DD298928A5 - NEW SUBSTITUTED HETEROCYCLIC FOOT RINGS, THEIR MANUFACTURE AND USE - Google Patents

Abstract

The invention relates to expandable polymer beads, to a process for their preparation and to materials and moldings obtainable therefrom. The bead polymers are prepared by polymerizing at least one vinylaromatic monomer in aqueous suspension in the presence of from about 0.01 to 0.6 * of at least one polyethylene wax and from about 0.005 to 0.1 * of at least one nonionic surfactant having an HLB of from 7 to 16 , It is possible with the expandable bead polymers according to the invention to produce materials and moldings which in particular can have a low thermal conductivity. In the production of materials and molded articles from the novel bead polymers, very short cooling times and thus correspondingly short demoulding times can be achieved {polymer beads; Method; Formkoerper; vinyl aromatic monomer; Suspension; Polyethylene wax; cooling time; demolding; interfacial agent; thermal conductivity}

Description

implemented by conventional methods

and, if desired, converting bases obtained into acid addition salts, and / or racemates into enantiomers or enantiomerically enriched forms, respectively, and / or quaternizing compounds with tertiary nitrogen in R ₃ , such as in pyridyl, with suitable lower alkyl derivatives.

Dio invention relates to new substitute hotorocyclic five-membered rings, their preparation according to known methods and their prewound as Wirk toffo In Arznolmittoln. Dio nouon Vorbindungon ontsprechon dor formula

MU

I ¹ I

> ¹ l

R ₁ -QT vR

•, (I),

Q ¹

Q "-XYQ ^HI -R ₃

It says M, U is N, N-lower alkyl, CH, C-lower alkyl; T, V, W for N or Γ .;

In addition, M or V can be an S atom, if gleichzoitig V odor M stands for an N atom, while the

Ring members T, U, and W are C atoms;

and the condition between M, T, U, V, and Wslnd as far as possible double bonds, B for an o- or bipartite ring constituent of a monohydric aromatic or

heteroaromatic ring system, in particular such, in dom B CH = CH, S, O, NR _{) e} bed tutetet; Q, Q ', Q ", Q'" for a single bond or Cr-C ₃ alkylene; R, for

EltER .. 10

(II) (III) (IV);

woboi

R ₄ , R ₅ : H, halogen, R ₁₁ , OR _n , aryl, O-aryl, aralkyl, O-aralkyl, N (R _n ) ;,

R ₄ and Rsgegemam also an optionally substituted fused Cü-C-cycloalkane ring or onkondensierten benzene ring or one dor bound to adjacent carbon atoms of the benzene ring Gruppon-N = CH-NH -, - N = CH-CH = CH-, -0- CHrCH, -, -D-CHr-CH ₁ -CHR-, -O- (CH ₂ I ₁ -JO-, -NH-CO-NH -, - N = CH-CH = N-, -HN-CO- C (R ₁₈ ) JO -, - HN-CO-O -, - NH-CO-CH ₂ , -HN-CO-CH = CH -, - HN-CO-CH ₂ -CHr-;

R ₈ : H, halogen, R ₁₁ , ORnOilorAryl;

R ,: H, halogen, Ru, ORn, aryl or aralkyl;

R ,: H, halogen, R ₁₁ , ORn, aryl, aralkyl, N (Rn) ₁ ,

R / and Rigomolnsam also oinon onkondonslerton gogobononfalls substitiorton

C ₆ -C 12 cycloalkeno benzene ring, R ₉ , R _tO : H, halogen, Rn, ORn, N (Ru)], aryl, O-aryl, arolky I, O-aralkyl,

R (and Rio gomolnsam also olnen gogobononfalls substitiorton Hondondonsiortcn

C ₆ -C ₇ CyClOlkOn- or benzene ring; D: S, O, NR ,,;

E, E ', E ", E'" CH, N, where in the case of group III not more than two, in case of group IV not more than

droldt r Symbolo E-E '"for N stohen; Rn: H, C ₁ -C ₁₁ -Aikyl, the unsubstituted or unsubstituted dicorin soin may be substituted by up to

5 haloatomo, N (R ,,); Aryl, O-aryl, a Cj-C ₇ cycloaliphaton or an N-hotorocycle which is bonded to the alkyl via the ring nitrogen atom and may contain it as woitoros hoterorimglgliod O, S, or NR ₁₈ ; Alkenyl or alkynyl with a total of up to

OC-atomon;

for H, a saturated or unsaturated aliphatic radical having up to 8C atoms, the 0-, S- or NR ₁₈ -interrupted and substituted by up to five haloamines, OH, O-acyl, oxo, aryl or O-aryl substituted soin and which may also be linked to the five-membered hoterocycle via oxygen; for an optionally substituted by R, g, OH, oxo, N (R ₁ (Ij, substituted, saturated or unsaturated, gogebononfalls via Sauorstoff or C, -C ₄ alkylene to the five-membered heterocycle C) -C; cycloaliphatic ring; for a group (CH ₂ I _n -NR ₁ R ₀ In = O ₁ U or 3), R and Rt, H, or a saturated or unsaturated, gobobonon-based, dodecarbonate aliphatic rust with up to CCAtomon, also OH or N (R _In addition, for a Cj-C ₇ -cycloaliphatic rust, the entire group of NR, R _{b may} also be substituted for a 5-7gliodrigen ring which may contain, as additional ringglio, O, S or NR ₁₉ ; mono- or multigrain donor substituents preferably as aromatic carbocyclic or nitrogen-containing heterocyclic rust, the latter optionally being a nitrogen or a carbon atom on Q-Y-gundenes, insbosondorone

(V)

(V)

SX

14 R

15

(VI)

(VII)

(VIII)

(IX)

(X)

4

13

(X ¹ )

G: S, O, CH ₁ CH = CH, N-CH, CH = N, NN, NR ₁₆ ;

L, L ': N, CR ₁₆ ;

