U.S. patent number 3,755,332 [Application Number 05/159,061] was granted by the patent office on 1973-08-28 for substituted 4 indazolaminoquinolines.
This patent grant is currently assigned to Ciba-Geigy Corporation. Invention is credited to Abraham Wajngurt, Jan W. F. Wasley.
United States Patent |
3,755,332 |
Wasley , et al. |
August 28, 1973 |
SUBSTITUTED 4 INDAZOLAMINOQUINOLINES
Abstract
Substituted indazolaminoquinolines, acid addition salts thereof
as well as N-oxides thereof are anti-inflammatory,
anti-hypertensive and anti-malarial agents. Illustrative
embodiments are 7-chloro-4-(6-indazolamino)-quinoline and ethyl
7-chloro-4-(6-indazolamino)-quinoline-3-carboxylate.
Inventors: |
Wasley; Jan W. F. (Ossining,
NY), Wajngurt; Abraham (Riverdale, NY) |
Assignee: |
Ciba-Geigy Corporation
(Ardsley, NY)
|
Family
ID: |
22570921 |
Appl.
No.: |
05/159,061 |
Filed: |
July 1, 1971 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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818044 |
Apr 21, 1969 |
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725176 |
Apr 29, 1968 |
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Current U.S.
Class: |
546/160; 514/895;
546/153; 546/156; 546/90; 548/361.1 |
Current CPC
Class: |
C07D
215/54 (20130101); C07D 215/18 (20130101); C07D
215/233 (20130101); C07D 215/60 (20130101); C07D
215/56 (20130101); Y10S 514/895 (20130101) |
Current International
Class: |
C07D
215/18 (20060101); C07D 215/00 (20060101); C07D
215/233 (20060101); C07D 215/54 (20060101); C07D
215/60 (20060101); C07D 215/56 (20060101); C07d
033/50 () |
Field of
Search: |
;260/287R,288R |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Daus; Donald G.
Parent Case Text
CROSS-REFERENCE
This is a continuation-in-part of copending application, Ser. No.
818,044, filed Apr. 21, 1969, and of application, Ser. No. 725,176,
filed Apr. 29, 1968, both now abandoned.
Claims
What is claimed is:
1. A compound of the formula ##SPC3##
wherein
R.sub.1 is hydrogen or halogen;
R.sub.2 is hydrogen, primary and secondary lower alkyl of one to
six carbon atoms, benzyl, phenyl, p-bromophenyl, p-chlorophenyl, or
trifluoromethyl; each of
R.sub.3 and R.sub.6 is hydrogen, hydroxy, halogen, primary and
secondary lower alkyl of one to six carbon atoms, lower alkoxy of
one to four carbon atoms, or when R.sub.3 is hydrogen, R.sub.6 is
also trifluoromethyl; or R.sub.3 and R.sub.6 are methylenedioxy
when combined and adjacent;
R.sub.4 is hydrogen or lower alkyl of one to six carbon atoms;
R.sub.5 is hydrogen or primary and secondary lower alkyl of one to
six carbon atoms, and wherein the amino bridge is attached to
indazole at the 3-, 4-, 5-, 6- or 7- position; the pharmaceutically
acceptable acid addition salts, or the N-oxides thereof, wherein
the oxide is at the 1-position of the quinoline moiety.
2. A compound as defined in claim 1 which is
4-(5-indazolamino)-quinaldine.
3. A compound as defined in claim 1 which is
4-(6-chloro-3-indazolamino)-quinaldine.
4. A compound as defined in claim 1 which is
4-(6-indazolamino)-quinaldine.
5. A compound as defined in claim 1 which is
4-(6-indazolamino)-2-trifluoromethylquinoline.
6. A compound as defined in claim 1 which is
2-(4-chlorophenyl)-4-(6-indazolamino)quinoline.
7. A compound as defined in claim 1 which is
7-chloro-4-(6-indazolamino)quinaldine.
8. A compound as defined in claim 1 which is
4-(6-indazolamino)-6-methoxyquinoline.
9. A compound as defined in claim 1 which is
6-chloro-4-(6-indazolamino)-2-phenylquinoline.
10. A compound as defined in claim 1 which is
4-(6-indazolamino)quinoline.
11. A compound as defined in claim 1 which is
4(6-indazolamino)-2-phenylquinoline.
12. A compound as defined in claim 1 which is
4-(6-indazolamino)-7-methyl-2-phenylquinoline.
13. A compound as defined in claim 1 which is
4-(6-indazolamino)-6-methoxy-2-phenylquinoline.
14. A compound as defined in claim 1 which is
4-(6-indazolamino)-6-hydroxy-2-phenylquinoline.
15. A compound as defined in claim 1 which is
4-(6-indazolamino)-6-methoxy-2-phenyl-7-trifluoromethyl-quinoline.
16. A compound as defined in claim 1 which is
4-(6-indazolamino)quinaldine.
Description
DETAILED DESCRIPTION
The present invention relates to a novel class of chemical
compounds.
More specifically, the present invention pertains to compounds of
the general formula ##SPC1##
Wherein
R.sub.1 is hydrogen or halogen;
R.sub.2 is hydrogen, lower alkyl, benzyl, phenyl, p-bromophenyl,
p-chlorophenyl, carboxy, carbo(lower alkoxy), or
trifluoromethyl;
R.sub.3 and R.sub.6 are each hydrogen, hydroxy, halogen, lower
alkyl, lower alkoxy, or trifluoromethyl, or R.sub.3 and R.sub.6 are
methylenedioxy when combined and adjacent;
R.sub.4 is hydrogen or lower alkyl;
R.sub.5 is hydrogen, lower alkyl, carboxy or carbo(lower
alkoxy);
And pharmaceutically acceptable acid addition salts and N-oxides
thereof.
It should be noted that the amino bridge between the indazole
moiety and the quinoline moiety can be attached to the 3-, 4-, 5-,
6-, or 7- position of the indazole moiety. R.sub.1 can be on any of
the four ranging free carbon atoms of these positions.
The expression "halogen" as used herein is intended to cover
chlorine, bromine and iodine, preferred is chlorine; "lower alkyl"
is intended to cover alkyl groups of from one to six carbon atoms
such as methyl, ethyl, propyl, butyl, sec.-butyl, pentyl,
isopentyl, hexyl, and the like. The preferred substituent is
methyl; "lower alkoxy" is intended to cover alkoxy groups
containing from one to four carbon atoms such as methoxy, ethoxy,
propoxy or butoxy, preferably methoxy and ethoxy.
The expression "pharmaceutically acceptable acid addition salts",
as used herein, is intended to cover salts of the basic amino
compounds, said salts being derived from non-toxic inorganic or
organic acids such as hydrochloric, hydrobromic, sulfuric,
phosphoric, methanesulfonic, acetic, lactic, succinic, malic,
maleic, aconitic, phthalic, tartaric, pamoic, etc.
The expression "N-oxides thereof" as used herein is intended to
cover compounds of Formula I in which the 1-oxide is at the
1-position of the quinoline moiety.
The compounds of the present invention may be further substituted
by a lower aklyl (methyl) group at either the 2-position of the
indazole moiety or at the 1-position of the quinoline moiety. In
such a case, the compounds exist as substituted tautomers of
general formula I and specific illustrations are
4-[2-methyl-6-indazolamino]quinaldine and
7-chloro-1-methyl-4-(6-indazolamino)-1,4-dihydroquinoline.
The compounds represented by Formula I supra can exist in
tautomeric forms and the tautomeric forms of these compounds are
within the purview of this invention.
The compounds of the present invention may be prepared by the
method illustrated diagrammatically below. ##SPC2##
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as
defined above and X is halogen, preferably chlorine, bromine, or
iodine.
As indicated above, a 4-hydroxyquinoline of Formula II is reacted
with a halogenating agent to form the corresponding 4-haloquinoline
(IIa). The 4-haloquinoline (IIa) is then condensed with the
aminoindazole of choice (III) to yield the hydrohalide salt of the
indazolaminoquinoline (IV) which, if desired, may be converted to
the free base by treatment with a base in the usual manner.
Where R.sub.2 or R.sub.5 is a carboxy moiety, this group may, if
desired, be removed by decarboxylation procedures known to the art
to form compounds of general Formula I supra wherein R.sub.2 or
R.sub.5 is hydrogen.
Where R.sub.2
1-methyl-4-(6-indazolimino)-R.sub.5 in a compound of Formula I is
carboxy, the corresponding compound wherein R.sub.2 and R.sub.5 is
carbalkoxy is first prepared and saponified in the usual
manner.
In a specific embodiment of the present invention illustrating the
preparation of the active compounds, a 4-hydroxyquinoline of
general Formula II is reacted with a halogenating agent, such as, a
phosphorous pentahalide and illustratively phosphorous
pentachloride, by refluxing the reactants in a solution of a
phosphorous oxyhalide, in particular, phosphorous oxychloride.
After heating for from about 1 to about 3 hours, the reaction
mixture is cooled, and the product isolated. Generally, the
isolation procedure is carried out by quenching the reaction
mixture with ice, neutralizing with aqueous ammonia and collecting
the solid precipitate thus formed. This solid is thoroughly
extracted with hot organic solvents such as ether, or petroleum
ether, to yield the 4-haloquinoline of general Formula (IIa).
The condensation of the aminoindazole (III) with the
4-haloquinoline (IIa) may be accomplished by any of three general
procedures. The two components may be fused together; or they may
be heated together in a solvent which is inert to the present
reaction, such as acetone, dimethylformamide, dimethylsulfoxide,
chloroform, acetonitrile, etc., or the reaction may be carried out
in dilute mineral acid such as, for example, dilute hydrochloric
acid. While the ratio of reactants is not critical, it is preferred
to utilize a 1:1 molar ratio of quinoline to indazole.
In the fusion process, the components are heated to a temperature
of about 130.degree.-160.degree.C for a period of from about 3 to
about 10 minutes. The reaction mixture becomes solid, and is then
cooled, dissolved in aqueous alkanol, suitably aqueous ethanol,
made basic by the addition of, most suitably, aqueous ammonia and
the product precipitated by the addition of water. The product is
then removed by filtration and recrystallized most suitably from
ethanol or ethyl acetate.
In the procedure involving the use of an inert solvent such as
acetone, the reactants are dissolved in dry acetone and heated
under reflux for a period of from about one-half to about 40 hours.
The reaction mixture is then cooled and the product isolated as the
hydrochloride salt. If desired, this hydrochloride salt may be
converted to the free base by solution in aqueous alcohol,
basification, suitably with aqueous ammonia, and precipitation with
water. The precipitate is then collected, dried and recrystallized
from a suitable solvent such as ethanol or ethyl acetate.
In the procedure involving the use of a mineral acid such as dilute
hydrochloric acid, the components are suspended in dilute
hydrochloric acid, suitably from about 0.1N to about 5N acid and
heated under reflux from about 2 to about 10 hours. The reaction
mixture is cooled, and the hydrochloride salt of the product
isolated by filtration. If desired, the hydrochloride salt is then
converted into the base in the manner set forth above.
As stated above, the indazolaminoquinolines of the present
invention are characterized by anti-inflammatory, anti-hypertensive
as well as anti-malarial properties. Pharmacological test data has
been obtained illustrating the therapeutic activity characterizing
the compounds of the present invention. The daily dosages are
between about 10 mg/kg and 400 mg/kg of the mammal.
