NO843171L - PROCEDURE FOR THE PREPARATION OF NEW ACYLATED HYDRAZINE COMPOUNDS - Google Patents

Abstract

The invention relates to pharmaceutical compositions containing acylated hydrazine compounds of the formula. wherein R represents an optionally substituted aliphatic or aromatic hydrocarbon residue and Ac an acyl residue and n is an integer from 1-4, or their salts, as well as novel compounds of this kind, or their salts, process for the preparation of such compounds, pharmaceutical preparations containing such novel compounds and their use in the manufacture of pharmaceutical preparations.

Description

The object of the invention is a method for the production of new acylated hydrazine compounds with the formula:

where R means an optionally substituted aliphatic or aromatic hydrocarbon residue and Ac an acyl residue, and n is an integer from 1-4, whereby, if n means a value from 2-4, the residues R can be the same or different and bound in each of the possible positions in the pyridine ring, under the condition that R as lower alkyl which is bound in the 3-position has 2-7 carbon atoms, and n has the value 1, when Ac means an acyl group, and with the further condition that R as lower alkyl which are bonded in the 3-, 4-, 5- or 6-position have 2-7 carbon atoms, when Ac means the benzoyl group, such as racemate mixtures, racemates, optical antipodes or their salts.

An optionally substituted aliphatic hydrocarbon residue R is

e.g. optionally substituted lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxyl lower alkyl,

as hydroxyl lower alkyl, lower hydroxy lower alkyl or halogen lower alkyl, or optionally substituted, as lower alkylated or acylated amino lower alkyl, as amino lower alkyl, N-lower alkyl amino lower alkyl or N,N-di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonyl amino lower alkyl, lower alkyl which is optionally substituted with esterified or amidated carboxy, as carboxy, lower alkoxycarbonyl or optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl or also lower alkyl which is substituted with an oxo group, such as carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamoyl lower alkyl, N-lower alkyl carbamoyl lower alkyl or N,N-di lower alkyl-carbamoyl lower alkyl or also oxo lower alkyl , further

Cyan lower alkyl, optionally substituted aryl lower alkyl,

where aryl is a monocyclic aromatic hydrocarbon residue,

e.g. phenyl, or a bicyclic aromatic hydrocarbon residue, such as 1- or 2-naphthyl or partially saturated naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl, in which the substituents may be lower alkyl, hydroxy and/or halogen, optionally etherified or esterified hydroxy lower alkyl, e.g. as indicated, possibly lower alkyl lower alkyl or halogen lower alkyl, lower alkoxy optionally etherified or esterified hydroxyl lower alkyl, such as lower alkoxy lower alkyl or halogen lower alkyl, lower alkenyloxy, lower alkynyloxy, or optionally substituted, such as lower alkylated or acylated amino lower alkyl, e.g. as stated above, e.g. mono- or dilower alkylaminoalkyl or lower alkanoylaminolower alkyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, cyan, nitro or optionally substituted, such as acylated amino, e.g. amino, lower alkanoyl-amino, lower alkoxycarbonylamino, further lower alkylamino or dilower alkylamino, whereby such substituents are the same or different and single or multiple, especially 1-3 times.

An optionally substituted aromatic hydrocarbon residue R is

a mono- or bicyclic, carbocyclic or heterocyclic aromatic hydrocarbon residue, e.g. phenyl, 1- or 2-naphthyl or partially saturated naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl. As mono- or bicyclic heteroaryl, R is a residue, preferably with 5 or 6 ring members containing an oxygen, sulfur or nitrogen atom and optionally 1-3 further nitrogen atoms as ring members which are connected to the pyridine residue via a ring carbon atom, which can at least partially be hydrogenated and in this case substituted with oxo, whereby the second ring in a bicyclic heterocyclic residue may be an unfused benzo ring, and means especially pyridyl, e.g. 2-, 3- or 4-pyridyl, or dihydro-oxo-pyridinyl, e.g.

1,6-dihydro-6-oxo-2-pyridinyl, pyridazinyl, e.g. 3-pyridazinyl, pyrazinyl, e.g. 2-pyrazinyl, pyrimidinyl, e.g. 2-, 4- or 5-pyrimidinyl, or dihydro-oxo-pyrimidinyl, e.g. 3,4-dihydro-4-oxo-2-pyrimidinyl, furyl e.g. 2-or 3-furyl, pyrryl, e.g. 2- or 3-pyrryl, thienyl e.g. 2- or 3-thienyl, oxazolyl e.g. 2- or 4-oxazolyl, thiazolyl e.g. 2-, 4- or 5-thiazolyl, thiadiazolyl e.g. 1,2,4-triadiazol-3- or -5-yl or 1,2,5-thiadiazol-3-yl, imidazolyl, e.g. imidazol-2- or -4-yl, pyrazolyl, e.g. 3- or 4-pyrazolyl, triazolyl, e.g. 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, tetrazolyl and tetrazolyl-5-yl, further indolyl, e.g. indol-4-yl, quinolinyl, e.g. 2-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzimidazolyl, e.g. 2-benzimidazolyl, benzofuranyl, e.g. 4- or 5-benzofuranyl, benzothienyl, e.g. 4- or 5-benzothienyl or naphthyridinyl, e.g. 1,8-naphthyridin-2-yl.

Substituents in a mono- or bicyclic, carbocyclic or heterocyclic aryl residue R, whereby in the latter case primarily a ring carbon atom, but also a secondary ring nitrogen atom may be substituted, and such substituents may be present one or more times, preferably at most four times, is e.g. optionally substituted lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, such as hydroxy lower alkyl, lower alkoxy lower alkyl or halogen lower alkyl, or optionally substituted, such as acylated amino lower alkyl, such as lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, or lower alkenyl or lower alkynyl, optionally etherified or esterified hydroxy or mercapto, such as hydroxy, lower alkoxy, phenyl lower alkyl, halogen, mercapto, lower alkylthio, lower alkoxy which is optionally substituted with etherified or esterified hydroxy or mercapto or with acyl, e.g. lower alkoxy, phenyl lower aryl oxy, hydroxy lower rel oxy, lower alkoxy lower rel oxy, lower alkylthio lower rel oxy, halogen lower rel oxy or lower alkanoyl lower rel oxy or lower alkenyloxy, lower alkynyloxy, acyl, e.g. lower alkanoyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, cyan, nitro or optionally substituted, such as acylated amino, e.g. lower alkanoylamino, lower alkoxycarbonylamino, lower alkylsulfonyl, sulfamoyl, optionally substituted ureido, further amino, N-lower alkylamino or N,N-dilower alkylamino.

An acyl Ac corresponds to e.g. the formula -C(=0)-R^, where R.^

means an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residue, as optionally substituted lower alkyl, lower alkenyl or lower alkynyl, optionally substituted phenyl lower alkyl, phenyl lower alkyl or phenyl lower alkyl, optionally substituted mono- or polycyclic cycloalkyl, or as an aromatic residue stands for an optionally substituted mono- or bicyclic, carbocyclic or heterocyclic aryl radical, e.g. as defined above

for the group R, and corresponding to this, for example, stands for phenyl or pyridyl.

Substituents of lower alkyl, lower alkenyl or lower alkynyl as well as phenyl lower alkyl, phenyl lower alkenyl or phenyl lower alkynyl as well as mono- or polycyclic cycloalkyl, e.g. cycloalkyl, is e.g. optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy and/or halogen, optionally substituted as lower alkylated or acylated amino, such as amino, N-lower alkylamino or N,N-dilower alkylamino, lower alkanoylamino and/or optionally functionally converted carboxy, such as carboxy, esterified carboxy, e.g. lower alkoxycarbonyl, optionally substituted carbamoyl, cyan or nitro, whereby substituted residues may have one or more, especially up to three substituents, which may be the same or different in any positions suitable for substitution.

Substituents in a mono- or bicyclic, carbocyclic or heterocyclic aryl residue correspond to the substituents indicated for the group R, for example optionally substituted aliphatic hydrocarbon residues, such as optionally substituted lower alkyl.

An acyl residue Ac is further the residue from a monoester or

a monoamide of carboxylic acid, as unsubstituted or substituted, e.g. free or etherified hydroxy, such as lower alkoxy,

or unsubstituted or substituted amino, such as amino, lower alkylamino, and primarily disubstituted amino,

such as diloweralkylamino, N-loweralkyl-N-phenylloweralkylamino or loweralkyleneamino optionally interrupted by oxygen, sulfur or unsubstituted or, e.g. with lower alkyl, substituted nitrogen or lower alkoxycarbonyl containing unsubstituted or, e.g. with lower alkyl, lower alkoxy and/or halogen substituted phenyl, further N-unsubstituted or N-mono- or N,N-disubstituted carbamoyl, such as N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, or N,N-lower alkylene-carbamoyl which is optionally interrupted in the lower alkylene moiety by oxygen, sulfur or unsubstituted or, e.g. with lower alkyl substituted nitrogen.

The residues and compounds as in the present description

is denoted by "lower", preferably contains up to 7 and primarily up to 4 carbon atoms.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Corresponding to this is lower alkyl with 2-7 carbon atoms, e.g. ethyl, n-propyl or n-butyl. Substituted lower alkyl is particularly equivalent to methyl or 1- or 2-ethyl.

Lower range alkenyl is e.g. vinyl, allyl, 2- or 3-methallyl or 3,3-dimethylallyl.

Low real akinyl is especially propargyl.

Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy, while phenyl lower alkyloxy e.g. is benzyloxy or 1- or 2-phenylethoxy, lower alkenyloxy e.g. is allyloxy, 2- or 3-methylallyloxy or 3,3-dimethylallyloxy and lower alkynyloxy in particular is propargyloxy.

Lower alkylthio is e.g. methylthio, ethylthio, n-propylthio

or isopropylthio.

Lower alkyl sulfonyl is e.g. methylsulfonyl or ethylsulfonyl.

Halogen is preferably halogen with atomic number up to 35,

i.e. fluorine, chlorine or bromine.

Lowerealkanoyl is e.g. acetyl, propionyl or butyryl.

Optionally substituted lower alkoxycarbonyl is e.g. lower alkoxycarbonyl which is optionally substituted with acyl which is bonded over an oxygen atom, e.g. lower alkanoyl such as acetyl or pivaloyl, lower alkoxycarbonyl such as methoxy or ethoxycarbonyl or aroyl such as benzene, and are e.g. methoxycarbonyl, ethoxycarbonyl, 1- or 2-(acetyloxy)-ethoxycarbonyl, pivaloyloxymethoxycarbonyl, 1- or 2-(methoxycarbonyloxy)-ethoxycarbonyl or 1- or 2-(benzoyloxy)-ethoxycarbonyl.

Optionally substituted carbamoyl is e.g. carbamoyl, or N-lower alkyl or N,N-dilower alkylcarbamoyl such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl or N,N-diethylcarbamoyl.

Amino lower alkyl is e.g. aminomethyl or 2-aminoethyl.

Oxy-lower alkyl is e.g. 2-oxo-n-butyl.

Lower alkanoylamino is e.g. acetylamino or propionylamino.

Lower oxycarbonylamino is e.g. methoxycarbonylamino or ethoxycarbonylamino.

Optionally substituted ureido is e.g. ureido or 3-lower alkyl- or 3-cycloalkyl-ureido, in which cycloalkyl e.g. contains 5-7 ring joints, e.g. 3-methylureido, 3-ethylureido or 3-cyclohexylureido.

N-lower alkylamino and N,N-dilower alkylamino are e.g. methylamino, ethylamino, dimethylamino or diethylamino.

Hydroxyl lower alkyl is preferably hydroxymethyl or

1- and primarily 2-hydroxyethyl.

Lower alkyl lower alkyl is preferably lower alkoxymethyl or 1- and primarily 2-lower oxyethyl, e.g. methoxymethyl, ethoxymethyl, 2-methoxy-ethyl or 2-ethoxy-

ethyl.

Halogen-lower alkyl is preferably halomethyl, e.g. trifluoromethyl.

Hydroxylavereal oxy is e.g. hydroxymethoxy or 2-hydroxyethoxy.

Low-real oxylave-real oxy is e.g. 2-methoxyethoxy or 2-ethoxyethoxy.

Lower alkanoylaminolower alkyl is especially lower alkanoyl-aminomethyl or 1- and primarily 2-lower alkanoylamino-ethyl, e.g. acetylaminomethyl, 2-acetylamino-ethyl or 2-propionylamino-ethyl.