R ₁₁ : H, (O) ₀ -I- (C ₁ -C ₄ -alkyl), aryl, O-aryl, aralkyl, halogen, OH, R ₁₁ : H, (O) (M- (C ₁ -C ₄ -alkyl) wherein the alkyl chains are each OH or up to five times

alkenyl or alkynyl having up to 6C atoms or halogen, R ₁ ) and R _(J gomolnsam also oinon gogobononfalls substituiorton ankondonsiorton benzene ring,

R ₁₄ : H, halogen, CN, OH,

(0) oi- (C 1 -C ₄ -alkyl) (wherein the alkyl may be substituted by up to 5 halogeno), N (Rn) ₂ , alkonyl-odor alklnylrosto with up to 6C-atomone, CO- (C-) C ₄ -alkyr), CO-aryl, aralkyl, aryl, O-aryl, a rust of the forms! Ill or IV;

R ₁₅ : H, halogen, OH,

(0) o-HC, -C ₄ -alkyl),

optionally substituted by OH or up to 5 halogen atoms, R ₁₄ and R _{15 also} together represent an optionally substituted butiocene-fused homocyclic or heterocyclic five- to seven-membered ring, wherein up to two Ringgliedor heteroatoms from the group N, NRu, O and S soin can;

R _{16 is} H, C 1 -C ₄ -alkyl;

R ₁ , for H ₁ (O) (M-Ct-C ₄ -AlkVl, halogen; X-Y represents a single bond, a divalent bridging group of Formol CONR ₁₆ , CSNR ₁₆ ,

C (NH) NR ₁₆ , NR ₁₆ CO, SO ₂ NR ₁₆ NR ₁₆ SO "CONR" NR _le , NR ₁₆ CONR ₁₆ , NR ₁₆ C (NR ₁₆ ) NR ₁₆ , NH ₁₆ CONR ₁₆ NR ₁ ,, CO ( CH ₂ ) ,. ₃ NH, NH (CH ₂ ),. JCO, SOj (CH ₂ ),., NH, NH (CH ₂ ), ₃ SO ₂ , and when the grating R _{3 is} linked to Q '' via a carbon atom and at least one of the groups Q "and Q '" represents a single bond, also CO or O, with the proviso that the group 0 "-XY-Q" does not stand for -O-IC ^ C ^ alkylene) -, wonn R _{3 is} a gogebonenfalls substituiorton pyridyl, pyridazyl, pyrimidyl odor pyrazinyl and B is CH = CH.

The compounds may optionally be in the form of single spatial isomers and their mixtures and / or acid addition salts.

The symbols within the scope of the above definitions preferably have the following meaning: B: CH = CH, S, NR _ie or O;

R ₁ : a group of formula II wherein R ₄ , R _s , R ₆ H ₁ C ₁ -C ₄ -alkyl,

C ₁ -C ₄ -alkoxy or halogen, R ₄ also aryl, aralkyl, aryloxy or N (Rk)] sowlo C ₄ -C ₁ j-alkyl or -alkoxy, when R ₄ and R _{1 are} H, fotnor R ₄ and R ₆ gomol.isam ankondonslertos C ₄ -C ₇ cycloalkone, O- (CH ₁ I ₁ .. _r O odor N-CH-NH (gobundone an bonachbarto C-Atomo), and, where R _{4 is} hydrogen, also olnen ankondonslorton Bonzolring; j.no Qruppo dor Formol III, in which D obtains the above meaning, highests olnos dor Symbolo E, E ', E ", E'" N bodoutot, while dio

remaining CH are; R ,, R, H ₁ C ₁ -C ₄ -alkyl,

CrC ₄ -alkoxy, Halogon,

fornor, for R ₍ equal to H, Rr also C ₆ -C, j-alkyl or aryl,

R; and Ri together also olon ankonondonsiorton C ₆ -C ₇ CyClOnIkOn- odor benzo ring bodouton;

olno group dor Formol IV, in which of the symbols E, E ', E ", E'" are not more than twelve N; R ₉ , R ₁₀ Halogon, R ₁₄ , OR ₁₄ , N (R ₁₄ ) ,,

R ₁ also aryl, O-aryl, aralkyl and R _a and R _io gemolnsam also Elnon ankondonslorton Ct-C; Cycloalkonring or Bonzolring bodouton;

H, OH, saturated or unsaturated aliphatic rust with up to 8C-atom, Cj-Ce-cyclonyl, up to five-fold halogen-substituted C ₁ -C ₁ -alkyl, or CH) OCH ₁ CH; a group of formol V, V , V ", V", VII or IX, wherein

G, L, L ', R ₁₄ and R ₁₇ dio oblgo structure habon; Rn: Rietst;

Ri ₁ : Ri «, Aryl or Halogon, R ₍₎ : Ri ₄ . Alkenyl with up to 4 C atomons,

R ₁₁ and R _{1, in} turn, also extrude non-condonal bonzo ring; R ₁₄ : Ri ₄ . Halogen, CN, Cf ,, CO- (C _r C ₄ -alkyl), OR ₁₄ ;

R ₁₄ : R ₁₄ , Halogon odor OR ₁₄ ; A, Q, Q ', Q ", Q" and XY are as defined above.

Insofar as the compounds according to the invention comprise a pyridine ring, in particular in R ₁ , its nitrogen atom may be in quaternized form. As an additional group, the N-atom is N-N-alkyl or aralkyl. Horvorzuhobone are C, -C ₄ alkyl and Bonzyl.

In Formula V, olno (and only oine) thrusts gostricholton Linlon for oino Doppolvorbindung. Goht sio of dom nitrogen atom, falls (R ₁₄ ) (M weighed, ie, the index has don word "0".