The compounds of the present invention demonstrate the properties
of inhibiting and reducing inflammation, of lowering blood pressure
and of favorably influencing malaria. They are thus useful as
anti-inflammatory anti-hypertensive and anti-malarial agents. The
anti-inflammatory property of this class of compounds can be
conveniently observed in the laboratory model in such
art-recognized tests as the turbidity model, U.V. erythema test,
anti-carrageenin, and adjuvant arthritis screens. For instance, in
the turbidity model test, inhibition of heat coagulation of serum
proteins was observed in rats at dosages of 100 mg/kg on
subcutaneous administration.
In the anti-carrageenin screen, a diminution of swelling induced by
carrageenin was observed in rats at dosages of 50-100 mg/kg
p.o.
In the adjuvant arthritis screen protection was observed at dosages
of 100 mg/kg when administered orally per day.
The anti-hypertensive properties of the compounds of this invention
have been domonstrated in such art-recognized anti-hypertensive
tests as the tyrosine hydroxylase inhibition screen, the mouse
norepinephrine release screen and tests with unanaesthetized DOCA
hypertensive rats.
The compounds of the present invention also exhibit anti-malarial
properties. The efficacy of the compounds was determined in the
imidazole N-methyl transferase test. Inhibition was observed at
concentrations from between 10.sup..sup.-5 molar to 10.sup..sup.-7
molar.
The indazolaminoquinolines have very favorable therapeutic index;
they are active in low concentrations while their LD.sub.50 values
are very high.
The indazolaminoquinolines of the present invention are
administered topically, parenterally or orally to achieve an
anti-inflammatory, anti-hypertensive or anti-malarial effect, in
any of the usual pharmaceutical forms. These include solid and
liquid unit oral dosage forms such as tablets, capsules, powders,
suspension, solutions, syrups and the like, including sustained
release preparations, and fluid injectable forms such as sterile
solutions and suspensions. When administered topically, the
compounds are compounded into pharmaceutically acceptable lotions,
creams, ointments, powders or sprays. The term dosage form as used
in this specification and the claims refer to physically discrete
units to be administered in single or multiple dosage form to
animals, each unit containing a predetermined quantity of active
material in association with the required diluent, carrier or
vehicle. The quantity of active material is that calculated to
produce the desired therapeutic effect upon administration of one
or more of such units.
Powders are prepared by comminuting the compound to a suitably fine
size and mixing with a similarly comminuted diluent pharmaceutical
carrier such as an edible carbohydrate material as for example,
starch. Sweetening, flavoring, preservative, dispersing and
coloring agents can also be present.
Capsules ae made by preparing a powder mixture as described above
and filling formed gelatin sheaths. A lubricant such as talc,
magnesium stearate and calcium stearate can be added to the powder
mixture as an adjuvant before the filling operation; a glidant such
as colloidal silica may be added to improve flow properties; a
disintegrating or solubilizing agent may be added to improve the
availability of the composition when the capsule is ingested.
Tablets are made by preparing a powder mixture, granulating or
slugging, adding a lubricant and disintegrant and pressing into
tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base such as starch,
sucrose, kaolin, dicalcium phosphate and the like. The powder
mixture can be granulated by wetting with a binder such as syrup,
starch paste, acacia mucilage or solutions of cellulosic or
polymeric materials and forcing through a screen. As an alternative
to granulating, the powder mixture can be run through the tablet
machine and the resulting imperfectly formed slugs broken into
granules. The granules can be lubricated to prevent sticking to the
tablet forming dies by means of the addition of stearic acid, a
stearate salt, talc or mineral oil. The lubricated mixture is then
compressed into tablets. The medicaments can also be combined with
free flowing inert carriers and compressed into tablets directly
without going through the granulating or slugging steps. A
protective coating consisting of a sealing coat of shellac, a
coating of sugar or polymeric material and a polish coating of wax
can be provided. Dystuffs can be added to these coatings to
distinguish different unit dosages.
Oral fluids such as syrups and elixirs can be prepared in unit
dosage form so that a given quantity, e.g., a teaspoonful, contains
a predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous sucrose
solution while elixirs are prepared through the use of a non-toxic
alcoholic vehicle. Suspensions can be formulated by dispersing the
composition in a non-toxic vehicle in which it is insoluble.
For parenteral administration, fluid unit dosage forms can be
prepared by suspending or dissolving a measured amount of the
compound in a non-toxic liquid vehicle suitable for injection such
as an aqueous or oleaginous medium. Alternatively a measured amount
of the compound is placed in a vial and the vial and its contents
are sterilized and sealed. An accompanying vial or vehicle can be
provided for mixing prior to administration.
One important embodiment of the present invention, particularly for
preparing solid pharmaceutical formulations, is the
pharmaceutically acceptable non-toxic acid addition salts of these
indazolaminoquinolines as well as the N-oxides.
The following examples are given by way of illustrating the
procedure used in preparing the compounds of the present invention
without limiting the scope thereof in any way. The temperatures are
given in degrees Centigrade.
EXAMPLE 1
7-chloro-4-(6-indazolamino)-quinoline
13.3 g. (0.1 mole) of 6-amino-indazole was suspended in 500 ml. of
3N HCl and to this mixture was added 19.8 g. (0.1 mole) of
4,7-dichloroquinoline and this mixture was refluxed for 8 hours.
(Aftr refluxing for one hour, a precipitate appeared which went
back in solution after 2 hours. After refluxing for 3 hours, a new
precipitate appeared.) The reaction mixture was stirred overnight,
then cooled and the hydrochloride salt of the product was
collected. The 7-chloro-4-(6-indazolamino)quinoline HCl was
dissolved in 400 ml. of alcohol and 200 ml. of water and the
solution was treated with charcoal. The clear solution was made
basic to a pH 9-10 with 10% NH.sub.4 OH. The compound that
precipitated was collected on a Buchner funnel and washed well with
water. After two recrystallizations from ethanol, the product
melted at 253.degree.-254.degree.: Yield 8.0 g. after drying to
constant weight for 3 days in vacuum oven at 100.degree..
Analysis for C.sub.16 H.sub.11 ClN.sub.4
Calc'd.: C, 65.20; H, 3.76; N, 19.07
Found : C, 64.94; H, 3.67; N, 18.87
EXAMPLE 2
4-(6-indazolamino)-quinaldine
13.3 g. (0.1 mole) of 6-amino-indazole was suspended in 750 ml. of
2N HCl. To this mixture was added 17.7 g (0.1 mole) of
4-chloro-quinaldine and the mixture was refluxed for 5 hours. The
reaction mixture was cooled and the hydrochloride salt of the
product was collected. The 4-(6-indazolamino)quinaldine
hydrochloride was dissolved in 500 ml. of water and the pH of this
mixture was adjusted to 8-9 with 10% NH.sub.4 OH. The compound that
precipitated was collected on a Buchner funnel and washed well with
water and dried over-night in vacuo. After recrystallization from a
mixture of ethyl acetate and isopropanol 2:1 using charcoal, the
product melted at 240.degree.-241.degree.; Yield 3.8 g. (after
drying to constant weight for 3 days in vacuum oven at
100.degree.C).
Analysis for C.sub.17 H.sub.17 N.sub.4
Calc'd.: C, 74.73; H, 5.14; N, 20.43
Found : C, 74.55; H, 4.90; N, 20.36
EXAMPLE 3
4-(3-indazolamino)-quinaldine
A mixture of 3 g. (0.023 mole) of 3-aminoindazole and 4.07 g.
(0.023 mole) of 4-chloro-quinaldine (obtained by the procedure
described by A. Bamberger Berichte 55, 3371, (1922) was gently
warmed at 140.degree. for period of 5 minutes. The mobile reaction
mixture solidified and was then dissolved in a mixture of 200 ml.
50 percent ethanol and basified with 10% NH.sub.4 OH (pH 9-10). The
product was precipitated by the addition of 200 ml. of water. The
product was filtered and washed well with water. The compound was
recrystallized from ethanol; it melted at 264.degree.-265.degree.;
Yield 4.3 g.
Analysis for C.sub.17 H.sub.17 N.sub.4
Calc'd.: C, 74.73; H, 5.14; N, 20.43
Found : C, 74.94; H, 4.96; N, 20.58
EXAMPLE 4
4-(6-chloro-3-indazolamino)-quinaldine
A mixture of 8.3 g. (0.05 mole) of 6-chloro-3-amino-indazole and
8.5 g (0.05 mole) of 4-chloroquinaldine was gently warmed at
140.degree. for a period of 5 minutes. The mobile reaction mixture
solidified and was then dissolved in a mixture of 200 ml. 50
percent ethanol and basified with 10% NH.sub.4 OH (pH 9-10). The
product was precipitated by the addition of 400 ml. of water. The
product was filtered and washed well with water. The compound was
recrystallized from ethanol. It melted at 231.degree.-233.degree.;
Yield 6.2 g.
Analysis for C.sub.17 H.sub.13 ClN.sub.4
Calc'd.: C, 66.13; H, 4.24; N, 18.15
Found : C, 65.90; H, 4.17; N, 18.35
EXAMPLE 5
4-(5-indazolamino)-quinaldine
6.65 g. (0.05 mole) of 5-Aminoindazole was suspended in 220 ml. of
2N HCl. To this mixture was added 8.85 g (0.05 mole) of
4-chloroquinaldine and the mixture was refluxed for 5 hours. The
reaction mixture was cooled and the hydrochloride salt of the
product was collected. The 4-(5-indazolamino)quinaldine
hydrochloride thus obtained was dissolved in 300 ml. of water and
the pH of this mixture was adjusted to 8-9 with 10% NH.sub.4 OH.
The compound that precipitated was collected on a Buchner funnel
and washed well with water and dried overnight in vacuo. After
recrystallization from ethyl acetate, the product melted at
298.degree.-299.degree.; Yield 3.1 g.
Analysis for C.sub.17 H.sub.14 N.sub.4
Calc'd.: C, 74.43; H, 5.14; N, 20.43
Found : C, 74.18; H, 5.23; N, 20.22
EXAMPLE 6
7-trifluoromethyl-4-(6-indazolamino)quinoline
a. A mixture of 25 g. of 4-hydroxy-7-trifluoromethylquinoline and
150 ml. of phosphorous oxychloride was refluxed with stirring for a
period of four hours. The excess POCl.sub.3 was removed in vacuo to
give a syrupy residue. This was cooled, 100 ml. of ethanol was
added and the mixture was stirred for 30 minutes. The resulting
solid was filtered off and suspended in a mixture of alcohol and
water; the pH of this mixture was adjusted to 9-10 with 10%
NH.sub.4 OH. A crystalline compound precipitated which was filtered
off, washed well with water and dissolved in 300 ml. of ether. The
ether solution was dried over Na.sub.2 SO.sub.4, filtered and
concentrated in vacuo to give a crystalline compound identified as
4-chloro-7-trifluoromethylquinoline, m.p. 66.degree.-69.degree.
