CA1167842A - 6-hydrazono-pyrido[2,1-b]quinazoline-11-ones, and a process for the preparation thereof - Google Patents
6-hydrazono-pyrido[2,1-b]quinazoline-11-ones, and a process for the preparation thereofInfo
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- CA1167842A CA1167842A CA000380416A CA380416A CA1167842A CA 1167842 A CA1167842 A CA 1167842A CA 000380416 A CA000380416 A CA 000380416A CA 380416 A CA380416 A CA 380416A CA 1167842 A CA1167842 A CA 1167842A
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- pyrido
- quinazoline
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to novel 6-hydrazono-pyrido [2,1-b]quinazoline-11-ones of formula (I)
The invention relates to novel 6-hydrazono-pyrido [2,1-b]quinazoline-11-ones of formula (I)
Description
~ ~67~
6-Hydrazono-pyrido[2,1-b]quinazoline-11-ones, and a Process for the Preparation Thereof The present invention relates to new 6-hydrazono-pyrido[2,1-b]
quinazoline-ll-ones and salts thereof, geometrical and optical isomers and tautomers thereof as well as a process for the preparation of same.
The new compounds may be used as starting materials for the prepara-tion of alkaloids. The preparation of substituted derivatives of Rutecarpine from the compounds of this invention is the subject of our copending Patent Application Serial No. 380~445.
Pyrido[2,1-b]quinazoline~ ones are known partly as alkaloids ~Chem. Comm. 267/1965/; Austral J. Chem. 151/1966/; Chem. Ber, 68J 2221/1935/;
J. Chem. Soc. 4694/1956/; Chem. Ber. 95, 2182/1962/) and partly as compounds showing Pavourable pharmacological properties (DE-PS 2 812 585, BE-PS 849 542 and BE-PS 847 011~.
The compounds of the general formula .
~, - 1 - ~' `' ' .
: . ~
1 ~ 67S~ ~
Rl ~R3 R N
/ NH
are new pyrido[2,1-b]quinazoline-11-ones. The known pyrido[2,1-b]quinazoline-11-one are disclosed in Moshy: Heterocyclic Syst~ls with bridgehead nitrogen atoms, Vo].. 2, 1153-1159, Interscience Publishers, Inc. New York, 1961.
According to the invention the new pyrido[2,1-b]quinazollrle-11-orles and acid addi-tion salts, geometric and optical isomers thereoE, wherein R, Rl, R are the same or different and stand for hydrogen, halogen, nitro, carboxy, nitrile, alkoxy containing 1 to 4 carbon atoms, alkoxycarbonyl con-taining 1 to 4 carbon atoms in the alkoxy group, alkyl containing 1 to 4 carbon atoms, amino or hydroxy or R and R together stand for methylenedioxy, R stands for hydrogen, R represents hydrogen or alkyl containing 1 to 4 carbon atoms, R stands for phenyl optionally substituted by 1 to 3 same or different substituents selected from the group of halogen(s), alkyl containing 1 to 4 carbon atorns, alkoxy con-taining 1 to 4 carbon atoms, phenyloxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group, methylenedioxy, trifluoromethyl, phenyl and dialkylamino having 1 to 4 carbon atoms in the alkyl part; or naphthyl or pyridyl and the dotted line stands for an optional double bond, may be prepared by (a) reacting a pyrido[2,1-b]quinazoline-11-one derivative of the general formula ! - 2 -'" ' ~' ' , . .
1 ~ ~7~
Rl ~ II
R R
wherein R, R , R , R and the dotted line are as defined above and R is hydrogen or formyl, with a diazonium salt of the general formula R - N2~ Cl ~ III
wherein R is as defined above; or (b) reacting a pyrido~2,1-b]quinazoline-11-one derivative of the general formula ~ N ~
Rl ~ ~ 7 IV
\ N /
\ R7 wherein R, R , R , R and the dotted line are as defi.ned above and R represents an alkyl group of 1 to 4 carbon atoms, with a diazonium salt of the general formula III, wherein R is as defined above; or (c) reacting a pyrido~2,1-b~quinazoline-11-one derivative of the general formula ~ 3 1 3 ~'7~l2 Rl = R3 V
R R
wherein R, R , R , R and the dotted line are as defined above and R s-tands for hydrogen or halogen and R is halogen, with a hydrazine derivative of the general formula R
wherein R is as defined above, and, i~ required, converting an obtained compound of the general Eormula I containing an acid group into a salt by reaction with a base, or converting a compound of the general Eormula I wi-th acid into an acid addition salt by reaction with an acid, or setting Eree a compound of the general formula I from its salt Eormed with an acid or base.
~ ~ - 4 -i ~ 67~
Process variant a) i.e. the reaction of the compound of the general formula II with the diazonium salt of the general form~la III is conducted accord-ing to (Parmerter: Org. Reactions, 10, p. 1-142 /1959/; Phillips: Org. Reac-tions 10, p. 143-178 /1959/).
According to a preferred embodinent of the process the reaction is con-ducted below 50 &, preferably at -10 to 20 &. The co~ponents may be added by adding a given compound of the formula II to the solution of the diazonium salt of the general formula III or the other way round. m e components may preferably be used in an equlmolar amount, but one of the conponents may optionally be used in a small excess. The reaction may be conducted preferably in aqueous medium, if desired in the presence of a water-miscible inert organic solvent.
As inert organic solvent alkane carboxylic acids, preferably acetic acid, propionic acid, acid amides, preferably N,N-dimethyl-formamide, alcohols, preferably methanol, ethanol, propanol, isopropanol, ketones such as acetone, methyl ethyl ketone, aromatic bases, preferably pyridine may be e~ployed. The reaction may preferably be carried out in the presence of an acid binding agent.
As acid binding agent a~cali alkanoates, preferably sodium acetate, po-tassium acetate or alkali hydroxides, preferably sodium hydro~ide, potassium hydroxide or alkali carbanates, preferably sodium carbonate~ potassium carbonate, sodium bicarbonate etc. are used.
According to process variant b) a compound of the general formula IV is reacted with a diazonium salt of the general formula III. A preferred embodlment is as given for pro oess variant e).
According to process variant c) a com~ound of the general formula V is reacted with a hydræ ine of the general formula VI. As a compound of the general formula V preferably such compounds may be used which con-tain chlorine or bromine as halogPn in place of R8 and R9. Compounds of the general formula V and Vl are ,,~
7 ~:3 ~ 2 preferably reacted in the presence of an inert solvent. As inert solvents alkanols, preferably methanol, ethanol, propanol, iso-propanol etc. alkane-carboxylic acids, preferably acetic acid, propionic acid, acid amides, such as N,N-dimethylformamlde, aro~atic bases, preferably pyridine ma~ be used. The enumerated solvents may optionally be admixed with water and then the reaction is conducted in a mixture of water and a water-miscible organic solvent. If de-sired an acid binding agent may be employed. As acid binding agent substances given for process variant a) may be employed. An excess of the hydrazine of the general formula Vl may also serve as acid binding agent. According to a pre-ferred embodlment of the process 1- ~o 8 moles, particularly preferably 2.5- to 4.5 mDles of hydra2ine of the general formula VI may be used for 1 mole of the co~pound of the general formNla V. The reaction may be conducted at a tempera-ture from 0 & to 160 &, when using solvent pre~erably at the boiling point oE
the solvent or solvent mi~ture. me reaction time may change from 30 minutes to 10 hours depending upon the ., 7~2 react~nts. Compounds of the general formula I obtalnod in the ~ r~e of prooe8s varian~ a~, b) or c) precipl~e from the re~ctlon mixture or precipitate upon aqueou~
dilution ~ncl can be isolated by filtration, cen~rifuging ~5 or other conventional methods.
The compounds of the gener~l formula ~ form s31ts ~ieh or~anic or lnorganic acid~, thue salt~ ~uch as hydroahloride, hydrobromider sulphate~pho~phateg perchlor~te, m~laate, a¢et~te ete. may be prepared.