Bosondor's horvorzuhobon are erroneous dor obigon Dofinltionon dio compounds, in donon dor fivegliodrigo hotorocyclus oino of the groups

represents;

Q and Q ¹

R ₁ QN

N,

R ₁ Q-

'N

N -

CH = CH or S ost;

the obigo Bodoutung hai;

oino single bond or CH ₂ darstollone,

Ci-Ca-alkylene, preferably iodine oino single bond;

a single bond or, if XY is CO, also CH];

stands for the groups Il and III, where

R ₄ , R "and R ₄ dio have the above-mentioned preferred properties, such as D, E, E ', E", G, L, L ", R j, R ₁₁ , R ₁₄ , R ₁₄ ,

R -

R ₇ , R ₄ H, CC.-alkyl, C ₁ -C ₄ -alkoxy, R ₄ also aryl, R ₇ and R ₄ together also aonkondensiorton benzene ring or C " -C ₇ cycloalkene ring;

is H, C ₁ -C ₃ alkyl, cyclopropyl, phonyl, CF ₃ or allyl;

is one of the groups V, V, V ", V", VII or IX, wherein V is preferably NR ₁ J;

Ru (for R), phenyl, halogen;

Ri j (for R, 'odor gomoirisam with Rn also (for Elnon ankotulonslorton Boniolrlng ctoht;

R ₁₇ H ₁ CH) ₁ OCH) OdOrCIiSt, (for CONR ,,, CSNR ₁₆ , NR ,, CO, SO ₁ NH, *, NH "SO" NR _U CONR, (, CO (CH,),.) NH , COCH, odor o stoht.

Oio nouon Vorbindungon can vorliugon as froio Bason odor as Stluroadditlonssalto. Woorhin horvoriuhobon are the precursors of Formol

Q - XY-R,

woboi dor fün (gliodrigo hotorocycle

R ₁ QN, N,

N N

Ii "

or

CH = CH, S;

Q ":

Single bond /

 Η

16

R ,: R _k :

m, Rn. R ₀ :

R _16:

Ci-C ₄ -AlkVl ₁ CI ₁ Br,

Cj-Cj-cycloalkyl;

anconstituted Cs-Cfcycloalkene or benzene ring;

H, Cl, CH ₁ , C ₁ -C ₄ -alkoxy, CF ₃ , N (R, _e ); for the case of R ₀ , H is R _n and R _{n is} quomoinsam

also an ankondonsiortor Bonzolring odor OCH] gobundon an bonachbarto C-Atomo;

H, C, -C ₄ alkyl, N (R ") ₂ especially N (CH ₃ ), and N (C ₂ H ₆ ) ,;

CH ₁ , C ₁ H ₁ ;

CONH, CSNH, NHCO, SO ₁ NH, NHCONH, COCH ₁ , CH ₂ O;

NO.

where one of the symbols is L, L ', L "is N, dloandorone is CHtohon, and R _{p is} H or CHj. Wolter horvorzuhobone are the following compounds:

R _T

y -R

in which the five-membered hotorocycle

or

means

R ₁ : Naphthyl as well

R ¹

R ¹

R ⁽

C ₁ -C ₄ -alkyl ₁ CI ₁ Br,

fused cyclopontone or cyclohoxy ring;

H, Cl, C, -C ₄ alkoxy, Cl, CF ,, CHj; H, C ₁ -C ₄ alkoxy, Cl, CH ₁ ; boldo together OCH ₁ O on adjacent C atoms;

H, CHjO, CH ₁ ;

CONH ₁ CSNH.

For the above definitions:

Insofar as symbols in a formol occur several times, they can have the same or different meanings. Unless otherwise indicated, the hydrocarbon chains can be unbranched or branched. 'Halogen' means fluorine, chlorine, bromine and also iodine; Sls Halogenatomo in aliphatic radicals are fluorine and chlorine to emphasize. Corresponding radicals are z. CF ₃ , OCF ₃ , CF ₁ CF ₃ , CCIF ₁ . "Aryl" is preferably phonyl or naphthyl. "Hoteroaryl" is also to be understood as meaning those radicals which are composed of aromatic and hoteroaromatic rings, eg. For example, quinoline, quinazoline. As "aralkyl" are those aryls or Hetoroaryle referred to, which are bound via bine goradkettige or branched alkylene bridge.

The aromatic or heteroaromatic Gruppon may be mono- or polysubstituted and may each have the same or different substituents. Substituonton are halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy (which may also be halogen substituted), M (Ri ₈ Ij, NO _2, lower alkenyl or alkynyl, CN, aryl, Cj-C ₇ -Cycloalkyl, COOR ₁₉ , CON (R ₁₆ ) J, SO ₂ N (Ru) ₂ , 0-aryl, O-aralkyl, NHSOj- (C ₁ -C ₄ alkyl), OH, NR ₁₈ COR ₁ , (wherein R ₁₈ denotes an aliphatic or cycloaliphatic radical having up to 7 C atoms, N (R n) ₇ or H. The term "lower chloride" denotes rust with up to 6, preferably up to 4 C atoms.

While halogen, alkyl, or alkoxy can occur three times on a single ring as a substituent (in exceptional cases, four or five substituents are possible on the phenyl), the remaining substituents in allgomolnone occur only from oln to dhlmnl. The total number of substituents is generally not more than that of the olefin ring. In the case of halogen atoms, gegobononfalls In mixture with alkyl · or alkoxy rust, may gegobononfalls also up to 5 Substltuonton on elnom ring be present. It appears that the possibility of substitution by hotornatomo in the ring can be reduced. For example, if Group IV is the rust

N = N '

bodoutot, only oln substituent (i.e., Rj) may be present.

As substituents In the sense of the above statements, especially nonnon: F, Cl, Br, CHj, CjH ₁ , tC ₄ H |, n-Cj-H _; , 1-C ₁ H ₇ , OCHj, OC ₁ H ₄ , CF ,, OCF ,, benzyl, cyclopropyl, phenyl, allyl, propargyl, COOCH ₁ , COOC ₂ H ₆ , CON (C ₂ H,), SO ₂ N (CH,), NHSO ₂ CH ,, NHCOCH ₁ , NHCONH ₁ , phonoxy. Alkenyl and alkynyl radicals are bonded in the Rogol via a saturated C atom. Insofar as In don for XY angogobonone groups R _{) # is} included, its meaning is preferably H. Insofar as Rn is present as a substituent in groups II, III and IV in addition to other substituents, the chain length changes

preferably up to 4 gliodar. Insofar as Rn ol includes hetorocycle, it is a five to three-membered, preferably non-aromatic ring, e.g. Pyrrolidine, piperidine, piporozln, morpholine, such rings being e.g. Nioderalkylsubstituiort soinkönnon.

