U.S. patent number RE36,374 [Application Number 08/648,240] was granted by the patent office on 1999-11-02 for 1,2,3-triazole and tetrazole substituted piperidine or tetrahydropyridine compounds useful as acetylcholine agonists.
This patent grant is currently assigned to H. Lundbeck, A/S. Invention is credited to Klaus Peter Bogeso, Klaus Gundertofte, Ejner Knud Moltzen, Henrik Pedersen.
United States Patent |
RE36,374 |
Bogeso , et al. |
November 2, 1999 |
1,2,3-triazole and tetrazole substituted piperidine or
tetrahydropyridine compounds useful as acetylcholine agonists
Abstract
The present invention relates to novel compounds of the
following formula, where the dotted line designates in optional
bond: ##STR1## wherein "het" designates a five membered
heterocyclic ring which may include 1 or 2 double bonds and 1-4
heteroatoms selected from nitrogen, oxygen or sulphur, provided
that "het" may not designate a 1,4- or 1,3,4-oxadiazole, R.sup.1 is
selected from hydrogen, lower alkyl, optionally substituted with
phenyl which may be substituted with halogen, lower alkyl, or lower
alkoxy, or a group R.sup.6 --CO--NH--CH.sub.2 -- or R.sup.6
--O--CO--, wherein R.sup.6 is lower alkyl, branched or unbranched,
or phenyl optionally substituted with halogen, trifuoromethyl,
lower alkyl, hydroxy, lower alkoxy, or lower acyloxy; R.sup.2 and
R.sup.3 are the same or different, each representing hydrogen,
lower alkyl, cycloalkyl (3-6 C-atoms), lower alkenyl, lower
alkadienyl, lower alkynyl, optionally substituted with hydroxy,
halogen or phenyl, in which the phenyl group may be substituted
with halogen, trifluoromethyl, lower alkyl, hydroxy or lower
alkoxy; R.sup.2 and R.sup.3 may further, respectively, be selected
from trifluoromethyl or phenyl optionally substituted with halogen,
trifluoromethyl, lower alkyl, hydroxy, lower alkoxy or lower
acyloxy, or R.sup.2 and R.sup.3 may, respectively, be a group
OR.sup.7 or SR.sup.7 wherein R.sup.7 is defined as R.sup.2 or
R.sup.3, and if "het" includes 2 or more carbon atoms R.sup.4 and
R.sup.5 are the same or different, and each is defined as R.sup.2
or R.sup.3, and if "het" includes only one carbon atom, there is
only one substituent, R.sup.4, on the heterocyclic ring, and
R.sup.4 is defined as R.sup.2 or R.sup.3, as well as individual
stereo isomers and pharmaceutically acceptable acid addition salts
thereof. The invention moreover relates to methods for the
preparation of the compounds of formula 1, to novel intermediates,
to pharmaceutical compositions containing same and to methods for
the treatment of disorders, caused by malfunction of the
acetylcholine (AcCh) or muscarinic system, by administering a
non-toxic effective amount of a compound of formula I.
Inventors: |
Bogeso; Klaus Peter (Horsholm,
DK), Gundertofte; Klaus (Frederiksberg,
DK), Moltzen; Ejner Knud (Gentofte, DK),
Pedersen; Henrik (Bronshoj, DK) |
Assignee: |
H. Lundbeck, A/S
(Copenhagen-Valby, DK)
|
Family
ID: |
10619472 |
Appl.
No.: |
08/648,240 |
Filed: |
May 13, 1996 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
209994 |
Jun 22, 1988 |
04866077 |
Sep 12, 1989 |
|
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Foreign Application Priority Data
|
|
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Jun 24, 1987 [GB] |
|
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8714789 |
|
Current U.S.
Class: |
514/326; 514/340;
546/210; 546/268.1 |
Current CPC
Class: |
A61P
25/02 (20180101); C07D 417/04 (20130101); C07D
401/04 (20130101); C07D 413/04 (20130101); A61P
25/28 (20180101); A61P 21/00 (20180101) |
Current International
Class: |
C07D
401/00 (20060101); C07D 401/04 (20060101); C07D
417/00 (20060101); C07D 417/04 (20060101); C07D
413/04 (20060101); C07D 413/00 (20060101); A61K
031/445 (); C07D 401/04 () |
Field of
Search: |
;546/210,276
;514/326,340 |
References Cited
[Referenced By]
U.S. Patent Documents
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4112101 |
September 1978 |
Sellstedt et al. |
4769379 |
September 1988 |
Katoh et al. |
|
Other References
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Stevenson T "Drug therapy in the management of Parkinson'sdisease"
Mediline 09080873, 1997. .
Larsson et al. "In vitro binding of 3H-acetylcholine . . . " CA
107:71323, 1987. .
Appel, S.H. "Current Neurology" vol. 6, pp. 313-317, 1987. .
Marx, J. "Human brain disease recreated in mice" Science, vol. 250,
pp. 1509-1510, 1990. .
Brain Web News, Press Release, "Lundbeck to proceed at full speed
with preparations for the company's public listing--Sales of
Cipramil increased by 26% in first half of 1998", Valby, Aug. 19,
1998, 2 pages. .
Brain Web Press Cuttings, "Forest Laboratories' Licensed M1 Agonist
Not Effective in Alzheimer's Disease", PRNewswire, Aug. 19, 1998, 1
page..
|
Primary Examiner: Chang; Ceila
Attorney, Agent or Firm: Darby & Darby
Claims
We claim:
1. A novel compound of the following formula, where the dotted line
designates an optional bond: ##STR7## wherein "het" designates
1,2,3-triazole or tetrazole;
R.sup.1 is selected from hydrogen, lower alkyl, which may be
substituted with phenyl which may be substituted with halogen,
lower alkyl, or lower alkoxy, or .Iadd.R.sup.1 is .Iaddend.a group
R.sup.6 --CO--NH--CH.sub.2 -- or R.sup.6 --O--CO--, wherein R.sup.6
is lower alkyl, branched or unbranched, or phenyl which may be
substituted with halogen, trifluoro.Iadd.-.Iaddend.methyl, lower
alkyl, hydroxy, lower alkoxy, or lower acyloxy;
R.sup.2 and R.sup.3 are the same or different, each representing
hydrogen, lower alkyl, cycloalkyl (3-6 C-atoms), lower alkenyl,
lower alkadienyl, lower alkynyl, which may be substituted with
hydroxy, halogen or phenyl, in which the phenyl group may be
substituted with halogen, trifluoromethyl, lower alkyl, hydroxy, or
lower alkoxy, R.sup.2 and R.sup.3 may further respectively be
selected from trifluoromethyl or phenyl which may be substituted
with halogen, trifluoromethyl, lower alkyl, hydroxy, lower alkoxy
or lower acyloxy, or
R.sup.2 and R.sup.3 may respectively be a group OR.sup.7 or
SR.sup.7 wherein R.sup.7 is defined as R.sup.2 or R.sup.3
.Iadd.above.Iaddend., and
if "het" includes 2 or more carbon atoms, R.sup.4 and R.sup.5 are
the same or different, and each is defined as R.sup.2 or R.sup.3,
.Iadd.provided that R.sup.4 and R.sup.5 are not OR.sup.7 or
SR.sup.7, bonded to nitrogen.Iaddend., and
if "het" includes only one carbon atom, there is only one
substituent, R.sup.4, on the heterocyclic ring, and R.sup.4 is
defined as R.sup.2 or R.sup.3, .Iadd.provided that R.sup.4 is not
OR.sup.7 or SR.sup.1 bonded to nitrogen .Iaddend.
as well as individual stereo isomers and pharmaceutically
acceptable acid addition salts thereof.
2. A compound according to claim 1, wherein "het" designates
1,2,3-triazole or tetrazole;
R.sup.1, R.sup.2 and R.sup.3 designate each hydrogen or methyl,
and
R.sup.4 and R.sup.5 designate each hydrogen, methyl propargyl
methoxy or methylthio;
as well as individual stereo isomers and pharmaceutically
acceptable acid addition salts thereof.
3. A compound according to claim 1, selected from:
2-Methyl-5-(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole;
2-(2-Propynyl)-5-(5-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole;
2-Methyl-4-(1,2,5,6-tetrahydro-3-pyridyl)-1,2,3-triazole;
2-Ethyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole;
2-Allenyl-5-(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole;
2-Methyl-4-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-1,2,3-triazole;
well as stereo isomers and non-toxic pharmaceutically acceptable
acid addition salts thereof.
4. A pharmaceutical composition in unit dosage form comprising--as
an active ingredient--a compound as defined in claim 1, and one or
more pharmaceutical diluents or carriers.
5. A pharmaceutical composition in unit dosage form, according to
claim 4, wherein the active ingredient is present in an amount from
0.1-100 mg per unit dosage.
6. A method of treating .[.disorders caused by malfunction of the
acetylcholine (AcCh) or muscarinic system,.]. .Iadd.impaired memory
function associated with decreased acetylcholine activity in the
central nervous system .Iaddend.comprising the step of
administering to a subject suffering from such .[.disorder.].
.Iadd.impaired memory function .Iaddend.an effective amount of a
.Iadd.muscarinic receptor agonist .Iaddend.compound of claim 1.
7. A method of treating .[.disorders caused by malfunction of the
acetylcholine (AcCh) or muscarinic system,.]. .Iadd.impaired memory
function associated with decreased acetylcholine activity in the
central nervous system .Iaddend.comprising the step of
administering to a subject suffering from such .[.a disorder.].
.Iadd.impaired memory function .Iaddend.an effective amount of a
.Iadd.muscarinic receptor agonist .Iaddend.compound of claim 2.
8. A method of treating .[.disorders caused by malfunction of the
acetylcholine (AcCh) or muscarinic system,.]. .Iadd.impaired memory
function associated with decreased acetylcholine activity in the
central nervous system .Iaddend.comprising the step of
administering to a subject suffering from such .[.a disorder.].
.Iadd.impaired memory function .Iaddend.an effective amount of a
.Iadd.muscarinic receptor agonist .Iaddend.compound of claim 3.
9. A pharmaceutical composition in unit dosage form comprising--as
an active ingredient--a compound of claim 2 and one or more
pharmaceutical diluents or carriers.
10. A pharmaceutical composition in unit dosage form comprising--as
an active ingredient--a compound of claim 3 and one or more
pharmaceutical diluents or carriers.
