[0001] The present invention relates to compounds showing GABA--related activity.
[0002] GABA (gamma-aminobutyric acid) is known to be a neurotransmitter in the central nervous
system (CNS) in mammals. GABA is found predominantly in the brain where it is a dominant
inhibitory transmitter (Curtis, D.R. and Johnston, G.A.R., Ergebn. Physiol., 1974,
69, 97 - 188).
[0003] It has been reported (Arzneimittelforschung, 1968, 18, 311 - 315) that muscimol of
the formula

(a substance found in fly amanita (Amanita muscaria)) has various interesting pharmacological
properties and especially shows an inhibition of motoric functions. Later, it was
reported that muscimol is a very potent GABA agonist with respect to bicuculline-sensitive
postsynaptic receptors (Johnston et al., Biochem. Pharmacol., 1968, 17, 2488, and
Curtis et al., Brain Res., 1971, 32, 69 - 96), but it also shows activity as an inhibitor
of the high affinity uptake of GABA in rat brain slices (Johnston, Psychopharmacologia,'
1971, 22, 230 - 233). Reduced function in the GABA system is believed to be related
to the etiology of parkinsonism, epilepsy, Huntington's chorea (Thomas N. Chase and
Judith R. Walters, GABA in Nervous System Function, edited by E. Ro- berts, T.N. Chase
and D.B. Tower, Raven Press, New York, 197∈, 497 - 513), and schizophrenia, and administration
of agents influencing the GABA system is therefore under consideration and research
for the therapeutical treatment of such GABA system malfunction-related diseases.
It is also under consideration to administer agents influencing the GABA system against
diseases in which malfunctions of the pituitary hormones are involved, and it is,
furthermore, contemplated that such agents may be useful against artereoschlerotic
diseases in the brain where a vasodilata- tion is desired. However, unfortunately,
muscimol has poisoneous effects, such as narcotic effects (derealisation and depersonali-
sation), and the difference between the effective dose and the toxic dose of muscimol
is very small (Arzneimittelforschung, 1968, 18, 311 - 315), which may limit or prevent
the therapeutic use of muscimol. Furthermore, it would be highly desirable to provide
a substance having a more specific GABA activity than muscimol which, as mentioned
above, shows considerable GABA-uptake inhibitor activity in addition to its GABA agonist
activity. In an attempt to establish a structure/activity relation, various muscimol-analogues
or muscimol-like substances have been synthesized and tested (P. Krogsgaard-Larsen
et al., Jdurnal of Neurochemistry, 1975, 25, 797 - 803 and 803.- 809 . However, none
of the compounds tested showed a GABA agonist activity of the same potency as that
of muscimol.
[0004] The present invention relates to novel compounds showing GABA--related activity,
to salts thereof with acids or bases, and to pharmaceutical compositions containing
compounds having GABA--related activity or salts thereof as active ingredient. Moreover,
the present invention relates to methods for the preparation of the novel compounds
and salts thereof and to a method for the treatment of neurological and psychiatrical
disorders, such as epilepsy, parkinsonism, schizophrenia and Huntington's chorea,
or diseases in which malfunctions of the pituitary hormones are involved, or artereoschlerotic
diseases in the brain where a vaso- dilatation is desired, by administering a therapeutically
effective amount of the compounds or salts thereof to a living animal body including
human beings.
[0005] According to the present invention, it has been found that the novel compound of
the formula Ia

1,2,3,6-tetrahydroisonicotinic acid ("isoguvacine") is a specific and very potent
GABA receptor agonist, vide the section "Test Results" below. A comparison of the
formula Ia and GABA shows that GABA is incorporated as a structural element of the
molecule of compound Ia. However, zwitterions like the amino acid Ia may not be able
to pass the blood-brain barrier, which means that for practical administration, it
is often preferred to convert it into a form which will permit the compound to pass
the blood-brain barrier and which thereafter will be decomposed in situ in the brain
to yield the parent compound.
[0006] Recent investigations seem to indicate that GABA receptor agonists unable to penetrate
the blood-brain barrier interact directly with the anterior pituitary after systemic
administration and inhibit secretion of prolactin. Consequently, systemic administration
of compound Ia is expected to decrease prolactin secretion. An undesired effect observed
after treatment of patients with the traditional neuroleptics such as butyrophenones
and phenothiazines is an increased secretion of prolactin. The side effect of treatment
with neuroleptics might be avoided by treatment of patients with combinations of compound
Ia and neuroleptic drugs. Thus, the invention also relates to the use of compound
Ia in combination with neuroleptic drugs such as butyrophenones and phenothiazines
and to the use of Ia in pituitary malfunction-related diseases in humans and animals
in which decrease of prolactin secretion is desirable.
[0007] On this background, the present invention also provides novel compounds comprising
compound Ia and derivatives thereof in a "prodrug" or "transportation" form that is
compounds which will pass the blood-brain barrier and which thereafter will be decomposed
in situ in the brain to yield the parent compound (Ia), in particular compounds of
the general formula I

