Anticholinergic 3-[2-(mono- and dialkylamino)-propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]-pyridin- 5-ones useful for treating bronchospastic diseases in mammals are disclosed. Also disclosed are methods for preparing said compounds, pharmaceutical compositions containing them and methods for using said pharmaceutical compositions. A method for preparing the intermediate which is required to prepare the unsubstituted benzopyrano-[3,4-c]pyridin-5-ones of the invention is also disclosed.

BACKGROUND OF THE INVENTION 
The compounds of the invention are 3-[2-(mono-and 
dialkylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5- 
ones which have anticholinergic activity. The compounds are useful as 
bronchodilators. 
U.S. Pat. No. 4,276,296 discloses anticholinergic 3-[2-(1-pyrrolidinyl and 
1-piperidinyl)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5 
-ones. 
SUMMARY OF THE INVENTION 
The invention sought to be patented in its generic chemical compound aspect 
is a compound having the structural formula I 
##STR1## 
wherein R.sub.1 is H, alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 
to 6 carbon atoms, halo, or acetylamino; 
R.sub.2 is H, alkyl of from 1 to 6 carbon atoms, or alkoxy of from 1 to 6 
carbon atoms; 
R.sub.3 is H, or alkoxy of from 1 to 6 carbon atoms; 
R.sub.1 and R.sub.2 taken together are OCH.sub.2 O; 
R.sub.2 and R.sub.3 taken together are CH.dbd.CH--CH.dbd.CH; 
X is CH.sub.3, C.sub.2 H.sub.5, n-C.sub.3 H.sub.7, or n-C.sub.4 H.sub.9 ; 
Y is H, CH.sub.3, C.sub.2 H.sub.5 n-C.sub.3 H.sub.7, n-C.sub.4 H.sub.9, or 
s-C.sub.4 H.sub.9 ; 
and the pharmaceutically acceptable salts thereof, provided that R.sub.1 
and R.sub.2 are not both OCH.sub.3 when Y is H. 
The invention sought to be patented in a first subgeneric chemical compound 
aspect is a compound having structural formula I wherein R.sub.3 is H; and 
the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a second subgeneric chemical 
compound aspect is a compound having structural formula I wherein R.sub.3 
is H, X is C.sub.3 or C.sub.2 H.sub.5 ; and the pharmaceutically 
acceptable salts thereof. 
The invention sought to be patented in a first specific chemical compound 
aspect is the compound having the name 
3-[2-(dimethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopy 
rano[3,4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a second specified chemical compound 
aspect is the compound having the name 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a third specific chemical compound 
aspect is the compound having the name 
3-[2-(dimethylamino)propyl]-1,2,3,4-tetrahydro-8,9-diethoxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a fourth specific chemical compound 
aspect is the compound having the name 
3-[2-(dimethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[ 
3,4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a fifth specific chemical compound 
aspect is the compound having the name 
3-[2-(dimethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyr 
idin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a sixth specific chemical compound 
aspect is the compound having the name 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a seventh specific chemical compound 
aspect is the compound having the name 
3-[2-(ethylmethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in an eighth specific chemical compound 
aspect is the compound having the name 
3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3 
,4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a ninth specific chemical compound 
aspect is the compound having the name 
3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyri 
din-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in a tenth specific chemical compound 
aspect is the compound having the name 
3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one and the pharmaceutically acceptable salts thereof. 
The invention sought to be patented in its first generic chemical process 
aspect is a process for preparing a chemical compound having structural 
formula I which comprises reacting a compound having structural formula II 
with an amine having the formula H.sub.2 NX to produce a compound having 
the structural formula III and if desired, N-alkylating the so produced 
compound having formula III. 
The invention sought to be patented in its second generic chemical process 
aspect is a process for preparing a chemical compound having structural 
formula IV' which comprises contacting a compound having structural 
formula VIII with elemental hydrogen. 
The invention sought to be patented in its pharmaceutical composition 
aspect is a composition consisting essentially of a compound having 
structural formula I in combination with a pharmaceutically acceptable 
carrier. 
The invention sought to be patented in its pharmaceutical method aspect is 
a method for treating asthma or bronchitis in a mammal in need of such 
treatment, which comprises administering an effective amount of the above 
defined pharmaceutical composition to said mammal. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The compounds of the invention having structural formula I 
##STR2## 
wherein R.sub.1, R.sub.2, R.sub.3, X and Y are defined above may be 
prepared by different procedures which are considered equivalent for 
purposes of the invention. One such procedure involves the reaction of a 
compound of structural formula II with a primary amine of the formula 
##STR3## 
H.sub.2 NX under reducing conditions to produce a compound having 
structural formula III. 
##STR4## 
This reaction proceeds most conveniently by first contacting compound II 
and the amine in a convenient solvent in the presence of a dehydrating 
agent, such as anhydrous calcium sulfate, to produce the corresponding 
imine. The so produced imine is isolated and treated with H.sub.2 and a 
suitable catalyst such as Pt/C to produce compound III. 
The compounds of formula III are themselves compounds of the invention 
(i.e. compounds of formula I wherein Y is H) and may be converted into 
additional compounds of the invention having structural formula I wherein 
X is defined above and Y is CH.sub.3, C.sub.2 H.sub.5, n-C.sub.3 H.sub.7, 
n-C.sub.4 H.sub.9, or s-C.sub.4 H.sub.9 by known procedures. For example, 
a compound of formula III may be methylated by treatment with formaldehyde 
in the presence of a reducing agent such as sodium borohydride. Other 
alkylation procedures such as treatment with an alkanoic acid, ZCO.sub.2 H 
(wherein Z is an alkyl group containing one less carbon atom than the 
desired alkyl group being added) in the presence of sodium borohydride are 
also contemplated. Compounds of structural formula I wherein X and Y are 
both CH.sub.3 may also be conveniently prepared directly from compound II 
by treatment with (CH.sub.3).sub.2 NH under reducing conditions, e.g. 
H.sub.2, Pd/C. Additional alkylation procedures will be familiar to those 
skilled in the art, and are contemplated by the invention. 
The compounds of structural formula II may be prepared from a compound 
having structural formula IV 
##STR5## 
by treatment with a 1-halo-2-propanone, 1-chloro-2-propanone is preferred. 
This reaction proceeds conveniently in a nonreactive solvent such as 
methanol, preferably at reflux temperature, in the presence of an acid 
acceptor such as a tertiary amine, e.g. triethylamine. 
The requisite compounds of structural formula IV are prepared by condensing 
a properly substituted phenol having structural formula V with 
4-oxo-3-piperidine-carboxylic acid, VI. 
##STR6## 
This condensation is conveniently performed in concentrated sulfuric acid 
(preferably about 75% H.sub.2 SO.sub.4) utilizing VI in the form of its 
methyl ester, hydrochloride, which is commercially available (e.g. from 
Aldrich Chemical Co., Milwaukee, WI 53201, U.S.A.). The phenols of 
structural formula V are either commercially available or may be prepared 
by conventional procedures known to those skilled in the art. 
The intermediate of structural formula IV wherein R.sub.1 =R.sub.2 =R.sub.3 
=H (IV') is disclosed in British Pat. No. 1,455,522 example 2. The 
synthetic method described therein reports a 10% yield, but could not be 
consistently reproduced. This compound was successfully prepared according 
to the following reaction sequence. 