11. Method of claim 6, wherein the compound is administered in an
amount from 0.1 to 100 mg per unit dosage.
12. Method of claim 7, wherein the compound is administered in an
amount from 0.1 to 100 mg per unit dosage.
13. Method of claim 8, wherein the compound is administered in an
amount from 0.1 to 100 mg per unit dosage.
14. Composition of claim 9, in unit dosage form wherein the active
ingredient is present in an amount from 0.1 to 100 mg per unit
dosage.
15. Composition of claim 10, in unit dosage form wherein the active
ingredient is present in an amount from 0.1 to 100 mg per unit
dosage. .Iadd.
16. The method of claim 6 wherein said subject suffers from
Alzheimer's disease. .Iaddend..Iadd.17. The method of claim 7
wherein said subject suffers from Alzheimer's disease.
.Iaddend..Iadd.18. The method of claim 8 wherein said subject
suffers from Alzheimer's disease. .Iaddend.
Description
BACKGROUND OF THE INVENTION
AcCh is known to be a neurotransmitter in the peripheral as well as
the central nervous system (CNS). Reduced function of AcCh in the
CNS, probably as a result of degeneration of neurones utilizing
AcCh as a neurotransmitter, is believed to be related to the
etiology of various diseases such as Alzheimer's disease and Down's
syndrome (R. M. Marchbanks, J. Neurochem. 39 (1982) 9-15; R. D.
Terry and P. Davies, Ann. Rev. Neurosci., 3 (1980) 77; N. R. Sims,
D. M. Bowen, S. J. Allen, C. C. T. Smith, D. Neary, D. J. Thomas
and A. N. Davidson, J. Neurochem., 40 (1983) 503-509; E. Roberts,
in Ann. New York Acad. Sci. (F. Marott Sinex and C. R. Merril,
editors), 396 (1982) 165-178. Furthermore, senile dementia, which
may be associated with aging, appears to be somehow related to
decreased AcCh activity in the CNS, and similarly impaired learning
and memory functions have been associated with decreased functions
of the central AcCh-system (P. S. Anderson and D. Haubrich, Ann.
Rep. Med Chem., 16 (1981) 51-60.
Administrations of drugs which increase the level of AcCh by
blocking the enzymatic breakdown of the transmitter or directly
stimulate the AcCh-receptor, AcCh-agonists, have been found to
improve the cognitive malfunctions observed in patients with senile
dementia of the Alzheimer type to various degrees (Christie et al.,
Br. J. Phych. 138 (1981) 138-146; Harbaugh et al., Neurosurgery 15
(1984) 514-518; Beller et al., Pscyhopharmacol. 87 (1985) 147-151;
Schwartz and Kohlstaedt, Life Sci. 38 (1986) 1021-1028; Summers et
al., N. Engl. J. Med. 315 (1986) 1241-1245. Compounds capable of
activating the AcCh receptors are therefore of primary interest.
However, most known AcCh agonists, including AcCh itself, contain
quaternary ammonium groups and, consequently, these compounds do
not penetrate the blood-brain barrier (BBB) easily after peripheral
administration. As a result of this, such compounds do not reach
the AcCh receptors in the CNS but activate almost exclusively the
peripheral AcCh receptors, which are unrelated to the diseases
mentioned above, provoking various undesired effects.
Arecoline (methyl
1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is an AcCh
agonist, which does not contain a quatenary ammonium group.
Arecoline is a tertiary amine, and arecoline is capable of
penetrating the BBB after peripheral administration. The ester
group of arecoline is, however, very rapidly hydrolyzed in vivo,
and arecoline has very weak and frequently negligible central
effects aft peripheral administration.
SUMMARY OF THE INVENTION
According to the present invention, it his now surprisingly been
found that the novel compounds of Formula I have very potent AcCh
agonist activity. The 5-ring heterocyclic groups can be considered
as bioisosteric with the ester group in arecoline, but in contrast
to the ester group they are stable towards hydrolysis. Furthermore,
the new compounds readily penetrate the blood-brain barrier upon
peripheral administration.
The new compounds have high affinity to central cholinergic
receptors as measured by the ability of the compounds to displace
tritiated oxotremorine-M from rat brain homogenates. The compounds
also have high affinity to central muscarinic M-1 receptors, as
defined by their ability to displace tritiated .[.pirenzephine.].
.Iadd.pirenzepine .Iaddend.from rat brain homogenates.
The potent central activity of the compounds in vivo can be
demonstrated by the ability of the compounds to induce hypothermia
in mice or to prevent isoniazid induced convulsions in mice. It
shall be mentioned, however, that compounds with high selectivity
for M-1 receptors are without nativity in the hypothermia test.
Compared with the potent central activity they show only minor
peripheral side effects.
Moreover, the compounds of Formula I have very low toxicity as
compared to therapeutic effective doses.
This invention also includes pharmaceutically acceptable salts of
the compounds of Formula I formed with non-toxic organic or
inorganic acids. Such salts are easily prepared by methods known to
the art. The base is reacted with either the calculated amount of
organic or inorganic acid in an aqueous miscible solvent, such as
acetone or ethanol, with isolation of the salt by concentration and
cooling or an excess of the acid in aqueous immiscible solvent,
such as ethyl ether or chloroform, with the desired salt separating
directly. Exemplary of such organic salts are those with maleic,
fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis
methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,
propionic, tartaric, salicylic citric, .[.gluomic.].
.Iadd.gluconic.Iaddend., lactic, malic, mandelic, cinnamic,
citraconic, aspartic, stearic, palmitic, itaconic, glycolic,
p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic
acids as well as the 8-halotheophyllines, for example
8-bromo-theophylline. Exemplary of such inorganic salts are those
with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and
nitric acids. Of course, these salts may also be prepared by the
classical method of double decomposition of appropriate salts,
which is wellknown to the art.
When either R.sup.2 or R.sup.3 is different from hydrogen, or when
R.sup.2 and R.sup.3 are different and bound to the same carbon
atom, or when R.sup.2 and R.sup.3 are the same and bound to the
same carbon atom and the piperidine ring is saturated, the
compounds of formula I can be separated into two enantiomeric
forms. When either R.sup.2 or R.sup.3 is different from hydrogen
and the piperidine ring is saturated, or when R.sup.2 and R.sup.3
are the same or different and bound to different carbon atoms and
not being hydrogen, the compounds of formula I can be separated in
cis and trans forms, each separable in two enantiomeric forms. It
is understood, that the present invention encompasses all
enantiomers and mixtures thereof, as well as the E- and the Z-forms
and mixtures thereof.
In the present context, the term "lower alkyl" designates C.sub.1-6
alkyl which may be straight or branched, such as methyl, ethyl,
propyl isopropyl, butyl, tert. butyl, pentyl or hexyl. Preferably,
the term "lower alkyl" designates C.sub.1-4 alkyl which may be
straight or branched, such as methyl, ethyl, propyl isopropyl,
butyl, or tert.butyl. The term "lower alkenyl" designates a C.sub.2
-C.sub.6 straight or branched alkyl group which contains a double
bond, such as 2-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl,
2-ethyl-2-propenyl or 3-methyl-2-butenyl. The term "lower
alkadienyl" designates a C.sub.3 -C.sub.6 straight or branched
alkyl group containing two double bonds, such as allenyl, 1,2-,
1,3- or 2,3-butadienyl, 1,2-, 1,3- or 2,4-pentadienyl, or
2-methyl-2,4-pentadienyl. The term "lower alkynyl" designates a
C.sub.2 -C.sub.6 straight or branched alkyl group containing a
triple bond, such as 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl
or 4methyl-2-pentynyl. Where a phenyl group is substituted with
halogen, lower alkyl, or lower alkoxy, .[.they.]. .Iadd.it
.Iaddend.may be mono-, di- or tri-substituted, and when .[.they
are.]. .Iadd.it is .Iaddend.di- or tri-substituted the substituents
may be the same or different. The term "lower alkoxy" designates
oxy to which is attached a lower alkyl group. Preferred groups are
methoxy and ethoxy. The term "halogen" designates F, Cl, Br, or I;
F, Cl and Br are preferred.
Specific examples of the group "het" include oxazole, isoxazole,
thiazole, isothiazole, pyrazole, imidazole, 1,2,3- and
1,2,4-triazole, 1,2,4- and 1,3,4-thiadiazole and tetrazole and,
most preferably, oxazole, thiazole, 1,2,3-triazole or
tetrazole.
R.sup.1, R.sup.2 and R.sup.3 are, respectively, most preferably
hydrogen or methyl, R.sup.4 and R.sup.5 are, respectively, most
preferably hydrogen, methyl, 2-propynyl, methoxy or methylthio.
The compounds of formula I may--according to the present
invention--be prepared by
(a) hydrolysis or hydrogenolysis of a compound of the formula II:
##STR2## in which "het", R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
as defined above, and R.sup.8 is in amino-protecting group readily
removable,
or
(b) reducing a compound of the formula III: ##STR3## in which
"het", R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above,
R.sup.9 is defined as R.sup.1 excluding hydrogen and A may be a
conjugate base of an inorganic acid, with a reducing agent,
or
(c) treating a compound of the formula IV: ##STR4## where "het",
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above, with a
compound of Formula V, where R.sup.9 is defined as above and X is a
leaving group
or
(d) treating a compound of the formula VI: ##STR5## in which "het",
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above, and
R.sup.10 is hydrogen, lower alkyl or lower alkoxy with a reducing
agent,
or
(e) catalytic .[.hydrogenization.]. .Iadd.hydrogenation .Iaddend.of
compounds of formula VII or VIII: ##STR6## in which "het", R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined above,
or
(f) treating an amide of formula IX
wherein R.sup.6 is as defined above
with formaldehyde and a compound of formula IV,
or
(g) by treating compounds of formula IV with a compound of formula
X
wherein R.sup.6 is as defined above,
whereupon the compound of formula I is isolated as the free base or
a pharmaceutically acceptable acid addition salt thereof and, if
desired, separated in the individual stereo isomers.
Specific examples of R.sup.8 in formula II are the following.
Methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
propoxycarbonyl tert. butoxycarbonyl, benzyloxycarbonyl,
4-chlorobenzyloxycarbonyl, 4-methoxybenzyl, benzyl trityl, formyl
or acetyl.
As examples of the conjugate base A may be mentioned chloride,
bromide, iodide, and sulphate.