in which R" is hydrogen, acetyl or a group of the general formula II

wherein R
1 is C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy, or
lower alkyl; or phenylalkyl such as benzyl or phenylethyl in which, the phenyl group
may be substituted in the 4-position with halogen, lower alkoxy, or lower alkyl; and
R' is hydrogen; C
1-8 alkyl; phenyl; phenyl substituted in 4-position with halogen, lower alkoxy, lower
alkyl or hydroxy; phenylalkyl such as benzyl or phenylethyl; or phenylalkyl substituted
in the 4-position of the phenyl moiety with halogen, lower alkoxy, lower alkyl or
hydroxy; or indanyl; or R' is a group of the general formula III

wherein R
2 and R
3 are the same or different and each designate hydrogen; C
1-6 alkyl; or phenylalkyl such as benzyl or phenylethyl; and R
4 designates C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy or
lower alkyl; or phenylalkyl such as benzyl or phenylethyl; and salts thereof, with
the proviso that when R" is hydrogen, R' is different from ethyl. Among the compounds
of the general formula I, compounds in which at least one of R' and R" is hydrogen
are preferred for therapeutical administration, as salts; the compounds in which both
R' and R" are different from hydrogen tend to be oily substances.
[0008] In the present specification, "lower alkyl" and "lower alkoxy" designate such groups
containing 1 - 4 carbon atoms.
[0009] The compound excluded through the above proviso, that is, the compound of the formula
Ib

is known from German Offenlegungsschrift No. 2,221,770, and from Liebigs Ann. Chem.,
1972, 764, 21 - 27. In the Liebig article, the compound Ib and analogues having the
formula Ic