Compound~ of the general formula I conta~ning ~t l~Qst one carbo~yl group ~orm sslte wlth b~es, ~uch as ~lkali met~l 8alt8, e.~. sodiuM or pot~ssium s~lt3~, alkall ~arth metal 8alt9, such a~ calaium or magnesium ~alts, or a~le~ o~ tertiary ~mine~, ~uah ae triethyl amine salta or ath3nol amina ~alts etc~
The presant lnvention inaludee the preparat~on of opti~al and geometricfll ieomare ~nd t~uto~,er~ thereof~
Optical ieomeri~ln o~cure when in the fermula ~ R3 i3 other th~n hydrogen,, The 3tru~ re of the geometri~cal
6-Hydrazono-pyrido[2,1-b]quinazoline-11-ones, and a Process for the Preparation Thereof The present invention relates to new 6-hydrazono-pyrido[2,1-b]
quinazoline-ll-ones and salts thereof, geometrical and optical isomers and tautomers thereof as well as a process for the preparation of same.
The new compounds may be used as starting materials for the prepara-tion of alkaloids. The preparation of substituted derivatives of Rutecarpine from the compounds of this invention is the subject of our copending Patent Application Serial No. 380~445.
Pyrido[2,1-b]quinazoline~ ones are known partly as alkaloids ~Chem. Comm. 267/1965/; Austral J. Chem. 151/1966/; Chem. Ber, 68J 2221/1935/;
J. Chem. Soc. 4694/1956/; Chem. Ber. 95, 2182/1962/) and partly as compounds showing Pavourable pharmacological properties (DE-PS 2 812 585, BE-PS 849 542 and BE-PS 847 011~.
The compounds of the general formula .
~, - 1 - ~' `' ' .
: . ~
1 ~ 67S~ ~
Rl ~R3 R N
/ NH
are new pyrido[2,1-b]quinazoline-11-ones. The known pyrido[2,1-b]quinazoline-11-one are disclosed in Moshy: Heterocyclic Syst~ls with bridgehead nitrogen atoms, Vo].. 2, 1153-1159, Interscience Publishers, Inc. New York, 1961.
According to the invention the new pyrido[2,1-b]quinazollrle-11-orles and acid addi-tion salts, geometric and optical isomers thereoE, wherein R, Rl, R are the same or different and stand for hydrogen, halogen, nitro, carboxy, nitrile, alkoxy containing 1 to 4 carbon atoms, alkoxycarbonyl con-taining 1 to 4 carbon atoms in the alkoxy group, alkyl containing 1 to 4 carbon atoms, amino or hydroxy or R and R together stand for methylenedioxy, R stands for hydrogen, R represents hydrogen or alkyl containing 1 to 4 carbon atoms, R stands for phenyl optionally substituted by 1 to 3 same or different substituents selected from the group of halogen(s), alkyl containing 1 to 4 carbon atorns, alkoxy con-taining 1 to 4 carbon atoms, phenyloxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group, methylenedioxy, trifluoromethyl, phenyl and dialkylamino having 1 to 4 carbon atoms in the alkyl part; or naphthyl or pyridyl and the dotted line stands for an optional double bond, may be prepared by (a) reacting a pyrido[2,1-b]quinazoline-11-one derivative of the general formula ! - 2 -'" ' ~' ' , . .
1 ~ ~7~
Rl ~ II
R R
wherein R, R , R , R and the dotted line are as defined above and R is hydrogen or formyl, with a diazonium salt of the general formula R - N2~ Cl ~ III
wherein R is as defined above; or (b) reacting a pyrido~2,1-b]quinazoline-11-one derivative of the general formula ~ N ~
Rl ~ ~ 7 IV
\ N /
\ R7 wherein R, R , R , R and the dotted line are as defi.ned above and R represents an alkyl group of 1 to 4 carbon atoms, with a diazonium salt of the general formula III, wherein R is as defined above; or (c) reacting a pyrido~2,1-b~quinazoline-11-one derivative of the general formula ~ 3 1 3 ~'7~l2 Rl = R3 V
R R
wherein R, R , R , R and the dotted line are as defined above and R s-tands for hydrogen or halogen and R is halogen, with a hydrazine derivative of the general formula R
wherein R is as defined above, and, i~ required, converting an obtained compound of the general Eormula I containing an acid group into a salt by reaction with a base, or converting a compound of the general Eormula I wi-th acid into an acid addition salt by reaction with an acid, or setting Eree a compound of the general formula I from its salt Eormed with an acid or base.
~ ~ - 4 -i ~ 67~
Process variant a) i.e. the reaction of the compound of the general formula II with the diazonium salt of the general form~la III is conducted accord-ing to (Parmerter: Org. Reactions, 10, p. 1-142 /1959/; Phillips: Org. Reac-tions 10, p. 143-178 /1959/).
According to a preferred embodinent of the process the reaction is con-ducted below 50 &, preferably at -10 to 20 &. The co~ponents may be added by adding a given compound of the formula II to the solution of the diazonium salt of the general formula III or the other way round. m e components may preferably be used in an equlmolar amount, but one of the conponents may optionally be used in a small excess. The reaction may be conducted preferably in aqueous medium, if desired in the presence of a water-miscible inert organic solvent.
As inert organic solvent alkane carboxylic acids, preferably acetic acid, propionic acid, acid amides, preferably N,N-dimethyl-formamide, alcohols, preferably methanol, ethanol, propanol, isopropanol, ketones such as acetone, methyl ethyl ketone, aromatic bases, preferably pyridine may be e~ployed. The reaction may preferably be carried out in the presence of an acid binding agent.
As acid binding agent a~cali alkanoates, preferably sodium acetate, po-tassium acetate or alkali hydroxides, preferably sodium hydro~ide, potassium hydroxide or alkali carbanates, preferably sodium carbonate~ potassium carbonate, sodium bicarbonate etc. are used.
According to process variant b) a compound of the general formula IV is reacted with a diazonium salt of the general formula III. A preferred embodlment is as given for pro oess variant e).
According to process variant c) a com~ound of the general formula V is reacted with a hydræ ine of the general formula VI. As a compound of the general formula V preferably such compounds may be used which con-tain chlorine or bromine as halogPn in place of R8 and R9. Compounds of the general formula V and Vl are ,,~
7 ~:3 ~ 2 preferably reacted in the presence of an inert solvent. As inert solvents alkanols, preferably methanol, ethanol, propanol, iso-propanol etc. alkane-carboxylic acids, preferably acetic acid, propionic acid, acid amides, such as N,N-dimethylformamlde, aro~atic bases, preferably pyridine ma~ be used. The enumerated solvents may optionally be admixed with water and then the reaction is conducted in a mixture of water and a water-miscible organic solvent. If de-sired an acid binding agent may be employed. As acid binding agent substances given for process variant a) may be employed. An excess of the hydrazine of the general formula Vl may also serve as acid binding agent. According to a pre-ferred embodlment of the process 1- ~o 8 moles, particularly preferably 2.5- to 4.5 mDles of hydra2ine of the general formula VI may be used for 1 mole of the co~pound of the general formNla V. The reaction may be conducted at a tempera-ture from 0 & to 160 &, when using solvent pre~erably at the boiling point oE
the solvent or solvent mi~ture. me reaction time may change from 30 minutes to 10 hours depending upon the ., 7~2 react~nts. Compounds of the general formula I obtalnod in the ~ r~e of prooe8s varian~ a~, b) or c) precipl~e from the re~ctlon mixture or precipitate upon aqueou~
dilution ~ncl can be isolated by filtration, cen~rifuging ~5 or other conventional methods.
The compounds of the gener~l formula ~ form s31ts ~ieh or~anic or lnorganic acid~, thue salt~ ~uch as hydroahloride, hydrobromider sulphate~pho~phateg perchlor~te, m~laate, a¢et~te ete. may be prepared.
Compound~ of the general formula I conta~ning ~t l~Qst one carbo~yl group ~orm sslte wlth b~es, ~uch as ~lkali met~l 8alt8, e.~. sodiuM or pot~ssium s~lt3~, alkall ~arth metal 8alt9, such a~ calaium or magnesium ~alts, or a~le~ o~ tertiary ~mine~, ~uah ae triethyl amine salta or ath3nol amina ~alts etc~
The presant lnvention inaludee the preparat~on of opti~al and geometricfll ieomare ~nd t~uto~,er~ thereof~
Optical ieomeri~ln o~cure when in the fermula ~ R3 i3 other th~n hydrogen,, The 3tru~ re of the geometri~cal
2~ l~omer~ i8 illustrated by the gen~rel fQrmulae IA
( IA) 26 ~ / R
N H
~nd IB
.
1 ~67~3~2 6 R4 N~' N
H
The ~tru~ture of the po~ible t~utomer~ i~ shown by rhe re~c tion scheme At NH ,N H
~4.~ ~4/
1~ .
i~
. .
