidine ring

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is to be formed, a Jarboxamide group (ex-.v. formula V with -JuR ¹ = ^ uwiip), the reaction part YZ can be one of the above-mentioned ouDsxanzen, ie uyan or Y-CuR. However, if the reaction participant in whom the fused P / rimidine ring is to be formed contains an orboxamide group, ie if -JOR ¹ = carboxy, carbon alkoxy or halofornayl, the reaction participant YZ must supply the -iiH-G group.

after the preferably used method one uses as Reactants aas suitable 2-amino-3-carboxamide (formula V with Ii '= NHp), which is condensed with the reaction participant Y-Z, only that fragment with a carbon atom to generate that closes the pyrimidine ring.

The reaction of 2-aminoquinoline-3-carboxylic acid derivatives with ϊ-Ζ is carried out in a reaction-inert solvent - desirably, when Y = GOR or C (NH) -O-alkyl, in one that removes the by-product Alcohol and .vassers allowed by distillation. Typical solvents for this ring formation are the aromatic ones Hydrocarbons such as xylene, toluene, benzene, an excess of the selected dialkyl oxalate reactant, tetralin, and Decalin.

Suitable solvents can easily be found through experiments. 1st Y-Z a dialyloxalate, is a preferably used solvent an excess of dialkyl oxalate because of its ability to to solve the rearrangement participants and a simple removal of the alcohol and water that occurs as a product to allow. Although the reaction temperature is not critical, the reaction is generally carried out at an elevated temperature Temperature through to remove the alcohol and water to erxeicn "cern.! when using a dialkyl oxalate as solvent Temperatures of about 150 ° C to about Lö5 ° C are suitable. In the case of the more reactive uxalic acid derivatives (Y-Z) such as ethyl oxalyl chloride lower temperatures can be used. _jine The final period of warmth or warmth is sometimes for everyone

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-LuingDiiaung and a maximum yield of de.a

fyri ^ ido j_ 4, 5-b / Cxiinolin-4 (5Jti (-on-2-carDor-s ^; J-urederivat; <- j_'i.stig. common isx aacn the addition of a .small ... close ei-'ier _sase vie ^ atricüinyäriä una Alicaljalicoxiden useful for j; 'üraeruiig asr ^ i ^ üiidun ^, especially "in the preparation of compounds according to aer. jc'orael .II.

. ^ ιζίχ ^ ΐτ der jieajrcionteilneniiier iZ a -Jii-G-group, the k-jyanoeriv & t, not the 2-uOÄ -! »derivative is produced. & s. is converted by oil hydrolysis to form a corresponding 2-jarbox aid. If Y-Ü is a mono acid halide of an iialbalkyloxal acid ester, vex'v / ends at an ijäureazeptor, ie an organic or aiiorgaij-iöcne iase such as irietnylaiain, pyridine, n'atrine methoxide , xvaxriunhydroxia, among others. to neutralize the acid produced as a by-product.

5-3ubatixuierten compounds, the ^ oruel I "// ground also from i ^ ownexen 4-substituted E-aminocninoline-iJ-carboxamide ner _£ estellt, this in turn is made by the conversion of xlalonsäureiiitrii with dearecnent R -, - (2-aainophenyl ) ketone, to 2-A ^ iiiio-denzophenone (R-, = phenyl) and alindfcetophenone CR ₁ ⁼ ^ H,), produced. The 2-aiaino-3 ~ cyano-4-substituted jiinoline is given by jirv / arm 95> öiger sulfuric acid followed by aqueous work-up, to give the corresponding 4-suustituierten 2-aminoquinoline-3-carboxamide hydrolyzed. iJas Verfanren broom is rubbed by üaiapaigne inter alia, in J. Hetero.ühem. 8, 111-120 (1 → 71) .

Further veri'anren ^ meets the condensation of a suitable o_-Mtrobenzaldehyds with a dialkyl malonate to one <X-OarbalK: oxy-ß- (2-nitrophenyl) acrylic acid alkyl ester, the one then according to aeia ooen described procedure to the corresponding ^ - ■ Carbalkoxy-ß- (2-aminophenyl) acrylic acid alkyl ester reduced. The reduced product cyclizes spontaneously to form a 2-oxo-cninolin-3-carboxylic acid alkyl ester. The 2-oxo derivative heats up one uruaitxelbar with l-vjarbalkoxyformamidin in ethanol nxef Use of iaatriuniäthoxiä to make compounds of the Pormel

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I to reach, or the 2-oxo derivative is chlorinated with a suitable chlorinating agents such as phosphorus trichloride, phosphorus penta chloride or phosphorus oxychloride in an inert solvent like an aromatic hydrocarbon or a halogenated aliphatic or aromatic hydrocarbon (Benzene, l'oluene, xylene, Liethgrlenchlorid, Ethylenchlorid, Ghloro form, chlorobenzene) at a temperature of about 50 to 100 G.

Per thus prepared ^ -chloroquinoline-3-carboxylic acid alkyl ester becomes the corresponding one with an alicyl l-guanylformate Pyrimido / 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid alkyl ester implemented, this formation leads msn according to known Procedure through.

Another method is to build a middle pyridine ring by adding a suitable o.-nitrobenzidehyde with an ester - e.g. i3. an allyl ester of 4,5-dioxo (3H, 5H) -tetrahydropyrimidine-2-carboxylic acid - Condensed in the presence of a base to form the corresponding 4 »6-I) ioxo (3H, 5H) -5- (2-nitrobenzylidene) tetrahydropyrimidine-2-carboxylic acid ester to produce, after the subsequent reduction according to the ..eise described above spontaneously cyclizes to a compound of the formula I. laugh one Variation of this process condenses the o.-liitrobenzaldehyde-malonic acid diamide, followed by reaction of the product with a dialkyl oxalate to form those given above nitrobenzylidene compound.

Compounds of Formula II (R = COR) are prepared according to the procedure forth the compounds of the formula I given above for fy.r are similar, but instead of a 2-Am ± nochinolin-3-carboxamids a 2-aminonaphthalene-3-carboxamide is used, jjie are the reaction conditions for building up the pyrimidine rim essentially the same as they are for connections of the οDen i'ormel I are described.

The compounds of the formula III (R = GOR) are prepared accordingly from suitable 2-aminonicotinamide or its precursor

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runners - z.u. 2-aminonicotinic acid, 2-IIitropyridine-3-carboxamides or -3-carboxylic acids, 2-nitro- or 2-amino pyridine ? -carboxaldehydes. depending on the preparation of the compounds den- Marmeln II and III will preferably be Y-Z with the appropriate one Implement 2-iuüino-5-carboxamide reaction participants.

The hydroxamic acid derivatives of J ^ orüieln I, II and III (R = NHOH) are prepared from Y-GONHOH or by reacting the precursor alkyl ester of the formula I, II or III made with hydroxylamine. When the hydroxylamine is involved, the appropriate ester will usually be used with Hydroxylaiainhydrochlorid - usually in excess in React the presence of an acid acceptor such as triethylamine. The implementation is facilitated by! Heating under pressure, i.e. the reaction is carried out in a bomb in a solvent such as ethanol for about 4 to about 20 hours. The product is then obtained by suitable means.

The 2-ethyl and 2-ethyl analogs of the formulas I and III are prepared by ring closure of the appropriate 2-amino-quinoline-3-carboxamide or 2-aminonicotinamide with the appropriate alkanoic anhydride - for example acetic or propionic anhydride - or with i'riäthylorthoacetat or iCriäthylorthopropionat in the presence of sulfuric acid. Treatment of the product with dilute alkali followed by acidification again provides the 2-methyl and ^ -ethyl analogs, respectively. The preparation of 2-methylpyrijiido [_ ^ * - 'quinolin-4 (3H5-one by this process is described by l'ayler et al. In J. Am.Onem.Soc. 7_8, 5108-15 (1956), as already mentioned The 2-ethyl analogs which are new compounds are primarily from, / ert as intermediates for the corresponding 2-acetyl derivatives of I and III.

The 2-acetyl derivatives of the formulas I and III are put through Oxidation of the corresponding 2-ethyl derivatives with selenium dioxide in a suitable solvent such as dioxane. At the Conventional processes are used to add the 2-ethyl derivative and

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Selenium dioxide in a ..o! Ratio of about 2: 1 with increased ! Temperature, i.e. from about 50 to about 100 ° C. To avoid the oxidation to accelerate, kaxm: aan via the jiol ratio 2: lninaus use further selenium dioxide.

The alkylene glycol esters of the formulas I to III (R = - GOR ⁰ with R ⁰ = hydroxyalkoxy) can be conveniently prepared by means of a transesterification with catalysis with a base. A compound of the formulas I to III, in which R ° = alkoxy, is treated with an alkylene glycol (in an amount of about 5 to about 20% by weight relative to the alkylene glycol used) such as triethylamine or calcium hydroxide in uuft at a temperature of about 2½ G to about 50 G. Higher temperatures can be used, but are of no advantage.

Compounds of j'or / iiel I in which Y is not hydrogen, is prepared by alkylating compounds of the formula I in which X = H. Here one forms by implementing the suitable compound of formula I with hatriuin hydride in one suitable solvents such as e.g. N, Ii * dimethylformamide, the üatriumsalz, its reaction with I-Y, Br-Y (or Cl-Y) that alkylated derivative results. If Cl-Y is used as an alkylating agent, accelerates the presence of a small amount of sodium or potassium iodide (about Io to about 20 wt .- ^ of Gl-Y) the Reaction.

Compounds of the formulas I to III, in which R ₂ > Rz, R. or Rjeweils ^ .ethylsulfinyl, can easily be removed by oxidation with a suitable oxidizing agent - for example hydrogen peroxide or a peracid such as m-chloperbenzoic acid the corresponding liethylthioverbindungen according to methods that are known to the experts, produce.

For their part, methylthio compounds are easily produced, by adding the corresponding chlorine compound of formula IV, i.e. a £ -Cyan-ß- (2-nitrochlorophenyl) -acrylamide with iiatriunmiethyl mercaptide implements, iiodifications of this procedure are for

4098A5 / 1079

-ig -

the professional world obviously. 2 B. one can use the jiethylthioether according to formula IV by in-situ formation of the xiethyl mercaptide salt produce.

