DE1670533A1 - 5,8-dihydro-5-oxopyrido- [2,3-d] -pyrimidine derivatives and processes for their preparation - Google Patents

Description

and methods of making them

The invention relates to novel 5,8-dihydro-5-oxopyrido- ^ 2 _f 3-d7-pyrlmidinderiTate or gate products which have antibacterial activity against green-positive and graanegatite bacteria, as well as a process for their production.

The connections produced according to the invention have a high level of activity against important path sheets Bacteria, especially graanegatire bacteria such as Shigella, Saleonella and Hebiiella.

The connections made according to the invention can be used for the treatment of bacterial infections in humans and animals «white

00984SM851 BATH ORIGINAL

After that, the connections are in the fields of food medium and useful for agriculture.

In the case of the]! novel Compounds are 5 »8-dihydro-5-oxopyrido- - [2,3-d] -pyrimidine derivatives of the following general ones formula (IV); .

O »

CfOOR.

in the! formula, B means>. Hydrogen or a lower one Alkyl radical, Bg means hydrogen, a lower alkyl radical, a · hydroxyl group, "in Halogenato", a lower alkoxyreatte, an · aaino group or a lower alkylthio radical, H, means Waaaeretoff, a lower alkylreat, • a hydroxyl group, a, lower alkoxyreat, a lower alkylthio group or ¹ «in the radical of the formula -N <^^ h, wöbet H ¹ Waeserstöff, an alkyl radical, a cycloalkyl radical, a minoreate is a hydroxyalkyl radical or an alkyl substituted amino alkyl radical, R" for hydrogen or a llkylreet, B * and R ' ^{1 are} identical or different and R ¹ and R "can be connected to form a hetero-> cyclic ring, and R ^ means'

Waferstoff

or an alkyl group.

0098ΑΙ / 1 · 5Ι

BATH ORIGINAL

A lower alkyl radical of the definition used here is a straight-chain or branched one Alkyl radical with 1-6 carbon atoms; a lower alkoxy group and a lower alkylthio group of those used here Definition is an Alkoxyrest.bzw. an alkylthio radical of 1-6 carbon atoms each corresponding to the above mentioned lower alkyl radical.

The compounds of formula (IV) sometimes form organic amine salts in the position of R 1, and those according to the invention Compounds of formula (XV) prepared include such salts.

With regard to the remainder Rn represent hydrogen, a lower alkyl group, a hydroxyl group or a halogen atom represent preferred groups compared to other Ro radicals; as the alkyl radical of the group R ^ is a lower one Alkyl radical preferred.

So far, compounds which have other substituents in the 5-position and the 6-position on the same Hingst rulctur have been given as antibacterial agents. Typical examples of these known compounds are: that described in Belgian patent 658 069 Compound of the formula below

009846/1851 BAD ORIGINAU

in which R ,, denotes an alkyl radical having 1-4 carbon atoms, Rp is hydrogen or an alkyl or arallcyl radical having 1-4 carbon atoms and R _x . and R ^ can be linked to form a divalent alkylene bridge; the compound of the formula below described in Belgian patent specification 657 922

Alkyl group
in which R is an alkoxy or / with 1-4 carbon atoms

means; and

that described in British Patent 970,583

Compound of the following formula

in which R is an alkyl, phenalkyl or alkyl-substituted phenoyl group.

The ring structures common to these known connections are formed by similar measures. If , for example, the connection of Belgian patent specification 657 992 is used as an example, the

809846/1861

BATH ORIGINAL

Manufacture by. Halogenation of 3-tert-aminoaerolein the following formula

in the ABH is a tertiary amino group and R is an alkyl or alkoxy radical with 1-4 · carbon atoms, and heating the halogenated 3-tert-aminoacrolein with 2,4-, 6-triaminopyrimidine.

In the case of the method according to the invention prepared compounds of the formula (IV) and the compounds of the formula (III) given below, the Represent precursors of the compounds of the formula (IV) and in connection with the description of the invention intended mode of operation are explained in more detail, they are new, not previously known Links. The compounds of formula (IV) are better because they have a particularly high anti-microorganism activity show to many pathogenic microorganisms, and their production is easy.

Furthermore, in Belgian patent 612 258, a compound A of the formula given below has been described as an antibacterial gown of high activity. However, this connection has a different

009846/1861

BATH ORIGINAL.

kingstrulctur than the compounds prepared according to the invention.

Il

-COOH

(A)

It is true that this compound is one of the excellent antibacterial agents, but it has lower in vitro antibacterial activity and higher toxicity than the compounds according to the invention. For example, show ö-carboxy-SfS-dihydro ^ -dimethylamino- ■ 8-ethyl-5-oxo-pyrido ^ 2,3-d7-pyrimidine (compound B) and 6-carboxy-5,8-dihydro-8-ethyl 2-methylthio-5-oxo-pyrido- £ "2,3" Ä. _tm 7- ^ yTlmLain _t both of which belong to the compounds according to the invention, excellent antibacterial activities against a wide range of pathogenic microorganisms, as can be seen from Table III below, and the minimum inhibitory concentration MIC of compound (B) has that of Io mcg / ml against Staphyloooocua aureus, while the known compound (A) has a MIC-TTert of 100 mog / ml against the same organ! Emus.

00IIU / 1II1

BATH ORIGINAL

If one further compares the toxicity (3ADc _o ) of the "known compound (A) with that of the compound (B), it can be seen from the results listed in Table I below that the compound prepared according to the invention in terms of toxicity in comparison with the known antibacterial agent has excellent properties.

Tabel I. acute toxicity at Mice

Tested for survival (survived / tested)

Dose 'intraperitoneal p »o. Injection (ip »)

Compound (A) 1 g / kg 0/5 5/5 Compound (B) 1 g / kg 4/5 5/5 Observation on the seventh day after the administration.

The invention is accordingly based on the object of creating novel compounds with excellent antibacterial activity and a process for the preparation of these compounds. Further features and technical advantages of the invention emerge from the following drilling friction

Two examples of the novel compounds of the formula (IV) prepared according to the invention, which are listed under the

009846/1851
BAD ORlOINAU

Preferred from the point of view of a "wide range of application and an excellent medicinal effect are (i) 5, S-dihydro-5-oxo-pyrido- _< / ~ 2,3-d_7-pyrifflidine, in which in the formula (IY) R- , consist of hydrogen and R, consist of an alkyl radical, and (ii) 5,8-dihydro-5-oxo-pyrido- - ^ f * 2,3-d_7-pyrimidine, in which R-, and R. consist of hydrogen or a lower alkyl group and R ^ from a lower alkylthio radical or -1T <^ "(where R ^f and R" have the meaning given in formula (IV)). If, in the case of compound (ii), R ₁ consists of hydrogen and R 1 consists of an alkyl radical, the compound becomes an embodiment of case (i) with a further restriction with regard to

The following is the process for preparing the novel compounds of high antibacterial activity further explained.

The new compounds according to the invention can by ring closure when the intermediate products are heated Formula (III) given below, which are also novel compounds, are easily prepared will. A lI- (6-? Yrimidinyl) -aminomethylene malonic acid Derivative of formula (III) can be produced by two methods will; these can be seen from the following scheme:

009848/1851

BAD ORJGlNAt

(I)

Method b

ν R

^ CG CH

(ID

CH NH

(II)

(III)

(IV)

have H ₁ I »2» * j «Λ of the formula '(IT) · ηβ« § · 1> · 8 * ιι

914i / _f 1161

BADORJGfNAL

a lower alkyl group and Z represents a halogen atom.

To obtain the compounds of the formula (IV), an aminopyrimidine derivative, as it is represented by the above formula (I), can be reacted with a JUkoxymethyleneraalonic acid derivative, as it is represented by the above formula (II) ₄ 1 (method a), or a halopyrimidine derivative of the formula (I ¹ ) can be reacted with an aminomethylene malonic acid derivative of the formula (II ¹ ) by method b to form the novel precursors or intermediates of the formula (IH), and

the formal (IVl,
then this connection / ^ to bring about ring closure

heat·

The reaction of process route a can be carried out by heating the compound of the formula (I) and the compound of the formula (II) as such or in an inert solvent, such as alcohols or dioxane. The reac tion temperature is 80 to 150 ⁰ C, preferably 100 - 15O ⁰ C.

The ₁ reaction, the manufacturing method b. can be carried out by heating the compound of the formula (I *) and the compound of the formula (II ¹ ) in a closed tube. This reaction can also be carried out in its entirety

a solvent · The reaction is preferably carried out in an inert solvent such as an alcohol or dioxane. The reaction temperature is preferably within the range of aβ - O ⁰

00 · Ι46 / 1Ι81

BAD ORIGlNAU

The obtained R- (6-Ityrimidinyl) -aminomethylenmalonsäurederivat of the formula (III) is a novel compound, which by heating easily into a 5,8-Dihydro- -5-oxo-pyrido- ^ 2,3-d_7-Py ^r i ^mi ai ⁿ of .Formel (IV) can be converted; this induces a ring closure reaction.