##STR7## 
The condensation between resorcinol (V') and 
1-benzyl-3-carbethoxy-4-piperidone (VI') to produce compound VII is 
carried out in substantially the same manner as the condensation between 
compounds V and VI described above. The compound VI' may be prepared as 
described in Beilstein 22 (2) 216. Those skilled in the art will recognize 
that other carbalkoxy groups may be present at the 3-position of VI' and 
that the same product VII will thereby be produced. Carbethoxy is 
preferred. The reaction between VII and 5-chloro-1-phenyl-1H-tetrazole 
[Beilstein, 26, (2), 197] is carried out in a convenient non-reactive 
solvent such as dimethylformamide or dimethylsulfoxide in the presence of 
an acid acceptor such as sodium carbonate, potassium carbonate, and the 
like. This reaction proceeds efficiently at a temperature of about 
70.degree.-100.degree. C. and is substantially complete in about 3 to 
about 10 hours. Compound VIII is converted to IV' by reaction with 
elemental hydrogen using standard procedures. For example, the reaction 
proceeds efficiently at room temperature in acetic acid at about 50 
lbs/in.sup.2 hydrogen pressure in the presence of 20% Pd/C. The reaction 
is complete when hydrogen uptake ceases. Other hydrogenation procedures 
are considered equivalent for purposes of the reaction. In an alternate 
procedure, compound VIII may first be N-debenzylated by treatment with a 
catalyst such as Pd/C in a non-acidic medium such as methanol for example. 
The product of this reaction may then be treated with hydrogen using 
substantially the same conditions described above for converting VIII into 
IV' thereby producing IV'. 
##STR8## 
The compounds of the invention display anticholinergic properties when 
tested by the following procedure: 
Conscious guinea pigs, six at a time, are put into a sealed chamber and 
exposed for 10 minutes to an aerosol of methacholine. Untreated animals or 
those treated with vehicle will collapse in 1.9.+-.0.1 minutes. Groups of 
animals are injected intraperitoneally with 25 mg/kg of test compound and 
exposed in the chamber under the same conditions. Compounds which prolong 
the collapse time past that of the control animals are considered active. 
Activity in this procedure indicates that the compound would be of use in 
treating those bronchospastic diseases such as asthma and bronchitis which 
have a high degree of cholinergic-mediated vagal tone. 
Utilizing the above test procedure, the following results were obtained for 
representative compounds of the invention. 
______________________________________ 
##STR9## 
(Minutes 
R.sub.1 
R.sub.2 R.sub.3 X Y Protection) 
______________________________________ 
Control 1.9 to 2.0 
H Me H Me H 2.1 
H Me H Me Me 10.0 
H Me H Me Et 8.8 
H Me H Me n-Pr 5.4 
H Me H Me n-Bu 7.8 
H Me H Et H 10.0 
H Me H Et Et 6.6 
H Me H Et n-Pr 7.6 
Cl Me H Et H 3.1 
Cl Me H Et Et 3.4 
AcNH Me H Me H 10.0 
Me Me H Me Me 4.8 
H H H Me Me 10.0 
H H H Et Et 10.0 
OCH.sub.2O H Me Me 2.3 
H CHCHCHCH Me Me 5.9 
H H H Et H 10.0 
H H H Et Pr 6.4 
H MeO H Me H 8.6 
H MeO H Me Me 10.0 
H MeO H Me Et 9.1 
H MeO H Me n-Pr 10.0 
H MeO H Me n-Bu 8.6 
H MeO H Et H 7.5 
H MeO H Et Et 10.0 
H MeO H Et n-Pr 10.0 
MeO MeO H Me Me 5.2 
MeO MeO H Me Et 6.0 
MeO MeO H Me n-Pr 2.5 
MeO MeO H Et Et 7.8 
MeO MeO H Et n-Pr 3.7 
MeO MeO H Et Bu 3.7 
MeO MeO H Et s-Bu 5.4 
H MeO MeO Et H 9.1 
H MeO MeO Me Et 5.0 
H MeO MeO Et Et 7.6 
H MeO MeO Me Me 5.5 
EtO EtO H Me Me 7.3 
EtO EtO H Et Et 10.0 
______________________________________ 
In an additional testing procedure, mongrel dogs of either sex, 10.6 to 
15.3 kg, are anesthetized with sodium pentobarbital, 30 mg/kg i.v. and 
then prepared for the monitoring of pulmonary mechanics. A Buxco pulmonary 
mechanics computer is used to calculate pulmonary resistance, dynamic 
compliance, and tidal volume from transpulmonary pressure and flow data. 
Respiratory rate, heart rate and mean arterial blood pressure are also 
monitored. The femoral vein is cannulated for the delivery of drugs. 
Pilocarpine nitrate (0.2 mg/kg/hr) is than infused to induce a bronchospasm 
and salivary flow. Bunolol (0.5 mg/kg, i.v.) is given 30 minutes prior to 
the pilocarpine to reduce the protein content, hence, the viscosity of the 
saliva. Salivary output is collected from a catheterized Wharton's duct at 
five minute intervals. After salivation has stabilized, 3 control 
collections are taken at 5 minute intervals followed by a series of 
cumulative i.v. doses of test compound (1, 3, 10, 30, 100, 300, 1000, 
3000, and 10,000 .mu.g/kg) that are injected every 5 minutes for 45 
minutes. 
The percent inhibition of both the bronchospasm and salivation are 
calculated for each dose with a return to pre-pilocarpine resistance 
levels or cessation of salivation equal to a 100% inhibition. 
Utilizing this procedure the following results were obtained for 
representative compounds of the invention. 
______________________________________ 
##STR10## 
ID.sub.50 Pulmo- 
.mu.g/kg nary 
Broncho- 
ID.sub.50 .mu.g/kg 
Selec- 
R.sub.1 
R.sub.2 
R.sub.3 
X Y spasm Salivation 
tivity* 
______________________________________ 
H Me H Me Me 114 421 3.7 
H Me H Me Et 150 336 2.2 
H Me H Et Et 111 510 4.6 
H H H Me Me 192 4147 22 
H H H Et Et 336 2310 7 
H H H Et H 210 1232 6 
MeO MeO H Me Me 98 441 4.5 
MeO MeO H Et Et 73 257 3.5 
EtO EtO H Me Me 147 303 2.1 
______________________________________ 
##STR11## 
&gt;1 indicates the compound is more potent as a bronchodilator than as an 
antisecretory agent. 
The compounds of the invention form pharmaceutically acceptable salts with 
organic and inorganic acids. Those skilled in the art will recognize that 
both mono and di salts may be prepared. Examples of suitable acids for 
salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, 
oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, 
methanesulfonic, and the like. The salts are prepared by contacting the 
free base form with a sufficient amount of the desired acid to produce 
either a mono or di salt in the conventional manner. The free base forms 
may be regenerated by treating the salt form with a base. For example, 
dilute aqueous base solutions may be utilized. Dilute aqueous sodium 
hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions 
are suitable for this purpose. The free base forms differ from their 
respective salt forms somewhat in certain physical properties such as 
solubility in polar solvents, but the salts are otherwise equivalent to 
their respective free base forms for purposes of the invention. 
The compounds of the invention can exist in unsolvated as well as solvated 
forms, including hydrated forms. In general, the solvated forms, with 
pharmaceutically acceptable solvents such as water, ethanol, and the like 
are equivalent to the unsolvated forms for purposes of the invention. 
The alkyl groups and alkoxy groups contemplated by the invention comprise 
both straight and branched carbon chains of from 1 to about 6 carbon 
atoms. Representative of such groups are methyl, ethyl, isopropyl, pentyl, 
3-methylpentyl, methoxy, ethoxy, propoxy, 1-ethylbutoxy, pentoxy, and the 
like. 
The term halogen is intended to include fluorine, chlorine, bromine, and 
iodine. 
The compounds of the invention comprise an asymmetric carbon atom which is 
marked (*) in the structural formula I above. The pure D isomer, pure L 
isomer, as well as mixtures thereof are contemplated by the invention. 
Additional asymmetric carbon atoms may be present in a substituent such as 
an alkyl group. All such isomers as well as mixtures thereof are intended 
to be included in the invention. 
The compounds of the invention can be prepared and administered in a wide 
variety of oral and parenteral dosage forms. Sprays for both oral and 
nasal administration are also contemplated. It will be obvious to those 
skilled in the art that the following dosage forms may comprise as the 
active component, either a compound of formula I, or a corresponding 
pharmaceutically acceptable salt of a compound of formula I, or a mixture 
of such compounds and/or salts. 