Products according to the present invention and the pharmaceutical suitable cationic mats thereof are useful for the prophylactic and therapeutic treatment of allergic persons Symptoms and reactions "in mammals and can be used as individual therapeutic, / irkmittel or also as Mixtures of therapeutic, active agents - e.g. with ■ x'heophylline or sympathomimetic amines - administer. They are administered alone, but are generally administered Administered with a pharmaceutical excipient, the is chosen according to the chosen route of application and normal pharmaceutical practice. E.g. they can be used with different Pharmaceutically suitable inert excipients in the form of i'ab ^ rletten, capsules, lozenges, hard candies, powders, Aerosols, aqueous suspensions or solutions, injectable uosurigen, elixirs, syrups and the like. Combine, but also with solid diluents or fillers, sterile aqueous Media and various non-toxic organic solvents celn. In addition, the oral pharmaceutical compositions according to the present invention according to ./unscn can be sweetened and flavored by using different avlittel of this type, which are commonly used for this purpose.

The particular substrate one chooses and the ratio from active constituent to carrier substance through solubility and affects the chemistry of the therapeutic compound, mode of administration and pharmaceutical practice, One can use the compounds according to the present invention For example, administered orally in the form of tablets, excipients such as lactose, sodium citrate, calcium carbonate can be used and use calcium phosphate. Various dividing agents or disintegrants such as starch, alginic acid and certain complex silicates can be used together with lubricants such as

409845/1079

Magnesium tear at, sodium lauryl sulfate and i'alk use in the manufacture of! Tablets for oral administration. I ¹ Ur are oral "administration in the form of capsules lactose und.hochmolekulare polyethylene glycols among preferably for use as pharmaceutically acceptable! 'Rager materials used substances. </ O to be used for oral administration, aqueous suspensions, the compounds can by of the present invention with emulsifying and suspending agents. Diluents such as ethanol, propylene glycol, glycerol and chloroform and combinations thereof can be used as well as other materials.

For the purpose of parenteral administration and inhalation leave solutions or suspensions of these compounds in sesame or Peanut oil or in aqueous propylene glycol solutions as well use as sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein. These solutions are particularly suitable for intramuscular and subcutaneous injection if these modes of administration are desired should be. Lie aqueous solutions - including the solutions of salts dissolved in pure distilled (Yasser are also suitable for intravenous injections, provided the pH - »/ ert is set accordingly beforehand. Such solutions should also, if necessary, be buffered in a suitable manner and the liquid diluent is first isotonic with a sufficient amount of physiological saline solution or glucose do.

jjie connections can be Asüaniakranken, who from bronchial constriction by means of inhalers or other devices that allow the active compounds to be administered in direct contact with the constricted '!' rushes of the tissue of the crane.

, ieiw. if the compounds are administered by inhalation, they may (1) be in the form of a solution or suspension of the active compound in a liquid medium, as described above for

409845/1079

the administration with the nebulizer is mentioned - (2) in Porm-an ouspension or solution of the active constituents in a liquid! holder, or (3) as a mixture of the active ingredient and a solid diluent (e.g. lactose) for inhalation from a powder inhaler, compositions suitable for inhalation with a conventional nebulizer contain about 0.1 to about 1/6 of the active ingredient that for use with a pressure vessel is about 0.5 to about 2 -ρ of the active ingredient. Powder inhaler compositions can have an active ingredient to diluent ratio of from about 1: 0.5 to about 1: 1.5.

ü) It is necessary that the active ingredient constitute such a proportion of the composition that a suitable dosage form results. Obviously, multiple unit dosage forms can be administered at about the same time. Although one / ä in certain cases, compositions with less than o, ^u oo5 by weight of the active ingredient can use, it will be o, β preferably use compositions containing not less than oo5 / of the active ingredient; otherwise, the amount of the carrier fabric becomes excessive. The activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75-95 or even higher weight percent of the active ingredient.

The-reaction test used here to evaluate the compounds of the present invention shows an excellent correlation between the activity of the compounds and their usefulness in the treatment of allergic asthma. The ability of the agents to disrupt PGA reactions is measured on male Oharles xiiver .astar-ilatten with a body weight of 17o - 21o g. Wach _A , ± ota, Immunology X ₁ 681 (1964), one prepares a reaginic antiserum with chicken egg albumin and B-pertussis and an antiserum that is hyperimmune against chicken egg albumin

409845/1079

orange et al in J.Exptl. iled. 127, 767 (1968). 4-8 hours before the antigen immunity test, the reactive antiserum is injected intradermally (id) into the shaved skin of the back of a normal rat. 5 hours before the immunity test, the hyperimmune anti-serum is injected accordingly. 5 hours later, 60 meg. Histamine dihydrochloride is injected intradermally as a test for antih-istaminic and unspecified types of blocking at a third point. The compounds of the present invention or physiological saline solution are then administered intravenously, immediately followed by 2.5 mg Bvans-Jölue -I 'dye and 5 mg of albumin in physiological saline solution. In the case of oral administration, the dye and the albumin are given 5 minutes after the administration of the drug.3o minutes later the animals are suffocated with chloroform, the chicken skin is removed and Each injection site is assigned a value that is equal to the product of the diameter of the injection site in mm and a value of o, l, o, 5, 1, 2, 3 or 4, which is proportional to the The intensity of the coloration by the dye is. The vertices for a given injection site are summed up for each group of 8 and with those marked with physi compared to animals treated with saline. The difference is expressed as the percentage of blocking due to the connection used.

Typical compounds of the invention were made according to the above Procedure tested; the activities obtained are expressed as a percentage of protected relationships. For comparison is iiisodium chromoglycate, a commercially available antiallergic, listed.

409845/1079

.3-23 ^P.

Table I.

Antiallergic effectiveness of pyrimido / ~ 4 »5-" b_7 quinolin-4 (3H) -one-2-oarboxylic acid derivatives (formula I)

R ₁ R ₂ R _x ^E 4 Ϊ5_ mg / I.V. ₊ Orally 100 4 · % 80 _T & HHH H H 10 k £ 60 10Oi GOOC ₉ Hp- 3 100 30th 72 _X c- J 1 ⁹⁹ 4
1007 10 75n 0. 3 69q 0. 3 45 ° 1 12 " 0. 1 30 ⁶ 100 96 HHH . H H 1 03 92 30th 57 GOONa 0. 68 10 O 3

GOOCn-G.Ho) HHHHHl 90 30 50

^{4 y} 0.03 6

GONH ₂ HHHHH 3 98 60 23

GOOO _Ρ Ης HH OCH _x OGH _x H 1 10O _x 10 8θ1Ι

1 51 ²⁶

.03 30

H H OCH _x OGH _x H 1 10O _x 0.3 ⁹⁰ 12 0.1 ⁹⁰ 14
⁷⁵ I?
⁷⁰ IA 0.03 36 ¹⁴ • 0.01 90 0.003 94 H H OCH _x OCH _x H 3 100 j 0.3 64 0.03 0.003

000 (nC .Hq) HH OCH _x OCH _x H 3 90 30 81

Numbers indicate that the corresponding // is running is the average of two or more measured values.

A0 "9845/1079

Table I (Ports.)

I.V. 4 Oral f

R. R ₁ ^R 2 R ₅ ^R 4 ^H 5 mg / kg * 97
94
92 mg / kg 65 COOCH ₂ CH ₂ OH H H OCH ₅ OCH ₅ H 5
0.5
0.05 67 10 4th GOIH ₂ H H Supreme Court ₅ OCH ₅ H 5 92 30th 3 GONHOH H H OCH ₅ OCH ₅ H 5 100
96
71 60 17 ² GOONa H H OCH ₅ OCH ₅ H 0.1
0.05
0.01 _{? 7} 4
II ⁴ 10 43 ⁶ GH, H H OCH ₅ OCH ₅ H 5 '
0.5
U. 03 3
1

HH OCH ₅ OCH ₅ H 5 56 60 0

COCH, H H OCH, OCH-. H 5 100 10 15

^yy > 1 2I

5 100 0.1 I ₉ ² 5 97 ₂ 0.5 ⁹⁴ 2 0.1 0.05 * ύ 0.01 5ΐί

HH OGH, OGpH _R H 5 97p 30 8θ

^y ° 05 94 10 73X

5 52 °

1 - 44Λ

0.5 51 ^ 0.005 66 ^P.

High numbers indicate that the / is in question
the laittel is made up of two or more jueiäwerteii.

4098A5 / 1079

$ 241849

Ü'abelle I (cont.)

Üc

I.V.

mg / icg

Ural

MA '/ kA- Α.

COOC _Q H _R HH

-0-GH ₂ -O-

UuOC ₉ Hp- HH -O-GHpCHp-O -ogle ₂ H ₅ HH OG ₂ H ₅ OU ₂ H ₅

GOOu ₂ H ₅ HH OG ₂ H ₅ OGH5

GOOO ₂ H ₅ HH OC ₂ H ₅ Q-Cn-C ₄ H ₉ ) H

COOG ₂ H ₅ HH OG ₂ H ₅ OG ₇ H ₇

1 70 30th 0 0.1 O 3 72 1 64 3 10O ₉ - 10 81 0.1 90 3 64 0.03 60? 1 40 0.01 43 * 0.3 42 0.003 21 3 100p 10 92 0.1 99 ^ 3 83 0.03 1 76 0.01 72J
50 ⁴ 0.3 56 0.003 90 3 ⁹⁵ 3 10 67 1 3 43 0.3 28 1 3 0.1 O 0.03 74 3 30th 0 0.3 3 ² 10 0 0.1

Goog ₂ H ₅ HHH

OCH,

OCH., 3 100 60 26 0.3 39 10 0

Exponents, indicate that the relevant -y / ert is the mean of two or more readings.

409845/1079

l'a belle I (cont.)

IV ⁴ "ural *

COOG ₂ H ₅ HH

5 100 10 45 0.5 87 ₂ 5 52 0.1 68 5 90 10 45 0.5 20th 0.05 0

H __ fi ^ 2 t2 ΖΆ _5 ÜZ

up- HH Q \ stL-s H ti

Goog ₂ H ₅ HH H OGH ₅ H

Goog ₀ Hp H OCH. HH OCH ^> 100 50 '

^{25 3 5} 0.5 25

0.05 0

UOOC ₂ H ₅ HH

GOOC ₂ H ₅ HH

OCH, NS H OCH * 5 97 50 41 j 0.5 58 0.05 14th H H 5 68 50 100 SOCH ^ 0.5 91 10 66 j 0.05 8th 5 21 1 0 H H 5 100 50 12th 0.5 58 0.05 0

Ης H H OCK, OCK, OGH, 5 88 10

* -. ^{D 7} . ^p 0.5 25

0.05 55

Goog ₉ H, - HHH I ¹ H 0.1 2

Exponents indicate that the relevant y / ert is the mean of two or more measured values.