The ring closure reaction of the compound of formula (III) to the compound of formula (IV) can be carried out in the absence of a solvent. Preferably will the reaction, however, in the presence of an inert organic solvent, e.g. ethylene glycol monoalkyl ether, diphenyl ether and mineral oil, with heating oil. As inert Organic solvents are preferred which have a boiling point in the vicinity of the reaction temperature. Preferably, the reaction is carried out using such a solvent under reflux conditions. The reaction temperature has a wide range from relatively low temperatures to comparatively high temperatures, in consideration, usually will be at a Temperature of 100-3oo ° C and preferably in the region of 200 ° C, about 25o ° C, worked.

The reaction product obtained can be purified by recrystallization according to conventional methods for what, depending on the requirements of the individual case

009846/1851

BATH ORIGINAL

a suitable solvent such as methanol, ethanol, chloroform, butanol and acetone is used.

If in the connection manufactured according to the invention of formula (IV), i.e. the SjS-Dihydro-S-oxo-pyrido - ^ / S ^ -d / - -pyrimidine derivative, the group R. in the 8-position from hydrogen exists, it can be assumed that this new compound acts as a keto-enol-like tautonery with oxygen in the 5 position. It can be seen that the formula (IV) includes such a case.

Further, according to the invention, it is possible to establish a connection of formula (IV) to convert into another compound of the same general formula. Below are the main forms of implementation of the procedure according to the invention further illustrated.

(1) A compound of the formula ClV), in which R- from There is hydrogen, i.e. a free one in the 6-position Carboxyl group is bonded can be easily obtained by creating a compound in which the group R- consists of a ordered lower alkyl group, i.e. the 6-position is occupied by an ester group, with an alkaline or acidic Hydrolyzed saponifying agent.

As saponification agents, for example, caustic alkalis or alkali metal carbonates, such as Hatriurahydroxyd, ICaliumhydroxyd and potassium carbonate, as well as! .liner al acids, such as hydrochloric acid, sulfuric acid and phosphoric acid can be used. When using an alkaline saponifying agent

009846/1861

BATH ORIGINAL

v / ground caustic alkalis over alkali carbonates for carrying out the hydrolysis ".

I ¹ for the hydrolysis reaction, it is sufficient to heat this compound Kurae a long time with these alkalis or acids. Excessively high temperatures and / or excessive. "· Long heating times inconvenient" are due to the tendency to bring about side reactions Generally heating at a temperature below 10O ⁰ O for a few minutes is appropriate.

When a compound of the formula (IV) in which IL consists of a lower alkyl radical is converted by this hydrolysis into another compound of the same general formula in which Ryj consists of hydrogen, if R ^ is a lower alkyl group and R * consists of a lower alkoxy radical, a lower alkylthio radical or a radical of the formula - ^ d "( ^{in which Rl and ß} " have the meanings given in connection with the formula IV) - the substituent in the 2-position, ie the group R, , hydrolyzed simultaneously with the group H ^ and converted into a -OH group, ■ ·

It is also possible to 'hydrolyze a compound whose R ^ group consists of a hydrogen atom, i.e. which has a free carboxyl group in the 6-position, whose R ^ group consists of a lower alkyl group and whose R ^ group consists of a lower alkoxy radical, a lower alkylthio radical or a radical of the formula;

009846/1851

"- ■■: .. BAD ORIGINAL

ra of R ¹ and R ^{11 have} the meanings given in connection with the formula (IV)), and thereby converting this substituent in the 2-position into an -OH group «''

The reaction for converting a compound of formula (IV) into another compound of the same general Formula by hydrolysis can be represented by the following formula scheme:

RU here denotes an -OH group if R, represents a lower alkoxy group, a lower alkylthio group or the group -N ^ nii (where R 'and R "have the meanings given above) and R ^ is an alkyl radical, otherwise it is true ßUwith H, identical; H ₁ , R ₂ , R ₅ and R ^ have the meanings given above.

(2) Compounds of the formula (IV) in which the radical R ^ is formed by an alkyl group, ie the 8-position is occupied by an alkyl radical, can easily be prepared from compounds in which the group H4 consists of hydrogen, using a known alkylation method can be obtained

009846/1851

BATH

This reaction to convert a compound of formula (IV) into another compound of the same general formula (IV) by alkylation is represented by the following equation:

I ι Y ^

Here, R ^, Ro _4, R ^ and R ^ have the meanings given in connection with the formula (IV) and R ¹ ^ denotes a lower alkyl group.

This alkylation can be carried out using known alkylating agents, for example with a Alkyl halide, a dialkyl sulfate. or one Alkyl sulfonate. The reaction can be induced by removing the compound whose R ^ residue is made up of water, substance is only brought into contact with one of these alkylating agents. For example, if a dialkyl sulfate «Ti% HPe or an alkyl sulfonate is used, runs the reaction starts with stirring. When using jsines

Alkyl halide, it is usually better to carry out the reaction with heating.

It is usually convenient to carry out the reaction in water or an inert organic solvent, i.e. a Solvent that is inert to the reaction system, e.g. in water, dimethylformamide or aliphatic alcohol

0098 ^ 6/1851 BAD ORIGINAL * "

fetch, in which a connection whose R.Group consists of hydrogen, can be dissolved or suspended. The reaction can take place at room temperature or be carried out in the warmth. When heated, a temperature of about 100 O is normally suitable.

This conversion of a compound whose R. group consists of hydrogen into a "compound whose R. group is formed by an alkyl radical can be accelerated by adding an alkaline substance such as potassium hydroxide or potassium carbonate to your reaction system Alkylation of a compound whose · R «group consists of hydrogen and whose R -, - group is formed by a lower Alley 1 residue, using a strong alkali, for example a lye such as sodium hydroxide or potassium hydroxide, as the alkaline substance sometimes the group R ₁ is hydrolyzed at the same time, so that this compound is converted into another compound of the same general formula whose R .. group consists of hydrogen, ie in which the 6-position is occupied by a free carboxyl group.

(3) Compounds of the formula (IV) with an amino substituent in which the group R ¹ consists of -N \ j> «(where R 1 and R" have the meanings given in connection with the formula (IV)) can be prepared v / grounding by adding amines of the formula HIi ^ ₁ , in which R ¹ and R "are the above

009846/1861

BATH ORIGINAL

Have given meaning, with a compound of the formula (IV), in which R, of a lower alkoxy radical or a lower alkylthio is formed, converts.

This reaction of transforming a compound of the. Formula (IV) into another compound of the same general Formula (IV) using the amination can be represented by the following equation:

: ·; "Ο Rp 0

! j ^λ * _R , II jl

Here, R, -, R «, R ¹ and R» have the meanings given in connection with the formula (IV), R ¹ is a lower alkoxy radical or a lower alkylthio ^{radical and R 1} ^ means an alkyl radical.

The amination is usually carried out in a solvent. * As the solvent, a solvent such as water, aliphatic alcohols, benzene, toluene, xylene, haloalkanes, tetrahydrofuran, dioxane and the like is used against the reaction system under the reaction conditions. The reaction proceeds already at room temperature, preferably however, it is carried out in heat at a temperature of about 50 ⁰ C -'150. Furthermore, the reaction can take place under or under atmospheric conditions. Pressure are made } is preferably

* 00904 $ /

. . . - BAD.ÖRJGtNAl ♦! '^ - -A- ^ v

the reaction under a pressure of, for example, 2-10 At-

Running biospheres. "

(4 ·) Compounds of the formula (IV), their R 1 group from Hydrogen are made up of other compounds of the general formula (IV) in which the R, radical is from a lower one Alkylthio group is formed by desulfurization.

This reaction involves the conversion of a compound of formula (IV) into another compound of the same general Formula (IV) by desulfurization can be represented by the following formula scheme:

Γ T V ** ¹

here the groups R ^, Rg and R ^ have the _{meanings given in 4} connection with the formula (IV),

The aforesaid reaction can be in a suitable inert solvent, for example alcohols or dioxane, at a temperature of, 50-200 ⁰ C in the presence of a Metal catalyst & lysators, such as Raney nickel, are performed.

At. the method according to the invention thus graze ^ the novel compounds of formula (IV), i.e. # 5 »8-dihydro * -

through Erliitsen and 'ftingeefelufl.

py (^,

at '''■"^; ' i ■ ·· %? ϊ . ^

/ Heating of a likewise novel connection of the 3 sleeves (lll} _t

d; li. a lI- (6-pyrimidinyl) -aminomethyleneraalonic acid derivative which is formed by reacting a compound of the formula (I) with a compound of the formula (II) or by reacting a compound of the formula (I ¹ ) with a compound of the formula (II ¹ ) Furthermore, according to the methods (1) - (4) given above, it is possible to convert the product to be prepared by the process according to the invention by converting a compound of the formula (IV) into another compound of the same general formula (IV ) to win.

The process according to the invention thus comprises procedures for the preparation of a compound of the formula (III), a procedure for the preparation of a compound of the formula (IV) and procedures for converting a compound of the formula (Iv ^r ) into another compound of the same general formula. el (IV), so that every connection desired in the individual case can be earthed through a suitable combination of these working methods.

In Table II below are some examples of the teeth produced by the process of the invention novel compounds, cl.r .. 5 »8-dihydro-5-oxopyrido- £ 2,3-dJ-pyrimidine derivatives, compiled. The connections 1 - 6, 51 »52 U.5Ü are examples of the Pre- or intermediate products d & r, which when heated with ring closure pass into the corresponding compounds of the formula (IV).

009846/1851 BAD OFlIQlNAi.