For preparing pharmaceutical compositions from the compounds described by 
this invention, inert, pharmaceutically acceptable carriers can be either 
solid or liquid. Solid form preparations include powders, tablets, 
dispersable granules, capsules, cachets, and suppositories. A solid 
carrier can be one or more substances which may also act as diluents, 
flavoring agents, solubilizers, lubricants, suspending agents, binders, or 
tablet disintegrating agents; it can also be an encapsulating material. In 
powders, the carrier is a finely divided solid which is in admixture with 
the finely divided active compound. In the tablet the active compound is 
mixed with carrier having the necessary binding properties in suitable 
proportions and compacted in the shape and size desired. The powders and 
tablets preferably contain from 5 or 10 to about 70 percent of the active 
ingredient. Suitable solid carriers are magnesium carbonate, magnesium 
sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, 
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low 
melting wax, cocoa butter, and the like. The term "preparation" is 
intended to include the formulation of the active compound with 
encapsulating material as carrier providing a capsule in which the active 
component (with or without other carriers) is surrounded by carrier, which 
is thus in association with it. Similarly, cachets are included. Tablets, 
powders, cachets and capsules can be used as solid dosage forms suitable 
for oral administration. 
Liquid form preparations include solutions suspensions and emulsions. As an 
example may be mentioned water or water-propylene glycol solutions for 
parenteral injection. Liquid preparations can also be formulated in 
solution in aqueous polyethylene glycol solution. Aqueous solutions 
suitable for oral use can be prepared by dissolving the active component 
in water and adding suitable colorants, flavors, stabilizing, and 
thickening agents as desired. Aqueous suspensions suitable for oral use 
can be made by dispersing the finely divided active component in water 
with viscous material i.e., natural or synthetic gums, resins, methyl 
cellulose, sodium carboxymethyl cellulose, and other well-known suspending 
agents. 
Preferably, the pharmaceutical preparation is in unit dosage form. In such 
form, the preparation is subdivided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of preparation, 
for example, packeted tablets, capsules and powders in vials or ampoules. 
The unit dosage form can also be a capsule, cachet, or tablet itself or it 
can be the appropriate number of any of these packaged forms. 
The quantity of active compound in a unit dose of preparation may be varied 
or adjusted from 1 mg to 100 mg according to the particular application 
and the potency of the active ingredient. 
In therapeutic use as agents for treating asthma and bronchitis, the 
compounds utilized in the pharmaceutical method of this invention are 
administered at the initial dosage of about 0.5 mg to about 5 mg per 
kilogram daily. A daily dose range of about 2.0 mg to about 20 mg per 
kilogram is preferred. The dosages, however, may be varied depending upon 
the requirements of the patient, the severity of the condition being 
treated, and the compound being employed. Determination of the proper 
dosage for a particular situation is within the skill of the art. 
Generally, treatment is initiated with smaller dosages which are less than 
the optimum dose of the compound. Thereafter, the dosage is increased by 
small increments until the optimum effect under the circumstances is 
reached. For convenience, the total daily dosage may be divided and 
administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferred 
methods for preparing the compounds of the invention. 
EXAMPLE 1 
1,2,3,4-Tetrahydro-5H-[1,3]benzodioxolo[5',6':5,6]pyrano[3,4-c]pyridin-5-on 
e hydrochloride 
A mixture of 3,4-methylenedioxyphenol (125 g, 0.91 moles) and methyl 
4-oxo-3-piperidinecarboxylate hydrochloride (125 g, 0.65 moles) is cooled 
in ice and treated over one hour with 600 ml of 72% sulfuric acid. The 
mixture is then stirred at room temperature for 64 hours. Ice/water (1.0 
kg) is added, followed by conc. ammonium hydroxide, until the pH of the 
mixture is 9.0. The crude product is filtered, stirred briefly in 2.5% 
aqueous sodium hydroxide (1.0 l), and refiltered. Several 
recrystallizations from dilute aqueous hydrochloric acid yielded the 
product (86.2 g) as the hydrochloride, mp 258.degree.-259.degree. C. 
EXAMPLE 2 
1,2,3,4-Tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
hydrochloride 
Prepared by the method described in Example 1, except that the 
2,3-dimethoxyphenol (42.0 g, 0.27 moles) is added in portions to a cooled 
mixture of the piperidone (30.3 g, 0.15 moles) and 75 ml of conc. sulfuric 
acid. Recrystallization from methanol with the addition of gaseous 
hydrogen chloride yielded the product (18.6 g) as the hydrochloride, mp 
265.degree.-267.degree. C. 
EXAMPLE 3 
1,2,3,4-Tetrahydro-8,9,10-trimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
hydrochloride 
Prepared by the method described in Example 1 from 3,4,5-trimethoxyphenol 
(25 g, 0.14 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride 
(18.8 g, 0.097 moles). Recrystallization from dilute aqueous hydrochloric 
acid yielded the product (17.5 g) as the hydrochloride, mp 
232.degree.-234.degree. C. 
EXAMPLE 4 
1,2,3,4-Tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described in Example 1 from 3,4-dimethylphenol (10.0 
g, 0.082 moles) and methyl 4-oxo-3-piperdinecarboxylate hydrochloride 
(11.3 g, 0.058 moles). Recrystallization from 2-methoxyethanol yielded the 
product (11.2 g), mp 172.degree.-l74.degree. C. 
EXAMPLE 5 
1,2,3,4-Tetrahydro-12H-naphtho[2',1':5,6]pyrano[3,4-c]pyridin-12-one 
Prepared by the method described in Example 1 from 1-napthol (10.0 g, 0.069 
moles) and 4-oxo-3-piperidinecarboxylate hydrochloride (9.6 g, 0.05 
moles). Recrystallization from 2-propanol/N,N-dimethylformamide yielded 
the product (3.7 g), mp 227.degree.-230.degree. C. 
EXAMPLE 6 
1,2,3,4-Tetrahydro-8-(1-methylethyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
hydrochloride 
Prepared by the method described in Example 1 from 3-isopropylphenol (150 
g, 0.66 moles) and 4-oxo-3-piperidinecarboxylate hydrochloride (114 g, 
0.59 moles). Recrystallization from dilute aqueous hydrochloric acid 
yielded the product (46.6 g) as the hydrochloride, mp 
257.degree.-261.degree. C. 
EXAMPLE 7 
1,2,3,4-Tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described in Example 1 except that the 
3,4-dimethoxyphenol (61.5 g, 0.40 moles) is added in one portion to an 
ice-cooled mixture of ethyl 4-oxo-3-piperidinecarboxylate hydrochloride 
(75 g, 0.36 moles) and 200 ml of 72% sulfuric acid. Recrystallization from 
acetonitrile yielded the product (71 g), mp 186.degree.-188.degree. C. 
EXAMPLE 8 
1,2,3,4-Tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described for Example 1 from 3-methoxyphenol (16 g, 
0.126 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (25 g, 
0.129 moles). Recrystallization from ethanol gave the product (10.43 g), 
mp 179.degree.-183.degree. C. 
EXAMPLE 9 
8-Ethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described for Example 1 from 3-ethylphenol (12.2 g, 
0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 
0.1 moles). The crude material is washed with water and dried to give the 
product (6.6 g), mp 80.degree.-85.degree. C. 
EXAMPLE 10 
8-Phenyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described for Example 1 from 3-phenylphenol (17 g, 
0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 
0.1 moles). The crude material is washed with water and dried to give the 
product (15 g), mp 250.degree.-270.degree. C. 
EXAMPLE 11 
8-(1,1-Dimethylethyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5- 
one 
Prepared by the method described for Example 1 from 3-t-butylphenol (15 g, 
0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 
0.1 moles). Recrystallization from ethyl acetate gave the product (14.7 
g), mp 181.degree.-186.degree. C. 
EXAMPLE 12 
1,2,3,4-Tetrahydro-8-hydroxy-3-(phenylmethyl)5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one 
Prepared by the method described for Example 1 from resorcinol (22 g, 0.2 
moles) and 1-benzyl-3-carbethoxy-4-piperidone hydrochloride (59.6 g, 0.2 
moles). The product (55 g) is converted to 
1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H- 
[1]benzopyrano [3,4-c]pyridin-5-one without further purification. 