409845/1079

'Table I ports. )

UOOG ₀ H ₁ - H

Ro Rz R IV

Orally

Η Η

H 01 H H

Cl H H H

HHHH

Oinatriui achromoglycate

mg / kg <fe mg / kg <k 5 82 50 17th 1 90 0.05 0 1 70 0.05 0 1 96 50 57 0.05 11 5 100 10 0 1 95 1 0 0.5 51 0.1 9 10Ö 100p 100 0 50 10 89 5
1 ⁷ 6 ⁸ 0.5 29 ^ 0.1 19 ⁵

¹ exponents indicate that the relevant Vert is the mean of two or more measured values.

409 845/1079

II Antiallergic Activity of Benzo / _ g_J-

quinazolin-4 (3H) -one-2-carboxylic acid derivatives (formula II)

BRAT'

I.Y.

Orally

ο R ₂ R ₅ ^R 4 ^R 5 mg / kg JL mg / kg ! _ Goog ₂ H ₅ H H H H 10 27 100 38 COOH ⁺ H H H H 10
3
1 100
36
14th 100
30th
10 9
0
33

Tested as iinatriuai salt.

i'aöelle III antiallergic activity of pyrido-

L 2,3-d_7pyrimidin-4C3H) -on-2-carbon-

acid derivatives (formula III)

I.V.

Orally

UG ₂ H ₅ HHH

mg / kg 10

95

mg / kg 100

With full consideration of the above factors, it is assumed that that a daily dose of the compounds after of the present invention in humans, from about 10 to about 1500 mg per ag at a preferred range from about Io to about 600 mg per day in a single dose or in multiple doses or from about 0.2 to about 12 mg / kg of body weight effectively dissolves a bronchial constriction in humans.

409845/1079

Liese .i'erte are given for explanatory purposes only and can In individual cases, higher or lower doses may be preferred.

for intravenous administration or inhalation "is the effective daily dose about 0.5 to about 400 mg per day and preferably about 0.25 to 200 mg per day or about 0.05 to 4 mg per leg of body weight in one dose or several doses.

7 »ö-dimethoxypyriiaido /. 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester is effective when administered orally, intravenously and intraperitoneally and also when administered intraperitoneally at 0.3 to 1 mg / kg and orally at 0.3 to 50 mg / kg. When administered in aerosol form, it leaves a sensitivity Observe depending on the concentration in solutions of 0.3 to 3o mg / ml. When administered intravenously, it is down to 0.03 mg / kg active.

jiis has been found that 7,8-diinethoxypyrimido J_ 4,5-b_7chinolin-4 (3H) -one-2-carboxylic acid ethyl ester nat a marked, but transient decrease in blood pressure and bradycardia result in dogs. The effect appears to be species-specific. The . Compound appears to be relatively free of toxic effects, since intravenous doses of 100 mg / kg in mice did not lead to the first day.

Example I.

Pyrimido J_ 4, 5-b_7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A. 2-Aminocninolin-3-carboxamide

Iyanacetamide (19.4 g, ½, 23 μl) is added to a solution of sodium ethoxide C6 »o5 g, 0.29 mol) in absolute ethanol (40 ml) kept at 50 ° C. Lian stirs the mixture and adds' o-aminobenzaldehyde (2d, og, υ, 23 .viol) in absolute ethanol (100 ml), after stirring for 15 minutes at 5-0, the reaction mixture is cooled in an ice bath, filtered and dried ; 3-4.5 g of the product were obtained (yield 4 ft) at a temperature of 24 ° -242 ° above sea level.

409845/1079

B. Pyriiaido j_ 4,5-b Zincinolin-4 (5H-one-2-carT3onsäxireäth, ylester

Mixture of 2-ainoquinoline-3-carboxamide (25, ο g, o, 154 kol) and ϊ / iäthyloxalat (500 ml) is refluxed for 4 hours while uian the ethanol-water that is formed is distilled off, .uie reaction mixture is then cooled to liaum temperature, the solid product filtered off, washed with Mäthyloxalat and air-dried containing 22.6 g of a brownish-green solid substance. Melting point 245-246 O. This product is purified by recrystallization with decolorization from hot chloroform. The resulting off-white solid substance (16.2 g, yield 45 i ') melting at 247-248 ⁰ G.

Analysis: Calculated for C ₁₄ H ₁₁ ^ ₅ O ₅ : G-, 62.51; H, 4.24; II, 15.67 * found: G, 62.44? H, 4.24; N, 15th

the same connection is obtained. if one (a) equimolar Amounts of 1-carbethoxyformimidate and 2-AmInOcMnOHn-J ethyl acid ester in ethanol for 3 hours under reflux. The reaction mixture is concentrated, the product is collected by filtration and crystallized from hot chloroform um, or (b) equiinolar amounts of 1-carbethoxyformamidine are heated and 2-aminoquinoline-3-carboxamide in ethanol for 3-4 hours in the presence of an equimolar amount of sodium ethoxide at reflux. The reaction mixture is worked up, as described in (a) above.

Example II

7,8 -Direthoxy-pyrimido ] _ 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A. dC-uyan-β- (2-nitro-4 _t 5-dimethoxyphenyl) acylamide

Piperidine (2.1 g, o, o237 M) and 2-cyanoacetamide (22, og, o, 263 Hol) are a slurry of 6-nitroveratraldehvd (5o, og, 0.237 mol) in ethanol (500 ml) was added. The mixture is refluxed for 2 hours, then cooled in an ice bath and filtered. The light yellow filter cake is mixed with cold

409845/1079

Washed isopropanol (300 ml) and then air dried. Yield = 6o, lg (93 #), melting point 265-266 ⁰ C.

Analysis: Calculated for C ₁₂ H ₁₁ H ₅ Q ₅ ^: ® ' ^5: » ^9y » H, -4.00; N, $ 15.16 Found: C, 51.96; H, 4.2o; N, 15.23 #

According to the above procedure but with the appropriate alkoxy substituted one Nitrobenzaldehyde, are those listed below Connections made:

ONHc

_Ώ melting point ■ yield

ti ' ( ⁰ C.) j

H OCH ₅ H OCH ₅ 231-2 (dec.) 20 ^(a) OCH ₅ HH OCH ₅ 247-8 (dec.) 82.5

HH H ₅ OCH 157-2 (dec.) 42 H OCH OCH _{5 5 5} OCH 244.5 "(dec.) 73.5 H OC ₂ H ₅ 0-Bi-C ₄ H ₉ H 54

H OC ₂ H ₅ OC ₇ H ₇ H 167-167.5 (dec.) 73

H OC ₂ H ₅ OCH ₅ . H 243-4 (decomp.) 62 H -OCH ₂ -CH ₂ OH 301.5 '(decomp.) 98.2 (a) at reflux for 18 hours

₅ OC ₂ H ₅ H 191-3 (dec.) ■ 79 B. 6 ₁ 7-Dimethoxy-2-aminoquinoline-3-carboxamide

Within half an hour, iron powder (65.2 g, 1.22 mqI) is converted into a slurry of e-cyano-β- (2-nitro-4,5-dimethoxyphe'nyl) acrylamide (75, ο g, ο, 271 Mol) in a 5% solution of acetic acid-N, Ii ¹ -dimethylformamide (750 ml) -at 75 ⁰ C-

409845/1079

wear. After the addition of the sisen powder is complete, the mixture becomes heated to 90 ° 0, held there for 4 hours and then in the hot State filtered. The filter cake is washed with hot acetic acid (150 ml) and the dark red filtrate gradually becomes given in 1 normal hydrochloric acid (1500 ml). The unusual one pink substance is obtained by filtration and recrystallization from a lo ^ ige excess of aqueous sodium hydroxide. The 'solid substance is filtered off with cold isopropanol washed and dried; the product given is the compound given in the heading in the form of yellow crystals. Yield 57.1 g (65.5 #) f m.p. 274-275 ° C.

Analysis * Calculated for G ₁₂ H ₁₅ N ₅ O ₅ : C, 58.3o; H, 5.29; Έ, $ 16.99 Found G, 58.06; H, 5.29; N, $ 17.25

Repeating procedure B, but using the suitable <* - cyano-ß- (2-nitro-alkoxyphenyl) acrylamides from the Method A the following compounds are made:

_a * 3-γ R ₅ Supreme Court ₅ CONH ₂ (Decomp.) yield OCH ₅ H -I OCH ₅ Lnh ₂ (Decomp.) H H (Decomp.) 52 H H OCH ₅ 78.5, - = ■ Supreme Court ₅ H ₄ H ₉ H (Decomp.) 82 H OC ₂ H ₅ OCH ₅ H Melting point
(Location \
V ν. J (Decomp.) 83.2 Supreme Court ₅ OC ₂ H ₅ Supreme Court ₃ H (Decomp.) 85 H OC ₂ H ₅ 0-n-C H 284-286 (Decomp.) 73 H OC ₂ H ₅ OC ₇ H ₇ H 263-4 83.7 H -OH OCH ₅ 281-2 90.8 H OC ^ H ₅ 240-1.5 26.5 H : ₂ CH ₂ o- 252 H 279-80 H 234-5 243-4 269.5

409845/1079

-33- 241849a

C7 * ö-Diiüethoxypyrimido /. 4> 5-b_7ehinolin-4 (3H) -one-2- carboxylic acid ethyl ester

In a bottom flask with a stirrer, return condenser and Dean-Stark device containing a mixture of diethyloxalate (50 ml) and xylene (10 ml) at reflux, 6,7-dimethoxy-2-aminoquinoline-3-arboxamide is added (3 »ο g, o, ol2 M). The xylene, water and ethanol are distilled off and caught within 4 hours. When all of the xylene has been removed, the reaction mixture is brought to 185 ° C. and cooled to about 100 G and slowly pour it into chloroform (300 ml). The chloroform solution is cooled and that which forms is removed brown precipitate by filtration. The filtrate is decolorized by treating it with charcoal, concentrates and cools it to a crystalline mass. The crystals are taken in hot chloroform up, treat the solution with charcoal, filter and concentrate it into pale yellow crystals; Yield 0.59 g ($ 15). F .: 273-273 ° C (dec. ').