- 20 Table II

link

structure

.1. Ethyl-N- (2, dimethyl-6-pyriraidinyl) aminomethylene £ - malonate *

CH

CHj / COOCpHt =

l ^ J] "J ^ cOOC ₂ H ₅

2. ethyl N- (2-hydroxy-if-pyrimidinyl) · ■ COOC ₂ H ₅

aminomethyleneftnalonatt ^^ \ \ /

'[Jl IjSjOOC ₂ H ₅

HCT ^ N

102-105

j. "

3. Ethyl N-Cf-fflethyl-6-pyrimidinyl) ^CH 3

anjinomethylenefmalonate ^ ^

l ·. ethyl N- (4-hydroxy-2-methylthio-6-pyriraidinyl) aminomethylenef-

• CH * SN H
OH

5. Ethyl N-C ^ -chloro - ^ - methyl-

thio-6-pyrimidinyl) aminooethylene ^ - ' ^cl

cH, s

6. Ethyl N- (2-diiaethylamino-4-pyrioidinyl) aminomethylene ^ mal <matji

: ^H 5

₂ H ₅

COOC ₅ H

, COOC ₂ H ₅

7. Jjö-Dihydro ^^ - dlHiethyl-ß-oithoxycarb <myl-5-caco «pyrido-C2,3-dI) -

CH3 p

²⁶⁶ - ⁷

0Ό98Α6 / 1851

BAD ORiQiNAL Mr. - Connection structure Fp .. ⁰ Q

8. 5i8-Dihydro- ^ 6- * thoxycarbonyl-2- · '"".' 'Q COOC ^ He' · ·

methylthiori-oxo-pyridiO ^ dl- 'Λ · ^Λ / ^ ⁵ ^ _A _, ■ pyrimidin L Jl J' 269-27I

'CH ₅ S

9 ·! Jtyy

Ethyl-2-ethylthio-5-oxo-pyrido *

A, CH ₃ O -H

11. SiP-Whydro-o-Abhoxycarbonyl-

Ethyl-S-ethoocy-S-oxo-. ^ N ^ V

.pyridof2,3-d J pyrimidine. tv X '

W hydroxy-5-oxo-pyrido ([

il *. 5.8-dihydro ^, i | -di "ethyl -" - t tthcatycarbooyl-e-ÄbhyS / C 2.3-4 Jp3ri «ldin Γ

* 5,8-Uihydro-2-di »« thylÄ «ii» -6-Ahid

10. Shock

■ BethypyC,>] ^^ nJ ^

'. pyrimidine. ·. · ■ ^: .: "M  IT T · -: 235-7

^r ! 'pyrido [2,3-d JpyrinidiB ·'"·': ^Λ 3 XKJ · 163-16 & .5

: O

■ h ■■ "

BATH ORIGINAL

No. ₁

link

st «« «» 16 7533 * 0

16.

hydroxy-2-aethylthio-5 "Oxopyridof 2,3-d Jpyriniidin

17th

■ tthyl-a-tthyl-5-oxo-pyrido-Γ 2,3-d] pyriline

2,3-d] pyrilin

18th

"Ethyl-5-oxo-pyrldoL.2,3-dJ pyriraidin

19th

y5, y 2-hydroxy-5-oxo-pyrldoC 2, pyrimidine

20. 6-Carboxy-5,8-dlhydro-8- * thyl-2-niethylthio-5-oxo-pyrido-Γ 2,3-d'jpyrimldine

21. 6-Carboxxr! 5,8-dihydro-8- * ethyl- ·. aHnethyliuBlno-J-ox [2,3-d "] pyrl> ddln

pyrlaidlB

2V eCirboityJtedlljydroaiet thie-5-oxo-pyrldoT 2,3-d > pyrli-idi *

CH _T O

COCH

CH, C

3 .COOH

CXJ

¹ JH

ν * CM, COOH

COOH

QO98 ^ 6/1111

'.- · BAD-QRIGfNAL. *> ·

222-22 ^

266-7

287-292

253-256

27 ^ -6

: · ■■;? ■ ■

link

structure

> · 6-Ciurboxy-5t8-dihydro-A-4thylpyrimidine

25. G-Carboxy ^ .S-dihydro-a-ethyl-2-aorpholino ~ 5-oxo-pyrido-

ca-c XCT

25 ^ -6

.0

COOH

270-272

G N

26. 6-CarbQxy-5, e-dihydro-8-ethyl-5-oxo-2-piperidino-pyrido-Γ 2,3-d-pyrimidine

C ₂ H ₅ C

.COOH

267-270

C ₂ Il ₅

6-carboxy-5-8-dihydro-8-4thyl-2- (2-hydroxy4thylJnino-5-oxopyrido L 2,3-d 1 pyriaidln

6-Cnrboxy-£, F-dihy.iro-f.-4thyl 5-oxo-2-pyrrole di «o-iqrridot 2,3-dtpyrieidine

CCCH

268-270

C ₂ H ₅

^CCOH

6-carboxy-5,8-dihydro- € -tthjl-2-icopΓoκrlκnine-5-oxo »|> yrido L 2,3-d pyrinidia

30. o-Carboxy - ^. P-dlhydro-Z-dieethyl • uino-ft-Ethyl-J-oxoA L 2,3-d jpyriaiidin

COCU

^CH 233-235

C ₂ Il ₅

COCH

• «

cn

* r 286-291

31. 6-carboxy-5.B-dihydro- $ - * thyi J-oxo-pyridof. 2 »3-d jpyriBidine

ι ■.

009846/1861

219-222

BATH ORIGINAL

link

structure

Pp .. ⁰ C

32. ö-Carboxy-S-cyclohescylaslno-Ji ^ dihydro-P ^ Athyl-J-oxo-

, pyridor.2,3-di; pyriKidin

33. G-Carboxy-S.e-dihydro-S-Athyla-n-hexyi

C 2, M

yyJi dihyUro -? - 4thyl-5-oxo-pyrido L2.3-d] pyrimidine

35. 6-Carboxy-2-C 3- (dlIthyla * ino) -propyl.'iinino 1] -51β-dlhydro-8-ethyl-S-oxo-pyridoC 2,3-d> pyrifflldin-.

«T * ^^ - ^CC0H * [\ H 209-211

Il! '

r -tr '

A ₂ H ₅

^ Jl

l I '

192-19 ¹ «

160-162

36. 6-CaΓboxy-5,8-dihydro-2-ti 3- (dioethylainino) propyl-8

yppy tiv

amino j-8-4thyl "5-oxo", CH "". jL Ii

pyridoC 2,3-d pyrimidine ^ ΙίΗ- (ΟΙ ₃ ), - 1ΠΙ '^ ^ν Η Η

II 1) 165-7

37. 6-Curbaxy-5,8-dihydro-8-2 i3-d 3 pyrinddifi

38. 6-varbaxy-5,8-dihydro-8-eethyl- 'Z-eethylthio - ^ - oxo-pyrido-Π 2,3-d] pyrinidine ..

39. ß-Corboxy-Sie-dihydro ^ - diinethylaraino-S-methyl-5-ακο-pyridoC 2,3-djpyrijnidin · _CH

009846 / 1βδί> Ν J I

0 _{C () CH} LD

^CH

3.

269-272

299-302

312-315

BATH ORIGINAL

ß-Carboxx-Sfe-dlhydro-SHiMithyl thio »5-oxo - $ - n-Fropyl <» pyrido-

C2,3-d "Jpjri" idin

e-n-Butyl-ß-carbexy-Jie-dlhydro- · 2-eeth ^ thiC 25d] pyri »« idia

Ϊ CCCH

C T

pyyJ L2,3-djpyrimidln

2-dimethylaaino-5-oxo-pyrido ~ Γ 2,3-dJpyri ^ .dia " CH, «3

"P! 'Ι

ia (cu ₃ ) ₂

yy • jnino-5-oxo-S-n-propyl-pyrido C2,3-d "'ipyriaidln

ClI ₅ L 1 J

^CH U

. C-carboxy ^ tS-dihydro-S-diMthyl- ^

araino-P-ieopropyl-5roxo-pyrido · W ^ 'S ·' If

C 2,> d "" pyri "idin '.CU ,. ΐ tt j

f »6. C-Carboxy ^^ - dihydro-i'-tthyl-2-HYdWHnO-SrOXO-PyTIdO-L 2.3-d ¹ PyTImIdIn. · '

«»? β-Corbexy-S.β-dihydro-α-dodecyl-.

j?

ry

üalneals

• «r *

^k cH. (

0098A6 / 19S1 Ϊ f

197-9

2> l-233

205-7

251-253

259-261

BATH ORIGINAL No connection

oeta C 2,

tad «cylMino-5-oxopyrid <» 2> <) i

yS.y «• ino-S-oxopyridoQ2,3-4

Fd., ⁰ C

52. Ethyl-H- (2- ^ tboxy - ^ - pyrl * idinyl)

287-9

300-305

106-7

123-125

^ 250

009848 / 1Θ51

BATH OFIIÖINAL

The novel compounds prepared according to the invention, d, a · 5 »8-Mhydro-5-oxopyrido-C2 _f 3-dJ-pyrimidine derivatives, have antibacterial activity against gram-positive and gram-negative bacteria and tubercle bacilli. They are useful as medicine and as gate products for the preparation of other compounds with antibacterial activity.