EXAMPLE 13 
1,2,3,4-Tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
An 80% sulfuric acid solution (80 ml) is stirred and cooled to 5.degree. C. 
in an ice bath and 3-methylphenol (10.8 ml, 0.10 moles) is added, followed 
by methyl-4-oxo-3-piperidine carboxylate hydrochloride (20.0 g, 0.10 
moles). The mixture is allowed to warm gradually to room temperature. 
After 48 hours the solution is poured into ice water (400 ml) and stirred 
until a crystalline precipitate forms. Concentrated ammonium hydroxide is 
added until the mixture is strongly basic. After one hour the precipitate 
is filtered off, rinsed with concentrated ammonium hydroxide, then water, 
and dried. Recrystallization from acetonitrile gave the product (4.5 g), 
mp 128.degree.-130.degree. C. 
EXAMPLE 14 
1,2,3,4-Tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
A stirred suspension of 
1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.0 g, 
0.046 moles) in water (10 ml) is cooled in an ice bath. Concentrated 
sulfuric acid (25 ml) is added, followed after 15 minutes by the dropwise 
addition of concentrated nitric acid (12 ml). The ice bath is removed and 
the mixture allowed to warm to room temperature. After 48 hours the 
mixture is poured over crushed ice, stirred, and made strongly basic by 
the addition of concentrated ammonium hydroxide. The precipitated product 
is filtered off, rinsed with water and dried. Recrystallization from 
acetonitrile gave the product (8.7 g), mp 197.degree.-199.degree. C. 
EXAMPLE 15 
1,2,3,4-Tetrahydro-8-methoxy-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
1,2,3,4-Tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.0 g) 
is dissolved in a mixture of concentrated sulfuric acid (3 ml) and water 
(2 ml). The resulting solution is cooled in an ice bath and concentrated 
nitric acid (1 ml) is added. The reaction mixture is stirred at room 
temperature for 20 hours. The reaction mixture is poured over ice and made 
basic with aqueous ammonium hydroxide solution. The product is filtered 
off and washed with water. Recrystallization from ethanol gave the product 
(535 mg), mp 200.degree.-205.degree. C. (dec.). 
EXAMPLE 16 
9-Amino-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
A solution of 
1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(6.0 g, 0.023 moles) in N,N-dimethylformamide (100 ml) and methanol (50 
ml) is hydrogenated at 50 psi in the presence of Raney Nickel (0.5 g) at 
room temperature for 20 hours. Additional Raney Nickel (0.5 g) in 
N,N-dimethylformamide (50 ml) is then added, and hydrogenation resumed 
until hydrogen uptake ceases. The catalyst is filtered off and rinsed with 
warm N,N-dimethylformamide. The filtrate is concentrated under reduced 
pressure and filtered to afford the product (4.3 g), mp 
283.degree.-284.degree. C. 
EXAMPLE 17 
9-Amino-1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one 
1,2,3,4-Tetrahydro-8-methoxy-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(13.0 g) in N,N-dimethylformamide (130 ml) is hydrogenated over Raney 
Nickel (2 g). The Raney Nickel is filtered off. The solvent is evaporated 
to give a light brown solid. The solid is triturated with methanol, washed 
with methanol, and dried to give the product (8.2 g), mp 
178.degree.-180.degree. C. 
EXAMPLE 18 
9-Chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
Concentrated hydrochloric acid (8 ml) is added to a stirred suspension of 
9-amino-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(1.5 g, 0.0065 moles) in water (5 ml). The solution is cooled to 
-5.degree. C. and a solution of sodium nitrite (0.45 g, 0.0065 moles) in 
water (4 ml) is added dropwise. After 15 minutes the mixture is added to a 
solution of freshly prepared cuprous chloride (0.8 g, 0.008 moles) in 20% 
HCl (8 ml) and stirred for 15 minutes. The suspension is warmed on the 
steam bath for one hour, allowed to cool, and 10% aqueous potassium 
carbonate is added until the mixture is basic. The precipitate is filtered 
off, rinsed with water, dissolved in warm dilute hydrochloric acid, 
filtered, and reprecipitated by the addition of concentrated ammonium 
hydroxide. The precipiate is filtered off, rinsed with water, and dried. 
Recrystallization from ethyl acetate gave the product (0.8 g), mp 
184.degree.- 185.degree. C. 
EXAMPLE 19 
1,2,3,4-Tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyran[3,4-c]pyr 
idin-5-one 
A mixture of 
1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(26.1 mg, 1.0 mole), 1-chloro-2-propanone (170 g, 1.8 moles), and 
triethylamine (130 g, 1.3 moles) in 3.5 l of methanol is stirred at reflux 
for 40 hours. After cooling, the crude product is filtered, stirred 
briefly in cold water (1.0 l), and refiltered. Recrystallization from 
methanol/N,N-dimethylformamide yielded the product (228 g), mp 
171.degree.-173.degree. C. 
EXAMPLE 20 
1,2,3,4-Tetrahydro-3-(2-oxopropyl)-5H-[1,3]benzodioxolo[5',6':5,6]pyrano[3, 
4-c]pyridin-5-one 
Prepared by the method described in Example 19 from 
1,2,3,4-tetrahydro-5H-[1,3]-benzodioxolo[5',6':5,6]pyrano[3,4-c]pyridin-5- 
one (56.3 g, 0.20 moles). Recrystallization from 2-methoxyethanol/water 
yielded the product (30 g), mp 167.degree.-170.degree. C. 
EXAMPLE 21 
1,2,3,4-Tetrahydro-7,8-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]py 
ridin-5-one 
Prepared by the method described in Example 19 from 
1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(6.3 g, 0.021 moles). Recrystallization from absolute ethanol yielded the 
product (4.6 g), mp 145.degree.-147.degree. C. 
EXAMPLE 22 
1,2,3,4-Tetrahydro-8,9-dimethyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyr 
idin-5-one 
A mixture of 
1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (30 
g, 0.13 mole), 1-chloro-2-propanone (23.6 g, 0.25 moles), and 
triethylamine (27.3 g, 0.27 moles) in 550 ml of absolute ethanol is 
stirred at reflux for 21 hours. The reaction mixture is evaporated, and 
the residue is partitioned between dichloromethane (700 ml) and water (500 
ml). The two-phase mixture is made basic with conc. ammonium hydroxide, 
the layers are separated, and the aqueous phase is extracted with fresh 
dichloromethane. The combined organic layers are backwashed with water, 
dried over sodium sulfate, and evaporated. Recrystallization of the 
residue from absolute ethanol yielded the product (23.5 g), mp 
136.degree.-138.degree. C. 
EXAMPLE 23 
1,2,3,4-Tetrahydro-8,9,10-trimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one 
Prepared by the method described in Example 22 from 
1,2,3,4-tetrahydro-8,9,10-trimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(10.0 g, 0.031 moles). Recrystallization from ethanol/hexane yielded the 
product (6.6 g), mp 114.degree.-116.degree. C. 
EXAMPLE 24 
1,2,3,4-Tetrahydro-8-(1-methylethyl)-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one 
Prepared by the method described in Example 22 from 
1,2,3,4-tetrahydro-8-(1-methylethyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(28.0 g, 0.097 moles). Recrystallization from 95% ethanol yielded the 
product (12.4 g), mp 76.degree.-79.degree. C. 
EXAMPLE 25 
1,2,3,4-Tetrahydro-2-(2-oxopropyl)-12H-naphtho[2',1':5,6]pyrano[3,4-c]pyrid 
in-12-one 
Prepared by the method described in Example 22 from 
1,2,3,4-tetrahydro-12-naphtho[2',1':5,6]pyrano[3,4-c]pyridin-12-one (19.0 
g, 0.076 moles). Recrystallization from absolute ethanol yielded the 
product (11.8 g), mp 142.degree.-145.degree. C. 
