JPS6054366A - Acylated hydrazine compound, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention provides pharmaceutical formulations containing acylated hydrazine compounds,
for use as pharmacologically active preparations, new compounds of this type and
The M-pickling method and the method for producing pharmaceutical preparations of the compound.
Use as pharmacologically active compounds and new starting materials
Regarding. The pharmaceutical preparation according to the invention has the general formula (I): /4\\N/ [wherein R is an optionally substituted aliphatic or aromatic carbonized
represents a hydrogen group, 肚 represents an acyl group, n is an integer from 1 to 4
represents a racemic mixture of such compounds,
Contains in the form of racemates, optical antipodes or salts. n is 2
to 4, the radicals R are the same or different, pyri
It may be bonded to any possible position on the gin ring. The present invention further provides that R, n and the constant given to the general formula (T)
However, when n is 1 and the bladder represents an acetyl group,
In this case, R as the lower alkyl group bonded to the 3-position is
has 2 to 7 carbon atoms, furthermore, n is 1 and ^C
When represents a benzoyl group, 3-14-15- or
2 to 7 R as a lower alkyl group bonded to the 6-position
A racemic mixture, a racemic mixture of general formula (1) having carbon atoms of
New compounds in the form of semi-compounds or optical enantiomers or
Regarding the salts of such compounds. The optionally substituted aliphatic hydrocarbon group R can be, for example,
Lower alkyl groups substituted by combination, e.g. lower alkyl
hydrogen group, optionally etherified or esterified
Roxy-lower alkyl group, e.g. hydroxy-lower alkyl
Kyl group, lower alkoxy-lower alkyl group or halo lower
alkyl groups or optionally substituted, e.g.
Rukylated or acylated amino-lower alkyl
groups, such as amino lower alkyl groups, N-lower alkyl groups,
Minnow lower alkyl group or N,N-di lower alkyl group
Ruamino - lower alkyl group, lower alkanoylamino -
Lower alkyl group or lower alkoxycarponylamino
Lower alkyl group, or optionally esterified or amino
Hydrogenated carboxy groups, such as carboxy groups, lower atom
alkoxycarbonyl group or optionally substituted carbonyl group
Rubamoyl group, e.g. carbamoyl group, N-lower alkyl group
carbamoyl group or N, N-di lower alkyl group
a lower alkyl group substituted with a bamoyl group or an oxo group,
For example, carboxy-lower alkyl group, lower alkoxy group
Rubonyl-41 alkyl group, carbamoyl-lower alkyl group
N-lower alkylcarbamoyl-lower alkyl group
or N,N-di-lower alkylcarbamoyl-lower alkyl
Kyl group, or oxo-lower alkyl group, as well as cyano-lower
alkyl group, or optionally substituted aryl-lower
class alkyl group (aryl group is a monocyclic aromatic hydrocarbon group,
For example, a phenyl group, or a bicyclic aromatic hydrocarbon group, e.g.
1- or 2-naphthyl group or partially saturated
Naphthyl group, for example 1°2, . 3.4-teI dihydro
-5-naphthyl group, and the substituents are lower alkyl group, hydrogen
Droxy group and/or halogen, optionally etherified
or esterified hydroxy-lower alkyl group
, e.g. groups as mentioned above, e.g. lower alkoxy-lower
Alkyl group or halo lower alkyl group, lower alkoxy
group, optionally etherified or esterified
droxy-lower alkoxy group, e.g. lower alkoxy-
Lower alkoxy group or low m alkoxy group, lower alkoxy group
alkenyloxy group, lower alkynyloxy group, or case
Substituted by, e.g. lower alkylated or acylated
amino-lower alkyl groups, such as those mentioned above,
For example, mono- or di-lower alkylamino-lower alkyl
alkyl group or lower alkanoylamino-lower alkyl group
, an optionally esterified carboxy group, e.g.
Ruboxy group or lower alkoxycarbonyl group, amidation
Carboxy groups, e.g. optionally substituted carbamoyls
carbamoyl group, N-(1 alkylcarbamoyl group,
Moyl group or N,N-di-lower alkylcarbamoyl group
, cyano group, nitro group or optionally substituted, e.g.
amino groups such as amino groups, lower alkanoyl
Ruamino group, lower alkoxycarbonylamino group, and
Lower alkylamino group or di-lower alkylamino group
Yes, one or more such substituents, especially 1 to 3 such substituents are present
may be the same or different). The optionally substituted aromatic hydrocarbon group R is monocyclic or
is a bicyclic carbon homocyclic or heterocyclic aromatic hydrocarbon
groups, such as phenyl groups, 1- or 2-naphthyl groups or
partially saturated naphthyl groups, e.g. 1,2,3,4-
Tetrahydro-5=naphthyl group. Monocyclic or bicyclic
As a heteroaryl group of the formula, R is preferably 5 or
has 6 ring members, and the pyridine has 6 ring members.
Oxygen atom, sulfur atom or nitrogen atom as a ring member
Contains elementary atoms and optionally 1 to 3 additional nitrogen atoms
The groups (at least t) may be partially hydrogenated, and this
optionally substituted with an oxo group, a bicyclic heterocycle
the second ring in the formula group may be a fused benzene ring), and
and especially pyridyl groups, such as 2-13- or 4-pyridyl groups.
a zyl group or a dihydroxo-pyridinyl group, e.g. 1
．． 6-sihydro-6-oxo-2-pyridinyl group, pyri
dazinyl group, e.g. 3-pyridazinyl group, pyrazinyl group
, e.g. 2-pyrazinyl group, pyrimidinyl group, e.g. 2-pyrazinyl group, pyrimidinyl group, e.g.
-14- or 5-pyrimidinyl group, or dihydro-
Oxo-pyrimidinyl groups, e.g. 3,4-dihydro-4
-oxo-2-pyrimidinyl group, furyl group, e.g. 2-
or 3-furyl, pyryl, e.g. 2- or
3-pyryl group, chenyl group, e.g. 2- or 3-thi
phenyl group, oxacylyl group, e.g. 2- or 4-oxa
Silyl group, thiazolyl group, e.g. 2-14- or 5-thi
Azolyl group, thiadiazolyl group, e.g. 1,2,4-thi
adiazol-3- or 5-yl group or 1,2.5
-thiadiazol-3-yl group, imidazolyl group, e.g.
baimidazol-2- or -4-yl group, pyrazol
a 3- or 4-pyrazolyl group, a triazol group, such as a 3- or 4-pyrazolyl group,
Lyle group, e.g. 1,2.1-)lyazol-4-yl group
Also number; I: ], 2. , l-triazol-3-yl group
, a tetrazolyl group, such as a te-1-razol-5-yl group
and indolyl groups, such as indol-4-yl groups,
nolinyl group, e.g. 2-quinolinyl group, isoquinolinyl group
groups, such as the 1-isoquinolinyl group, benzimidazolyl
groups, e.g. 2-benzimidazolyl group, benzofuranyl
groups, such as 4- or 5-benzofuranyl groups, benzoche
a nyl group, such as a 4- or 5-benzochenyl group, or a
phthyridinyl group, e.g. 1,8-naphthyridin-2-y
Represents a group. monocyclic or bicyclic carbohocyclic or heterocyclic aryl
The substituents of the group R (in the latter case, in particular, ring carbon atoms are substituted)
However, the secondary ring nitrogen atom may be substituted.
, and one or more, preferably up to 4, substituents are present
), e.g. in the case -t; I/JW changed
Lower alkyl groups, such as lower alkyl groups, optionally
-terified or esterified hydroxy-lower atom
alkyl groups, e.g. hydroxy-lower alkynyl groups, lower
Alkoxy-lower alkyl group or halo lower alkyl group
, or optionally substituted, e.g. acylated amino
alkyl groups, e.g. lower alkanoylamino-lower alkyl groups, e.g.
Alkyl group or lower alkoxycarbonylamino-lower alkyl group
Alkyl group, or lower alkenyl group or lower alkynyl group
, optionally etherified or esterified
Roxy or mercapto groups, such as hydroxy groups,
alkoxy group, phenyl-lower alkoxy group, halogen
mercapto group, lower alkylthio group, or optionally
etherified or esterified hydroxy group or
or lower alkyl substituted with a mercapto group or an acyl group.
xy group, e.g. lower alkoxy group, phenyl-lower alkoxy group
Koxy group, hydroxy-lower alkoxy group, lower alkoxy group
xy-lower alkoxy group, lower alkylthio-lower alk
Koxy group, halo lower alkoxy group or lower alkanoyl
-lower alkoxy group, or lower alkenyloxy group,
Lower alkynyloxy groups, acyl groups, e.g. lower alkyl groups
noyl group, optionally esterified carboxy group,
For example, a carboxy group or a lower alkoxycarbonyl group,
Amidated carboxy groups, e.g. optionally substituted carbon
Rubamoyl group, e.g. carbamoyl group, N-lower alkyl group
carbamoyl group or haN,N-di lower alkylcarba
Moyl, cyano, nitro or optionally substituted, e.g.
For example, acylated amino groups, e.g. lower alkanoyl
Amino group, lower alkoxycarbonylamino group, lower a
Rukylsulfonyl group, sulfamoyl group, optionally substituted
Substituted urei I group and amino group, N-lower alkyl
Amino group or N, N-di (IU alkylamino
It is the basis. Acyl promiscuity is, for example, the formula -C(-〇) R+ (in the formula R1
is an optionally substituted aliphatic, cycloaliphatic, aromatic or
aromatic aliphatic hydrocarbon groups, e.g. optionally substituted lower
Alkyl group, lower alkenyl group or lower alkynyl group,
optionally substituted phenyl-lower alkyl group,
Nyl-lower alkenyl group or phenyl-lower alkynyl group
group, optionally substituted monocyclic or polycyclic cyclo
represents an alkyl group or as an aromatic group, optionally
substituted monocyclic or bicyclic carbocyclic or heterocyclic ring
represents an aryl group of the formula, for example a group listed for the group R, and
(represents, for example, a phenyl group or a pyridyl group)
Ru. Lower alkyl group, lower alkenyl group or lower alkynyl
group, phenyl-lower alkyl group, phenyl-lower alke
Nyl group or phenyl-lower alkynyl group and monocyclic or
or polycyclic cycloalkyl group, e.g. cycloalkyl group
The substituents may be optionally etherified or esterified, for example.
Tellated hydroxy groups, e.g. hydroxy groups, lower
Alkoxy groups and/or halogens, optionally substituted, e.g.
For example, lower alkylated or acylated amino groups,
For example, an amino group, an N-lower alkylamino group, or N,
N-di lower alkylamino group, lower alkanoylamine
carboxyl group and/or optionally modified with a functional group
a group such as a carboxy group, an esterified carboxy group,
For example, lower alkoxycarbonyl groups, optionally substituted
carbamoyl group, cyano group or onitro group,
Substituted groups may be substituted with the same or different at any suitable position for substitution.
may contain one or more, in particular up to three, substituents. Monocyclic or bicyclic carbocyclic or heterocyclic aryl
The substituents of the group R are the substituents listed for the group R, for example
optionally substituted aliphatic hydrocarbon groups, e.g.
corresponds to a lower alkyl group substituted with The acyl group ^C is further a carbonic acid modiester or monoamide.
do groups, e.g. unsubstituted or substituted droxy groups, e.g.
free or etherified hydroxy groups, e.g.
alkoxy groups, or unsubstituted or substituted amino groups, e.g.
For example, amino groups, lower alkylamino groups, and especially
substituted amino groups, such as di-lower alkylamino groups, N-lower
alkyl-N-phenyl-lower alkylamino group or
optionally oxygen, sulfur or unsubstituted or substituted, e.g.