In Table III below are the in vitro antibacterial
/ Activities of a group of compounds against a number of microorganisms compiled. The minimum inhibitory concentration (MlO) was determined according to the known serial dilution method

009846/1851 BAD ORIQiNAt

Table III

Antibacterial activity in-vitro

O
ö • Organism ~~~ "" - (20) (30) (MO (21) (24; , (25) v._c) (23) _§ (37) ■ i3? 5 * : 30 y 30th , (U ₇ ) - I. • I. _m (O
• cd . Staphylococcus aureus 30th 10 30th 30th • ZC 30th 10 : 30 30th I io. 10 1 I.
I. ro
ω Ertbarichia coll ! 3 1 3 '10 . 10 ¹ 3 j ¹⁰ ; 1 ; 10 '10 ! ι-! 10 .30 t I. Ί851 Shi ^ ella flexneri 2a ¹ 3 3 10 '30 30th 10 ¹ 30 10 ^! ok 30th 10;
10 10
3 30th I.
t Ghisella sonnei
Salnonella typhirauriun ; 3 1
1 3
3 '10
10 10
30th 3
10 10
10 VM VM ^; ok
: ¹⁰ ok
; ok 10 10 30th
10 i Proteus vulgatis 3 1 3 10 10 3 10 1 3 10 ι 3 10 Klefasiella pneumoniv.e ' 1 O. 3 1 3 3 1 3 1 ι 3 3 · 10 3 ¹ Salnonella enteritidis 1 1 5 10 10 3 • ic 3 ZO 10 io ·,
\ \ 30th . 30th f CD liycobacteriun tuberculosis 30th 10 30th
I. 10 3C 10 '30
1 ... . '30 t CD co
co

Table IV below shows the in vivo activities of some compounds against infection with Salmonella typhi « murium in mice.

Table IV Therapeutic effect in mice

Organisms: Salmonella typhimurium Type of infection: ip Route of administration: po

survivors g etested (survived / tested)

Connection no 9 . 12th 20th 30th Art PO PO PO PO Dose ⁺ ) 100 mg / kg 6/10 8/10 6/10 6/10 50 " VlO 7/10 2/10 5/10 25 " 1/10 5/10 4/10 12.5 " 3/10 3/10

The survival ratio of the untreated control was 0/10 +) 2 times a day for a period of 4 days.

The 5,8-dihydro-5-oxopyrldo- ^ 2,3-d7-pyrimidine (derivative) prepared according to the invention can be used externally, orally and through Injection used or given in combination with other drugs. In all cases there are antibacterial agents which contain a compound of the formula (IV) included as an effective component.

Some embodiments of the method according to the invention are further illustrated in the following examples.

009845/1851

- 3ο -

example 1

Preparation of a compound of the formula (III) according to Working method a: '·

12.2 g of 6-amino-2,4-dimethylpyriBidinund 23.0 g ethyl -äthoxymethylenmalonat were added with stirring 35 Hinuten at a -temperature of 110 - 120 ⁰ O heated. The resulting product was cooled and recrystallized from ethanol. 18.5 6 ethyl H- (2,4-dimethyl-6-pyrimidinyl) -aainoiiethylenmalonat with a melting point of 102-103 ° C were obtained.

Example 2

Preparation of a compound of the formula (III) according to Working method a:

29.0 g of 4-amino-2-methylthiopyrinidine and 60.0 g of ethyl ethoxymethylene malonate were stirred for 1 hour and 40 minutes heated at a temperature of 135-14O ° 0. The resulting Product was cooled and crystallized from ethanol. There were 33 »7 g of ithyl N- (2-methylthio-6-pyrieidinyl) -aiainoaethylene malonate obtained with a melting point of 106-107 ° C.

Example 3

Preparation of a compound of the formula (III) according to procedure a: "

2.06 g of 4-amino-2-methoxypyrimidine and 4.20 g of ethyl ethoxymethylene malonate were heated for 1 hour and 10 minutes at a temperature of 135-140 ° C. with stirring. The resulting product was cooled and crystallized from ethanol. 2.66 g of ethyl-N- (2-oethoiy - ^ - pyriaidiGylJ - m & ltto-, methylenmoloiuit jnit a «M Sobaeispv ^ M Wa 123 - 125 ⁹ O would be obtained,

009Θ46 / 1Θ51.

. = · JV- '; : ^ν ί;? ο BAD ORIGINAL "*

Example 4

Preparation of a compound of the formula (III) according to procedure a:

1,4 g of 4-amino-2-hydroxypyrimidine and 3,0 g Äthyläthoxymethylenmalonat were 20 minutes at 150 - 160 ⁰ C implemented. After cooling the reaction product, the obtained crystals were recrystallized from ethanol · There were 2,4 g of ethyl-N- (2-hydroxy-4-pyrimidinyl) -aminomethylenmalonat having a melting point of 191 - received 19 ^ ⁰ · C

The following compounds were prepared using the same procedure outlined above: (1) Ethyl N- (4-methyl-6-pyrimidinyl) aminomethylene malonate with a melting point of 101.5-102 ° C from 6-amino-4-methyl-

pyrimidine and ethyl fithoxymethylene malonate. (2) Ethyl-Η- (^ -hydroxy-S-niethylthio-e-pyrimidinyl) -ami'no methylenemalonate with a melting point from 228 to 230 ⁰ C from 6-amino-4-hydroxy-2- «ethylthiopyrimidine and ethylethoxy

methylene malonate. * (3) Ethyl-N- (4-chloro-2-methyli; hio-6-pyrimidinyl) aminomethylene malonate with a melting point of 132 - 13 * ° C from 6-amino 4-chloro-2-methylthio-pyrimidine and xthylethoxymethylene malonat.

Ithyl-N- (2-diJaβthyla ■ ino-ί ^ -pyrimidinyl) -aminomethylene malonate a with a melting point of ^{59-63 0} C. From 4-Amino-2-diaethylaminopyrimidine and Ithyläthoxyeethylenoaloiiat.

009846 / 18S1

BAD-ORlQINAU Example 5

Preparation of a compound of the formula (III) according to procedure a:

A mixture of 1.0 g of 2-dimethylamino-4-ethylaminopyrimidine and.1.4 g of ethyl ethoxymethylene malonate was added for 2 hours stirred at 145 ° C and then distilled under reduced pressure. There were 760 mg of ethyl N- (2-dimethylamino-4-pyrimidinyl) -N-ethylaminomethylene malonate obtain. The picrate of this ■ compound has a melting point of 148 - 150 ° C ·

Example 6

Preparation of a compound of the formula (III) according to procedure b:.

POO mg of 4-chloro-2-dimethylaminopyrimidine and 300 mg Ethyl aminomethylene malonate was added to 30 ml of ethanol and the mixture was 6 hours at 140 ° C in a closed- ' NEN tube reacted. After the completion of the reaction, the solvent was reduced by distillation under reduced pressure Pressure removed. The resulting product was recrystallized from ethanol to yield 280 mg of ethyl N ~ (2-dimethylamino-4-pyrimidinyl) aminomethylene malonate with a melting point of 64 - 65 ° C.

The following compounds were made in the same way se, as explained above, produced;

(1) Ithyl-TT- (2-methylthio-4-pyrimidinyl) -aminomethylenmalonat having a melting point 106-107 ⁰ C, from 4-chloro-2-methylthiopyrimidine and ÄthylamiTiomethylenmalonat.

009846/1851 BAD

(2) Ethyl IT- (2-methoxy-4-pyrimidinyl) aminomethylemnalonate with a melting point of 123-125 C from 4-chloro-2-methoxypyrimidine and ethyl aminomethylene malonate.

Example 7

Preparation of a compound of formula (IV) from a compound of formula (III):

4.20 g of the ethyl N- (2 _> 4-dimethyl-6-pyrimidinyl) aminomethylene malonate obtained in Example 1 were added to 60 g of boiling diphenyl ether and the mixture was vigorously refluxed for 15 minutes. After cooling, 300 ml of η-hexane 'was added to the product. The deposited crystals were collected by filtration and recrystallized from ethanol, whereby 2.30 g of 5,8-dihydro-2,4-dimethyl-6-ethoxycarbonyl-5-oxo-pyrido-L2,3-dJ-pyrimidine with a melting point from 266 - 267 ° 0.

Example 8

Preparation of a compound of formula (IV) from a compound of formula (III);

43.0 g of the ethyl IT- (2-methylbhlo-6-pyrimldinyl) -aminome bhylenmalonats obtained in Example 2 were added to 270 ml of boiling diphenyl ether and the mixture was refluxed for 25 minutes. After cooling - ¹ KiO mL ti-IIoxane was added to the product. The separated Ki'LsbalLii were removed by filtration and with ilbhanol - :; £! 7 /? Ιπ «ΐ.ίίη, j esi« rgabezi r.Lch 2ύ ^ \ - ν; 5, aI) ih / di? Or) -ät; hoxycapbon, yL -.'- .. lüti 7 Hn 10-5-0 ::;) -p / r · LdO -. [Ji ₁ 5-dj-pyrLDildIn ult ο1ΐι »: α Üc imnlcb ί -ι ίί69 ·· ^# ti7L ^J ti,

ti -j Ί «', 6 / I fl f) BAD

Example 9

Preparation of a compound of the formula (IV) from a compound of the formula (III) s

1.16 g of the ethyl n- (2-methoxy-6-pyrimidinyl) aminomethylene malonate obtained in Example 3 was added to boiling diphenyl ether and the mixture was vigorously refluxed for 10 minutes. Tray for cooling, 50 ml of η-hexane was added to the product. The deposited crystals were removed by filtration and recrystallized from ethanol. 0.64 g of 5,8-dihydro-6-ethoxycarbonyl-2-methoxy-5-oxo-pyrido-i [2 _f 3-dI-pyrimidine with a melting point of 235-237 ° C. were obtained. _v .