Analysis; Calculated for C ₁₆ H ₁₅ N ₅ O ₅ : 0 »58.41? H, 4.60; N, 12.77 # J Found C, 57.91? H, 4.53; N, 12.370.

According to an alternative way of preparing this product, a mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxylic acid ethyl ester (1.3 g, 5, o mM), ethyl 1-carbethoxyformimidate hydrochloride (1.82 g, Io mM), triethylamine (5.1 g, 5, o mM), ethanol (50 ml) and Ν, Ν-dimethylformamide (20 ml) on a steam bath for 17 hours. The reaction mixture is cooled; the solid.substance which settles out is filtered off, triturated with hot chloroform and recrystallized from chloroform. o, 17o g are obtained as product. Vt 273-274 ° C (dec.).

Another alternative method is the following: Ethyloxalyl chloride is added (8o ml) 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (2, ο g, o.81 ml) and holds the mixture for 2 l'age to 95 ° C. The reaction mixture is then cooled and filtered. The solid product is triturated with chloroform and crystalline

409845/1079

converts it from hot chloroform.

can also keep a mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (o _f 5 g> 2 mM), ethyl cyanoformate (o.43 g, 44 mmol) and uenzene (30 ml) 3! Cage at reflux . The mixture is then cooled, filtered and the solid substance is extracted with chloroform. Concentration of the chloroform extract yields the product, which is recrystallized from chloroform.

awake dem.oben indicated method (C), but substituted alkoxy with the appropriate 2-aminoquinoline-3-carboxamide from (B) and the appropriate Oxalsäureester to set the following connections _»r.

• ρ

5 melting pk-fc. yield

( ⁰ C.) g

OnC ₄ H ₉ H OGH ₃ OCH ₃ H 263-4 (dec.) 14.5

OC ₂ H ₅ H OCH ₃ H OCH ₃ 256-7 (dec.) 35

OC ₂ H ₅ OCH ₃ HH OCH ₃ 254-5 (dec.) 24.

OG ₂ H ₅ HH OGH ₃ H 263-4 (decomp.) 9

OC ₂ H ₅ H OCH ₃ OCH ₃ OCH ₃ 250 (dec.) 31.4

OC ₂ H ₅ H OC ₂ H ₅ 0-nC ₄ H _g H 201-3 (dec.) 16

UC ₂ H ₅ H OC ₂ H ₅ OC ₇ H ₇ H 241-2 (dec.) 41.

UC ₂ H ₅ , _{HOC 2} H ₅ OCH ₃ H 264-5 (dec.) 16

OC ₂ H ₅ H OC ₂ H ₅ OC ₂ H ₅ H 243-4 (dec.) 19.1 '

OC ₂ H ₅ H -OCH ₂ CH ₂ O-H 252.5 (dec.) 11.2

A098A5 / 1079

D. - 7,8-Dijaethoxypyrimido j_ 4,5-bJfcihinolin-4 (3H) -one-2 "Oarbo.n-

acid . . "

7,8-dimethoxypyrimido / ~ 4,5-b-7-quinolin-4 (3H) -οή-2-carboxylic acid ethyl ester (250 mg, 7.4 mmol) in aqueous sodium hydroxide ( 37.5%) is stirred at room temperature for 20 hours . The ester

.sicn

rust / within "io minutes, followed rom gradual appearance of a light colored precipitate. The reaction mixture is acidified by slowly adding lo ^ iger aqueous solution Hydrochloric acid (13 ml). The light colored precipitate dissolves to form a yellow precipitate. The sour one is stirred Mix for 45 minutes and then filter, wash the filter cake with water and dry it in vacuo.

14o mg ($ 63) of a yellow solid substance are obtained. · Ι ».ι 277-2So ⁰ C (decomp.) · The analysis shows a purity of .86 io, the remainder being sodium chloride and a small amount of water. The substance is purified by recrystallization from trifluoroacetic acid. acid. The trifluoroacetate salt monohydrate thus obtained melts at 281-283 ° 0 (decomp.).

Analysis »Calculated for C ₁ ^ H ₁₁ O ₅ N ₅ .CF ₅ GOOH-H ₂ Oι

C, 44.34; Η, 3.25; N, 9.69; P, $ 13.15; Found »C, 43.95; H, 3.17; N, 9.99; P, $ 13.75.

7-Methoxy-8-ethyypyrimido £ ~ 4,5-b_7-quinolin-4 (3H) -one-2-oarboxylic acid ethyl ester is prepared according to procedures AC, starting from 3-methoxy-4-ethoxy ^ 6-nitrobenzaldehyde. Pi 264-265 ^p C (dec.).

This and the other products of Example HC are hydrolyzed according to procedure D in order to obtain the corresponding acids.

Example III

7-ffluoropyrimido L 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid, ethyl ester

A09845 / 1079

A. O C-Oyan-β- (2-nitro-5-fluorophenyl) acrylamide

Am mixture of 3-fluoro-6-nitrobenzaldehyde (o, o g, o, o592 mol), 2-uyanacetsunid (5.24 g, o, o622 mol), piperidine (o, 37 g, 4.36 mmol) and Ethanol (92 ml) is heated in a steam bath for 2 hours under a flow of water, then cooled in an ice bath, the product precipitating and being recovered by filtration. It is washed with cold ethanol and dried. Yield: 9.1 g (6-5 ^c jo) of the crude product. F .: 162-166 ⁰ G. The purity • is sufficient for use in the next process step.

B. 6 "jFluoro-2- * aminoquinoline-3-carbon" boxamide

Iron powder (8.52 g, 0.152 mol) is gradually added over 40 minutes to a suspension of <X-cyano-β- (2-nitro-5-fluorophenyl) acrylamide in acetic acid (100 ml) at Ö5 ° O. When the addition of the Exseu.pu.Uers is complete, the mixture is heated to 95-100 G for 1.5 hours and then filtered hot through silica, the filtrate is cooled in an ice bath and a beige-colored crystalline solid substance is then filtered off. The solid substance is treated with ethyl acetate and water, the organic phase is separated off, dried over anhydrous sodium sulfate and concentrated. The yield is 6.34 g (90 ° ^C ß>) in the form of yellow crystals. F .: 232-236 ⁰ G.

Q. 7-Fluoropyrimido £ ~ A _t 5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A mixture of diethyl oxalate (57 »2 g, 0.392 mol) and 6-fluoro-2-aminoquinoline-3-carboxamide (5.34 g, 0.0261 mol) is heated at 160 ° C. in a nitrogen atmosphere for 18 hours then lets cool down to barely any temperature. Lian adds hexane (300 ml), the mixture is stirred and the desired product is filtered off, washed with hexane and dried. Yield: 4.9 g (71 St) I ι F. 272 ⁰ C (dec.).
Analysis :

Calculated for C ₁₉ H ₁₀ FN ₃ O ₅ : C, 58.54; H, 3.51? N, 14.63, Ϊ, $ 6.61; Found »C, 58.29; H, 3.47; N, 14.69; F, 6.7o.

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.Example IY

δ-ifluoropyriolido J_ 4 »5-fo_7" quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A. oC-Oyannj- (2-nitro-4-fluorophenyl) acrylamide

Ivlan rünrt a mixture of ¹ 4-3J luor-2-nitrobenzaldehyde (8,7o g, 51.5 mi 'lol), 2-Oyanazetamid (4.7 g »54,4MIoI), piperidine (o, O52 g, o , 37 ml) and ethanol (80 ml) for 28 hours at skin temperature. The solid substance that forms is filtered off, washed in ethanol (45 ml) and dried. Yield: Io g 5 10) in the form of light beige crystals, melting point: 278-279 ° C.

B. 7 -I ¹ IuQ r - 2 -amino c hinolin-3-ο ar b oxami d

After dissolving the product from process stage A (lo, og, o, o42 mol) in acetic acid (192 ml) at Ho ⁰ C, bison powder (lo, 3.g, o, 192 mol) is gradually added over the course of 40 minutes . The mixture is stirred for one hour and then concentrated under reduced pressure to a thick paste. The paste is treated with ethyl acetate (100 ml) and water (100 ml) and the phases are separated. This partial step is repeated three more times. ivian dries the combined ethyl acetate layers (WapSO . ), filtered and concentrated to a small volume. The solid substance is filtered and dried. Yield: 4.72 g (57.3 %) of the crude product. Ϊ .: 259 ^ 262 ⁰ G. The product is used immediately in the next process stage.

G. 8-fluoropyrimido J_ 4, 5-b_7-quinolin-4 (3H) -one-2-carboxylic acid, ethyl ester

Oxalsäurediäthylester (47.5 g, o, 326 moles) and 7-i ¹ luor-2-aminoquinoline-3-carboxamide (3.7 g, o, OL5 mole) are mixed and kept for 7 hours at 16o G. The reaction mixture is cooled to the Auoite temperature, hexane (300 ml) is added, the brown solid substance which has precipitated is filtered off and washed with hexane (bo ml). Then one slurries them in hot chloro form (25o ml)

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up and removes the insoluble material through, filter. The hot piltrate is decolorized with charcoal, then filtered and dried (Na ₂ SOi). The light brown precipitate which forms on cooling is filtered off and recrystallized from isopropyl alcohol. Yield I, o4 g (29 »2 ^e / 4) of the ethyl ester of the heading. F. ι 24 ° -251 ° C.

Analysis: Calculated for G ₁ . H

C, 5ö, 54 | H, 3.51? N, 14.63, F, 6.61 -fa * Found: C, 53.52? H, 3.61; N, 14.76; F, 6.56 #.

Example Y

7-chloropyrimido / ~ "4, 5-b-7-quinolin-4C3H) -one * -2-carboxylic acid ethyl ether

A. <x-Gyan-β- (2-nitr6-5-chlorophenyl) acrylamide

üa mixture of 5-chloro-2-nitrobenzaldehyde (47, ο g, o, 25 H), 2-cyanaoetamide (21, ο g _f o, 25 M), diethylamine (0.5 ml) and ethanol (5oo ml) is heated to reflux for one hour. Sodium ethoxide (10 mg) is added to the clear mixture and the refluxing is continued for a further 2.5 hours, then the mixture is cooled and the crystalline precipitate is filtered off. Yield: 52.3 g (Ö8 #). F. 183-185 ° C of the raw material. The product is used in the process stage without purification.