For example, a nitrogen-blocked lower alkyl group is substituted with a lower alkyl group.
alkyleneamino group, or unsubstituted or substituted, e.g.
alkyl group, lower alkoxy group and/or halogen
Lower alkoxycarbonyl containing substituted phenyl group
and N-unsubstituted or N-mono- or N,N-di
-substituted carbamoyl group, e.g. N-lower alkylcarba
Moyl group, N,N-di-lower alkylcarbamoyl group,
or if the lower alkylene moiety is oxygen, sulfur or
unsubstituted or substituted, e.g. substituted with a lower alkyl group
N,N-lower alkylene carbamoys blocked by nitrogen
The group is represented by t. In the description of this specification, groups and compounds indicated as "lower"
preferably contains up to 7 carbon atoms, especially up to 4 carbon atoms.
nothing. Lower alkyl groups include, for example, methyl group, ethyl group, n-
Propyl group, isopropyl group, n-butyl group, isobutyl group
or tert-butyl group. Therefore, a lower alkyl group having 2 to 7 carbon atoms, for example
is an ethyl group, n-propyl group or n-butyl group,
Substituted lower alkyl groups are especially substituted with the corresponding methyl group or 1- or
Alternatively, it is a 2-ethyl group. Lower alkenyl groups are, for example, vinyl groups, allyl groups or
- or 3-methallyl group or 3,3-dimethylallyl
It is the basis. A lower alkynyl group is especially a propargyl group. Lower alkoxy groups include, for example, methoxy group, ethoxy group,
n-propoxy group, isopropoxy group, n-propoxy group
or isobutoxy group, phenyl-lower alkoxy
The group is, for example, a benzyloxy group or a 1- or 2-
-phenyl-1-oxy group, lower alkenyloxy
The group may be, for example, an allyloxy group, a 2- or 3-metallic group,
is a ruoxy group or a 3,3-dimethyl ruoxy group.
, lower alkynyloxy groups are especially propargyloxy groups.
It is. Lower alkylthio groups include, for example, methylthio group and ethylthio group.
o group, n-propylthio group or isopropylthio group.
Ru. Lower alkylsulfonyl groups are, for example, methylsulfonyl
or ethylsulfonyl group. Halogen preferably has an atomic number up to 35.
rogens, i.e. fluorine, chlorine or bromine. Lower alkanoyl groups include, for example, acetyl group, provinio group, etc.
or butyryl group. An optionally substituted lower alkoxycarbonyl group is
For example, an acyl group optionally bonded via an oxygen atom,
For example, a lower alkanoyl group, such as an acetyl group or
pivaloyl group, lower alkoxycarbonyl group, e.g.
Toxycarbonyl group or ethoxycarbonyl group or
lower alkyl substituted with an aroyl group, e.g.
Koxycarbonyl group, for example methoxycarbonyl
group, ethoxycarbonyl group, 1- or 2-(aceto
xy)-ethoxycarbonyl group, pivaloyloxymetho
xycarbonyl group, ■- or 2-(methoxycarbonyl group)
Nyloxy)-ethoxycarbonyl group or 1- or
2-(benzoyloxy)-ethoxycarbonyl group
Ru. An optionally substituted carbamoyl group is, for example, carbamoyl
moyl group, or N-lower alkyl group or N,N-di
-lower alkylcarbamoyl group, e.g. N-methylcarbamoyl group
Bamoyl group, N,N-diethylcarbamoyl group, N-ethylcarbamoyl group,
Tylcarbamoyl group or N,N-diethylcarbamoyl
It is the basis. The amino lower alkyl group is, for example, an aminomethyl group or 2
-Aminoethyl group. Oxy-lower alkyl groups are, for example, 2-oxo-n-butyl groups.
It is a chill group. A lower alkanoylamino group is, for example, an acetylamino group.
or a propionylamino group. Lower alkoxycarbonylamino groups are, for example, methoxy
Carbonylamino group or hydroxycarbonylamino group
It is. An optionally substituted ureido group may be, for example, a ureido group.
or 3-lower argyru or 3-cycloalkyl-
Ureido group (cycloalkyl group has, for example, 5 to 7 ring members)
0), e.g. 3-methylureido group, 3-ethyl
It is a ureido group or a 3-cyclohexylureido group. N-lower alkylamino group and N,N-di-lower alkyl
Ruamino group is, for example, methylamino group, ethylamino group
, dimethylamino group or diethylamino group. Hydroxy-lower alkyl groups are preferably hydroxy-lower alkyl groups.
with a methyl group or a 1- and especially a 2-hydroxyethyl group
be. Lower alkoxy-lower alkyl groups are preferably lower alkyl groups.
alkoxymethyl group or 1- and especially 2-lower alkoxy
ethyl group, e.g. methoxymethyl group, ethoxymethyl group
group, 2-methoxyethyl group or 2-ethoxymethyl group
be. Halo lower alkyl groups are preferably halomethyl groups, e.g.
For example, trifluoromethyl group. Hydroxy-lower alkoxy groups include, for example, hydroxymethane.
It is a toxy group or a 2-hydroxyethoxy group. Lower alkoxy-lower alkoxy groups are, for example, 2-meth
It is a xyethoxy group or a 2-ethoxyethoxy group. Lower alkanoylamino-lower alkyl groups are particularly
Alkanoylaminomethyl group or 1- and especially 2-lower
Alkanoylaminoethyl groups, e.g. acetylaminomethyl
thyl group, 2-acetylaminoethyl group or 2-propio
It is a nylaminoethyl group. The lower alkoxycarbonylamino-lower alkyl group is
Especially a lower alkoxycarbonylaminomethyl group, or 1
- and especially 2-lower alkoxycarbonylaminoethyl
groups, such as the methoxycarbonylaminomethyl group, the 2-methoxycarbonylaminomethyl group,
Toxycarbonylaminoethyl group or 2-ethoxylic
It is a bonylaminoethyl group. Carboxy-lower alkyl group is, for example, 2-carboxy
It is an ethyl group. Lower alkoxycarbonyl-lower alkyl group is e.g.
Toxycarbonylmethyl group or 2-engineered toxycarbonyl
It is an ethyl group. A cyano-lower alkyl group is, for example, a cyanomethyl group.
Ru. Lower alkoxy - A lower alkoxy group is particularly a lower alkoxy group.
Koxymethoxy group or 1- and especially 2-lower alkoxy
Ethoxy group, e.g. methoxymethoxy group, 2-methoxy group
It is an ethoxy group or a 2-ethoxyethoxy group. The lower alkylthio-lower alkoxy group is particularly
Kylthiomethoxy group or 1- and especially 2-lower alkyl
thioethoxy group, such as 2-methylthioethoxy group or
It is a 2-ethylthioethoxy group. Halo lower alkoxy groups are particularly 2-haloethoxy groups,
For example, 2-chloroethoxy group. Lower alkanoyl-lower alkoxy groups are, for example, lower alkanoyl-lower alkoxy groups.
Lucanoylmethoxy group or 1- or 2-lower alkali
Noylethoxy group, for example acetylmethoxy group. A phenyl-lower alkyl group is, for example, a benzyl group or a
- phenylethyl group. N-lower alkyl-N-phenyl-lower alkylamino
The group can be, for example, an N-methyl-N-pendylamino group or an N-
-methyl-N-(2-phenylethyl)-amino group
Ru. A phenyl-lower alkenyl group is, for example, phenyl-hini
l: I-phenyl-2-propenyl group
Ru. A phenyl-lower alkynyl group is, for example, 1-phenyl-
It is a 2-propynyl group. The lower alkylene amino group preferably has 4 to 6 ring carbons.
having an elementary atom, such as a pyrrolidino group or a piperidino group
A lower alkylene amino group blocked by oxygen, e.g.
For example, it may be a morpholino group, such as a 4-morpholino group.
stomach. A sulfur-blocked lower alkylene amino group is
a thiomorpholino group, such as a 4-thiomorpholino group;
optionally substituted nitrogen, e.g. lower alkali
Nitrogen-blocked lower alkylene atom substituted with a kill group
A mino group is, for example, a piperazino group or a 4-methylpiperazino group.
It is a radical. N,N-lower alkylenecarbamoyl group is, for example, pyro
lysinocarbonyl group or piperidinocarbonyl group, lower
Alkylene group is oxygen, sulfur, or unsubstituted or substituted nitrogen
the corresponding group blocked with, e.g. 4-morpholinocarbo
Nyl group, 4-thiomorpholinocarbonyl group, 1-pipera
dinocarboni, base or 4-methyl-1-piperazinoca
It is a rubonyl group. Where appropriate, monocyclic groups, including polycyclic cycloalkyl groups,
A cycloalkyl group of the formula preferably has 3 to 10 carbon atoms.
cyclopropyl group, cyclopentyl group or
Chlorhexyl group, polycyclic cycloalkyl group, e.g.
For example, bicycloC2,2゜1]heptyl (norbornyl)
group, bicyclo [2゜2.2. ) octyl group or adamane
A thyl group, for example a 1-adamantyl group. The novel compounds are useful in their salts, such as acid addition salts and especially in pharmaceutical
may be in the form of non-toxic acid addition salts that are acceptable to humans. Appropriate
Salts include, for example, inorganic acids, e.g. hydrohalic acids, e.g.
acids or hydrobromic, sulfuric, or phosphoric acids, or organic acids;
For example aliphatic, cycloaliphatic, aromatic or heterocyclic carbon
acids or sulfonic acids, such as formic acid, acetic acid, propionic acid,
Succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid,
Enoic acid, maleic acid, hydroxymaleic acid, pyruvin
acid, fumaric acid, benzoic acid, 4-aminobenzoic acid, ant
Ranilic acid, 4-hydroxybenzoic acid, salicylic acid, ene
Bonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hyperoxylic acid
Droxychetane sulfonic acid, ethylene sulfonic acid, tolu
Ensulfonic acid, naphthalenesulfonic acid or sulfani
or other acidic organic substances, such as ascorbic acid.
It is salt. Salts also include bases, especially pharmaceutically acceptable
General containing non-toxic bases and acidic groups such as carboxy groups
A salt formed using a compound of formula (H).A suitable salt
The radicals can be, for example, inorganic bases, such as alkali metals or alkali metals.
Carbonates or hydroxides of alkaline earth metals, e.g.
Carbonates of aluminum, potassium, magnesium or calcium
or hydroxide, and ammonia, or organic bases, e.g.
A suitable nitrogen base, e.g. a suitable amine, e.g.
primary, secondary or
is a tertiary aliphatic or cyclic amine, e.g. triethylamine
, N-ethylpiperidine, di- or triethanol
Ruamine, pyrrolidine, N-(2-hydroxyethyl)
-pyrrolidine, piperazine, N-(2-hydroxyethyl
)-piperazine and N-methyl-glucosamine.
. The present invention includes an acylated hydrazine compound of general formula (1)
The pharmaceutical formulation and the novel compound of general formula (1) itself are:
Has useful pharmacological effects. In detail, these are special
In a way that affects renal blood flow and sodium excretion. That is, these were determined by hemodynamic measurements in rats.
It has been shown to have a selective renal vasodilatory effect. hemp
Intoxicated rats were exposed to such substances, particularly Ac, to T-glue.
Approximately 3ttg/k of the compound of the general formula (1>) representing a tamil group
After intravenous injection of ~15 μg/kg, blood pressure and renal blood
Continuous measurement of flow (electromagnetic flow needle) lowers blood pressure.
It is possible to observe dilation of renal blood vessels without
A much larger amount, approximately 70 μ/kg, was administered by intravenous injection.
After administration, approximately -20mm and 11g of blood ("
(The following occurs. Cardiac output (thermodilution) and renal 1 @, intestinal
Blood flow through the membranous region and pelvic edge (electromagnetic flow if Rt)
In Laso I, which simultaneously measures
When administered intravenously at a dose of 4 kg/kg, the resistance of the renal convoluted canal is reduced.
Mesenteric and femoral vessels and all
The resistance of the distal curve of the tube does not change. Doppler ultrasonic flow
A conscious spontaneous patient with a long-term implantation of a volume-measuring head.
Similar studies on sexually hypertensive rats showed that such compounds
The dosage is approximately 3■/kg to approximately 10■/kg (intravenous injection).
Within the dosage range, it lowers the resistance of the renal 1st and 2nd rn ducts and lowers the resistance of the mesenteric region.
and vascular resistance at the pelvic end are unaffected. Significantly higher doses, 'Wt (approximately 30 dawn/kg, static
Three of the curved canal areas tested only when administering intravenous injection
A decrease in blood pressure and vasodilation occurs everywhere. Yo
Only when higher doses are administered, i.e. in a conscious patient.
approximately 301 μg/kg intravenously or 60 μg per kg.
After oral administration of /kg, it is approximately -25n+m1lR.
Blood pressure decreases, but the effect is small (lasts for about 4 hours).
After intravenous injection into rats at a dose of 15 μ/kg, these
The compound increases sodium excretion and its action lasts for 3 hours
Continue. Studies on anesthetized rats have shown that, in particular, ^C is γ-
A compound of general formula (1) representing a glutamyl group is administered by intravenous injection.