Example 10

Preparation of a compound of formula (IV) from a compound of formula. (III);

610 mg of ethyl N- (2-hydro3 £ y-4-pyrimidinyl) aminomethylene malonate were added to 5 ml of boiling diphenyl ether and the mixture was refluxed for 10 minutes. After cooling, 10 ml of η-hexane was added to the product. The precipitated crystals were removed by filtration and recrystallized from methanol. 330 mg of 5 »8-DihydiO-6-etho: ^ carbonyl-2-hyd: roxy-5-oxo-.pyrido- [2,3-d3 were obtained -pyrimidine with a melting point of 258-261 ⁰ O,

Example 11

• Production of a compound of the formula (IV) from a compound of the formula (TII) ι

00904 η / 1351

BATH ORIGINAL.

2.10 mg of ethyl IT - (^ hydroxy-2-methylthio-6-pyrimidinyl) aminomethylene malonate was added to 3 ml of diphenyl ether and the mixture was refluxed for 13 minutes. 15 ml of η-hexane were added to the product. The precipitated crystals were removed by filtration and recrystallized from ethanol-chloroform. There were 20 mg of 5 * e-dihydro-G-ethoxycarbonyl - ^ - hydroxy ^ -methylthio ^ -oxopyrido-j_2,3-d ^ -pyrimidine with a melting point of 261 263 ⁰ C.

Example 12

Preparation of a compound of formula (IV) from a compound of formula (III):

10 g of ethyl N- (2-dimethylamino-4-pyrimidinyl) aminomethylene malonate were added to 50 ml of diphenyl ether under reflux and the mixture was brought into relation for 20 minutes. After cooling, 200 ml of η-hexane was added to the product. The deposited crystals were removed by filtration and washed with ethanol. 8.0 g of 5,8-dihydro-2-dimethylalainQ-6-ethoxycaΓbonyl-5-'OXO-pyrido- ~ C ² »3-d] -pyrimidine with a melting point of 290-295 ° C. were obtained.

Example 15

Conversion of a compound of the formula (IV) into another compound of the formula (IV) by alkylation:

A mixture of 2.9 g of 5>& - dihydro-2,4-dimethyl-6-ethoxycarbonyl-5-oxo-pyriöo-l2 _t 3-d3-pyrimidine, 25 g of dimethylformamide, 10 g of ethyl iodide and 10 ml of a 20% igen watery

0098A6 / 1851

Solution of potassium carbonate was stirred for 1 hour at 10O ⁰ C. The precipitated potassium iodide was separated by filtration, and dimethylformamide was removed by distillation under reduced pressure * To give the resulting product

Sodium chloride
saturated aqueous / added and the product was extracted with 'chloroform,' followed by recrystallization from ethanol, 1.95 6 5 »8-dihydro-2,4-dimethyle-ethoxycarboriyl-e-ethyl ^ -oxo-pyrido- £ 2 3-dJ-pyrimidin having a melting point of 156 * 5 - 158 ⁰ C obtained.

example

Conversion of a compound of the formula (IV) into another compound of the formula (IV) by alkylation:

A mixture of 0.32 g of 5 »8-dihydro-6-ethoxycarborudyl-2-methylthio-5-oxo-pyrido- {2,3-dJ-pyrimidine, 2.6 g of dimethylformamide, 1.1 g of ethyl iodide and 2 ml of a 20% aqueous solution of potassium carbonate was treated in the same else · V / _v as in example 13 to give 0.30 g of 5,8-dihydro-g-ethoxycarbonyl-e-ethyl ^ -oxo ^ -methylthio-pyrido - ££., 3-dJ pyrimidine with a melting point of 144.5-145.5 ° C.

' Example 15

Conversion by alkylation:

. A mixture of 100 mg of 5f8-dihydro-6-ethoxycarbonyl-2-methoxy-5-oxo-pyrido- [Ϊ2,3-dJ-pyrimidine, 1.0 g of dimethylformamide, 300 ml of ethyl iodide and 1 ml of a 20% aqueous Potassium carbonate solution was treated in the same manner as in Example 13. Bass reaction product was made from acetone / η-hexane recrystallized and gave 82 mg of 5 »8-bihydro-6-ethoxy-

■ 009846/1861 '

carbonyl-3-ethyl-2-methoxy-5-oxo-pyrido-r2,3-d ^ -pyrimidine with. a melting point of 14-7 - ⁰

Example 16

Conversion by alkylation:

7.0 g of 6-carboxy-5 _i B-dihydro-2-methylthio-5-oxo-pyrido-L2,3-dI-pyrimidine were dissolved in a 4% strength aqueous solution of potassium hydroxide, and "when 5 The solution was stirred vigorously at room temperature for 2 hours> 0 g of diethyl sulfate ^1. After standing overnight, the reaction product was acidified with acetic acid. The precipitated crystals were collected by filtration, washed with water and recrystallized from methanol. 7 | 2 g of 6- Carboxy-5 % 8-dihydro-8-ethyl-2-methylthio-5-oxo-pyrido ~ £ 2,3-d] -pyrimidine with a melting point of 253 - '256 ⁰ O. · ·

Example 17 . -

Conversion by alkylation:

100 mg of 6-carboxy-5 "8- ^d i ⁿ y ^<3-3 o-2-methoxy-5-oxo-pyrido - |? _2,3-dJ-pyrimidin were dissolved in 5 * & 1 of a 4% aqueous Solution of potassium hydroxide dissolved and with addition of diethyl sulfate, the solution was treated in the same manner as in Example 16. The resulting product was ^{unkris.tallisiert from chloroform-1} acetone and gave 98 mg of 6-carboxy-5,8-dihydro-8-ethyl-2'-methoxy-5-oxo-pyrido- [2,3-d) - ^v pyrimidine with a melting point of 254 - 256 ⁰ C.

Example 18 'Conversion by alkylation:

g 6-σarboxy-5 | 8-dihydro-2-mβthyltlaio-5 ^Λ · oxo-

& 09846/1851

BAP ORIGINAL ·,

pyrido - ^^ - d ^ -pyrimidine were dissolved in 30 ml of a 4 # aqueous solution of potassium hydroxide. To the resulting solution, 2 g of dimethyl sulfate was added with cooling, and the mixture was stirred for 4 hours. After standing overnight, the resulting product was acidified with acetic acid. The deposited crystals were collected by filtration and recrystallized from a large amount of methanol-chloroform. There were 1.10 g ö-carboxy ^ jS-dihydro-S-mefchyl - ^ - methylthio-5-oxo-pyrido [2,3-d} pyrimidine having a melting point of 299 ° -302 ⁰ C.

Example 19

Conversion by alkylation:.

200 mg of 5,8-dihydro-6-ethoxycarbonyl-2-methylthio-5-oxo-pyrido-12,3TcQ-pyrimidine were suspended in 10 ml of ethanol-water (1 i 1) which contained 0.4 g of potassium hydroxide when 5OO mg of diethyl sulfate were added, the suspension was stirred for 4 hours while cooling. After standing overnight, the product was acidified with acetic acid. dihydro-8-ethyl-2-methylthio-5-o-P3rrido ° ^{x-jj2,3-dJ-pyrimidin} having a melting point of 253 ~ 255 ⁰ C *. .

Example 20 -

Conversion by alkylation}

The following compounds were made in the same Way as in example, 19 made!

0098A6 / 1 ÖS 1

'BAO..OFUGHNAL.

(1) 6-Carboxy-5, e-dihydro ^ -methylthio- ^ - oxo-ene-propylpyrido- [2,3-d} -pyrimidine with a melting point of 197-199 ⁰ Oj

(2) Sn-butyl-ö-carboxy ^ ie-dihydiK ^ -methylthio-IIJ-oxo-pyriäo- - {2,3-d] pyrimidine having a melting point of 174 - 1-76 ⁰ Cj

(3) 6-0arboxy-5 * e-dihydro-S-isopropyl ^ -methylthio- ^ - oxopyrido- - [2,3-dI-pyrimidine with a cutting point of 231-233 ⁰ O.

Example 21

Conversion by hydrolysis:

20.0 g ^, e-DihydM-e-ethoxyceTbonyl ^ 5-oxopyrido-U2,3-d3-pyrimidine were added to 200 ml of an aqueous solution of sodium hydroxide and the solution was ^{heated at 100 °} C. for 20 minutes. The product was acidified with acetic acid. The deposited crystals were collected by filtration and recrystallized from a large amount of methanol. There were 12 _f 5 g 6-0arboxy-5 "8-dihydro-2-methylthio-5-oxopyrido" [2,3-d3-pyrimidine having a melting point of 279-281 ⁰ C.