B. 6-chloro-2-aminoohinolin-3-arboxamide

According to the procedure of Example IY-B, one treats öt-cyano-ß- (2-nitro-5-chlorophenyl) acrylamide (51, ο g, ο, 2 mol) with iron powder (56 g, l, o mol) and receives 19 g (43 ¹ Jo) of the carboxamide derivative given in the heading. 3P .: 25o ° -251 ° C after recrystallization from ethanol.

C. 7-Chlorpyrimido / ~ 4,5-b_7 "quinolin-4 (3H) ~ one-2-carboxylic acid ethyl ester

A mixture of 6-chloro-2-aniinochinolin-3-carboxamide (2.2 g, 0.2 moles), sodium hydride (0.52 g, q, ol2 moles as a 56 ^: / ige dispersion in UI) and Ν is added , Ν-dimethylforioamide (2o ml) to one

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Solution of diethyl oxalate (5 ml) and H, N-dimethylformamide, stirs the reaction mixture for 15 minutes, gives a second Add portion of lithium hydride (0.52 g, 0.02 mol) and stir another 15 minutes. ! Then carefully add acetic acid (25 ml) and then water (50 ml). The beige-colored precipitate is removed by filtration and dried (2.0 g of crude ester). It is purified by chromatography on silica gel with chloroform 2B ethanol (99 si) as eluant. That by concentrating The product obtained from the bluate is recrystallized from acetic acid. Yield «1.3 g (37.3 #). F .: 26o.5 ° C (dec.). The mass spectrum gives m / e «3o3 ·

Example YI

7,8-methylenedioxypyrimido / ~ 4 »5-b_7-quinolin-4 (3H) -one-2-carbon-

^^ M ^ ■ '.1.1 »I. . .- I ■■ Il ■■ I ..Μ. - ^ __ »^ _ I li ■ - ■■■ III» I., .. ■ .— ■ Il ■ M, .Ml M. .1 I. ^ - ■ «

ethyl ester

A. 6,7-Ethylenedioxy-2-aminoquinoline-3-carboxamide

Priority 4 »5-methylenedioxy-2-aminobenzaldehyde (5» g ο, o.o3 mol) and 2-Gyanacetamid (2,5o g, o, o3 mol) of sodium methoxide (l, 9o g, o _f o3 Mol ) in methanol (50 ml), reflux the mixture for 15 minutes and then cool it in an ice bath. The pale yellow solid substance is filtered off and recrystallized from acetic acid. 6.18 g (89.3 #) of the desired product are obtained. F .: 3o8 ° 0 (decomp.) Jm / e «231.

B. Ring closure of 6,7 ~ methylenedioxy-2-aminoquinoline-3-carbox-

amide

A mixture of 6,7-methylenedioxy-2-aminoquinoline-3-carboxamide (1.5o g, 6.5 mmol), sodium methoxide (0.05 g, 1.25 mmol) and diethyl oxalate (150 ml) is kept 3.5 hours at 150 ° C., the mixture is then cooled to room temperature in order to precipitate the product, which is recovered by filtration (l, above). It is purified by chromatography on silica gel with chloroform! Methanol (99 t 1) as the eluent. The product is recovered by evaporating the eluate and recrystallizing the residue from ethanol. The yield is 0.414 g (2ο, · 4) of

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obtained from the cyclized product, F .: 267 0 (dec.) · Analysis: Calculated for C ₁₅ H ₁₁ N ₅ O ₅ : C, 57.51; H, 3.54; F, 13.41 /:?; Found: G, 57.19; H, 3.67; N, £ 15.33.

Example YII

7, d-Dimethoxypyrimido £ 4,5-b ^ quinolin-4 (3H) -one-2-carboxamide

Anhydrous ammonia is left in a mixture of 7,8-dimethoxypyrimido / 4 »5-to ^ ciiinoiin-4 (3H) -one-2-carbo: n-acid ethyl ester (300 mg, 900 mmol) in absolute ethanol (75 ml) 15 minutes. A clear solution forms, followed by a few minutes from the formation of a precipitate. The reaction mixture is placed in a pressure bomb (Monell) and heated they "overnight in a 95 ° G oil bath. The bomb is then cooled room temperature and removes the contents. The bomb is washed out with ethanol and the washing liquid is filtered off the reaction mixture to recover the product. The filter cake is washed with ethanol and dried in the air. Yield »260 mg (95 #). F .: 31o ° C (dec.).

Example YIII Pyrimido / T * 4> 5-b_7Ohinolin-4 (3H) -one-2- carboxylic acid n-butyl ester

Pyrimido /, ~ "4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester (300 g, 1.12 mmol) is added to n-butanol (35o ml) with ten drops of hydrochloric acid. The mixture is kept Reflux for 36 hours, cool and then filter, dissolve the solid in hot chloroform, remove the insoluble material by filtering and concentrate the filtrate to give 1.19 g of the n-butyl ester (36% yield).
M.p. * 218-219.5 ° C.

Analysis * Calculated for C ₁ OH ₁₅ N ₅ O ₅ : δ, 64.71; H, 5, o9 #; Found: C, 64.12; H, 5.2o #.

Example IX

Pyrimido £ ~ A, 5-b_7 "quinolin-4 (3H) -one-2-carboxamide

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erväriiit a (reaical from 2-alainocninolin-3-carboxainid (2.0 g, 1.15 mmol), ethyloxamate (2.71 g, 23.1 milol), ethylene glycol (Io ail) and iiatrium / ffioxid (Io mg) for one hour at 170 ° G ,. the product falls by slowly adding ice-cold methanol (50 ml) to the heating lieaCtion mixture, followed by a Cool off in the ilis bath. ± ian filtered off, wäaoht with cold ^ ethanol and dry in vacuo. Yield: o, 768 g (28 ^. F .: 32o ° 0.

Analysis: Calculated for G ₁₂ H ₀ O ₂ N ₄ : G, 59.96; H, 3.35; N, 23.32%; Found: G, 59.9o; H, 3.43; N, 22, lo #.

Example X

6-ghlorpyriiaido [_ 4, 5-b ^ quinoline-4 (3H) -one-2-carboxylic acid ethyl ester

A. 5-Chloro-2-aminoohinolin-3-carboxamide

Follow the procedure of Example IA with 2-amino-6-chlorobenzaldehyde (5.4 g, 0.035 mol), 2-cyanoacetamide (2.94 g, 0.035 mol), sodium ethoxide (3.04, 0.044 Mol) in ethanol (50 ml) produces the carboxamide given in the heading with a yield of 5.92 g (77 1 <>) . F .: 270-273 ° C (dec.).

3. 6-chloropyrimido / 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

The ethyl acetate (35o ml) and 5-chloro-2-aminoquinoline-3-carboxamide (5.9 g, 0.0267 mol) are heated together at 170 ° C. for 4 hours. The water and ethanol obtained as neo-product are distilled off from the reaction mixture. The dark reaction mixture is cooled, treated with hexane (300 ml) and filtered, lust the brown solid substance in methylene chloride / ethanol (1: 1), decolorized with charcoal and concentrated to a beige solid substance, which is recrystallized from methylene chloride-hexane and then further purify by chromatography on silica gel with methylene chloride-ethanol (9 '· 1) as the bluing agent. The product obtained by evaporating the jsluate is recrystallized from diethylene chloride-ethanol. The end-

AG 9 8 4 5/1 O 7 9

Prey: ο, 756 g (9.3 ^C / OP: 27ö - 279 ° 0 (dec.). Analysis: Calculated for Ο - ^. Η ^ ΟΙΝ, Ο ^ ί

C, 55.5o; H, 3.55; N, 13.87 ^ j Found: δ.55.03; H, 3.21; Π, $ 13.85>.

■ Example XI

Disodium salt of pyrimido ] - 4,5-P-7Ohinolin-4 (3H) -one-2-carboxylic acid

Pyrimido £ ~ A _t 5-b ^ quinolin-4 (3H) -one-2-carboxylic acid ethyl ester (5.0 g, o _f ol85 mol) to a 15 $ aqueous solution of sodium hydroxide (200 ml) and the stirred Mix for 20 hours at ambient temperature. The yellow solid substance that forms is filtered off from the reaction mixture, dissolved in water and the solution is adjusted to pH 7 by slowly adding 10% hydrochloric acid. The precipitate is filtered off, triturated with methanol and dried. The slurry is filtered, the filter cake is washed with methanol and dried. A yield of ^{4.0 g (73.4 c 1} o) of the disodium hemihydrate salt is obtained, i 1.: 345-347 ° C. (dec.).

Example XII

7-methoxypyrimido / ~ 4, 5-b-7 ^F quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A. oC-cyano-ß- (5-methoxy-2-nitrophenyl) acrylamide

Following the procedure of Example HA, 5-IIIethoxy-2-nitrobenzaldehyde is reacted to give the acrylamide derivative mentioned in the title. Yield: 86 j>. I ¹ .: 2o7-2o8 ° C (dec.)

B. o-alethoxy ^ -aminoquinoline ^ -carboxamide

The procedure described in Example H-B <? C-cyano-β- (5-methoxy-2-nitrophenyl) acrylamide is used to the corresponding ohinoline derivative. Yield: 79.5 76. M.p. 251-232 ° G (dec.).

C. 7-Methoxypyrimido / ~ 4,5-b-7 * quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

Using the procedure of Example H-G 6-i.iethox, y-

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2-a.ainoquinoline-3-carboxamide to the compound mentioned in the heading. Yield: £ 10. J ^1st : 263-264 ° C (dec.). -

Analysis: Calculated for ₁₅ H ₁₅ H ₅ O ₄ : C, 60.19; H, "4 £ 8; N, $ 14.04; Found" C, 60.28; H, 4.34;. N, $ 14.26.

Example XIII · ■ ·

8,9-Dimethoxypyrimido ^ ~ 4,5- "b-7-quinolin-4 (3H) -one-2 * carboxylic acid ethyl ester

The procedures of Example II-A-C are repeated, but instead of 6-nitroveratraldehyde, 2-nitrovertraldehyde (2.08 g) a. The yields and melting points of the intermediate and the end product are summarized below:

A. oL -Cyan-β- (2-nitro-3,4-dimethoxyphenyl) acrylamide: yield $ 64; Melting point 194-195 ° C.

B. 7,8-Dimethoxy-2-aminoquinoline-3-carboxamide: Yield 50 $; Melting point 219-219 ⁰ G.

C. 8,9-Dimethoxypyrimido / ~ 4,5-bJ7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester: Yield 3o #; Melting point 233-234 ° 0 (dec.).