(22.3 g.).
b. 7.0 g. (0.053 mole) of 6-Aminoindazole was dissolved in 200 ml.
of dry acetone. To this mixture was added 12.0 g. (0.053 mole) of
4-chloro-7-trifluoromethylquinoline obtained above and the mixture
was heated under reflux for 36 hours. The reaction mixture was
concentrated in vacuo and the hydrochloride salt of the product was
collected. The 7-trifluoromethyl-4-(6-indazolamino)-quinoline
hydrochloride was suspended in 200 ml. of a mixture of 50 percent
of alcohol and water and made basic with NH.sub.4 OH (pH 8-9). The
crystalline compound that precipitated was filtered and washed well
with water. After crystallization from ethanol, the product melted
at 266.degree.-268.degree.; Yield 4.0 g.
Analysis for C.sub.17 H.sub.11 F.sub.3 N.sub.4
Calc'd.: C, 62.19; H, 3.38; N, 17.06; F, 17.36
Found : C, 62.27; H, 3.47; N, 17.00; F, 17.36
EXAMPLE 7
2-phenyl-4-(6-indazolamino)quinoline
6-Aminoindazole (5.6 g., 0.42 mole) was dissolved in dry acetone
(100 ml.). 2-Phenyl-4-chloro-quinoline (5.0 g., 0.042 mole) was
added to this solution and the resulting solution then boiled under
reflux for 16 hours. 2-Phenyl-4-(6-indazolamino)quinoline
hydrochloride precipitated.
The hydrochloride salt was collected, suspended in EtOH/HOH(1:5),
the pH was adjusted to 10-11 with 3N NaOH, and the free base was
collected and washed well with water. After two recrystallizations
from ethanol, the product melted at 245.degree.-247.degree.C.
Yield: 300 mg.
Analysis for C.sub.22 H.sub.16 N.sub.4
Calc'd.: C, 78.54; H, 4.80; N, 16.66
Found : C, 78.30; H, 4.92; N, 16.77
EXAMPLE 8
7-chloro-4-(5-indazolamino)quinaldine
A mixture of 7.3 g. of 4,7-dichloroquinaldine and 4.6 g. of
5-aminoindazole were dissolved in 200 ml. of 2 N HCl and heated
under reflux for 7 hours. The reaction mixture was allowed to cool
overnight and the hydrochloride salt of the product was collected.
The 7-chloro-4-(5-indazolamino)quinaldine hydrochloride was
suspended in 50 ml. of ethanol and was basified with concentrated
NH.sub.4 OH. The suspension was stirred for 30 minutes, the solid
product was collected and was washed well with water. After
recrystallization from ethyl acetate, the product melted at
300.degree.-302.degree.. Yield: 2.1 g.
Analysis for C.sub.17 H.sub.13 ClN.sub.4
Calc'd.: C, 66.13; H, 4.24; N, 18.15
Found : C, 65.97; H, 4.47; N, 17.86
EXAMPLE 9
4-(7-indazolamino)-quinaldine
A mixture of 6.1 g. of 7-aminoindazole and 8.1 g. of
4-chloroquinaldine were dissolved in 100 ml. 3N HCl and the
solution was heated under reflux for 8 hours. The reaction mixture
was allowed to stand overnight and then heated under reflux for an
additional 8 hours. The hydrochloride salt of the product was
collected and suspended in a mixture of 160 mls. of water and 40
mls. of ethanol and basified with 10% NH.sub.4 OH. An additional
200 ml. of water were added to ensure complete precipitation of the
product, which was collected by filtration. After recrystallization
from ethanol, the product melted at 255.degree.-257.degree.; Yield
3.3 g.
Analysis for C.sub. H.sub.14 N.sub.4
Calc'd.: C, 74.43; H, 5.14; N, 20.43
Found : C, 74.71; H, 5.33; N, 20.29
EXAMPLE 10
4-(4-indazolamino)-quinaldine
A mixture of 10 g. of 4-aminoindazole and 13.4 g. of
4-chloroquinaldine were dissolved in 100 ml. of 3N HCl and the
solution was heated under reflux for 16 hours. The reaction mixture
was cooled and the hydrochloride salt of the product was collected,
suspended in a mixture of 160 ml. of water and 40 ml. of ethanol
and basified with 3N NaOH. The compound that precipitated was
collected by filtration and washed well with water. After
recrystallization from ethanol using charcoal, the product melted
at 274.degree.-276.degree.. Yield 3.0 g.
Analysis for C.sub.17 H.sub.14 N.sub.4
Calc'd.: C, 74.43; H, 5.14; N, 20.43
Found : C, 74.12; H, 5.08; N, 20.17
EXAMPLE 11
4-(3-chloro-6-indazolamino)quinaldine
A solution of 7.5 g. (0.045 mole) of 6-amino-3-chloroindazole and
7.95 g. (0.045 mole) of 4-chloroquinaldine in 200 ml. of 2N HCl was
heated under reflux for 7 hours. The reaction mixture was cooled
and the hydrochloride salt of the product was collected. The
4-(3-chloro-6-indazolamino)-quinaldine hydrochloride was suspended
in a mixture of 200 ml. of ethanol and 200 ml. of water and
basified with 3N NaOH. The compound that precipitated was collected
by filtration and washed well with water. After two
recrystallizations from ethyl acetate, the product was obtained
melting at 269.degree.-270.degree.. Yield: 4.5 g.
Analysis for C.sub.17 H.sub.13 ClN.sub.4
Calc'd.: C, 66.13; H, 4.28; N, 18.15
Found : C, 66.22; H, 4.51; N, 18.09
EXAMPLE 12
4-(5-indazolamino)-7-trifluoromethylquinaldine
a. A mixture of 3-trifluoromethylaniline (129.0 g. 0.8 mole) and
ethyl acetoacetate (104.2 g., 0.8 moles) was stored in a vacuum
dessicator over CaCl.sub.2 until the water uptake totalled 16.5 g.
This mixture was then poured into refluxing phenyl ether (700 ml.).
The mixture was boiled under reflux for 40 minutes, cooled to
70.degree. and filtered. The resulting solid was triturated with
ether and collected. m.p. 324.degree.-330.degree.; Yield 16.3
g.
b. A solution of 4-hydroxy-7-trifluoromethyl quinaldine obtained
above (16.3 g., 0.072 mole) in POCl.sub.3 was boiled under reflux
(oil bath 120.degree.) for 1 hour. This solution was cooled, poured
onto a mixture of cracked ice and 50% NaOH (200 ml.), the pH was
adjusted to 10-11 and the mixture was extracted with ether; the
ether solution was dried over Na.sub.2 SO.sub.4, charcoaled and
evaporated to dryness yielding an oil which crystallized on
triturating with petroleum ether. Yield: 15.1 g., m.p.
42.degree.-46.degree..
c. 5-Aminoindazole (8.1 g., 0.061 moles) was dissolved in dry
acetone and to this solution 4-chloro-7-trifluoromethylquinaldine
obtained above (15.1 g., 0.061 mole) was added; the resulting
solution was boiled under reflux (oil bath 100.degree.) for 11
hours precipitating 4-(5-indazolamino)-7-trifluoromethyl-quinaldine
hydrochloride. The hydrochloride salt was suspended in EtOH/water
(400 ml., 1:3), the suspension was basified with 3N NaOH and
filtered; the product was washed well with water. The product
melted at 278.degree. after two recrystallizations from ethyl
acetate. Yield: 1.4 g.
Analysis for C.sub.18 H.sub.13 F.sub.3 N.sub.4
Calc'd.: C, 63.15; H, 3.83; N, 16.37
Found : C, 63.06; H, 3.94; N, 16.55
EXAMPLE 13
Ethyl 4-(6-indazolamino)quinaldine-3-carboxylate
6-Aminoindazole (1.6 g.) and ethyl 4-chloroquinaldine-3-carboxylate
(3.0 g.) were combined and gently warmed. The mobile reaction
mixture solidified. This was dissolved in hot ethanol, basified
with 10% NH.sub.4 OH, and the product precipitated with water.
Recrystallization of the product from aqueous ethanol yielded pale
yellow prisms (1.5 g.: 33%), m.p. 226.degree.-7.degree..
Analysis for C.sub.20 H.sub.18 N.sub.4 O.sub.2
Calc'd.: C, 69.35; H, 5.24; N, 16.18
Found : C, 69.05; H, 5.30; N, 16.40
EXAMPLE 14
Ethyl 4-(4-indazolamino)-quinaldine-3-carboxylate
4.66 g. (0.035 mole) of 4-Amino-indazole was dissolved in 200 ml.
of dry acetone. To this mixture was added 8.7 g. (0.035 mole) of
ethyl 4-chloroquinaldine-3-carboxylate and the mixture was refluxed
for 24 hours. The reaction mixture was cooled and the hydrochloride
salt of the product was collected. The ethyl
4-(4-indazolamino)-quinaldine-3-carboxylate hydrochloride was
dissolved in 100 ml. of alcohol and 100 ml. of water and the pH of
this mixture was adjusted to 8-9 with 10% NH.sub.4 OH. The compound
that precipitated was collected on a Buchner funnel, washed well
with water and dried overnight in vacuo. Yield 7.0 g. After two
recrystallizations from ethyl acetate (charcoal), the product
melted at 177.degree.-178.degree.. Yield 3.9 g. after drying to
constant weight for 2 days in vacuum oven at 100.degree.C.
Analysis for C.sub.20 H.sub.18 N.sub.4 O.sub.2
Calc'd.: C, 69.35; H, 5.24; N, 16.18
Found : C, 69.05; H, 5.34; N, 16.06
EXAMPLE 15
Ethyl 7-chloro-4-(6-indazolamino)-quinoline-3-carboxylate
a. A mixture of 32.6 g. (0.13 mole) of ethyl
7-chloro-4-hydroxyquinoline-3-carboxylate, 60 ml. of phosphorous
oxychloride and 27 g. (0.13 mole) of phosphorous pentachloride was
boiled under reflux for 2 hours and cooled. This mixture was poured
slowly wwth stirring onto 1.5 Kg. of ice and 1.5 liters of NH.sub.4
OH keeping the mixture alkaline to phenolphthalein at all times.
Stirring was continued for 2 hours and the precipitate was
collected by filtration and air dried overnight. The solid was
leached with several portions of boiling ether. The ether solution
was dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The
crystalline residue was leached with several portions of boiling
petroleum ether and the residue was discarded. The petroleum ether
extracts were combined, treated with charcoal (KB), -- concentrated
until crystallization began, and then cooled. The colorless
crystals that separated were collected by filtration and dried. The
product, ethyl 4,7-dichloro-3-quinolinecarboxylate, was obtained in
a yield of 10 g., m.p. 78.degree.-80.degree.. In the literature,
m.p. 80.degree.-82.degree., Edward F. Elslager and coworkers, J.
Pharm. Chem., 5, 558 (1962).
b. 4.6 g. (0.035 mole) of 6-aminoindazole was dissolved in 250 ml.
of dry acetone. To this mixture was added 9.5 g. (0.035 mole) of
ethyl 4,7-dichloro-3-quinoline carboxylate obtained above and the
mixture was refluxed for 8 hours. The reaction mixture was cooled
and the hydrochloride salt of the product was collected. The ethyl
7-chloro-4-(6-indazolamino)quinoline-3-carboxylate hydrochloride
was dissolved in a mixture of alcohol and water and the pH of this
mixture was adjusted to 8-9 with 10% NH.sub.4 OH. The compound that
precipitated was collected on a Buchner funnel, washed well with
water. After two recrystallizations from ethanol and charcoal, the
product melted at 208.degree.-209.degree.. After drying to constant
weight for two days in a vacuum oven at 100.degree., yield was 4.0
g.