As a typical representative of the groups II to IV, solon mentions: Phenyl, benzyl, 3-M> .thoxy ·, dimethylamine) · or 3-chloro-phonono, 3,5-dimethoxy, 3,5-dimothyl ·, S-mothoxy-B-trifluoromethyl, Trimothoxy or 3,5-dichloro-phonyl; Thionyl-2-yl and B-N-alkyl, 5-Phop / 1,4-Cyclopontyl, 5-Cyclohoxyl, 5-Chloro-Odor

5Bromthion-2-yl, 5-Allylthinn-2-yl;

is

wherein dioso ring systems may optionally also contain additional substituents, in particular halogeno, lower alkyl and alkoxy groups, and N (R _{I (} ) ₂ ) groups representative of R ₂ are lower alkyl and alkoxy radicals, C ₃ -C ₄ -

Cycloalkyls, halogen-substituted alkyl and alkoxy groups wio CF ₃ , OCF ₃ , C ₂ F ₆ , OCjF ₆ , furthermore CH ₂ N (Ek), as well as otv / a Methoxyethyl, ethoxyethoxy, allyl and propargyl. The group R ₃ can be varied in a particularly varied manner. Mention may be some eintachere Ringsystemo, of which R ₃

Derives: pyrrole, Pyra.'ol, N-methylpyrrole, imidazo !, thiazole, triazole, tetrazole, 1,2,4- and 1,3,4-thiadiazole, pyridine, pyridazine,

Pyrimidine, pyrazole, wherein said rings may also be substituted, e.g. by lower alkyl groups or halogen atoms. Furthermore, it should be mentioned: Phenyl, phenylphenyl, phenoxyphenyl, where these radicals, for example, by lower alkyl, Niodoralkoxy, N (R _{) e} ) ₂ , CF ₃ , halogen

may be substituted; residues derived from condensed systhemes, wio theophylline, benzimidazole,

£} ö · O-

NH '

The condylated systems may also contain additional substituent clay, such as OH, CHj, OCH, Cl. If the groups II to X 'represent fused ring systems, they may also be bound via the attached ring. The five-membered hotorocycle

can, according to the definitions of M, T, U, V, W, ol, triazole ring as

N .. N =

-N N

o in totrazole ring as N-

N-N

 N

oin imidazole ring such as R-N

: N

oin pyrazole ringing like

NO

NO

oinPyrroIring wio

NO

-NO

N-R R-N -

L-L

a thiazole ring such as N

(R = * H or lower alkyl)

The new compounds were prepared by methods known per se. Such ancestors are for example

described in:

A. Weissberger E.C. Taylor, "The Chemistry of Heterocyclic Compounds" John Wiley & Sons, New York 1981 (for the triazoles: Vol. 37, p. 34ff. and 66ff .; for the thiazoles: Vol. 34, Part 1, p. 175ff). or in S. Coffey and M. F. Onsell, "Rodd's Chomistry of Carbon Compounds "Elsevier Science Publishers, Amsterdam 1986 (for the tetrazoles in Vol. IV, Part D, μ, 211 ff, for the pyrazoles

or imidazoles in Vol. IV, Part C, p. 1 ff. «Resp. 12Off.)

Suitable processes for the preparation of the compounds according to the invention are accordingly known e.g.

1. For the preparation of the tetrazoles of the formulas Ia and Ib:

N-

 N

R ₁ QN

N (Ia) or

Q ¹

Q ¹

'S

Q "-XYQ ^MI -R.

Q ^H -XYQ "'- R ₃

Reaction of imidchloride with metal azides in solvents wlo dimethylformamide at tomporaturone of 6O-120 ° C,

N-Na

R ₁ QN ^ p. Q ¹

or Na-N

Cl R ₁ QC

N INI

NI

Q '

(XI)

Q "-XYQ ^M '-R.

2. For the Preparation of the Triazoles of Formol Ic:

- N

Q ^M -XY-Q '"- R ₃

R ₁ -N ^ .. N

Q *

Q ^M -XYQ "'- R ₃

Reaction of Imide Chlorides of Formula XI with Acyihydraziden OC (R) -NH-NHj In aprotic solvents such as toluene. 3. For the preparation of the pyrroles of formula Idundle:

(Id)

Q ^M -XYQ ¹ "R,

Reaction of 1,4-diketones or -Ketoaldehyden with suitable amines in the presence of an acid such as Tolnolsulfonsäuro with elimination of water.

(XIII) LR "H.

O O

NH ₂ Q '

or (XV)

R ₁ Q-NH ₂

(XIV) Q "-XYQ -'- R ₃

(XVI)

Q "-XYQ"'- R ₃

4. For the fulness of the Pyrnzolo dor Formol I (and Ig: N NH '

R ₁ Q-

-R,

and B (if)

NH

4 = /

QH_X_Y_Q «'- R ₃ Q" -XYQ "' - R ₃ Reversal of Corresponding Kotoaldohydes in Protic Solvents Ethanol with Hydrazine Under Heating:

H ₂ N

HCO

Q '

bsw.

(XVII)

H ₂ N

H ₂ N

(XVIII)

 \

Q "-XY-Q ^MI -R ₃

Q ^M -XY-Q '"- R ₃

5. For the preparation of the thiazoles of the formulas I h and Ii: N-

R ₁ Q

Q '

(Ih) and

Q '

-XY-Q '' - R,

»3 Q" -XY-Q "'- R ₃

Reaction of a-halo ketones with thioformamide in aprotic Lösungsmittoln as Acotonitril at 0-25 ⁰ C:

Q ¹ (XIX) or

Q ^M -XY-Q ^MI -R ₃

R ₁ Q-

NH,

Q "-X-Y-Q '' -

(XXI

β. For the preparation of compounds of formula I, in dones XY CONH, CSNH, CO (Cl I ₂ Ii ₀ NH, SO ₁ NH or SO, (CH,),., NH bodoutot: reaction of compounds of the formula

MU

Q ·

(XXl)

Q "-X * -Z

(Z - OH, halogen, Nioderalkoxy, Nioderacytoxy; X '·> CO, CS, CO (CH)),.], SO ₂ , SO _a (CH ₂ ),. ₃ )

with Amir> n dor formula

H, N-Q '' '- Ri under usual conditions, eg as described in Houben-Weyl VIII, 653 (f and E 5,941 (F.sbeschriobon.