EXAMPLE 26 
1,2,3,4-Tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin 
-5-one 
A mixture of 
1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 
0.009 moles), triethylamine (1.4 ml, 0.010 moles), and 
1-chloro-2-propanone (0.8 g, 0.009 moles) in ethanol (50 ml) is stirred 
and heated to reflux. After 20 hours the mixture is cooled and the 
precipitate filtered off, rinsed with ethanol, and dried to give the 
product (1.9 g), mp 128.degree.-129.degree. C. 
EXAMPLE 27 
1,2,3,4-Tetrahydro-8-methyl-9-nitro-3-(2-oxopropyl)-5H-[1]benzo-pyrano[3,4- 
c]pyridin-5-one 
Prepared by the method described for example 26 from 
1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(2.0 g, 0.008 moles), triethylamine (2.3 ml, 0.017 moles), and 
1-chloro-2-propanone (0.7 g, 0.008 moles). Recrystallization from methanol 
gave the product (0.9 g), mp 166.degree.-168.degree. C. 
EXAMPLE 28 
9-Chloro-1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzo-pyrano[3,4 
-c]pyridin-5-one 
Prepared by the method described for example 26 from 
9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(1.6 g, 0.006 moles), triethylamine (1 ml, 0.007 moles) and 
1-chloro-2-propanone (0.57 g, 0.006 moles). Recrystallization from 
isopropanol gave the product (0.5 g), mp 172.degree.-175.degree. C. 
EXAMPLE 29 
1,2,3,4-Tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano-[3,4-c]pyrid 
in-5-one 
Prepared by the method described for Example 26 from 
1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.46 
g, 0.015 moles) and 1-chloro-2-propanone (2.0 g, 0.022 moles). 
Recrystallization from methanol gave the product (2.37 g), mp 
123.degree.-125.degree. C. 
EXAMPLE 30 
1,2,3,4-Tetrahydro-8-methoxy-9-nitro-3-(2-oxopropyl)-5H-[1]benzo-pyrano[3,4 
-c]pyridin-5-one 
Prepared by the method described for Example 26 from 
1,2,3,4-tetrahydro-8-methoxy-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(5.52 g, 0.02 moles) and 1-chloro-2-propanone (3.5 g, 0.038 moles). 
Recrystallization from methanol gave the product (5.7 g), mp 
222.degree.-225.degree. C. 
EXAMPLE 31 
1,2,3,4-Tetrahydro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one. 
Prepared by the method described for example 26 from 
1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.14 g, 0.025 
moles), triethylamine (3.8 g, 0.027 moles), and 1-chloro-2-propanone (2.5 
g, 0.027 moles). Recrystallization from ethanol gave the produce (3.8 g) 
mp 128.degree.-130.degree. C. 
EXAMPLE 32 
9-Amino-1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c 
]pyridin-5-one 
A solution of 
1,2,3,4-tetrahydro-8-methyl-9-nitro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one (17.2 g, 0.054 moles) in N,N-dimethylformamide (300 ml) is 
hydrogenated at 50 psi at 24.degree. C. in the presence of Raney Nickel 
until the required amount of hydrogen has been taken up. The catalyst is 
filtered off and rinsed with hot N,N-dimethylformamide until free of 
organic material. The filtrate is slightly concentrated and cooled to give 
the product (10.9 g), mp 196.degree.-198.degree. C. 
EXAMPLE 33 
9-Amino-1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one 
Prepared by the method described for Example 32 from 
1,2,3,4-tetrahydro-8-methoxy-9-nitro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4 
-c]pyridin-5-one (13 g). The crude solid is washed with methanol to give 
the product (8.2 g), mp 178.degree.-180.degree. C. 
EXAMPLE 34 
N-[1,3,4,5-Tetrahydro-8-methoxy-5-oxo-3-(2-oxopropyl)-2H-[1]benzopyrano[3,4 
-c]pyridin-9-yl]acetamide 
9-Amino-1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzoprano[3,4-c 
]pyridin-5-one (5.5 g) is dissolved in water (50 ml) and concentrated 
hydrochloric acid (4 ml). The solution is heated to 50.degree. C. Acetic 
anhydride (2.4 ml), sodium acetate (3.0 g) and water (10 ml) are added. 
The reaction mixture is stirred for 10 minutes, cooled in an ice bath and 
made basic with ammonium hydroxide solution. The solid is filtered, washed 
with water and dried to give the product (3.03 g), mp 
210.degree.-215.degree. C. 
EXAMPLE 35 
N-[1,3,4,5-Tetrahydro-8-methyl-5-oxo-3-(2-oxopropyl)-2H-[1]benzopyrano[3,4- 
c]pyridin-9-yl]-acetamide 
Prepared by the method described for Example 34 from 
9-amino-1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one (1.4 g 0.005 moles). Basic work-up gave a crystalline 
precipitate which was filtered off, rinsed with water, and dried. 
Recrystallization from methanol gave the product (1.1 g), mp 236.degree. 
C. (dec.). 
EXAMPLE 36 
1,2,3,4-Tetrahydro-8,9-dihydroxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]py 
ridin-5-one hydrobromide 
A solution of 
1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]p 
yridin-5-one (5.0 g, 0.016 moles) in 40 ml of 48% aqueous hydrobromic acid 
is stirred at reflux for 16 hours. The mixture is cooled, and the 
precipitated product is filtered and washed several times with cold 
acetone. The product (5.7 g, mp 280.degree. C. dec.) is used as an 
intermediate without additional purification. 
EXAMPLE 37 
1,2,3,4-Tetrahydro-8,9-diethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyr 
idin-5-one 
A mixture of 
1,2,3,4-tetrahydro-8,9-dihydroxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]p 
yridin-5-one hydrobromide (108 g, 0.29 moles), potassium carbonate (155 g, 
1.12 moles), and diethyl sulfate (118 g, 0.76 moles) in 2.5 l of acetone 
is stirred at reflux for 21 hours. Additional diethyl sulfate (59 g, 0.38 
moles) is added, and the mixture is heated for an additional 30 hours. The 
cooled mixture is filtered, and the filter cake is digested twice in hot 
acetone (500 ml) and refiltered. The combined filtrates are evaporated, 
and the residue is distributed between dichloromethane (1500 ml) and water 
(750 ml). The organic layer is separated, washed 4 times with 2.5% aqueous 
sodium hydroxide (750 ml), dried over sodium sulfate, and evaporated. The 
residue is recrystallized as the free base from methanol and washed with 
cold hexane to yield the final product (36.3 g), mp 
146.degree.-148.degree. C. 
EXAMPLE 38 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one dihydrochloride 
A mixture of 
1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)5H-[1]benzopyrano[3,4-c]py 
ridin-5-one (72.5 g, 0.23 moles), dimethylamine (112 g, 2.48 moles), and 
acetic acid (2.5 ml) in 400 ml of methanol is rocked at room temperature 
for 20 hours. Hydrogenation catalyst (3.8 g of 10% palladium on charcoal) 
is added, and the mixture is hydrogenated (90.degree. C., 4300 psi) for 6 
hours. The catalyst is removed by filtration and the filtrate is 
evaporated. The residue is dissolved in hot methanol or ethanol, and the 
solution is treated with excess gaseous hydrogen chloride and filtered 
hot. After addition of warm diethyl ether to the hot filtrate, cooling 
yielded the product as the dihydrochloride, which is filtered and washed 
with cold acetone. A second recrystallization as above yielded the final 
product (39.1 g), mp 201.degree.-205.degree. C. 
EXAMPLE 39 
2-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-12H-naphtho-[2',1':5,6]pyran 
o[3,4-c]pyridin-12-one dihydrochlorine 
Prepared by the method described in Example 38 from 
1,2,3,4-tetrahydro-2-(2-oxopropyl)-12H-naphtho[2',1':5,6]pyrano[3,4-c]pyri 
din-12-one (8.2 g, 0.027 moles) and dimethylamine (8.0 g, 0.18 moles). 
Recrystallization from methanol followed by treatment with gaseous 
hydrogen chloride yielded the product as the dihydrochloride. A second 
recrystallization from water/dioxane yielded the final product (3.7 g), mp 
254.degree.-257.degree. C. 