Example 22

Covering by hydrolysis:

[2,3-dJ-pyrimidin 400 mg 5i8-dihydro-6-ethoxycarbonyl-2-methoxy-5-oxopyrido was added to 8 ml of a 5% aqueous solution of sodium hydroxide igea added and the solution was heated for 15 minutes at 90 ⁰ C. . The resulting product was acidified with acetic acid. The deposited crystals were collected by filtration and recrystallized from a large amount of ethanol-acetone. We obtained 290 mg of 6-carboxy-5,8-dihydro-2-oethoxy-5-oxopyrido- {z , 3-dj -pyrimidine

009846/1851 BAD-OR) GINAC

with a melting point above

Example 23

Conversion by hydrolysis:

1,2, s 5,8-Billydro-2 _t 4-dimethyl-6-ethoxycarbonyl- -8-ethyl-5-oxopyrido- [2,3-cL3-pyrimidine were added to 15 ml of a. 10% strength aqueous solution of sodium hydroxide was added and the solution was ^{heated at 125 0} O for 1 hour and 50 minutes. The resulting product was acidified with acetic acid. The deposited crystals were collected by filtration and recrystallized from ethanol. The result was 0.77 g
6-carboxy-5,8-dihydro-2,4-dimethyl-8-ethyl-5-oxopyrido-
-C2 »3-i-pyrimidine having a melting point of 222-224 ⁰ C.

Example 24

Conversion by hydrolysis:

165 mg of 5.8-dihydro-2,4-dimethyl-6-ethoxycarbonyl--5-oxopyrido- [2,3-dI-pyrimidine was added to 8 ml of a 10% aqueous solution of sodium hydroxide and the solution was allowed to stand for 1 hour and heated for JO minutes at 120-130 ^{° C.} Of
the resulting product was acidified with acetic acid. The precipitated crystals were collected by filtration
and recrystallized from ethanol. It resulted in 109 mg
6-carboxy-5,8-dihydro-2,4-dinethyl-5-oxopyrido- \ 2,3-dJ-pyrimidine with a melting point of 266-267 ° C.

Example 25

Conversion by hydrolysis:
47 mg 6-carboxy-5i8-dihydro-8-ethyl-2-methylthio-

09846/1851 BAD ORIGJNAL

-5-oxopyrido- [2,3-dJ-pyrimidine were added to 1 ml of a sodium hydroxide solution and the mixture was heated at 90-95 ° C. for 15 minutes. After cooling, the resulting product was acidified with acetic acid. The deposited crystals were collected by filtration and removed from a large amount. JLthanol recrystallized · There were 31 mg 6-carboxy -5, e-dihydro-S-ethyl ^ -hydroxy ^ -oxopyrido- [2,3-d] pyrimidine having a melting point of 287-292 ⁰ C.

Example 26

Conversion by hydrolysis:

50 mg of 5 | 8-dihydro-6-ethoxycarbonyl-8-ethyl-2-methoxy--5-oxopyrido- [ 2,3-dJ-gyrimidine were added to 1 ml of a 5% sodium hydroxide solution and the mixture was 5 Heated at 95 ^° C. for minutes. When the resulting product was subjected to the same treatment as in Example 25, there was obtained 33 mg of 6-carboxy-5 * S-ethyl ^ -hydroxy ^ -oxopyrido- [ 2,3-d3-pyrimidine.

Example 27

Conversion by hydrolysis:

200 mg of 5,8-dihydro-6-ethoxycarbonyl-8-ethyl-2-methylthio-5-oxopyrido- (2,3-d} -pyrimidine were added to 4 ml of a 5% sodium hydroxide solution and the mixture was stirred for 15 minutes 90 - heated 95 ⁰ C the resulting product was subjected to the same treatment as in example 25 to give 123'mg 6-carboxy-5, S-.
- [2,3-d] pyrimidine

009346/1351 BAD ORIGINAL

Example 28

Conversion by hydrolysis: 500 mg iJjS-dihydro-e-ethoxycarbonyl - ^ - hydroxy-

5 "-d.xof> yr! ELo '

-2-methylthio- [j2,3 - d3-pyrimidine were added to 10 ml of a

Sodium hydroxide solution was added and the mixture was ^{heated at 90 0} O for hydrolysis for 13 minutes. The product was acidified with acetic acid. The deposited crystals were collected by filtration and recrystallized from methanol-chloroform. 37O mg of 6-0arboxy-5,8-dihyd: ro-4-hyd: roxy-2-methylthio- -5-oxopyrido- [2,3-dI-pyrimidine with a melting point of 287-289 ° 0 were obtained.

Example 29

Conversion by hydrolysis:

7.0 g of 5,8-dihydro-2-dimethylamino-6-etho3q5rcarbonyl--5-oxopyrido-C2 »3-cL] -pyrimidine were added to 100 ml of 7% strength sodium hydroxide solution and the mixture was hydrolyzed for 30 minutes 140 ⁰ C heated. The product was acidified with acetic acid. The deposited crystals were collected by Filtratior and recrystallized from acetonitrile · There were 5.6 g of 6-carboxy-5, 8 -dihydro ^{s-2-dimethylamino-5-oxopyrido} \ 2, 3-d] pyrimidine having a melting point of 3OO - 303 ⁰ C obtained

Example 30

Conversion of a compound of the formula (IT) by amination into another compound of the formula (IV):

700 mg 5,8-dihydro-6-ethoxycarbonyl-8-ethyl -2-methylthio-5-03-copyrido- [2,3-clI-pyrimidine were added to 30 ml absolute v> ethanol containing 2 g dimethylamine,

BATH

was added and the mixture was heated in a closed tube at 95 ° C for 6 hours. The solvent was removed by distillation and the residue was recrystallized from ethanol. 560 mg of 5 % 8-dihydro-2-dimethylamino-e-ethoxycarbonyl-S-ethyl - ^ - oxopyrido-jjSjJ-dJ-pyrimidine with a melting point of 163-164.5 ⁰ O were obtained.

Example 31

Conversion by amination:

700 mg e-carboxy- ^ e-dihydro-S-ethyl-a-methylthio- -5-oxopyrido- £ 2,3-dj [-pyriBiidin were made in the same way treated as in example 30. 530 mg of 6-carboxy -5, S-diby-dro ^ -dimethylamino-B-ethyl-S-oxopyridopyrimidine obtained with a melting point of 288-291 ° C.

Example 32

Conversion by amination:

150 mg of 6-carboxy-5,8-dihydro-8-ethyl-2-methyithio--5-O3-copyrido-j_2,3-d3-pyrimidine were added to 30 ml of absolute ethanol. 2.0 g of methylamine were dissolved in this mixture and the solution was heated in a closed bore ^{at 105 ° C. for 7 hours.} The solvent was removed by distillation and the residue was washed with ethanol and recrystallized methanol-chloroform. 120 mg of 6-carboxy-5,8-dihydro-8-ethyl-2-meth.ylamino-5-oxopyrido- | j2 _t 3-d] J-pyrimidine with a melting point of 27-276 ° C. were obtained .

00 9846/18 51 ORIGINAL BATHROOM

1570533

When performing the same treatment using n-butylamine, n-hexylamine, isopyropylamine, cyclohexylamine Ethanolamine, diethylaminopropylamine, dimethylaminopropylamine and ethylamine instead of methylamine were the obtained compounds listed below:

(1) 2-n-Butyl amino-6-carboxy-5,8-dihydro-8-ethyl-5-o: x: opyrido- - [2,3-dJ-pyrimidine (126 mg; melting point 192-194 ° C);

(2) 6-> carboxy-5-yo e-dibydro-S-ethyl ^ -n-hexylamino -oxopyrido- ^ - [2,3-dj-pyrimidine (137 mg; melting point 164-166 ⁰ C);

(3) 6-Garboxy-51 S-dihydro-S-ethyl- ^ - isopropylamino ^ -oxopyrido- -C2 _i 3-d] -pyriinidine (124 mg; melting point 233-235 ° C); e-Carboxy ^ -cyclohexylamino ^ S-dihydiO-S-ethyl ^ -oxopyrido-2,3-dI-pyrimidine (13 mg; melting point 209-211 C); 6-carboxy-5,8-ddhydro-8-ethyl-2- (2-hydroxyethyl) amino-5-oxopyrido - [2,3-d] -pyramidin (118 mg; 263-270 ⁰ C);

(6) 6-Carboxy-2- {3- (diäthylaiiiiio) propylamino3-5,8-dihydro-8-ethyl-5-oxopyrido-f2,3-d] pyrimidine (142 mg; 160-162 ⁰ C);

(7) 6-carboxy-5i8-dihydro-2- [3- (dimethylamino) -propylaminoX-8-ethyl-5-oxopyrido [2,3-d3-pyrinidin (135 mg; 165-167 ⁰ C);

(8) _6-carboxy-5> 3-dihydro-8-ethyl-2-ethylamino-5-oxopyrido - [2,3-d] pyrimidine (107 mg; melting point 269-272 ⁰ C).

At apiel 33

Conversion by amination:

200 mg 6-0arbox7-5,8-dihydro-8-ethyl-2-methylthiio-5-oxopyrido-12,3-dj-pyrimidine were added to 30 ml of absolute il-hanol * weltjhea. 1/2 g of ammonia and the /

009846 / 18B1

BAD OBK & NÄL

Gemiocli was 5t 5 hours

* Reacted in a closed tube at 1O5 ° C. The solvent was removed by distillation and the residue was recrystallized from ethanol. There were 127 mg of 2-amino-6-carboxy-5,8-dihyd: ro-8-ethyl-5-oxopyrido - [2,3-DJ pyrimidine having a melting point of 291-293 ⁰ C.