(XXII)

7. For the preparation of compounds dor Formol I, in new X-Y NHCO or NHCONH bodoutot: Umsotiung of amines of formol

R ₁ QT VR.

ν » _f y '

(XXIII)

Q '

Q ^M -NH ₂

with carboxylic acid or carboxylic acid derivatives

Z-CO-Q - R, (XXIV)

or isocyanates

OCN-Q '"- Rj (XXV)

still common methocion.

If desired, according to methods 1 to 7, first of all, Oasbn is transferred into standard catfish into sow addition salts or quatorniort, firstly containing salts in froio bases. Dio starting materials for dioic ancestors 1 to 7 may have been prepared according to bokannton methode.

Dio or inventive compounds have PAF-antagonistscho effect.

It is known that boi PAF (platelet activiorondar factor) is the phospholipid acotyl-glycoryl-other-phosphorylcholln (AGEPC), which is known as a potent lipid mediator and is released from animal and human proinflammatory cells. Among such cells are mainly basophilic and nodophilic granulocytes, macrophages (from blood and Gowebe) as well as platelets that are botoiligt at Entzündungsroaktionon. PAF shows in pharmokologischon Exporimont bronchoconstruction, blood pressure, triggering a Fhrombozytonaggrogation sowio a prolnflammotorischo effect.

Diose experimentally demonstrable effect of PAF directly or indirectly indicates possible functions of the mediator in anaphylaxis, in the pathophysiologues of bronchial asthma, and generally in inflammation. PAF antagonists have been required to elucidate further pathophysiological functions of the mediator on animals and humans as well as pathological conditions and diseases involving PAF, in particular inflammatory and allergic processes. Examples of possible indications oinos PAF antagonist are inflammatory processes of the tracheobronchial tree (acute and chronic bronchitis, bronchial asthma) or kidney (glomorulonophritis), joints (rheumatic diseases), anaphylactic conditions, allergies and inflammation in the area of the dermis (rhinitis, conjunctivitis) and the skin (eg psoriasis) as well as sepsis, endotoxins or burns due to shock conditions. Other important indications for a PAF antagonist are lesions and inflammations in the region of the gastrointestinal mucosa, wio. Shock ulcer, colitisulcorosis, Crohn's disease, stressulcus, in general peptic ulcer, but especially insulin of the stomach and ulcer duodeni; obstructive pulmonary diseases, such. Bronchial hyporreactivity, inflammatory lung disease, wio e.g. Chronic bronchitis;

Cardiovascular diseases such. B. Polytrauma, anaphylaxis, Artorioskloroso, inflammatory echo intestinal diseases, EPH-Gostoso (ederma-protoinuria hypertension), diseases of extrakorporalon circulation, e.g. Heart failure, Horzinforkt, organ damage in hypertension, ischemic diseases, inflammatory and immunological diseases, immune modulation boi transplantations of Fromdgowebon, slightly the rejection of kidney, liver and anderon transplants, immune modulation boi leukemia. Motastasone spread (e.g., boi bronchial neoplasia), CNS disorders such as. As migraine, multiple sclerosis, endogenous depression, agarophobia (panic disordor), continue to prove the compounds of the invention as cyto- and organoprotection z. For example, for nouroprotoction, such as boi Leborzirrhoso, DIC (disinhibited intravascular coagulation);

Side effects of drug therapy, e.g. anaphylactoid cataract reactions, contrast agent incidents, side effects in tumor therapy; Incompatibilities with blood transfusions; fulminant liver failure (CC ^ -indication) Amanitephalloides intoxication (tuber-toed mushroom poisoning);

Symptoms of parasitic diseases (e.g., worm diseases); Autoimmune diseases (e.g., M.Werlhof); Autoimmune haemolytic anemia, autoimmune glomerulonephritides, thyroiditis hashimoto, primary myxedema, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, iuvenilor diabetes, good pasture

Syndrome, idlopathltch «leukopenia, primarily biliary cirrhosis, ektlvo biw. chronic aggressive hepatitis (HBsAg-neg.), colitis

ulceroia and syatemltcher lupus erythomatodo »(SLE), epithelial thrombocytopenic parpura (ITP).

Immune function in AIDS, Kaposl's sarcoma, Dlabotos, juvonilo diabolo *, diabolic rotinopalhia, polytraumatic shock,

hämhaglscher shock; PAF-assozllerto interaction with Qowob hormones (autocoid hormonos), lymphokinone and others

Modlatorone, inhibition of unwanted anglogonoeo. Also, it can be used in combinations, especially boi such indications, for the PAF antagoniston gooignot

are. Accordingly, the PAF antagonists z. B. with ß-adrenergics, parasympatholytics, corticostoroidone,

Antiallorgika, Sokretolytlka, antibiotics have been combined. BoI of the combination with TNP (Tumor Nokroso factor) becomes olno

bossero Compatibility (elimination of interfering side effects) of TNF orlorcht; TNF can therefore be used also in höhoron doses elnsotzon as boi soinor alloinigon application.

(Undo combination is also the application of both agents in separate Zuboroitungon and oinom gowissonzoitlichen distance projecting.) Boi dor the common application of the erfindungsgomäßon compounds with ß-Adnororgikokann a synorgltischbestor effect achieved wordon, eg In dor broncholysis. SoIu vortoilhoft Is also dlo combination dor

PAF antagonistone with immunosuppressants, e.g. Don vorschlodonone cyclosporinone. Dio noto compounds can be administered topically, orally, transdermally, parenterally or by inhalation wordon. Dio Precursors are hiorboi as active Bostandtoilo In usual Darroichungsformon before, for. in compositions, dio im

wosontlichon from an inert pharmaceutical carrier and an effective dose of the active substance bestohon, wio z. B.