Lower oxycarbonylaminolower alkyl is especially lower alkoxycarbonylaminomethyl, or 1- and primarily 2-lower oxycarbonylaminoethyl, e.g. methoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl or 2-ethoxycarbonylaminoethyl.

Carboxyl lower alkyl is e.g. 2-carboxyethyl.

Lower oxycarbonyl lower alkyl is e.g. methoxycarbonylmethyl or 2-ethoxycarbonylethyl.

Cyanolower alkyl is e.g. cyanomethyl.

Lavereal oxylavereal oxy is i.a. lower alkoxy methoxy or 1- and especially 2-lower methoxy ethoxy, e.g. methoxy-methoxy, 2-methoxy-ethoxy or 2-ethoxy-ethoxy.

Lower alkyl thiolavereal oxy is in particular lower alkyl thiomethoxy or 1- and primarily 2-lower alkyl thioethoxy, e.g. 2-methylthio-ethoxy or 2-ethylthio-ethoxy.

Halogen-lower oxy is especially 2-haloethoxy, e.g. 2-chloroethoxy.

Lowerealkanoyllaverealcoxy is e.g. lower alkanoylmethoxy or 1- or 2-lower alkanoylmethoxy, e.g. acetylmethoxy. Phenyl lower alkyl is e.g. benzyl or 2-phenylethyl.

N-lower alkyl-N-phenyl lower alkyl-amino is e.g. N-methyl-N-benzylamino or N-methyl-N-(2-phenylethyl)-amino.

Phenylvarealalkenyl is e.g. phenylvinyl or 1-phenyl-2-propenyl. Phenylaveralkynyl is e.g. 1-phenyl-2-propynyl.

Lower alkyleneamino preferably contains 4-6 ring carbon atoms and is e.g. pyrrolidino or piperidino, while lower alkyleneamino interrupted by oxygen is e.g. morpholino such as 4-morpholino, lower alkyleneamino which is interrupted by sulfur is e.g. thiomorpholino, such as 4-thiomorpholino, and lower alkylene amino which is interrupted by nitrogen optionally substituted with lower alkyl, are e.g. piperazino or 4-methyliperazino.

N,N-lower alkylene-carbamoyl is e.g. pyrrolidinocarbonyl or piperidinocarbonyl, whereby corresponding residues in which the lower alkylene part is interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, means e.g. 4-morpholinocarbonyl, 4-thiomorpholinocarbonyl, 1-piperazinocarbonyl or 4-methyl-1-piperazinocarbonyl.

Monocyclic cycloalkyl including polycyclic cycloalkyl preferably contains 3-10 carbon atoms and is e.g. cyclopropyl, cyclopentyl or cyclohexyl, while polycyclic cycloalkyl e.g. is bicyclo[2,2,1]heptyl (norbornyl), bicyclo[2,2,2]octyl or adamantyl, such as 1-adamantyl.

The new compounds may exist in the form of their salts, such as their acid addition salts and primarily their pharmaceutically usable, non-toxic acid addition salts.

Suitable salts are e.g. those with inorganic acids, such as halogen hydrogen acids, e.g. hydrochloric acid or hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids, e.g. ant-, vinegar-, propion-, amber-, glycol-, milk-,

apple, wine, lemon, maleic, hydroxymaleic, pyrrhotite, fumaric, benzo, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, embonic, methanesulfonic, ethanesulfonic, 2 -hydroxyethanesulfonic, ethylenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid, or with other acidic organic substances, such as ascorbic acid. Salts are further those formed with bases, especially pharmaceutically usable, non-toxic bases and acidic groups, e.g. compounds of formula I

containing carboxyl groups. Suitable bases are e.g.

those of an inorganic nature, such as the carbonates or hydroxides of alkali metals or alkaline earth metals, e.g. carbonates or hydroxides of sodium, potassium, magnesium or calcium, further ammonia, or organic bases, e.g. suitable nitrogen bases, such as suitable amides, which optionally substituted, e.g. with hydroxy substituted primary, secondary or tertiary, aliphatic or cyclic amines, such as e.g. triethylamine, N-ethylpiperidine, di- or triethanolamine, pyrrolidine, N-(2-hydroxyethyl)-pyrrolidine, piperazine, N-(2-hydroxyethyl)-piperazine, and further N-methylglucosamine.

The pharmaceutical preparations according to the invention which contain acylated hydrazine compounds of formula I which also

the new compounds of formula I have valuable pharmacological properties. In particular, they work in a specific way

on renal blood flow and sodium excretion. thus they cause a selective renal vasodilatation, which can be shown by hemodynamic measurements on rats, thus on anesthetized rats, whose blood pressure and renal perfusion are measured continuously (electromagnetic flow meter), after intravenous administration of approx. 3 mg/kg to approx. 15 mg/kg of such substances, especially such compounds of formula I, where Ac means the Y-glutamyl residue, a renal vasodilatation is observed without blood pressure lowering, while after application of much higher doses, of approx. 70 mg/kg intravenously causes a blood pressure reduction of approx. -20 mm Hg. In rats in which the cardiac output (thermodilution), the perfusion of the kidney, the mesenteric area and the hind limb (electromagnetic flow meter) are simultaneously measured, the intravenous administration of a dose of 4 mg/kg of such compounds leads to an approx. 25% reduction in renal intestinal resistance, while mesenteric, femoral and total peripheral vascular resistance remains unchanged.

In similar experiments on adult, spontaneously hypertensive rats with chronically implanted Doppler ultrasound flow measuring heads, it can likewise be shown that such compounds in a dose range from approx. 3 mg/kg to approx. 10 mg/kg intravenously lowers the renal vascular resistance, while the vascular resistance in the mesenteric area and in the hind limb is not affected. First, clearly higher doses (approx. 30 mg/kg intravenously) lead to a drop in blood pressure and a vasodilatation in all three vascular areas examined. Only higher doses cause, after intravenous application of approx. 30 mg/kg or per oral administration of 60 mg/kg in awake rats a drop in blood pressure of approx. -25 mm Hg that lasts for at least 4 hours. After intravenous administration of doses in the range of 15 mg/kg to rats, these compounds lead to an increase in sodium excretion that lasts

for 3 hours. In experiments on anesthetized rats, it can be shown that especially such compounds of formula I, where Ac means a y-glutamyl residue, in a dose of 10 mg/kg intravenously leads to an increase in the glomerular filtration rate

(measured as "inulin clearance") of approx. 50%. Of this can

it is inferred that such compounds cause a predominantly preglomerular vasodilation. The chronic oral administration of such compounds in a dose of 10 mg/kg twice a day for three weeks leads to a sustained blood pressure reduction of approx. -20 to -25 mm Hg, whereby the heart rate remains unaffected. Similar effects can be observed during treatment with 10 mg/kg i.v.

per day, supplied via osmotic mini-pumps for a week. Compounds of formula I where Ac means a Y-L-glutamyl residue are cleaved in the kidney by Y-glutamyl-trans-peptidase. In addition to this, distinct blood pressure-lowering effects can be determined, especially of such compounds of formula I, where Ac means the residue of a monoester of carbonic acid. Compounds of this kind in particular cause a marked lowering of blood pressure in renal hypertensive male rats (Goldblatt method), which is indirectly calculated in non-anesthetized rats according to the method of Gerold et al. (Heiv. Physiol. Acta 24, 58 (1966)). Thus, after daily oral administration of such compounds for four days, whereby the measure of blood pressure reduction is determined on the fourth day, two hours after administration of the last dose, a blood pressure reduction of -27 mm Hg can be determined at a daily dose of 3 mg/kg , at a daily dose of 10 mg/kg a blood pressure reduction of -81 mm Hg and at a daily dose of 100 mg/kg a blood pressure reduction of -108 mm Hg.

Because of these properties, the pharmaceutical preparations containing compounds of formula I or the new compounds of formula I prove suitable for use as renal vasodilators and as antihypertensives.

Compounds of formula I where Ac means the pyridylcarbonyl residue also have antileukemic activity, as can be shown, for example, in mice with leukemia P 388 which is caused by intraperitoneal transplantation, with the quotient T/C amounting to 129% after intraperitoneal administration of 100 mg/kg of such compounds for five consecutive days once a day, respectively the quotient T/C amounts to 125% after intraperitoneal administration of 50 mg/kg of such compounds once a day for five consecutive days. On leukemia L 1210 which is caused by intraperitoneal transplantation in mice, a value for the quotient T/C of 151% can be determined after intraperitoneal administration of 100 mg/kg of such compounds once a day for nine consecutive days, respectively to 123% after intraperitoneal administration of 60 mg/kg of such compounds in the same manner and duration. These findings were obtained at the behest of the applicant in test models such as the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland (USA). Because of these properties, compounds of formula I, where Ac means the pyridylcarbonyl residue, appear to be suitable for the treatment of leukemia.

The new compounds of formula I can also be used as valuable intermediates for the production of other valuable, particularly pharmaceutically active compounds.

The invention relates in particular to methods for the preparation of new compounds of formula I, where n is an integer from 1-4 and R means optionally substituted lower alkyl, lower alkenyl or lower alkynyl, or a mono- or bicyclic, carbocyclic or heterocyclic, aromatic hydrocarbon residue, Ac means a residue of the formula -C(=O)-R^, where R-^ means an optionally substituted" aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residue, or the residue of a monoester or a monoamide of carbonic acid, on the condition that R as lower alkyl which is bound in the 3-position, has 2-7 carbon atoms, when Ac means the acetyl group, and with the additional proviso that R as bound lower alkyl in the 3-, 4-, 5- or 6-position has 2-7 carbon atoms, when Ac means the benzoyl group, such as racemate mixtures, racemates, optical antipodes or their salts.

The invention relates in particular to methods for the preparation of compounds of formula I, in which n is an integer from 1-4 and R means lower alkyl, optionally etherified or esterified hydroxyl lower alkyl, such as hydroxyl lower alkyl, lower hydroxy lower alkyl or halogen lower alkyl or optionally substituted, such as lower alkylated or acylated amino lower alkyl, which amino lower alkyl, N-lower alkyl amino lower alkyl or N,N-di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, lower alkyl optionally substituted with esterified or amidated carboxy, such as carboxy, ethoxycarbonyl or optionally substituted carbamoyl, such as carbamoyl, such as carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamoyl lower alkyl, oxo-lower alkyl, further Cyan lower alkyl, optionally substituted aryl lower alkyl, in which aryl is a monocyclic, aromatic hydrocarbon residue, e.g. phenyl, or a bicyclic aromatic hydrocarbon residue, such as 1- or 2-naphthyl, or partially saturated naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl, whereby the substituents are lower alkyl, hydroxy and/or halogen, hydroxy lower alkyl, lower hydroxy lower alkyl , halolower alkyl, lower alkoxy, lower alkenyloxy or optionally lower alkylated or acylated amino lower alkyl, e.g. mono- or dilower alkyl-aminolower alkyl or lower alkanoylamino lower alkyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, cyan, nitro or optionally acylated amino, e.g. amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylamino or dilower alkylamino and such substituents may be the same or different and be present 1-3 times, or R and R-, which are contained in the group Ac each stand for aryl, such as phenyl, 1- or 2-naphthyl or partially saturated naphthyl, such as 1,2,3,4-tetra-hydro-5-naphthyl or a residue preferably with 5 or 6 ring members containing an oxygen, sulfur or nitrogen atom and optionally 1-3 further nitrogen atoms as ring members which is connected to the pyridine residue via a ring carbon atom, which may be at least partially hydrogenated and in this case substituted with oxo, whereby the second ring in a bicyclic, heterocyclic residue may be a fused benzo ring, and in particular means pyridyl, e.g. 2-, 3- or 4-pyridyl or dihydro-oxo-pyridyl, e.g. 1,6-dihydro-6-oxo-2-pyridinyl, pyridazinyl, e.g. 3-pyridazinyl, pyrazinyl, e.g. 2-pyrazinyl, pyrimidinyl, e.g. 2-,