Approximately 50% glomeruli at a dose of 10 mg/kg? over speed
(measured as inulin clearance)
can be proven. From the above facts, such
It is inferred that the compound has a remarkable glomerular vasodilatory effect.
can be done. A dose of 10μ/kg of such a compound
When administered orally twice a day for 3 weeks, idiopathic
In sexually hypertensive rats, approximately -20 to -25 mm11
A sustained decrease in blood pressure occurs by an amount of g, and heart rate is unaffected.
stomach. A similar effect can be obtained by using an osmotic mini pump for one week, once a day.
What should be observed when administering a dose of 0/kg intravenously for treatment?
can be done. ^ch< represents r-L-glutamyl group
The compound of general formula (1) produces T-glutamyl-
Decomposed by trans-peptidases. Furthermore, special
The general formula (1) in which the bladder represents a monoester group of carbonic acid
Significant antihypertensive activity can be observed in the compound
. Specifically, this class of compounds has been shown to be effective in male rats with renal hypertension.
(GoldblaLt method)
Significantly lowers blood pressure, which Gerold
(llelv, Physiol. Acta 24.58.1966) without anesthesia.
detected by indirect method in young rats. After daily oral administration of such compounds for 4 days (blood pressure
The extent of the decrease was measured on day 4B, 2 hours after the last dose.
), one 7n+ at a dose of 103 mg/kg
Blood pressure decreased by 111g, 1O■/kg per day 7
lfn pressure drop of 81 mm11H in volume, 100 m1 per day
At a dose of r/kg, -108 mm 11 g of 1 ■ pressure drop was achieved.
can be observed. Based on these effects, compounds containing general K (1)
The pharmaceutical preparation or the novel compound of general formula (H itself)
Suitable for use as duct dilator and anti-high surface pressure agent
. Furthermore, in the general formula (1) where 肚 represents a pyridylcarbonyl group,
The compound exhibits antileukemic activity, which can be demonstrated by e.g. intraperitoneal transfer.
In mice infected with leukemia P388 by explantation,
100 μ/kg of such a compound for 5 consecutive days
After a single intraperitoneal administration, the quotient T/C was 129%;
50μ/kg of such a compound once a day for 5 days
After intraperitoneal administration, the quotient T/C should be 125%.
It can be proven with. into mice by intraperitoneal implantation
When infected with leukemia LI 210, such changes occur.
Administer 100 kg of the compound intraperitoneally once a day for 9 days.
After administration, a quotient T/C of 151% can be measured.
Then, 60 nw/kg of such a compound was added in the same manner.
After intraperitoneal administration for the same period, a value of 123% was measured.
I can do that. [These observations are made for the benefit of the applicant in the United States.
National Cancer Institute (National Cancer Institute, Bethesda, Maryland, United States)
tional CancerInstHute) cancer
Division of CancerTr
developmental therapy program (1) ev
elop-mental therapy! cs
What was obtained from the test model as
]. Based on these properties, Ac is
Compounds of general formula (1) representing a rubonyl group are used for the treatment of leukemia.
seems to be appropriate. In addition, the compound of general formula 〇), other useful compounds, special
as a useful intermediate for the production of pharmaceutically active compounds in
You can also use The present invention particularly represents an integer from 1 to 4, where R is an integer from 1 to 4;
lower alkyl group, lower alkenyl group or
is a lower alkynyl group, or an alicyclic or bicyclic carbon homologous group.
Represents a monocyclic or tetracyclic aromatic hydrocarbon group;
is the formula -C(=O) -R+ (in the formula, R1 may be replaced depending on the case)
aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons
(represents a base group), or 80 is a carbonic acid group.
Compounds of general t (T) representing a ter or monoamide group
as its racemic mixture, racemate, optical enantiomer or -
relates to pharmaceutical formulations containing it in salt form. The present invention particularly provides that n represents an integer of 1 to 4 and R is a lower atom
alkyl group, optionally etherified or esterified
hydroxy-lower alkyl groups, e.g. hydroxy-lower
Alkyl group, lower alkoxy-lower argyl group or halo
-lower alkyl group, or optionally substituted, e.g.
Lower alkylated or acylated amino-lower a
alkyl groups, such as amino lower alkyl groups, N-lower alkyl groups,
kylamino-lower alkyl group or N,N-di-lower
Alkylamino - lower alkyl group, lower alkanoyl group
Mino-lower alkyl group or lower alkoxycarbonyl group
mino-lower alkyl group, or optionally esterified or
is an amidated carboxy group, e.g. a carboxy group,
Ethoxycarbonyl group or optionally substituted carbonyl group
lower substituted with a rubamoyl group, e.g. a carbamoyl group
Alkyl groups, e.g. carboxy-lower alkyl groups, lower
Alkoxycarbonyl - lower alkyl group, carbamoyl
- lower alkyl groups, oxo-lower alkyl groups, and
ano-lower alkyl group, or an optionally substituted aryl group;
-lower alkyl group (aryl group is monocyclic aromatic hydrocarbon
elementary groups such as phenyl groups or bicyclic aromatic hydrocarbon groups
, for example 1- or 2-naphthyl groups or partially saturated
naphthyl group, e.g. 1,2,3,4-tetrahydro
It is a lo-5-naphthyl group, and the substituent is a lower alkyl group,
Hydroxy group and/or halogen, hydroxy-lower atom
alkyl group, lower alkoxy-lower alkyl group, halo lower
alkyl group, lower alkoxy group, lower alkenyloxy group
cy group, or optionally lower alkylation or acylation
amino-lower alkyl groups, such as mono- or
di-lower alkylamino-lower alkyl group or lower alkyl group
Kanoylamino - lower alkyl group, optionally ester
carboxy group, such as a carboxy group or a lower atom
Rukoxycarbonyl group, amidated carboxy group, e.g.
Optionally substituted carbamoyl groups, e.g. carbamoyl
yl group, N-lower furkylcarbamoyl group or N, N
-di-lower alkylcarbamoyl group, cyano group, nitro
groups or optionally acylated amino groups, e.g.
group, lower alkylamino group, lower alkoxycarbonyl group
Ruamino group, lower alkylamino group or di-lower alkyl
Ruamino group, and there are ~3 such substituents.
may be the same or different), or R
and the group R1 contained in the group ^C is an aryol group, e.g.
For example, phenyl group, ■- is 2-naphthyl group or partially
Saturated naphthyl groups, e.g. l,2,3,4-tetra
hydro-5-naphthyl group, or preferably 5 or
has 6 ring members, with a pyridyl group via a ring carbon atom
with an oxygen atom, a sulfur atom, or a nitrogen atom as a ring member.
and optionally 1 to 3 additional nitrogen atoms (
It may be at least partially hydrogenated, in which case
Optionally substituted with oxo groups, in bicyclic heterocyclic groups
may be a fused benzene ring), and especially
Pyridyl group, e.g. 2-13- or 4-pyridyl group
, or a dihydroxo-pyridinyl group, e.g. 1,6-
sihydro-6-oxo-2-pyridinyl group, pyridazine
3-pyridazinyl group, pyrazinyl group, e.g.
2-pyrazinyl group, pyrimidinyl group, e.g. 2-14
- or 5-pyrimidinyl group, or dihydro-oxo
-pyrimidinyl group, e.g. 3,4-dihydro-4-ox
so-2-pyrimidinyl group, furyl group, e.g. 2- or
is a 3-furyl group, a pyryl group, such as a 2- or 3-pyryl group.
lyl group, chenyl group, e.g. 2- or 3-chenyl group
group, oxasilyl group, e.g. 2- or 4-oxasilyl
group, thiazolyl group, e.g. 2-14- or 5-thiazolyl
a thiadiazolyl group, e.g. 1,2,4-thiadiazole
sol-3- or 5-yl group or],]2,5-yl group
Asiazol-3-yl group imidazolyl group, e.g.
dazol-2- or -4-yl group, pyrazolyl group,
For example, 3- or 4-pyrazolyl group, l.riazolyl
groups, such as the 1.2.3-1-lyazol-4-yl group,
Or 1°2,. 1-1-riazol-3-yl group, tet
Lazolyl groups, such as tetrazol-5-yl groups, and
indolyl group, e.g. indol-4-yl group, quinolinyl group,
group, such as 2-quinolinyl group, isoquinolinyl group,
For example, 1-isoquinolinyl group, benzimidazolyl group,
For example, 2-benzimidazolyl group, benzofuranyl group,
For example, 4- or 5-benzofuranyl group, benzochenyl
groups, such as 4- or 5-benzochenyl groups, or naphthi
Lysinyl group, e.g. 1,8-naphthyridin-2-yl group
, and such aryl groups are especially composed of ring carbon atoms.
, it may be present in the secondary nitrogen atom of the ring, and 1
(from 11a) 2, preferably up to 4 (If!)
a lower alkyl group more substituted, e.g. a lower alkyl group
, optionally etherified or esterified
Roxy-lower alkyl group, e.g. hydroxy-lower alkyl
Kyl group, lower alkoxy-lower alkyl group or halo lower
lower alkyl group, or optionally substituted, e.g.
or acylated amino lower alkyl groups, e.g.
For example, amino-lower alkyl group, N-lower alkylamino
-lower alkyl group, N,N-di-lower alkylamino-
Lower alkyl group, lower alkanoylamino-lower alkyl group
or lower alkoxycarbonylamino-lower alkyl group
or a lower alkenyl group or a lower alkynyl group,
Hydroxyl etherified or esterified by
hydroxy group or mercapto group, such as hydroxy group, lower atom
alkoxy group, phenyl-lower alkoxy group, halogen,
Mercapto group, lower alkylthio group, phenyl-lower alkylthio group
alkylthio group, or [optionally etherified or
Stellated hydroxy group or mercapto group or esterified hydroxy group or mercapto group
Lower alkoxy groups substituted with syl groups, e.g.
Koxy group, phenyl-lower alkoxy group, hydroxy-
Lower alkoxy group, lower alkoxy-lower alkoxy group
, lower alkylthio lower alkoxy group, halo lower alkyl
koxy group or lower alkanoyl-lower alkoxy group, or
is a lower alkenyloxy group, a lower alkynyloxy group,
lower alkylthio groups, acyl groups, e.g. lower alkanoyl
optionally esterified carboxy groups, e.g.
carboxy group or lower alkoxycarbonyl group, amino
hydrogenated carboxy groups, e.g. optionally substituted carboxy groups
Moyl group, such as carbamoyl group, N-lower alkyl group
rubamoyl group or N,N-di-lower alkylcarbamoy
group, cyano group, dil, or optionally substituted, e.g.
acylated amino groups, e.g. lower alkanoyl
mino group, lower alkoxycarbonylamino group, lower alkyl
Killsulfonyl group, sulfamoyl group, optionally substituted
ureido group and amino group, N-lower alkylamine
or N, N-di-lower alkylamino group
may be substituted with a substituent that is included in the group ^C
Group R1 is a lower alkyl group, a lower alkenyl group, a lower alkyl group
Quinyl group, phenyl-lower alkyl group, phenyl-(I
n-alkenyl group, phenyl-lower alkynyl group, monocyclic
or polycyclic cycloalkyl groups, e.g.
and each group is optionally etherified or esterified.
Tellated hydroxy groups, e.g. hydroxy groups, lower
Alkoxy groups and/or halogens, optionally substituted, e.g.
For example, lower alkylated or acylated amino groups,
For example, an amino group, an N-lower alkylamino group, or N,
N-di lower alkylamino group, lower alkanoylamine
carboxyl group and/or optionally modified with a functional group
a group such as a carboxy group, an esterified carboxy group,
For example, optionally substituted lower alkoxycarbonyl
group, optionally substituted carbamoyl group or cyano group
and the substituted group R1 can be substituted at any suitable position for substitution.
containing one or more, especially up to three, the same or different substituents at each position.
In addition, Ac is also a lower alkoxycarbohydrate.
Nyl group, unsubstituted or substituted hydroxy group, e.g. free
Alternatively, etherified hydroxy groups, such as (tU-class
an alkoxy group, or an unsubstituted or substituted amino group, e.g.
amino groups, lower alkylamino groups, and especially di-substituted
Amino groups, such as di-lower alkylamino groups, N-lower
Alkyl-N-phenyl-lower alkylamino group or field
optionally oxygen, sulfur or unsubstituted or substituted, e.g.