Tablets, DrageOs, Capsules, Oblaton, Pulvor, Solutions, Suspensions, Inhalation Aerosols, Ointments, Emulsions, Syrups, Suppoditorien. The therapeutic and prophylactic dose depends on the nature and seriousness of the patient Krankhoitszustandes. An effective dose of the compounds of the present invention is between 1 and 100% by oral application, preferably

between 10 and 80 mg / dose, with intra-venous or intramuscular administration between 0.001 and 50, preferably between 0.1 and 30 mg / dose. For inhalation, solutions containing from 0.01 to 1.0 preferably 0.1 to 0.5% of active ingredient, forner powder and suspensions in liquefied trolbgasone should be used.

For a representative group of organometallic compounds, the following are data for the inhibition dor PAF-induced thrombocyte aggrogation IC _M mol / l (A) and the ¹ H PAF rozoptin binding solute (B) (cf., EP-A 0254245, pp. 20/21)

zusammongostollt:

Compound A (IC _M × 10 "') B (Ki (MI × 10" ×)

Tab. 1/1 3.2 1.6

Tab. 11/1 0.11 0.25

Tab. 11/2 0.12 0.19

Tab. Hl / 4 0.36 5.1

Tab. V / 2 0.63 2.8

Formullerungsbelsplelo

1. tablets

Composition: Active ingredient according to the invention 30Gow.-Toile Stearic acid ÖGow.-Great Grape sugar 564Gow.-Tollo The ingredients wordon in standard Woiso to Tabletton of 600mg weight prepares. If desired, the active substance content can be increased or decreased and the amount of glucose reduced accordingly

or increased.

2. Supposltorlen

Composition: Active ingredient according to the invention 80 parts by weight Lactose, powdered 45Gow.-Toilo Cocoa butter 1 575 parts by weight The Bostandtoile are vorarboitet in the usual way to Suppositorion of 1.7g weight.

3. Inhalation powder

Micronized active ingredient powder (compound of formula I, particle size about 0.5 to 7 pm) wordon in an amount of 0.02 mg with 10 mg of micronized lactose and gegobenonfalls appropriate amounts of other active ingredients in hard gelatin capsules filled. The powder is made from conventional Behandlungsgeräte, z. B. according to DE-A 3345722, inhaled.

4. Doseraarosol

Active ingredient according to the invention 0, BGow .-%

Sorbitan trioleate O, 5% by weight monofluorotrichloromethane and

Difluorodichloromethane (2: 3) 99.0% by weight The mixture is filled in Dosleraerosolgorttte usual kind. The Doslorvorrichtung is ouegelogt example, that

0.05 ml of the preparation has been abgogobon per stroke.

The Boschiolo Boispiolo below are intended to explain the Hoistollungsvorfahron nflhor. example 1

2.0 g 1 · (4Χβ ^ βΟιοχνρΙιβηνΙ) · 5 · ηιοΐΙινΙ · 2 · (3.5 · ΙοΙιΙθφΙιοηνϊ) · ΙηιΜβζοΙ, (horgestollt from S.B-dichloro-a-acotamldocotophon, m.p.

95-98 ⁰ C, by reaction with 4-Aminobonznosiluroothylostor), in 60 ml of ethanol and 20 ml of 10% sodium hydroxide solution

Sour soap. The SBure is then refluxed with 50 ml of chloroform and 2 ml of thionyl chloride for 2 hours, the chloroform

Abdostilliort and SSurochlorid in 60ml dioxane spiked. The solution is heated at 80 ° C for 30 minutes, then with 200 ml

Diluted with ice water. The product is extracted with chloroform, gotrocknot and distilled off. The title prelude is converted from ethanol; Mp: 94-98'C Example 2

4 (5- (3S-dimethoxyphenyl) -1Hletrazol-1-yl] -N (3pyrldyl) -benzamld

3.0 DimothoxybonzoosiUiro is converted into the chlorosulphuron in chloroform reflux with thionyl chloride and converted to the amide diososulphonylated with 4-aminobonozoic acid liquor in the presence of triethylamine in warm water.

The amide is refluxed in toluene under reflux with phosphorus pentachloride. After removal of the solvent, the imide chloride in dimethylformamide with sodium azide is brought to room temperature Dor erheltone ester is heated in methanol with 20% aqueous sodium hydroxide solution for 60 minutes under reflux. The solution will be

acidified, dioic acid isolated and recrystallized from methanol; Mp 220-222'C.

6.6 g of the resulting acid were boiled in 150 ml of chloroform and 6 ml of thionyl chloride for 2 hours under reflux, dos

Chloroform is distilled off and the acid chloride is heated in 100 ml of dioxone with 4,6 g of 3-aminopyridine at 80 ° C. for 30 minutes. It is then diluted with ice water, the precipitate precipitated off and recrystallized from ethanol. The title compound is obtained in a yield of 4 g (49.8% of theory), mp 217-219'C. According to don first-hand examples, the compounds of the folly-London tables can also become orhalton. Table I Compounds of the formula

CONH-R,

R

Mp I ⁰ CI

phenyl

6-Mothylthien-2-yl

3,5-Dimethoxyphonyl

3,5-di-t-butyl-4-hydroxyphenyl

3-methoxyphenyl

3,5-dichlorophenyl

3,5-dichlorophenyl

methyl

methyl

methyl

methyl

methyl

isopropyl

methyl

3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl

179-181

94-98

Table II compounds of the formula

CONH-R.

"ι

Mp I ⁰ C

3,5-Oimothoxyphonyl

3,5-Oichlorphonyl

2-thionyl

3,5-di-t-butyl-4-hydroxyphonyl

3-Dimothylaminophonyl

3-chlorophenyl

Table III Compounds of Formol

CONH-R,

Methyl Methyl Methyl Mothyl Mothyl Mothyl

3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 4-pyridyl 4-pyridyl

179-101 187-190

p. ra

1 2-naphthyl 3-pyridyl 203-204 2 2-Thlonyl 3-pyridyl 195-200 3 2-Chlorphonyl 3-pyridyl 4 3,5-Dimethoxyphonyl 3-pyridyl 217-219 5 3,5-di-t-butyl! -Hydroxyphenyl 6 3-Mothoxy ·! mothylphonyl 4-pyridyl 7 3-Trifluormethylphonyl 3-pyridyl 8th 3-Chlorohonyl 3-pyridyl 217-220 9 phenyl 3-pyridyl 176

Table IV Compounds of the formula

CONH-R.