in which X is cyano or a group -(CH
2)
n-COOR
S in which n is an integer from 0 to 5, and R
5 is an optionally substituted alkyl or aryl group, are stated to be valuable intermediates
for the preparation of pharmaceutically active substances, especially chloretics,
but neither the Liebig article nor the Offenlegungsschrift contain any indication
whatsoever of any GABA-related activity of any of these compounds.
[0010] Among the compounds of the general formula I, in which R' is one of the hydrocarbon
groups stated above are:
methyl 1,2,3,6-tetrahydroisonicotinate,
propyl 1,2,3,6-tetrahydroisonicotinate,
isopropyl 1,2,3,6-tetrahydroisonicotinate,
butyl 1,2,3,6-tetrahydroisonicotinate,
tert.butyl 1,2,3,6-tetrahydroisonicotinate,
phenyl 1,2,3,6-tetrahydroisonicotinate,
4-chlorophenyl 1,2,3,6-tetrahydroisonicotinate,
4-methoxyphenyl 1,2,3,6-tetrahydroisonicotinate,
benzyl 1,2,3,6-tetrahydroisonicotinate, r
4-hydroxyphenyl 1,2,3,6-tetrahydroisonicotinate,
and acid addition salts thereof.
[0011] Examples of compounds of the general formula I in which R' is hydrogen, and R" is
acetyl or a group of the general formula II are:
1-acetyl-1,2,3,6-tetrahydroisonicotinic acid, 1-methoxycarbonyl-1,2,3,6-tetrahydryisonicotinic
acid, 1-ethoxycarbonyl-1,2,3,6-tetrahydroisonicotinic acid, l-propoxycarbonyl-l,2,3,6-tetrahydroisonicotinic
acid, 1-butyloxycarbonyl-1,2,3,6-tetrahydroisonicotinic acid, 1-tert.butyloxycarbonyl-1,2,3,6-tetrahydroisonicotinic
acid, 1-phenoxycarbonyl-1,2,3,6-tetrahydroisonicotinic acid, 1-(4-chlorophenoxycarbonyl)-1,2,3,6-tetrahydroisonicotinic
acid, 1-benzyloxycarbonyl-1,2,3,6-tetrahydroisonicotinic acid, 1-(4-methoxyphenoxycarbonyl)-1,2,3,6-tetrahydroisonicotinic
acid, 1-(4-methylphenoxycarbonyl)-1,2,3,6-tetrahydroisonicotinic acid, and salts thereof
with bases.
[0012] Examples of compounds of the general formula I in which R' is a group of the general
formula III, which compounds constitute preferred compounds of the general formula
I, are:
acetoxymethyl 1,2,3,6-tetrahydroisonicotinate, propionyloxymethyl 1,2,3,6-tetrahydroisonicotinate,
butyryloxymethyl 1,2,3,6-tetrahydroisonicotinate, isobutyryloxymethyl 1,2,3,6-tetrahydroisonicotinate,
pivaloyloxymethyl 1,2,3,6-tetrahydroisonicotinate, 2-ethylbutyryloxymethyl 1,2,3,6-tetrahydroisonicotinate,
benzoyloxymethyl 1,2,3,6-tetrahydroisonicotinate, 4-chlorobenzoyloxymethyl 1,2,3,6-tetrahydroisonicotinate,
4-methoxybenzoyloxymethyl 1,2,3,6-tetrahydroisonicotinate, phenylacetoxymethyl 1,2,3,6-tetrahydroisonicotinate, l-(acetoxy)ethyl
1,2,3,6-tetrahydroisonicotinate, l-(pivaloyloxy)ethyl 1,2,3,6-tetrahydroisonicotinate,
1-acetoxy-l-methylethyl 1,2,3,6-tetrahydroisonicotinate, 1-pivaloyloxy-l-methylethyl
1,2,3,6-tetrahydroisonicotinate, l-acetoxy-2-phenylethyl 1,2,3,6-tetrahydroisonicotinate,
l-pivaloyloxy-2-phenylethyl 1,2,3,6-tetrahydroisonicotinate, and acid addition salts
thereof.
[0013] Examples of salts of the compounds of formula I in which R" is hydrogen, are acid
addition salts thereof, such as pharmaceutically acceptable salts with inorganic acids,
e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, or
with organic acids, such as organic carboxylic acids, e.g. acetic, propionic, glycolic,
malonic, succinic, maleic, fumaric, malic, tartaric, citric, glucuronic, benzoic,
pamoic acid and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane
sulfonic, benzene sulfonic, toluene sulfonic acid and the like, which salts may be
prepared by procedures known per se, e.g. by adding the acid in question to the base,
preferably in a solvent. When R" is different from hydrogen, the compounds of formula
I may form pharmaceutically acceptable salts with bases, such as metal salts, e.g.
sodium, potassium, calcium or aluminum salts, and ammonium and substituted ammonium
salts, e.g. salts of amines such as triethylamine, triethanolamine, ethylpiperidine,
procaine, dibenzylamine, and the like.
TEST RESULTS.
Affinity Binding Experiments.
[0014] In order to study the interactions of compound Ia with the central GABA receptors
in vitro, compound Ia was tested in affinity binding experiments. The affinity binding
(sodium-independent binding) of GABA to membranes isolated from rat brains was studied
as described by Enna, S.J. and Snyder, S.H., Brain Res., 1975, 100, 81 - 97. IC
50 values, inhibitor concentrations causing 50% inhibition of GABA binding, were determined.

*)
[0015] In farlier studies 1.4 ± 0.1 µM was found. The value stated (0.015 ± 0.001 µM) is
based on studies of 5 different concentrations of Ia, each determined in triplicate,
and the stated IC
50 value is calculated by log-probit analysis. The difference between the two TC
50 values determined for Ia is the result of the development of an improved technique
for the prepa- cation of rat brain membranes.
Microelectrophoretic Experiments.
[0016] In order to study the interactions of compound la with the central GABA receptors
in vivo, compound Ia was tested in microelectrophoretic experiments. Experiments were
performed on lumbar dorsal horn interneurones and Renshaw cells of cats anaesthetized
with pentobarbitohe sodium. The approximate potency of the depressant actions of the
compound was assessed relative to that of GABA on the basis of electrophoretic currents
required to produce equal and submaximal inhibitions of the firing of the central
neurones. The inhibitory action of Ia on central neurones was antagonized by the specific
GABA antagonism bicuculline methochloride (BMC).