Nitrogen-blocked lower alkyl substituted with lower alkyl group
Kylenamino group, or unsubstituted or W-substituted, e.g. lower
Substituted with alkyl group, lower alkoxy group and/or halogen
Lower alkoxycarbonyl group containing substituted phenyl group
, and N-unsubstituted or N-mono- or N,N-di
-Substituted carbamoyl groups, e.g. lower alkylcarbamoy
a di-lower alkylcarbamoyl group, or optionally
lower alkylene moiety is oxygen, sulfur or unsubstituted or
is substituted, e.g. blocked by a nitrogen substituted with a lower alkyl group
N. General formula (I) representing an N-lower alkylene carbamoyl group
compounds as their racemic mixtures, racemates, and optical pairs.
It relates to pharmaceutical preparations, including in the form of monomers or salts. The present invention particularly provides that n represents 1 or 2 and R is lower alkyl
groups, such as methyl groups, lower alkoxy-lower alkyl groups
, e.g. 2-methoxyethyl group, halo lower alkyl group
, e.g. trifluoromethyl group, or lower alkanoyl
Amino-lower alkyl groups, e.g. acetylaminomethyl
R1 in the base film represents a phenyl group or a pyridyl group.
, each optionally containing a lower alkyl group, e.g.
lower alkoxy-lower alkyl groups, e.g.
toxyethyl group, halo lower alkyl group, e.g.
fluoromethyl group, lower alkanoylamino-lower alkyl group
group, such as 2-acetylaminoethyl group, hydroxy
groups, lower alkoxy groups, such as methoxy groups, lower alkoxy groups,
xy-lower alkoxy group, e.g.
cy group, halogen, lower alkoxycarbonyl group, e.g.
Ethoxycarbonyl group, carbamoyl group, cyano group,
mino group or lower alkanoylamino group, e.g. acetyl
Substituted with an amino group or a sulfamoyl group,
or R4 is optionally a lower alkoxy group, e.g.
cy group, amino group, lower alkanoylamino group, e.g.
Cetyl amino group, carboxy group, optionally substituted
Lower alkoxycarbonyl groups, e.g. ethoxycarbonyl
or 2- or preferably 1-(lower alkyl group)
carbonyloxy)-lower alkoxycarbonyl group or carbonyl group
Lower alkyl groups substituted with bamoyl groups, e.g. ethyl
or n-propyl group;
Alkoxycarbonyl group, e.g. ethoxycarbonyl group
or an unsubstituted carbamoyl group or lower alkoxy group, e.g.
Carbamoyl substituted with methoxy group or amino group
A racemic mixture of the compound of general formula (1) representing a group
, in the form of racemic compounds, optical enantiomers or salts.
Regarding drugs. In particular, in the present invention, n represents 1, R is a lower alkyl group,
For example, methyl group, lower alkoxy-lower alkyl group, e.g.
For example, 2-methoxyethyl group or halo lower alkyl group
, for example, represents a trifluoromethyl group, and R7 in the base film is
Represents a phenyl group or a pyridyl group, each optionally
Lower alkyl groups, such as methyl, lower alkoxy-lower
alkyl groups, e.g. 2-methoxyethyl group, halo lower
alkyl groups, such as trifluoromethyl groups, hydroxyl groups, etc.
cy group, lower alkoxy group, such as methoxy group, lower alkoxy group,
koxy-lower alkoxy group, e.g. 2-ethoxyethoxy
cy groups, halogens, lower alkoxycarbonyl radicals, e.g.
Ethoxycarbonyl group, carbamoyl group, cyano group,
substituted with a mino group or a sulfamoyl group, or
R1 is optionally a lower alkoxy group, such as a methoxy group
, amino group, lower alkanoylamino group, e.g.
Ruamino group, and carboxy group or optionally substituted
](class alkoxycarbonyl group, e.g.
carbonyl group or 2- or preferably 1-(lower alkyl group)
(kylcarbonyloxy)-lower alkoxycarbonyl group
or a lower alkyl group substituted with a carbamoyl group, e.g.
represents an ethyl group or n-propyl group, or Ac
is further a lower alkoxycarbonyl group, e.g.
Compounds of the general formula (2) representing a carbonyl group or a carbamoyl group
a substance as its racemic mixture, racemate, optical diagonal or
relates to pharmaceutical formulations containing in salt form. The invention particularly provides that n represents 1 and R is a lower alkyl group, e.g.
For example, a methyl group, or a lower alkoxy-lower alkyl group,
For example, it represents a 2-methoxyethyl group, and R1 in C to the group is
Optionally (It class alkyl group, e.g. methyl group, halo
-lower alkyl groups, e.g. trifluoromethyl, hydrogen
Roxy group, lower alkoxy group, e.g. methoxy group, halo
gen, carbamoyl group, cyano group and/or sulfamo group
phenyl group substituted with yl group, or optionally amino
groups, lower alkanoylamino groups, e.g. acetylamino
group, and carboxy group or optionally substituted lower atom
alkoxycarbonyl group, e.g. lower alkoxycarbonyl group
a group such as an ethoxycarbonyl group or a 2- or preferably
or 1-(lower alkylcarbonyloxy)-lower a
alkoxycarbonyl group, e.g. pivaloyloxy-meth
Lower alkyl groups substituted with oxycarbonyl groups, e.g.
Represents an ethyl group, n-propyl group or n-butyl group
or the bladder may further contain lower alkoxycarbonyl groups, e.g.
A compound of general formula (1) representing an ethoxycarbonyl group is
of racemic mixtures, racemates, optical antipodes or salts of
PHARMACEUTICAL FORMULATION. The invention particularly represents an integer from n months to 4, where R is
lower alkyl group, lower alkenyl group or
or lower alkynyl group, or monocyclic or bicyclic carbon
represents a homocyclic or heterocyclic aromatic hydrocarbon group,
The bladder is expressed by the formula -〇 (=○) -R1 (in the formula, R1 is replaced depending on the case).
aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons
(represents a base group), or the bladder is further a carbonic acid mosier.
It may represent a ster or monoamide group, but if n is 1,
If there is, and 肚 represents an acetyl group, the bond at the 3-position is
R as a lower alkyl group has 2 to 7 carbon atoms.
and further when n is 1 and AC represents a benzoyl group
is a lower alkyl bonded to the 3-14-15- or 6-position.
R as a kill group has a general formula having 2 to 7 carbon atoms
Racemic mixture, racemic compound, optical, represented by (I)
The present invention relates to novel compounds in the form of antipodes or salts. The present invention particularly provides that n represents an integer of 1 to 4 and R is a lower atom
alkyl group, optionally etherified or esterified
hydroxy-lower alkyl groups, e.g. hydroxy-lower
Alkyl group, lower alkoxy-lower alkyl group or halo
-lower alkyl group, or optionally substituted, e.g.
Lower alkylated or acylated amino-lower a
alkyl groups, such as amino lower alkyl groups, N-lower alkyl groups,
kylamino-lower alkyl group or N,N-di-lower
Alkylamino - lower alkyl group, lower alkanoyl group
Mino-lower alkyl group or lower alkoxycarbonyl group
mino-lower alkyl group, or optionally esterified or
is an amidated carboxy group, e.g. a carboxy group,
Ethoxycarbonyl group or optionally substituted carbonyl group
lower substituted with a rubamoyl group, e.g. a carbamoyl group
Alkyl groups, e.g. carboxy-lower alkyl groups, lower
Alkoxycarbonyl - lower alkyl group, carbamoyl
- lower alkyl groups, oxo-lower alkyl groups, and
Ano-lower alkyl group, or optionally substituted ali
-lower alkyl group (aryl group is a monocyclic aromatic carbonized
Hydrogen groups, such as phenyl groups, or bicyclic aromatic hydrocarbons
groups, such as 1- or 2-naphthyl groups or partially saturated
hydrated naphthyl groups, e.g. 1,2.3.4-tetrahydryl
It is a doro-5-naphthyl group, and the substituent is a lower alkyl group.
, hydroxy group and/or halogen, hydroxy-lower
Alkyl group, lower alkoxy-lower alkyl group, halo
Lower alkyl group, lower alkoxy group, lower alkenyl group
xy group, or optionally lower alkylated or acyl
amino-lower alkyl groups, such as mono- or
is di-lower alkylamino-lower alkyl group or lower alkyl group
lucanoylamino-lower atom-badol group, optionally es
terified carboxy groups, e.g. carboxy groups or lower
alkoxycarbonyl group, ami-1' carboxy group,
For example, an optionally substituted carbamoyl group, e.g.
Rubamoyl group, N-lower alkylcarbamoyl group or N
, N-di lower alkylcarbamoyl group, cyano group, di
1-lo groups or optionally acylated amino groups, e.g.
amino group, lower alkylamino group, lower alkoxy group
Rubonylamino group, lower alkylamino group or di-lower
It is an alkylamino group, with 3 to 3 such substituents
may exist and may be the same or different;
or R and the group R1 contained in C are each aryl
groups, such as phenyl groups, 1- or 2-naphthyl groups or
partially saturated naphthyl groups, e.g. ], ]2,3.4
-te]lahydro-5-naphthyl group, or preferably 5
or has 6 ring members and has a ring via a carbon atom of the ring.
It is bonded to a lysyl group, and the ring member i is an oxygen atom, a sulfur atom, or
is a nitrogen atom and optionally 1 to 3 additional nitrogen atoms
(also may be partially hydrogenated,
In this case, it may be substituted with an oxo group, and the bicyclic hetero group may be substituted with an oxo group.
The second ring in the rocyclic group may be a fused benzene ring)
, and especially pyridyl groups, such as 2-13- or 4-
Pyridyl group or dihydroxo-pyridinyl group, e.g.
1゜6-sihydro-6-oxo-2-pyridinyl group,
Pyridazinyl group, e.g. 3-pyridazinyl group, pyrazinyl group
2-pyrazinyl group, pyrimidinyl group, e.g.
2-14- or 5-pyrimidinyl group, or dihydro
lo-oxo-pyrimidinyl group, e.g. 3,4-dihydro
-4-oxo-2-pyrimidinyl group, furyl group, e.g.
2- or 3-furyl group, pyryl group, e.g.
or 3-pyryl group, chenyl group, e.g. 2- or
3-chenyl group, oxacylyl group, e.g. 2- or
4-oxacylyl group, thiazolyl group, e.g. 2-14-
or 5-thiazolyl group, deadiazolyl group, e.g.
l, 2,4-thiadiazol-3- or 5-yl group
or 1.2.5-thiadiazol-3-yl group, imida
a zolyl group, e.g. imidazole-2- or -4-y
pyrazolyl group, e.g. 3- or 4-pyrazolyl group
triazolyl group, e.g. 1.2.1-) lyazole
-4-yl group or 1,2,4-1-riazole-3-
yl group, tetrazolyl group, e.g. tetrazol-5-y
and indolyl groups, such as indol-4-yl groups
, quinolinyl group, e.g. 2-quinolinyl group, isoquinolinyl group
Nyl group, e.g. 1-isoquinolinyl group, benzimidazo
Lyle group, such as 2-benzimidazolyl group, benzofura
nyl group, such as 4- or 5-benzofuranyl group, benzofuranyl group,
a chenyl group, such as a 4- or 5-benzochenyl group, or
is a naphthyridinyl group, e.g. 1,8-naphthyridin-2
-yl group, and such an irisyl group is particularly suitable for a ring carbon atom.
It may exist not only in the child but also in the secondary nitrogen atom of the ring,
Also, one or more, preferably up to four, optional
Substituted lower alkyl groups, e.g.
Hydroxy etherified or esterified by
-lower alkyl groups, e.g. hydroxy-lower alkyl groups
, lower alkoxy-lower alkyl group or halo lower alkyl group
Kyl group, or optionally substituted, e.g. lower alkylated or
or acylated amino-lower alkyl groups, e.g.
Amino-lower alkyl group, N-lower alkylamino-lower
alkyl group, N,N-di-lower alkylamino-lower
Alkyl group, lower alkanoylamino-lower alkyl group
or lower alkoxycarbonylamino-lower alkyl group
, or a lower alkenyl group or a lower alkynyl group, in some cases
More etherified or esterified hydroxy groups
or a mercapto group, such as a hydroxy group, a lower alkyl
xy group, phenyl-lower alkoxy group, halogen, mel
capto group, lower alkylthio group, phenyl-lower alkyl
ruthio group, or optionally etherified or ester
Hydroxy group or mercapto group or acyl group
a lower alkoxy group substituted with, e.g. lower alkoxy
group, phenyl-lower alkoxy group, hydroxy-lower alkoxy group
alkoxy group, lower alkoxy-lower alkoxy group, lower
Alkylthio-lower alkoxy group, halo lower alkoxy group
or lower alkanoyl-lower alkoxy group, or silk lower
alkenyloxy group, lower alkynyloxy group, lower
Alkylthio group, acyl group, e.g. lower alkanoyl group
, an optionally esterified carboxy group, e.g.