Mp I ⁰ Cl

3,5-Dlmothoxyphenyl

2-Thlenyl

3,5-di-t-butyM-hydroxyphonyl

3-pyridyl-3-pyridyl-3-pyridyl

232-236

Table V Preliminaries of the formula

CONH-R.

R ₁

Mp CC]

2-thienyl 3,5-oxethoxyphenyl

Methyl methyl

3-pyridyl-3-pyridyl

164-166 185-187

Claims (7)

Claim ": in the dor
M ₁ U
T, V, W Q "-X-Y-Q '' - for N, N-N-alkyl, CH, C-N-undorolkyl; stands for N or C and; M or V may additionally co-routinate an S atom if simultaneously V or M is an N atom, while the ring members are T, U, and W are C atoms; and the Bodingungon between M, T, U, V, and W as far as possible double bonds are,
B for oinone one- or two-membered ringbostand oily oinos one or moschkornigon aromatic or hotoroaromatic ring system, in particular one those in which B is CH = CH, S, O, NR ₁₆ bodoutet;
Q, Q ', Q ", Q'" stand for a single bond or C, -C ₃ alkylene; R, for ^l 5 ^[ 6 N V " ' E ¹ 10 (ID stands, where (III) (IV); R ₆ : R ₇ : R ₈ : D: H, halogen, R ₁₁ , OR _n , aryl, O-aryl, aralkyl, O-aralkyl, N (R _n ) ₂ , R ₄ and R ₅ together also represent an optionally substituted benzene ring or one of adjacent C atoms of the benzene ring bonded groups -N = CH-NH-, -N = CH-CH = CH-, -O-CH ₂ -CH ₂ -, -O-CH ₂ -CH ₂ -CH ₂ -, -O- (CHj ) ₁ -JO-, -NH-CO-NH-, -N = CH-CH = N-, -HN-CO-C (R ₁₆ J ₂ -O-, -HN-CO-O-, -NH-) CO-CH ₂ , -HN-CO-CH-CH-, -HN-CO-CH ₂ -CH ₂ -; H, halogen, Ru, OR ₁₁ or aryl; H, Haloßen, R ₁₁ , OR ₁₁ , aryl or Aralkyl, H, halogen, R ₁₁ , OR ₁₁ , aryl, aralkyl, N (Ru) ₂ , R ₇ and R ₈ together also have a fused optionally substituted C ₆ -C ₇ -cycloalkyl or benzene ring, H, halogen, R ₁₁ , OR ₁₁ , N (Rn) ₂ , aryl, O-aryl, aralkyl, O-aralkyl, Rg and R ₁ together also formulated a given rut fused Cj-Crcycloalkene or benzene ring; S, O, NR ₁₆ ; E, E ', E ", E'" CH, N, where Im foil doi group III not more than two, in the case dor Group IV is not more than three of the E-E '' symbols for N; R _{n is} H, C 1 -C 4 -alkyl, which may be interrupted or substituted by oleic acid may be substituted by up to 5 halogon atoms, N (Ri ₆ ) I, aryl, O-aryl, or C 3 -C 7 cycloaliphatic or ozone N-heterocycle, via which the ring nitrogen atom is bonded to the alkyl and dor as woitoros hotororing member O, S, may contain NR ₁₈ ; Alkenyl or alkynyl with a total of up to 6C atoms; mean; for H, oinone saturated or unsaturated aliphatic radical having up to 8C atomon, the 0-, S- or NR \ o- interrupted and joined by up to five hologon atoms, OH, O-acyl, oxo, aryl or O-aryl substituted join and may also be bound by oxygen to the five-glottal hotorocycle; for oyone gogobononefolls by Ru, OH, Oxo, N (Ri ₈ ), substitiortone, gosättigton odor unsaturated, gogebononfalls via oxygen or C, -C4 alkylene to the five-membered heterocycle pobundononCa - ^ - cycloaliphatsch ring; or for a group (CH ₂ ) _n -NR "R _b (n = 0, _{1, 2,} or 3), R ₁ and R _b H, or a saturated or unsaturated, gobobone case acid-interrupted aliphatic radical having up to 6C atoms, dor also OH or N (R, _e ) ₂ may be substituted; R _a also represents a C 1 -C 7 cycloaliphatic radical; the whole group NR ₁ Ru can also be an oonon-7gliodrigone ring, which can be an additional ring member O, S or NR ₁₆ onthaltone; is a mononuclear or polynuclear, optionally substituted, preferably aromatic, carbocyclic or nitrogen-containing heterocyclic radical, the latter being bonded to -Q '"-Y- via a nitrogen or a carbon atom, in particular for L ¹ .R ₁ ^R 12 ^R 16 (VI) (VI J) N L N - L (VIII) (IX) (X) J R 13 R ₁₄ : is; R, ₇ for XY for S, O, CH, CH = CH, N = CH, CH = N, N = N, NR ₁₆ ; N ₁ CR ₁₆ ; H, (Oo-i-ICi-C-alkyl), aryl, O-aryl, aralkyl, halogen, OH, H, (O) (M- (Cr-C ₄ -AlkVl), wherein the alkyl chains each OH- or up to can be five-fold halogen substituent, alkenyl or alkynyl alkynyl with up to 6C atoms or Halogen, R ₁₂ and R ^ gemoinsam also optionally substituted fused benzene ring, H, halogen, CN, OH, (O) (M - (Ci - (»alkyl) (wherein the alkyl is replaced by up to 5 halogen atoms substituted soyne), N (R ₁₆ ) *. Alkenyl or alkynyl radicals with up to 6C-AtOPiOM, CO- (C 1 -C ₄ -alkyl), CO-aryl, aralkyl, aryl, O -aryl Remainder of formula III or IV; H, halogen, OH, (O) (M- (C 1 -C ₄ -alkyl) optionally substituted by OH or up to 5 halogen atoms, Ri ₄ and Risgemeinsam also an