4- or 5-pyrimidinyl, or dihydro-oxo-pyrimidinyl, e.g. 3,4-dihydro-4-oxo-2-pyrimidinyl, furyl, e.g. 2-or 3-furyl, pyrryl, e.g. 2- or 3-pyrryl, thienyl, e.g. 2- or 3-thienyl, oxazolyl, e.g. 2- or 4-oxazolyl, thiazolyl, e.g. 2-, 4- or 5-thiazolyl, thiadiazolyl, e.g. 1,2,4-thiadiazol-3- or 5-yl or 1,2,5-thiadiazol-3-yl, imidazolyl, e.g. imidazol-2- or -4-yl, pyrazolyl. e.g. 3- or 4-pyrazolyl, triazolyl, e.g. 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, tetrazolyl such as tetrazol-5-yl, further indolyl, e.g. inol-4-yl, quinolinyl, e.g. 2-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzimidazolyl, e.g. 2-benzimidazolyl, benzofuranyl, e.g. 4-or 5-benzofuranyl, benzothienyl, e.g. 4- or 5-benzothienyl, or naphthyridinyl e.g. 1,8-naphthyridin-2-yl, whereby such aryl residues primarily stand for a ring carbon atom, but also for a secondary ring nitrogen atom and may be substituted one or more times, preferably at most four times, with optionally substituted lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, such as hydroxyl lower alkyl, lower hydroxy lower alkyl or halogen lower alkyl, or optionally substituted, as lower alkylated or acylated amino lower alkyl such as amino lower alkyl, N-lower alkyl amino lower alkyl, N,N-di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, or lower alkenyl or lower alkynyl, optionally etherified or esterified hydroxy or mercapto, such as hydroxy, lower alkoxy, phenyl lower alkyl, halogen, mercapto, lower alkylthio, phenyl lower alkylthio, lower alkoxy which is optionally

substituted with etherified or esterified mercapto or with acyl, e.g. lower alkoxy, phenyl lower aryl oxy, hydroxy lower aryl oxy, lower alkoxy lower rel oxy, lower alkylthio lower rel oxy, halogen lower rel oxy or lower alkanoyl lower rel oxy, or lower alkenyloxy, lower alkynyloxy, lower alkylthio, acyl, e.g. lower alkanoyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, cyan, nitro or optionally substituted, such as acylated amino, e.g. loweralkanoylamino, loweralkylcarbonylamino, loweralkylsulfonyl, sulfamoyl, optionally substituted ureido, further amino, N-loweralkylamino or N,N-diloweralkylamino, which in a group Ac containing R-^ also means loweralkyl, loweralkenyl, loweralkynyl, phenylloweralkyl, phenylloweralkenyl, phenylloweralkynyl, mono - or polycyclic cycloalkyl, e.g. cycloalkyl, which is optionally substituted with optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy and/or halogen, optionally substituted as lower alkylated or acylated amino, such as amino, N-lower alkylamino or N,N-dilower alkylamino, lower alkanoylamino and/or optionally functionally converted carboxy, such as carboxy, esterified carboxy, e.g. optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, or cyan, whereby substituted residues may have one or more substituents which may be the same or different and be present 1-3 times, in any positions suitable for substitution, or Ac is also unsubstituted or substituted, e.g. free or esterified hydroxy, such as lower alkoxy, or unsubstituted or substituted amino, such as amino, lower alkylamino, and primarily disubstituted amino, such as dilower alkylamino, N-lower alkyl-N-phenyl lower alkylamino, or lower alkylene amino which is optionally interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, e.g. with lower alkyl, or lower alkoxycarbonyl containing phenyl which is unsubstituted or substituted e.g. with lower alkyl, lower alkoxy and/or halogen, further N-unsubstituted or N-mono- or N,N-disubstituted carbamoyl, such as lower alkylcarbamoyl, dilower alkylcarbamoyl, or N,N-lower alkylenecarbamoyl which in the lower alkylene part is interrupted by oxygen, sulfur or nitrogen which is unsubstituted or substituted, e.g.

with lower alkyl, with the proviso that R as lower alkyl bound in the 3-position has 2-7 carbon atoms and e.g. is ethyl, n-propyl or n-butyl, when Ac is the acetyl group, and with the further proviso that R as in 3-, 4-, 5-

or 6-position bonded lower alkyl has 2-7 carbon atoms,

and e.g. means the aforementioned ethyl, n-propyl or n-butyl, when Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.

The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1 or 2 and R means lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, lower alkanoylaminolower alkyl, e.g. acetylaminomethyl, and R^ in the group Ac means phenyl or pyridyl which is optionally substituted with lower alkyl, e.g.

methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, lower alkanoylaminolower alkyl, e.g. 2-acetylaminoethyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkyl lower alkyl, e.g. 2-Ethoxyethoxy, Halogen, Lower Alkoxycarbonyl,

e.g. ethoxycarbonyl, carbamoyl, cyano, amino or lower alkanoylamino, e.g. acetylamino, or sulphamoyl, further lower alkyl which is optionally substituted with lower alkoxy, e.g. methoxy, amino, lower alkanoylamino, e.g. acetylamino, carboxy, optionally substituted lower alkoxycarbonyl, e.g. ethoxycarbonyl or 2- or 1-(lower alkylcarbonyloxy)-lower oxycarbonyl or carbamoyl, e.g. ethyl or n-propyl, or Ac also means lower alkoxycarbonyl which is unsubstituted or substituted with lower alkoxy, such as methoxy, or amino, such as ethoxycarbonyl, or carbamoyl,

under the condition that R as lower alkyl bound in the 3-position has 2-7 carbon atoms, and e.g. means ethyl, n-propyl or n-butyl, when Ac is the acetyl group, and with the further proviso that R as a 3-, 4-, 5- or 6-position bonded lower alkyl has 2-7 carbon atoms, and means e.g. . aforesaid ethyl, n-propyl or n-butyl, if Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.

The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1, and R is lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, R^ in the group Ac is phenyl or pyridyl which is optionally substituted with lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkoxy lower real oxy, fe.ks. 2-ethoxyethoxy, halogen, lower alkoxycarbonyl, e.g. ethoxycarbonyl, carbamoyl, cyano, amino or sulfamoyl, further lower alkanoyl lower alkyl which is optionally substituted with lower alkoxy, e.g. methoxy, amino, e.g. 2-Methoxyethyl, R^

in the group Ac is phenyl which is optionally substituted with lower alkyl, e.g. methyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, halogen, carbamoyl, cyano and/or sulfamoyl, further lower alkyl which is optionally substituted with amino, lower alkanoylamino, e.g. acetylamino, and carboxy or optionally substituted lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. ethoxycarbonyl or 2- or preferably 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. ethyl., n-propyl or n-butyl, or Ac also means lower alkoxycarbonyl, such as ethoxycarbonyl, under the condition that R as lower alkyl bound in the 3-position has 2-7 carbon atoms, and means e.g. ethyl, .n-propyl or n-butyl, when Ac means the acetyl group, and with the further proviso that R as a 3-, 4-, 5- or 6-position bonded lower alkyl has 2-7

carbon atoms, and e.g. means the aforementioned ethyl, n-propyl or n-butyl, if Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.

The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1, and R means lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, R^ in the group Ac is phenyl which is optionally substituted with lower alkyl, e.g. methyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, halogen, carbamoyl, cyano and/or sulfamoyl, further lower alkyl which is optionally substituted with amino, lower alkanoylamino, e.g. acetylamino, and carboxy or optionally substituted lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. ethoxycarbonyl or 2- or preferably 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. ethyl, n-propyl or n-butyl, or Ac is also lower alkoxycarbonyl, such as ethoxycarbonyl, under the condition that R as lower alkyl bound in the 3-position has 2-7 carbon atoms, and e.g. means ethyl, n-propyl or n-butyl, when Ac means the acetyl group, and with the additional proviso that R as a lower alkyl bound in the 3-, 4-, 5- or 6-position has 2-7 carbon atoms and e.g. means the aforementioned ethyl, n-propyl or n-butyl, if Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.

The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1 and R

is lower alkyl, e.g. n-butyl, further lower alkyl lower alkyl, e.g. 3-methoxy-n-propyl and R^ in the group Ac means lower alkyl which is preferably substituted in the w-position with carboxy, or lower alkoxycarbonyl, e.g. ethoxycarbonyl, further 2- or preferably 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. pivalyl-carbonyloxy-methoxycarbonyl, or carbamoyl, e.g. ethyl or n-propyl, as racemate mixtures, racemates, optical antipodes, or

their salts, especially their pharmaceutically acceptable salts.

The invention relates in particular to methods for the production of new compounds of formula I, where n stands for 1

and R is in the 5-position bonded lower alkyl, e.g. n-butyl, further lower alkyl lower alkyl, e.g. 3-methoxy-n-propyl, and R^ in the group Ac is n-propyl which is substituted in the two position with amino or primarily with lower alkanoylamino, e.g. acetylamino, and with carboxy or lower alkoxycarbonyl, e.g. ethoxycarbonyl, further 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. pivalyl-carbonyloxy-methoxycarbonyl, whereby a compound with a group R 1

which are defined in this way, preferably present in optically active form, especially in the L-form, or their salts, especially their pharmaceutically usable salts.

The invention relates in particular to methods for the preparation of the new compounds of formula I which are described in the examples.

The new compounds of formula I are prepared in a manner known per se. They can be obtained by a compound with the formula

is reacted with a compound with the formula

or a reactive derivative of such a carboxylic acid, or with a reactive derivative of a monoester or a monoamide of carboxylic acid (IV), and if desired, a thus obtained compound of formula I is converted into another form

bond with formula I, and/or if desired, an obtained racemate mixture is split into the racemates, or an obtained racemate into the optical antipodes, and/or if desired, an obtained free compound with formula I is transferred to a salt or an obtained salt to a free compound or another salt.

Reactive derivatives of the carboxylic acids defined by formula III are e.g. acid anhydrides, for example acid anhydrides which are formed by intramolecular ring closure of dicarboxylic acids which are covered by formula III, e.g. similarly substituted glutaric anhydride, further mixed acid anhydrides, e.g. those with hydrohalic acids, such as the chlorides or bromides, or with e.g. lower alkane carboxylic acids, such as acetic or propionic acid, lower alkoxyalkane carboxylic acids, such as 2-methoxyacetic acid, further the azides, cyanides or amides of such carboxylic acids. Reactive derivatives of carboxylic acids of formula III are especially esters, e.g. lower alkyl, such as methyl or tert-butyl esters, further activated esters, e.g. with cyano-methanol, N-hydroxysuccinimide or N-hydroxybenztriazole, further esters formed with aryl lower alkanols, e.g. benzyl alcohol which is optionally substituted with lower alkyl, e.g. methyl or lower alkoxy, e.g. methoxy, or phenols, which are optionally activated with suitable substances, e.g. with halogen, e.g. 4-halogen, such as 4-chloro, lower alkoxy, e.g. 4-lower oxy such as 4-methoxy, 4-nitro or 2,4-dinitro, such as e.g. 4-chlorophenol, 2,3,4,5,6-penta-chlorophenol, 4-methoxyphenol, 4-nitro- or 2,4-dinitrophenol, further esters which are formed with cycloalkanols, such as e.g. cyclopentanol or cyclohexanol, which may optionally be substituted with lower alkyl, e.g. methyl. Reactive derivatives of monoesters or monoamides of the carbonic acid are e.g. the halides, e.g. the chlorides or bromides thereof. The reaction is carried out in a manner known per se in the absence or presence of a solvent or solvent mixture and, if necessary, during cooling or heating, in an open or closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen. The reaction between free carboxylic acids of formula III and compounds of formula II takes place if necessary in the presence of an acidic, water-splitting catalyst, such as a protonic acid, e.g. hydrochloric, hydrobromic, sulphurous, phosphoric or boric acid, benzenesulphonic or toluenesulphonic acid, or a Lewis acid, e.g. boron trifluoride etherate, if necessary under distillate, e.g. azeotrope, removal of the water released by the reaction. Furthermore, the reaction can also be carried out in the presence of water-binding condensation agents, such as suitably substituted carbodiimides, e.g. N,N'-diethyl-, N,N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide, in inert organic solvents. Mixed anhydrides, especially acid halides, react for example in the presence of acid binding agents, e.g. organic, especially tertiary nitrogen bases, such as triethylamine, ethyldiisopropylamine or pyridine, or alcohols, e.g. alkali metal lower-area anolates, e.g. sodium methylate, or also inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide respectively--carbonate.

The reactions with esters, e.g. those of the aforementioned kind, or with reactive esters, e.g. cyanomethyl or penta-chlorophenyl or N-hydroxysuccinimide esters are carried out, for example, in a solvent which is inert towards the reactants at elevated or lowered temperatures.