Re~ktlon ~cheme A
2~A co~pound of the generfll f ormul~ I m~y be set free from their ~alt~ formad wlth an acid or b~e by m3thod~ known per ~e., An obt~lned compound of the general formul~ I may .
,. ' : , ~ 1 1 6~3'1 2 q ',~
be converted to ~n acid addirion salt by reactiny eame with an org~niG or inorganic acid~ Tha galt formation may be parformed by me~hods knewn per se comprising r~aetlng a ao~pound of the formula I with a correspondlng a~ld in mol~r equivalent amount or in excess in the pre~ence of an inert organ~c solven~.
Compoundo o~ the general formul~ I containing a ~rboxyl group may be cenverted to sel~e by react~ng aa~e wl~h a suitable base, such a8 alkali me~al n hydroxide~ alkall earth metal hidroxidey organic amine by method~ known per ~e~
Moat of the starting materials are known. 5tarl:ing matsrial~ of the gener~l formu}ae Il~ IV an~ V are dieoloseds Kokal Tokkyo Koho 7~ 130 435 and ~E-PS
16 . 849 542 and 847 011 and DE-PS 2 812 585 and 2 ~12 586, Mo3by~ Heterocycllc Systems with bridgehead nitrogen stom~, Vol~ 2, p. 1153-1159, Int~rsaience Publisher~, Inc. New York, 196~, Him. Geterocyal. ~oed~
1664 1569~ 1979, 684-6gl or may be prepared by methode :20 dl~clo~ed in tha above mentioned reference.
Compound3 of the general formula I are intermediats pfoducts of Rutecarp~ne alk~loides and Rutecarpine ~naloguesO
Further detail~ of the lnvention ~re lllu6trated by 26 ~ha followlng Ex~mples whlch serve merely for ~ llu~tratlon ~nd not for llmitation~
1:7~7~
~o ~.` ~r O~l mole anil~ne-darivative i9 admixed with 5 ml.
of 28 VJW~ ef hydrochloric acid ~olutlon of l:l dllution ~nd the mixture i~ cooled to -5 C. A solution of 0~69 9~ (~lmole) sodium ,nitrite in ~ ml~ of water 18 310wly a~ded drepwiee under ~teady stirr~ng and coolinga The reaction mixture i~ then stirred ~or 30 minute~ at a tempHrature ranging ~rom -5 G to 0 ~C, wheraafte~ th0 pH
of the reaGtion mixture i% adjusted to p~-4 by ~dding ~odlum a~et~teO The mixture is diluted with 5 ml~
gl~cial acotlc nci.d ~nd a ~olu~ion of 2.,0 9. (O.C)l mole) ll-oxo-6 ~7 ~3~9-tet rahydro-llH-pyrlcloL2 ~ a] qulnazollne in 10 ml., of 60 Vol~6 ace~ia aaid is ~dded dropwi~e,D
The reactien mixture 19 stlrrad for 3 hours at -5 C to 16 0 C~ The mlxture is then allowed to stand overnight in a refrl~;er~tor,. The precipita~ed crys~al9 are filt~red and washed wirh water~ The obtalned 6-phenylhydrazone-ll-oxo-6,7~,9-tetrahydro-11H-pyridoL2,l-h~quinazoline~
ere purifled if neeessary by recrystalllzation from 2 n-propanol. The prepared compounds are summ~rized in Table 1.
Exa m--~? le 9 23-24 One may proceed as disclosed in Example~ 1 to ~2 but a9 otartlng material 11-oxo-1,2~3~4,6,7~8,9-octahydro-26 11H-pyrldoC~ b3quinazoline is used in~te~d of 11-oxo-6c7,8,9-tetrahydro-11H-pyridoC~ b~quina2oline~
The prepared compound~ are summarlzed in Table 2 t ~ 67~3~2 ~1 ~: oP ~ O 1 U~ ~S ~ s tD (D ~ r~ ~ ~ ~ ~ ~
U) (D ~ ~ ~ u~ D ~S 1~ .
~o ~
~ O i0 ~ ~ N Lo ~) ~t) ct~ Cl) a~ a) o ~ o ~11 10 ~ ~ oo u . O ~ S~l ~ ~1 ~ ~ ~ 0;~ ~ C) ~ O) ~ C~
. 1~ (~ 1~ U) l~ f~ s'D
>~ 1-~ ~) ~ ~S ~ O ) t~ J O
~!s Z ~ O ~ U) 10 0 U') s 0 D 1~ ~ u~ ~ ~D ~D U~ 1~ ~ ~ ~D ~ U~
~; ~ ~ s r~~ ~ ~ ~ ~ ~ ~ ~1 ~ ~ s~
~--~S ~ o o ~ ~ I~ ~D o ~ 9 S~ ~ . t~ S--~S r~
. ~ O tc~ Ds ~ ~ ~S ~ ~3 r~ u) Z~ ~ ~ ~S -- ~S C~ o ~ ~
~ .. ~ u ~ Y a a 0, 0 ~
~ ~ S ~ ~S ~
.
~ . S ~ G o ~
0 ~ . ! ~ '~ ~ N ~ ~ - ~JS
Q~ ~L. L I I ~L r I S ~ I I
~! : D! t~ ta ~ E T
as ~S
~Ir I ~ S S 3~r I T
O O
I I S S ~ C :C r Q ~
13 C r~S J ~: S S I I C IC S :1: S C :r: T S
~ cn . t~: I I ~ ~ C3 U I ~' ~L O I
~ 0 C~
tD Q
X ~ C~ ~ ~ ~ ~ ~ CD a~ ~ " c~
, . ~ ' ~ , , 8 ~ ~
o a ;z o~ a o u~
~ ~ o ~ U~
o ~ a~ ~D O tO ~ ~
N ~1 ~ (D, U) .
ID ~ 10 ~ !oi r~.
. ~ ~ to o ~ ~n C~J 10 u~ D
~
z u~ 2 ~ U~
.
10 :C U~
. ~ ~ . ~ .
~3 IIU~ T
E~ ~ Ya~ X~ S2 a~ c~ s . ' ~ ~ ~
~3 lD ~ ~) CD ~ ~
. ~ ~J N C~J ~ ~I C~l S r S r-l ~y Q o~ L I ~L
r ,~ ~ Z O ~ Z
O O ~ ~ I I
~1 s :~: s ~1 E C O
. ~0 ~ ~ ~ r T I I
o 1~ I :C I S ~ I ~
_~ N
~1 Q
x ~ o ~J
,'12~
;
.
1 :1 67~3ll~
r~ I~' o ~
z a C ~ ,, S~ u~ a . ~ ~o t, o~ o ~Q ~ r~ ., o~ ~, ~, ~ z ~
I~
a) ) 0 C ~D ~9 , o~
o ~ o o .~ .
,1 ' ¦ L E ¦ Z Z~ ~
'O t~ t~
~ >~
~_z ~ ~ æ~
. C~ L. O_ :
O
S~
L
c~ O ~Y ~ E
_~ a) O ~: I :C
E C
vcn~ ~ ~
. ~
. ~: I :~:
~D
,4 q~ ~
~ Ul . ~ ~
.: ~ ' . .
1 1 67~A2 ~ ~ / y Example 25 10-B 9~ (0-03 mole) 6y6-Dibromo-6~7~8,9-tetr~hydro-ll-oxo--llH-pyridot2,1-b]quinazollne and 13.0 9~ (0012 mole) of phenyl hydrazine ere heated in 120 ml ethanol ~or 4 6 hours~ The precipitated cry~tal~ are filtered after cooling~
When e~aporatlng t~e mother 1iquor further cry5tal3 are precipitatîngS which are filtered and wa~hed with ~ome alcoholO The combined filtered product i5 suspended ln 150 ml ., of water containing B r4 9 ~ (0~06 mole) of sodium ~cetat~ wherea~ter it ~ filtered and washed with waterO
8fi4 9~ (81 %) of 6-phenylhydra20no-6,7~8,9~tetrahy~ro~
oxo-llH-pyrido~7,}-b~quinazoline are obtained which after re~ tallization from i~opropanol melte at 177-17g ~
and whiah do~s not give a dsgres~ion of melting point when ~dmixed with the produ~t accordin~ to Example 1~
~e~.
( IA) 26 ~ / R
N H
~nd IB
.