As examples of the leaving group X may be mentioned chloride,
bromide, iodide, or the like.
In method (a) the hydrolysis is performed under acidic or basic
conditions in a solvent, preferably water, ether, ethyl acetate,
acetic acid or an alcohol. Preferred acids are hydrochloric acid,
hydrobromic acid or trifluoroacetic acid; preferred bases include
sodium or potassium hydroxide and potassium .[.tertbutylate.].
.Iadd.tert-butylate.Iaddend.. Hydrogenation may be performed in
wellknown manner at pressures ranging from 1-150 atm. at
temperatures from 20.degree.-150.degree. C. for 1-72 hours.
In method (b) the reducing agent may be sodium borohydride, sodium
cyanoborohydride, lithium aluminium hydride or the like. Reaction
with metal borohydride is normally performed in an alcohol
containing 0-50% of water at temperatures from -10.degree. C. to
the boiling point of the mixture. Using lithium aluminiumhydride
preferred solvents are diethylether, tetrahydrofuran or a mixture
of these at temperatures from 0.degree. C. to the boiling point of
the solvent. When using formic acid as a reducing agent, potassium
formate, formic acid and the compound of formula III is heated to
reflux for 1-6 hours.
In method (c) the reaction is preferably performed in a solvent,
e.g. alcohol, dichloromethane, DMF, or a mixture of these, the
solvent containing 0-50% of water in the presence of a base, e.g.
metal hydroxide, quaternary amine, a metal carbonate or
-alcoholate. The reaction is carried out at temperatures from
0.degree. C. to the boiling point of the solution.
Reaction conditions for method (d) are as defined for method (b).
Of particular importance is the well-known Eschweiler-Clarke
methylation.
In method (e) preferred solvents are lower alcohols, water or
aqueous acids or mixtures thereof. Hydrogen pressure preferably
1-150 atm. using Raney-nickel, rhodium, palladium, or platinum as
catalysts. Ammonium formate may be used as hydrogen donor instead
of hydrogen gas.
Preferred solvents for method (f) are water or lower alcohols.
In method (g) inert solvents as dichloromethane in the presence of
a tertiary amine, e.g. triethylamine, are used.
The invention may be illustrated by the following examples, which
may not be construed as limiting.
EXAMPLE 1
3-Cyano-1-methylpyridinium Iodide (2)
3-Cyanopyridine (1) (104 g, 1 mol) and methyl iodide (150 g, 1.06
mol) in acetone (500 ml) was stirred for 5 hours at room
temperature. Then more methyl iodide (20 g, 0.14 mol) was added,
and the reaction mixture was stirred overnight at room temperature.
The mixture was filtered and the solid product was washed with
acetone (100 ml) and then thoroughly with ether. After drying, 199
g (0.81 mol, 81%) of the title compound were obtained, M.P.
145.degree.-150.degree. C.
EXAMPLE 2
3Cyano-1-methyl-1,2,5,6-tetrahydropyridine (3)
To a solution of 2 (133 g, 0.54 mol) in methanol (1000 ml) and
water (200 ml) was added sodium borohydride (41 g, 1.08 mol) in
portions at temperatures below 28.degree. C. After the addition the
mixture was stirred for 1 hour at room temperature. Most of the
methanol was distilled off. To the residue was added saturated
ammonium chloride solution (200 ml), and the mixture was extracted
three times with ether (300 ml). The combined organ phases wee
washed once with water and were then extracted three times with 4M
hydrochloric and (300 ml). The colored aqueous phases were kept for
1 hour at room temperature, and pH was then adjusted to 14. The
mixture was extracted three times with ether (250 ml), and the
combined organic phases were separated from the solid byproducts.
The organic phase was washed with 4 portions of saturated sodium
chloride solution (200 ml), dried over magnesium sulphate and
evaporated. This yielded 17.4 g (0.143 mol, 26%) of crude oily
title compound, which was sufficiently pure according to the .sup.1
H NMR spectrum.
EXAMPLE 3
Ethyl
3-Cyano-1,2,5,6-tetrahydropyridine-5-carboxylate (4)
A mixture of 3 (23.9 g, 0.2 mol), ethyl chloroformate (25 g, 0.23
mol) and potassium carbonate (30 g, 0.22 mol) in
1,1,1-trichloroethane (200 ml) was refluxed to overnight.
The mixture was filtered and the organic phase was washed three
times with 4M hydrochloric acid (100 ml) and then twice with
saturated sodium hydrogencarbonate solution (100 ml). Drying over
magnesium sulphate and evaporation of the solvent in vacuo yielded
14.8 g (0.08 mol. 41%) of oily 4, which was homogeneous according
to the .sup.1 H NMR spectrum.
EXAMPLE 4
5-(1-.[.Carboxyethyl.].
.Iadd.Ethoxycarbonyl.Iaddend.-1,2,5,6-tetrahydro-3-pyridyl)-tetrazole
(5)
A mixture of 4 (14.3 g, 0.079 mol), aluminium chloride (11 g, 0.083
mol) and sodium azide (23.8 g, 0.37 mol) in tetrahydrofurane was
refluxed under nitrogen overnight. Cold 6M hydrochloric acid (150
ml) was added at 20.degree. C. The mixture was extracted three
times with ether (100 ml), and the combined organic phases were
washed three times with saturated sodium chloride solution (50 ml).
Drying over magnesium sulphate and evaporation in vacuo yielded
12.7 g of crude product, which crystallized from ethanol, yielding
8 g of 5 (0.036 mol, 45%),
M.P. 113.degree.-116.degree. C.
EXAMPLE 5
2-Methyl-5-(1-.[.carboxyethyl.].
.Iadd.ethoxycarbonyl.Iaddend.-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole
(6) and 1-Methyl-5-(1-.[.carboxyethyl.].
.Iadd.ethoxycarbonyl.Iaddend.-1,2,5,6-tetrahydro-3-pyridyl)-1H-tetrazole
(7)
A mixture of 5 (7.0 g, 0.031 mol), sodium hydroxide (1.5 g, 0.038
mol), methyl iodide (6.0 g, 0.042 mol), water (15 ml) and acetone
(60 ml) was refluxed for 4 hours. The mixture was filtered, and the
filtrate was evaporated in vacuo. The residue was dissolved in
ether (100 ml), and the solution was washed once with water (50 ml)
and then three times with saturated sodium chloride solution (50
ml). The organic phase was dried over magnesium sulphate and
evaporated in vacuo leaving 8.3 g of oily product, which contained
6 and 7 in the ratio 2:1 as judged from the .sup.1 H NMR spectrum.
The product mixture was applied to a column of silica gel. Elution
with ethyl acetate-heptane (1:3) yielded 3.8 g of 6 (0.016 mol.
52%), which crystallized spontaneously, M.P. 92.degree.-94.degree.
C. Further elution with ethyl acetate yielded 1.8 g of 7 (0.0076
mol, 24%) which crystallized spontaneously, M.P.
85.degree.-90.degree. C. The structural assignment of the two
isomers was based on the .sup.1 H NMR data, since it has been shown
(A. K. S.o slashed.rensen and N. A. Klitgaard, Acta Chem. Scand.,
26 (1972), 541-548) that the signals of the protons of the methyl
groups directly attached to a nitrogen atom in the tetrazole ring
occur at a higher field for the 1-isomers compared to those of the
2-isomers. The CH.sub.3 --N-- shift for 6 was 4.3 ppm, and the
CH.sub.3 --N-- shift for 7 was 4.1 ppm.
EXAMPLE 6
2-Methyl-5(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole, hydrobromide
(8)
A mixture of 6 (2.2 g, 0.0093 mol) and 30% hydrogen bromide in
acetic acid (50 ml) was stirred for 3 day at room temperature. The
yellow solution was evaporated in vacuo, and ethanol was evaporated
three times (50 ml). The crystalline residue was recrystallized
from ethanol. This yielded 1.5 g (0.0064 mol, 69%) of title
compound, M.P. 203.degree.-205.degree. C. Anal. (C.sub.7 H.sub.12
BrN.sub.5) C, H, N.
EXAMPLE 7
1-Methyl-5(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole, fumarate
(9)
A mixture of 7 (1.8 g, 0.0076 mol) and 30% hydrogen bromide in
acetic acid (30 ml) was stirred for 3 days at room temperature. The
solution was then evaporated in vacuo. The residue was dissolved in
water (50 ml), and the aqueous solution was extracted two times
with ether (25 ml). The aqueous solution was then made basic with
28% sodium hydroxide, and was then extracted three times with
dichloromethane (50 ml). The combined organic phases were washed
four times with saturated sodium chloride solution (25 ml). Drying
over magnesium sulphate and evaporation in vacuo yielded 0.60 g of
oily compound, which was dissolved in acetone (20 ml) and treated
with fumaric acid until acidic reaction. Crystalline 9 was filtered
off and dryed, yielding 0.66 g (0.0023 mol, 31%), M.P.
170.degree.-173.degree. C. Anal. (C.sub.11 H.sub.15 N.sub.5
O.sub.4) C, H, N.
EXAMPLE 8
2-Methyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)2H-tetrazole
(10)
A solution of 8 (0.70 g. 0.0028 mol) in formic acid (20 ml) and 35%
formaldehyde (7 ml) was refluxed overnight. The solution was
evaporated in vacuo, and the residue was taken up in ether (20 ml)
and 28% sodium hydroxide (20 ml). The phases were separated, and
the aqueous phase was extracted three times with dichloromethane
(20 ml). The combined organic phases were washed four times with
saturated sodium .[.chdloride.]. .Iadd.chloride .Iaddend.solution
(20 ml). The organic phase was dried over magnesium sulphate and
evaporated in vacuo yielding 0.60 g of crude 10. Crystallization
from ether-light petroleum gave 0.37 g (0.0021 mol, 74%) of title
compound, M.P. 86.degree.-87.degree. C. Anal. (C.sub.8 H.sub.13
N.sub.5) C, H, N.
EXAMPLE 9
2-Methyl-5-(3-pyridyl)-2H-tetrazole (12)
5-(3-pyridyl)-tetrazole (11) (J. M. McManus and R. M. Herbst, J.