Analysis for C.sub.19 H.sub.15 ClN.sub.4 O.sub.2
Calc'd.: C, 62.21; H, 4.12; N, 15.28
Found : C, 62.09; H, 4.00; N, 15.26
EXAMPLE 16
Ethyl 4-(5-indazolamino)-quinaldine-3-carboxylate
4.65 g. (0.035 mole) of 5-Aminoindazole was dissolved in 250 ml. of
dry acetone. To this mixture was added 8.7 g. (0.035 mole) of ethyl
4-chloroquinaldine-3-carboxylate and the mixture was refluxed for 8
hours. The reaction mixture was cooled and the hydrochloride salt
of the product was collected. Ethyl
4-(5-indazolamino)-quinaldine-3-carboxylate hydrochloride was
dissolved in 500 ml. of 50 percent alcohol and the pH of this
mixture was adjusted to 8-9 with 10% NH.sub.4 OH. The compound that
precipitated was collected on a Buchner funnel and washed well with
water and dried overnight in vacuo. After two recrystallizations
from ethyl acetate, the product melted at 225.degree.-226.degree..
Yield 3.6 g. (after drying to constant weight for three days in
vacuum oven at 100.degree.).
Analysis for C.sub.20 H.sub.18 N.sub.4 O.sub.2
Calc'd.: C, 69.35; H, 5.24; N, 16.18
Found : C, 69.41; H, 5.34; N, 16.08
EXAMPLE 17
Ethyl 4-(7-indazolamino)-quinaldine-3-carboxylate
9.3 g. (0.07 mole) of 7-amino-indazole was dissolved in 500 ml. of
dry acetone. To this mixture was added 17.4 g. (0.07 mole) of ethyl
4-chloroquinaldine-3-carboxylate and the mixture was refluxed for
21 hours. The reaction mixture was cooled and the hydrochloride
salt of the product was collected. The ethyl
4-(7-indazolamino)-quinaldine-3-carboxylate hydrochloride was
dissolved in 500 ml. of 50 percent alcohol and the pH of this
mixture was adjusted to 8-9 with 10% NH.sub.4 OH. The compound that
precipitated was collected on a Buchner funnel and washed well with
water. After two recrystallizations from ethanol the product melted
at 197.degree.-198.degree.; Yield 6.5 g. (after drying to constant
weight for 2 days in vacuum oven at 80.degree.-90.degree.).
Analysis for C.sub.20 H.sub.18 N.sub.4 O.sub.2
Calc'd.: C, 69.35; H, 5.24; N, 16.18
Found : C, 69.24; H, 5.29; N, 16.28
EXAMPLE 18
Ethyl
7-trifluoromethyl-4-(6-indazolamino)-quinoline-3-carboxylate
a. A mixture of ethyl
4-hydroxy-7-trifluoromethylquinoline-3-carboxylate, 60 ml. of
phosphorous oxychloride and 15 g. of phosphorous pentachloride was
heated under reflux for 8 hours and cooled. This mixture was poured
slowly with stirring into 1.5 Kg. of ice and made basic pH 10-11
with 10N NaOH. Stirring was continued for additional 2 hours and a
gummy precipitate was obtained which crystallized upon standing.
The crystalline compound was filtered and washed well with water.
The solid was leached with 300 ml. of ether. The ether solution was
dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. With the
addition of petroleum ether, the compound, ethyl
4-chloro-7-trifluoromethylquinoline-3-carboxylate, crystallized. It
melted at 62.degree.-64.degree.. Yield: 4.6 g.
Analysis for C.sub.13 H.sub.9 ClF.sub.3 NO.sub.2
Calc'd.: C, 51.41; H, 2.99; N, 4.61
Found : C, 51.46; H, 2.99; N, 4.81
b. 1.79 g. (0.0133 mole) of 6-Aminoindazole was dissolved in 100
ml. of dry acetone. To this mixture was added 4.1 g (0.0133 mole)
of ethyl 4-chloro-7-trifluoromethyl quinoline-3-carboxylate
obtained above and the mixture was refluxed for 7 hours. The
reaction mixture was cooled and the hydrochloride salt of the
product was collected. The ethyl
7-trifluoromethyl-4-(6-indazolamino)-quinoline-3-carboxylate
hydrochloride was dissolved in a mixture of alcohol and water and
the pH of this mixture was adjusted to 8-9 with 10% NH.sub.4 OH.
The compound that precipitated was collected on a Buchner funnel
and washed well with water. After recrystallization from a mixture
of cyclohexane and ether, the product melted at
158.degree.-160.degree.. Yield 2.4 g.
Analysis for C.sub.20 H.sub.15 F.sub.3 N.sub.4 O.sub.2
Calc'd.: C, 60.00; H, 3.78; N, 13.99
Found : C, 59.96; H, 3.80; N, 13.78
EXAMPLE 19
4-(6-indazolamino)-quinaldine-3-carboxylic acid
Methyl acetoacetate (315 g.), isatoic anhydride (300 g.), sodium
hydroxide (5 g.) and dioxane (750 ml.) were mixed together with
moderate stirring and the mixture was refluxed for a period of 24
hours during which time carbon dioxide was evolved. The reaction
mixture was cooled and the product precipitated. The compound,
methyl-4-hydroxyquinaldine-3-carboxylate was filered and washed
with ether. Yield: 135 g., m.p. 237.degree.-238.degree..
b. 135 g. of methyl 4-hydroxyquinaldine-3-carboxylate obtained
above and 450 ml. of phosphorous oxychloride were refluxed for a
period of 2 hours. The excess POCl.sub.3 was removed in vacuo to
give a syrupy residue. This was cooled, 200 ml. of ethanol was
added and the mixture was stirred for 30 minutes. The solid was
filtered and dissolved in 500 ml. of water. The pH of this mixture
was adjusted to 8-9 with 10% NH.sub.4 OH. The reaction mixture was
extracted with ether The ether extract was washed with water, dried
over MgSO.sub.4 and concentrated in vacuo to give a solid, methyl
4-chloroquinaldine-3-carboxylate, melting at 58.degree.-60.degree..
Yield 78.8 g.
c. 26.6 g. of 6-Aminoindazole were dissolved in 850 ml. of dry
acetone and to this mixture was added 47 g. (0.2 mole) of methyl
4-chloroquinaldine-3-carboxylate obtained above. The mixture was
refluxed with stirring for 6 hours. The reaction mixture was cooled
and the hydrochloride salt of the product was collected. The salt
(methyl 4-(6-indazolamino)-quinaldine-3-carboxylate hydrochloride)
was dissolved in 400 ml. of 50 percent alcohol and the pH of this
mixture was adjusted to 8-9 with 10% NH.sub.4 OH. The compound that
precipitated was collected on a Buchner funnel and washed well with
water. After two recrystallizations from ethanol the product,
methyl 4-(6-indazolamino)-quinaldine-3-carboxylate melted at
232.degree.-233.degree.. Yield 30 g.
d. 11 g. (0.033 mole) of methyl
4-(6-indazolamino)-quinaldine-3-carboxylate obtained above was
suspended in 100 ml. of 3N NaOH and the reaction mixture was
refluxed for a period of 4 hours. The reaction mixture was cooled
and 100 ml. of water was added. The aqueous mixture was extracted
with ethyl acetate (to remove unreacted ester). The water solution
was made acid to pH 3.8 with 3N HCl. The compound precipitated. The
precipitate was collected and washed well with water. After
recrystallization from 600 ml. of methanol using charcoal, the
compound, 4-(6-indazolamino)-quinaldine-3-carboxylic acid, melted
at 273.degree.-275.degree.. Yield: 5.0 g. The same compound was
obtained when methyl 4-(6-indazolamino)-quinaldine-3-carboxylate
was hydrolyzed with LiI in pyridine solution.
Analysis for C.sub.18 H.sub.14 N.sub.4 O.sub.2
Calc'd.: C, 67.92; H, 4.43; N, 17.60
Found : C, 67.90; H, 4.23; N, 17.42
EXAMPLE 20
Methyl 4-(5-indazolamino)-quinaldine-3-carboxylate
13.3 g. (0.1 mole) OF 5-Aminoindazole was dissolved in 350 ml. of
dry acetone. To this mixture was added 23.5 g. (0.1 mole) of methyl
4-chloroquinaldine-3-carboxylate and the mixture was refluxed for 7
hours. The reaction mixture was cooled and the hydrochloride salt
of the product was collected. The
methyl-4-(5-indazolamino)-quinaldine-3-carboxylate hydrochloride
was dissolved in 200 ml. of 50 percent ethanol and the pH of this
mixture was adjusted to 10-11 with 3N NaOH. The compound that
precipitated was collected on a Buchner funnel and washed well with
water. Recrystallization from ethanol and charcoal afforded a
compound which melted at 243.degree.-245.degree.. Yield: 10.4
g.
Analysis for C.sub.19 H.sub.16 N.sub.4 O.sub.2
Calc'd.: C, 68.66; H, 4.85; N, 16.86
Found : C, 68.40; H, 4.95; N, 16.74
EXAMPLE 21
Methyl 4-(6-indazolamino)-quinaldine-3-carboxylate
26.6 g. of 6-aminoindazole were dissolved in 850 ml. of dry acetone
and to this mixture was added 47 g. (0.2 mole) of methyl
4-chloroquinaldine-3-carboxylate. The mixture was refluxed with
stirring for 6 hours. The reaction mixture was cooled and the
hydrochloride salt of the product was collected. The salt [methyl
4-(6-indazolamino)-quinaldine-3-carboxylate hydrochloride] was
dissolved in 400 ml. of 50 percent alcohol and the pH of this
mixture was adjusted to 8-9 with 10% NH.sub.4 OH. Thp compound that
precipitated was collected on a Buchner funnel and washed well with
water. After two recrystallizations from methanol, the product
melted at 232.degree.-233.degree.. Yield: 30 g.
Analysis for C.sub.19 H.sub.16 N.sub.4 O.sub.2
Calc'd.: C, 68.66; H, 4.85; N, 16.86
Found : C, 68.71; H, 5.05; N, 16.93
EXAMPLE 22
7-chloro-4-(6-indazolamino)-quinoline-3-carboxylic acid
A mixture of 3.5 g of ethyl
7-chloro-4-(6-indazolamino)-quinoline-3-carboxylate and 25 ml. of
3N sodium hydroxide was heated under reflux for 3 hours. During
this time a yellow solution was obtained, which was then diluted
with 75 ml. of water and acidified to pH 6. The solid which
precipitated was collected by filtration and then suspended in hot
methanol and refiltered to yield a yellow solid, m.p. 289.degree.;
Yield: 2.4 g.
Analysis for C.sub.17 H.sub.11 ClN.sub.4 O.sub.2
Calc'd.: C, 60.27; H, 3.27; N, 16.54; Cl, 10.47
Found : C, 60.10; H, 3.43; N, 16.27; Cl, 10.47
EXAMPLE 23
Ethyl 2-phenyl-4-(5-indazolamino)-quinoline-3-carboxylate
a. A mixture of 138 g. (0.82 mole) of isatoic anhydride, 253.8 g.