The reactions with reactive derivatives of monoesters or monoamides of carbonic acid, e.g. the halides, usually takes place in a solvent that does not participate in the reaction, during cooling or heating, possibly in the presence of an acid-binding agent, e.g. an organic base, e.g. a nitrogen base, such as triethylamine, or an excess of starting material of formula II, or in the presence of an inorganic base, such as an alkali metal or alkaline earth metal carbonate or

-hydroxide, such as sodium or magnesium carbonate or -hydroxide. These reactions are carried out in the usual way. Starting substances with formula II are known or can be prepared in a manner known per se. thus, these compounds can be obtained by e.g. a connection with the formula

where X means a suitable departure group, e.g. optionally reactive esterified hydroxy, such as halogen, e.g. chlorine or bromine, or a hydroxy group which is esterified with an organic sulphonic acid, e.g. an aliphatic or aromatic, such as a lower alkyl sulphonic acid, e.g. methanesulfonic acid or an aromatic, as an optionally substituted, as lower alkylated, and/or halogenated arylsulfonic acid, e.g. benzoic acid, or lower alkoxy such as methoxy, optionally etherified mercapto, such as mercapto or lower alkylthio, lower alkylsulfinyl,

as methylsulfonyl, lower alkylsulfonyl, as methylsulfonyl or the residue -SO^H or the group -NH-NC^, is reacted with anhydrous hydrazine or its hydrate or with hydrazine having up to three protecting groups as substituents,

and then any protective groups present are split off and replaced with hydrogen.

Protection groups are e.g. such as split off and replaced with hydrogen, by means of reduction including hydrogenolysis, or by means of solvolysis, e.g. hydrolysis, e.g. aryl lower alkyl groups such as a phenyl lower alkyl group, e.g. benzyl, which in the aromatic part is optionally substituted with lower alkyl, such as methyl, halogen, such as chlorine, lower alkoxy, such as methoxy, and/or nitro. The reaction with hydrazine or its hydrate as well as the cleavage of any protective groups present takes place in the usual way at an elevated or lowered temperature, in the presence or absence of a further acid-binding agent, e.g. an organic or inorganic base, usually using an excess of hydrazine compounds, possibly in the presence of a solvent, e.g. ethanol, in an open or closed vessel and/or in a protective gas atmosphere, e.g. nitrogen. If the group X is present in a compound of formula IIa as a free hydroxy group, then the reaction with a hydrazine compound takes place under stricter reaction conditions, e.g. at elevated temperature. On the other hand, the presence of an agent which favors the splitting off of water, e.g. a carbodiimide, such as N,N-dicyclohexylcarbodiimide would be advantageous.

Starting substances with the formula II can further be obtained by

a connection with the formula

is reacted with hydroxylamine-O-sulfonic acid (Ile). The reaction takes place in the usual way, at normal or elevated temperature, in the absence or presence of a solvent, e.g. water, suitably in a protective gas atmosphere, e.g. under nitrogen. Starting substances with formula II can also be obtained by the nitro group in a compound with the formula

is reduced to an amino group, the reduction takes place in the usual way, e.g. using a suitable metal in an acidic medium, e.g. in the presence of an aqueous mineral acid, such as sulfuric acid,

but especially in alkaline medium, e.g. in an aqueous solution of a base, such as an inorganic base, e.g. sodium hydroxide.

Starting materials of formula 11c can in turn be obtained from compounds of the aforementioned formula Ilb by nitration, in the usual way, e.g. by means of nitric acid in the presence of concentrated sulfuric acid.

Starting substances of the formula IIa, where R means a mono- or bicyclic heteroaryl group R is formed as described below by compounds of the formula VI, in a compound of the formula

where R_ denotes a substituent capable of forming a mono- or bicyclic heteroaryl residue R, and any protective groups present are removed and replaced with hydrogen. Thus, for example, a compound of formula Ild where R^ is a formyl group can be reacted with a 1,2-dicarbonyl compound of formula Via and ammonia to a compound of formula Ild in the manner described there, in which an imidazolyl residue stands in place of the group R£ , which is linked in its 2-position to the pyridine ring.

Reactive derivatives of starting substances of formula III can be obtained in the usual way. Thus the turnover gives

with an agent that has a halogenating effect in a suitable way, e.g. thionyl chloride, the corresponding carboxylic acid chloride, while the esterification with an alcohol, e.g. an unsubstituted or substituted lower alkanol, or with N-hydroxysuccinimide or N-hydroxybenztriazole or the reaction with suitable diazo compounds, such as unsubstituted or substituted diazoalkanes, leads to corresponding carboxylic acid esters of formula III.

Such compounds can also be obtained when salts are used as starting materials, especially alkali metal or alkaline earth metal salts of free carboxylic acids and these are treated with reactive esters of alcohols, such as unsubstituted or substituted lower alkanols, such as reducing halides, e.g. chlorides, bromides or iodides, or organic sulphonic acid esters, e.g. lower alkanesulphonic acid or arenesulphonic acid esters, such as methanesulphonic acid or p-toluene sulfonic acid esters, or when corresponding hydrolyzable imino esters, such as corresponding imino lower alkyl esters are hydrolyzed to the esters.

Carboxylic acid azides or cyanides of formula III can be obtained in the usual way by reacting a carboxylic acid halide, e.g. the chloride with a salt of nitrous acid or hydrocyanic acid, e.g. the sodium salt, conveniently in the presence of an inert solvent, such as benzene.

The new compounds of formula I can also be obtained

in that in a connection with the formula

where X-^ and X 2 each means hydrogen or a substituent that can be replaced by hydrogen or X-^ or X 2 together means a divalent residue that can be replaced by two hydrogen atoms, and/or functional groups that are present in the groups R and Ac are optionally present in protected form under the condition that at least one of the residues X-^ and X2

is different from hydrogen, or at least X^ and X2 together constitute a divalent residue that can be replaced by two hydrogen atoms, or at least the present functional groups in the group R and/or Ac are in protected form, or

in a salt thereof, the groups X-^, X2 or X^ and X2 together which are different from hydrogen are replaced by hydrogen atoms, and/or in a group R and/or Ac the protective groups attached to one or more functional groups are removed and is replaced with hydrogen, and if desired, the further method steps described in connection with the first method are carried out.

Protected functional groups in a residue R and/or Ac

is e.g. protected hydroxy, amino, mercapto or carboxylic acid groups, whereby the latter are present as esters or imidoesters, whose imido groups can be replaced with an oxygen atom by means of hydrolysis and the ester group can be cleaved to the carboxylic acid group. The spin-off of. the groups X-^ and X2 or X-^ and X2 together as well as protective groups standing in a residue R and/or Ac to functional groups, -e.g. to hydroxy and/or amino or carboxylic acid groups, is carried out by means of solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by means of reduction including hydrogenolysis.

A particularly suitable, cleavable group X₂ or X₂, or a hydroxy, mercapto or amino protecting group in a residue R and/or Ac is primarily a hydrogenolytically cleavable α-aryl-lower alkyl group, such as an optionally substituted 1-polyphenyl -lower alkyl or 1-phenyl lower alkyl group, e.g. benzhydryl or trityl, in which substituents, especially in the phenyl part, e.g. can be lower alkyl, such as methyl, or lower alkoxy such as methoxy, and primarily benzyl. A group X^ and X 2 as well as hydroxy, mercapto and/or amino protecting groups in a residue R and/or Ac can also be a solvolytic, such as hydrolytic or acidolytic, further a' reductive, including hydrogenolytic, cleavable residue, in particular a corresponding acyl residue, such as the acyl residue from an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, further the acyl residue from a half-ester of carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloro-ethoxycarbonyl or 2-iodo-ethoxycarbonyl, optionally substituted 1-phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, e.g. as stated above, and primarily trityl.

A cleavable residue formed by X-^and X~ together is

primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-lower alkylidene, in which substituents, particularly in the phenyl part, e.g. can be lower alkyl or lower alkoxy, and especially benzylidene, or cycloalkylidene, e.g. cyclopentylidene or cyclohexylidene.

Protected carboxylic acid groups that exist as esters or imidoesters are especially those that are cleaved using the methods described above, especially by means of reduction including hydrogenolysis in the basic carboxylic acid and the corresponding alcohol. As ester components in the correspondingly suitable protective groups, e.g. in consideration hydrogenolytically cleavable α-aryl lower alkyl groups, such as an optionally substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, e.g. benzhydryl or trityl, in which substituents, especially in the phenyl part, e.g. can be lower alkyl, such as methyl, lower alkoxy, e.g. methoxy, and/or halogen, and primarily benzyl.

Usable starting materials in the form of salts are primarily used in the form of acid addition salts, e.g. with mineral acids, as well as with organic acids.

Hydrogenolytically cleavable residues X-^ or X2, especially optionally substituted 1-phenyl lower alkyl groups, further also suitable acyl groups, such as optionally substituted 1-phenyl lower alkoxycarbonyl, as well as optionally substituted 1-phenyl-lower alkylidene groups which are formed together with the groups X-^ and X £, as well as hydroxy, mercapto and/or amino protecting groups of this type present in a group R and/or Ac, further α-aryl lower alkyl present in carboxylic acid esters or -imido esters as a cleavable group, can be cleaved by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a catalyst, such as a suitable noble metal catalyst, e.g. palladium or platinum.

Hydrolytically cleavable groups X-^ and X2 / as acyl residues

of organic carboxylic acids, e.g. lower alkanoyl, and of half-esters of carboxylic acid, e.g. lower alkoxycarbonyl, further e.g. trityl residues, as well as lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups which are formed together with the residues X^ and X 2 , as well as protective groups of this kind which in a residue R and/or Ac stand for functional groups, such as hydroxy, mercapto and/or amino groups, depending on the nature of such residues, can be split off by treatment with water under acidic or basic conditions, e.g. in the presence of a mineral acid, such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate, or an amine, such as isopropylamine.

The hydrolysis of iminoester groups, for example, to corresponding residues of monoesters or monoamides of carbonic acid takes place, for example, with the aid of hydrous mineral acids, such as hydrochloric or sulfuric acid, whereby the imidoester salt, e.g. -hydrochlorides, such as obtained by addition of hydrogen chloride to the nitrile and reaction with anhydrous alcohols, especially unsubstituted or substituted lower alkanols, can be hydrolyzed after addition of water directly to the corresponding esters.

Acidolytically cleavable residues X-^ and X2 and/or to functional groups, e.g. the aforementioned, e.g. to hydroxy, mercapto and/or amine standing protective groups in a residue R and/or Ac, are especially certain acyl residues of half-esters of carboxylic acid such as e.g. tert-lower oxycarbonyl or optionally substituted diphenylmethoxycarbonyl residues, further also a tert-lower alkyl residue. Such residues can be split off, e.g. by treatment with suitable strong, organic carboxylic acids, such as lower alkane carboxylic acids optionally substituted with halogen, especially fluorine, primarily with trifluoroacetic acid (if necessary, in the presence of an activating agent, such as anisole), as well as with formic acid.

Under reductively cleavable residues X^ and X^ and/or protective groups that stand for functional groups, e.g.

the aforementioned, e.g. to hydroxy, mercapto and/or amino,

in a residue R and/or Ac, such groups are also understood which can be split off by treatment with a chemical reducing agent (especially with a reducing metal or a reducing metal compound). Such residues are especially 2-halogen lower oxycarbonyl or arylmethoxycarbonyl, which can be cleaved off e.g. by treatment with a reducing heavy metal, such as zinc or with a reducing heavy metal salt, such as a chromium (II) salt, e.g. -chloride or -acetate, usually in the presence of an organic carboxylic acid such as formic or acetic acid, and of water.

Protecting groups, which stand for functional groups, e.g. hydroxy, mercapto and/or amino groups present in a residue R and/or Ac correspond to the aforementioned groups which are cleavable and can be replaced by hydrogen, using the described methods, whereby such groups during the described method split off with other groups or later in a separate method ratio rule.

The above reactions are usually carried out in the presence of a solvent, or a solvent mixture, whereby suitable reaction participants can also function as such, and if necessary, during cooling or heating, e.g. in an open or closed vessel and/or in an inert gas atmosphere, e.g. nitrogen.

Starting substances with formula IV can be obtained in the usual way, as a compound of the aforementioned formula IIa is reacted with a compound of the formula

where X^, X2 and Ac have the above meanings. It is expedient to work in the presence of a condensing agent, for example in the case that X is a reactive esterified hydroxy group, in the presence of an acid binder, e.g. an alkaline condensing agent, e.g. an organic base, such as triethylamine, or an inorganic base, such as an alkali carbonate or bicarbonate, such as sodium carbonate or bicarbonate. If X in a compound of formula IIa is a free hydroxy group, the reaction with a compound of formula IVb can take place in the presence of a water-binding agent, e.g. a carbodiimide, such as N,N'-dicyclohexylcarbodiimide or N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide in an inert solvent, e.g. tetrahydrofuran. It can also be worked out so that for the described reaction instead of a compound of formula IVb a compound of the formula is used

and in the obtained compound of formula IV, which has a hydrogen atom instead of a group Ac, the group is introduced

Ac, e.g. using a corresponding carboxylic acid, which is optionally present as a reactive derivative, as a halide or anhydride, or as a reactive ester. These reactions usually take place in the presence of a suitable inert solvent in the presence or absence of a condensing agent at elevated or lowered temperature and if necessary under a protective gas atmosphere, such as nitrogen.