Ruboxy group or lower alkoxycarbonyl group, amidation
Carboxy groups, e.g. optionally substituted carbamoyls
carbamoyl group, N-lower alkylcarba
Moyl group or N,N-di-lower alkylcarbamoyl group
, cyano group, 21.4 group or optionally substituted, e.g.
sylated amino groups, e.g. lower alkanoylamino
group, lower alkoxycarbonylamino group, lower alkyl
Sulfonyl group, sulfamoyl group, optionally substituted
ureido group, amino group, N-lower alkylamino group
or N,N-di-lower alkylamino group
A group R1 that may be substituted with a substituent and is included in the group ^C
is lower alkyl group, lower alkenyl group, lower alkynyl group
group, phenyl-lower alkyl group, phenyl-lower alke
Nyl group, phenyl-lower alkynyl group, monocyclic or
Representing a polycyclic cycloalkyl group, e.g.
However, each group may be etherified or esterified as the case may be.
hydroxy groups, such as hydroxy groups, lower alkoxy
cy group and/or halogen, optionally substituted, e.g. lower
Alkylated or acylated amino groups, e.g.
mino group, N-lower alkylamino group or N,N-di-lower
alkylamino group, lower alkanoylamino group and/or
or carboxy groups optionally modified with functional groups, e.g.
If a carboxy group, an esterified carboxy group, e.g.
a lower alkoxycarbonyl group substituted by, in some cases
substituted with a carbamoyl group or a cyano group substituted with
, the substituted group R1 is the same or substituted at any suitable position for substitution.
may contain one or more, especially up to three, different substituents.
In addition, the bladder further contains lower alkoxycarbonyl groups,
substituted or substituted hydroxy groups, e.g. free or ether
hydroxy groups, such as lower alkoxy groups, or
is an unsubstituted or substituted amino group, e.g. amino group, lower
alkylamino groups, and especially di-substituted amino groups, e.g.
di-lower alkylamino group, N-lower alkyl-N-ph
phenyl-lower alkylamino group or optionally oxygen, sulfur
Yellow or unsubstituted or substituted, e.g. with a lower alkyl group
a lower alkylene amino group interrupted by a substituted nitrogen;
or unsubstituted or substituted, e.g. lower alkyl group, lower
Phenyl substituted with alkoxy group and/or halogen
lower alkoxycarbonyl groups, including groups, and N-unsubstituted
or N-mono- or N,N-di-substituted carbamoys
lower argylcarbamoyl group, lower argylcarbamoyl group,
alkylcarbamoyl group, or optionally lower alkylene
If the moiety is oxygen, sulfur or unsubstituted or substituted, e.g.
N blocked by a nitrogen substituted with a class alkyl group, N-
It may represent a lower alkylenecarbamoyl group, but if n is
1, and when Ac represents an acetyl group, at the 3-position
R as a bonded lower alkyl group has 2 to 7 carbon atoms
for example ethyl, n-propyl or n-butyl
represents a thyl group, further n represents 1, and Ac represents a benzoyl group
When it represents, it is bonded to the 3-14-15- or 6-position.
R as a lower alkyl group represents 2 to 7 carbon atoms.
For example, the above-mentioned ethyl group, n-propyl group or n-butyl group
Racemic mixture, racemization of general formula (1) representing a chill group
It relates to novel compounds in the form of compounds, optical antipodes or salts. The present invention particularly provides that n represents 1 or 2 and R is lower alkyl
groups, such as methyl groups, lower alkoxy-lower alkyl groups
, e.g. 2-methoxyethyl group, halo lower alkyl group
, e.g. trifluoromethyl group, or lower flucaryl group
Amino-lower alkyl groups, e.g. acetylaminomethyl
represents a group, and R1 in the pronunciation represents a phenyl group or a pyridyl group.
, each optionally containing a lower alkyl group, e.g.
lower alkoxy-lower alkyl groups, e.g.
toxyethyl group, halo lower alkyl group, e.g.
fluoromethyl group, lower alkanoylamino-lower alkyl group
group, such as 2-acetylaminoethyl group, hydroxy
groups, lower alkoxy groups, such as methoxy groups, lower alkoxy groups,
xy-lower agar: 1 xy group, e.g.
Toxy group, halogen, lower alkoxycarbonyl group, e.g.
For example, ethoxycarbonyl group, carbamoyl group, cyano group
, an amino group or a lower alkanoylamino group, e.g.
Substituted with delamino group or sulfamoyl group
or R1 is optionally a lower alkoxy group, e.g.
Toxy group, amino group, lower alkanoylamino group, e.g.
For example, an acetylamino group, a carboxy group, optionally substituted
lower alkoxycarbonyl groups, such as ethoxyl
Bonyl group or 2- or preferably 1-(lower alkyl
carbonyloxy)-lower alkoxycarbonyl group or
Lower alkyl groups substituted with carbamoyl groups, e.g.
represents a thyl group or n-propyl group, or AcLJ
Furthermore, lower alkoxycarbonyl groups, such as ethoxyl
Bonyl group or non-fFZ Ifi carbamoyl group or lower
substituted with an alkoxy group, such as a methoxy group or an amino group.
may represent a substituted carbamoyl group, but if n is 1,
When Ac represents an acetyl group, it is bonded to the 3-position.
R as a lower alkyl group represents 2 to 7 carbon atoms.
For example, ethyl group, n-propyl group or n-butyl group
, furthermore, n represents 1, the bladder represents a benzoyl group, and the field
In the case of
R as alkyl group represents 2 to 7 carbon atoms, e.g.
For example, the above-mentioned ethyl group, n-propyl group or n-butyl group
Racemic mixture, racemic compound, light of the general formula (I) represented by
It relates to novel compounds in the form of their chemical enantiomers or salts. The present invention particularly represents n months, R is a lower alkyl group,
For example, methyl group, lower alkoxy-lower alkyl group, e.g.
For example, 2-methoxyethyl group or halo lower alkyl group
, for example, represents a trifluoromethyl group, and R1 in the base film is
Represents a phenyl group or a pyridyl group, each optionally
Lower alkyl groups, such as methyl, lower alkoxy-lower
alkyl groups, such as 2-methoxyethyl group, haloyl group, etc.
[(alkyl group, e.g. trifluoromethyl group, hydrogen
Roxy group, lower alkoxy group, such as methoxy group, i1
(class full ml x-(I(class alkoxy group, e.g. 2-
ethoxyethoxycarbonyl group, e.g. ethoxycarbonyl group, carbonyl group,
Bamoyl group, cyano group, amino group or sulfamoyl group
And Wlj! ! or R1 is optionally lower
Alkoxy groups, such as methoxy groups, amino groups, lower alkyl
Canoylamino groups, such as acetylamino groups, and carbonyl
Boxy group or optionally substituted lower alkoxy group
Bonyl group, such as ethoxycarbonyl group or 2- or
Preferably 1-(lower alkylcarbonyloxy)-lower
substituted with an alkoxycarbonyl group or a carbamoyl group
lower alkyl groups, such as ethyl or n-pro
represents a pyr group, or the bladder is further a lower alkoxycarbonyl group.
radicals, such as engineered 1-oxycarbonyl groups or carbamoyl groups.
It may represent a group, but if ^C represents an acetyl group,
, R as the lower alkyl group bonded to the 3-position is 2-7
carbon atoms, e.g. ethyl group, n-propyl group
or represents an n-butyl group, and further the bladder represents a benzoyl group
In some cases, lower
R as an alkyl group represents 2 to 7 carbon atoms, e.g.
For example, the above-mentioned ethyl group, n-propyl group or n-butyl group
A racemic mixture, a racemic compound of the general formula (1) representing
It relates to novel compounds in the form of optical antipodes or salts. The invention particularly provides that n represents 1 and R is a lower alkyl group, e.g.
For example, a methyl group, or a lower alkoxy-lower alkyl group,
For example, it represents a 2-methoxyethyl group, and R in the group Ac is
Optionally lower alkyl groups, such as methyl groups, halo lower
alkyl groups, such as trifluoromethyl groups, hydroxyl groups, etc.
cy group, lower alkoxy group, e.g. methoxy group, halogen
, carbamoyl group, cyano group and/or sulfamoyl group
a phenyl group substituted with a group, or optionally an amino group,
lower alkanoylamino groups, such as acetylamino groups,
and carboxy group or optionally substituted lower alkyl
oxycarbonyl group, for example (1ξ-alkoxycarbonyl group)
a group such as an ethoxycarbonyl group or a 2- or preferred
Preferably 1-(lower alkylcarbonyloxy)-lower
a lower alkyl group substituted with an alkoxycarbonyl group,
For example, ethyl group, n-propyl group or n-butyl group
or lower alkoxycarbonyl
may represent a group, such as an ethoxycarbonyl group, but
represents an acetyl group, the lower atom bonded to the 3-position
R4)I as alkyl group represents 2 to 7 carbon atoms
, for example, an ethyl group, n-propyl group or n-butyl group
and when 肚 represents a benzoyl group, 3-14
-15-Alternative 11°Low-grade bar 1-bar connected to the 6-position
Rill as a group: represents 2 to 711M carbon atoms
, for example the above-mentioned ethyl group, n-propyl group or n-butyl group
Racemic mixtures, racemic compounds of the general formula N) that do not represent a group
, optical enantiomer or salt form of the novel compound. The present invention particularly represents n months, R is a lower alkyl group,
For example, n-butyl group, or lower alkoxy-lower alkyl
represents a group such as 3-methoxy-n-propyl, and
R1 in the ω-position is preferably an amino group or especially a lower
Alkanoylamino groups, such as acetylamino groups and carbon
ruboxy group, or lower alkoxycarbonyl group, e.g.
Ethoxycarbonyl group, 2- or preferably 1-(lower
alkylcarbonyloxy)-lower alkoxycarbonyloxy
group, such as pivaloylcarbonyloxymethoxycal
Lower alkyl substituted with a bonyl group or a carbamoyl group
a general group representing a group, such as an ethyl group or an n-propyl group;
Racemic mixture, racemic compound, optical diagonal of formula (1)
Novel compounds in the form of compounds or salts, especially pharmaceutically acceptable salts
Regarding. The invention particularly provides that n represents 1 and R is bonded to the 5-position.
Lower alkyl groups, such as n-butyl groups, or lower alkyl groups
xy-lower alkyl group, e.g. 3-methoxy-n-pro
represents a pyr group, and R7 in AC is an amino group at the ω-position or
Especially lower alkanoylamino groups, e.g. acetylamino
groups and carboxy groups, lower alkoxycarbonyl groups, e.g.
For example, ethoxycarbonyl group or 1-(lower alkyl group)
(bonyloxy)-lower alkoxycarbonyl group, e.g.
Substituted with pivaloylcarbonyloxymethoxycarbonyl group
General formula representing the substituted n-propyl group (new compound of
, preferably in optically active form, in particular in which the group R1 has the above definition.
The L-form of the compound, or a salt thereof, especially a pharmaceutically acceptable
Regarding salt. The present invention particularly relates to novel compounds of general formula (I) as described in the Examples.
Regarding compounds. The new compound of general formula (T) can be produced by a method known per se.
It will be done. These compounds are, for example, a compound of the general formula (■): /\ to/ a compound of the general formula (■): HOOCR+ (Ill) or a reactive derivative of such a carboxylic acid or
Reacts with reactive derivatives of modiesters or monoamides of carbonic acid.
and, if necessary, the generated compound of general formula (1)
into a different compound of general formula (I) and/or if necessary
Separate the resulting racemic mixture into racemic compounds depending on
or separate the resulting racemate into its optical antipodes.
and/or as necessary, the generated general formula (1)
Convert the free compound into a salt, or convert the resulting salt to the free compound.
can be obtained by converting it into salts or different salts
. Reactivity of carboxylic acid represented by general formula (TIT)
Derivatives include, for example, acid anhydrides, such as general formula (III)
formed by intramolecular ring closure of dicarboxylic acids that fall within the range of
correspondingly substituted glutaric acid anhydrides, such as correspondingly substituted glutaric acid anhydrides.