(1.31 mole) of ethyl benzoylacetate, 4.6 g. of sodium hydroxide and
530 ml. of p-dioxane were heated under reflux for 8 hours. The
solution was cooled; the product, ethyl
2-pheyl-4-hydroxyquinoline-3-carboxylate, was collected and washed
with ether. Yield: 48.5 g., m.p. 252.degree.-255.degree..
b. A mixture of 48.5 g. (0.164 mole) of ethyl
2-phenyl-4-hydroxyquinoline-3-carboxylate, obtained above, and 130
ml. of phosphorous oxychloride was heated under reflux for 3
1/2hours. The excess phosphorus oxychloride was removed by
distillation under reduced pressure, leaving a reddish gum which
was dissolved in ethanol. The solution was basified with 3N NaOH
and diluted with water. The aqueous solution was extracted with
ether and the ethereal extracts were dried over sodium sulfate and
evaporated to dryness yielding an oil which crystallized on
trituration with petroleum ether. Yield: 40.2 g., m.p.
62.degree.-65.degree..
c. To a solution of 11.6 g. (0.864 mole) of 5-aminoindazole,
dissolved in dry acetone, was added 35.2 g. (0.864 mole) of ethyl
2-phenyl-4-chloroquinoline-3-carboxylate, obtained above The
reaction mixture was heated under reflux for 8 hours, and the
hydrochloride salt of the product was collected. A suspension of
the ethyl 2-phenyl-4-(5-indazolamino)-quinoline-3-carboxylate
hydrochloride in a mixture of 150 ml. of water and 15 ml. of
ethanol and was basified with 3N NaOH. The compound that
precipitated was collected and washed well with water. After two
recrystallizations from ethanol, using charcoal, the product melted
at 220.degree.-222.degree.. Yield: 5.6 g.
Analysis for C.sub.25 H.sub.20 N.sub.4 O.sub.2
Calc'd.: C, 73.50; H, 4.94; N, 13.72
Found : C, 73.27; H, 4.87; N, 13.76
EXAMPLE 24
Methyl 4-(3-chloro-6-indazolamino)-quinaldine-3-carboxylate
a. To a solution of ferrous sulfate (326 g.) in water (400 ml.) was
added to a hot solution of 3-chloro-6-nitroindazole (39.4 g., 0.2
mole) in ethanol (410 ml.); concentrated NH.sub.4 OH was then added
(246 ml.). This mixture was heated under reflux on the steam bath
for 20 minutes, NH.sub.4 OH (400 ml.) was again added and heating
was continued for an additional 20 minutes. The suspension was
filtered hot, the salts were washed several times with boiling
ethanol, the washings and filtrate were evaporated to dryness in
vacuo; the residue was dissolved in ethyl acetate, the solution was
dried over Na.sub.2 SO.sub.4, charcoaled and evaporated to dryness,
m.p. 177.degree.-182.degree.; Yield; 24.3 g. (Lit: m.p.
185.degree., Robert R. Davies, J. Chem. Soc. 1955, 2,414).
b. 3-Chloro-6-aminoindazole, obtained above, (13.5 g., 0.08 moles)
was dissolved in dry acetone (100 ml.) and then methyl
4-chloroquinaldine-3-carboxylate (17.7 g., 0.08 mole) was added.
The resulting solution was boiled under reflux (oil bath,
100.degree.) for 8 hours, precipitating methyl
4-(3-chloro-6-indazolamino)-quinaldine-3-carboxylate hydrochloride.
The hydrochloride salt was collected, suspended in ethanol, water
(400 ml., 1:3), the suspension was basified with 3N NaOH and
diluted with water. The precipitate was collected, and washed with
water. After two recrystallizations from a mixture of ethyl acetate
and methanol with charcoal treatment, the product melted at
258.degree.. Yield: 15.1 g.
Analysis for C.sub.19 H.sub.15 ClN.sub.4 O.sub.2
Calc'd.: C, 62.21; H, 4.12; N, 15.28; Cl, 9.67
Found : C, 61.80; H, 3.92; N, 15.12; Cl, 9.63
EXAMPLE 25
Ethyl 4-(5-indazolamino)-quinoline-2-carboxylate
5-Amino-indazole (9.2 g., 0.069 mole) was dissolved in dry acetone
(125 ml.) with heating and stirring. Ethyl
4-chloroquinoline-2-carboxylate prepared according to the procedure
described by Byron, Riegel, J. Amer. Chem. Soc., 68, 2,685 (1946),
(163 g., 0.069 mole) was added and the resulting solution was
boiled under reflux (oil bath, 100.degree.) for 16 hours, and ethyl
4-(5-indazolamino)-quinoline-2-carboxylate hydrochloride
precipitated. This hydrochloride salt was suspended in dilute
ethanol (400 ml.); the suspension was basified with 3N NaOH,
diluted with water to 1 L. and filtered; the product was washed
well with water and recrystallized from ethanol. Yield: 1.8 g.,
m.p. 258.degree..
Analysis for C.sub.19 H.sub.16 N.sub.4 O.sub.2
Calc'd.: C, 68.66; H, 4.85; N, 16.86
Found : C, 68.07; H, 4.90; N, 16.70
EXAMPLE 26
7-chloro-4-(6-indazolamino)-quinoline
0.5 g. of 7-Chloro-4-(6-indazolamino)-quinoline-3-carboxylic acid
was suspended in 50 ml. of diphenylether and the mixture was heated
under reflux for 70 minutes (reflux temperature approximately
257.degree.-259.degree.). The reaction mixture was cooled to
80.degree. and filtered. The crystalline compound was washed well
with ether and was obtained in a yield of 0.35 g. After
recrystallization from ethanol, the compound melted at
251.degree.-253.degree.. The IR spectrum confirmed the structure of
the product as set out in Example 1 supra.
EXAMPLE 27
4-(2-methyl-6-indazolamino)-quinaldine
4-Chloroquinaldine (4.71 g., 0.0265 moles) was added to a solution
of 2-methyl-6-aminoindazole (3.9 g., 0.0265 moles) in hydrochloric
acid (3N, 80 ml.) and the resulting solution was heated under
reflux for 16 hours. A yellow crystalline solid was precipitated on
cooling. This solid was dissolved in dilute ethanol (20% -- 500
ml.) and the solution was made basic with 3N sodium hydroxide (pH
9-11) precipitating a white crystalline product which was
collected, washed well with water, recrystallized first from hot
ethanol and then recrystallized twice from ethyl acetate/ethanol.
Yield: 1.45 g., m.p. 255.degree.-257.degree..
Analysis for C.sub.18 H.sub.16 N.sub.4
Calc'd.: C, 74.97; H, 5.59; N, 19.44
Found : C, 74.57; H, 5.66; N, 19.80
Using the procedure described above,
4-(1-methyl-6-indazolamino)-quinaldine was obtained in a yield of
50-51%, m.p. 330.degree.-331.degree. (dec.).
EXAMPLE 28
Ethyl 4-hydroxy-7-methylquinoline-3-carboxylate
m-Toluidine (53.6 g., 0.5 moles) and diethyl
ethoxymethylenemalonate (108.1 g., 0.5 moles) were mixed together
and placed in a dessicator under vacuum over anhydrous calcium
chloride. (water uptake of 4.9 g.) for 7 days. The resulting
crotonate was added to refluxing phenyl ether (500 ml.), the
solution was heated under reflux for 10 minutes, filtered at
70.degree. and the product was triturated twice in ether (1 liter).
There was obtained a yield of 6.1 g., m.p. 275.degree.-280.degree.
dec.
EXAMPLE 29
Ethyl 4-(5-indazolamino)-7-methylquinoline-3-carboxylate
A solution of ethyl 4-hydroxy-7-methylquinoline-3-carboxylate (6.1
g., 0.0264 moles) was heated under reflux in phosphorous
oxychloride (35 ml.) for 1 hour. The reaction mixture was then
poured into cracked ice (about 1 liter), the pH was adjusted to
9-11 with 3N sodium hydroxide precipitating a white crystalline
compound which was filtered and washed with water. A solution of
the product in ether was dried over sodium sulfate/magnesium
sulfate, charcoaled and evaporated to dryness yielding a solid on
cooling with a melting point of 40.degree.-42.degree. (5.7 g.).
5-Aminoindazole (3.28 g., 0.0247 moles) was dissolved in dry
acetone (100 ml.) with heating and stirring. Ethyl
4-chloro-7-methylquinoline-3-carboxylate (5.7 g., 0.0247 moles)
obtained above, was added and resulting solution was heated under
reflux (oil bath 90.degree.) for 8 hours precipitating a yellow
crystalline solid. The crystals were collected, dissolved in dilute
alcohol (200 ml., 50%) and the precipitate was adjusted to a pH of
9-11 with 3N sodium hydroxide. 600 ml Of water was added and the
resulting precipitate was collected and washed well with water. The
compound was first recrystallized from alcohol and after two
additional recrystallizations from ethyl acetate, the product
melted at 239.degree.-240.degree.; yield of 2.2 g.
Analysis for C.sub.20 H.sub.18 N.sub.4 O.sub.2
Calc'd.: C, 69.34; H, 5.24; N, 16.17
Found : C, 69.00; H, 5.52; N, 15.70
EXAMPLE 30
1-methyl-4-(b 6-indazolimino)-1,4-dihydro-quinaldine
A mixture of 4-chloroquinaldine (33.7 g., 0.192 mole) and
methyliodide (79 g.) was boiled under reflux in acetonitrile (250
ml.) for 3 hours. The reaction mixture was cooled, the crystalline
salt collected on a Buchner funnel and washed with acetonitrile (1
.times. 55 ml.). The product, 1-methyl-4-chloroquinaldinium iodide,
melted at 226.degree.-228.degree.C. dec; yield 16.4 g.
1-Methyl-4-chloro-quinaldinium iodide (10 g., 0.032 mole) was added
to a solution of 6-aminoindazole (4.26 g., 0.032 mole) dissolved in
2B EtOH (500 ml.) and this mixture was boiled under reflux for 20
hours. The reaction mixture was cooled and filtered yielding a
yellow solid which was suspended in water/EtOH (3:1, 400 ml.); the
suspension was basified wth 3N NaOH to PH 8-9. The resulting
crystalline compound was collected on a Buchner funnel, washed well
with water, (5 .times. 100 ml.), dissolved in hot methanol,
charcoaled twice and then recrystallized from EtOH/MeOH (1:1),
yielding a yellow crystalline solid (1.8 g., m.p.
299.degree.-301.degree.).
EXAMPLE 31
7-chloro-1-methyl-4-(6-indazolimino)-1,4-dihydro-quinoline
A mixture of 4,7-dichloroquinoline (32.5 g., 0.17 mole) and methyl
iodide (42. g., 0.51 mole) was boiled under reflux in 250 ml. of
acetonitrile for a period of 2.5 hours. The reaction mixture was
cooled and the crystalline salt collected on a Buchner funnel and
washed with acetonitrile. The product,
4,7-dichloro-1-methyl-quinolinium iodide, melted at
258.degree.-259.degree.. Yield: 31.7 g.