Analysis: Calculated for G ₁₆ H ₁₅ N ₅ O ₅ : C, 58.35; H, 4.60; N, $ 12.76; Found »· C, 58.52; H, 4.47; N, 12,

Example XIV

7,8-Dimethoxypyrimido £ ~ 4r 5-b_7quinolin-4 (3H) -one-2-hydroxamic acid Add 7,8-dimethoxypyrimido /.""4,5-b_/quinoline-4("3H)-one-2 -carb'onsäureäthylester (2oo mg, 6.08 mmol) to a solution of hydroxylamine hydrochloride (69 mg, loo mmol) and triethylamine (loo mg, loo mmol) in absolute ethanol (50 ml), holds "the mixture over power in a bomb to 95 ° C and then cools down. The insoluble yellow solid substance is filtered off, washed with hot ethanol and dried. It gives 143 mg ($ 74) of the product named in the heading. F .: 337 ° 0 (decomp.)

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Example XV

7,8-Dimethoxy-pyrimidine / ~ 4,5-b-7-quinolin-4 (3H) -one-2-carbonic acid 2-hydroxyethyl ester

Trylamine (1 ml) is added to a slurry of 7,8-dimethoxypyrimidine [_ 4,5-b ^ quinolin-4 (3H) -one-2-carboxylic acid ethyl ester (500 mg) in ethylene glycol (5 ml). The mixture is stirred for 6 hours and then diluted with water (30 ml). The clear yellow solution obtained is acidified with acetic acid and the precipitate which forms is filtered off. Br is recrystallized from Ν, Ν-dimethylformamide (2o ml) while still moist. Yield: 285 mg ($ 53.5). F. * 252 ⁰ G.

Analysis »Calculated for ^^ Χ ^^ β ^{1 C} » ^{55 '65} * ^H » ⁴ ' ⁴⁸ * ^N » ¹² ^ - ⁷ ^ l Found »C, 55.35? H, 4.51? N, $ 12.39.

In the same way, the alkyl esters of the examples II-XIV, XVI and XIII-XXVI to the corresponding 2-hydroxyethyl. ester interesterified »The replacement of ethylene glycol with propylene glycol, Butylene glycol or 1,4-dihydroxybutane gives the corresponding Hydroxyalkoxy ester.

Example XYI

7-methylthiopyrimido / ~ 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A. <x-Gyan-β- (2-nitro-5-methylthiophenyl) acrylamide

A solution of the sodium salt of HethyMercaptan is made (2.78 g, o, o398 mol) in Ν, Ν-dimethylformamide (50 ml) by adding methyl mercaptan to a mixture of sodium hydride (I »67 g of 57% HaH) in Ν, Ν-dimethylformamide (50 ml) pearls leaves. The reaction mixture is cooled by means of an ice bath until the reaction has ended.

Then the sodium methyl mercaptide solution is added dropwise a mixture of oC-cyano-β- (2-nitro-5-chlorophenyl) acrylamide (Io g, o, o398 E) in Ν, Ν-dimethylformamide (35 ml), which is

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bathroom is cooled. The mixture is stirred for one hour, then removed from the ice bath and stirred for a further 2 hours. The reaction mixture is then poured into water (600 ml) and the mixture obtained is stirred thoroughly. Ether (30 ml) is added, the bodice is filtered off, washed with ether and dried. Yield: 8.4 g. i ^1st : 227r229 ° G.

B. 6-ulethylthio-2-aminoquinoline-3-arboxamide

The o (-uyan-β- (2-nitro-5-methylthiophenyl) acrylamide is heated (-ö, 4 g, o, o32 mol) in a 1: 1 mixture of acetic acid and Ιί, ϊί-Ijixiiethylformamid (llo ml) in a bath at 75 ° C. One gives

, to

Iron powder (2, ο g) / and stir the mixture until the internal temperature rises to 95 0, add more iron powder (a total of 6.16 g iron = 0.146 mol) in small doses over a period of 15 minutes, stir the Reaction mixture for one hour after the end of the addition and then filtered hot. The iron residue is washed with hot acetic acid and the J filtrate and the washing solution are poured together into 1N hydrochloric acid (200 ml). The precipitating hydrochloride salt is filtered off and dissolved in hot, dilute aqueous sodium hydroxide. Which separates out when cooled yellow solid substance is filtered off, what has been with isopropyl alcohol "and air-dried. Yield:. 3.26 g (44 $) 229-242 ϊ.ΐ ⁰ O.

This product is used in process stage G without further purification used.

G. 7-Methylthiopyrimido / ~ 4 »5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

In a round-bottomed flask with stirrer, probe, thermometer and Dean-Stark pallet, which contains a mixture of 6-lethylthio-2-aminoquinoline-3-carboxamide (l, above, 4.3 mLlol), diethyloxalate (2o ml) and xylene (15 ml) is converted into a. Immersed in an oil bath at 2oo ° G. Xylene, water and ethanol are distilled off from the reaction mixture until the internal temperature of the mixture reaches 165 ° G. Then, the mixture is stirred for 3 hours at 165 ⁰ G and poured

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then in chloroform (40 ml). After this. Cool down to room temperature the mixture is filtered. The brown filter cake is air-dried and then slurried in hot chloroform (loo ml) to which activated charcoal is added. the Slurry is filtered hot and the filtrate evaporated to half volume and chilled in ice. Which The yellow precipitate that forms is filtered off and air-dried. Yield 142 mg (11%). F .: 24o-242 ° C.

Analysis: · Calculated for C ₁₅ H ₁₅ N ₅ O ₅ SrG, 57.2; H, 4.16; N, 13.3fr; Found: C, 56, -72 j H, 4.13? N, 13.22> £.

Example XYII

7-Methylsulfynylpyrimido / ~ 4,5-b-7bhinolin-4 (3H) -one-2-carboxylic acid ethyl ester

A solution of 7-ethylthiopyrimido / T ~ 4,5-b_7 is heated Quinolin-4 (3H) -one-2-carboxylic acid ethyl ester (315 mg, 1 mlol) in i'rifluoroacetic acid (2. ml) in an oil bath at 55 ° C. Jlan there Hydrogen peroxide (113 mg of 3o # HpOp, 1 mHol) is added and stirs the solution Io Minucen. After cooling to room temperature absolute ethanol (6 ml) is added! the received yellow precipitate is filtered off, washed with ether and air-dried. Recrystallization from absolute ethanol results in 1Ö5 mg (56> ό) of the product. F .: 257-259 ° C.

Analysis: Calculated for C ₁₅ H ₁₅ N ₅ O ₄ Si C, 5.4.4; H, 3.97} N, $ 12.7 \ Found "" C, 54.23; H, 3.97; N, $ 12.69.

Example XYIII IyI ^ t β-dimethoxypyrimido / ~ 4,5-b.7-quinolin-4 (3H) -one

Concentrated sulfuric acid (1.5 ml) is added to a slurry of 6,7-I> iJiethoxy-2-aminoquinoline-3-carboxamide (5, o g, o, o2 mol) and acetic anhydride (4o ml). The Aufscülämmung dissolves to a dark-orange solution from which a heavy yellow precipitate separates out. One gives Acetic anhydride (Io ml) to make stirring easier and continues heating for an additional 75 minutes. x »ann one cools

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the mixture, add water (50 ml) and make the obtained Make the solution alkaline by adding 5 normal sodium hydroxide solution (225 ml). It is then cooled, the precipitate is filtered off and dried in the air. The yellow solid substance is made from ethanol recrystallized. Yield: 2.37 g. F .: 300-3002 ° C (dec.).

Example XIX

2-ethyl-7,8-dimethoxypyrimidine £ ~ 4 , 5-b.7ohinolin-4 (3H) -one

A mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (500 mg, 0.02 M) in propionic anhydride (10 ml) at 60 ° C., concentrated sulfuric acid (0.5 ml) is added with stirring. The reaction mixture is stirred for one hour, cooled to room temperature and added to water (25 ml). The watery one The mixture is stirred and made basic with 6 normal sodium hydroxide solution. The mixture is then stirred overnight and acidified then with lo ^ iger hydrochloric acid up to a pH value of 5, o. The yellow precipitate that forms is filtered off and recrystallized from ethanol. Yields 283 mg. F .: 29o-291 ° C (Zersi A second crop of the product is obtained by separating

Both
rend of standing. / from interpretations are united and:

recrystallized from chloroform / ethanol (1: 1). Yield: '. 225 mg (39 #). F. " 293 ° C. ":

Example XX 'j

2-acetyl-7,8-dimethoxypyrimido / ^ 4,5-b_7-quinolin-4 (3H) -one

A solution of selenium dioxide (24.5 mg, 2.2 mmol) in dioxane water (11 ml in a ratio of 10: 1) becomes 2-ethyl-7,8-dimethoxy-pyrimide® /. "4.5 -b_7 "quinolin-4 (3H) -one (125 mg, 4.4 mmol) added, the mixture is heated to reflux for 48 hours, and then" more selenium dioxide (24.5 mg) is added and under reflux held \ further 24 hours. the mixture is cooled, the selenium is filtered off, and the filtrate is concentrated to dryness. the residue is dissolved in ethanol / chloroform (1 t 99) was added and when on a silica column using the! calibrate solution Eluent (25 ml) followed by

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Ethanol / chloroform (2:93), chromatographed. Am concentrating the second eluate (625 ml) gives a yellow solid substance (23 mg). P. 3oo ° G (decomp.).

Example XXI

5-phenylpyrimido £ ~ A, 5-b ^ ohinolin-4 (3H) -one-2-carboxylic acid

ethyl ester

jiiirie mixture of 2-amino-4-phenylquinoline-3-carboxamide (263 mg, l, o mmol), oxalic acid diethyl ester (5 ml) and acetic acid (5 ml) is heated to reflux for eighth, then cooled with ether (50 ml), and then the brown solid substance which forms is filtered off, the Mltrat is evaporated in vacuo and the oily residue is saturated with a aqueous Sodium bicarbonate solution digested. The obtained solid substance (Ho mg) is filtered and recrystallized recovered from hot ethyl acetate (8 ml). A small amount of insoluble Material is filtered off from the hot solution. JWhen cooling, the product named in the heading is separated crystalline from (25 mg). P. 1 255 ° C (decomp.).