[0017] The compound Ia did not interact with the GABA uptake system at concentrations of
5 x 10
-4 M, and did not interact with the GABA metabolizing enzymes GABA:2-oxo-glutarate aminotransferase
and L-glutamate 1-carboxylase at concentrations of 10
-3 M.
[0018] Based on the above-mentioned experiments, compound Ia is a specific and very potent
GABA receptor agonist.
Pharmacological Results in Mice.
[0019] Preliminary pharmacological results of tests with the hydrobromide of the compound
of the formula I in which R' = CH
3 and R" = H, "isoguvacine methylester hydrobromide" (ISM), and the hydrobromide of
the compound of the formula I in which R' has the formula III in which R
4 is tert.butyl, and R
2, R
3,and R" are hydrcgen, "isoguvacine pivaloyloxymethylester hydrobromide" (ISP), in
doses of 160 mg/kg i.p.:
1. ISM and ISP antagonize/enhance the latency time of isoniazide- induced convulsions.
2. ISM restrains morphine-induced hypermotility in minor degree. ISP totally restrains
morphine-induced hypermotility for 165 minutes (it is not yet established if ISP in
itself has a sedative effect).
[0020] The compounds of the invention of the general formula I may be prepared via the acid
Ia which, in itself, is suitably prepared as shown in Reaction Schemes I and II:

[0021] In accordance with Reaction Schema II, intermediates for the preparation of compound
Ia are, on a generalized level, compounds of the general formula V

in which Z is hydrogen or an amino-protecting group removable by hydrolysis or hydrogenolysis,
suitably a group R" as defined above or a trityl or formyl group, and W is hydrogen
or a group readily removable, e.g. by hydrolysis, to yield the free carboxyl group,
such as a group R' as defined above or tetrahydropyranyl.
[0022] In accordance with Reaction Scheme I, intermediates for the preparation of compound
Ia are, on a generalized level, compounds of the general formula IV

in which Z' and W have the same meaning as Z and W as defined above, with the proviso
that at least one of Z' and W' is different from hydrogen.
[0023] For the preparation of compounds of the general formul a in which R' is lower alkyl,
aryl, substituted aryl, aralkyl, or substituted aralkyl, compound Ia or compound IV
in which W is hydrogen may be esterified to introduce the desired group R', in accordance
with any of the well known methods for the preparation of an ester of an amino acid,
followed, by removal of any group Z' different from R" and if desired, removal of
any group Z' which falls under the definitions of R". For the preparation of compounds
of the general formula I in which R' is a group of the general formula III, a salt,
e.g. a potassium salt of compound Ia or a compound of the general formula IV in which
W' is hydrogen, is treated with a compound of the general formula

in which R
21 R
3 and R
4 are as defined above, in which X' is a halogen atom, e.g. chlorine, in the presence
of an acid binding agent, e.g. potassium carbonate as used for the formation of the
salt of Ia, and then, removing any group Z' different from R" and, if desired, any
group Z' which falls under the definition of R".
[0024] The introduction of the group R" may be performed by manners known per se . Thus,
for example, when R" is a group of the above formula II, the introduction may be performed
by treatment with the appropriate formic acid ester of the general formula

wherein X" is a leaving group, especially halogen or azido, etc., in the presence
of an acid acceptor, for example an alkali carb- onate. For example, the BOC-derivative
can be made by means of tert.butylazidoformate. When R" is acetyl, a reactive derivative
of acetic acid, e.g. acetyl chloride or acetanhydride may be used for the introduction
of the group R".
[0025] More detailed aspects of the above processes of the invention appear from the claims.
[0026] The compounds of formula I and salts thereof may be formulated for administration
in any convenient way by analogy with other pharmaceuticals.
[0027] Thus, the composition comprising the compounds of the invention may be in the form
of pharmaceutical preparations, e.g. in solid, semisolid or liquid form, which contain
the active compound of the invention in admixture with a pharmaceutical or inorganic
carrier or excipient suitable for enteral or parenteral application. The active ingredient
may, e.g., be formulated with the usual carriers for tablets, pellets, capsules, suppositories,
solutions, emulsions, aqueous suspensions and other suitable administration forms.
Examples of carriers are glucose, lactose, gum acacia, gelatin, mannitol, starch paste,
magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch,
urea, and other carriers suitable for use in manufacturing compositions in solid,
semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, colouring,
flavouring, and preservative agents can be contained in the composition of this invention.
is active compound is included in the composi- tions of the invention in an amount
sufficient to produce the desired therapeutical effect upon administration. The dosage
or therapeutically effective quantity of the compound varies and also depends upon
the age and condition of each Andividual patient being treated.
[0028] A preferred tablet or capsule formation for oral administration contsins 0.1 - 200
mg, preferably 1 - 100, especially 5 - 50, mg of a compound of formula I, or a salt
thereof per unit dosage which may be administered 1 - 4 times per day or as a sustained
release composition.
[0029] Injection preparations preferably contain 0.1 - 200 mg, preferably 1 - 100, especially
5 - 50, mg of a compound of formula I or a salt thereof per unit dosage. A preferred
injected dose is about 0.5 to 2 ml.
[0030] The invention also relates to the use of the compounds of the general formula I,
and salts thereof in medicaments for treating GABA system malfunction-related diseases,
and a process of treating GABA system malfunction-related diseases in human beings
by administering, to the human being, an effective dose of a compound of the general
formula I, or a salt thereof.
[0031] In its above-mentioned compositions and the above-mentioned uses, it may be suitable
or preferred to combine the compound of the general formula I at a salt thereof with
minor tranquillizers such as