Am. Chem. Soc., 24 (1959) 1462-64) (10 g, 0.068 mol), sodium
hydroxide (2.73 g, 0.068 mol), and methyl iodide (14.5 g, 0.1 mol)
in ethanol (100 ml) was stirred at 40.degree. C. overnight. The
mixture was filtered and the filtrate was evaporated. The residue
was dissolved in dichloromethane (100 ml), and the solution was
washed three with water (100 ml). The organic phase wan dried over
magnesium sulphate and evaporated yielding 3.21 g (0.020 mol 30%)
of 12 with M.P. 108.degree.-110.degree. C. According to the .sup.1
H NMR spectrum the product contained less than 10% of the
1-isomer.
EXAMPLE 10
2-Methyl-(3-piperidyl)-2H-tetrazole, hydrochloride (13)
To a solution of 12 (1.93 g, 0.012 mol) in acetone (50 ml) was
added hydrogen chloride in ether until acidic reaction. The
precipitate was filtered off, dried, and dissolved in methanol (25
ml). 5% palladium on charcoal (0.6 g) was added, and the mixture
was shaked overnight under 3 atm. of hydrogen pressure. The
catalyst was filtered off and the filtrate was evaporated to
dryness. Crystallization from ethanol yielded 0.63 g (0.0031 mol,
26%) of title product M.P. 168.degree.-172.degree. C. Anal.
(C.sub.7 H.sub.14 ClN.sub.5) C, H, N.
EXAMPLE 11
2-Methyl-5-methyl-3-piperidyl)-2H-tetrazole, oxalate (14)
The title compound was prepared from 13 (2.0 g, 0.0098 mol) as
described in Example 8. Yield: 0.72 g (0.0026 mol, 27%), M.P.
113.degree.-115.degree. C. Anal. (C.sub.10 H.sub.17 N.sub.5
O.sub.4) C, H. N.
EXAMPLE 12
5-(1-Methyl-3-pyridylium)-tetrazole iodide (15)
A solution of 11 (47.0 g, 0.32 mol) in N,N-dimethylformamide (250
ml) was treated with methyl iodide (90 g, 0.63 mol) at 40.degree.
C. for 2 hours. The reaction mixture was then evaporated at
60.degree. C./1 torr, until the residue formed a thick oil. The
product was crystallized from ethanol (100 ml) to yield 15 (75.3 g,
0.26 mol, 82%), M.P. 150.degree.-155.degree. C.
EXAMPLE 13
2-Isopropyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
fumarate (16)
A solution of 15 (7.6 g, 0.026 mol), sodium hydroxide (1.1 g, 0.028
mol), isopropyl iodide (6 g. 0.035 mol) and water (10 ml) in
N,N-dimethylformamide (100 ml) was stirred overnight at 70.degree.
C. The mixture was filtered and the filtrate was evaporated to
dryness at 60.degree. C./1 torr. The residue was dissolved in
ethanol (100 ml), and to the mixture was added sodium borohydride
(5 g, 0.13 mol) in portions at less than 10.degree. C. After the
addition the mixture was stirred one hour at 10.degree. C. and then
one hour at room temperature. The clear solution was evaporated to
dryness water (50 ml) was added, and the mixture was extracted
three times with ether (100 ml). The combined organic phases were
washed once with water (50 ml) and were then extracted three times
with 4N hydrochloric acid (50 ml). The combined acidic aqueous
phases were washed twice with ether (50 ml) and were then made
basic with sodium hydroxide solution. The basic aqueous phase was
then extracted three is with ether (100 ml), and the combined
organic phases were washed with saturated sodium chloride solution
until neutral reaction. The etheral phase was dried over magnesium
sulphate/activated carbon and was evaporated yielding 1.0 g of an
oil, which was applied to a column of silica gel which was eluted
with ethyl acetate-heptane-triethylamine (45:45:10). Yield: 0.50 g
of oily product, which was converted to the title fumarate. Yield;
0.67 g (0.0046 mol, 18%), M.P. 108.degree.-110.degree. C. Anal.
(C.sub.4 H.sub.21 N.sub.5 O.sub.4), C, H, N.
EXAMPLE 14
2-Isopropyl-5-(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
hydrobromide (17)
Compound 5 (2 g, 0.0090 mol) was treated with isopropyl iodide
instead of methyl iodide as described in Example 5. The product was
transformed into the title compound as described in Example 6.
Yield: 0.82 g (0.0030 mol, 33%). M.P. 158.degree.-160.degree. C.
Anal. (C.sub.6 H.sub.16 BrN.sub.5) C, H, N.
EXAMPLE 15
2-Ethyl-5-(1carboxyethyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole
(18)
The title compound was prepared by treating 5 (5.97 g, 0.027 mol)
with ethyl iodide instead of methyl iodide as described in Example
5. Yield: 4.14 g (0.0164 mol, 61%) as an oil.
EXAMPLE 16
2-Ethyl-5-(1,2,5,6-tetraydro-3-pyridyl)-2H-tetrazole, hydrobromide
(19)
The title compound was prepared from 18 (1.5 g, 0.0060 mol) as
described in Example 6. Yield: 0.91 g (0.0035 mol, 58%), M.P.
160.degree.-162.degree. C.). Anal. (C.sub.8 H.sub.14 BrN.sub.5) C,
H, N.
EXAMPLE 17
2-Ethyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
oxalate (20)
To a cooled solution of anhydrous aluminium chloride (3.85 g) and
lithium aluminium hydride (0.96 g) in ether (50 ml) was dropwise
added a solution of 18 (2.55 g, 0.010 mol) in tetrahydrofurane (20
ml) at less than 10.degree. C. After the addition was completed the
mixture was stirred for 2 hours at room temperature. The reaction
was quenched in the cold with water and aqueous sodium hydroxide
followed by filtration. The filtrate was washed twice with
saturated sodium chloride solution. The organic phase was dried
over magnesium sulphate and evaporated in vacuo to yield an oil,
which was transformed into the crystalline oxalate. Yield: 1.3 g
(0.0046 mol, 46%), M.P. 170.degree.-172.degree. C. Anal. (C.sub.11
H.sub.17 N.sub.5 O.sub.4) C, H, N.
EXAMPLE 18
5-(1-t-Butyloxycarbonyl-1,2,5,6-tetrahydro-3-pyridyl)-1H-tetrazole
(21)
A solution of 5 (2.07 g, 0.0093 mol) in 30% hydrogen bromide in
acetic acid (20 ml) was left at room temperature for 3 days. The
solution was evaporated in vacuo, and the residue was dissolved in
water (20 ml). Potassium carbonate (13 g) and a solution of
pyrocarbonic acid di-tert-butylester (3.4 g) in tetrahydrofurane
(20 ml) was added, and the mixture was stirred overnight at room
.[.temprature.]. .Iadd.temperature.Iaddend.. The .[.mixing.].
.Iadd.mixture .Iaddend.was evaporated in vacuo to half the original
volume, and the reside was washed once with ethyl acetate. The
aqueous phase was acidified to pH=3 with hydrochloric acid and was
extracted 3 times with ethyl acetate. The combined organic phases
were washed twice with saturated sodium chloride solution and dried
over magnesium sulphate. Removal of solvent in vacuo yielded 1.33 g
(0.0053 mol, 57%) of title compound as an oil.
EXAMPLE 19
2-(2-Propynyl)-5-(1,2,5,6-tetrahydropyridyl)-2H-tetrazole,
hydrochloride (22)
To a solution of 21 (1.33 g, 0.0053 mol) in acetone (50 ml) was
added triethylamine (1 ml) and propargyl bromide (2 ml). The
mixture was heated to reflux for 4 hours and was then evaporated in
vacuo. The residue was dissolved in ether and the solution was
washed twice with saturated sodium chloride solution. The organic
phase was dried over magnesium sulphate and evaporated in vacuo to
yield an oil (1.19 g) which was eluted from silica gel with ethyl
acetate-heptane (2:3). The product (0.63 g) was dissolved in ether
(150 ml) saturated with hydrogen chloride. The mixture was stirred
for 2 hours and filtered. The crystalline product was washed with
ether and dried. Yield: 0.20 g (0.00088 mol, 17%), M.P.
173.degree.-175.degree. C. Anal. (C.sub.9 H.sub.12 ClN.sub.5), C,
H, N.
EXAMPLE 20
2-Allenyl-5-(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
hydrochloride (23)
The title compound was prepared from 21 (2.7 g, 0.011 mol) as
described in Example 19 using sodium hydroxide instead of
triethylamine. Yield: 0.28 g (0.0012 mol, 11%), M.P.
166.degree.-170.degree. C. (dec.). Anal. (C.sub.9 H.sub.12
ClN.sub.5), C, H, N.
EXAMPLE 21
5-(1-.[.Carboxyethyl.].
.Iadd.ethoxycarbonyl.Iaddend.-3-piperidyl)-1H-tetrazole (24)
To a solution of 5 (14.9 g, 0.078 mol) in ethyl acetate (160 ml)
acetic acid (25 ml) and 5% palladium on charcoal (1.25 g) were
added. The mixture was shaken for 24 hours with 3.5 atm. of
hydrogen pressure. The mixture was filtered and evaporated to yield
the title compound as an oil (12.07 g, 80%).
EXAMPLE 22
5-(1-t-Butyloxycarbonyl-3-piperidyl)-1H-tetrazole (25)
The title compound was prepared from 24 (6.6 g, 0.0341 mol) as
described in Example 18. Yield: 6.9 g (0.027 mol, 79%) as an
oil.
EXAMPLE 23
2-(2-Propynyl)-5-(3-piperidyl)2H-tetrazole, hydrochloride (26)
The title compound was prepared from 25 (6.9 g, 0.027 mol) as
described in Example 19. Yield: 0.92 g (0.004 mol, 15%), M.P.
162.degree.-164.degree. C. Anal. (C.sub.9 H.sub.14 ClN.sub.5), C,
H, N.
EXAMPLE 24
5-(1-.[.Carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-6-methyl-1,2,5,6-tetrahydro-3-pyridyl)-tetr
azole (28)
The title compound was prepared from 3-cyano-6-methylpyridine (27)
(Plattner et al., Helv.Chem.Acta, 37 (1954) 1379-86) as described
in Examples 1-5, using methyl chloroformate instead of ethyl
chloroformate in Example 3. Overall yield 10%. M.P.
136.degree.-138.degree. C.
EXAMPLE 25
2-Methyl-5-(1-.[.carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-6-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-t
etrazole (29)
The title compound was prepared from 28 (5 g, 0.023 mol) as
described in Example 5. Yield: 3.8 g (0.016 mol, 70%) as an
oil.