Analysis: Calculated for ο ₂ Ο ^Η 15 ^Ν 3 ° 3 * ^{Cf 69} ' ^{55j E} ' 4t38 | ^{Έ> 12} Found: ^ C, 69.94 * H, 4.31; N, 12

+) Mean values from two analyzes.

Example XXII

3-methyl-7,8-dimethoxypyrimido / ~ 4,5-b-7-quinolin-4 (3H) -one-2- carboxylic acid ethyl ester

Disodium hydride (47o mg of a 50% oil solution, o, oll mol) is added to a suspension of 7,8-l) imethoxypyrimido / 4,5-b_ [7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester (3 »3 g, o, ol mol) in Ü, N-Dimethylformaiaid (75 ml). The mixture is stirred, heated on a steam bath for 10 minutes and then kept at ambient temperature for half an hour. It is cooled in an ice bath and iodomethane (2.1 g, 0.05 M) is added dropwise over the course of 30 minutes. When the addition is complete, the mixture becomes more

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The reaction mixture is poured into ice water (2oo ml) and the solid substance obtained is filtered off, air-dried and recrystallized from ethanol. Bs are 2.1 g of yellow crystals obtained ( $ 61.2>). P. » 211.5 ⁰ O (dec.)

Analysis: Calculated for C ₁₇ H ₁₇ N ₅ O ₅ : C, 59.47; H, 4.99J 'N, 12.24 / *; Found C, 59.55; H, 5, o2; II, $ 12.45.

Example XXIII

5-Oarbäthox ymethyl-7, e-dimethoxypyri; Qiido / 4,5-b-7-quinolin - 4 (5H) -one-2-carboxylic acid ethyl ester

To a slurry of 7,8-dimethoxypyrimido [_ 4 »5-b_7chinolin-4- (3H) -one-2-carboxylic acid ethyl ester (1.6 g, 5" ο mmol) in ^^ - dimethylformamide (3o ml) is added sodium hydride ( 235 mg, 5.5 mmol in 56/6 solution) "is added, and the slurry is heated on a steam bath for 10 minutes and then cooled to room temperature. Ethyl bromoacetate (968 mg, 5 mM) is added and the reaction mixture is heated one hour on a steam bath.After it has been left to stand at room temperature over itfold, the mixture is diluted with v / ater (75 ml), the yellow solid substance obtained (1.4 g) is filtered off and chromatographed on a silica gel column with chloroform as Purified solvent and eluent, evaporate the blood (300 ml) to give 1.2 g of a yellow solid which is recrystallized from hot ethanol containing enough chloroform to make a solution 900 mg of loose yellow crystals (43 »4 ⁰ Jo) obtained. .JP. 1 19ö- 199 ° above sea level (decomp.).

Analysis: Calculated for C ₂₀ H ₂₁ N ₃ O ₇ : C, 57.63} H, 5, lo; N, lo

Found: C, 59.67; H, 4.99; N, 9.9o #

Example XXIV

Ethyl 3- (3-carbethoxypropyl) -7, a-dimethoxypyrimido ff, 5-b-7-quinoline-4 (3H) -one-2-carboxylic acid ethyl ester

A09845 / 1079

The procedure according to example * XXIII is repeated after with ethyl 4-bromobutyrate (1.1 g, 5.8 mmol). instead of the ethyl acetate. Pie "when diluting the reaction mixture with wet The solid substance obtained is filtered off, dried and recrystallized from benzene / hexane (40 ml of a 1: 1 mixture), whereby 615 mg (29.1 / 6) of the compound named in the title are obtained as loose yellow crystals. F .: 144-146 0.

Analysis: Calculated for ^ ₂ 2 ^Η 25 ^Ν 3 ° 7 ^{ι G} ' ⁵⁹ ' ^5b * ^H »5.6öj N, 9.48 ^; Found: G, 59, Ö4 | H, 5.98; Ii, 9.61 ^.

Example XXV

3-Aoetoxyäthyl-7,8-diaiethoxypyrimidi'n [_ 4,5-b-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester

The procedure of Example XXIII is repeated, but with bromoethyl acetate (969 mg, 5.8 mM) as the alkylating agent instead of the ethyl bromoacetate. The solid product, which separates out when the reaction mixture is diluted with water, is filtered off, dried and recrystallized from ethanol (20 ml), which contains sufficient acetonitrile to achieve a solution. Yield: 55o mg (26.5 fi. I ¹ .: 195-196 ⁰ G (dec.).

Analysis: Calculated for C ₂₀ H ₂₁ N ₅ O ₇ : C, 57.83? H, 5, loj U, lo Found: C, 57.95j H, 5.14j N, 1o

EXAMPLE XXVI

Benzo /, g_ / quinazolin-4 (3H) -one-2-carboxylic acid ethyl ester

A. Benzo-isatoic anhydride ("benzo-isatoic anhydride")

Anthranilic acid (25, ο g, o, 133 Hol) is - if necessary under Warming - dissolved in a mixture of water (50 ml), concentrated hydrochloric acid (50 ml) and dioxane (100 ml). In this solution phosgene is introduced with thorough stirring so quickly that bubbles of the gas are slowly released into an ammonia tank weicnen attached to the reaction flask. The temperature is kept below 50 ° C by increasing the speed of the

409845/1079

Controls phosgene supply. After phosgene has been introduced into the dilution for 4 hours, the phosgene residue is blown out by passing air through it, the mixture is cooled and the product is filtered off, washed with cold water and dried, as earth 26.46 g (93.570) of the anhydride obtain. jp. i ; 59o ° J (dec.).

jb. 2-aminoaphthalene-3-carDoxamide

«Ian let ammonia bubble two layers long intermittently into a suspension of benzoisatoic anhydride (5, above, 2.25 mulol) and ethanol (.10 ml). The purple-green, solid southern substance that forms is filtered off from the reaction vessel, dried, and recrystallized from ethanol. Yield of the amide mentioned in the literature: 1.95 g (46%). ¥ .: 254-235 ° 0 (m / e = 186).

ΰ. -üenzo £ g_ / quinazolin-4 (jH) -one-2-carboxylic acid ethyl ester

Ethyl oxalate (2.35 g, 16.1 mmol), sodium methoxide (10 mg) and 2-aminonaphthalene-3-carboxamide (1.5o g, 8.05 mol) are mixed with one another and refluxed for two days. The mixture is then cooled in an ice bath, the brown precipitate is filtered off and 1.76 g (79% yield) of the desired iilster are recrystallized from ethanol. J ^1st : 24o-242 ° C.

Analysis: Calculated for ₁₅ H ₁₂ N ₂ O ₅ : C, 67.15; H, 4.51j N, 10 found :. C, 65.44; H, 4.5o; N, lo

D. The ester is hydrolyzed to the disodium salt as follows:

i.ian Giot the iiister (I, o5 g, 3.92 mi) to 15'Mgem aqueous i ^ atriumhydroxid (2o ml) and the mixture stirred for two days. then acidify it at skin temperature with 10/6 hydrochloric acid up to a pxi - »/ ert 2 and evaporate it to dryness under reduced pressure. The residue is treated with ethanol (water 1: 1, 50 ml) and the suspension is filtered; 0.7o g of yellow crystals result. These crystals are placed in a saturated solution of aqueous jiatrium bicarbonate (35 ml) and water (20 ml), the mixture is stirred for half an hour

A098A5 / 1079

filter off the yellow solid Suostanz and dry it. Yield: ο, 641 g of C54.7 ρ). i ^1st : 34o ° C (dec.).

Analysis: Calculated for C ₁₅ HgN ₂ O ₅ J & a.2HgOi

G, 51.31? H, 3.28; N, 9, o6; Na, 14, Io - / «; Found: G, 51.34; H, 3, o5; N, 9.24; Na, 11.14> i.

Example XXVII Pyrido / 7 ~ 2,3-d ^ pyriiaidin-4 (3H) -one-2-carboxylic acid ethyl ester

A mixture of diethyl oxalate (53o mg, 3.65 HL) and 2-aminonicotinainide (500 mg, 3.65 ml) is heated under reflux, the mixture is then cooled in an ice bath and the yellow precipitate is filtered off , which is recrystallized from benzene / hexane (1: 1). Yield: 196 mg (3o>). F. " 19Ο-192 ⁰ G.

Analysis: Calculated for G ₁₀ HqN ₅ O ₅ IC, 54.79; H, 4.13; N, 19.17 ^ \ Found: G, 54.86; H, 4.11; K, 19.33 / 0.

vie hydrolysis of iOsters according to the procedure of Example XXVI-D gives the acid and the Dinatriuiasalz.

Example XXVIII

2-Ethylpyriaido £ ~ Z, 3-d_7pyrimido-4 (3H) -one

It is concentrated sulfuric acid (o, 5 ml) g to a ilischung of 2-amino, cotinamid Co, 24 o, oo2 mole) in propionic anhydride CIo ml) at 60 ⁰ G and the resultant mixture is stirred for one hour, cooled then to room temperature and pour it into wet (25 ml). The aqueous mixture is stirred, made basic with 6N sodium hydroxide solution and again roasted overnight. When acidifying with lo ^ iger hydrochloric acid to pH "5, ο the desired product precipitates, which is filtered off and dried.

409845/1079

Example XXIX Injectable preparation

One veriaiscnt and marries looo g of pyrimido / 4,5-b_7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester intimately with 2500 g of sodium ascorbate, the ground, dry jasching is filled into vials and sterilized with ethylene oxide, after which the vials are sealed sterile. I ¹ for the intravenous application is sufficiently "wet added to the öuostanzen in the vials that e-ine solution having 5, ο mg active ingredient per ml of injectable solution is obtained.

Example XXX Tablets

A tablet base material is prepared by using the following Components in the specified weight percentages mixed:

Cane sugar, USP 8o, 3

Tapioca starch 13.2

Magnesium stearate 6.5

A sufficient amount of 7,8-dime is mixed into this ubiquitous base material thoxypyrimido- / ~ 4,5-13-7-quinolin-4 (3H) -one-2-carboxylic acid ethyl ester one that results in tablets with 20, 100 and 25o mg of the active ingredient per tablet. The compositions are compressed by conventional means into tablets, each bending 36o mg.