EXAMPLE 40 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described in Example 38 from 
1,2,3,4-tetrahydro-7,8-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]p 
yridin-5-one (11.4 g, 0.036 moles) and dimethylamine (12.0 g, 0.27 moles). 
After conversion to the dihydrochloride salt in methanol, the product is 
recrystallized from ethanol/N,N-dimethylformamide to yield 2.7 g, mp 
193.degree.-197.degree. C. 
EXAMPLE 41 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one 
Prepared by the method described in Example 38 from 
1,2,3,4-tetrahydro-8,9-dimethyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]py 
ridin-5-one (7.3 g, 0.026 moles) and dimethylamine (10.0 g, 0.22 moles). 
Several recrystallizations from acetonitrile yielded the product as the 
free base (0.7 g) mp 105.degree.-107.degree. C. 
EXAMPLE 42 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-8,9,10-trimethoxy-5H-[1]benz 
opyrano[3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described in Example 38 from 
1,2,3,4-tetrahydro-8,9,10-trimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4 
-c]pyridin-5-one (9.9 g, 0.029 moles) and dimethylamine (1.4 g, 0.030 
moles), except that the reaction solvent is 2-methoxyethanol. The residue 
after catalyst removal and evaporation is partitioned between 
dichloromethane and dilute aqueous base. After conversion to the 
dihydrochloride in ethanol, recrystallization from 
ethanol/N,N-dimethylformamide yielded the final product (0.50 g), mp 
218.degree.-224.degree. C. 
EXAMPLE 43 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1,3]benzodioxolo]5',6':5 
,6]pyrano[3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described in Example 38 from 
1,2,3,4-tetrahydro-3-(2-oxopropyl)-5H-[1,3]benzodioxolo[5',6':5,6]pyrano[3 
,4-c]pyridin-5-one (11.6 g, 0.039 moles) and dimethylamine (20 g, 0.44 
moles). The product is converted to the dihydrochloride with gaseous 
hydrogen chloride in methanol. Additional recrystallization from aqueous 
methanol yielded the final product (2.7 g), mp 236.degree. C. (dec.). 
EXAMPLE 44 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-8,9-diethoxy-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described in Example 38 from 
1,2,3,4-tetrahydro-8,9-diethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]py 
ridin-5-one (35.9 g, 0.10 moles) and dimethylamine (50 g, 1.11 moles). The 
product is converted to the dihydrochloride with gaseous hydrogen chloride 
in methanol. An additional recrystallization from methanol/diethyl ether 
yielded the final product (6.8 g), mp 210.degree. C. (dec.). 
EXAMPLE 45 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[ 
3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described for Example 38 from 
1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyrid 
in-5-one (2.12 g, 0.0074 moles) and dimethylamine (3.0 g, 0.07 moles). 
Recrystallization from ethanol gave the product (2.05 g), mp 
240.degree.-245.degree. C. 
EXAMPLE 46 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]-benzopyrano[ 
3,4-c]pyridin-5-one 
Prepared by the method described for Example 38 from 
1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one (2.0 g, 0.007 moles) and dimethylamine (5 g, 0.111 moles). 
Recrystallization from ethanol gave the product (1.2 g) as the 
dihydrochloride 10:7 hydrate, mp 224.degree. C. (dec.). 
EXAMPLE 47 
3-[2-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyri 
din-5-one 
Prepared by the method described for Example 38 from 
1,2,3,4-tetrahydro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(3.0 g, 0.012 moles) and dimethylamine (3 g, 0.067 moles). The product was 
obtained as the dihydrochloride 10:7 hydrate, mp 241.degree. C. (dec.). 
EXAMPLE 48 
N-[3-(2-Dimethylamino)propyl]-1,3,4,5-tetrahydro-8-methoxy-5-oxo-2H-[1]benz 
opyrano[3,4-c]pyridin-9-yl acetamide 
Prepared by the method described for Example 38 from 
N-[1,3,4,5-tetrahydro-8-methoxy-5-oxo-3-(2-oxopropyl)-2H-[1]benzopyrano[3, 
4-c]pyridin-9-yl]acetamide (2.7 g, 0.0078 moles) and dimethylamine (3.0 g, 
0.067 moles). Recrystallization from ethyl acetate gave the product (1.7 
g), mp 168.degree.-172.degree. C. 
EXAMPLE 49 
3-[2-(Ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano 
[3,4-c]pyridin-5-one dihydrochloride 
A mixture of 
1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-benzopyrano[3,4-c]pyri 
din-5-one (95.3 g, 0.30 moles), ethylamine (26.8 g, 0.60 moles), anhydrous 
calcium sulfate (65 g, 0.48 moles), and glacial acetic acid (3.0 ml) in 
3300 ml of tetrahydrofuran is shaken overnight at 40.degree. in a pressure 
reactor. The reaction mixture is filtered, and the filtrate is 
hydrogenated over platinum/charcoal (10.0 g catalyst, 25.degree., 50 psi) 
for 48 hours. The catalyst is removed by filtration, and the filtrate is 
evaporated. The residue is dissolved in hot absolute ethanol, and the 
solution is treated with excess gaseous hydrogen chloride, filtered hot, 
and the filtrate is treated with warm diethyl ether. Cooling gave the 
product as the dihydrochloride salt, which is filtered and washed with 
cold acetone. A second recrystallization as above yielded the final 
product (75.5 g) mp 210.degree. C. (dec.). 
EXAMPLE 50 
3-[2-(Ethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1] 
benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described in Example 49 from 
1,2,3,4-tetrahydro-7,8-dimethoxy-3-(2-oxopropyl)-5H-benzopyrano[3,4-c]-pyr 
idin-5-one (49.6 g, 0.16 moles) and ethylamine (21.2 g, 0.47 moles). 
Recrystallization from ethyl acetate/hexane yielded the product (30.7 g) 
as the free base, mp 125.degree.-127.degree. C. 
EXAMPLE 51 
3-[2-(Ethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin 
-5-one 
A mixture of 
1,2,3,4-tetrahydro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
(18.2 g, 0.071 moles), ethylamine (10 ml, 0.153 moles), anhydrous calcium 
sulfate (15 g), and glacial acetic acid (1 ml) in tetrahydrofuran (450 ml) 
is shaken at 40.degree. C. in a pressure vessel. After 18 hours the 
mixture is cooled and filtered. The filtrate is hydrogenated at 25.degree. 
C. and 50 psi in the presence of 10% platinum or carbon until hydrogen 
uptake ceases. The catalyst is removed by filtration, and the filtrate is 
evaporated under reduced pressure. Recrystallization of the residue from 
ethyl acetate gave the product (10.5 g), mp 104.degree.-105.degree. C. 
EXAMPLE 52 
9-Chloro-3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopy 
rano[3,4-c]pyridin-5-one 
Prepared by the method described for example 51 from 
9-chloro-1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4 
-c]pyridin-5-one (6.2 g, 0.020 moles) and ethylamine (6 ml, 0.092 moles). 
Recrystallization from ethyl acetate gave the product (1.4 g), mp 
162.degree.-163.degree. C. 
EXAMPLE 53 
N-[1,3,4,5-Tetrahydro-8-methyl-3-[2-(methylamino)propyl]-5-oxo-2H-[1]benzop 
yrano[3,4-c]pyridin-9-yl]acetamide 
Prepared by the method described for Example 51 from 
N-[1,3,4,5-tetrahydro-8-methyl-5-oxo-3-(2-oxopropyl)-2H-[1]benzopyrano[3,4 
-c]pyridin-9-yl]acetamide (5.1 g, 0.016 moles) and methylamine (2.2 ml, 
0.050 moles). Sufficient methanol is added to effect solution. 
Recrystallization from ethanol gave the product (3.0 g), mp 
187.degree.-188.degree. C. 
EXAMPLE 54 
3-[2-(Ethylamine)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4- 
c]pyridin-5-one 
Prepared by the method described for Example 51 from 
1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one (20.2 g, 0.074 moles), and ethylamine (12 ml, 0.183 moles). 