1 ~67~3~2 6 R4 N~' N
H
The ~tru~ture of the po~ible t~utomer~ i~ shown by rhe re~c tion scheme At NH ,N H
~4.~ ~4/
1~ .
i~
. .
Re~ktlon ~cheme A
2~A co~pound of the generfll f ormul~ I m~y be set free from their ~alt~ formad wlth an acid or b~e by m3thod~ known per ~e., An obt~lned compound of the general formul~ I may .
,. ' : , ~ 1 1 6~3'1 2 q ',~
be converted to ~n acid addirion salt by reactiny eame with an org~niG or inorganic acid~ Tha galt formation may be parformed by me~hods knewn per se comprising r~aetlng a ao~pound of the formula I with a correspondlng a~ld in mol~r equivalent amount or in excess in the pre~ence of an inert organ~c solven~.
Compoundo o~ the general formul~ I containing a ~rboxyl group may be cenverted to sel~e by react~ng aa~e wl~h a suitable base, such a8 alkali me~al n hydroxide~ alkall earth metal hidroxidey organic amine by method~ known per ~e~
Moat of the starting materials are known. 5tarl:ing matsrial~ of the gener~l formu}ae Il~ IV an~ V are dieoloseds Kokal Tokkyo Koho 7~ 130 435 and ~E-PS
16 . 849 542 and 847 011 and DE-PS 2 812 585 and 2 ~12 586, Mo3by~ Heterocycllc Systems with bridgehead nitrogen stom~, Vol~ 2, p. 1153-1159, Int~rsaience Publisher~, Inc. New York, 196~, Him. Geterocyal. ~oed~
1664 1569~ 1979, 684-6gl or may be prepared by methode :20 dl~clo~ed in tha above mentioned reference.
Compound3 of the general formula I are intermediats pfoducts of Rutecarp~ne alk~loides and Rutecarpine ~naloguesO
Further detail~ of the lnvention ~re lllu6trated by 26 ~ha followlng Ex~mples whlch serve merely for ~ llu~tratlon ~nd not for llmitation~
1:7~7~
~o ~.` ~r O~l mole anil~ne-darivative i9 admixed with 5 ml.
of 28 VJW~ ef hydrochloric acid ~olutlon of l:l dllution ~nd the mixture i~ cooled to -5 C. A solution of 0~69 9~ (~lmole) sodium ,nitrite in ~ ml~ of water 18 310wly a~ded drepwiee under ~teady stirr~ng and coolinga The reaction mixture i~ then stirred ~or 30 minute~ at a tempHrature ranging ~rom -5 G to 0 ~C, wheraafte~ th0 pH
of the reaGtion mixture i% adjusted to p~-4 by ~dding ~odlum a~et~teO The mixture is diluted with 5 ml~
gl~cial acotlc nci.d ~nd a ~olu~ion of 2.,0 9. (O.C)l mole) ll-oxo-6 ~7 ~3~9-tet rahydro-llH-pyrlcloL2 ~ a] qulnazollne in 10 ml., of 60 Vol~6 ace~ia aaid is ~dded dropwi~e,D
The reactien mixture 19 stlrrad for 3 hours at -5 C to 16 0 C~ The mlxture is then allowed to stand overnight in a refrl~;er~tor,. The precipita~ed crys~al9 are filt~red and washed wirh water~ The obtalned 6-phenylhydrazone-ll-oxo-6,7~,9-tetrahydro-11H-pyridoL2,l-h~quinazoline~
ere purifled if neeessary by recrystalllzation from 2 n-propanol. The prepared compounds are summ~rized in Table 1.
Exa m--~? le 9 23-24 One may proceed as disclosed in Example~ 1 to ~2 but a9 otartlng material 11-oxo-1,2~3~4,6,7~8,9-octahydro-26 11H-pyrldoC~ b3quinazoline is used in~te~d of 11-oxo-6c7,8,9-tetrahydro-11H-pyridoC~ b~quina2oline~
The prepared compound~ are summarlzed in Table 2 t ~ 67~3~2 ~1 ~: oP ~ O 1 U~ ~S ~ s tD (D ~ r~ ~ ~ ~ ~ ~
U) (D ~ ~ ~ u~ D ~S 1~ .
~o ~
~ O i0 ~ ~ N Lo ~) ~t) ct~ Cl) a~ a) o ~ o ~11 10 ~ ~ oo u . O ~ S~l ~ ~1 ~ ~ ~ 0;~ ~ C) ~ O) ~ C~
. 1~ (~ 1~ U) l~ f~ s'D
>~ 1-~ ~) ~ ~S ~ O ) t~ J O
~!s Z ~ O ~ U) 10 0 U') s 0 D 1~ ~ u~ ~ ~D ~D U~ 1~ ~ ~ ~D ~ U~
~; ~ ~ s r~~ ~ ~ ~ ~ ~ ~ ~1 ~ ~ s~
~--~S ~ o o ~ ~ I~ ~D o ~ 9 S~ ~ . t~ S--~S r~
. ~ O tc~ Ds ~ ~ ~S ~ ~3 r~ u) Z~ ~ ~ ~S -- ~S C~ o ~ ~
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as ~S
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O O
I I S S ~ C :C r Q ~
13 C r~S J ~: S S I I C IC S :1: S C :r: T S
~ cn . t~: I I ~ ~ C3 U I ~' ~L O I
~ 0 C~
tD Q
X ~ C~ ~ ~ ~ ~ ~ CD a~ ~ " c~
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1 1 67~A2 ~ ~ / y Example 25 10-B 9~ (0-03 mole) 6y6-Dibromo-6~7~8,9-tetr~hydro-ll-oxo--llH-pyridot2,1-b]quinazollne and 13.0 9~ (0012 mole) of phenyl hydrazine ere heated in 120 ml ethanol ~or 4 6 hours~ The precipitated cry~tal~ are filtered after cooling~
When e~aporatlng t~e mother 1iquor further cry5tal3 are precipitatîngS which are filtered and wa~hed with ~ome alcoholO The combined filtered product i5 suspended ln 150 ml ., of water containing B r4 9 ~ (0~06 mole) of sodium ~cetat~ wherea~ter it ~ filtered and washed with waterO
8fi4 9~ (81 %) of 6-phenylhydra20no-6,7~8,9~tetrahy~ro~
oxo-llH-pyrido~7,}-b~quinazoline are obtained which after re~ tallization from i~opropanol melte at 177-17g ~
and whiah do~s not give a dsgres~ion of melting point when ~dmixed with the produ~t accordin~ to Example 1~
~e~.
3.74 g (0~01 mol~) of 616-d~bromo-9-methyl~ oxo-~ /_b 6 ~7 98 o9~ te t rahydro-llH-pyrido~ ~ }qzinazoline and 4.32 g. ~0.04 mole~ of phenyl hydrazlne are he~ted in 40 snl., .
20 of ethanol for 10 hoursO The precipi~at~d cry~als ~re filtered after cooling. The filt~red produc~ lg au~pended in 100 ml. water containlng 2~72 9~ to.o2 mole), ~odlum acetste~ filtered and washed with water~ Z04 9 (76 %) orange 6-phenylhydrazono-9-methyl~ oxo-6,7~,9-2~ tetrahydro-llH pyrldo~2,1-b]qulna~oline are o~tained ~hlch after recrys~alllz~tion from ethanol melts at 18~ 7 C~
~7~3 /S' Analysi!3 for the formula C19~ll8N40 calculated ~ C 71~67 ~6 H 5.69 % N 17.59 %
found: C 71.62 9~ H 5.58 ~ N 17.55 96~
6 2.79 9. (0.01 mole) of 6-bromo~ oxo-6,7~8J9-tetra hydro-llH-pyridoC2,1-b]qulna201ine ~nd 2~16 9. (0.02 mole) of phenyl hydrazine are heated in 30 ml~ of ethanol for 6 houre at ~0 C~ Ethanol is then concen~rated to a third volumeO The mixture i9 then allowed to cryst~ e in ~n ice-box~ The precipitated yellow crystals are filtered, and washed wlth ethanol and water~ 2.1 9~ (69~) of 6-phenyl-hydra~ono~ oxo-6,7,8,9-~etrahydro-pyrldo-~2,1-b~quinazollne are obtained. which after recryst~lliza-tion from isopropanol melt~ a~ 179-180 C which when ad-16 nllxed with the product according to E)~ample 1 or Exempla 25 does r.ot glve any melting point degression~
Analysls for the ~ormula C18H16N40 cYlcula~ed: C 71.,03 96 H 5~29 % N lB.41 %
found: C 7C~.,88 % H 5025 5~ N 18038 %0 Examp le_28 0.93 9O (0.,9 ml., 0.01 mole) of aniline ar~
dissolved ln 6 ml. 38 V/W% of hydrochloric acid of lsl dilution ~nd the Bolution i8 cooled to -5 C~
solution of 0~65 9~ (0.01 mols) ~odium nitri~s ln 5 ml~
2~ wator i~ added dropwi~e under steady coollng and ~eirr1n~
The r~actlon mlxture i8 6tirred for 30 minute6 at a temperature of -5 C to û C whereafter the pH of the ~ ~ ~7~2 solution is adjusted to pH = 4 by adding sodi~lm acetate and it is diluted with 10 ml. of acetic acid. To the solution of the diazonium salt a solution of 2.55 g. of 6-(dimethylamino-methylene)-11-oxo-6,7,8,9-tetrahydro-llH-pyrido~2,1-b]-quinazoline in 25 ml. of dimethylforma~ide is slowly added dropwise at -5 &.