or

for example butyropsenones such as haloperidol, phenothiazines such as chloropromazine,
thioxanthene, and the like. In such combinations, compositions and combined usages,
the neuroleptics are suitably administered in their effective amounts or, in a preferred
embodiment in lower amounts than the amounts in which they would be effective when
used alone.
[0032] An interesting aspect of the invention is compound Ia as intermediate in the preparation
of derivatives of compounds of the formula I wherein R" is different from hydrogen.
[0033] The invention is further illustrated by the below working examples. All compounds
prepared according to the working examples have been subjected to elemental analysis
for C, H, N and halogen, when present, and all agreed within
± 0.3% with the calculated values.
Example 1. (Reaction Scheme I).
Ethyl 1-ethoxycarbonyl-1,2,3,6-tetrahydroisonicotinate (IVa).
[0034] A solution of l-methyl-l,2,3,6-tetrahydroisonicotinic acid hydrochloride (5.31 g;
30 mmol) in a solution of hydrogen chloride in ethanol (200 ml; 5%) was refluxed for
10 hours. Upon evaporation in vacuo the residue was dissolved in ice water (10 ml)
and an iced aqueous solution of sodium hydrocide (15 ml; 30%) was added. The mixture
was extracted with four 50 ml portions of methylene chloride. The combined and dried
(K
2CO
3) organic phases were evaporated to give 4.49 g of an oily TLC-pure product [R
F: 0.29; eluent: 1-butanol-water-acetic acid (4:1:1)]. A solution of this product (4.49
g) and ethyl chloroformate (25 ml) in dichloroethane (120 ml) was refluxed for 24
hours. The reaction mixture was filtered and evaporated in vacuo to give an oil. Ball-tube
distillation at 95 Pa (oven temperature 160°C) gave IVa (5.52 g; 81%) as a colourless
oil. IR (film): 2980. (m), 2930--2810 (several bands, m-w), 1700 (s), 1655 (m).
1,2,3,6-Tetrahydroisonicotinic acid hydrosromide (Ia salt).
[0035] A solution of ethyl l-ethoxycarbonyl-1,2,3,6--tetrahydroisonicotinate (4.54 g; 20
mmol) in an aqueous solution of hydrogen bromide (30 ml; 48%) was refluxed for 2 hours.
The solution was filtered and evaporated in vacuo to give a crystalline residue. Recrystallization
(water--2-propanol-ether) gave Ia hydrobromide (2.45 g; 59%), m.p. 284--287°C (decomp.).
IR (KBr): 3600--3300 (m), 3300--2850 (s), 2790 (s), 2700--2200 (several bands, m-w),
1710 (s), 1655 (s), 1630 (w), 1585 (m).
[0036] Using 8N hydrochloric acid instead of 48% aqueous hydrogen bromide and refluxing
for 10 hours, the hydrochloride of Ia was obtained, m.p. 270--271.5°C (decomp.).
1,2,3,6-Tetrahydroisonicotinic acid zwitterion (Ia).
[0037] To a solution of 4.90 g of Ia hydrochloride in 45 ml of water a solution of triethylamine
(3.18 g) in ethanol (90 ml) was added. The precipitate (2.5 g) was collected and recrystallized
from water-ethanol yielding the title compound, m.p. 249--252°C. (decomp.).
Example 2. (Reaction Scheme II).
Ethyl 1-methoxycarbonyl-3-hydroxypiperidin-4-carboxylate (Va).
[0038] A solution of 15 g of ethyl l-methoxycarbonyl-3-oxopiperidine--4-carboxylate (P.
Krogsgaard-Larsen, Acta Chem. Scand., 1977, B31, 584) in 150 ml EtOH was mixed with
Raney-nickel (from 10 g of Raney alloy) and hydrogenated at 10 MPa for 20 hours. The
reaction mixture was filtered and evaporated to dryness in vacuo. An amount (4 g)
of the residue was distilled yielding 3.4 g, b.p. at 0.2 mm
Hg
: 145--147°C.
1,2,3,6-Tetrahydroisonicotinic acid hydrobromide (Ia salt).
[0039] A mixture of the above hydroxy compound (Va) (0.5 g) and 1 ml of 48% aqueous hydrobromic
acid was refluxed for 24 hours. after cooling a compound crystallized. The compound
was proved vertical to the abcve prepared Ia hydrobromide by T.L.C.., IR- spectra,
and m.p.
[0040] An derivative route from Va to Ia is via 3-hydroxypiperidine--4-carboxylic acid hydrochloride
as described below:
3-Hylcoxypiperidine-4-carboxylic acid hydrochloride.
[0041] A mixture of Va (3.0 g) and 6 ml of conc. HC1 in 5 ml of water was rafluxed for 2
hours and evaporated to dryness in vacuo. The residue was recrystallized from water--glacial
acetic acid-ether yielding 1.2 g (52%) of the title compound, m.p. 237--240°C.
Example 3.
[0042] Methyl 1,2,3,6-tetrahydroisonicotinate hydrochloride.
[0043] To a suspension of 4.91 g of Ia hydrochloride in 250 ml of methsnol kept at 40°C
was added a stream of hydrochloric acid (gas) for 1 hour. The solution obtained was
left overnight and evaporated, yielding 4.25 g (80%) of the title compound, m.p.:
158--159°C. Recrystallization from acetonitrile raised the m.p. to 160--161°C.
Example 4.
.
[0044] 
[0045] To a suspension of Ia hydrochloride (0.49 g) in 10 ml of pyridine was added 0.57
ml of acetic acid anhydride. The mixture was stirred at 20°C for 1 hour and then at
70°C for 1 hour. The reaction mixture was evaporated in vacuo and water (10 ml) was
added to the residue followed by 4N HC1 to pH = 2. The aqueous solution was extracted
with four 10 ml portions of CHC1
3. The combined chloroform layers were washed with 10 ml of water, dried and evaporated
in vacuo. The residue was treated with 10 ml of ether and 0.28 g (55%) was obtained.
Recrystallizations from ethyl acetate gave the title compound, m.p. 177--182°C.
Example 5.
1-tert.Butyloxycarbonyl-1,2,3,6-tetrahydroisonicotinic acid.
[0046] To a solution of Ia hydrochloride (1.64 g) in water (15 ml) was added triethylamine
(5.6 ml) followed by a solution of tert.- butyl azidoformate (1.7 ml) in dioxane (15
ml). The mixture was stirred at 20°C for 15 hours and the dioxane was evaporated in
vacuo. The aqueous solution was washed with two 20 ml portions of ether, cooled to
3
0C and acidified with 1N NCl. The precipitate (1.95 g, 86%) was collected and recrystallized
from toluene yielding the title compound, m.p. 148--150°C.
Example 6.
1-Benzyloxycarbonyl-1,2,3,6-tetrahydroisonicotinic acid.
[0047] A solution of Ia hydrochloride (1.63 g) in 50 ml of 2N NaOH was cooled to 0°C. To
this solution were added simultaneously benzyl chloroformate (7.8 ml) and 2N NaOH
(27.5 ml) during 10 min. The mixture was stirred at 0°C for 1 hour, and washed with
25 ml of ether. The aqueous phase was cooled and acidified with 4N HC1. The white
precipitate was collected and recrystallized from a mixture of toluene and petroleum
ether yielding 8.7 g (67%) of the title compound, m.p. 106--108°C (decomp.).
Example 7.
Pivaloyloxymethyl 1-tert.butyloxycarbonyl-1,2,3,6-tetrahydroisonicotinate.
[0048] To a solution of l-tert.butyloxycarbonyl-l,2,3,6-tetrahydroisonicotinic acid (1.36
g) in 85 ml of acetone potassium carbonate (1.24 g) was added. The mixture was stirred
for 10 minutes and pivaloyloxymethyl chloride (0.96 ml) was added dropwise. The mixture
was stirred for 2 hours and then refluxed for 7 hours. The cooled reaction mixture
was filtered and the filtrate was evaporated in vacuo. The residue was extracted with
30 ml of ether and the ether was evaporated leaving the title compound as a colourless
oil (1.56 g, 76%).
Example 8.
[0049] Pivaloyloxymethyl 1,2,3,6-tetrahydroisonicotinate hydrobromide.
[0050] To a solution of pivaloyloxymethyl 1-tert.butyloxycarbonyl--1,2,3,6-tetrahydroisonicotinate
(1.45 g) in 10 ml of ethyl acetate was added a 48% solution of HBr in glacial acetic
acid (1.2 ml). After 5 minutes at 20°C ether (80 ml) was added in small portions.
The precipitate was collected and recrystallized from ethyl acetate-ether leaving
549 mg (40%) of the title compound, m.p. 70--73°C.
Example 9.
Butyl 1,2,3,6-tetrahydroisonicotinate hydrobromide.
[0051] Butyl 1-tert.butyloxycarbonyl-1,2,3,6-tetrahydroisonicotinate was obtained in the
same manner as described in Example 7 using butyl bromide instead of pivaloyloxymethyl
chloride. Treating the compound obtained in the same way as described in Example 8
yielded the title compound, m.p. 105--106°C (from methanol--ether
Example 10.
Methyl 1-triphenylmethyl-1,2,3,6-tetrahydroisohicotinate.
[0052] To a solution of methyl 1,2,3,6-tetrahydroisonicotinate hydrobromide (1.1 g) in 10
ml of chloroform were added 1.53 ml of triethylamine and 1.39 g of triphenyl chloromethane.
The mixture was stirred at 20°C for 6 hours. The reaction mixture was washed with
two 10 ml portions of water, dried, and evaporated in vacuo. The residue was triturated
with warm methanol leaving 1.60 g (83%). One recrystallization from ethanol yielded
the title compound, m.p. 172--174°C.
Example 11.
1-Triphenylmethyl-1,2,3,6-tetrahydroisonicotinic acid.
[0053] A suspension of the methyl ester of the title compound (1.5 g) in a solution of 0.24
g potassium hydroxide in 10 ml of ethanol was refluxed for 17 hours. Water (40 ml)
was added and the mixture was acidified with a 50% acetic acid (5 ml). The precipitate
(1.45 g) was collected and recrystallized from chloroform-petroleum ether yielding
the title compound, m.p. 161--165°C (decomp.).
Example 12.
[0054] Piyaloyloxymethyl 1,2,3,6-tetrahydroisonicotinate hydrobromide.
[0055] Reacting the potassium salt of 1-tyiphenylmethyl-1,2,3,6-tetrohydrois