Recrystallization from isopropyl ether/ethyl acetate 4:1 gave the product 
(18.5 g), mp 120.degree.-121.degree. C. 
EXAMPLE 55 
1,2,3,4-Tetrahydro-8-methyl-3-[2-(methylamine)propyl]-5H-[1]-benzopyrano[3, 
4-c]pyridin-5-one 
Prepared by the method described for example 51 from 
1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one (16.7 g, 0.062 moles) and methylamine (8 ml, 0.18 moles). 
Recrystallization from ethyl acetate gave the product (15.0 g), mp 
123.degree.-125.degree. C. 
EXAMPLE 56 
3-[2-(Ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4 
-c]pyridin-5-one 
Prepared by the method described for Example 51 from 
1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyrid 
in-5-one (14.9 g, 0.052 moles) and ethylamine (5 ml, 0.07 moles). 
Recrystallization from ethyl acetate gave the product (7.1 g), mp 
97.degree.-100.degree. C. 
EXAMPLE 57 
1,2,3,4-Tetrahydro-8-methoxy-3-[2-(methylamino)propyl]-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one 
Prepared by the method described for Example 51 from 
1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyrid 
in-5-one (16.5 g, 0.057 moles) and methylamine (8 ml, 0.18 moles). 
Recrystallization from ethyl acetate gave the product (12.0 g), mp 
109.degree.-111.degree. C. 
EXAMPLE 58 
1,2,3,4-Tetrahydro-8,9-dimethoxy-3-[2-(methylamino)propyl]-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one 
Prepared by the method described for Example 51 from 
1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]p 
yridin-5-one (25.0 g, 0.08 moles) and methylamine (5 g, 0.016 moles). 
Recrystallization from acetonitrile gave the product (15.5 g), mp 
137.degree.-139.degree. C. 
EXAMPLE 59 
3-[2-(Ethylmethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one 
A solution of 
1,2,3,4-tetrahydro-8-methyl-3-[2-(methylamino)propyl]-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one (3.0 g, 0.010 moles) in glacial acetic acid (20 ml) is 
heated to 55.degree. C. under nitrogen. Sodium borohydride (2.4 g, 0.630 
moles) is added portionwise. The mixture is stirred, heated for 20 hours, 
cooled, diluted with ice water (150 ml), made strongly basic by the 
addition of concentrated ammonium hydroxide, and extracted with 
dichloromethane (3.times.75 ml). The combined extracts are dried over 
magnesium sulfate and evaporated under reduced pressure. The oily residue 
is treated with a small amount of diisopropyl ether, filtered, and the 
filtrate evaporated under reduced pressure. The syrup obtained is 
dissolved in absolute ethanol, cooled in an ice bath and saturated with 
HCl gas. After overnight refrigeration the product is filtered off, rinsed 
with acetone, and sucked dry. Recrystallization from ethanol gave the 
product (3.0 g) as the dihydrochloride, 20:9 hydrate, mp 245.degree. C. 
(dec.). 
EXAMPLE 60 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3 
,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one (3.0 g, 0.009 moles), glacial acetic acid (20 ml), and 
sodium borohydride (2.5 g, 0.066 moles). The free base is obtained 
crystalline. Recrystallization from isopropyl ether gave the product (1.9 
g), mp 83.degree.-85.degree. C. 
EXAMPLE 61 
3-[2-(Ethylpropylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one (3.0 g, 0.009 moles), propionic acid (20 ml), and sodium 
borohydride (2.0 g, 0.053 moles). The free base is obtained crystalline. 
Recrystallization from acetonitrile gave the product (2.0 g), mp 
100.degree.-101.degree. C. 
EXAMPLE 62 
3-[2-(Ethylmethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
1,2,3,4-tetrahydro-8-methoxy-3-[2(methylamino)propyl]-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one (3.0 g, 0.010 moles), acetic acid (20 ml), and sodium 
borohydride (2.0 g, 0.053 moles). The product crystallized as the free 
base. Recrystallization from isopropyl ether gave the product (2.5 g), mp 
102.degree.-104.degree. C. 
EXAMPLE 63 
1,2,3,4-Tetrahydro-8,9-dimethoxy-3-[2-(methylpropylamino)propyl]-5H-[1]benz 
opyrano[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
1,2,3,4-tetrahydro-8,9-dimethoxy-3-[2-(methylamino)propyl]-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one (4.0 g, 0.012 moles), propionic acid (25 ml), and 
sodium borohydride (2.2 g, 0.057 moles). The product crystallized as the 
free base. Recrystallization from isopropyl ether gave the product (2.0 
g), mp 81.degree.-85.degree. C. 
EXAMPLE 64 
1,2,3,4-Tetrahydro-8-methoxy-3[2-(methylpropylamino)propyl]-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
1,2,3,4-tetrahydro-8-methoxy-3-[2-(methylamino)propyl]-5H-[1]benzopyrano[3 
,4-c]pyridin-5-one (3.0 g, 0.010 moles), propionic acid (20 ml), and sodium 
borohydride (2.0 g, 0.053 moles). During aqueous workup the product 
precipitates as the free base and is filtered off, rinsed, and dried. 
Recrystallization from hexane/pentane, 3:2, gave the product (1.9 g), mp 
69.degree.-71.degree. C. 
EXAMPLE 65 
1,2,3,4-Tetrahydro-8-methyl-3-[2-(methylpropylamino)propyl]-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
1,2,3,4-tetrahydro-8-methyl-3-[2-(methylamino)propyl]-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one (3.0 g, 0.010 moles), propionic acid (20 ml), and sodium 
borohydride (2.4 g, 0.063 moles). Recrystallization from ethanol gave the 
product (2.2 g) as the dihydrochloride, 5:1 hydrate, mp 238.degree. C. 
(dec.). 
EXAMPLE 66 
3-[2-(Butylmethylamino)propyl)]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
1,2,3,4-tetrahydro-8-methoxy-3-[2-(methylamino)propyl]-5H-[1]benzopyrano[3 
,4-c]pyridin-5-one (3.0 g, 0.010 moles), n-butyric acid (20 ml), and sodium 
borohydride (2.0 g, 0.053 moles). Recrystallization of the free base from 
isopropyl ether gave the product (0.9 g), mp 57.degree.-59.degree. C. 
EXAMPLE 67 
9-Chloro-3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzo 
pyrano[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
9-chloro-3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzop 
yrano[3,4-c]pyridin-5-one (0.9 g, 0.003 moles), glacial acetic acid (5 ml), 
and sodium borohydride (0.6 g, 0.016 moles). Recrystallization from 
isopropyl ether gave the product (0.45 g), mp 78.degree.-80.degree. C. 
EXAMPLE 68 
3-[2-(Butylmethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
1,2,3,4-tetrahydro-8-methyl-3-[2-(methylamino)propyl]-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one (3.0 g, 0.010 moles, n-butyric acid (20 ml), and sodium 
borohydride (2.4 g, 0.063 moles). Recrystallization from ethanol gave the 
product (1.6 g) as the dihydrochloride, 10:7 hydrate, mp 242.degree. C. 
(dec.). 
EXAMPLE 69 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3, 
4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4 
-c]pyridin-5-one (3.0 g, 0.010 moles), glacial acetic acid (20 ml), and 
sodium borohydride (2.3 g, 0.061 moles). Recrystallization from ethanol 
gave the product (2.0 g) as the dihydrochloride, mp 254.degree. C. (dec.). 
EXAMPLE 70 
3-[2-(Ethylpropylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one 
Prepared by the method described for Example 59 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4 
-c]pyridin-5-one (3.0 g, 0.010 moles), propionic acid (20 ml), and sodium 
borohydride (2.3 g, 0.061 moles). Recrystallization from ethanol gave the 
product (3.0 g) as the dihydrochloride, 5:1 hydrate, mp 248.degree. C. 
(dec.). 