EXAMPLE 26
2-Methyl-5-(6-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
hydrobromide (30)
The title compound was prepared from 29 (1.6 g, 0.0068 mol) as
described in Example 6. Yield: 1.24 g (0.0048 mol, 70%), M.P.
193.degree.-196.degree. C. Anal. (C.sub.8 H.sub.14 BrN.sub.5), C,
H, N.
EXAMPLE 27
2-Methyl-5-(1,6-dimethyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole
(31)
The title compound was prepared from 29 (2.0 g, 0.0084 mol) as
described in Example 17. Yield: 0.93 g (0.0048 mol, 57%), M.P.
93.degree.-95.degree. C. Anal. (C.sub.9 H.sub.15 N.sub.5), C, H,
N.
EXAMPLE 28
2-Isopropyl-5-(1-.[.carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-6-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-t
etrazole (32)
The title compound was prepared from 28 (5 g, 0.022 mol) as
described in Example 5, using isopropyl iodide instead of methyl
iodide. Yield: 3.23 g (0.012 mol, 55%) as an oil.
EXAMPLE 29
2-Isopropyl-5-(6-methyl-1,2,5,6-tetraydro-3-pyridyl)-2H-tetrazole,
hydrobromide (33)
The title compound was prepared from 32 (1.62 g, 0.0061 mol) as
described in Example 6. Yield: 0.83 g (0.0043 mol, 71%), M.P.
183.degree.-185.degree. C. Anal. (C.sub.10 H.sub.18 BrN.sub.5), C,
H, N.
EXAMPLE 30
2-Isopropyl-5-(1,6-dimethyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole
(34)
The title compound was prepared from 32 (1.57 g, 0.0059 mol) as
described in Example 17. The crude product was purified by
chromatography on silica gel using ethyl
acetate-heptane-triethylamine (45:45:10) as eluent. Yield: 0.68 g
(0.0032 mol, 55%) as an oil. Anal. (C.sub.11 H.sub.19 N.sub.5), C,
H. N.
EXAMPLE 31
5-(1-t-Butyloxycarbonyl-6-methyl-1,2,5,6-tetrahydro-3-pyridyl)-tetrazole
(35)
The title compound was prepared from 28 (2.9 g, 0.012 mol) as
described in Example 18. Yield: 1.6 g (0.0060 mol, 50%) as an
oil.
EXAMPLE 32
2-(2-Propynyl-5-(6-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
hydrochloride (36)
The title compound was prepared from 35 (1.5 g, 0.0057 mol) as
described in Example 19. Yield: 0.7 g (0.0030 mol, 51%), M.P.
174.degree.-176.degree. C. Anal. (C.sub.10 H.sub.13 ClN.sub.5), C,
H, N.
EXAMPLE 33
2-Methyl-5(1,4-dimethyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
oxalate (38)
To a solution of 5-(4-methyl-3-pyridyl)-tetrazole (37, Crow et al.,
Aust. J. Chem., 28 (1975) 1741-54) (3.74 g, 0.023 mol) in acetone
(44 ml) and water (11 ml), sodium hydroxide (1.1 g) and methyl
iodide (3 ml) were added. The mixture was refluxed overnight and
evaporated in vacuo. The residue was dissolved in water and the
solution washed with dichloromethane. The aqueous solution was
evaporated in vacuo, and the residue was dissolved in methanol (40
ml) and water (7.5 ml). Sodium is borohydride (1.08 g) was added in
portions at less than 20.degree. C. After stirring for 1.5 hours at
room temperature the mixture was evaporated in vacuo, and the
residue was dissolved in dichloromethane. The solution was washed 3
times with saturated sodium chloride solution, dried over magnesium
sulphate and evaporated in vacuo to yield an oil, which was eluted
from silica gel with ethyl acetate-heptane (3:2). Yield: 1.5 g as
an oil, which was crystallized as the oxalate. Yield: 0.9 g (0.003
mol, 13%), M.P. 153.degree.-155.degree. C. Anal. (C.sub.11 H.sub.19
N.sub.5 O.sub.4), C, H, N.
EXAMPLE 34
2-Methyl-5-(4-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
0.75 oxalate (39)
Compound 38 (6.3 g, 0.033 mol) was treated with ethyl chloroformate
as described in Example 3. The product was transformed into the
title compound as described in Example 6. The resulting
hydrobromide was transformed to the base which was crystallized as
the oxalate. Yield: 0.30 g (0.0013 mol, 5%), M.P.
212.degree.-214.degree. C. Anal. (C.sub.9.5 H.sub.14.5 N.sub.5
O.sub.3), C, H, N.
EXAMPLE 35
N-(2-Cyanoethyl)-2-methyl-3-aminopropionitrile (41)
A solution of 2-methyl-3-aminopropionitrile (40) (Eastman Kodak
Co., U.S. Pat. No. 2,659,739 (1950)) (197 g, 2.35 mol) and
acrylonitrile (170 ml) in ethanol (250 ml) was refluxed overnight
and then evaporated in vacuo to yield 41 (316 g, 98%) as a light
oil.
EXAMPLE 36
Methyl
3-cyano-4-oxo-5-methylpiperidine-1-carboxylate (42)
To a well stirred solution of potassium tert.-butylate (270 g) in
toluen (1.5 l) was slowly added 41 (316 g, 2.3 mol), and the
mixture was stirred at reflux temperature for 1.5 hour. The mixture
was cooled to room temperature and filtered. The wet filtercake was
dissolved in 6N hydrochloric acid (2.5 l) and refluxed for 20
minutes. The mixture was cooled on an ice bath and neutralized with
sodium hydroxide (pH=7, T less than 30.degree. C.). More sodium
hydroxide was added with cooling (185 g), and then methyl
chloroformate (170 ml) was added at 10.degree. C. After the
addition the mixture was stirred for 1 hour at room temperature.
The mixture was washed 2 times with ethyl acetate. The aqueous
phase was acidified to pH=3 with concentrated hydrochloric acid and
extracted 3 times with ethyl acetate. The combined extracts were
washed twice with saturated sodium chloride solution, dried over
magnesium sulphate and evaporated in vacuo to yield 42 (295 g, 63%)
as an oil. Crystallization from ether gave .[.11.]. .Iadd.42
.Iaddend.with M.P. 65.degree.-68.degree. C.
EXAMPLE 37
1-.[.Carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-4-chloro-3-cyano-5-methyl-1,2,5,6-tetrahydr
opyridine (43)
To a solution of 42 (40 g, 0.192 mol) in toluene (250 ml) was added
tetrachloromethane (115 ml) and triphenyl phosphine (32 g), and the
mixture was refluxed for 24 hours. More triphenyl pbosphine (32 g)
was added, and reflux was continued for 48 hours, The mixture was
cooled, filtered and evaporated in vacuo. Ethyl acetate was added,
and the solution was left overnight at 5.degree. C. Filtration and
evaporation gave a heavy oil, which was applied to a column of
silica gel. Elution with ethyl acetate-heptane (3:1) yielded 24 g
(0.105 mol, 55%) of title compound as an oil.
EXAMPLE 38
1-.[.Carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-3-cyano-5-methyl-1,2,5,6-tetrahydropyridine
(44)
To a solution of 43 (24 g, 0.105 mol) in toluene (400 ml) was added
azobisisobutyronitrile (6 g) and tri-n-butyltin hydride (90 g). The
mixture was refluxed overnight and then evaporated in vacuo.
Elution from a column of silica gel with ethyl acetate-heptane
(1:2) gave the title compound as an oil. Yield: 10.4 g (0.0538 mol,
51%).
EXAMPLE 39
5-(1-.[.Carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-5-methyl-1,2,5,6-tetrahydro-3-pyridyl)-tetr
azole (45)
The title compound was prepared from 44 (10.4 g, 0.054 mol) as
described in Example 4, Yield: 5.2 g (0.022 mol, 41%), M.P.
150.degree.-152.degree. C.
EXAMPLE 40
2-Methyl-5-(1-.[.carboxymethyl.].
.Iadd.methoxycarbonyl.Iaddend.-5-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-t
etrazole (46)
The title compound was prepared from 45 (2.5 g, 0.011 mol) as
descried in Example 5. Yield: 1.5 g (0.006 mol, 55%) as an oil.
EXAMPLE 41
2-Methyl-5-(5-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
hydrobromide (47)
The title compound was prepared from 46 (0.60 g, 0.0024 mol) as
described in Example 6. Yield: 0.30 g (0.0011 mol, 48%), M.P.
157.degree.-159.degree. C. Anal. (C.sub.8 H.sub.14 BrN.sub.5), C,
H, N.
EXAMPLE 42
2-Methyl-5-(1,5-dimethyl-1,2,5,6-tetrahydro-3-pyridyl)-2H
tetrazole, oxalate (48)
The title compound was prepared from 46 (0.9 g, 0.0036 mol) as
described in Example 17. Yield of crystalline oxalate: 0.24 g
(0.00085 mol, 24%). M.P. 136.degree.-139.degree. C. Anal. (C.sub.11
H.sub.17 N.sub.5 O.sub.4), C, H, N.
EXAMPLE 43
5-(1-t-Butoxycarbonyl-5-methyl-1,2,5,6-tetrahydro-3-pyridyl)-1H-tetrazole
(49)
The title compound was prepared from 45 (2,7 g, 0.011 mol) as
described in Example 18. Yield: 2.64 g (0.0099 mol, 90%) as an
oil.
EXAMPLE 44
2-(2-Propynyl)-5-(5-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole
hydrochloride (50)
The title compound was prepared from 49 (2.64 g, 0.0099 mol) as
described in Example 19. Yield: 0.25 g (0.001 mol, 11%), M.P.
151.degree.-152.degree. C. Anal. (C.sub.10 H.sub.14 ClN.sub.5), C,
H, N.
EXAMPLE 45
3-Methyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-isoxazole (52)
and 5-Methyl-3-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-isoxazole
(53)
3-(1,3-Butadione)-pyridine (51, Mors et al., J. Am. Chem. Soc., 79
(1957) 4507-10) (7.3 g, 0.045 mol) was treated with methyl iodide
as described in Example 1. The product was dissolved in ethanol
(100 ml) and hydroxylammonium chloride (3 g) was added. The mixture
was refluxed for 3 hours and was then cooled and sodium borohydride
(7 g) was added in portions at less than 10.degree. C. After
stirring at room temperature overnight, the mixture was evaporated
in vacuo. The residue was dissolved in dichloromethane, and the
solution was washed twice with saturated sodium chloride solution.