The new compounds of formula I can likewise be obtained by a compound of the formula

where X is a suitable leaving group and R has the above meaning, is reacted with a compound of the formula

where Ac has the above meaning, and if desired, the further method steps described in connection with the first method are carried out. A suitable group X is e.g. optionally reactive esterified hydroxy, such as hydroxy, or halogen, such as chlorine or bromine, or a hydroxy group which is esterified with an organic sulphonic acid, e.g. an aliphatic sulfonic acid, such as a lower alkanesulfonic acid, such as methanesulfonic acid, or an aromatic, such as an optionally substituted, such as lower alkylated and/or halogenated arylsulfonic acid, e.g. benzoic acid, further lower alkoxy, e.g. methoxy, optionally preferred mercapto, such as mercapto or lower alkylthio, such as methylthio, lower alkylsulfinyl, such as methylsulfinyl, lower alkylsulfonyl such as methylsulfonyl, nitro, the residue -SO^H or the group -NH-NC>2 .

The reaction is carried out in a manner known per se, suitably in a suitable solvent in the absence or presence of a condensing agent, for example, when X is a reactive esterified hydroxy group, an acid binding agent, such as a base, e.g. an organic nitrogen base, such as triethylamine, or a metal alkoxide, such as a metal lowereal alkoxide, e.g. sodium methylate or an inorganic base, such as an alkali metal or alkaline earth metal carbonate or hydroxide, such as sodium or magnesium carbonate. Solvents can thereby serve as condensation agents, i.e. accelerate turnover. As a solvent of this kind which is possibly used in a mixture with other solvents, e.g. those of a non-polar character, primarily those of a polar character come into consideration, e.g. lower alkanols, such as methanol or ethanol, further amides of lower alkane carboxylic acids, e.g. dimethylformamide, N-methyl-acetamide, N,N-dimethylacetamide, further phosphoric acid amides,

like for example. hexamethylphosphoric acid triamide, as well as poly-methylated ureas such as N,N,N<1>,N<1->tetramethylurea, so

as well as sulfolane, also optionally lower alkylated, such as N-methylated 2-pyrrolidone, further dimethylsulfoxide, as well as mixtures of such substances. If X in a compound of formula IIa stands for hydroxy, the reaction is carried out, if necessary, in the presence of an agent which favors the elimination of water. As such, e.g. in consideration of acid-reactive substances, such as e.g. mineral acids, such as hydrogen chloride or sulfuric acid, further organic acids, especially sulphonic acids, e.g. benzene or p-toluenesulfonic acid, which in the presence of a suitable, inert solvent, e.g. butanol, or an aromatic compound, such as benzene or toluene, accelerates the distillative, e.g. azeotrope, removal of the water of reaction formed. However, the condensation according to the method during binding of the formed water can also take place with the help of a carbon diimide, e.g. N,N-diethyl or N,N-dicyclohexylcarbodiimide in an inert solvent.

These reactions are carried out in the usual way at elevated or lowered temperatures in open or closed vessels, if necessary under a protective gas such as nitrogen. The starting materials are known or, if they are new, can be prepared according to usual methods. Thus, starting substances of formula V are obtained by reacting hydrazine which optionally contains protective groups, or its hydrate, which are cleavable and can be replaced with hydrogen, e.g. by means of reduction and hydrogenolysis, or by means of solvolysis, such as hydrolysis, for example α-aryl lower alkyl groups such as benzyl, or acyl groups, e.g. lower alkanoyl, such as acetyl, with a compound which allows the introduction of an acyl residue Ac, e.g. a corresponding carboxylic acid or a reactive derivative thereof, e.g. as described above, and subsequent removal of any protective groups present and their replacement with hydrogen.

The new compounds of formula I, where n stands for 1 and

R is a mono- or bicyclic heteroaryl radical, can likewise be obtained by that in a compound with the formula

where hydroxy and/or amino groups are protected with protective groups, and R2 is a substituent capable of forming a mono- or bicyclic heteroaryl residue R, the mono- or bicyclic heteroaryl group R is formed, any protective groups present simultaneously or subsequently are cleaved off and replaced with hydrogen, and if desired, the further method steps described in connection with the first method are carried out. Protection groups are e.g. acyl, such as lower alkanoyl, e.g. acetyl which is cleaved off under the process conditions used to form the heteroaryl radical R and replaced with hydrogen. Thus, for the preparation of a compound of formula I, where R means an imidazolyl residue, such as e.g. is attached to the substituted pyridyl group in the 2-position, a compound of formula VI, where R 2 is the formyl group, is reacted in the usual way with a 1,2-dicarbonyl compound of the formula

where R^ and/or R^ each means hydrogen or a residue which substitutes the heteroaryl group, e.g. as described above, in the presence of ammonia or with a monooximino compound corresponding to formula Via. Depending on the nature of the radicals R^ and/or R^, the compound of formula Via can be used as such or it can be formed in situ in the reaction mixture from a suitable precursor. Precursors suitable for this are e.g. derivatives of hydroxyacetone and are e.g. 1,1-dihalo-, such as e.g. 1,1-dibromoacetone, which is optionally substituted in the 1- and/or 3-position with the group R^ and/or R^. Other precursors are those in which the dicarbonyl compound of formula Via is present in a converted form, e.g. as acetal, as dimethyl acetal, as hydrate or as bisulphite addition compounds. In the case of 1,1-dihaloacetone derivatives, treatment with hydrolysing agents, preferably weak alkalis, e.g. sodium acetate, or in the case of acetals or bisulphite addition compounds with aqueous acids, the compound of formula Via is obtained in situ. In this way, compounds of formula I are obtained, where the substituted pyridyl residue substitutes a 2-position, a group R^ and/or R^ each 4- or The 5-position in the formed imidazole residue.

For the preparation of compounds of formula I, in which an imidazole residue R e.g. is substituted in the 4-position with the substituted pyridyl residue, one can e.g. by reacting a compound of formula VI, where R 2 is the group with a compound of formula

and obtains ammonia. In this way, the groups can

with formula VIb or VIc also exist in functionally converted form, e.g. as acetals, as dimethyl acetals,

as hydrates or as bisulphite addition compounds,

from which the free compounds are formed in situ by treatment with aqueous acids, and are then reacted further in the same reaction mixture. These transactions are carried out in the usual way, e.g. in the presence of a solvent or solvent mixture, and if necessary, during cooling and heating, if necessary in a closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen.

The starting materials can be produced in a manner known per se.

Thus, compounds of formula VI can be prepared, where R ? is the formyl group or the group of formula VIb,

by reacting a compound with the formula P^-Py-OH (Vid), where the formyl group or the group with formula VIb corresponding to the residue P^, is preferably present in protected form, e.g. as acetal, as dimethyl acetal, as hydrate or as bisulphite addition compound, e.g. the one formed with sodium sulphite, and the hydroxy group is also present in a reactive, esterified form, e.g. as halogen, as chlorine or bromine, or as a hydroxy group which is esterified with a sulfonic acid, such as methane- or an aryl-, such as benzenesulfonic acid, with a compound of the above formula IVb or V in the manner described there, e.g. . in the presence of a carbodiimide, such as N,N-dicyclohexylcarbodiimide, or if the hydroxy group is reactively esterified, in the presence of a basic condensing agent, and removal of protecting groups present, e.g. as described.

A compound of formula I, where R means the thiazolyl radical, which e.g. is substituted in the 2-position with the substituted pyridyl group, can be obtained by a compound of formula VI, where R 2 is the group of the formula

is reacted with a compound with the formula where Hal stands for halogen, e.g. for chlorine and especially for bromine, and R^ and/or R^ each means hydrogen or a residue substituting the heteroaryl group, e.g. as described above. Depending on the nature of the radical R^ and/or R^, a compound of formula VIf can be used in the form of its derivatives, e.g. the acetals, such as the diethyl acetals. For the preparation of compounds of formula I, where R is a thiazolyl residue which is substituted in the 4- or 5-position with the substituted pyridyl group, e.g. a compound of formula VI, where R 2 is the group with the formula or the formula and the carbonyl group is optionally present in protected, e.g. acetal form, where Hal each stands for halogen, e.g. for chlorine or bromine, and R^ and R^ have the above meanings, is reacted with a compound of the formula

These reactions are carried out in a manner known per se, e.g. in the presence of a suitable solvent, e.g. a lower alkanol such as ethanol, or an ethereal liquid, such as dioxane, optionally at elevated temperature and optionally in the presence of a basic agent, e.g. a metal, such as alkali or alkaline earth salt of a weak acid, such as carbonic acid or acetic acid, e.g. magnesium carbonate or sodium acetate, and if necessary, in a closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen.

The starting materials can be produced using known methods. Thus, a compound of formula VI can be obtained with the group Vie as R2, being in a compound of the formula

the group N=C- is converted to the group Vie by reaction with hydrogen sulphide in a suitable, e.g. a basic organic solvent, such as e.g. pyridine or triethylamine or mixtures thereof. Starting substances with the formula Vik can, in turn, be obtained by a compound with the formula

where the hydroxy group is possibly present in reactive

esterified form, e.g. such as halogen or a sulfonyloxy group, e.g. as described above, is reacted with a compound of the formula IVb or V, e.g. as described there, and any protective groups present are cleaved off and replaced with hydrogen.

Starting substances with the formula VI, where R^ stands for a group with the formula Vlh or VIi, can e.g. is achieved by a compound with the formula

or the formula

where Hal stands for halogen, e.g. chlorine or bromine, and the hydroxy group can also be present in a reactive form, e.g. as described, as halogen, as chlorine or bromine, is reacted with a compound of formula IVb or V, e.g. as described, and any protective groups present are split off and replaced with hydrogen.

A compound of formula I, where R means a pyrimidinyl residue which is linked to the substituted pyridyl group in the 4(6) position, can be obtained by e.g. a compound of formula VI, where R 2 is the group of the formula

where the carbonyl group(s) may be present in a protected form, e.g. acetalized form, e.g. as dimethyl acetal, or as bisulphite addition compound, e.g. with sodium bisulphite, is reacted with a compound of the formula

where R. and have the above meanings.

This reaction is carried out in the usual way and preferably under acidic conditions, e.g. in the presence of an acidic reacting agent, such as ammonium chloride.

The starting materials can be produced in a manner known per se.

Thus, e.g. a starting material of the formula VI

with the group VIo as R^ is prepared by a compound of the formula

with preferably protected, e.g. as described, e.g. acetalised carboxaldehyde groups are reacted with a compound of formula IVb or V, e.g. as described and any protective groups present are cleaved off.

For the preparation of compounds of formula I, where R means a pyrimidinyl residue, such as e.g. is linked to the substituted pyridyl group in the 2-position, can e.g. a compound of formula VI, where R^ is the group of the formula is reacted with a compound of the formula

where the carbonyl group(s) may be present in a protected form, e.g. acetalized form, e.g. as dimethyl acetals, and and R^ have the indicated meanings. This turnover is carried out in a manner known per se, e.g. under acidic conditions, e.g. as described, e.g. in the presence of ammonium chloride.

The starting materials can be produced in a manner known per se. Thus, a compound of formula VI with the group Vir as R2 can be obtained by converting a compound of the above-mentioned formula (Vik) into the corresponding iminoester, e.g. by saturating an absolute ethanolic solution of such a compound with hydrogen chloride, and from this a compound of formula VI is obtained by reaction with anhydrous ammonia

containing the group (Vir) as R2, preferably in the form

of a salt, e.g. with a strong acid, e.g. as hydrochloride, and optionally present protective groups are removed at the same time or later and replaced with hydrogen.

When selecting the suitable above method for preparing compounds of formula I, care must be taken that the substituents present are not converted or split off, if such conversions or splits off are not desired. Thus, especially functionally converted carboxyl groups, such as esterified or amidated carboxyl groups, as well as cyano groups, can participate in the reaction and be converted during solvolysis, especially hydrolysis, further also by reductions. On the other hand, it may be desired with simultaneous conversions of substituents, e.g. can unsaturated substituents, such as lower alkenyl, under the conditions of a reduction method used according to the invention, e.g. is reduced to lower alkyl.