me reaction nLLYture is stirred at 0 C for 3 hours whereafter it is allowed to stand ove m ight in an ice-box. The mixture is then diluted with water and the precipitated crystals are filtered and washed with water. 2.61 g. (86 %) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-llH-pyrido[2,l-blqulnazoline are ob-tained which after recrystallization from iso-propanol melts at 182-184 C, and the product does not give any melting point degression when admixed with the pro-duct according to Example 1.
Analysis for the formNla C18H16N40 calculated: C 71.03 % ~ 5.29 % N 18.41 %
found: C 70.93 % H 5.24 % N 18.33 %.
Example_29 0.93 g. (0.01 mole) of aniline are dissolved in 5 ml. of 38 V/W~ hydro-chloric acid of a dilution of 1:1 and it is cooled to -5 C. ~ solution of 0.69 g. (0.01 mole) of sodium nitrite in 5 ml. of water is added dropwise under steady stirring and cooling. The reaction mixture is stirred for half an hour at -5 & to 0 C whereafter the pH of the solution is adjusted to p~ = 4 by addin~
sodium acetate and the solution is diluted with 10 ml. of acetic acid. To the reaction mixture a solution of .
.
. ~
J ~7~
/1 .
2~28 g. (0~01 mole) of 6-formyl~ oxo-~,7,8,g-te~rahydro~
llH-pyrldo~2,1-b~quinazoline in 30 ml. of ~cetlc ~cld 1~
alonly added dropwise~ The mi~ture 1B ~tlrred for 1 hour ~t a temperature below O C and ~he flolution i~ then 6 . ~11Q~ed to ~t~nd ln the refriger~tor~ The preclpitflted ~Fy~tal~ ~re ~iltered and washed with water~ 3~1 gO t~l%) of 6-phenyl-hydrazono-6,7~,9 tetrahydro-11-oxo-llH-pyrido~2,1-~o quin~zolln~-hydrochlori~e are obtained meltiny at 255 C~
Analy~i~ on the bsais of C18H17N40Cl ~o calcul~e~ds C 63.60 % H 5.04 ~ N 1604B % Cl 10~16 %
~ound: C 63~44 % H 4~9~ % N 16.59 ~ Cl 10.11 %.
e3 e__ 3U ~o ~a One m~y proceed a~ dl9clo~ed ln Example 1-2~ ~nd ~u ctarting materi~ls in Ex~mple 30 a~ pyridoC2Jl-b]quinazollna 16 d6rivative 2,3~4-trimethoxy-11 oxo-6~7,8,9~teerahydro-llH-: pyrido~2,1-b]quina2011ne and ln Ex~mple 31~ oxo-6,7~8J9 eetr~hydro-llH-pyrido~2~l-b]qu~nazoline-2;c~rboxylic ~ald ~nd in Example 32 ethyl~ oxo-6~7D8~9-tetr~hydro-llH-pyrldo(2,1-b)~uln~zoline 2-carboxylate ~nd in Example 3 11-oxo-6j7~8,9-~etrahydro-ilH pyrido~2,1-b]quln~zoline le u~ed and 6-phenylhydrazono l,l-oxo-6~708,,9-tetrahydro-llH-pyrldo~2~1-b]quin~zolines ~ccordlng to Table ~ 6ra obtaln~d. Th~ product~ are recry~tallized from n-prop~nolO
26 ~ e~ t ~
One ~ay proceed ~8 dl~clo~ed ~n Example~ 23 to 24 and c8 st~rtlng m~terials 11-oxo~lJ2~3,4~6,7,8,~-oce~hydro-llH-pyridoL2,1~b]quin~zollnes are used which re~ult in 6~phsnyl-J67~3~Z
~g -, , '!, hydrazono-4-oxo-lJ2,3~4,,6,7,~,g-oc~ahydro-llH-pyrldo-t2,1-b~quina~ollnes according to Table 4.
In Ex~mple~ 4Z and 43 aryetala preclplt~ed from the diazo-coupling re~ction mlxtura are suspended in a 5 ~ % ~W % sodium hydroxide solutlon and the ~queou~
solution 13 3haken QUt with chloroform~ The chloroform eolu~ion drled above anhydrous sod~ um sulph~te 16 ~v~porated and the res~due is crys~allized.
0~46 9 ~ ~0 .005 mole) aniline i6 dis~olv~d in 3 ml~
of hydro~hloric ~cid (36 V/W%) of fl dilution o~ lsl and th~ aolution i~ cooled to -5 C. A 3alution of 0.~
~0.006 mole) o~ sodium nitrlte ln 3 ml~ of water iq add~d drop~iae. The reac~lorl mlxture i9 etirred for half en 1~ hour at -8 C to 0 C wher~a~ter the pH o~ ths 801ution ie ~dJu~t~d to 4 by adding aodlu~ ~¢~tateO To ~he r0~ctlon mixture a ~olution of 1023 9- (0~005 mole) of 6-formyl~ oxo-1~2,3,4~6~7,8,9-octahydro-llH-pyrido-t2~1-b]quinaaol~ne in 15 ml~ 76 V~ acetic acid ~ ~los~ly ~dded dropwi~a and the ~olution 15 stirred for 3 hour~ a.t ~ eemperaturo below 0 C wher6after the mixture 1~
allowed to stand overnlght in refrigerator end dllutad with 30 ml~ water. The precipltated crystal~ ~re flltered and wa~hed with water. 1.3 9. (73 %) of 6-phenyl-hydrazono-11-oxo-1,2~3,4y6r~7.8~9-oxtahydrQ~ pyrido~2~1-b]
qulna201ine-hydrochlorlde are obtained m91tin~ at 242 244C
An~ly~l~ for the formula ClgH23~40Cl calculated: C 63.59 ~ ~ 6.46 % N 15~61 % Cl 9~88 %
found2 C 63.21 % H 6~28 % N 15~5 % Cl 9~65 %~
3 ~ ~
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O ~ ~ Cr) ID, 1~ -1 :) (D (D l~
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20 of ethanol for 10 hoursO The precipi~at~d cry~als ~re filtered after cooling. The filt~red produc~ lg au~pended in 100 ml. water containlng 2~72 9~ to.o2 mole), ~odlum acetste~ filtered and washed with water~ Z04 9 (76 %) orange 6-phenylhydrazono-9-methyl~ oxo-6,7~,9-2~ tetrahydro-llH pyrldo~2,1-b]qulna~oline are o~tained ~hlch after recrys~alllz~tion from ethanol melts at 18~ 7 C~
~7~3 /S' Analysi!3 for the formula C19~ll8N40 calculated ~ C 71~67 ~6 H 5.69 % N 17.59 %
found: C 71.62 9~ H 5.58 ~ N 17.55 96~
6 2.79 9. (0.01 mole) of 6-bromo~ oxo-6,7~8J9-tetra hydro-llH-pyridoC2,1-b]qulna201ine ~nd 2~16 9. (0.02 mole) of phenyl hydrazine are heated in 30 ml~ of ethanol for 6 houre at ~0 C~ Ethanol is then concen~rated to a third volumeO The mixture i9 then allowed to cryst~ e in ~n ice-box~ The precipitated yellow crystals are filtered, and washed wlth ethanol and water~ 2.1 9~ (69~) of 6-phenyl-hydra~ono~ oxo-6,7,8,9-~etrahydro-pyrldo-~2,1-b~quinazollne are obtained. which after recryst~lliza-tion from isopropanol melt~ a~ 179-180 C which when ad-16 nllxed with the product according to E)~ample 1 or Exempla 25 does r.ot glve any melting point degression~
Analysls for the ~ormula C18H16N40 cYlcula~ed: C 71.,03 96 H 5~29 % N lB.41 %
found: C 7C~.,88 % H 5025 5~ N 18038 %0 Examp le_28 0.93 9O (0.,9 ml., 0.01 mole) of aniline ar~
dissolved ln 6 ml. 38 V/W% of hydrochloric acid of lsl dilution ~nd the Bolution i8 cooled to -5 C~
solution of 0~65 9~ (0.01 mols) ~odium nitri~s ln 5 ml~
2~ wator i~ added dropwi~e under steady coollng and ~eirr1n~
The r~actlon mlxture i8 6tirred for 30 minute6 at a temperature of -5 C to û C whereafter the pH of the ~ ~ ~7~2 solution is adjusted to pH = 4 by adding sodi~lm acetate and it is diluted with 10 ml. of acetic acid. To the solution of the diazonium salt a solution of 2.55 g. of 6-(dimethylamino-methylene)-11-oxo-6,7,8,9-tetrahydro-llH-pyrido~2,1-b]-quinazoline in 25 ml. of dimethylforma~ide is slowly added dropwise at -5 &.