Example 54

Ura conversion by amination:

150 mg of 6-carboxy-5,8-dihydro-8-ethyl-2-methylthi9-5-oxopyrido- (2,3-dJ-pyrimidine were added to 30 ml of absolute ethanol, which dissolved 1.1 g of piperidine and the mixture was reacted in a closed tube for 5 hours at 95 ° C. The solvent was removed by distillation and the residue was recrystallized from methanol-chloroform. 112 mg of 6-carboxy-5, S-dihydro- S-ethyl - ^ - ^ oxo -piperidinopyrido- - [2,3-d J-pyrimidine with a melting point of 267 - received 270 ⁰ C ■ -.,

Example 35

Conversion by amination:

When using morpholine instead of piperidine in the procedure according to Example 34, 121 mg of 6-carboxy-5, S-dihydro-e-ethyl ^ '- mörpholino-iT-oxopyrido -f2,3-d3-pyrimidin ^mi * ^m.p. from 270 - 272 ⁰ O obtained.

Example 36

Conversion by Amination: If in place of piperidine in the procedure

009846/1851

BATH ORIGINAL · ''

According to Example 34 pyrrolidine was used, the result was 111 mg of ö-Carboixy ^ iS-dihydro-S-ethyl ^ -oxo ^ -pyrrolidinopyrido- -L2,3-d) -pyrimidine with a melting point of 3 * ^{1.4-316 0} O.

Example 37

Conversion by amination:

200 mg of ö-carborxy ^ jS-dihydro-S-methyl ^ -methylthio- -5-oxopyrido-j [2,3-d3-pyrimidine were suspended in 30 ml of absolute ethanol containing 6 g of dimethylamine, and the suspension was 6 Hours implemented at 105 ° C in a closed tube. The product was heated and filtered. The solvent was separated from the filtrate by distillation and the residue was recrystallized from chloroform-methanol. 124 mg of 6-carboxy-5,8-dihydro-2-dimethylamino-8-methyl-5-oxopyrido-f2,3-dJ-pyrimidine with a melting point of 312-315 ⁰ O were obtained,

Example 38

Conversion by amination:

The compounds listed below were prepared in the same manner as in Example 37:

(1) 8-n-Butyl-6-carboxy-5 «8-dihydro-2-dimethylamino-5-oxopyrido- [2 _t 3-dj-pyrimidine with a melting point of

205 - 207 ⁰ Oj ^

(2) 6-Carboxy-5 _^ 8-dihydΓO-2-dimethylamino-.5-oxo-8-n-pΓopylpyrido- £ 2,3-dJ-pyri «idin with a melting point of

261 - 262 ° 0 | ^v

003846/1851 BAD

(3) 6-Car "boxy-5 | 8-dihydro-2-dimethylamino-8-isopropyl-5-oxo pyrido - ^^ - dj-pyrimidine with a melting point of 251 - °

Example 39

Conversion by amination:

200 mg of e-carboxy ^ e-dihydiO-S-ethyl ^ -methyltliio- -5-oxopyrido- [2 _t 3-d3-pyrimidine and 100 mg of hydrazine were added to 40 ml of ethanol and the mixture was refluxed for 15 minutes. The deposited crystals were collected by filtration and, after washing with ethanol, suspended in water. 3-5 drops of 10% hydrochloric acid were added to the suspension and the crystals were dissolved. The resulting solution was filtered. The filtrate was made alkaline with potassium carbonate and then acidified with acetic acid. The deposited crystals were collected by filtration and recrystallized from methanol. There were 121 mg G-carboxy ^ S-äihydro-S-äihyl - hydrazino -5-oxopyrido [2 _i 3-dl-pyrimidine having a melting point of 259 - - 261 ⁰ C ^ obtained. .

Example AO

Conversion by amination:

200 ml of G-carboxy-5,8-dihydro-8-ethyl-2-methyli; hio- -ÜJ-oxopyrido-O ^ j ^ -dJ-pyrinidine ^and ^ 1> ° β dodecylamine were added to 30 ml of ethanol and the mixture was reacted for 6 hours at 105 ^° C. in a closed tube, and after the reaction had ended, the solvent was permeated

0098 AG / 18 51 BATH ORIGINAL

Distillation removed and the residue obtained was recrystallized from ethanol. There were 285 mg of a salt of dodecylamine G-carboxy ^ iS ^ -dodecylamino-dihydro-S-ethyl-5-oxopyrido-L2,5-dJ-pyrimidine having a melting point of 160 - 163 obtained ^0C.

Example 41

Conversion by amination:

200 mg of 6-0arboxy-5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido * £ 2,3-dI-pyrimidine and 1.0 g of octadecylamine were added to 30 ml of ethanol and the mixture was 6, Brought to reaction in a closed tube at 105 ^{° C. for 5 hours.} The solvent .wurde was removed by distillation and the residue was recrystallized from ethanol. There were 347 mg of an octadecylamine salt of 6-0arboxy-5f8-dihydro-. -8-ethyl-2-octadecylamino-5-oxo-pyrido [2,3-dJ-pyrimidine having a melting point of 160-163 ⁰ C.

Example 42

Conversion through desulfurization:

7OO mg of 6-carboxy-5,8-dihydro-8-ethyl-2-methylthio- -5-oxopyrido- | ^ 2,3rdJ-pyrimidine were dissolved in 30 ml of dioxane and, with the addition of 4 g of Raney-Hickel (W- 4) the solution was refluxed for 3 hours. After the reaction had ended, the Raney nickel was separated off by filtration. The piltrate was distilled and the residue was recrystallized from ethanol. 420 mg of 6-0arboxy-5,8-dihydro-8-ethyl-5-oxopyrido resulted _! - |] 2,3-dJ-pyriinidin melting at 219-222 ⁰ O.

009846 // I 851 -. 'BAD ORIGINAL

Claims (1)