The aforesaid product (10 g., 0.031 mole) was added to a solution
of 6-aminoindazole (4.1 g., 0.031 mole) dissolved in 500 ml. of
ethanol and this mixture was boiled under reflux for a period of 24
hours. The reaction mixture was cooled and filtered yielding a
solid which was suspended in 300 ml. of 50% ethanol and was
basified with 3N NaOH to pH 8-9. The resulting crystalline compound
was collected on a Buchner funnel and washed well with water. After
recrystallization from a mixture of ethanol + methanol (1:1) the
desired compound melted at 266.degree.-267.degree.. Yield: 2.8
g.
Analysis for C.sub.17 H.sub.13 ClN.sub.4
Calc'd.: C, 66.12; H, 4.25; N, 18.14
Found : C, 66.09; H, 4.54; N, 18.23
EXAMPLE 32
4-(1-methyl-5-indazolamino)-quinaldine
a. 1 and 2-Methyl-5-nitroindazoles were prepared and separated as
described by I. Barclay et al., J. Chem. Soc., 1941, 113.
b. To a solution of 26.4 g of 5-nitro-1-methylindazole (0.208 mole)
in 1,000 ml of ethanol was added a solution of ferrous sulfate 430
g in 650 ml of hot water, followed by the addition of 500 ml of
concentrated ammonium hydroxide. The resulting mixture was heated
on a steam bath for 3 hours and 320 ml of concentrated ammonium
hydroxide was added at 30 minute intervals. The reaction mixture
was filtered hot and the residue was washed with 2,000 ml of hot
methanol. The filtrate and the washings were combined and
concentrated in vacuo. The residue was extracted with 1,500 ml (6
.times. 250 ml) of hot ethyl acetate and the solution was dried
over Na.sub.2 SO.sub.4, and the solvent was removed under reduced
pressure. After recrystallization from water the obtained
5-amino-1-methylindazole melted at 151.degree.-153.degree.. Yield
12.7 g.
c. A mixture of 5-amino-1-methylindazole (12.6 g: 0.855 mole) and
4-chloroquinaldine (15.2 g: 0.855 mole) was dissolved in 375 ml of
3 HCl and the solution was heated under reflux for 8 hours. The
reaction mixture was reduced to circa 200 ml under reduced pressure
and the hydrochloride salt of the product was collected. The salt
was suspended in a mixture of 160 ml of water and 40 ml of ethanol
and basified with 3 N NaOH solution. An additional 200 ml of water
was added to ensure complete precipitation of the product, which
was collected by filtration. After recrystallization from the ethyl
acetate the obtained 4-(1-methyl-5-indazolamino)-quinaldine melted
at 213.degree.-214.degree.. Yield 3.4 g.
Analysis for C.sub.18 H.sub.16 N.sub.4
Calc'd.: C, 74.97; H, 5.59; N, 19.44
Found : C, 74.71; H, 5.46; N, 19.60
EXAMPLE 33
Ethyl 7-chloro-4-(6-indazolamino)-quinaldine-3-carboxylate
a. A mixture of 63.8 g of 3-chloroaniline and 101.6 g of
diethylacetylmalonate was stored in vacuo in a dessicator over
anhydrous CaCl.sub.2 for 10 days. 7.0 g of water was taken up. The
resulting crotonate was poured into 500 ml of refluxing diphenyl
ether and the mixture was heated under reflux for 40 minutes. Upon
cooling to 70.degree.C the precipitate was collected by filtration
and purified by trituration in a mixture of ether and hexane. After
recrystallization from ethanol the obtained ethyl
7-chloro-4-hydroxy-quinaldine-3-carboxylate melted at
297.degree.-300.degree.C. Yield 22.7 g.
A mixture of the above product and the isomeric ethyl
5-chloro-4-hydroxyquinaldine-3-carboxylate has been described
previously by B.P. Bangdivalo and C.M. Desai, J. Ind. Chem. Soc.,
31, 555 (1954) utilizing a different procedure.
b. A mixture of 22.7 g of ethyl
7-chloro-4-hydroxyquinaldine-3-carboxylate and 100 ml of
phosphorous oxychloride was heated under reflux for 3 hours. The
phosphorous oxychloride was then removed by distillation under
reduced pressure. The reaction mixing was cooled and 75 ml of
ethanol was added with stirring. The hydrochloride salt which
precipitated was collected by filtration and dissolved in 500 ml of
dilute ethanol (80 percent). The solution was rendered basic with 3
N NaOH. Additional water was added to ensure complete precipitation
of the product, which was collected by filtration. The obtained
ethyl 4,7-dichloro-quinaldine-3-carboxylate melted at
58.degree.-61.degree.C. Yield 9.8 g.
c. 6-Aminoindazole (4.6 g., 0.0345 mole) was dissolved in dry
acetone (100 ml) with heating and stirring; ethyl
4,7-dichloroquinaldine-3-carboxylate (9.8 g, 0.0345 mole) dissolved
in dry acetone (100 cc) was added to the solution of aminoindazole
and the mixture was boiled under reflux for 8 hours precipitating
the hydrochloride. After two recrystallizations from dilute alcohol
the hydrochloride of ethyl
7-chloro-4-(6-indazolamino)-quinaldine-3-carboxylate melted at
261.degree.-263.degree.. Yield 4.3 g.
d. The above salt was suspended in dilute alcohol (50%, 250 cc),
the solution was basified with NH.sub.4 OH and diluted with water.
The precipitate was collected and washed well with water. After two
recrystallizations from dilute alcohol the title compound was
obtained which melted at 214.degree.-215.degree.. Yield 3.1 g.
Analysis for C.sub.20 H.sub.17 ClN.sub.4 O.sub.3
Calc'd.: C, 63.07; H, 4.50; N, 14.52
Found : C, 62.87; H, 4.64; N, 14.86
EXAMPLE 34
Ethyl 4-(2'-methyl-6-indazolamino)quinaldine-3-carboxylate
a. A mixture of 600 g (0.611 mole) of 6-nitroindazole, 34.25 g
(0.611 mole) of potassium hydroxide, 173.8 g (1.222 mole) of methyl
iodide and 800 ml of methanol were heated under reflux for 4 hours.
The reaction mixture was poured into 2.5 l of ice water and the
resulting precipitate collected by filtration. The dried
precipitate 2-methyl-6-nitroindazole was recrystallized from
methanol and melted at 158.degree.-160.degree.C. (Lit. Barclay, J.
Chem. Soc. 113 (1941) reported m.p. 159.degree.-160.degree.C.).
b. 21.1 g, (0.1184 mole) of 2-methyl-6-nitroindazole was dissolved
in 450 ml of EtOH with heating and stirring. 180 g of FeSO.sub.4
dissolved in 300 ml of hot water was added to the indazole solution
followed immediately by the addition of 275 ml of conc. NH.sub.4
OH. The resulting mixture was heated on the steam bath for 3 hours
and 275 ml of concentrated NH.sub.4 OH was added at 30 minute
intervals. The reaction mixture was filtered hot; the filter cake
was dried overnight in vacuo; the filtrate was concentrated to
dryness in vacuo. The filter cake and filtrate residues were
combined, extracted with 1,000 ml (4 .times. 250 ml) of hot ethyl
acetate and the solution was dried over Na.sub.2 SO.sub.4
/MgSO.sub.4, and the solvent removed under reduced pressure. After
two recrystallizations from water, the obtained
2-methyl-6-amino-indazole melted at 82.degree.-85.degree.C. Yield
4.6 g.
c. To a solution of 2-methyl-6-aminoindazole (4.6 g: 0.03122 mole)
in dry acetone (75 ml) was added a solution of ethyl
4-chloroquinaldine-3-carboxylate (7.8 g: 0.03122 mole) dry acetone
(25 ml) and the resulting mixture was heated under reflux for 8
hours precipitating the hydrochloride salt of ethyl
4-(2-methyl-6-indazolamino)-quinaldine-3-carboxylate.
This salt was collected and dissolved in 10 percent dil. EtOH (500
ml); the solution was cooled and basified with conc. NH.sub.4 OH
and diluted with H.sub.2 O; the precipitate was collected by
filtration and washed well with H.sub.2 O.
After two recrystallizations from dilute EtOH, the title compound
melted at 122.degree.-124.degree.C. Yield 4.1 g.
Analysis for C.sub.21 H.sub.20 N.sub.4 O.sub.2
Calc'd.: C, 69.98; H, 5.59; N, 15.54
Found : C, 70.26; H, 5.52; N, 15.88
EXAMPLE 35
Ethyl 4-(6-indazolamino)-quinaldine-3-carboxylate-1-oxide
a. Ethyl 4-chloroquinaldine-3-carboxylate (23.4 g: 0.175 mole) was
dissolved in CHCl.sub.3 (250 ml). m-Chloroperbenzoic acid (29.4 g:
0.175 mole) was dissolved in CHCl.sub.3 (250 ml) and added to the
quinaldine solution; the resulting mixture was allowed to stand at
room temperature for 72 hours.
The reaction mixture was extracted with 5% Na.sub.2 CO.sub.3 (4
.times. 150 ml), then washed with H.sub.2 O (3 .times. 200 ml). The
chloroform solution was dried over K.sub.2 CO.sub.3 and the solvent
removed under reduced pressure to yield a residue which
crystallized on cooling, and trituration with petroleum ether.
Yield 21 g., m.p. 127.degree.-129.degree.C. The obtained compound
was ethyl 4-(6-indazolamino)-quinaldine-3-carboxylate-1-oxide.
b. 6-Aminoindazole (10.01 g.: 0.0753 mole) was dissolved in EtOH
(310 ml) and H.sub.2 O (45 ml). Ethyl
4-chloroquinaldine-3-carboxylate-1-oxide (20 g.; 0.0753 mole)
dissolved in EtOH (50 ml) was added to the indazole solution with 5
drops of concentrated HCl. The resulting mixture was refluxed for
24 hours and concentrated in vacuo to a residual solid. This solid
was suspended in H.sub.2 O, the suspension was basified with
concentrated NH.sub.4 OH, and the resulting precipitate was
collected and washed with H.sub.2 O.
After two recrystallizations from acetone (1 .times. charcoal) the
title compound melted at 239.degree.-240.degree.C (dec.). Yield 6.5
g.
EXAMPLE 36
7-chloro-4-(6-indazolamino)-quinoline-1-oxide
a. 4,7-Dichloroquinoline (99 g, 0.5 mole) was dissolved in
CHCl.sub.3 (300 ml) at room temperature. m-Chloroperbenzoic acid
(80%, 101.4 g, 0.5 mole) suspended in CHCl.sub.3 (1 liter) was
added to the quinoline solution. The resulting mixture was allowed
to stand at room temperature for 48 hours. The CHCl.sub.3 solution
was washed with 10% Na.sub.2 CO.sub.3 solution (3 .times. 500 ml),
then with H.sub.2 O (3 .times. 1 liter), dried over K.sub.2
CO.sub.3 and concentrated in vacuo.
Recrystallization from EtOH yielded 37.7 g of
4,7-dichloro-quinoline-1-oxide, m.p. 162.degree.-164.degree.C.