me reaction nLLYture is stirred at 0 C for 3 hours whereafter it is allowed to stand ove m ight in an ice-box. The mixture is then diluted with water and the precipitated crystals are filtered and washed with water. 2.61 g. (86 %) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-llH-pyrido[2,l-blqulnazoline are ob-tained which after recrystallization from iso-propanol melts at 182-184 C, and the product does not give any melting point degression when admixed with the pro-duct according to Example 1.
Analysis for the formNla C18H16N40 calculated: C 71.03 % ~ 5.29 % N 18.41 %
found: C 70.93 % H 5.24 % N 18.33 %.
Example_29 0.93 g. (0.01 mole) of aniline are dissolved in 5 ml. of 38 V/W~ hydro-chloric acid of a dilution of 1:1 and it is cooled to -5 C. ~ solution of 0.69 g. (0.01 mole) of sodium nitrite in 5 ml. of water is added dropwise under steady stirring and cooling. The reaction mixture is stirred for half an hour at -5 & to 0 C whereafter the pH of the solution is adjusted to p~ = 4 by addin~
sodium acetate and the solution is diluted with 10 ml. of acetic acid. To the reaction mixture a solution of .
.
. ~
J ~7~
/1 .
2~28 g. (0~01 mole) of 6-formyl~ oxo-~,7,8,g-te~rahydro~
llH-pyrldo~2,1-b~quinazoline in 30 ml. of ~cetlc ~cld 1~
alonly added dropwise~ The mi~ture 1B ~tlrred for 1 hour ~t a temperature below O C and ~he flolution i~ then 6 . ~11Q~ed to ~t~nd ln the refriger~tor~ The preclpitflted ~Fy~tal~ ~re ~iltered and washed with water~ 3~1 gO t~l%) of 6-phenyl-hydrazono-6,7~,9 tetrahydro-11-oxo-llH-pyrido~2,1-~o quin~zolln~-hydrochlori~e are obtained meltiny at 255 C~
Analy~i~ on the bsais of C18H17N40Cl ~o calcul~e~ds C 63.60 % H 5.04 ~ N 1604B % Cl 10~16 %
~ound: C 63~44 % H 4~9~ % N 16.59 ~ Cl 10.11 %.
e3 e__ 3U ~o ~a One m~y proceed a~ dl9clo~ed ln Example 1-2~ ~nd ~u ctarting materi~ls in Ex~mple 30 a~ pyridoC2Jl-b]quinazollna 16 d6rivative 2,3~4-trimethoxy-11 oxo-6~7,8,9~teerahydro-llH-: pyrido~2,1-b]quina2011ne and ln Ex~mple 31~ oxo-6,7~8J9 eetr~hydro-llH-pyrido~2~l-b]qu~nazoline-2;c~rboxylic ~ald ~nd in Example 32 ethyl~ oxo-6~7D8~9-tetr~hydro-llH-pyrldo(2,1-b)~uln~zoline 2-carboxylate ~nd in Example 3 11-oxo-6j7~8,9-~etrahydro-ilH pyrido~2,1-b]quln~zoline le u~ed and 6-phenylhydrazono l,l-oxo-6~708,,9-tetrahydro-llH-pyrldo~2~1-b]quin~zolines ~ccordlng to Table ~ 6ra obtaln~d. Th~ product~ are recry~tallized from n-prop~nolO
26 ~ e~ t ~
One ~ay proceed ~8 dl~clo~ed ~n Example~ 23 to 24 and c8 st~rtlng m~terials 11-oxo~lJ2~3,4~6,7,8,~-oce~hydro-llH-pyridoL2,1~b]quin~zollnes are used which re~ult in 6~phsnyl-J67~3~Z
~g -, , '!, hydrazono-4-oxo-lJ2,3~4,,6,7,~,g-oc~ahydro-llH-pyrldo-t2,1-b~quina~ollnes according to Table 4.
In Ex~mple~ 4Z and 43 aryetala preclplt~ed from the diazo-coupling re~ction mlxtura are suspended in a 5 ~ % ~W % sodium hydroxide solutlon and the ~queou~
solution 13 3haken QUt with chloroform~ The chloroform eolu~ion drled above anhydrous sod~ um sulph~te 16 ~v~porated and the res~due is crys~allized.
0~46 9 ~ ~0 .005 mole) aniline i6 dis~olv~d in 3 ml~
of hydro~hloric ~cid (36 V/W%) of fl dilution o~ lsl and th~ aolution i~ cooled to -5 C. A 3alution of 0.~
~0.006 mole) o~ sodium nitrlte ln 3 ml~ of water iq add~d drop~iae. The reac~lorl mlxture i9 etirred for half en 1~ hour at -8 C to 0 C wher~a~ter the pH o~ ths 801ution ie ~dJu~t~d to 4 by adding aodlu~ ~¢~tateO To ~he r0~ctlon mixture a ~olution of 1023 9- (0~005 mole) of 6-formyl~ oxo-1~2,3,4~6~7,8,9-octahydro-llH-pyrido-t2~1-b]quinaaol~ne in 15 ml~ 76 V~ acetic acid ~ ~los~ly ~dded dropwi~a and the ~olution 15 stirred for 3 hour~ a.t ~ eemperaturo below 0 C wher6after the mixture 1~
allowed to stand overnlght in refrigerator end dllutad with 30 ml~ water. The precipltated crystal~ ~re flltered and wa~hed with water. 1.3 9. (73 %) of 6-phenyl-hydrazono-11-oxo-1,2~3,4y6r~7.8~9-oxtahydrQ~ pyrido~2~1-b]
qulna201ine-hydrochlorlde are obtained m91tin~ at 242 244C
An~ly~l~ for the formula ClgH23~40Cl calculated: C 63.59 ~ ~ 6.46 % N 15~61 % Cl 9~88 %
found2 C 63.21 % H 6~28 % N 15~5 % Cl 9~65 %~
3 ~ ~
~ ~ ~ ~ ,1, ~, ~ U~ ~ ~ .
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: ID U~
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~ ~ ~ o a E~ ,_1 ~ LO O O
O ~ ~ Cr) ID, 1~ -1 :) (D (D l~
J- a~ n) 0~ 0~ 0~ 0 O O O N --~ N N t~) lll O C~
6 .~ .