Claims 1) 5,8-dihydro-5-oxopyrido- ^ 2,3-d7-pyrimidine derivatives the general formula given below: wherein R ^ is hydrogen or a lower alkyl radical, Κλ is hydrogen, a lower alkyl radical, a hydroxyl group, a halogen atom, a lower alkoxy radical, an amino group or a lower alkylthio radical, R, hydrogen, a lower alkyl radical, a hydroxyl group, a lower alkoxy radical, a lower one Alkylthio group or a radical of the formula -N (^ ₁₁ , where R ^{1 is} hydrogen, an alkyl radical, a cycloalkyl radical, an amino radical, a hydroxyalkyl radical or an alkyl-substituted aminoalkyl radical, R "is hydrogen or an alkyl radical, R ¹ and R" are the same or different and R ¹ and R ^N can be connected to form a heterocyclic ring, and R ^ are hydrogen or «Inen alkyl radical · 009846/1851 BAD GRlQlNAl. 2) 5,8-dihydro-2,4-dimethyl-6-ethocycarbonyl-5-oxopyrido- ^ 2,3-d7-pyrimidine. 3) 5, e-Dihydro-δ-ethoxycarbonyl-S-methylthio-S-oxopyrido- ^ 2,3-d7-pyrimidine. 4) 5,8-Dihydro-6-ethoxycarbonyl-8-ethyl-2-methythio-5-oxopyrido- ^ 2,3-d7-pyrimldine. 5) 5,8-Dihydro-6-ethoxycarbonyl-2-methoxy-5-oxopyrido £ 2,3-d7-pyrimidine. 6) 5, S-Dihydro-ö-ethoxycarbonyl-e-ethyl ^ -methoxy-5-oxopyrido- ^ 2,3-d7-pyrimidine. 7) 5,8-DihydΓo-2-dimβthylamino-6-ethoxycaΓbonyl-8-ethyl-5-oxopyrido- ^ 2 _f 3-d7-pyrimidine. 8) 5,8-Dihydro-6-ethoxycarbonyl-2-hydroxy-5-oxopyrido 1 3-d7-pyrimidine. 9) 5,8-dihydro-2, A-dimethyl-ö-ethoxycarbonyl-e- 10) 5,8-DihydΓO-2-dimethylamino-6-ethoxycaΓbonyl-5-oxopyrido- / 5,3-d7-pyrimidine. 11) 5,8-dihydro-6-ethoxycarbonyl-4-hydroxy-2-methylthio-5-oxopyrido- / 2,3-d7-pyrimldine 12) 6-carboxy-5,8-dihydro-2, Α-dimethyl-e-ethyl-S-oxopyrido- ^ 2,3-d / -pyrimldine 13) e-carboxy-S · 3-d7-pyrimidine. 001 ^ 3/1 * 11 'Λ ■ 14) 6-carboxy-5,8-dihydro-8-ethyl-2-hydroxy-5-oxopyrldo- ^ 2,3-d7-pyrimidine. 15) 6-Carboxy-5, e-dihydro-e-ethyl ^ -methylthio-S-oxopyrido- ^ 2,3-d7-pyrimidine 16) 6-Carboxy-5> 8-dihydro-8-ethyl-2-methylamino-5-oxopyrIdo- ^ 2,3-d7-pyrimldine 17) 2-Amino-6-carboxy-5ιe-dihydro-e-ethyl-S-oxopyrido ^ 2, 3-d7-pyrimidine. 18) 6-Carboxy-5 »8-dihydΓO-2-lnβthylthio-5-oxopyΓido- IjL, 3-d7-pyrimldine. 19) 6-carboxy-5> 8-dihydΓO-8-ethyl-2-methoxy-5-oxopyrido- ^ 2,3-d7-pyrimidine. 20) 6-Carboxy-5, e-dihydro-e-ethyl ^ -morpholiro-S-oxopyrido- ^ 2,3-d7-pyrimidine. 21) 6-Carboxy-5, e-dihydro-e-ethyl-S-oxo ^ -piperidinapyrido- ^, 3-d7-pyrimidine. 22) 6-carboxy-5,8-dihydro-8-ethyl-2- (2-hydroxyethyl) - amino-5-oxopyrido ^ 2,3-d7-pyrimidine. 23) 6-Carboxy-5 ₍ 8-dihydΓO-8-ethyl-5-oxo-2-pyΓΓolidinopyrido- / 2,3-d7-pyrimidine. 24) 6-carboxy-5 > e-dihydro-e-ethyl ^ -isopropylamino-S-oxopyrido- ^ 2,3-d7-pyrimidine. 25) 6-carboxy-5,8-dihydΓO-2-dimβthylamino-8-ethyl-5-oxopyrido- ^ 5,3-d7-pyrimldine 26) 6-Carboxy-5 , e-dihydro-e-ethyl-S-oxopyrido- 1 3-d7- * pyrimIdin 0 0 9 8 4 6/1851 BAD ORtGINAU " 21) Ci-carboxy-a-cyclohexyl amino-5,8-dihydro «8-ethyl-5-oxopyri do- ^ 2 ₁ 3 ~ d7-pyrimidine, 28) 6-carboxy-5 , e-dihydro-8-ethyl-2-n-hexylaraino- "5-oxopyrido -, / 2,3-d7-pyrimidine" 29) Zn-Butj'lamino-G-carboxy-S, 8-dihydro-8-ethyl-5'-oxopyrido- ^ 2 , 3-d7-'i> yrimi din. 30) 6 «carboxy-2
dihydro 'O-l'thyl- ^ 31) 6-Carboxy-5 _f 8-dihydro-2- / 5- (dimGthyla! Nino) · propy 1 amino7-8 ~ ethyl - ¹ J- oxc> pyri άο- / 1ί, 3-d7 ~ pyr imidi n « 3 2) f »-Carbox; r ~ i>, 0-di hydro-8-äthy3 - 2- Sthylanü no - ^ - oxo- 33) 6-carboxy ~ 5,8 ~ dihydro-8 ~ methyl-2-methylthlo- i "« oxopyrido ~ / 2, 3-d7 ~ pj "rimidin" 34) 6-carboxy-5 ₁ 8-dihydro "2-dimetbyliimlno-ii-raetliyl- 5-oxopyrido- / 2,3 -d7 ~ pyi imidine, 35 ) 6-Carboxy ~ 5, e-dihydro-Z-methylthio-S-oxo-e-n-propylpyrido- ^ 2,3-d7-pyrimidine. 36) 8-n-Butyl-6-carboxy-5 _# 8-dihydro-2-methylthio- P-1 3-d7-pyrimldin 37) 6-Carboxy-5 ₁ 8-dihydΓO-8-isopΓopyl-2-IBβthylthio-> - ^ 2,3-d7-pyrimldine. 38) 8-n-Butyl-6 ~ carboxy-5 , e-dihydro- ^ - dimethylamino- ' • 5-oxopyride- / 2,3-d / -pyrimidine. 39) f-carboxy- ^ ye-dihydro-? fi-nj rof pji. Uo / pt ^ - ^ - pyrimid'η BADORfQiNAl. 4ο) 6-carboxy-5,8-dihydro-2-dimethylamino-8-iso-. oxopyrIdo- ₁ / 2,3-d7-pyrimidine. 42) 6-Carboxy-5, S-dihydro- ^ - dodecylamino-e-ethyl-5-oxop7rido- ^ _f 3-d7 ~ pyi * imidindodecylamine salt. 45) 6-Carboxy-5,8-dihydro-8-ethyl-2-octadecylamine! No ~ Jt 5-oxopyrido- ^ 2,3-d7-pyrimidinoctadecyclamine salt, 44) 6-carboxy-5,8-dihydro-4-hydroxy-2-methylthio ^r > -oxopyr Ldo- / 2,3-d7-pyrimidine. 45) 6-carboxy · 5,8-dihydΓO-2-dimethylamino-5-oxopyrLdo- ^ 2,3 ~ d7 "pyrimidine. 46) Ethyl-N- (2-inefchylfchlo-4-pyrimidinyl) -aminomebhylOiimalonab. 47) Äfchyl-N- (2-me fchoxy-4-pyrlmidinyl) -aminomethylenmaLon-At, 4a) 6-carboxy-5,8-dihydΓo-2-Illethüxy-5-oxopyrLdo- * ^ 2,3-d7-pyrImLdIn. 49) I thy1-N- (2-dime bhylamino-4-pyrimidinyl) -N-äthylaminome fchylenmalonat. 50) Process for the preparation of 5,8-dihydro-5-oxo ~ pyrido- ^ 2,3-d7-pyrimidlnderivaben according to claim 1, characterized characterized in that an aminopyrimidine derivative of the formula: 009846/1861 BATH ORIGINAL (D Alkoxymethylene malonic acid derivative of the formula 'COOR ^ COOR RO or a shark pyrimidine derivative of the formula (II) mLt an aminomethylene malonic acid derivative of the formula HN (ix) 0098A6 / 1851
BADORLGiNAL to an N- (6-pyrimidinyl) aminomethylene malonic acid derivative the formula C- Il IJ ' Π / COOR COOR (III) reacting "aieeo compound of formula (III) put bringing about a Ringschiussee to form the 5 _f 8-dihydro-5-oxo ~ pyrido / 2 _f 3 ~ d7-pyrimidine derivative of the formula: 00R « (IV) heated and optionally the compound of formula (IV) obtained by hydrolysis in the presence of an alkaline or acidic saponification agent, treatment with an alkylating agent, amination with an amine of the formula -N ^ η der Erhiteen in the presence of a desulfurization ε-katnlyfatcrs ru another derivative of the formula (IV) \ m-BQi " i,! ei in the torsteiiden formulas BATH ORIGINAL. R _{1 is} hydrogen or a lower alkyl radical, R _{2 is} hydrogen, a lower alkyl radical, a Hydroxyl group, a halogen atom, a lower alkoxy group, an amino group or a lower one Alkylthirest, R, hydrogen, a lower alkyl radical, a hydroxyl group, a lower alkoxy radical, a lower alkylthio radical or a radical of
Formula -N (^ ₁ ", in which R ^{1 represents} hydrogen, an alkyl radical, a cycloalkyl radical, an amino radical, a hydroxyalkyl radical or an alkyl-substituted aminoalkyl radical and R" represents hydrogen or an alkyl radical, R ¹ and R "are identical or
different and R ¹ and R ″ can be linked to form a heterocyclic ring
R ^ hydrogen or an alkyl radical,
R is a lower alkyl radical and
X is a halogen atom
mean. 51) Process according to claim 50, characterized in that a compound of the formula (IV) in which Rj, Rg and R ^ have the meaning given above and the radical R _{5 is} an «OH group, a lower alkoxy radical, a lower one Alkylthirest or «ϊΚ ^ _{ί {} (R ¹ and R" (Ϊ098Α6 / Ί 851 BATH ORIGINAL the meaning given above) represents »in the presence of an alkaline or acidic saponification agent to form a compound of the formula below hydrolyzed, in which R _{1 is} hydrogen and R * represents an OH group. 52) Process according to claim 50, characterized in that a compound of the formula (IV) in which R ₁ , Rg and R, have the meanings given above and R ^ is hydrogen, with an alkylating agent for the preparation of a compound of the formula below 0OR, 009846/185 1 in which R ^ consists of a lower alkyl radical and R ₁ , Rg and R, the meaning given above, treated. 53) Process according to claim 50, characterized in that a compound of the formula (IV) in which R ₁ and Rg have the meaning given above, R is a lower alkoxy radical or a lower alkylthio radical and R ^ is an alkyl radical »nit an amine of the formula -N ^ * to prepare a compound of the formula below 0OR. ^R 4 in which the radicals R ₁ , R ₂ and R ^ as well as R 'and R * have the meaning given above. 54) Process according to claim 5o, characterized in that a compound of formula (IV) ₉ in which Rj »R ₂ and R ^ have the meaning given above and R _{5 is} an alkylthioreate, in the presence of a ·· desulfurization catalyst for the preparation of a Compound - the formula below 009848/1851 II COOR in which the radicals R ₁ , R ₂ and R ^ have the meaning given above, heated, 55) Modification of the process according to claim 50 for the preparation of an N- (6-pyrimidinyl) «- aniinoraethylenmalonsäurederivats of the formula (III), characterized in that an aminopyrimidine derivative of the formula (T) with an alkoxymethyteimalonic acid derivative of the formula (II) or a halopyrimidine derivative of the formula (I ¹ ) is reacted with an aminomethylene malonic acid derivative of the formula (II ¹ ) and the compound thus formed is isolated. 009846/185 1 BAD ORtGfNAL