Compounds obtained according to the invention can, within the framework of the definition of the compounds of formula I, be transferred in the usual way to other end substances, e.g. in that suitable substituents are converted, introduced or cleaved off.

Free carboxyl groups can be esterified in the usual way, for example by reaction with a corresponding alcohol, advantageously in the presence of an acid, such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by reaction with a corresponding diazo compound, e.g. diazomethane. The esterification can also be carried out by converting a

salt, preferably an alkali metal salt of the acid with a reactive esterified alcohol, e.g. a corresponding halide, such as chloride.

Free carboxyl groups can be amidated in the usual way, for example by reaction with ammonia, or with a primary or secondary amine, advantageously in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by transferring the carboxyl group to a halocarbonyl, e.g. chloro-carbonyl group and subsequent reaction with ammonia or with a primary or secondary amine.

In compounds containing an esterified carboxyl group, this can be in the usual way, e.g. by hydrolysis, preferably in the presence of strong bases, such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, or strong acids, e.g. a strong mineral acid, such as a hydrohalic acid, e.g. hydrochloric acid or sulfuric acid, is transferred to a free carboxyl group.

In compounds containing an esterified carboxyl group, this can, in the presence of another alcohol, preferably in excess, be converted into a carboxyl group containing the other alcohol as an ester component, e.g. in the presence of a basic catalyst, e.g. an alkali metal compound of the alcohol used for the transesterification, or a suitable

catalyst, e.g. a noble metal catalyst, such as

a palladium-on-charcoal catalyst.

In compounds with an esterified carboxyl group as a substituent, this can be used in the usual way, e.g. by ammonolysis or aminolysis with ammonia or a primary or secondary amine is transferred to the corresponding carbamoyl group.

Compounds with an unsubstituted carbamoyl group can in the usual way, e.g. by the action of water-extracting agents, such as phosphorus pentoxide, phosphorus oxychloride or trifluoroacetic anhydride, preferably at higher temperatures, are dehydrated to the corresponding cyan compounds.

In compounds with an esterified carboxyl group as a substituent, the esterified carboxyl group can be used in the usual way, e.g. by impact of an organic, e.g. a dilave alkyl aluminum amide compound, e.g. diethylaluminium amide, is converted to a cyano group.

Compounds containing a cyano substituent can be conventionally, e.g. in the presence of concentrated aqueous mineral acids or alkali metal hydroxides, are hydrolysed to the corresponding carbamoyl or directly to carboxyl compounds.

Compounds with a cyano group as a substituent can in the usual way, e.g. by addition of alcohols in the presence of an anhydrous acid, such as hydrogen chloride, and subsequent hydrolysis of the obtained imido ester is alcoholized to the corresponding compounds with esterified carboxyl groups.

Compounds which contain an amino group as a substituent can, in the usual way, be converted into corresponding acylamino compounds, such as e.g. lower alkanoylamino compounds,

e.g. by reacting a corresponding carboxylic acid, such as a lower alkane carboxylic acid or a reactive derivative

thereof, as a halide, or an anhydride or an ester, such as a lower alkyl ester.

Compounds, which contain an amino group as a substituent, can be converted in the usual way to the corresponding lower alkylamino or dilower alkylamino compounds, for example by reaction with a lower alkyl halide, such as a bromide or an iodide thereof.

Compounds having a lower alkylthio-, e.g. methylthio group in an aromatic ring, can e.g. by suitable agents that have a desulfurizing effect, e.g. Raney nickel, in a suitable solvent, e.g. dioxane, is converted to the sulphur-free compounds.

As with the production methods, care must also be taken when carrying out the additional steps that unwanted side-reactions, which may result in the transformation of further groupings, do not occur.

The reactions described above can optionally be carried out simultaneously or one after the other, further in random order.

If necessary, they take place in the presence of diluents, condensing agents and/or agents that act as catalysts at a lowered or elevated temperature, in a closed vessel under pressure and/or in an inert gas atmosphere.

Depending on the process conditions and starting materials, the new compounds are obtained in free form or in the form of their salts, which are likewise covered by the invention, whereby the new compounds or their salts can also be present as hemi-, mono-, sesqui- or polyhydrates thereof. Acid addition salts of the new compounds can on i and

known manner, e.g. when treated with basic agents, such as alkali metal hydroxides, -carbonates or -hydrogen-

carbonates or ion exchangers, are transferred to the free compound. On the other hand, free bases obtained can form acid addition salts, e.g. with the aforementioned acids, whereby for their preparation such acids are particularly used, which are suitable for the formation of pharmaceutically acceptable, non-toxic salts. Salts of the new compounds with bases can in a manner known per se, e.g. by treatment with acidic agents, such as dilute mineral acids, such as hydrochloric or sulfuric acid, or with organic acids, such as acetic acid, or with acidic ion exchangers are transferred to the free carboxylic acids. These can in turn form corresponding salts by reaction with bases, e.g. inorganic or organic bases, whereby pharmaceutically acceptable, non-toxic bases are particularly used, for example those mentioned.

These or other salts, especially acid addition salts

of the new connections, such as oxalates or perchlorates, can also serve to purify the free bases obtained, as the free bases are transferred to salts, these are separated and purified, and the bases are released from the salts again.

Depending on the choice of starting materials and method of working, the new compounds can exist as optical antipodes or racemates, or if they contain two asymmetric carbon atoms, also as racemate mixtures. The starting materials can also be used as specific optical antipodes.

Obtained racemate mixtures can, due to the physico-chemical differences in the diastereoisomers, in a known manner, e.g. by chromatography and/or fractional crystallization, are divided into the two stereoisomeric (diastereomeric) racemates.

Obtained racemates can be divided in a manner known per se

in the antipodes, e.g. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance that forms salts with the racemic compound, which acids

or bases, and separation of the salt mixture obtained in this way, e.g. due to different solubilities, in the diastereomeric salts, from which the free antipodes can be liberated by the action of suitable agents. Particularly usable optically active acids are e.g. The D and L form of tartaric acid, di-0,0'-(p-toluoyl)-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Especially usable optically active bases are e.g. optically active amines, such as optically active amino acid esters, (-)-brucine, (+)-quinidine, (-)-quinine, (+)-quin-conine, (+)-dehydroabiethylamine, (+)- or (- )-ephedrine. Advantageously, the most effective of the two antipodes is isolated.

The invention also applies to those embodiments of the method, according to which it is started from a compound obtained as an intermediate product at any step in the method, and the missing method steps are carried out, or the method is interrupted at any step, or in which under the reaction conditions, a starting substance is formed, or in which a reaction component is possibly present in the form of its salt.

Expediently, when carrying out the reactions according to the invention, such starting substances are used, which lead to the groups of end substances mentioned in particular at the beginning and in particular to the particularly described or highlighted end substances.

The starting materials are known or, if they are new, can be obtained using methods known per se, as described above, e.g. analogous to the examples. New starting substances, especially those with the above-mentioned formula II, where R and n have the meanings given under formula I, n in particular stands for 1 and R stands for \ 3- or 6-position, but especially in the 5-position, and means lower alkoxy lower alkyl,

e.g. 2-methoxyethyl, or phenyl lower alkyl, e.g. benzyl, or if n is 1, is lower alkyl of 2-7 carbon atoms

as ethyl, n-propyl or n-butyl and with the further proviso that R as lower alkyl in the 4-position has 3-7 carbon atoms and for example means n-propyl or n-butyl, when n is 1, or their salts, especially pharmaceutical applicable non-toxic acid addition salts, as well as the process for their preparation, likewise form an object of the invention. The invention also relates to new intermediates that can be obtained by means of the method, as well as to the method for their production.

The invention likewise relates to the use of the compounds of formula I or of pharmaceutically usable salts of such compounds, especially as pharmacologically active compounds, especially in the renal and cardiovascular area. Thereby, they can be used, preferably in the form of pharmaceutical preparations, in a method for prophylactic and/or therapeutic treatment of hypertension. The dosage of the active substances, which are supplied alone or together with the usual carrier and auxiliary materials, depends on the species to be treated, its age and individual condition, as well as the method of administration. The total daily dose of the antihypertensive compounds to be administered in one or more, preferably no more than four single doses, is for mammals with a body weight of approx. 70 kg, depending on the nature of the disease, individual condition and age, preferably between 150 and 750 mg.

The invention further relates to pharmaceutical preparations, which contain a pharmacologically effective amount of the active substance, optionally together with pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral, or parenteral administration, and can be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or potassium stearate, and/or polyethylene glycol. Tablets can also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, explosives, such as e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, colourings, flavorings and sweeteners.

Furthermore, the new pharmacologically active compounds can be used in the form of preparations that can be administered parenterally or in the form of infusion solutions. Such solutions are preferably isotonic, aqueous solutions or suspensions, whereby these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, cross-linking and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers. Present pharmaceutical preparations which, if desired, can contain other pharmacologically active substances, are prepared in a manner known per se, e.g. by means of conventional mixing, granulation, coating, solution or lyophilization methods, and contains from approx. 0.1 to 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

Example 1

A solution of 15.1 g of N-(benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester in 150

ml of methanol is hydrogenated after adding 1.5 g of palladium-on-charcoal catalyst (5%) under normal conditions until hydrogen absorption is complete. The suspension is diluted with methanol,

is heated and filtered through a filter aid. The filtrate is evaporated to a small volume on a rotary evaporator, stirred with isopropanol and then filtered.

By recrystallization of the residue from methanol and drying

in high vacuum, L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-hemihydrate is obtained with melting point 155-157°, [a]p°: + 27° ±1° (c = 0.5 - 1% in methanol).

The starting material can be prepared as follows:

A solution of 6.9 g of 2-hydrazino-5-n-butyl-pyridine in 175

ml of dry tetrahydrofuran is cooled in an ice bath, 19.6 g of N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester are added in portions while stirring, and then stirred for a further 2 hours at 0°. After removal of the solvent on a rotary evaporator and chromatography of the residue over silica gel using ethyl acetate as eluent, N-(benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl )-hydrazide]-1-benzyl ester as oil, which is further processed as such.

Example 2

To a suspension of 1.47 g of L-glutamic acid-5-[N<2->5-n-butyl-2-pyridyl)-hydrazide and 1.33 g of anhydrous sodium carbonate in 20 ml of dimethylformamide, while stirring at room temperature, a of 0.53 g of acetic anhydride in 5 ml of dimethylformamide during 15 minutes. It is stirred for a further 15 hours at room temperature, then filtered through a filter aid and the filtrate is freed of solvent on a rotary evaporator. The remaining yellowish foam is chromatographed on silica gel with a solvent mixture of chloroform/methanol/ammonia 5:3:1. The main fractions are combined and freed from solvent on a rotary evaporator. To prepare the ammonium salt, the residue is dissolved in an excess of methanolic ammonia, the solution is evaporated and the product is recrystallized from isopropanol, whereby the ammonium salt of N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2 -pyridyl)-hydrazide], m.p. 147-149°; [a]£ 7 o: +29° ± 1°, (c = 0.5-1% in methanol); Rf value in the system methylene chloride/methanol/NH^OH conc.

(5:3:1) 0.76.

Example 3

A solution of 2.7 g of N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester in 50 ml of methanol is hydrated after adding 0 .5 g of palladium-on-charcoal catalyst (5%) under normal conditions until hydrogen absorption is complete.

The catalyst is filtered off and the filtrate is freed of solvent on a rotary evaporator. The residue is chromatographed on silica gel with a solvent mixture of chloroform/methanol/ammonia 5:3:1. The main fractions are combined and freed from solvent. To prepare the ammonium salt, the residue is dissolved in an excess of methanolic ammonia, the solution is evaporated again and the product is recrystallized from isopropanol, whereby the ammonium salt of N-acetyl-L-glutamic acid-5- [ N2 -(5-n-butyl-2- pyridyl)-hydrazide];

m.p. 147-149°, [a]£ ? n: +29° ± 1°, (c = 0.5-1% in methanol).

The starting material can be prepared as follows:

A suspension of 3.17 g of 2-hydrazino-5-n-butyl-pyridine dihydrochloride in 60 ml of dry tetrahydrofuran is cooled to 5° and, with stirring, first 4.2 ml of triethylamine and after 5 minutes 5.0 g of N-acetyl are added -L-glutamic acid 1-benzyl ester 5-(N-hydroxysuccinimide) ester. The mixture is then stirred for 15 hours at room temperature, triethylamine hydrochloride is filtered off and the filtrate is freed of solvent at a bath temperature of 30-40°. The slightly greenish residue is chromatographed on silica gel with a chloroform-methanol mixture (95:5).