Anhydrides and mixed acid anhydrides, e.g. anhydrides with hydrohalic acids
substances, such as chlorides or bromides or, for example, lower alkalis.
carboxylic acids, such as acetic acid or propionic acid, or
Lower alkoxyalkane carboxylic acids, such as 2-methoxy
acid anhydrides with cyacetic acid, and azides of such carboxylic acids.
cyanide or amide. Carbo of general formula (I)
Reactive derivatives of phosphoric acids are particularly suitable for example lower alkyl esters.
tert, such as methyl ester or tert-butylene
esters and activated esters, e.g.
Tanol, N-hydroxysuccinimide or N-
Es formed using hydroxybenzotriazole
ter, and ok-ru lower alkanol, e.g.
lower alkyl groups, such as methyl groups or lower alkyl groups,
benzyla substituted with a koxy group, e.g.
alcohol, or phenols (optionally with appropriate substituents)
, e.g. halogen, e.g. 4-halogen, e.g. 4-salt
lower alkoxy, e.g. 4-lower alkoxy, e.g.
For example 4-methoxy, 4-nitro or 2,4-dinitro
activated), e.g. 4-chlorophenol, 2
,3,4,5゜6-pentachlorophenol, 4-meth1
~xyphenol, 4-ditrophenol or 2.4-
dinitrophenol, and cycloalcohols, e.g.
Clopentanol or cyclohexanol (optional)
is an ester formed using a lower alkyl group (optionally substituted with a methyl group). Reactive derivatives of modiesters or monoamides of carbonic acid are
For example, its halides, such as chlorides or bromides.
Ru. The reaction is carried out in an open or closed container in a manner known per se.
and/or in an inert gas atmosphere, e.g. under a nitrogen stream.
, in the absence or presence of a solvent or solvent mixture, as required.
Perform the test while cooling or heating. General formula (TII)
The reaction between a free carboxylic acid and a compound of general formula (TI) is
Optionally acidic dehydration catalysts, e.g. protic acids, e.g.
Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or boric acid, benzenesulfur
In the presence of fonic acid or toluenesulfonic acid, or Lewis acid
, if necessary, e.g. in the presence of hydrogen trifluoride etherate.
The water liberated during the reaction is distilled, for example by azeotropic distillation.
Perform this while removing. The reaction is carried out in an inert organic solvent.
water-binding condensing agents, e.g. suitably substituted carbodiimides;
for example N,N'-diethyl, N,N'-dicyclohexyl
xyl or N-ethyl-N'-(3-dimethylaminopropylene)
It can also be carried out in the presence of carbodiimide. Mixed anhydrides, especially acid halides
For example acid binders, such as organic, especially tertiary, nitrogen bases,
For example triethylamine, ethyldiisopropylamine
or pyridine, or alkoxides such as alkali metals
lower alkoxides, such as sodium methoxide, or
Inorganic bases such as alkali metals or alkaline earth metals
'Hydroxides or carbonates, e.g. lithium, potassium
or reacted in the presence of calcium hydroxide or carbonate.
Ru. Esters, such as esters of the above types or reactive esters
such as cyanomethyl or pentachlorophenyl or
The reaction with N-hydroxysuccinimide ester is an example of
For example, by raising the temperature in a solvent inert to the reactants or
Implement at a low level. Reactive derivatives of modiesters or monoamides of carbonic acid, e.g.
For example, reactions with halides usually do not participate in the reaction.
optionally an acid binder, while cooling or heating in a solvent;
For example, organic bases, such as nitrogenous bases, such as triethyl acetate,
or in the presence of an excess of starting material of general formula (H), or in the presence of an inorganic base, e.g.
Carbonates or hydroxides of alkali metals or alkaline earth metals
substances, such as sodium or magnesium carbonates or water
Performed in the presence of oxides. These reactions are carried out in a conventional manner. The starting material of general formula (1'l) is produced by a method known per se.
can do. For example, these compounds are:
It can be obtained by General formula (Ha): /\ [In the formula, X is a suitable leaving group, e.g.
Esterified hydroxy groups, e.g. halogens, e.g.
chlorine or bromine, or organic sulfonic acids such as fatty acids
or aromatic sulfonic acids, such as lower alkanesulfonic acids.
fonic acids, such as methanesulfonic acid, or aromatic sulfones;
acids, e.g. optionally substituted, e.g. lower alkylated and
/ or halogenated arylsulfonic acids, e.g.
Venom 02 Hydroxy group or lower alkoxy group esterified with acid
groups, such as methoxy groups, optionally etherified
a mercapto group, such as a mercapto group or a lower alkyl group
o group, (1(class argylsulfinyl group, e.g. methyl
Sulfinyl group, lower alkylsulfonyl group, e.g.
Tylsulfonyl group, or group -3Oq tT or group -N
HN O2] is added to anhydrous hydrazine or its
Hydrates or compounds with up to 3 protecting groups as substituents
゛React with radine, then remove the protecting group and replace with hydrogen.
exchange. Protecting groups can be used for reduction, solvation, including e.g. hydrogenolysis.
solution, e.g. removed by hydrolysis and replaced by hydrogen.
groups, such as aryl-lower alkyl groups, such as phenyl
-(1() class alkyl group, such as benzyl group;
These groups may optionally contain lower alkyl in the aromatic part.
groups, such as methyl groups, halogens, such as chlorine,
Alkoxy groups, e.g.
May be substituted with a co group. Hydrazine or its hydrate
The reaction with 03 and the removal of the protecting group can be carried out in a conventional manner by raising or lowering the temperature.
and further the presence of an acid binder, such as an organic or inorganic base.
or absent, usually with an excess of hydrazine compound
, optionally in the presence of a solvent, e.g. ethanol.
in a closed container and/or in a protective gas atmosphere, e.g. nitrogen.
Conducted in an atmosphere. Groups in compounds of general formula (Tra)
If X is present in the form of a free hydroxy group, hydra
The reaction with the gin compound can be carried out under even stronger reaction conditions, such as temperature.
Increase and implement. On the other hand, preferred substances for water removal, e.g.
For example, carbodiimides, such as N,N-dicyclohexyl
The presence of carbodiimides is advantageous. In addition, a compound of the general formula (Trb): /\,
) can also be used to obtain a starting material of general formula (II)04. The reaction is carried out in a conventional manner at room temperature or
is increased in temperature and in the presence or absence of a solvent, e.g. water,
Preferably carried out in a protective gas atmosphere, e.g. under a nitrogen stream
do. Ilc formula: By reducing the 21-part in the compound /\ to an amino group.
A starting material of general formula (II) can also be obtained. return
The source is prepared in a conventional manner, e.g. in an acidic medium, e.g. an aqueous mineral acid, e.g.
For example in the presence of sulfuric acid, but especially in alkaline media, e.g.
Aqueous solutions of bases, e.g. inorganic bases, e.g. sodium hydroxide
It is carried out in liquid using suitable gold scraps. The starting materials of the general formula (n c) are sequentially the starting materials of the general formula C
Hb) in a conventional manner, for example in the presence of concentrated sulfuric acid.
It can be obtained by nitration using 05 General formula in which R represents a monocyclic or bicyclic heteroaryl group (
The starting materials for na) are for compounds of general formula (Vl)
Similarly to the method described below, the general formula (Tld): /゛\ [wherein R2 represents a monocyclic or bicyclic heteroaryl group R]
[Representing substituents that can be formed], monocyclic or bicyclic
Form a heteroaryl group R and remove existing protecting groups
and can be obtained by replacing it with hydrogen. example
For example, a compound of general formula (Ild) in which R2 represents a formyl group
1,2-dicarbonyl compound of general formula (Via) and
and ammonia by the method described below to form pyri at the 2-position.
The imidazolyl group bonded to the gin ring is at the position of the group R2.
Compounds of general formula (Id) can be formed where
Ru. The reactive derivatives of the starting materials of general formula (III) are oxidized using the conventional 06 method. That is, it has a halogenation effect
) When reacted with a suitable reagent such as thionyl chloride, the
The corresponding carboxylic acid loli 1' is formed, and alcohol, e.g.
For example, unsubstituted or substituted lower alkanols, or N-hydro
oxysuccinimide or N-hydroxybenzotriazo
or a suitable diazo compound.
, for example, when reacted with unsubstituted or substituted diazoalkanes
, the corresponding carboxylic acid ester of general formula (TTt) is produced.
to be accomplished. Salts of free carboxylic acids, especially alkali metals, as starting materials
or using alkaline earth metal salts and alcohols, e.g.
Reactive esters of unsubstituted or substituted lower alkanols, e.g.
For example, the corresponding halides, such as chlorides, chlorides or
iodides, or organic sulfonic acid esters, such as lower alkyl
Cansulfonic acid or arenesulfonic acid esters, e.g.
Methanesulfonic acid or p-toluenesulfonic acid ester
or the corresponding hydrolyzable iminoester.
esters, e.g. the corresponding imino-lower alkyl esters
Compounds such as those described above can also be obtained by hydrolyzing 07 to form esters. Carboxylic acid azide or sia corresponding to general formula (III)
Nido can be prepared by conventional methods using carboxylic acid halides such as chloride.
The electrode is preferably oxidized in the presence of an inert solvent, such as benzene.
dihydride or salts of hydrocyanic acid, e.g.
It can be obtained by reacting with mu salt. -a> A new compound of formula (T) can be obtained as follows.
Can also be done. General formula (■): /\ [In the formula, X and Xl are each replaced with hydrogen or hydrogen.
or Xl and Xl together represent two substituents
Represents a divalent group that can be substituted with a hydrogen atom, and/or a group
R and the functional groups present in the membrane are optionally in protected form.
However, at least one of the groups X1 and Xl is hydrogen.
other than Table 08, or at least Xl and Xl together are two hydrogen atoms.
represents a divalent group that can be substituted with the original
The group R and/or the functional groups present in the membrane are in protected form.
exists) or its salt, other than hydrogen.
The groups X I , X 2 or together Xl and Xl
is replaced with a hydrogen atom, and/or the group R and/or in the film is replaced with a hydrogen atom.
Protecting groups attached to one or more functional groups are removed and replaced with hydrogen.
and, if necessary, the additional methods listed after the first method.
Carry out the processing steps. The group R and/or the protected functional group in the no.
For example, a protected hydroxy group, amino group, mercapto group or
is a carboxylic acid group, and the carboxylic acid group is an ester or an ionic acid group.
Imides in which the mido group is replaced by oxygen by hydrolysis
It exists in the form of an ester, and decomposes the ester group to form a carboxyl group.
It may be one that can form an acid group. Group X
1 and the group X2 or Xl and Xl together and the groups R and
and/or protective groups present on functional groups in the bladder, e.g.
Removal of the protective groups present in the
solution, alcoholysis or acidolysis, or hydrogenation
It is carried out by reduction including decomposition. Particularly suitable removable groups X, or Xl or groups R and/or
is a hydroxy-protecting group, a mercapto-protecting group, or an amino group in the membrane.
The protecting group can be removed especially by hydrogenolysis.
-ok-ru lower alkyl group, e.g. optionally substituted
1-polyphenyl-lower alkyl group or 1-phenylene
-lower alkyl group, such as benzhydryl group or tri-
Substituents on the thyl group (particularly on the phenyl group, for example,
alkyl groups, such as methyl groups, or lower alkoxy groups, e.g.
For example, a methoxy group (especially a benzyl group)
It is. groups X+ and Xl and groups R and/or ^C
Droxy protecting group, mercapto protecting group and/or amino protecting group
Protecting groups can be used for solvolysis, e.g. hydrolysis or acidolysis.
or by reduction, including hydrogenolysis.
groups, especially the corresponding acyl groups, e.g. of organic carboxylic acids.
Acyl groups, such as lower alkanoyl groups, such as acetyl
0 groups, or aroyl groups, such as benzoyl groups, and carbonic acid groups.
The acyl group of the half ester, e.g. lower alkoxycarbo
Nyl group, such as methoxycarbonyl group, ethoxycarboxylic group
Nyl group or tert-butoxycarbonyl group, 2-halo
-lower alkoxycarbonyl group, e.g. 2,2.2-1
-lichloroethoxycarbonyl group or 2-iodoethoxy group
cycarbonyl group, optionally substituted 1-phenyl-
Lower alkoxycarbonyl groups, such as benzyloxycarbonyl groups
carbonyl group or diphenylmethoxycarbonyl group or
loylmethoxycarbonyl group, e.g. phenacyloxy
a carbonyl group, and further optionally substituted 1-poly
phenyl-lower alkyl group, e.g.