Example XXXI

Capsules

A mixture is made from the following components:

Calcium carbonate, USP 17 * 6

l'icalcium phosphate Ib, 8

Magnesium trisilicate,

USP 5.2

Lactose, USP 5.2

Potato starch 5.2

^ 09845/1079

- 54 - 2418498 0.0 Liagnesium stearate A 0.55 Magnesium stearate B

Sufficient 7,8-Mmethoxypyriinido is added to this mixture / _ ~ 4 »5-l3_Zcixinolin-4 (3H) -one-2-carboxylic acid ethyl ester to that capsules with Io, 25 and 5o mg of the active ingredient per Capsule. The compositions are filled into conventional hard gelatin capsules at 35o mg each.

Example XXXII Bus boarding

j ^ ine suspension of pyrimido [_ 4,5-b; _7-quinolinT-4 (3H) ~ one-2-carboxylic acid is prepared in the following composition:

Active ingredient 25 »oo g 70 $ Aqueous Borbitol 741.29 g Glycerin, USP 185.35 g acacia gum

(lo ^ ige solution) Ιοο, οο ml Polyvinylpyrrolidone 0.5o g of distilled water sufficient to make 1 liter

to manufacture.

Various sweeteners and flavor enhancers are added to this suspension too, to make them more palatable. The suspension contains approximately 25 mg of the active ingredient per ml

■ Example XXXIII solution

A solution of 2-ethylpyrimido / 7 * 4, 5-b__7-quinoline-4 (3H) -one-2-carboxylic acid ethyl ester is produced in the following composition:

active ingredient 6, o4 g magnesium chloride

hexahydrate 12.36 g

4098Α5 / Ί079

_ionoethanolamine 8.85 ml propylene glycol 376, oo g distilled ./water ^- 94, oo ml.

The solution obtained has a concentration tone that is effective Component of Io mg / ml and is suitable for parenteral and especially intramuscular administration.

Example XXXIV Aerosol suspension

Mixture of 7,8-dimethoxypyrimidine / 4,5-b-7-quinolin-4

(3H) -one-2-carboxylic acid ethyl ester (antiallergic agent) and the other substances given under (a) in the following examples are converted into a particle size in a ball mill grind from 1 to 5 / µm. The resulting slurry is introduced into a container provided with a valve and aas! 'friction agent (b) under pressure through the valve nozzle to

to an overpressure of about 2.46-2.81 kg / cm (35-4o psi) Filled at-2o ° G.

(a)

(b)

Suspension A percent Antiallergic 0.25 Isopropyl myristate o, Io Ethanol 26.4o 6o-4o56 mixture of
1,2-dichlorotetrafluoro-
ethane /
1-ühlörpentafluor-
ethane 73.25 Suspension B Antiallergic o, 25 Ethanol 26, 5o

(a)

(b) 6o-40% mixture of 1,2-dichlorotetrafluoroethane /

1-chloropentafluoroethane 73 ^ 25

409845/1079

Example XXXV Administration as an aerosol

An aqueous solution of ethyl 7,8-dimethoxypyrimido / ~ 4,5-b_7 quinolin-4 (3H) -one-2-carboxylic acid (agent A with 3 mg of substance per ml of solution) is placed in a normal nebulizer, as it was from the J? a. Yaponephrine Co., Edison, N.J.

is. The solution is under an air pressure of 0.42 kg / cm (6 psi) in a sealed plastic container measuring 2o, 3 x 2o, 3 x 3o, 5 cm (8 χ 8 χ 12 inch) for 6 minutes brought in. Jier container has four openings that cover the heads of "four had ingesting. Four rats are given the means each exposed at the same time, with only their heads coming into contact with the aerosol. As a comparative substance Disodium chromoglycate used (agent B, 50 mg / ml). The in The results obtained from the PCA test are presented in the following Table specified:

Mean Concentration Period between Ver Percentage

3 mg / ml administration of the agent the gun- 3 mg / ml and the immunity test th iDiere A. 5o mg / ml O min. 82 A. 5o mg / ml 5 min. 56 B. O min. O B. 5 min. O

Claims

409845/1079

Claims (1)

P 805 Claims Compound selected from the group with the formulas III and the pharmaceutically acceptable cationic salts thereof, wherein R is selected from the group consisting of methyl, ethyl, acetyl and COH ⁰ and Ä ° is selected from the group consisting of hydroxy, alkoxy, hydroxyalkoxy, amino and hydroxyamino, Ϊ is selected from the group consisting of (a) Hydrogen and (b) alkyl, carbalkoxyalkyl, oxyalkyl, - (CHg ^ -O-CO-CgH, - and - (CH ₂ ) -0-alkanoyl groups, where, when, R is methyl or ethyl, Y is selected from of group (b) is selected, and when R is COR ⁰ with R ⁰ 5 = amino or hydroxyamino, Y is hydrogen, where 409845/1079 furthermore m = 2 "to 4, E-, is selected from the group consisting of hydrogen, alkyl and phenyl, R ₂ » IU, B ₇ , and R, - each from the group consisting of hydrogen, alkyl, alkoxy, halogen, benzyloxy , Methylthio and Ilethylsulfinyl are selected, where Rp ^ ¹³³ · ^ ^ v ^ -3 ^urL ^ · ^ a » ^{when taken} together, are selected from the group consisting of methylenedioxy and ethylenedioxy. 2. Compound according to claim 1, formula I. 3. A compound according to claim 2, in which R- ,, Rp, R ,, S., Y and Rf- are each hydrogen and R = alkoxy. 4. A compound according to claim 2, in which R- ,, R ₂ , R ^ and Y are each «hydrogen and R ⁰ , R ₅ and R. are each alkoxy. 5. A compound according to claim 2, wherein R - ,,. Rp, R ₅ and Y are each hydrogen, R ⁰ is alkoxy and R, and R- taken together are alkylenedioxy. 6. A compound according to claim 2, in which R ₁ , R 1, R _t, Y and Rc are each hydrogen, R is amino and Rp is chlorine. 7. A compound according to claim 3, in which R ⁰ = ethoxy. 8. A compound according to claim 4 _f in which R ⁰ is ethoxy and Rrz and R. are each methoxy. 9. "A compound according to claim 5" in which R ⁰ is ethoxy and R, and R., when taken together, are Ilethylenedioxy. 10. A compound according to claim 1, formula II. 11. A compound according to claim Io, in which Rp, R-, and R. are each hydrogen and R ^{0 is} hydroxy. 12. A compound according to claim Io, in which Rp = hydrogen, R ^ and R4 are each alkoxy and R ⁰ = hydroxy. 409845/1079 2A18498 Ij,. A compound according to claim Io, _{wherein R 2} and IU are each hydrogen, R 1 is fluoro and R ^{0 is} alkoxy. 14. Connection to. Claim 12 wherein 'R, and R ^ each iiethoxy are. 15. Compound according to claim 15, in which R ⁰ = methoxy. 16. A compound according to claim 1, formula III. 17. A compound according to claim 16, in which R ₂ , R, and R- are each hydrogen and R ⁰ is alkoxy. lü. A compound of Claim 16 wherein Rp is hydrogen 'and R ⁰ , R ^ and R are each alkoxy. 19. The compound of claim 16, wherein Rg is hydrogen, R, and R are each alkyl and R ^{0 is} alkoxy. 20. The compound of claim 17, wherein R is ethoxy. 21. A compound according to claim 18, wherein R ^{0 is} ethoxy and R 1 and R are each methoxy. 22. The compound of claim 19, ^{wherein R 0 is} ethoxy and R ^ and R ^ are each methyl. 23. Fused pyrimidine, essentially as before 'described. 24. Pharmaceutical agent for use as an antiallergic, characterized in that it consists of a compound, which is selected from the group with the formulas 409845/1079 III and the pharmaceutically acceptable cationic salts thereof, where R is selected from the group consisting of methyl, ethyl, acetyl and GOR ⁰ and R ^{0 is selected} from the group consisting of hydroxyl, alkoxy, hydroxyalkoxy and hydroxyamines, Y is selected from the group consisting of ( a) hydrogen and (b) alkyl, jarbalkoxyalkjrl, carboxyalkyl, - (GHp) -U-UO-GgHc and - (GHp) -0-alkanoyl is selected with the proviso that Y = hydrogen when R ^{0 is} amino or hydroxyamino, where v is furthermore equal to 2 to 4, R-, is selected from the group consisting of hydrogen, alkyl and phenyl, Rp, R ^, R. and R ₁ - each from the group consisting of, as he material , Alkyl, alkoxy, .halogen, .benzyloxy, ^ ethylthio and methylsulfinyl-best G group are selected, and .vobei R ₂ and R-, and R-, and R ,, -Neiva taken together, from that of iiethylenedioxy and ütnylenedioxy Groups are selected as long as it consists of a pharmaceutical excipient, "with the antiallergic linear substance in one, _r ; e from about 0.5 to about 35 / o of the weight of the material is present or the compound is present in the form of a specific pnarjiaceutical xjusification period. 25 ·, littel n ^ cli j ^ nspruch 24, daöarcii sj aali dar antiailei'f.'ibcne. iricstoff a </: r bond of the formula I. 409845/1079 26 .. Means naoii claim 24, characterized in that ₂ , Y "and K ₁ - each hydrogen, R, and R. each group and K is a methyl group. 27. Uittel according to claim 24, characterized in that ii,, K ₀ , I and K, - jev / eils »hydrogen, £ U and K, each one and K = OQR with K as ethoxy group. 2ö. Pharmaceutical agents according to claim 24 in one suitable for administration by inhalation. 29. Pharmaceutical agent according to claim 24 in lorm a solution or suspension of the antiallergic active ingredient in. ”'ater. 3Ü. Iriiaria pharmaceutical mitoel according to claim 24 in the form a suspension of the antiallergic / active ingredient in a liquefied one propellant. ^ l. Pharmaceutical xditcel according to claim 24 in the form of the solid antiallergic agent in a solid diluent. yi, xj.it uel according to claim 24 in the form of a tablet. y $. i, iit "cel according to one of claims 24 to 31, in which the aarin contained compound is one according to claim Dr. Ve / Jja 409845/1079