The N-acetyl-L-glutamic acid-5-[N<2->5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester obtained from the main fractions in the form of a colorless foam is further processed as such, Rf value in the system methylene chloride/methanol (9:1) on silica gel 0.29.

Example 4

A solution of 7.0 g of 2-hydrazino-5-n-butyl-pyridine in 210

ml of dry tetrahydrofuran is added to 5.9 ml of triethylamine, then a solution of 10.8 g of 3-sulfamoyl-4-chloro-benzoyl chloride in 120 ml of tetrahydrofuran is added dropwise at room temperature with stirring over the course of one hour and further stirred for 2 hour at this temperature. Triethylamine hydrochloride is filtered off, and the filtrate is added with stirring to 300 ml of aqueous 2N acetic acid. The crystallisate that is formed is filtered off, dried and recrystallized twice from acetic acid ethyl ester, whereby 2.5 ml of glacial acetic acid is added to the solvent in the last recrystallization.

After filtering off and drying the precipitate, N2 - is obtained

(5-n-butyl-2-pyridyl)-3-sulfamoyl-4-chloro-benzoic acid hydrazide acetate with m.p. 142-144°.

Example 5

To a suspension of 3.2 g of sodium hydride in 40 ml of toluene, a solution of 10.0 g of 2-hydrazino-5-n-butylpyridine in 150 ml of toluene is added over the course of 15 minutes and then over the course of 10 minutes a solution of 9 .2 g of picolinic acid ethyl ester in 20 ml of toluene. It is then gently heated for one hour at 40° (first exothermic reaction),

so continue for 2 hours until boiling under reflux. After cooling, the reaction mixture is extracted with a total of 200

ml of 2N hydrochloric acid, the aqueous-acidic phase is washed with ether, the aqueous-acidic phase is made alkaline with caustic soda and extracted exhaustively with ether. After drying the ether solution, a 5N solution of hydrogen chloride in ether is added to this for a strongly acidic reaction, the precipitate is filtered off and recrystallized from ethanol, after which N2 -

(5-n-butyl-2-pyridyl)-picolinic acid hydrazide dihydrochloride is obtained as slightly yellowish crystals with a melting point of 186-191° (decomposition).

Example 6

To a solution of 8.55 g of 2-hydrazino-5-n-butylpyridine i

100 ml of toluene is added in the course of 15 minutes to a solution of 6.5 g of chloroformic acid ethyl ester in 50 ml of toluene while cooling, stirring and passing through a stream of nitrogen. The reaction product is separated in an oily form as a lower layer. To make the reaction complete, the mixture is heated under reflux for a further 2 hours, finally evaporated to dryness, the resinous residue is taken up in a mixture of 250 ml of water and 10 ml of 4N hydrochloric acid and the cloudy solution is washed with 100 ml of ether. From the aqueous phase, the reaction product is released as a base by alkalization with 25 ml of 4N soda solution, extracted with 100 ml of ether and isolated as a crude product after drying the ether solution over sodium sulphate and evaporating to dryness. This crude product is dissolved in a mixture of 100 ml of ether and 50 ml of anhydrous ethanol and 10 ml of a 5N solution of hydrogen chloride in ether is added, after which N-ethoxycarbonyl-N<2->(5-n-butyl-2-pyridyl)- hydrazine is obtained as monohydrochloride as colorless crystals with melting point 133-135°, (from ethanol-ether).

Example 7

To a solution of 4.0 2-hydrazino-5-n-butylpyridine in 40

ml of ether is added over the course of one hour to a solution of 2.5 g of acetic anhydride in 20 ml of ether while cooling and vigorous stirring. After standing for 3 hours, while stirring and cooling, a solution of 7.3 ml of a 5N solution of hydrogen chloride in ether, which is diluted with 50 ml of ether, is added dropwise, the precipitate that has formed is separated and recrystallized from ethanol-ether. N<2->(5-n-butyl-2-pyridyl)-N-acetic acid hydrazide is obtained as monohydrochloride in the form of faintly colored crystals with a melting point of 211-212°.

Example 8

To a suspension of 3.2 g of sodium hydride in 40 ml of toluene, a solution of 10.0 g of 2-hydrazino-5-n-butylpyridine in 150 ml of toluene is added over the course of 5 hours and then over the course of 10 minutes a solution of 11.7 g of fusaric acid ethyl ester in 20 ml of toluene, the mixture is heated during one hour to 60° and then boiled for 2 hours under reflux. After cooling, the reaction mixture is extracted with a total of 200 ml of 2N hydrochloric acid, the aqueous-acidic phase is washed with ether, the aqueous phase is made alkaline with concentrated caustic soda, extracted exhaustively with ether, the ether solution is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 200 ml of anhydrous ether and the solution is added 20

ml of a 5N solution of hydrogen chloride in ether, the precipitate that precipitates is suctioned off and this is recrystallized from ethanol.

N<2->(5-n-butyl-2-pyridyl)-N-fusaric acid hydrazide is obtained as dihydrochloride in the form of slightly yellowish needles with a melting point of 175° (decomposition).

Example 9

A solution of 11.5 g of the N-acetyl-L-glutamic acid 5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester obtained according to example 3 in 120 ml anhydrous methanol is stirred in the presence of 2.3 g of palladium-on-charcoal catalyst (5%) for 24 hours at room temperature. After filtering off the catalyst, the filtrate is evaporated on a rotary evaporator, and the residue is chromatographed over silica gel ("FLUKA" 60) using a chloroform-methanol mixture (95:5). This results in N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridy1)-hydrazide]-1-methyl ester, whose Rf value in the system methylene chloride/methanol (9:1 ) on silica gel is 0.23.

Example 10

Analogously, as explained in the general description and described in examples 1-9, the following compounds of formula I or their salts can also be prepared using suitable starting materials and reaction conditions: a) N-acetyl-L-glutamic acid-5-[N< 2->(5-n-butyl-2-pyridyl)-hydrazide]-1-ethyl ester by transesterification of the N-acetyl-L-glutamic acid-5-[N2-(5-n-butyl) obtained according to example 3 -2-pyridyl)-hydrazide]-1-benzyl ester with excess anhydrous ethanol in the presence of a palladium-on-charcoal catalyst (5%) at room temperature, work-up and chromatography of the residue obtained after evaporation of excess ethanol, over silica gel ("FLUKA" 60) as described in example 9, Rf value in the system methylene chloride/methanol (9:1) on silica gel 0.25. b) N-acetyl-L-glutamic acid 5-[N<2->(5-n-butyl1-2-pyridyl)-hydrazide]-1-(2,2-dimethylpropyl)-ester by transesterification of the according to example 3 obtained N-acetyl-L-glutamic acid-5-[N2-(5-n-butyl-2-pyridyl)-hydrazine]-1-benzyl ester with excess anhydrous 2,2-dimethylpropanol in the presence of a palladium-on- charcoal catalyst (5%), at room temperature, work-up and chromatography on silica gel ("FLUKA" 60) of the residue obtained after evaporation of excess 2,2-dimethylpropanol as described in example 9. Rf value in the system methylene chloride/ methanol (9:1) on silica gel 0.28. c) N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-n-butyl ester by transesterification of the N-acetyl obtained according to example 3 -L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester with excess anhydrous n-butanol in the presence of a palladium-on-charcoal catalyst at a temperature of 40-50°, filtering off the catalyst, evaporating the filtrate on a rotary evaporator and chromatographing the residue on silica gel ("FLUKA" 60), as described in example 9. Rf value in the system methylene chloride/methanol (9: 1) on silica gel 0.27.

d) N-acetyl-L-glutamic acid-5-[N2 7(5-n-butyl-2-pyridyl)-hydrazide]-1-amide by reacting it according to example 1

obtained L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] hemihydrate with excess methanol in the presence of cyclohexylcarbodiimide at room temperature to L-glutamic acid-5-[N< 2->(5-n-butyl-2-pyridyl)-hydrazide]-1-methyl ester, whose subsequent reaction with excess ammonia dissolved in methanol in a closed vessel for 5 hours at room temperature and work-up of the reaction mixture to L-glutamic acid-5-

[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-1-amide and its subsequent reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at room temperature for 15 hours, as well as working up and chromatography of the residue as described in example 2. Rf value in the system methylene chloride/methanol (9:1) on silica gel 0.15.

e) N-propionyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reaction of the obtained according to example 1

L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-hemi-hydrate with propionic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at room temperature for 20 hours, work-up and chromatography of the rest on silica gel then

as well as further processing of the main fractions as described in example 2. Rf value in the system methylene chloride/methanol/NH4OH concentrated (5:3:1) 0.78.

f) N-pivaloyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reacting the L-glutamic acid-5-[N<2 obtained according to example 1 ->(5-n-buty1-2-pyridyl)-hydrazide]-hemihydrate with pivalic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at a temperature of 40-50° for 20 hours, working up and chromatography of the residue on silica gel, as well as further processing of the main fractions as described in example 2. Rf value in the system methylene chloride/methanol/NH4OH conc. (5:3:1) 0.80.

g) N-benzoyl-L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide] by reacting the obtained according to example 1

L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-hemi-hydrate with benzoic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at a temperature of 40-50°

for 25 hours, working up and chromatography of the residue on silica gel as well as further processing of the main fractions as described in example 2. Rf value in the system methylene chloride/methanol/NH4OH conc. (5:3:1) 0.79.

h) N-acetyl-L-glutamic acid-5-[N<2->(5-methyl-2-pyridyl)-hydrazide] by reaction of 2-hydrazino-5-methyl-pyridine

with N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporation of the solvent and chromatography of the residue on silica gel using -ethyl acetate as eluent and work-up of the main fractions to (N-benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(5-methyl-2-pyridyl)-hydrazide]-1-benzyl ester, whose subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), recrystallization from methanol of L-glutamic acid-5-[N<2->(5-methyl-2-pyridyl)-hydrazide] which is obtained after work-up,

and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatography of the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3:1 and work-up of the main factions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.70.

i) N-benzoyl-L-glutamic acid-5-[N2-(5-methyl-2-pyridyl)-hydrazide] by reacting the L-glutamic acid-5-[N<2->(5 -methyl-2-pyridyl)-hydrazide] with benzoic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 20 hours at room temperature, evaporation of solvent, chromatography of the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3: 1 and processing of the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.73.

j) N-acetyl-L-glutamic acid-5-[N<2->(5-benzyl1-2-pyridyl)-hydrazide] by reaction of 2-hydrazino-5-benzyl-pyridine with N-(benzyloxycarbonyl)-L -glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide) ester in anhydrous tetrahydrofuran

at 0° for 2 hours, evaporating the solvent and chromatographing the residue on silica gel using ethyl acetate as eluent and working up the main fractions to (N-benzyloxycarbonyl)-L-glutamic acid-5-[ N2-(5-benzyl-2-pyridyl )-hydrazide]-1-benzyl ester, this subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), recrystallization from methanol of the L-glutamic acid-5-[N2- (5-benzyl-2-pyridyl)-hydrazide] as

was obtained after the work-up, and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatography of the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3: 1 and processing of the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.81.

k) N-acetyl-L-glutamic acid-5-[N<2->(5-phenyl-2-pyridyl)-hydrazide] by reaction of 2-hydrazino-5-phenyl-pyridine with N-(benzyloxycarbonyl)-L -glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporation of the solvent and chromatography of the residue on silica gel using ethyl acetate as eluent and work-up of the main fractions to (N-benzyloxycarbonyl )-L-glutamic acid-5- [ N2 -(5-phenyl1-2-pyridyl)-hydrazide]-1-benzyl ester, its subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5 %), recrystallization from methanol of the L-glutamic acid-5-[N<2->(5-phenyl-2-pyridyl)-hydrazide] obtained after work-up, and its N-acetylation by reaction with acetic anhydride in the presence of dimethylformamide of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatography of the residue on silica gel by

using a mixture of chloroform/methanol/ammonia 5:3:1 and working up the main fractions. Rf value in the system

methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.79.