Liphenyl - a lower alkyl group, and especially a trityl group.
You can. - removable formed by xl and xl joined together
The groups are in particular groups that can be removed by hydrogenolysis, e.g.
For example, optionally substituted 1-phenyl-lower alkyl
Dene group (substituents on the phenyl group, for example,
alkyl group or lower alkyl group) and especially a benzylidene group, or
is a cycloalkylidene group, such as a cyclopentylidene group
Or it is a cyclohexylidene group. Protected compounds present in the form of esters or imidoesters
Carboxylic acid groups can be treated in particular by the aforementioned methods, especially by hydrogenolysis.
decomposed by reduction to its original carboxylic acid and
A group that forms the corresponding alcohol. Therefore, esthetics
Examples of protective groups suitable as a hydrogenation group include hydrogenated moieties.
α-aryl-lower alkoxy that can be removed by solution
groups, e.g. optionally substituted 1-polyphenyl-low
or 1-phenyl-lower alkyl group, e.g.
For example, benzhydryl or trityl groups (especially phenyl groups)
Substituents on the moieties include, for example, lower alkyl groups, such as methyl
groups, lower alkoxy groups, such as methoxy groups and/or
), and in particular benzyl groups.
can be lost. Starting materials which can be used in salt form are in particular acid addition salts, e.g.
It is used in the form of acid addition salts with acids and acid addition salts with organic acids.
Ru. 12 Groups X and Xl that can be removed by hydrogenolysis, especially
1-phenyl-lower alkyl group optionally substituted with
, and a suitable acyl group, e.g. optionally substituted 1
-phenyl-lower alkoxycarbonyl group, and - together
formed by Xl and Xl, optionally substituted
1-phenyl-lower alkylidene group and groups R and
and/or hydroxy protecting groups of this type present in Ac,
Mercapto and/or amino protecting groups and carbo
As a removable group in the phosphoric acid ester or imide ester
The α-aryl-lower alkyl group present in
activated hydrogen, e.g. a catalyst, e.g. a suitable noble metal.
treated with hydrogen in the presence of a catalyst, e.g. palladium or platinum.
It can be removed by Groups X1 and Xl that can be removed by hydrolysis, e.g.
Acyl groups of organic carboxylic acids, such as lower alkanoyl groups and
and half esters of carbonic acid, acyl groups of, for example, lower alkoxy
cycarbonyl groups, and e.g. trityl groups, and lower alkyl groups.
Kylidene, 1-phenylene 13-lower alkylidene group or - together with Xl and Xl
The cycloalkylidene group thus formed, as well as the groups R and
and/or protecting groups of this type present on functional groups in Ac, e.g.
For example in hydroxy, mercapto and/or amino groups
Depending on the nature of such groups, the protecting groups present in
under normal or basic conditions, such as mineral acids such as hydrochloric acid or
Hydroxylation of sulfuric acid or alkali metals or alkaline earth metals
or carbonates, or amines such as isopropylamine
can be removed by treatment with water in the presence of
Ru. For example, by hydrolyzing imidiester groups,
Reactions to form the corresponding groups of esters or monoamides are examples.
For example, using hydrous mineral acids such as hydrochloric acid or sulfuric acid, e.g.
For example, addition of hydrogen chloride to nitrile and absolute alcohol,
Especially by reaction with unsubstituted or substituted lower alkanols.
The imidoester salt obtained by
After addition, it can be directly hydrolyzed to the corresponding ester.
can. 14 Groups X1 and X2 which can be removed by acidolysis and
and/or functional groups in the radicals R and/or C, such as the above-mentioned
Functional groups such as hydroxy groups, mercapto groups and/or
Protecting groups present on amino groups are particularly important for half-esters of carbonic acid.
Acyl groups, e.g. tert-lower alkoxycarbo
Nyl group or optionally substituted diphenylmethoxyca
rubonyl group, and ter is -lower alkyl group;
, such groups can be, for example, suitable strong organic carboxylic acids, e.g.
For example, lower amines optionally substituted with halogens, especially fluorine.
Lucancarboxylic acids, especially trifluorocarboxylic acid (if necessary)
in the presence of an activator, e.g. anisole) and formic acid.
It can be removed by treatment. Groups X1 and X2 and/or groups that can be removed by reduction
Functional groups in R and/or the functional groups such as those mentioned above, e.g.
For example, hydroxy, mercapto and/or amino groups
Protecting groups present are defined as chemical reducing agents (particularly reducing metals or
are removed by treatment with reducing metal compounds).
15 meaning a glutinous group. Such groups are particularly suitable for reducing heavy metals such as zinc.
or usually treated with an organic carboxylic acid such as formic acid or
In the presence of acetic acid and water, heavy metal salts such as chromium (
n) salts, such as chromium (II) chloride or chromium acetate (H
) can be removed by treatment with
Alkoxycarbonyl group or arylmethoxycarbonyl group
is a group. Functional groups in the radicals R and/or Ac, such as hydroxy groups,
The protecting group present on the mercapto group and/or amino group is
can be removed by the method described above and replaced with hydrogen.
Corresponding to the above-mentioned groups that can be
removed at the same time as other groups or later in a separate processing step
be able to. The above-mentioned reactions are usually carried out in a solvent or a mixture of solvents (at the same time as
in the presence of a suitable reactant (which may function as
, with cooling or heating as necessary, e.g. open or
in a closed container and/or in an atmosphere of an inert gas, e.g. nitrogen.
Perform in the air. The starting material of general formula (TV) can be prepared by a conventional method, for example, 16.
[In the formula, XI, X2 and ^C represent the above]
It can be obtained by reacting with a compound. reaction
It is advantageous to carry out in the presence of a condensing agent. For example,
represents a reactive esterified hydroxy group, the acid linkage
synthetic condensing agents, e.g. alkaline condensing agents, e.g. organic bases
, such as l-ethylamine or inorganic bases such as alkaline
Potassium metal carbonates or bicarbonates, such as sodium carbonate or
is carried out in the presence of sodium bicarbonate. General formula (Ha)
X in the compound is play! 411 When representing a hydroxy group,
The reaction with the compound of general formula (rVb) is carried out using an inert solvent, e.g.
A water binder, such as a carboxylic acid, is added in tetrahydrofuran.
mido, such as N,N'-dicyclohexylcarbodiimide
or N-ethyl-N'-(1-dimethylaminopropylene)
) can be carried out in the presence of carbodiimide. However, for the above reaction, instead of the 17 compound of general formula (TVb), a compound of general formula (IVc):
and has a hydrogen atom instead of the base film, the generated general formula
(TV), for example, the corresponding carboxylic acid (if
by reactive derivatives, e.g. halides or anhydrides.
or in the form of a reactive ester) to form a group A
It is also possible to introduce c. These reactions are carried out using conventional methods and in the presence of a suitable inert solvent.
, with or without a condensing agent, increasing or decreasing the temperature.
and, if necessary, under a protective gas atmosphere, e.g. nitrogen atmosphere.
Implement with dignity. The new compound of general formula (1) has the general formula (Tra)/\ [wherein X represents a suitable leaving group and R represents the above-mentioned one]
] is reacted with a compound of the general formula (■): 18 H2N-N H-^c (V) [in the formula, the bladder represents the above], and the necessary
If necessary, additional processing steps described after the first method
It can also be obtained by implementing suitable group X
is an optionally reactive esterified compound, e.g.
Roxy groups, e.g. hydroxy groups, or halcogens, e.g.
chlorine or bromine, or organic sulfonic acids such as aliphatic sulfonic acids.
sulfonic acids, such as lower alkanesulfonic acids, such as meth
sulfonic acids or aromatic sulfonic acids, e.g. optionally
Substituted, e.g. lower alkylated and/or halogen
Esthetics with modified arylsulfonic acids, e.g. benzoic acid.
hydroxy groups, and also alkoxy groups, e.g.
methoxy group, optionally etherified mercapto
groups, such as mercapto groups or lower alkylthio groups, e.g.
methylthio group, lower alkylsulfinyl group, e.g.
Methylsulfinyl group, lower alkylsulfonyl group, e.g.
For example, methylsulfonyl group, nitro group, group -S Os I
T or the group -NH-NO2. 19 The reaction is carried out in a manner known per se, preferably in a suitable solvent.
It is carried out in the presence or absence of a condensing agent. For example, X reacts
When representing an esterified hydroxy group, an acid binder,
For example, bases, such as organic nitrogen bases, such as triethyl acetate,
or metal alkoxides, e.g. metal lower alkoxides.
acids, such as sodium methoxide, or inorganic bases, e.g.
e.g. alkali metal or alkaline earth metal carbonates or water
oxides such as sodium carbonate or magnesium carbonate
Carry out the reaction in the presence of The solvent acts as a condensing agent
In other words, the reaction may be accelerated. In some cases other
This type is used in combination with a solvent, e.g. a non-polar solvent.
In particular, polar solvents, such as lower alkanoyl
such as methanol or ethanol, and also lower
Amides of alkanecarboxylic acids, e.g. dimethylformamide
mido, N-methylacetamide, N,N-dimethylacetamide
toamides and also phosphoric acid amides, such as hexamethyl phosphoric acid
triamides, and polymethylated ureas such as N, N, N
“, No-tetramethylurea, 20 and sulfolane, and optionally lower alkylation,
For example N-methylated 2-pyrrolidone, and also dimethyl
Sulfoxides and mixtures of such substances are applicable.
. In the compound of general formula (IT a), X is hydroxy
When representing a radical, the reaction optionally assists in the removal of water.
It is carried out in the presence of reagents. Such reagents include
For example, substances that exhibit acidic reactions, such as mineral acids, such as hydrochloric acid.
or sulfuric acid, and organic acids, especially sulfonic acids, such as benzene.
sulfonic acid or p-)luenesulfonic acid.
They can be prepared using a suitable inert solvent, e.g. butanol, or aromatic
In the presence of group substances such as benzene or toluene,
facilitates the removal of reaction water by distillation, e.g. azeotropic distillation.
. However, along with the water binding produced, the reduction caused by this method
If the carbodiimide, e.g. N, N-
Diethylcarbodiimide or N,N-dicyclohexyl
It can be carried out using carbodiimides. These reactions can be carried out by raising the temperature in an open or closed container using conventional methods.
If necessary, carry out under protective gas, for example nitrogen gas. The starting materials are known or, if new, are always
It can be manufactured by the method. The starting material for general formula (V) is
, hydrazine or its hydrate (optionally, e.g. reduced
and hydrogenolysis or solvolysis, e.g.
protecting groups that can be removed and replaced with hydrogen, e.g. α-
-lower alkyl group, such as benzyl group, or
Syl groups, such as lower alkanoyl groups, such as acetyl groups
(including) to introduce an acyl group, for example
The corresponding carboxylic acid or its reactive derivative, e.g.
and then remove the protecting groups present.
Obtained by removing and replacing with hydrogen. n represents 1, R is a monocyclic or bicyclic heteroaryl group
A new compound of general formula (1) representing
You can also get it. That is, general formula (): In formula c, the hydroxy group and/or amino group are protected with a protecting group.
and R2 is a monocyclic or G-obicyclic heteroaryl group R
[representing substituents that can be formed] monocyclic or bicyclic
to form a heteroaryl group R, present simultaneously or subsequently.
Remove any existing protecting groups, replace with hydrogen, and if necessary
Perform the f1 additional treatment step described after method 1. The protecting group is, for example, for forming a heteroaryl group R.
Atoms that can be removed and replaced with hydrogen under the processing conditions used.
Syl groups, such as lower alkanoyl groups, such as acetyl groups
It is. 23 Thus, formula 1 (wherein R is substituted pyri, e.g. at the 2-position)
(representing an imidazolyl group linked to a zyl group)
For the production of products, the formula ■ (wherein R2 represents a formyl group)
A compound represented by the formula: % formula % (in the formula, each of R4 and/or R3 is hydrogen or
For example, it represents a group substituting a heteroaryl group such as those mentioned above.
1,2-dicarbonyl compound of
In the presence of ammonia as above, or corresponding to formula VIa
can be reacted with monooximino compounds. base
Depending on the nature of R4 and/or R3, compounds of formula VTa
The product can be used as is or with a suitable precursor.
can be generated in situ in the reaction mixture. this
Precursors suitable for the purpose include, for example, hydroxyl
Derivatives of cyacetone and e.g. lfl, 1-dihaloacetate
(e.g. 1,1-dibromoacetone).