Drying over magnesium sulphate and evaporation in vacuo gave 6.1 g
(0.034 mol, 76%) of a 1:1 mixture of 52 and 53.
EXAMPLE 46
3-Methyl-5(1,2,5,6-tetrahydro-3-pyridyl)-isoxazole, maleate (54)
and 5-Methyl-3-(1,2,5,6-tetrahydro-3-pyridyl)-isoxazole,
hydrochloride (55)
The crude mixture of 52 and 53 (6.1 g, 0.034 mol) was treated with
ethyl chloroformate as described in Example 3, and the product
mixture (4.7 g) was treated as described in Example 6. The mixture
of hydrobromides was transformed into a mixture of bases (3.53 g)
in the usual manner. Maleates of this mixture were crystallized
form ethanol. The first crop contained pure 54 (0.73 g, 0.0026
mol), M.P. 139.degree.-142.degree. C. Anal. (C.sub.13 H.sub.16
N.sub.2 H.sub.2 O.sub.5), C, H, N. The remaining product was
transformed to the bases, and 55 was crystalline as the
hydrochloride which was recrystallized twice from ethanol to give
55 still containing about 25% of 54. Yield: 0.2 g (0.001 mol), M.P.
149.degree.-152.degree. C. Anal. (C.sub.9 H.sub.13 ClN.sub.2 O) C,
H, N.
EXAMPLE 47
Methyl nicotino-amidrazone (56)
A solution of 6.0 g (0.040 mol) of ethyl nicotinoimidate in 50 ml
of dry ether was treated dropwise with a solution of 2.0 g (0.045
mol) of methyl hydrazine in 20 ml of dry ether at room temperature.
After stirring for 1 h the solvent was removed in vacuo yielding
6.0 g (0.040 mol, 100%) of crude 56 as a yellow oil which was
sufficiently pure.
EXAMPLE 48
1-Methyl-3-(3-pyridyl)-1,2,4-triazole (57)
To 6.0 g (0.040 mol) of 56, 9 ml (0.240 mol) of neat formic acid
was slowly added at 5.degree. C. The mixture was stirred for 1/2 at
room temperature followed by reflux for 1 hour. After cooling the
mixture was poured into aqueous K.sub.2 CO.sub.3. Extraction with
3.times.100 ml of dichloromethane, drying of the organic phase over
magnesium sulphate and evaporation in vacuo gave a yellow oil.
Separation by chromatography (silica gel; eluent:
methanol/ether=1/9) gave a colorless oil, 57.
Yield. 3.6 g (0.023 mol, 57%).
EXAMPLE 49
1-Methyl-3(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-1,2,4-triazole,
hemifumarate (59)
A suspension of 6.3 g (0.020 mol) of the methiodide of 57 (prepared
from 57 by the procedure described in Example 1) in 75 ml of
methanol was cooled to -10.degree. C., and 1.0 g (0.026 mol) of
sodium borohydride was added. When the gas evolution had ceased,
the mixture was stirred for 3 h at room temperature. Evaporation in
vacuo give a red oil which was dissolved in 100 ml of a saturated
sodium chloride solution. Extraction with 4.times.100 ml of
dichloromethane, drying of the organic phase over magnesium
sulfate, and evaporation in vacuo gave a red oil. The oil was
dissolved in 50 ml of ether and stirred with charcoal. Filtration
and evaporation gave the base of 59 as a colorless oil, 58. Yield:
1.6 g (0.009 mol, 45%). A 0.5 g portion of 58 was converted to the
title compound. M.P. 181.degree.-183.degree. C. Anal. (C.sub.11
H.sub.16 N.sub.4 O.sub.2) C, H, N.
EXAMPLE 50
1-Methyl-3-(1,2,5,6-tetrahydro-3-pyridyl-1,2,4-triazole,
dihydrobromide (60)
The title compound was prepared form 58 (1.0 g, 0.0056 mol) by the
procedure described in Examples 3 and 6. Yield: 0.21 g (0.0006 mol,
12%). M.P. 237.degree.-239.degree. C. Anal. (C.sub.8 H.sub.14
Br.sub.2 N.sub.4) C, H, N.
EXAMPLE 51
1,5-Dimethyl-3-(3-pyridyl)-1,2,4-triazole (61)
To 12.0 g (0.080 mol) of 56, 9 ml (0.100 mol) of neat acetic acid
anhydride was slowly added at 5.degree. C. under stirring. The
mixture was stirred for 1/2 h at room temperature followed by
reflux for 1 h. After cooling the mixture was poured into aqueous
potassium carbonate. Extraction with 3.times.100 ml of
dichloromethane, drying of the organic phase over magnesium
sulphate, and evaporation in vacuo gave a yellow oil which was
applied to a silica gel column (eluent: methanol/ether=1/9)
yielding a colorless solid, 61 (8.0 g, 0.046 mol, 57%).
EXAMPLE 52
1,5-Dimethyl-3-(1-methyl-1,2,5,6-tetraydro-3-pyridyl)-1,2,4-triazole,
fumarate (63)
The title compound was prepared from 61 (8.0 g, 0.046 mol) by the
procedure described in Example 49. Yield of free base, 62: 3.9 g
(0.016 mol, 35%). A 0.8 g portion of 62 was converted to the title
compound. Yield: 1.0 g (0.003 mol, 75%). M.P.
171.degree.-173.degree. C. Anal. (C.sub.14 H.sub.20 N.sub.4
O.sub.4) C, H, N.
EXAMPLE 53
1,5Dimethyl-3-(1,2,5,6-tetrahydro-3-pyridyl)-1,2,4-triazole,
dihydrobromide, dihydrate (64)
The title compound was prepared from 62 (2.8 g, 0.015 mol) by the
procedures described in Examples 3 and 6. Recrystallization from
methanol/ether gave 0.65 g (0.0017 mol, 12%) of 64. M.P.
254.degree.-255.degree. C. Anal. (C.sub.9 H.sub.20 Br.sub.2 N.sub.4
O.sub.2) C, H, N.
EXAMPLE 54
3-Mercapto-5(3-pyridyl)-1,2,4-triazole (65)
To a solution of 19 g (0.200 mol) of thiosemicarbazide in 175 ml of
dry pyridine, 29 g (0.200 mol) of nicotinoyl chloride was slowly
added at 10.degree. C. After reflux for 40 min. the reaction
mixture was concentrated to half the original volume, 500 ml of
water was added, and stored in the cold overnight The precipitate
formed was removed by filtration, and the filtrate was evaporated
in vacuo. The resulting heavy, yellow oil was dissolved in 300 ml
of water, and 64 g (0.600 mol) of sodium carbonate in 400 ml of
water was added. After reflux for 4 h the solution was cooled and
acidified with conc. hydrochloric acid to pH=4. The formed,
colorless precipitate, 65, was isolated by filtration and dried in
vacuo. Yield: 35 g (0.297 mol, 98%).
EXAMPLE 55
3-Methylthio-5-(3-pyridyl)-1,2,4-triazole (66)
A solution of 20 g (0.100 mol) of 65 and 7.5 g (0.150 mol) of
potassium hydroxide in 100 ml of water was mixed with a solution of
10 ml (0.160 mol) of methyl iodide in 100 ml of ether. After
addition of 1 g of tetrabutylammonium hydrogen sulphate the mixture
was stirred overnight at room temperature. The ether phase was
separated and the aqueous phase extracted with 3.times.100 ml of
ether. The combined organic phases were dried over magnesium
sulphate. Removal of the solvent in vacuo gave a colorless solid,
66. Yield: 17.0 g (0.089 mol, 89%).
EXAMPLE 56
3-Methylthio-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-1,2,4-triazole,
fumarate (67)
The title compound was prepared from 66 (9.6 g, 0.050 mol) by the
procedure described in Example 49. The crude product obtained was
purified by chromatography (silica gel; eluent:
triethylamine/methanol=1/99) giving 0.4 g (0.0019 mol. 4%) of the
free base, which was converted to the title fumarate, 67. Yield:
0.37 g (0.0011 mol, 58%). M.P. 189.degree.-191.degree. C. Anal.
(C.sub.13 H.sub.18 N.sub.4 O.sub.4) C, H, N.
EXAMPLE 57
4-(3-Pyridyl)-1,2,3-triazole (68)
In a glass-coated bomb tube 6.5 g (0.063 mol) of 3-pyridyl
acetylene (T. Sakamoto et al., Synthesis (1983) 312) and 8.7 g
(0.075 mol) of trimethylsilyl azide were mixed and heated to
150.degree. C. for 20 h. After cooling the mixture was poured into
water. A colorless solid, 68, formed, which was isolated by
filtration and dried. Yield: 4.0 g (0.028 mol, 44%).
EXAMPLE 58
2-Methyl-4-(3-pyridyl)-1,2,3,-triazole (69)
A solution of ca. 3.0 g (0.070 mol) diazomethane in ether was added
dropwise to a solution of 6.0 g (0.04 mol) of 68 in 150 ml of
ethanol at room temperature. The solution was stirred overnight at
ambient temperature. Ca. 1 ml of acetic acid was added and the
mixture was evaporated in vacuo. Water (75 ml) was added and the
solution made basic with ammonia. Extraction with 3.times.100 ml of
ether, drying of the organic phase over magnesium sulphate, and
removal of the solvent in vacuo gave a brown solid which as applied
to a silica gel column (eluent: ethyl acetate) giving a colorless
solid, 69. Yield: 2.8 g (0.018 mol, 43%).
EXAMPLE 59
2-Methyl-4-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-1,2,3-triazole,
1.5 fumarate (70)
The title compound was prepared from 69 (4.0 g, 0.014 mol) by the
procedure described in Example 49. Yield of free base, 71: 2.5 g
(0.014 mol, 100%). A 0.6 g portion (0.0034 mol) of 71 was converted
to the title fumarate, 70. Yield: 0.18 g (0.0005 mol, 15%). M.P.
144.degree.-145.degree. C. Anal. (C.sub.15 H.sub.20 N.sub.4
O.sub.6)C, H, N.