1) N-acetyl-L-glutamic acid-5-[N2-(5-(2-oxo-n-butyl)-2 - pyridyl)-hydrazide] by reaction between 2-hydrazino-5-(2-oxo-n -butyl)-pyridine and N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporating the solvent and chromatographing the residue on silica gel using of acetic acid ethyl ester as eluent and processing of the main fractions to (N-benzyloxy-carbonyl)-L-glutamic acid-5-[N2-(5-(2-oxo-n-buty1-2-pyridyl)-hydrazide]-1-benzyl ester, its subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), recrystallization from a methanol/ethanol mixture of the L-glutamic acid-5-[N<2->

(5-(2-oxo-n-butyl)-2-pyridyl)-hydrazide] which is obtained after the work-up, and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatographing the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3:1 and working up the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.71.

m) N-acetyl-L-glutamic acid-5-[N<2->(5-acetyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-5-acetyl-pyridine and N-(benzyloxycarbonyl)-L -glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporation of the solvent and chromatography of the residue on silica gel using ethyl acetate as eluent and work-up of the main fractions to (N-benzyloxycarbonyl )-L-glutamic acid-5-[N<2->(5-acetyl-2-pyridyl)-hydrazide]-1-benzyl ester, its subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), ambient

stallation from methanol of the L-glutamic acid-5-[N<2->(5-acetyl-2-pyridyl)-hydrazide] which is obtained after the work-up, and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporating the solvent and chromatographing the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3:1 and working up the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.65.

n) N-acetyl-L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-1-(pivaloyloxymethyl)-ester by reaction of the intermediate product obtained according to example 3 N-acetyl-L-glutamic acid-5-[N2-(5-n-2-pyridyl)-hydrazide], and its sodium salt obtained by neutralization with caustic soda and evaporation to dryness, with pivalic acid iodomethyl ester in dimethylformamide at a temperature of 0-50° and subsequent stirring for 17 hours at room temperature, evaporation of the reaction mixture under high vacuum, extraction with acetic acid ethyl ester and flash chromatography of the residue obtained after evaporation of the solvent,

with a methylene chloride/methanol mixture 9:1. Rf value in the system methylene chloride/methanol (9:1 on silica gel 0.26.

In an analogous manner to the preparation of the compounds indicated under h) - n), the following compounds can also be prepared via the corresponding intermediate stages: o) N-acetyl-L-glutamic acid-5-[N<2->(3- n-butyl-2-pyridyl)-hydrazide] from 2-hydrazino-3-n-butyl-pyridine and its derivative by reaction with N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide) -ester obtainable (N-benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(3-n-buty1-2- pyridyl)-hydrazide], its debenzylation to L-glutamic acid-5- [ N2 -( 3 -n-butyl-2-pyridyl)-hydrazide] and its acetylation to the above-mentioned N-acetyl compound.

Rf value in the system methylene chloride/methanol/concentrate

ammonium hydroxide (5:3:1) 0.78.

p) N-acetyl-L-glutamic acid-5-[N<2->(4-n-butyl-2-pyridyl)-hydrazide] from 2-hydrazino-4-n-butyl-pyridine, and the derivative by reaction with N-(benzyloxycarbonyl)-L-glutamic acid-l-benzyl ester-5-(N-hydroxysuccinimide)-ester obtainable (N-benzyloxycarbonyl)-L-glutamic acid-L-glutamic acid-5-[N 2-(4-n- butyl-2-pyridyl)-hydrazide] and its acetylation to the above-mentioned N-acetyl compound. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.77.

q) N-acetyl-L-glutamic acid-5-[N<2->(6-n-butyl-2-pyridyl)-hydrazide] from 2-hydrazino-6-n-butyl-pyridine, and that by reaction with N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester obtainable (N-benzyloxycarbonyl)-L-glutamic acid-5-( N2-(6-n-butyl-2-pyridyl )-hydrazide], its debenzylation to L-glutamic acid-5-[N2-( 6-n-butyl-2-pyridyl)-hydrazide] and its acetylation to the above-mentioned N-acetyl compound Rf value in the system methylene chloride/methanol /concentrated ammonium hydroxide (5:3:1) 0.77.

r) L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-5-n-butylpyridine and L-alanine methyl ester by heating for 2 hours under refluxing in benzene under a nitrogen atmosphere, evaporating the solvent, dissolving the residue in toluene, washing with water, and extracting the organic phase with 2N hydrochloric acid, washing the aqueous-acidic solution with ether, adding to the aqueous solution concentrated sodium hydroxide solution to strongly alkaline reaction, and extracting the mixture with ether, washing the ether solution with water and adding to the ether solution dried with sodium sulfate a 5N solution of hydrogen chloride in ether to strongly acid reaction and separating the obtained L-alanyl -[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-dihydrochloride in the form of white crystals. Rf value of the free base in the system

methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.92.

s) L-alanyl-[N<2->(6-n-butyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-6-n-butylpyridine and L-alanine methyl ester and subsequent work-up as described under r) and separation of the obtained L-alanyl-[N<2->(6-n-butyl-2-pyridyl)-hydrazide]-dihydrochloride in the form of white crystals. Rf value for the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.90.

t) N-acetyl-L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reacting the L-alanyl-[N<2->(5 -n-butyl-2-pyridyl-hydrazide]-dihydrochloride with concentrated caustic soda and the base thus obtained with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at room temperature for 10 hours, evaporation of the solvent under reduced pressure, absorption of the residue in ether , washing the ether solution with water, adding to the ether solution a 5N solution of hydrogen chloride for a strongly acidic reaction and separating the obtained N-acetyl-L-alany1-[N2-(5-n-butyl 1-2-pyridyl) -hydrazide] hydrochloride in the form of white crystals Rf value of the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.85.

u) N-acetyl-L-alany1-[N<2->(6-n-butyl-2-pyridyl)-hydrazide] by reacting the L-alany1-[N<2->(6 -n-butyl-2-pyridyl)-hydrazide dihydrochloride with concentrated caustic soda, reaction of the base thus obtained with acetic anhydride analogously to that described under s), work-up of the reaction mixture and separation of the obtained N-acetyl-L-alanyl-[N<2 ->(6-n-butyl1-2-pyridyl)-hydrazide]-hydrochloride in the form of white crystals. Rf value for the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.83.

v) From the free base obtained by treating the L-alanyl-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-dihydrochloride obtained by the treatment according to r) with concentrated caustic soda, by reaction with the corresponding acid anhydride, the following compound can be obtained in the form of its hydrochloride analogous to t): N-propionyl-L-alany1-[N<2->(5-n-butyl-2-pyridyl)-hydrazide ]. Rf value for the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.85.

w) N-benzoy1-L-alanyl-[N<2->(6-methyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-6-methylpyridine and L-alanine methyl ester by heating under reflux for 3 hours in benzene in a nitrogen atmosphere, evaporating the solvent, dissolving the residue in toluene, washing with water, and extracting the organic phase with 2N hydrochloric acid, washing the aqueous-acidic solution with ether, adding concentrated caustic soda to the aqueous phase to strongly alkaline reaction, and extracting the mixture with ether, washing the ether solution with water and adding a 5N solution of hydrogen chloride in ether to the ether solution dried with sodium sulfate, to strongly acid reaction and separation of the obtained L-alany1 -[N<2->(6-methyl-2-pyridyl)-hydrazide]-dihydrochloride in the form of white crystals. Treatment of an aqueous solution of the obtained dihydrochloride with concentrated sodium hydroxide solution to a strongly alkaline reaction, shaking off the free base with ether, washing the ether solution with water, drying the sodium sulfate and evaporating the solvent, reaction between the residue consisting of L-alanyl -[N<2->(6-methyl-2-pyridyl)-hydrazide] and benzoic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 24 hours at room temperature and working up the reaction mixture to N-benzoyl-L-alanyl-[N<2 ->(6-methyl-2-pyridyl)-hydrazide]. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.80.

Example 11

Tablets containing 20 mg of active substance are produced in the usual way with the following composition:

Manufacturing

The ammonium salt of N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)hydrazide is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is run through a sieve. A further part of the wheat starch is pasted with five times the amount of water in a water bath and the powder mixture is rubbed out with this paste, until a slightly plastic mass has formed.

The plastic mass is pressed through a sieve of approx. 3 mm mesh size, is dried and the resulting dry granulate is run through a sieve again. Then the rest of the wheat starch, talc and magnesium stearate are mixed in and the mixture is pressed into tablets with a weight of 145 mg and with a break section.

Example 12

Tablets containing 1 mg of active substance are produced in the usual way with the following composition:

Composition Preparation L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-hemihydrate is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is run through a sieve. A further part of the wheat starch is pasted with five times the amount of water in a water bath and the powder mixture is rubbed out with this paste, until a weak plastic mass has formed.

The plastic mass is pressed through a sieve with approx. 3 mm mesh size, is dried and the resulting dry granulate is passed once more through a sieve. Then the rest of the wheat starch, talc and magnesium stearate are mixed in and the mixture is pressed into tablets with a weight of 145 mg and with a break section.

Example 13

Capsules containing 10 mg of active substance are produced

in the following way:

Composition

Manufacturing

The active substance is mixed well with talc and colloidal silicic acid, the mixture is passed through a sieve with a mesh size of 0.5 mm and this is filled in portions of 11 mg each in hard gelatin capsules of a suitable size.

Example 14

A sterile solution of 5.0 g of the ammonium salt of N-acetyl-L-glutamic acid-5-[ N2 -(5-n-butyl-2-pyridyl)-hydrazide] in 5000 ml of distilled water is filled into ampoules of 5 ml, which 5 ml of solution contains 5 mg of active substance.

Example 15

3.62 g of N<2->(5-n-butyl-2-pyridyl)-3-sulfamoyl-4-chloro-benzoic acid hydrazide acetate are dissolved in distilled water to a volume of 18100 ml. The sterilized solution is filled in ampoules of 5.0 ml, which contain 1 mg of active substance.

Example 16

Instead of the compounds that were used as active substances in examples 11 to 15, the following compounds of formula I or their pharmaceutically usable, non-toxic acid addition salts can also be used as active substances in tablets, dragees, capsules, etc.: N2-(5-n -buty1-2-pyridyl)-picolinic acid hydrazide, N-ethoxycarbonyl-N<2->(5-n-buty1-2-pyridyl)-hydrazide,N<2->(5-n-buty1-2-pyridyl) -N-acetic acid hydrazide or N<2->(5-n-buty1-2-pyridyl)-N-fusaric acid hydrazide, N-acetyl-L-glutamic acid-5 - [ N2-( 5-n-buty 1-2-pyridyl) hydrazide] - 1-methyl ester,

or the compounds of formula I or their salts described in Example 10, especially pharmaceutically usable, non-toxic acid addition salts.

Claims (1)

1. Process for the preparation of new acylated hydrazine compounds of the formula where R means an optionally substituted aliphatic or aromatic hydrocarbon residue and Ac an acyl residue, and n is an integer from 1-4, whereby, if n has a value from 2-4, the residues R can be the same or different and bound in each of the possible positions in the pyridine ring, under the condition that R as in the 3-position bonded lower alkyl has 2-7 carbon atoms, and n means the value 1, when Ac means the acetyl group, and with the further condition that R as in the 3-, 4- , 5- or 6-position bonded lower alkyl has 2-7 carbon atoms, when Ac means the benzoyl group as racemate mixtures, racemates, optical antipodes or their salts, characterized by ata) a compound with the formula is reacted with a compound with the formula or a reactive derivative of such a carboxylic acid, or with a reactive derivative of a monoester or a monoamide of carboxylic acid (IV), orb) in a compound of the formula where and X^ each means hydrogen or a substituent that can be replaced by hydrogen, or X^ and X2 together mean a divalent residue that can be replaced by two hydrogen atoms, and/or functional groups present in the groups R and Ac are possibly in protected form, with the proviso that at least one of the residues X^ and X^ are different from hydrogen, or at least X-^ and X2 together are a divalent residue that can be replaced by two hydrogen atoms, or functional groups in the group R and/or Ac are at least present in protected form, or in a salt thereof, the groups X^ , X2 or X^ and X^ together which are different from hydrogen are replaced by hydrogen atoms, and/or in a group R and/or Ac the protective groups attached to one or more functional groups, and is replaced by hydrogen, orc) a compound with the formula where X is a suitable leaving group, is reacted with a compound of the formula or d) for the preparation of a compound of formula I, wherein n stands for 1, in connection with the formula where hydroxy and/or amino groups are protected with protecting groups, and is a substituent capable of forming a mono- or bicyclic heteroaryl residue R, which form the mono- or bicyclic heteroaryl group R, any protective groups present are removed simultaneously or subsequently and replaced with hydrogen, and if desired, a thus obtained compound of formula I is converted into another compound of formula I, and/or if desired, a racemate mixture obtained is divided into the racemates, or a racemate obtained into the optical antipodes, and/or if desired, a obtained free compound of formula I to a salt or an obtained salt to a free compound or another salt.