solid with pivaloyloxymethyl chloride in the same manner as described in Example 7
yielded pivaloyloxymethyl 1-triphenyl- methyl-l,2,3,6-tetrahydroisonicotinate as an
oil. Treating this oil with hydrobromic acid in glacial acetic acid in the same way
as described in Example 8 yielded a compound, which was proved identical to the compound
prepared in Example 8 by T.L.C. and m.p.
1. Compounds of the general formula I

in which R" is hydrogen, acetyl or a group of the general formula II

wherein R
1 is C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkcxy, or
lower alkyl; or phenylalkyl such as benzyl or phenylethyl in which the phenyl group
may be substituted in the 4-position with halogen, lower alkoxy, or lower alkyl; and
R' is hydrogen; C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy, lower
alkyl or hydroxy; phenylalkyl such as benzyl or phenylethyl; or phenylalkyl substituted
in the 4-position of the phenyl moiety with halogen, lower alkoxy, lower alkyl or
hydroxy; or indanyl; or R' is a group of the general formula III-

wherein R
2 and R
3 are the same or different and each designate hydrogen; C
1-6 alkyl; or phenylalkyl such as benzyl or phenylethyl; and R
4 designates C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy or
lower alkyl; or phenylalkyl such as benzyl or phenylethyl; and salts thereof, with
the proviso that when R" is hydrogen, R' is different from ethyl.
2. A compound according to claim 1,
characterized in that it is 1,2,3,6-tetrahydroisonicotinic acid, and salts thereof.
3. Compounds according to claim 1,
in which R" is hydrogen, and R' is a group of the general formula III as defined in
claim 1; and salts thereof.
4. A compound according to claim 3,
characterized in that it is pivaloyloxymethyl 1,2,3,6-tetrahydroisonicotinate, and
salts thereof.
5. Compounds of the general formula V

in which Z is hydrogen or an amino-protecting group removable by hydrolysis or hydrogenolysis,
and W is hydrogen or a group readily removable to yield the free carboxyl group, and
salts thereof.
5. Compounds of the general formals IV

in which Z' and W' have the same meaning as Z and W as defined in claim 5, with the
proviso that at least one of Z' and W' is different from hydrogen, and salts thereof.
7. A pharmaceutical composition comprising as active ingredient a compound of the
general formula I'