Lit. Ref: E.F. Elslager et al., J. Med Chem., 1, 6 (1964). Reported
m.p. 165.degree.-166.degree.C.
b. 6-Aminoindazole (13.7 g, 0.096 mole) was dissolved in EtOH (400
ml) and H.sub.2 O (60 ml). 4,7-Dichloroquinoline-1-oxide (20.6 g,
0.096 mole) suspended in cold EtOH (200 ml) was added to the
indazole solution. After the addition of 6 drops of concentrated
HCl, the mixture was heated under reflux for 24 hours. The solvent
was concentrated in vacuo and the residue was suspended in H.sub.2
O (500 ml). The suspension was stirred with cooling and filtered.
The precipitate was suspended in dilute EtOH (20%, 400 ml) and was
basified with conc. NH.sub.4 OH, diluted well with H.sub.2 O to
give precipitate which was collected.
After two recrystallizations from dilute MeOH (1 .times. charcoal),
the title compound melted at 281.degree.-283.degree.C. Yield 5.4
g.
Analysis for C.sub.18 H.sub.11 ClN.sub.4 O
Calc'd.: C, 61.84; H, 3.57; N, 18.03
Found : C, 61.81; H, 3.46; N, 18.31
EXAMPLE 37
7-chloro-4-(6-indazolamino)-quinoline Methanesulfonate
6-Aminoindazole (13.1 g; 0.1 mole) was dissolved in acetonitrile
(500 ml) and concentrated hydrochloric acid (1.0 ml) was added. The
precipitated hydrochloric salt was dissolved by the addition of
dimethylformamide to the mixture. 4,7-Dichloroquinoline (19.8 g;
0.1 mole) was added and the solution was refluxed for 4 hrs. The
reaction mixture was cooled to room temperature and the product was
filtered off and suspended in ethanol (500 ml) with warming.
Concentrated aqueous ammonia was added to pH 9 followed by water
(2.0 l). The mixture was cooled and the free base filtered off.
This material was vacuum dried (27.6 g) and suspended in ethanol
(500 ml) and methanesulfonic acid (8.85 g; 1 equiv.) was added. The
solution was evaporated to dryness and the residue was
recrystallized from ethanol to give 28.6 g of the methane-sulfonate
salt. m.p. 253.degree.(dec).
EXAMPLE 38
4-(6-indazolamino)-2-trifluoromethylquinoline
Dimethane-sulfonate
a. 4-Hydroxy-2-trifluoromethylquinoline was prepared by the method
of A. S. Dey and M. M. Joulie', J. Heterocyclic Chem., 2, 113
(1965), [2-trifluoromethyl-4-quinolinols--general method a.] .
b. 4-Chloro-2-trifluoromethylquinoline was prepared by the method
of H. R. Snyder et al., J. Amer. Chem. Soc., 69, 371 (1947). A
mixture of phosphorous pentachloride (16.4 g) and phosphorous
oxychloride (18.4 g) was heated to 90.degree. ,
4-hydroxy-2-trifluoromethylquinoline (16.0 g) was added, and the
solution was refluxed for 40 minutes. The solution was evaporated
under vacuum and the residue was added to ice water (125 ml). The
resultant precipitate was filtered off and recrystallized from
aqueous ethanol to give 9.4 g of the 4-chloro-compound.
c. 6-Aminoindazole (9.4 g; 0.033 mole) was dissolved in
acetonitrile (165 ml) and concentrated hydrochloric acid (0.33 ml)
was added. The precipitated hydrochloride salt was dissolved by the
addition of dimethylformamide (80 ml) to the mixture.
4-Hydroxy-2-trifluoromethylquinoline (9.4 g; 033 mole) was added
and the reaction mixture refluxed for 31/2 hrs., then cooled to
room temperature. The solution was evaporated under vacuum and the
residue dissolved in ethanol (400 ml). Concentrated aqueous ammonia
was added to pH 9. The mixture was cooled and the free base (1.2 g)
was filtered off and vacuum dried. This material was suspended in
ethanol (50 ml) and methanesulfonic acid (700 mg, 2 equiv.) was
added. The resulting solution was evaporated to dryness and the
residue recrystallized from ethanol to give 350 mg of the
methanesulfonate. m.p. 218.degree.-220.degree..
EXAMPLE 39
2-(4-chlorophenyl)-4-(6-indazolamino)quinoline Methanesulfonate
Hemi-ethanol Solvate
6-Aminoindazole (0.66 g, 0.005 mole) was dissolved in acetonitrile
(25 ml) and concentrated hydrochloric acid (0.05 ml) was added. The
hydrochloride salt was dissolved by the addition of
dimethylformamide (12.5 ml). 4-Chloro-2-(4-chlorophenyl)quinoline
[1.3 g, 0.005 mole; prepared by the method of R.M. Peck, R.K.
Preston, and H.J. Creech, J. Amer. Chem. Soc., 81, 3984 (1959)] was
added and the solution was refluxed for 3 hr. After cooling, the
hydrochloride salt of the product was filtered off and dissolved in
70 percent aqueous ethanol (50 ml). Concentrated aqueous ammonia
was added to pH 8; the precipitated free base was filtered off and
vacuum dried. This material was suspended in ethanol (25 ml) and
methanesulfonic acid (1 equivalent) was added. The solution was
evaporated and the residue recrystallized four times from ethanol
to give 0.8 g of the hemi-ethanol solvate. The presence of the
ethanol was confirmed by NMR; the solvate was stable to prolonged
vacuum drying. The compound decomposed at 233.degree. .
EXAMPLE 40
7-chloro-4-(6-indazolamino)quinaldine Methanesulfonate
6-Aminoindazole (1.62 g; 0.012 mole) was dissolved in acetonitrile
(61 ml) and concentrated hydrochloric acid (0.12 ml) was added. The
precipitated hydrochloride salt was dissolved by the addition of
dimethylformamide (30 ml). 4,7-Dichloroquinaldine [2.6 g, 0.012
mol., prepared by the method of A.K. Sen and U.P. Basu, J. Indian
Chem. Soc., 34, 833 (1957)] was added and the solution refluxed for
3 hrs. After cooling, the hydrochloride was filtered off and
dissolved in ethanol (100 ml) and water (20 ml). Concentrated
aqueous ammonia was added to pH 8, and after refrigeration, the
free base was filtered off and vacuum dried (2.0 g). This material
was suspended in ethanol (100 ml) and methanesulfonic acid (0.62 g;
1 equiv.) was added. The solution was evaporated and the residue
recrystallized from ethanol to give 1.8 g of the methanesulfonate,
m.p. 256.degree.-258.degree. .
EXAMPLE 41
4-(6-indazolamino)-6-methoxyquinoline Methanesulfonate
6-Aminoindazole (0.66 g; 0.005 mole) was dissolved in acetonitrile
(25 ml) and concentrated hydrochloric acid (0.05 ml) was added. The
precipitated hydrochloride salt was dissolved by the addition of
dimethylformamide (12.5 ml) to the mixture,
4-chloro-6-methoxyquinoline (1 g; 0.005 mole) was added and the
solution was refluxed for 3 hrs. The reaction mixture was cooled,
and the product was filtered off then suspended in ethanol (100 ml)
with warming. Concentrated aqueous ammonia was added to pH 9 and
after refrigeration the free base was filtered off. This material
was vacuum dried then suspended in ethanol (50 ml). Methanesulfonic
acid (1 equivalent) was added and the resulting solution evaporated
to dryness. Recrystallization of the residue from ethanol/ethyl
acetate gave the methanesulfonate (1.3 g), m.p.
258.degree.-260.degree. dec.
EXAMPLE 42
6-chloro-4-(6-Indazolamino)-2-phenylquinoline Methanesulfonate One
Third Hydrate
6-Aminoindazole (533 mg; 4 m mole) was dissolved in acetonitrile
(20 ml) and concentrated hydrochloric acid (0.04 ml) was added. The
precipitated hydrochloride salt was dissolved by the addition of
dimethylformamide (10 ml) to the mixture.
4,6-Dichloro-2-phenylquinoline (1.1 g; 4 m mole) was added and the
reaction mixture refluxed for 31/2 hr. then cooled to room
temperature. The crystalline material was filtered off and
dissolved in a mixture of water (7 ml) and ethanol (33 ml).
Concentrated aqueous ammonia was added to pH 9. The mixture was
cooled and the free base (1.15 g) was filtered off and vacuum
dried. This material was suspended in ethanol (25 ml) and
methanesulfonic acid (310 mg) was added. The resulting solution was
evaporated to dryness and the residue re-crystallized from
ethanol/ethyl acetate to give the methanesulfonate, m.p.
290.degree.-295.degree. dec.
EXAMPLE 43
4-(6-indazolamino)quinoline Methanesulfonate
6-Aminoindazole (4.0 g, 0.03 mole) was dissolved in acetonitrile
(150 ml) and concentrated hydrochloric acid (0.3 ml) was added. The
precipitated hydrochloride salt was dissolved by the addition of
dimethylformamide (75 ml) to the mixture. 4-Chloroquinoline (4.91
g, 0.03 mole) was added and the reaction mixture was refluxed for 2
hrs. and cooled to room temperature. The crystalline material was
filtered off and then dissolved in a mixture of 2B ethanol (100 ml)
and water (5 ml) with warming. Concentrated ammonia was added to pH
8, which precipitated the free base. After refrigeration the
product was filtered off (3.2 g), and suspended in 2B ethanol (70
ml). Methanesulfonic acid (1.2 g) was added and the resulting
solution evaporated to dryness. Recrystallization from
ethanol/ethyl acetate gave the methanesulfonate salt (2.6 g), m.p.
224.degree.-227.degree..
EXAMPLE 44
4-(6-indazolamino)-2-phenylquinoline Methanesulfonate
7 grams (.0208 moles) of 4-(6-indazolamino)-2-phenylquinoline (Ex.
7) was partially dissolved in 100 ml hot ethanol. With the addition
of 2 g (0.0208 mole) methanesulfonic acid the solution became
homogeneous. The solvent was removed under reduced pressure, and
the product was recrystallized twice from ethanol/ether to give 6
grams (67 percent) m.p. 305.degree.-310.degree. dec.
EXAMPLE 45
4-(6-Indazolamino)-7-methyl-2-phenylquinoline Methanesulfonate
a. 4-Chloro-7-methyl-2-phenylquinoline was prepared by the method
of B.P. Bangdiwala and C.M. Desai, J. Indian Chem. Soc., 31, 43
(1954), m.p. 80.degree.-82.degree. .
b. 6-Aminoindazole (0.85 g) was dissolved in acetonitrile (35 ml)
and concentrated hydrochloric acid (0.07 ml) was added. The
precipitated hydrochloride salt was dissolved by the addition of
dimethylformamide (17.5 ml). 4-Chloro-7-methyl-2-phenylquinoline
(1.7 g) was added and the reaction mixture was refluxed for 31/2
hr. The reaction mixture was cooled to room temperature and the
crystalline product filtered off, and dissolved in ethanol (100
ml). Concentrated aqueous ammonia was added to pH 8 and the free
base was precipitated by the addition of water (200 ml). The free
base was suspended in ethanol (50 ml) and methanesulfonic acid (1
equivalent) was added. The solution was evaporated and the residue
recrystallized from ethanol to give 1.4 g. of the
monomethanesulfonate, m.p. 278.degree.-9.degree. .