EXAMPLE 71 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyrid 
in-5-one 
Prepared by the method described for Example 59 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one (3.0 g, 0.010 moles), glacial acetic acid (20 ml), and sodium 
borohydride (2.4 g, 0.063 moles). The product was obtained as the 
dihydrochloride, 5:4 hydrate (3.3 g), mp 234.degree. C. (dec.). 
EXAMPLE 72 
3-[2-(Ethylpropylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]p 
yridin-5-one 
Prepared by the method described for Example 59 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridi 
n-5-one (3.0 g, 0.010 moles), propionic acid (20 ml), and sodium 
borohydride (2.4 g, 0.063 moles). The product was obtained as the 
dihydrochloride 5:4 hydrate (1.9 g), mp 238.degree. C. (dec.). 
EXAMPLE 73 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one dihydrochloride 
A mixture of 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one dihydrochloride (46.6 g, 0.11 moles), sodium acetate 
(18.2 g, 0.22 moles), and glacial acetic acid (166 g, 2.77 moles) in 
tetrahydrofuran (750 ml) is stirred and heated to 50.degree.-55.degree. 
under a nitrogen atmosphere. Sodium borohydride (22.8 g, 0.60 moles) is 
added to the mixture over a 3 hour period. After heating for an additional 
43 hours, the mixture is cooled in ice, treated cautiously with ice water 
(1 kg), and condensed to a volume of 1.0 l. The mixture is again cooled in 
ice and 50% aqueous sodium hydroxide is added until the pH is 11.0. 
Dichloromethane is used to extract the product, and the combined organic 
layers are washed with brine, dried over sodium sulfate, and evaporated. 
The residue is dissolved in hot 95% ethanol, treated with gaseous hydrogen 
chloride, filtered hot, and the filtrate is treated with diethyl ether. 
Cooling gives the product as the dihydrochloride salt, which is filtered 
and washed with cold acetone. A second recrystallization as above yielded 
the final product (36.0 g), mp 205.degree. C. (dec.). 
EXAMPLE 74 
3-[2-(Butylethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzop 
yrano[3,4-c]pyridin-5-one 
Prepared by the method described in Example 73 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one dihydrochloride (6.7 g, 0.016 moles), sodium acetate 
(5.2 g, 0.063 moles), sodium borohydride (3.3 g, 0.087 moles), and 
n-butyric acid (28.9 g, 0.33 moles) instead of acetic acid. Several 
recrystallizations from diisopropyl ether yielded the final product as the 
free base (3.0 g), mp 108.degree.-111.degree. C. 
EXAMPLE 75 
3-[2-(Ethylpropylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzo 
pyrano[3,4-c]pyridin-5-one 
Prepared by the method described in Example 73 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one dihydrochloride (6.7 g, 0.016 moles), sodium acetate 
(2.6 g, 0.032 moles), sodium borohydride (3.3 g, 0.087 moles), and 
propionic acid (29.8 g, 0.40 moles) instead of acetic acid. Several 
recrystallizations from diisopropyl ether yielded the product as the free 
base (2.4 g), mp 93.degree.-96.degree. C. 
EXAMPLE 76 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one 
Prepared by the method described in Example 73 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one (10.0 g, 0.029 moles), sodium acetate (4.7 g, 0.058 
moles), acetic acid (43.2 g, 0.72 moles), and sodium borohydride (5.9 g, 
0.16 moles). Several recrystallizations from ethyl acetate/hexane yielded 
the product as the free base (2.3 g), mp 99.degree.-100.degree. C. 
EXAMPLE 77 
3-[2-[Ethyl(2-methylpropyl)amino]propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5 
H-[1]benzopyrano[3,4-c]pyridin-5-one 
Prepared by the method described in Example 73 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one dihydrochloride (6.7 g, 0.016 moles), sodium acetate 
(2.6 g, 0.032 moles), sodium borohydride (3.3 g, 0.087 moles), and 
2-methylpropionic acid (28.5 g, 0.32 moles) instead of acetic acid. 
Several recrystallizations from diisopropyl ether yielded the final 
product as the free base (1.4 g), mp 108.degree.-111.degree. C. 
EXAMPLE 78 
3-[2-(Ethylmethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzo 
pyrano[3,4-c]pyridin-5-one dihydrochloride 
A suspension of 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one dihydrochloride (6.9 g, 0.017 moles) in methanol (100 
ml) is cooled in ice and treated with triethylamine (1.6 g, 0.016 moles) 
followed by 37% aqueous formaldehyde (6.4 g, 0.21 moles). The ice bath is 
removed and the mixture is stirred at reflux under nitrogen for 2 hours. 
The mixture is again cooled in ice while sodium borohydride (2.2 g, 0.058 
moles) is added over 30 minutes. After removal of the ice bath, the 
mixture is again stirred at reflux for 16 hours. The product is then 
isolated as the dihydrochloride by the method described in Example 73. 
Several recrystallizations of the dihydrochloride from ethanol/diethyl 
ether yielded the final product (2.3 g), mp 187.degree. C. (dec.). 
EXAMPLE 79 
3-[2-(Ethylmethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzo 
pyrano[3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described in Example 78 from 
3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one (10.0 g, 0.029 moles), except that the addition of 
the triethylamine is omitted, and instead, a few drops of conc. 
hydrochloric acid are added before the addition of the formaldehyde 
solution. After conversion to the dihydrochloride, several 
recrystallizations from 2-propanol yielded the final product (1.5 g), mp 
182.degree.-184.degree. C. 
EXAMPLE 80 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dihydroxy-5H-[1]benzopyra 
no[3,4-c]pyridin-5-one dihydrobromide 
Prepared by the method described in Example 36 from 
3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one dihydrochloride (23.3 g, 0.052 moles) and 48% 
aqueous hydrobromic acid (200 ml). After washing several times with cold 
acetone, the product (25.0 g, mp 257.degree.-258.degree. C.) is used as an 
intermediate without additional purification. 
EXAMPLE 81 
3-[2-(Diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-diethoxy-5H-[1]benzopyran 
o[3,4-c]pyridin-5-one dihydrochloride 
Prepared by the method described in Example 37 from 
3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dihydroxy-5H-[1]benzopyr 
ano[3,4-c]pyridin-5-one dihydrobromide (17.0 g, 0.034 moles), potassium 
carbonate (27.6 g, 0.20 moles), and diethyl sulfate (20.0 g, 0.13 moles). 
The crude free base product is converted to the dihydrochloride in 
absolute ethanol. A second recrystallization from ethanol yielded the 
final product (1.8 g), mp 148.degree.-152.degree. C. 
EXAMPLE 82 
1,2,3,4-Tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H-[ 
1]benzopyrano[3,4-c]pyridin-5-one 
A mixture of 
1,2,3,4-tetrahydro-8-hydroxy-3(phenylmethyl)-5H-[1]benzopyrano[3,4-c]pyrid 
in-5-one (15 g, 0.049 moles), 5-chloro-1-phenyl-1H-tetrazole (9 g, 0.0498 
moles), and potassium carbonate (30 g) in dimethylformamide (250 ml) is 
heated at 85.degree.-95.degree. C. for 5 hours. The reaction mixture is 
cooled and poured over ice water. The aqueous mixture is allowed to stand 
at room temperature overnight. The solid is filtered off and washed with 
water. Recrystallization from ethyl acetate gave the product (10.14 g), mp 
165.degree.-166.degree. C. 
EXAMPLE 83 
1,2,3,4-Tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one 
A solution of 
1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H- 
[1]benzopyrano[3,4-c]pyridin-5-one (21.3 g, 0.047 moles) in acetic acid 
(210 ml) is hydrogenated at room temperature and 50 psi in the presence of 
20% palladium on carbon until hydrogen uptake ceases. The catalyst is 
removed by filtration and the filtrate evaporated under reduced pressure. 
The residue is dissolved in water (300 ml) and made strongly basic by the 
additon of concentrated ammonium hydroxide. The precipitate is filtered 
off, rinsed with water, and dried. Recrystallization from ethyl acetate 
gave the product (6.1 g), mp 125.degree.-128.degree. C.