EXAMPLE 60
2-Methyl-4-(1,2,5,6-tetrahydro-3-pyridyl)-1,2,3-triazole, fumarate
(72)
By the procedure described in Example 3, 1.9 g (0.011 mol) of 71
was converted to the corresponding ethyl carboxylate (yield: 1.5 g,
0.0064 mol, 58% of a colorless oil) which was dissolved in 25 ml of
methanol. After addition of 1 g (0.025 mol) of sodium hydroxide and
1 ml (0.056 mol) of water, the mixture was refluxed for 24 h. After
evaporation in vacuo, 20 ml of saturated sodium chloride solution
was added followed by extraction with 4.times.20 ml of
dichloromethane. Drying of the organic phase over magnesium
sulphate and removal of the solvent in vacuo gave crude free base
of 72 as a yellow oil, which was converted to the title fumarate,
72. Yield: 0.5 g (0.0018 mol, 28%). M.P. 126.degree.-127 C. Anal.
(C.sub.12 H.sub.16 N.sub.4 O.sub.4)C, H, N.
EXAMPLE 61
N-Acetylmethyl-nicotinamide (73)
To a suspension of 40 g (0.370 mol) of aminoacetone in 500 ml of
dry dichloromethane, 50 g (0.350 mol) of nicotinoyl chloride was
added dropwise at room temperature under a nitrogen atmosphere. The
mixture was refluxed 5 h followed by stirring overnight at room
temperature. The colorless precipitate was collected by filtration
and dissolved in 400 ml of water. After basification with ammonia
the aqueous solution was extracted with 3.times.400 ml of
dichloromethane. The combined organic phases were treated with
charcoal and dried over magnesium sulphate. Removal of the solvent
in vacuo gave a colorless solid, 73. Yield: 30.0 g (0.170 mol,
48%).
EXAMPLE 62
5-Methyl-2-(3-pyridyl)-oxazole (74)
A mixture of 20 g (0.110 mol) of 73 and 100 ml of conc. sulphuric
acid was heated to 120.degree. C. for 4 h. After cooling the
mixture was poured over ice followed by basification with ammonia.
Extraction with 3.times.400 ml of dichloromethane, drying of the
combined organic phase over magnesium sulphate, and removal of the
solvent in vacuo gave crude 74 as a red oil, which was sufficiently
pure. Yield: 17 g (0.100 mol, 97%).
EXAMPLE 63
5-Methyl-2-(1-methyl-1,2,5,6-tetraydro-3-pyridyl)-oxazole, oxalate
(75)
The title compound was prepared from 74 (9.0 g, 0.056 mol) by the
procedure described in Example 49 giving 5.2 g (0.029 mol, 52%) of
the crude, free base of 75. A 1.5 portion of the base was converted
to the title oxalate, Yield: 1.6 g (0.006 mol, 75%). M.P
166.degree.-167.degree. C. Anal. (C.sub.12 H.sub.16 H.sub.2
O.sub.5)C, H, N.
EXAMPLE 64
5-Methyl-2-(1,2,5,6-tetrahydro-3-pyridyl)-oxazole, fumarate
(76)
The title compound was prepared from the free base of 75 (3.6 g,
0.020 mol) by the procedure described in Example 60 with the
.[.extension.]. .Iadd.exception .Iaddend.that the intermediate
ethyl carboxylate was purified on a silica gel column (eluent:
ether). The crude free base obtained was converted to the title
fumarate, 76. Yield: 1.3 g (0.0046 mol, 23%). M.P.
139.degree.-141.degree. C. Anal. (C.sub.13 H.sub.16 H.sub.2
O.sub.5)C, H, N.
EXAMPLE 65
N-Methoxycarbonylmethyl-nicotinamide (77)
A mixture of 50.0 g (0.400 mol) of nicotinic acid, 50.0 g (0.400
mol) of methyl glycinate hydrochloride, 90 g (0.440 mol) of
dicyclohexylcarbodiimide, and 2 g of p-toluenesulfonic acid in 500
ml of dry pyridine was stirred overnight at room temperature.
Filtration and evaporation in vacuo gave a heavy oil which was
dissolved in 500 ml of water. After basification with ammonia the
aqueous solution was extracted with 3.times.300 ml of
dichloromethane. The organic phase was dried over magnesium
sulphate, and removal of the solvent in vacuo gave crude 77 as a
heavy yellow oil. Yield: 63.0 g (0.320 mol, 81%).
EXAMPLE 66
5-Methoxy-2-(3-pyridyl)-oxazole (78)
A solution of 19.0 g (0.100 mol) of 77 in 300 ml of dry chloroform
was refluxed under vigorous stirring with 40 g of P.sub.2 O.sub.5
for 24 h. The mixture was filtered after cooling. The filtrate was
evaporated in vacuo leaving a red oil. The precipitate was
dissolved in water at 0.degree.-5.degree. C. and the aqueous
solution made basic with sodium carbonate. Extraction with
3.times.200 ml of dichloromethane, drying of the combined organic
phases over magnesium sulphate, and removal of the solvent in vacuo
gave a red oil which was combined with the above mentioned oil
obtained from the chloroform phase. The oil was applied to a silica
gel column (eluent; methanol/ether=1/19) giving a colorless oil,
78. Yield: 5.9 g (0.034 mol, 34%).
EXAMPLE 67
5-Methoxy-2-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-oxazol, oxalate
(80)
The title compound was prepared from 78 (5.3 g, 0.028 mol) by the
procedure described in Example 49. The crude free base 79, obtained
was purified on a silica gel column (eluent methanol/ether=1/9).
Yield of 79: 1.2 g (0.006 mol, 22%). A 0.5 g portion of 79 was
converted to the title oxalate, 80. Yield: 0.55 g (0.0019 mol,
74%). M.P. 113.degree.-115.degree. C. Anal. (C.sub.12 H.sub.16
N.sub.2 O.sub.6)C, H, N.
EXAMPLE 68
5-Methoxy-2-(1,2,5,6-tetrahydro-3-pyridyl)-oxazole, 1.25 fumarate
(81)
The title compound was prepared from 79 (5.2 g, 0.027 mol) by the
procedure described in Example 60. The obtained free base was
converted to the title fumarate, 81. Yield: 0.56 g (0.0031 mol,
11%). M.P. 159.degree.-160.degree. C. Anal. (C.sub.14 H.sub.17
N.sub.2 N.sub.7)C, H, N.
EXAMPLE 69
4-Methyl-2-(3-pyridyl)-oxazole (82)
To 10 g (0.140 mol) of acetone oxime cooled to -10.degree. C. neat
nicotinoyl chloride (40 g, 0.280 mol) was added dropwise under a
nitrogen atmosphere. A violent reaction occured and the mixture
became quickly solid. The solid was heated to 120.degree. C. for 3
h. After cooling the mixture was dissolved in ice water and
ammonia. After addition of 300 ml of ether the mixture was treated
with charcoal, filtered, and the ether phase separated. The aqueous
phase was extracted with 2.times.200 ml of ether, and the combined
organic phase dried over magnesium sulphate. Removal of solvent in
vacuo gave crude 82 as a red oil. Yield: 3.9 g (0.024 mol,
17%).
EXAMPLE 70
4-Methyl-2-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-oxazole, oxalate
(84)
The title compound was prepared from 82 (5.6 g, 0.035 mol) by the
procedure described in Example 49. The free base, 83, was obtained
as a red oil. Yield: 2.8 g (0.016 mol, 46%). A 0.8 g portion of 83
was converted to the title oxalate. Yield: 0.7 g (0.0026 mol, 58%).
M.P. 197.degree.-199.degree. C. Anal. (C.sub.12 H.sub.16 N.sub.2
O.sub.5)C, H, N.
EXAMPLE 71
4-Methyl-2-(1,2,5,6-tetrahydro-3-pyridyl)-oxazole, fumarate
(85)
The title compound was prepared from 83 (2.0 g, 0.011 mol) by the
procedure described in Example 60. The free base obtained was
converted to the title fumarate, 85. Yield: 0.4 g (0.0015 mol,
14%). M.P. 179.degree.-181.degree. C. Anal. (C.sub.13 H.sub.16
N.sub.2 O.sub.5)C, H, N.
EXAMPLE 72
4,4-Dimethyl-2-(3-pyridyl)-oxazoline (86)
A solution of 69 g (0.500 mol) of methyl nicotinoate and 45 g
(0.500 mol) of 2-amino-2,2,dimethyl-ethanol in 600 ml of toluene
was refluxed with a water separator overnight. The solvent was
removed in vacuo, 300 ml of water added, and the aqueous solution
extracted with 3.times.300 ml of dichloromethane. Drying of the
organic phase over magnesium sulphate and evaporation in vacuo gave
a red oil which was filtered through silica gel (eluent:
methanol/ether=1/19). Removal of solvents in vacuo gave a yellow
oil, 86. Yield: 30.0 g (0.170 mol, 34%).
EXAMPLE 73
4,4-Dimethyl-2-1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-oxazoline,
fumarate (87)
The title compound was prepared from 86 (10.0 g, 0.051 mol) by the
procedure described in Example 49. The crude product obtained was
applied to a silica gel column (eluent:
triethylamine/methanol/ether=1/5/44) giving 4.4 g of the free base
which was converted to the title fumarate, 87. Yield: 5.4 g (0.017
mol, 30%). M.P. 156.degree.-158.degree. C. Anal. (C.sub.15 H.sub.22
N.sub.2 O.sub.5)C, H, N.
EXAMPLE 74
5-Methyl-2-(3-pyridyl)-thiazole (88)
To a solution of 8.0 g (0.045 mol) of 73 in 125 ml of toluene, 10 g
(0.045 mol) of P.sub.4 S.sub.10 was added. The suspension was
refluxed for 4 h and left at room temperature overnight. The
mixture was poured into ice water followed by basification with
ammonia. The two-phase system was stirred with charcoal and
filtered. The toluene phase was separated and the aqueous phase
extracted with 2.times.100 ml of toluene. The combined organic
phase were dried over MgSO.sub.4 and evaporated in vacuo leaving a
heavy, yellow oil, 88. Yield: 2.3 g (0.013 mol), 29%).
EXAMPLE 75
5-Methyl-2-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-thiazole,
hemifumarate (90)
The title compound was prepared from 88 (2.2 g, 0.013 mol) by the
procedure described in Example 49. The crude free base obtained,
89, was converted to the title fumarate, 90. Yield: 0.8 g (0.0032
mol, 25%). M.P. 159.degree.-160.degree. C. Anal. (C.sub.12 H.sub.16
N.sub.2 O.sub.2 S)C, H, N.