in which R"" is hydrogen, acetyl or a group of the general formula II

wherein R
1 is as defined in claim 1; and R"' is hydrogen; C
1-8 alkyl phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy, lower
alkyl or hydroxy; phenylalkyl such as benzyl or phenylethyl; or phenylalkyl substituted
in the 4-position of the phenyl moiety with halogen, lower alkoxy, lower alkyl or
hydroxy; or indanyl; or R"' is a group of the general formula III

wherein R
2 and R
3 and R
4 are as defined in claim 1; or a salt thereof together with a pharmaceutical carrier
or excipient.
8. A pharmaceutical composition according to claim 7 which additionally contains a
minor tranquillizer or a neuroleptic.
9. A process for preparing compounds of the general formula I

in which R" is hydrogen, acetyl or a group of the general formula II

wherein R
1 is C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy, or
lower alkyl; or phenylalkyl such as benzyl or phenylethyl in which the phenyl group
may be substituted in the 4-position with halogen, lower alkoxy, or lower alkyl; and
R' is hydrogen; C
1-8 alkyl; phenyl; phenyl substituted in 4-position with halogen, lower alkoxy, lower
alkyl or hydroxy; phenylalkyl such as benzyl or phenylethyl; or phenylalkyl substituted
in the 4-position of the phenyl moiety with halogen, lower alkoxy, lower alkyl or
hydroxy; or indanyl; or R' is a group of the general formula III

wherein R
2 and R
3 are the same or different and each designate hydrogen; C
1-6 alkyl; or phenylalkyl such as benzyl or phenylethyl; and R
4 designates C
1-8 alkyl; phenyl; phenyl substituted in the 4-position with halogen, lower alkoxy or
lower alkyl; or phenylalkyl such as benzyl or phenylethyl; and salts thereof, with
the proviso that when R" is hydrogen, R' is different from ethyl, comprising
a) reacting a compound of the general formula VI

in which Alk is a lower alkyl group and W is hydrogen or group removable to yield
the free carboxy group, with a formic acid ester of the general formula

in which R1 is as defined above, to form a compound of the general formula I

removing any group W different from R'; if desired, removing the group

and, if desired, removing any group W different from hydrogen, if desired, converting
a resulting compound of formula Ia

if obtained as a salt thereof, into the zwitterion form thereof by treatment with
a base or into another salt, and, if desired, converting the compound Ia into a compound
VII

in which Z" is a group R" as defined above or a trityl or formyl group, by reacting
compound Ia with a formic acid ester of the general formula

in which R1 is as defined above, and X" is a leaving group, or with trityl chloride, or with
the mixed anhydride of acetic , acid and formic acid, or with a reactive acetic acid
derivative; if desired, esterifying the carboxy group in the resulting compound VII
or a salt thereof, to introduce a group R' which is lower alkyl, aryl, substituted
aryl, or substituted aralkyl, or treating a salt of compound VII with a compound of
the general formula

in which R2, R3 and R4 are as defined above, and X' is a halogen atom, in the presence of an acid binding
agent, and thereafter removing any group Z" different from R", and if desired, any
group Z", or
b) subjecting a compound of the general formula IV

in which Z' and W' have the same meanings as defined in claim 6, to removal of the
group W' and/or Z', with the proviso that any group W' or Z' different from R' or
R", respectively, is removed, or
c) subjecting a compound of the general formula V

in which Z and W have the same meanings as defined in claim 5, to dehydratisation,
or
d) converting the compound Ia into a compound VII as defined above by reacting compound
Ia with a formic acid ester of the general formula

in which R1 is as defined above, and X" is a leaving group, or with trityl chloride, or with
the mixed anhydride of acetic acid and formic acid, or with a reactive acetic acid
derivative; if desired, esterifying the carboxy group in the resulting compound VII
or a salt thereof, to introduce a group R' which is lower alkyl, aryl, substituted
aryl, or substituted aralkyl, or treating a salt of compound VII with a compound of
the general formula

in whcih R2, R3 and R4 are as defined above, and X' is a halogen atom, in the presence of an acid binding
agent, and thereafter removing any group Z" different from R", and if desired, any
group Z", or
e) esterifying the carboxy group in compound Ia or a salt thereof, to introduce a
group R' which is lower alkyl, aryl, substituted aryl, or substituted aralkyl, or treating
a salt of compound Ia with a compound of the general formula

in which R2, R3 and R4 are as defined above, and X' is a halogen atom, in the presence of an acid binding
agent.