EXAMPLE 46
4-(6-indazolamino)-6-methoxy-2-phenylquinoline
Methane-sulfonate
6-Aminoindazole (3.17 g; 23.8 mM) was dissolved in acetonitrile
(125 ml) and concentrated hydrochloric acid (0.24 ml) was added.
The precipitated hydrochloride salt was dissolved by the addition
of dimethylformamide (60 ml) to the mixture.
4-Chloro-6-methoxy-2-phenylquinoline (6.4 g; 23.8 mM) [prepared
according to the method of B.P. Bangdiwala and C.M. Desai, Jour.
Indian Chem. Soc., 31, 43 No. 1 (1954)] was added and the reaction
mixture refluxed for 3 hrs. and cooled to room temperature. The
precipitated material was suspended in hot ethanol (100 ml) and
concentrated ammonium hydroxide (20 ml) was added to give a clear
solution. The free base precipitated on standing at room
temperature (6.6 g) and was dissolved in hot ethanol (100 ml) by
the addition of methanesulfonic acid (1.9 g; 1.1 eq). The
methanesulfonate salt on recrystallization from ethanol (2 times)
gave 4.7 g of the pure compound, m.p. 316.degree.-318.degree. .
EXAMPLE 47
4-(6-indazolamino)-6-hydroxy-2-phenylquinoline Methanesulfonate
Monohydrate
4-(16-Indazolamino)-6-methoxy-2-phenylquinoline hydrochloride (Ex.
46) (2.5 g) was dissolved in 48 percent hydrobromic acid (250 ml)
and refluxed for 4 hrs. The crystalline material was filtered off,
suspended in ethanol (150 ml) and brought into solution with
concentrated ammonium hydroxide (25 ml). The free base was
precipitated with water (800 ml), filtered off and dried. It then
was dissolved in ethanol (100 ml), methanesulfonic acid (1.0 g) was
added, ether was added to the cloud point and the solution was kept
in the freezer to give 2.0 g of the pure compound, m.p.
210.degree.-212.degree. .
EXAMPLE 48
4-(6-indazolamino)-6-methoxy-2-phenyl-7-trifluoromethylquinoline
Methanesulfonate
a. 4-Hydroxy-6-methoxy-7-trifluoromethyl-2-phenylquinoline (11.2 g)
[prepared by the general procedure of B.P. Bangdiwala, C.M. Desai,
Jour. Indian Chem. Soc. 31, 43 (1954)] was dissolved in phosphorous
oxychloride (100 ml) and refluxed for 40 minutes. It was then
poured on ice and neutralized with strong ammonia. The precipitate
(11.5 g) was filtered off and crystallized from ethanol (900 ml) to
give 10.3 g of the pure product, m.p. 172.degree..
b. 6-Aminoindazole (1.33 g; 10 mM) was dissolved in acetonitrile
(50 ml) and concentrated hydrochloric acid (0.1 ml) was added. The
precipitated hydrochloride salt was dissolved by the addition of
dimethylformamide (25 ml) to the mixture.
4-Chloro-6-methoxy-7-trifluoromethyl-2-phenylquinoline (3.37 g; 10
mM) was added and the reaction mixture refluxed for 3 hr. and
cooled to room temperature. The precipitated material (3.8 g) was
suspended in hot ethanol (100 ml) and concentrated ammonium
hydroxide (25 ml) was added to give a clear solution. The free base
was precipitated by the addition of 800 ml water. 3.3 g of the free
base were suspended in hot ethanol (100 ml), methanesulfonic acid
(730 mg; 1 eq) was added to give 3.4 g of the methanesulfonate salt
which on recrystallization from ethanol/water (2 times) gave 2.4 g
of the pure product, m.p. 340.degree.-342.degree. .
EXAMPLE 49
4-(6-indazolamino)quinaldine Methanesulfonate
6-Aminoindazole (13.3 g; 0.1 M) was dissolved in acetonitrile (500
ml) and concentrated hydrochloric acid (1.0 ml) was added. The
partially precipitated hydrochloride salt was dissolved by the
addition of dimethylformamide (250 ml) to the mixture.
4-Chloroquinaldine (17.7 g; 0.1 M) was added and the reaction
mixture refluxed for 21/2 hours and cooled to room temperature. The
precipitated material (28.5 g) was dissolved in a hot mixture of
ethanol (500 ml) and water (150 ml), concentrated ammonium
hydroxide (60 ml) was added to the cooled solution and then diluted
with water (2 liters). The precipitated free base (25.0 g) was
dissolved in ethanol (650 ml) with warming and methanesulfonic acid
(8.75 g; 1 eq.) was added to yield 29.5 g of the methanesulfonate
salt which on recrystallization (3 times) from ethanol gave 15.8 g
of the product, m.p. 238.degree.,240.degree..
EXAMPLE 50
4-(6-indazolamino)-6-methoxyquinaldine Methanesulfonate
6-Aminoindazole (6.7 g) was dissolved in acetonitrile (400 ml) and
concentrated hydrochloric acid (0.5 ml) was added. The precipitated
hydrochloride salt was dissolved by the addition of
dimethylformamide (200 ml) to the mixture.
4-Chloro-6-methoxyquinaldine (10.5 g) [Schock, J. Amer. Chem. Soc.
79, 1,672, 1,675 (1957)] was added and the reaction mixture
refluxed for 4 hours. The precipitated material (16.5 g) was
suspended in ethanol (150 ml), concentrated ammonium hydroxide (30
ml) was added and the free base was precipitated from the clear
solution by the addition of water (800 ml). The base (14 g) was
suspended in ethanol (150 ml) and methanesulfonic acid (7 g) was
added. The precipitated methanesulfonate salt was recrystallized
from ethanol (3 times) followed by crystallization from water to
give 9 g of the product m.p. 202.degree.-204.degree.. (The m.p. was
300.degree. - 302.degree. after recrystallization from
ethanol).
EXAMPLE 51
2-benzyl-4-(6-indazolamino)quinoline Methanesulfonate One-Third
Hydrate
6-Aminoindazole (320 mg) was dissolved in acetonitrile (12 ml) and
concentrated hydrochloric acid (0.05 ml) was added. The
precipitated hydrochloric salt was dissolved by the addition of
dimethylformamide to the mixture. 2-Benzyl-4-chloroquinoline
[prepared by the method of A.K. Kiang, F.G. Mann, A.F. Prior, and
A. Topham, J. Chem. Soc., 1,319 (1956)] (600 mg) was added and the
solution was refluxed for 4 hours. The reaction mixture was cooled
to room temperature and the product was filtered off and suspended
in ethanol (25 ml). Aqueous ammonia was added to pH 9 followed by
water (8 ml). The mixture was refrigerated and the free base
filtered off. This material was vacuum dried (500 mg) and suspended
in ethanol and methanesulfonic acid (137 mg; 1 equiv.) was added.
The solution was evaporated to dryness and the residue
recrystallized from ethanol to give 650 mg of the methanesulfonate,
m.p. 253.degree.-255.degree. dec.
EXAMPLE 52
4-(6-indazolamino)-7-trifluoroquinaldine Methanesulfonate
7.5 g of 6-aminoindazole, 100 ml of acetonitrile, 0.7 ml of
concentrated hydrochloric acid, 50 ml of dimethylformamide and 13.8
g of 4-chloro-7-trifluoromethylquinaldine [prepared according to
the procedure of G. Franchi, P. Vigne, Farmaco, Ed. Sci. 22 (11),
923-929 (1967)] were refluxed for 4 hours. The hydrochloride of the
product formed a precipitate which was kept in the freezer
overnight and the precipitate was filtered off. It was suspended in
200 ml hot ethanol; 35 ml of ammonium hydroxide was added. The free
base dissolved to form a clear dark brown solution. 800 ml of water
was added and the free base precipitated. The precipitate was taken
up in acetone, evaporated and suspended in 100 ml of ethanol. 5.75
g of methanesulfonic acid was added to yield a clear solution which
crystallized on cooling and was recrystallized from aqueous ethanol
yielding 11.4 g, m.p. 305.degree.-307.degree. .
EXAMPLE 53
4-(6-indazolamino)-6,7-methylenedioxyquinaldine
Methanesulfonate
a. 33.5 g of 3,4-methylenedioxyaniline, 32 g of ethylacetoacetate,
100 ml of benzene and 4 drops of concentrated hydrochloric acid
were refluxed for 10 hours. 4.5 ml of water was separated and the
benzene solution evaporated. A dark red oil, 62.3 g, was obtained
which crystallized, m.p. 80.degree.-82.degree..
b. 150 ml of diphenylether was refluxed. 63 g of the product (a)
was dissolved in 60 ml diphenylether and added dropwise within 25
minutes. Precipitation took place during cyclization; heating was
continued for 31/2 hours. The reaction mixture was kept at room
temperature overnight. The precipitate was filtered off and washed
with petroleum ether. 4-hydroxy-6,7-methylenedioxyquinaldine as a
brown powder, 44 g, m.p. 347.degree. dec. was obtained.
c. 15 g of 6,7-Methylenedioxy-4-hydroxyquinaldine and 700 ml of
phosphorus oxychloride were refluxed for 20 hours. A clear brown
solution formed. Excess phosphorus oxychloride was evaporated. The
pH was adjusted to 7 with ammonium hydroxide. The precipitation was
filtered off and washed with water. The product was recrystallized
from a 200 ml methanol/70 ml water mixture. 8.2 g -- m.p.
130.degree.-131.degree. -- of the product was obtained.
d. 3.7 g of 6-Aminoindazole, 75 ml of acetonitrile, 0.33 ml of
concentrated hydrochloric acid, 30 ml of dimethylformamide and 6.1
g of 4-chloro-6,7-methylenedioxy-2-methylquinoline were refluxed
for 41/2 hours. The precipitate was kept overnight at room
temperature and then filtered off, yielding 9.8 g, m.p. 365.degree.
dec. It was suspended in 150 ml of hot ethanol; 50 ml of ammonium
hydroxide was added. The free base dissolved to form a clar
solution. 800 ml of water was added and the free base precipitated
after a few minutes, yielding 9.1 g, m.p. 256.degree.-258.degree..
It was suspended in 200 ml ethanol, heated, and 3.3 g of
methanesulfonic acid was added to form a clear solution which
precipitated after a few minutes. It was dissolved by adding 100 ml
ethanol/50 ml water, yielding 7.6 g, m.p.
288.degree.-290.degree..
EXAMPLE 54
7-fluoro-4-(6-indazolamino)quinaldine Methanesulfonate
6-Aminoindazole 13.6 g (0.103 m) was dissolved in 500 ml
acetonitrile, 1.0 ml concentrated hydrochloric acid was added, 250
ml dimethylformamide added to dissolve the hydrochloride salt, and
4-chloro-7-fluoroquinaldine [prepared by procedure of A.K. Sen,
U.P. Basu, J. Ind. Chem. Soc. 37, 836-838 (1957)] was added. The
solution was refluxed at 120.degree. for 31/2 hours. The
precipitate was filtered off and then suspended in 200 ml of
ethanol. The mixture was made basic with aqueous ammonia and 250 ml
of water was added. The free base was filtered off. It was
suspended in 500 ml of ethanol and 8.7 g of methanesulfonic acid
was added. The solution was evaporated to dryness and the residue
was recrystallized in ethanol/ether, m.p. 309.degree.-311.degree.
.
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