EXAMPLE 76
5-Methyl-2-(1,2,5,6-tetrahydro-3-pyridyl.[.)thiaole.]..Iadd.)-thiazole.Iadd
end., fumarate (91)
The title compound was prepared from 89 (1.8 g, 0.009 mol) by the
procedure described in Example 60. The free base obtained was
converted to the title fumarate, 91. Yield: 1.1 g (0.0037 mol.
41%). M.P. 206.degree.-209.degree. C. Anal. (C.sub.13 H.sub.16
N.sub.2 O.sub.4 S)C, H, N.
EXAMPLE 77
5-Methylthio-2-(3-pyridyl)-thiazole (92)
A solution of 8.2 g (0.042 mol) of 77 in 250 ml of toluene was
treated with 11.0 g (0.050 mol) of P.sub.4 S.sub.10 and refluxed
for 3 h. After cooling to 5.degree. C. 100 ml of conc. ammonia was
added dropwise followed by addition of 50 ml of water. The organic
phase was separated and the aqueous phase extracted with
2.times.100 ml of toluene. The combined organic phases were dried
over magnesium sulphate and evaporated in vacuo leaving a brown oil
which was applied to a silica gel column (eluent:
methanol/ether=1/19) yielding 0.5 g (0.0024 mol, 6%) of 92as a
yellow oil.
EXAMPLE 78
5-Methylthio-2-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-thiazole,
fumarate (93)
The title compound was prepared from 92 (0.5 g, 0.0024 mol) by the
procedure described in Example 49. The crude free base obtained was
converted to the title fumarate, 93. Yield: 0.18 g (0.0005 mol,
21%). M.P. 154.degree.-157.degree. C. Anal. (C.sub.14 H.sub.18
N.sub.2 O.sub.4 S.sub.2)C, H, N.
EXAMPLE 79
1,5-Dimethyl-3-(1-methyl-3-pyridinium)-pyrazole iodide (94)
To a solution of 7.0 g (0.044 mol) of
3-methyl-5-3-pyridyl)-pyrazole (V. J. Bauer et al., J. Med. Chem.
11 (1968) 981) in 90 ml of acetone and 20 ml of water was added 2.2
(0.055 mol) of sodium hydroxide and 11.7 ml (0.180 mol) of methyl
iodide at 0.degree. C. The mixture was for 21/2 h, cooled to room
temperature and filtered. The precipitate was washed with acetone
and dried, yielding 10.9 g (0.035 mol, 80%) of 94. M.P.
230.degree.-234.degree. C.
EXAMPLE 80
1,5-Dimethyl-3-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-pyrazole,
dihydrochloride (95)
The title compound was pared from 94 (10.8 g, 0.034 mol) by the
procedure described in Example 49. The crude free base obtained was
converted to the title hydrochloride, 95. Yield: 6.4 g (0.024 mol.
71%). M.P. 218.degree.-226.degree. C. Anal. (C.sub.11 H.sub.19
N.sub.3 Cl.sub.2)C, H, N.
The compounds of Formula I have been tested in reliable and
recognize pharmacological tests which may be described as
follows:
Affinity to central cholinergic receptors in vitro was measured as
the ability of the compounds to displace .sup.3 H-oxotremorine-M
(Oxo-M) from rat brain homogenates, while affinity to central
muscarinic M-1-receptors in vitro was measured as the ability of
the compounds to displace .sup.3 H-pirenzepin (Pz) from rat brain
homogenates.
.sup.3 H-oxotremorine M binding
was performed essentially as described by Birdsdall et al., 1980.
Briefly, rat brains were homogenized in 100 vol (w/v) 10 mM
Na,K-phosphate buffer (pH 7.4) and aliquots incubated with .sup.3
H-oxotremorine M (84.9 Ci/m-mol, NEN) alone or in the presence of
test compound in a total volume of 1.5 ml for 40 min. at 30.degree.
C. The reaction was stopped by adding 5 ml cold buffer and filtered
through Whatman GF/B filters soaked previously in 0.1%
polyethylenimin (Sigma) for minimum 30 min. The filters were washed
once with the same volume of buffer, transferred to scintillation
vials and extracted in scintillation fluid (Pico-fluor 15, Packard)
for at least two hours before counted in a liquid scintillation
spectrometer (Beckman LS 1800). Non-specific binding was estimated
at 10 .mu.M atropine and all estimations made in triplicate. At
least two displacement curves were made for each compound
tested.
Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V. (1980). "The
Character of Muscarinic Receptors in Different Regions of the Rat
Brain". Proc. Roy. Soc. London (Series B) 207, 1.
.sup.3 H-pirenzepine binding
was performed essentially as described by Watson et al., 1983, the
conditions being very much the same as for .sup.3 H-oxotremorine
binding, except that aliquots were incubated with 1.0 nM .sup.3
H-pirenzepine for 60 min. at 25.degree. C. and that the reaction
was stopped by direct filtration followed by 3 washes with 4 ml
buffer.
Watson, M., Yamamura, H. I., and Roeske, W. R. (1983). "A unique
regulatory profile and regional distribution of .sup.3 H-pirenzepin
binding in the rat provide evidence for distinct M1 and M2
muscarinic receptor subtypes". Life Sci. 32 (1983) 3001-3011.
______________________________________ RESULTS Compound Oxo-M,
IC.sub.50 (.mu.M) Pz, IC.sub.50 (.mu.M)
______________________________________ 8 0.0063 2.1 9 3.2 27.0 10
0.0087 0.39 13 0.047 3.6 14 1.7 7.4 16 0.12 0.13 17 0.28 0.48 19
0.032 1.5 20 0.016 0.13 22 0.014 0.38 23 0.14 1.1 26 0.044 0.40 30
0.25 1.4 31 0.31 0.14 33 0.32 0.90 34 0.18 0.35 36 0.39 0.25 38 1.0
1.2 39 0.81 1.5 47 0.098 0.28 48 0.68 1.8 50 0.062 0.068 54 0.23
4.0 55 1.0 2.5 59 0.28 0.61 60 1.4 4.9 63 0.71 0.16 64 2.1 2.4 67
1.5 2.0 70 0.0011 0.0055 72 0.00048 0.79 75 0.057 0.37 76 0.19 1.3
80 0.097 1.5 81 0.22 4.2 84 0.028 0.058 85 0.0075 1.4 87 0.13 0.40
90 0.18 0.42 91 0.36 1.0 93 0.018 0.13 95 0.35 0.18
______________________________________
The compounds of Formula I and the non-toxic acid addition salts
thereof may be administered to animals such as dogs, cats, horses,
sheeps or the like, including human beings, both orally and
parenterally, and may be used for example in the form of tablets,
capsules, powders, syrups or in the form of the usual sterile
solutions for injection..[.-Results upon administration to human
beings have been very gratifying..].
Most conveniently the compounds of Formula I are administered
orally in unit dosage form such as tablets or capsules, each dosage
unit containing the free amine or a non-toxic acid addition salt of
one of the said compounds in a amount of from about 0.10 to about
100 mg, most preferably, however, from about 5 to 50 mg, calculated
as the free amine, the total daily dosage usually ranging from
about 1.0 to about 500 mg. The exact individual dosages as well as
daily dosages in a particular case will, of course, be determined
according to established medical principles under the direction of
a physician.
When preparing tablets, the active ingredient is for the most part
mixed with ordinary tablet adjuvants such as corn starch, potato
starch, talcum, magnesium stearate, gelatine, lactose, gums, or the
like.
Typical examples of formulas for composition containing
2-methyl-5-(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole,
hydrobromide (Compound 8) as the active ingredient, are as
follows:
______________________________________ (1) Tablets containing 5
milligrams of Compound 8 .sup. calculated as the free base:
Compound 8 5 mg Lactose 18 mg Potato starch 27 mg Saccharose 58 mg
Sorbitol 3 mg Talcum 5 mg Gelatine 2 mg Povidone 1 mg Magnesium
stearate 0.5 mg (2) Tablets containing 50 milligrams of Compound 8
.sup. calculated as the free base: Compound 8 50 mg Lactose 16 mg
Potato starch 45 mg Saccharose 106 mg Sorbitol 6 mg Talcum 9 mg
Gelatine 4 mg Povidone 3 mg Magnesium stearate 0.6 mg (3) Syrup
containing per milliliter: Compound 8 10 mg Sorbitol 500 mg
Tragscanth 7 mg Glycerol 50 mg Methyl-paraben 1 mg Propyl-paraben
0.1 mg Ethanol 0.005 ml Water ad 1 ml (4) Solution for injection
containing per milliliter: Compound 8 50 mg Acetic acid 17.9 mg
Sterile water ad 1 ml (5) Solution for injection containing per
milliliter: Compound 8 10 mg Sorbitol 42.9 mg Acetic acid 0.63 mg
Sodium hydroxide 22 mg Sterile water ad 1 ml
______________________________________
Any other pharmaceutical tableting adjuvants may be used provided
that they are compatible with the active ingredient, and additional
compositions and dosage forms may be similar to those presently
used for neuroleptics, analgesics or antidepressants.
Also combinations of the compounds of Formula I as well as their
non-toxic acid salts with other active ingredients, especially
other neuroleptics, thymoleptics, tranquilizers, analgetics or the
like, fall within the scope of the present invention.
As previously stated, when isolating the compounds of Formula I in
the form of in said addition salt the acid is preferably selected
so as to contain an anion which is non-toxic and pharmacologically
acceptable, at least in usual therapeutic doses. Representative
salts which are included in this preferred group are the
hydrochlorides, hydrobromides, sulphate, acetates, phosphates,
nitrates, methanesulphonates, ethane-sulphonates, lactates,
citrates, tartrates or bitartrates, pamoates and maleates of the
amines of Formula I. Other acids are likewise suitable and may be
employed if desired. For example: fumaric, benzoic, ascorbic,
succinic, salicylic, bismethylenesalicylic, propionic, gluconic,
malic, malonic, mandelic, cannamic, citraconic, stearic, palmitic,
itaconic, glycolic, benzenesulphonic, and sulphamic acids may also
be employed as acid addition saltforming acids.
When it is desired to isolate a compound of the invention in the
form of the free base, this may be done according to conventional
procedure as by dissolving the isolated or unisolated salt in
water, treating with a suitable alkaline material, extracting the
liberated free base with a suitable organ solvent drying the
extract and evaporating to dryness or fractionally distilling to
effect isolation of the free basic amine.
* * * * *