optionally substituted fused homocyclic or heterocyclic five-bis Siebenring, where up to two ring members Hotero atoms from Dor Group N, NRi can be ₆ , 0 and S; H, C, -C ₄ -alkyl H, (O) _0-I-C is ₄ -alkyl, halogen; a single bond, a two chain bridging group of formula CONR ₁₆ , CSNR ₁₆ , C (NH) NR ₁₆ , NR, _e CO, SO ₂ NR ₁₆ NR ₁₆ SO ₂ , CONR ₁₆ NRi ₆ , NRi ₆ CONRi ₆ , NR ₁₆ C (NRi ₆ ) NR ₁₆ , NR ₁₆ CONRi ₆ NRi ₆ , CO (CH ₂ ) ₃ NH, NH (CH ₂ ) L ₃ CO, SO ₂ (CH ₂ ) NH, NH (CHj) ₃ SO ₂ , and, if the rust R ₃ is linked to Q '' via a carbon atom and at least one of the groups Q "and Q '" represents a single bond, also represents CO or O, with the proviso that the group Q "-XY-Q'"is not -O- (C, -C ₃ -alkylene) when R _{3 is} an optionally substituted pyridyl, pyridazyl, pyrimidyl or pyrazinyl rust and B is CH = CH, optionally also in the form of single spatial isomers and theirs Mixtures and / or of acid addition salts or Quaternisierungsprodukton. 2. Compounds according to claim 1, wherein the symbols have the following meanings: B: CH = CH, S, NR ₁₆ or O; R ₁ : a group of formula II wherein R ₄ , R ₅ / Re H ₁ C ₁ -C ₄ -alkyl, C ₁ -C ₄ -Alkoxy or halogen, R ₄ also aryl, aralkyl, aryloxy or N (Ri ₆ ) 2 and C ₆ -C ₁₂ alkyl or alkoxy when R ₆ and R _{6 are} H, further R ₄ and R ₅ together are fused Cg-Cv cycloalkene, O- (CH ₂ ) ₃ -O or N = CH-NH (attached to adjacent C atoms), and when R _{6 is} hydrogen, also a fused benzene ring; a group of formula III wherein D dio oblgo meaning hot, at most oinos dor symbols E, E ', E ", E'" N means while the rest are CH; R ₇ , R ₈ H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen, forner, R ₈ is H, R _{7 is} also C _B -C ₁₂ -alkyl or aryl, R ₇ and Ragomeinsam also elnon ankondonsiorten C ₆ -C ₇ -CyClOaIkOn- or benzene ring bedouton; a group of formula IV, wherein of the symbols E ₁ E ', E ", E'" are not more than two N; R ₉ , R _{10 is} halogen, R ₁₉ , OR ₁₆ , N (R ₁₆ J ₂ , Rg also aryl, O-aryl, aralkyl and Rg and R ₁₀ together also a fused C ^ -CrCycloalkenring or benzene ring meaning; R ₂ : H, OH, saturated or unsaturated oliphatic radical having up to 8C atoms, C ₃ -C ₈ -CyClOaIkyI, up to five-fold halogen-substituted C, -C ₃ alkyl or CH ₃ OCH ₂ CH ₂ ,
R ₃ : a group of the formula V, V, V ", V"', VlloderlX, wherein G, L, L ', Rie and R _{17 have} the above meaning; Ru: R _ie is; R ₁₂ : R ₁₆ , aryl or halogen, R ₁₃ : R ₁₆ , alkenyl with up to 4C atom, R ₁₂ and R ₁₃ gemoinsam also mean a fused benzene ring; R ₁₄ : R ₁₆ , halogen, CN, CF ₃ , CO- (C ₁ -C ₄ -alkyl), OR ₁₆ ; Ri ₆ : Ru, halogen or ORi ₆ ; A, Q, Q ', Q ", Q'" and XY are defined as above. 3. Pharmaceutical preparations, characterized by a content of a compound according to claim 1 or 2. 4. Use of compounds nech claim 1 or 2 in the treatment of diseases in which PAF is involved, in particular inflammatory and allergic processes and autoimmune diseases. 5. A process for the preparation of compounds according to claim 1 or 2 by methods known per se, characterized in that a) an imide chloride of the formula or. 9 * Q ' (XII) (T-X-Y-Q "'- R Q" -X-Y-Q -'-R., ° 3 with a metal azide in a suitable solvent at elevated temperature or that b) reacting a imide chloride of the formula XI with acylhydrocarbides OC (R) -NH-NH ₂ in aprotic solvents, such as toluene
or c) that 1,4-diketone or -Kotoaldehydo dor formula I I (XIII) O O or / ^Λ 2 Q ' (XVI) Q ^M -XYQ ¹ "R, with amines of formol or. R ₁ Q-NH ₂ (XV) (XIV) Q "-XYQ ^H '-R ₃ in the presence of an acid or that d) diketones or Keto aldehydes of the formula .0 R ₁ Q- ¹ HCO R ₁ Q- Q ' or. B (XVII) Q ' (XVIII) Q "-XY-Q"'- R ₃ in protic solvents or that one Q "-XY-Q" 'R, e) haloketones of formol O. R ₁ Q- br Q ¹ (XIX) or br Q ¹ Q "-XY-Q"'- R ₃ in aprotic solvents with thioformamide or that f) Preconnections of the formula MU R ₁ QT r-R, (XX) Q "-X-Y-Q '' - R, Q ¹  / Q "-X'-Z wherein Z = OH, halogen, lower alkoxy, lower acyloxy; X '= CO, CS, CO (CH ₂ ), _ 3, SO ₂ , SO ₂ (CH ₂ ) i-3) with amines of the formula H ₂ N-Cr-R ₃ reacting under customary conditions or g) amines of the formula MU R ₁ QT ..V-R, Q ¹ Φ = / Q "-NH, (XXI) (XXII) (XXIII) -7- 298 with carboxylic acids or carboxylic acid derivatives Z-CO-Q '"- R ₃ (XXIV) or.
isocyanates OCN-Q '"- R ₃ (XXV)