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E
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10 ~0 u) ~D (D 1~ 1~ 0 . ~ ~ ~1 C,~ N ~ -1 ~t7 ~; la eJ ~ a:
~ ~I d ~ O ~ O ~
o o ~ ~ ~ o m O
~D U) 10 l~ 1 a~ ~ ~ ~ t8 ~ ~ '` ~ r~
~) ~') Z ~
~ ~ ~D u~ r~ I~ (D U) U) U~ r~ ~ ~
D~ ~I r~ r,~ ~ ~ r~ ~ ~ ~ ~ _~
o~ 1~
C ~ U~ 07 ~ 0 ~ ~ ~0 10 a: ,, (D
~c ~5 u~ u~ o r~ 1~ (o ID ID U~ ~0 ~U ~ (D LO O a:) o r~ ~ aD
_~ ~ O O~ ~ I~
:1 ,1 ~ O ~1 ~D ~ t; 0 t;
. t~ t,) (O (~ (O 1~ t~ u~ r~
O , ~ ~ ~ t~ ~) N ~,) .C: ~ ~ O O ~ O ~ O O O O O O ,~
~- ~1 ~ ~ 10 e~ ~ ~ ~ ~ ~ ~ ~'t r Z Z :~ Z Z Z ~ Z Z :~:' :~:
E tn ~ l t~l ~ lO ~ ~ ~1 o C~J
O.,1 1., ~ N N C~J t~l t~ 1 t~l t~l ~1 O :C :I: r 1~ 1 1~ I I ~ Ia~ ICn Xo) W ~ l t~ r l C , O ~ V C~ U t.) t ) O t~ t ) t~
O ~ .
E3 ' ~ ~q o a~ ') a) .
O r~ 1 U) tr) U~
. .
t!) ' Ct1 C~ N
1~ O 1~ Q~ U~ (O t~ N O
C` ~ C~ Q ~ ~1 ~
~_ ~ 2: ~ r~ t~ I t~l .~-- ~ O ~D O a~ (0 ~ t`l 0~ ~ ~ . C~
Cl.
1~! ~ .1: ~C r r r .C I
~, ~ ~ ~ Cl~ ~ Q n~
~' ~ ?Y I I I I I I I ~:
_ ~ . ~ ~ t~ Q ~ ~
Q! . t~ t~ o ~ ~ ~ ~:
_l ~ 0 I I Z I I I :~; L I ~
n~ ~ ~ ~ o ` ~
o o tY ~ ~
~:
~ ~ l C ~_~ t tn ~ a) ~ ~ aD a) r~
O L_~
Q c~ ~ C ~ I :C
t~ O) .
~1 ~ ~ C J~ T
. .
I ~: T ~ I
~ _~ ' _I E . .
0 ~ r ~ o 1~ 1 0 X ~ Ir) ID 1~ ao a) O r~-~ N ~) ~
~_ lll ~ ) (~) t~) ~ ~ ~ ~ ~ ~ '~t .~ .
. .
.
Claims (35)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 6-hydrazono-pyrido[2,1-b]quinazoline-11-ones, salts thereof and optical and geometrical isomers and tautomers thereof of the general formula I
wherein R, R1 and R2 are the same or different and stand for hydrogen, halogen, nitro, carboxy, nitrile, alkoxy containing 1 to 4 carbon atoms, alkoxycarbonyl containing 1 to 4 carbon atoms in the alkoxy group, alkyl containing 1 to 4 carbon atoms, amino or hydroxy or R and R1 together stand for methylenedioxy and R2 stands for hydrogen, R3 represents hydrogen or alkyl containing 1 to 4 carbon atoms, R4 stands for phenyl optionally substituted by 1 to 3 same or different substituents selected from the group of halogen(s), alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, phenyloxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group, alkanoyl having 1 to 4 carbon atoms, methylenedioxy, trifluoromethyl, phenyl and dialkylamino having 1 to 4 carbon atoms in the alkyl part or naphthyl or pyridyl and the dotted line stands for an optional double bond, which com-prises:
(a) reacting a pyrido[2,1-b]quinazoline-11-one derivative of the general formula II
wherein R, R1, R2, R3 and the dotted line are as defined above and R6 is hydrogen or formyl, with a diazonium salt of the general formula R4 - N2?Cla? III
wherein R4 is as defined above; or (b) reacting a pyrido[2,1-b]quinazoline-11-one derivative of the general formula IV
wherein R, R1, R2, R3 and the dotted line are as defined above and R7 represents an alkyl group of 1 to 4 carbon atoms, with a diazonium salt of the general formula III defined above; or (c) reacting a pyrido[2,1-b]quinazoline-11-one-derivative of the general formula V
wherein R, R1, R2, R3 and the dotted line are as given above and R8 stands for hydrogen or halogen and R9 is halogen, with a hydrazine derivative of the general formula VI
wherein R4 is as defined above; and, if required, converting an obtained com-pound of the general formula I containing an acid group into a salt by reaction with a base, or converting a compound of the general formula I into an acid addition salt by reaction with an acid or setting free a compound of the general formula I from its salt formed with an acid or base.
wherein R, R1 and R2 are the same or different and stand for hydrogen, halogen, nitro, carboxy, nitrile, alkoxy containing 1 to 4 carbon atoms, alkoxycarbonyl containing 1 to 4 carbon atoms in the alkoxy group, alkyl containing 1 to 4 carbon atoms, amino or hydroxy or R and R1 together stand for methylenedioxy and R2 stands for hydrogen, R3 represents hydrogen or alkyl containing 1 to 4 carbon atoms, R4 stands for phenyl optionally substituted by 1 to 3 same or different substituents selected from the group of halogen(s), alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, phenyloxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group, alkanoyl having 1 to 4 carbon atoms, methylenedioxy, trifluoromethyl, phenyl and dialkylamino having 1 to 4 carbon atoms in the alkyl part or naphthyl or pyridyl and the dotted line stands for an optional double bond, which com-prises:
(a) reacting a pyrido[2,1-b]quinazoline-11-one derivative of the general formula II
wherein R, R1, R2, R3 and the dotted line are as defined above and R6 is hydrogen or formyl, with a diazonium salt of the general formula R4 - N2?Cla? III
wherein R4 is as defined above; or (b) reacting a pyrido[2,1-b]quinazoline-11-one derivative of the general formula IV
wherein R, R1, R2, R3 and the dotted line are as defined above and R7 represents an alkyl group of 1 to 4 carbon atoms, with a diazonium salt of the general formula III defined above; or (c) reacting a pyrido[2,1-b]quinazoline-11-one-derivative of the general formula V
wherein R, R1, R2, R3 and the dotted line are as given above and R8 stands for hydrogen or halogen and R9 is halogen, with a hydrazine derivative of the general formula VI
wherein R4 is as defined above; and, if required, converting an obtained com-pound of the general formula I containing an acid group into a salt by reaction with a base, or converting a compound of the general formula I into an acid addition salt by reaction with an acid or setting free a compound of the general formula I from its salt formed with an acid or base.
2. A process as claimed in claim 1 wherein process variant (a) or (b) is used and the reaction is carrled out at a temperature below 50°C.
3. A process as claimed in claim 1 wherein process variant (a) or (b) is used and the reaction is carried out at a temperature of from -10°C to 20°C.
4. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out in a mixture of water and an organic solvent.
5. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out in a mixture of water and a C2-4 alkane carboxylic acid.
6. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out in a mixture of water and acetic acid.
7. A process as claimed in claim 1 wherein process variant (c) is used and the reaction is carried out at a temperature ranging from 0 to 160°C.
8. A process as claimed in claim 1, 2 or 7 which comprises performing the reaction in the presence of a solvent.
9. A process as claimed in claim 1, 2 or 7 wherein the reaction is carried out in water.
10. A process as claimed in claim 1, 2 or 3 wherein the reaction is carried out in a C1-4 alkanol as solvent.
11. A process as claimed in claim 1 wherein process variant (c) is used and R8 is hydrogen or bromine and R9 is bromine.
12. A process as claimed in claim 1, 2 or 7 wherein R is hydrogen, chlorine in the 3-position, methoxy in the 2- or 3-position, carboxyl in the 2-position or ethoxycarbonyl in the 2-position, R1 is hydrogen or methoxy in the 2- or 3-position, R2 is hydrogen or methoxy in the 4-position, R3 is hydrogen or methyl in the 9-position and R4 is phenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chloro-phenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-phenoxyphenyl, 4-hydroxyphenyl, 4-acetoxyphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-carboxy-phenyl, 4-cyanophenyl, 4-ethylphenyl, 4-ethoxycarbonylphenyl, 3,5-dichlorophenyl, 1-naphthyl, 2-naphthyl or 3-pyridyl.
13. A compound of formula I as defined in claim 1 or a salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
14. A process as claimed in claim 1 wherein R, R1, R2 and R3 are hydrogen, R4 is phenyl and the dotted lines form double bonds.
15. A process for preparing 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline which comprises reacting phenyl diazonium chloride with 11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline.
16. A process for preparing 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline whichcomprises reacting 6,6-dibromo-6,7,8,9-tetra-hydro-11-oxo-11H-pyrido[2,1-b]quinazoline with phenyl hydrazine.
17. A process for preparing 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline which comprises reacting 6-bromo-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline with phenyl hydrazine.
18. A process for preparing 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline which comprises reacting phenyl diazonium chloride with 6-(dimethylamino-methylene)-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]-quinazoline.
19. A process for preparing 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline which comprises reacting phenyl diazonium chloride with 6-formyl-11-oxo-6l7l8l9-tetrahydro-11H-pyrido[2,1-b]quinazoline.
20. The compound 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido-[2,1-b]quinazoline when prepared by a process according to claim 15, 16 or 17 or an obvious chemical equivalent thereof.
21. The compound 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido-[2,1-b]quinazoline when prepared by a process according to claim 18 or 19 or an obvious chemical equivalent thereof.
22. A process as claimed in claim 1 wherein R, R1 and R2 are hydrogen, R3 is methyl in the 9-position, R4 is phenyl and the dotted lines form double bonds.
23. A process for preparing (?) 6-phenylhydrazono-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline which comprises reacting phenyl diaæonium chloride with 9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline.
24. A process for preparing t+) 6-phenylhydrazono-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,l-b]quinazoline which comprises reacting phenyl hydrazine with 6,6-dibromo-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline.
25. The compound (+) 6-phenylhydrazono-9-methyl-11-oxo-6,7,8,8-tetrahydro-11H-pyrido[2,1-b]quinazoline when prepared by a process according to claim 23 or 24 or an obvious chemical equivalent thereof.
26. A process as claimed in claim 1 wherein R, R , R and R are hydrogen, R is phenyl and the dotted lines do not Eorm double bonds.
27. A process Eor preparing 6-phenylhydrazono-11-oxo-1,2,3,4,6,7,8,9-octa-hydro-11H-pyrido[2,1-b]quinazoline which comprises reacting phenyl diazonium chloride with 11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazoline.
28. The compound 6-phenylhydrazono-11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazoline when prepared by a process according to claim 27 or an obvious chemical equivalent thereof.
29. A process as claimed in claim 1 wherein R, R1 and R2 are hydrogen, R3 is methyl in the 9-position, R4 is phenyl and the dotted lines do not form double bonds.
30. A process for preparing (?) 6-phenylhydrazono-9-methyl-11-oxo-1,2,3,4, 6,7,8,9 -octahydro-11H-pyrido[2,1-b]quinazoline which comprises reacting phenyl diazonium chloride with 9-methyl-11-oxo-1,2,3,4,5,6,7,8,9-octahydro-11H-pyrido-[2,1-b]quinazoline.
31. The compound (?) 6-phenylhydrazono-9-methyl-11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazoline when prepared by a process according to claim 30 or an obvious chemical equivalent thereof.
32. A process according to claim 1 wherein R, R1 and R3 are hydrogen, R2 is carboxyl in the 2-position, R4 is phenyl and the dotted lines form double bonds.
33. A process for preparing 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid which comprises reacting phenyl diazonium chloride with 11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid.
34. The compound 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido-2,1-b quinazoline-2-carboxylic acid when prepared by a process according to claim 33 or an obvious ~hemical equivalent thereof.
35. A process as claimed in claim 1 wherein R and R1 are both hydrogen, R2 is carboxyl in the 2- or 3-position, R3 is hydrogen or methyl in the 9-position and R4 is phenyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1559/80 | 1980-06-24 | ||
| HU801559A HU183173B (en) | 1980-06-24 | 1980-06-24 | Process for producing 6-hydrazono-pyrido-aracket-2,1-b-bracket closed-quinazolin-11-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1167842A true CA1167842A (en) | 1984-05-22 |
Family
ID=10955013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000380416A Expired CA1167842A (en) | 1980-06-24 | 1981-06-23 | 6-hydrazono-pyrido[2,1-b]quinazoline-11-ones, and a process for the preparation thereof |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5738781A (en) |
| AT (1) | AT379393B (en) |
| AU (1) | AU544360B2 (en) |
| BE (1) | BE889339A (en) |
| CA (1) | CA1167842A (en) |
| CH (1) | CH648312A5 (en) |
| CS (1) | CS296285A2 (en) |
| DD (1) | DD160060A5 (en) |
| DE (1) | DE3124577A1 (en) |
| DK (1) | DK277281A (en) |
| ES (1) | ES8203370A1 (en) |
| FI (1) | FI70897C (en) |
| FR (1) | FR2485534A1 (en) |
| GB (1) | GB2080291B (en) |
| GR (1) | GR74608B (en) |
| HU (1) | HU183173B (en) |
| IL (1) | IL63061A (en) |
| IT (1) | IT1144814B (en) |
| NL (1) | NL8102935A (en) |
| NO (1) | NO157142C (en) |
| PL (2) | PL129635B1 (en) |
| PT (1) | PT73248B (en) |
| SE (1) | SE441829B (en) |
| SU (2) | SU1192614A3 (en) |
| YU (1) | YU42722B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ194196A (en) * | 1979-07-17 | 1983-07-15 | Ici Australia Ltd | -(quinoxalin-2-yl(oxy or thio) phen (oxy or ylthio)-alkanoic acid derivatives or precursors |
| AT377586B (en) * | 1981-06-30 | 1985-04-10 | Erba Farmitalia | METHOD FOR PRODUCING SUBSTITUTED PYRROLO- (2,1-B) -QUINAZOLINES AND PYRIDO (2,1-B) -QUINAZOLINES |
| JPS5987269A (en) * | 1982-11-12 | 1984-05-19 | Nissan Motor Co Ltd | Fuel injection valve |
| JPS61126367A (en) * | 1984-11-24 | 1986-06-13 | Mitsubishi Heavy Ind Ltd | Fuel injection device |
| JPS61129457A (en) * | 1984-11-27 | 1986-06-17 | Mitsubishi Heavy Ind Ltd | Multi-fuel-valve injector |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU178496B (en) * | 1977-12-29 | 1982-05-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing 6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidine derivatives with antiallergic activity |
-
1980
- 1980-06-24 HU HU801559A patent/HU183173B/en not_active IP Right Cessation
-
1981
- 1981-06-09 IL IL63061A patent/IL63061A/en unknown
- 1981-06-18 NL NL8102935A patent/NL8102935A/en not_active Application Discontinuation
- 1981-06-18 CS CS852962A patent/CS296285A2/en unknown
- 1981-06-22 GR GR65305A patent/GR74608B/el unknown
- 1981-06-22 FR FR8112209A patent/FR2485534A1/en active Granted
- 1981-06-22 ES ES503266A patent/ES8203370A1/en not_active Expired
- 1981-06-23 PT PT73248A patent/PT73248B/en unknown
- 1981-06-23 AT AT0277081A patent/AT379393B/en not_active IP Right Cessation
- 1981-06-23 PL PL1981235214A patent/PL129635B1/en unknown
- 1981-06-23 PL PL1981231826A patent/PL129623B1/en unknown
- 1981-06-23 SU SU813301195A patent/SU1192614A3/en active
- 1981-06-23 SE SE8103940A patent/SE441829B/en not_active IP Right Cessation
- 1981-06-23 DE DE19813124577 patent/DE3124577A1/en not_active Withdrawn
- 1981-06-23 YU YU1564/81A patent/YU42722B/en unknown
- 1981-06-23 DK DK277281A patent/DK277281A/en not_active Application Discontinuation
- 1981-06-23 AU AU72081/81A patent/AU544360B2/en not_active Ceased
- 1981-06-23 GB GB8119298A patent/GB2080291B/en not_active Expired
- 1981-06-23 BE BE0/205178A patent/BE889339A/en not_active IP Right Cessation
- 1981-06-23 IT IT67869/81A patent/IT1144814B/en active
- 1981-06-23 NO NO812143A patent/NO157142C/en unknown
- 1981-06-23 CA CA000380416A patent/CA1167842A/en not_active Expired
- 1981-06-23 CH CH4143/81A patent/CH648312A5/en not_active IP Right Cessation
- 1981-06-23 FI FI811970A patent/FI70897C/en not_active IP Right Cessation
- 1981-06-24 JP JP9813381A patent/JPS5738781A/en active Pending
- 1981-06-26 DD DD81231194A patent/DD160060A5/en not_active IP Right Cessation
-
1982
- 1982-05-18 SU SU823436303A patent/SU1191449A1/en active
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