, which are optionally substituted in the l- and/or 24 positions by groups R4 and/or R3.
. Other precursors include dicarbonyl compounds of formula VIa.
modified forms, such as acetals (e.g.
tylacetal) or as a hydrate or
Examples include those in the form of bisulfite ffi adducts.
Compounds of formula 0 Via can be obtained in situ from such precursors.
It's okay. That is, 1,1-dihaloacetyl-one derivative
In this case, a hydrolyzing agent, preferably a weak alkali (e.g.
(e.g., sodium acetate) or
In the case of tar or bisulfite 10 adduct compounds. It may also be obtained by treatment with an aqueous acid solution. this
Thus, formula 1 (wherein the substituted pyridyl group is substituted at the 2-position)
The groups R4 and/or R3 are
placed at the 4- and/or 5-position of the midazole group, respectively.
The compound (converted) is obtained. Formula I (wherein the imidazole group R is e.g.
A compound of the formula ■ (substituted with a substituted pyridyl group) has the formula
wherein R2 represents a group (1)-c (VIb) \) is obtained by reacting a compound of the formula:
be able to. Groups of formulas b and VIc are functionally modified
forms such as acetals (e.g. dimethyl acetate)
may be in the form of hydrates or heavy sodium
May be in the form of sulfate addition compounds, free from which
The compound is produced in situ by treatment with aqueous acid.
and subsequent further reaction in the same reaction batch.
make them respond. These reactions can be carried out in conventional manner, e.g.
or in the presence of a solvent mixture and if necessary cooled or
with heating, if necessary in a closed container and/or
is carried out under an inert gas atmosphere (e.g. under nitrogen). This starting material can be produced by methods known per se.
Wear. Thus, the formula ■ (wherein R2 is a formyl group or the formula ■b
The compound (representing a group) can be produced as follows.
I can do that. That is, the formula R2-Pmer011 (Vl
d) (in the formula, a formyl group corresponding to the group R2, or
The group of formula (b) is preferably in protected form, for example
, in the form of an acetal (e.g. dimethyl acetal)
or hydrate or bisulfite addition compounds, e.g.
For example, it is an addition compound with sodium bisulfite and
Droxy groups can also be used in reactive esterified forms, e.g. halogen
(e.g. chlorine or bromine) or sulfur
fonic acid (e.g. methanesulfonic acid) or aryl
ethyl sulfonic acid (e.g. benzenesulfonic acid).
) is in the form of a stellated hydroxyl group.
, - a compound of formula TVb or V as described above and in a method as described above.
, for example, carbodiimide (e.g. N,N-dicyclo
xylcarbodiimide) or if hydroxylcarbodiimide)
If the group is a reactive ester, a basic condensing agent
and then the protecting group is removed, e.g. as described above.
and remove it. Formula 1 (wherein R is substituted, for example, at the 2-position by a pyridyl group)
The compound (representing a thiazolyl group substituted with
For example, a compound of the formula ■ (wherein R2 represents a group of the formula: 5=C-
and each of R4 and/or R3 is hydrogen or
or 1, for example, by substituting a heteroaryl group as described above.
(representing a group)
I can do that. Depending on the nature of the radicals R4 and/or R3,
Compounds of formula Vlf can be used in the form of derivatives, for example acetals.
(e.g. diethyl acetal).
Wear. 27 Formula I (wherein R is a pyridyl group substituted at the 4- or 5-position
(representing a thiazolyl group substituted by)
For the production of, for example, a compound of the formula (1) (wherein R7 represents a group of the formula % or a group of the formula % and the carbonyl group is optionally protected)
For example, in the form of an acetal, Hal is
in each case represents a halogen, such as chlorine or bromine, R
4 and R3 have the meanings given above) can be reacted with compounds of the formula: %formula%. These reactions are
in a manner known per se, e.g. with a suitable solvent, e.g.
alkanol (e.g. ethanol) or ethereal
in the presence of a liquid (e.g. dioxane), optionally at elevated temperature and optionally
Basic agents, such as metal salts, such as carboxylic acids or
Alkali or alkaline earth metals in weak acids such as acetic acid
salt (e.g. magnesium carbonate or sodium acetate)
and/or in a closed container if necessary.
Alternatively, it is carried out under an inert gas atmosphere (for example under nitrogen). Starting materials can be produced by known methods. mosquito
Thus, a compound of formula (2) having a group Vle as R2 has the formula
: In the compound, the group NEC- is replaced with the group Vle, hydrogen sulfide
and a suitable solvent, such as a basic organic solvent (e.g. pyridine).
or triethylamine or mixtures thereof).
It can be obtained by converting . The starting materials of formula VIk are sequentially of the formula:
, for example, /\logen or t±sulfony, as described above.
(in the form of a
reacting with formula IVb or V and protecting groups present
obtained by removing and replacing them with hydrogen
I can do it. of formula ■ (wherein R2 represents a group of formula ■h or ■i)
The starting material can be, for example, of the formula: or of the formula: /\ )1al
, represents chlorine or bromine, and represents a hydroxy group or
Reactive forms such as )\rogens, e.g. salts
(which may be in the chlorine or bromine form), e.g.
, as described above, with a compound of formula IVb or V.
, and remove the protecting groups present and replace them with hydrogen.
It can be obtained by Formula ■ (wherein R is a pyridyl group substituted at the 4(6)-position, for example)
The compound (representing a pyrimidinyl group linked to) is,
For example, the formula ■[wherein R2 is the formula 2〇\C-(:512-GO-(VT o )/3 (wherein the carbonyl group is optionally in a protected form,
For example, in acetalized form (e.g. dimethyl acetate)
), or bisulfite addition compounds, e.g.
(in the form of an addition compound with sodium sulfate)
A compound of formula: () % formula % (R4 and R3 in formula VIP and formula ■0 are each
by reacting with a compound (having the above meaning)
Obtainable. This reaction is carried out in a conventional manner, preferably under acidic conditions, e.g.
For example, the use of reagents that exhibit acidic reactions (e.g. ammonium chloride)
Do it in your presence. The starting materials can be obtained by methods known per se.
. Thus, for example, in the formula 1 with the group Vro as R2
The starting material has the formula:
Protected by sea urchins, e.g. acetalized
for example, a compound of formula TVb or
is reacted with compound V, and the following 1. Protecting groups present in %
It can be manufactured by removing. Formula I (wherein R is, for example, a pyridyl group substituted in the 2-position)
(representing a pyrimidinyl group linked to)
For example, a compound of formula (1) (wherein R2 represents a group of formula: ) is converted into a compound of formula:
Among them, the carbonyl group is optionally in protected form, e.g.
Acetalized forms (e.g. dimethyl acecool form)
), and R4 and R3 have the above meanings)
can be reacted with compounds of This reaction is that
By a method known per se, for example, under acidic conditions as described above,
For example, it is carried out in the presence of ammonium chloride. This starting material can be produced in a manner known per se.
Wear. Thus, for example, a formula with the group Vlr as R2
The compound (2) is, for example, a compound of the above formula (VTk),
The corresponding iminoester, e.g.
by saturating a solution of anhydrous ethanol with hydrogen chloride.
and from them, reacted with anhydrous ammonia.
By doing so, the formula ■ containing a group (Vl r) as R2
1, preferably in the 1n form, such as hydrogen chloride.
obtained in the form of a salt with a strong acid such as
sometimes or subsequently removing them and replacing them with hydrogen
It can be obtained by Select the appropriate method from above for the production of the compound of formula ■.
When selecting
In some cases, care must be taken to ensure that substituents are not transformed or removed.
Must. For example, solvation, especially hydrolysis
, or upon reduction, especially functionally modified carboxy
group (e.g. esterified or amidated carboxylic acid)
(cyan group) and cyan group participate in the reaction and can be converted.
be. On the other hand, simultaneous transformation of substituents may be preferred; e.g.
For example, unsaturated substituents, such as lower alkenyl, may be
, lower alkyl under the conditions of the reduction method used in the present invention
can be reduced to The compound obtained by this step is a compound of formula 1 by a conventional method.
For various end products within the definition of, e.g.
Can be transformed by modification, derivation or removal of substituents
Wear. The free carboxyl group can be converted in a conventional manner, e.g.
cole and an acid such as a mineral acid (e.g. sulfuric acid or hydrochloric acid)
Advantageously in the presence of or dicyclohexylcarbodiimide
By reacting in the presence of an ice-binding agent such as
or a corresponding diazo such as, for example, diazomethane.
It can be esterified by reacting with a compound.
Wear. This esterification also includes salts of acids, preferably alkaline acids.
Reactive esterification of potassium metal salts with alcohols, e.g.
By reacting with corresponding halides such as
You can also do more. Free carboxyl groups can be removed in a conventional manner, e.g. with ammonia.
, or with a 35-class or secondary amine, preferably with a freezing agent such as dicyclohexylcarbodiimide.
By reacting in the presence of a mixture, or by reacting in the presence of a carboxyl
A sil group can be replaced by a halocarbon such as a chlorocarbonyl group.
conversion to a bonyl group, followed by ammonia or primary
or amidation by reacting with a secondary amine.
I can do that. In compounds containing esterified carboxyl groups,
, this group can be added in a conventional manner, for example preferably with an alkali metal
Hydroxides (e.g. sodium hydroxide or potassium hydroxide)
strong bases such as
In the presence of strong mineral acids such as acids (e.g. hydrochloric acid or sulfuric acid)
Conversion to free carboxyl groups by hydrolysis
I can do it. In compounds containing esterified carboxyl groups,
, this group in the presence of various alcohols, preferably
In the presence of excess, various alkaline compounds as ester components
For example, a basic catalyst is added to the carboxyl group containing the call.
medium, e.g. 36 alkali of alcohol used for transesterification
in the presence of metal compounds or with suitable catalysts, e.g.
In the presence of a metal catalyst (e.g. palladium supported carbon catalyst)
can be converted. Compounds with esterified carboxyl groups as substituents
For example, ammonia
or using primary or secondary amines,
The corresponding carbamoyl group is
can be converted to . Compounds having an unsubstituted carbamoyl group can be prepared in a conventional manner, e.g.
, phosphorus pentoxide, phosphorus oxychloride or anhydrous trifluoro
Preferably at elevated temperatures by the action of water removing agents such as acetic acid.
can be dehydrated to produce the corresponding cyanide.
Ru. Compounds with esterified carboxyl groups as substituents
In this case, the esterified carboxy group is added in a conventional manner, e.g.
For example, organic compounds such as diethylaluminamide
Preparation of di-lower alkyl aluminum amide compounds such as
Depending on the use, it can be converted to a cyan group. Compounds containing cyanogen substituents can be prepared by conventional methods, e.g.
of highly concentrated aqueous solutions of mineral acids or alkali metal hydroxides.
in the presence of the corresponding carbamoyl compound or directly
Can be hydrolyzed to carboxy compounds. A compound having a cyano group as a substituent is prepared by a conventional method, e.g.
For example, alcohol in the presence of anhydrous acid (for example, hydrogen chloride)
followed by hydrolysis of the resulting imidoester
The corresponding compound with an esterified carboxy group is
Can be broken down into alcohols. Compounds containing an amine group as a substituent can be prepared using conventional methods.
and the corresponding carboxylic acid, e.g. lower alkane carboxylic acid.
acids or their reactive derivatives, such as halides or
or anhydrides or esters (e.g. lower alkyl ethers).
ster), the corresponding acylamino compound,
For example, converting it to a lower alkanoylamino compound
I can do that. A compound having an amine group as a substituent can be prepared by a conventional method.
, for example, the corresponding lower alkylamino or di-lower alkyl
These lower alkyl halides to rkylamino compounds,
For example, by reacting with these bromides or iodides.
It can be converted by A lower alkylthio group, such as methylthio, is present in the aromatic ring.
A compound having an o group can be used as a suitable reagent having a desulfurization effect,
For example, using Raney nickel, a suitable solvent, e.g.
, containing sulfur by treatment in dioxane.
It can be converted into a compound that does not exist. As in the manufacturing process, when carrying out additional steps
, no undesirable secondary reactions leading to conversion of the adduct group occur.
You must be careful. The above reactions may be performed simultaneously or sequentially.
and can be performed in any desired order. necessary
If so, these reactions can be carried out at low temperatures or in the presence of diluents, condensing agents, and/or catalyst activators.
at elevated temperature, in a pressurized closed container and/or under an inert gas.
It is carried out in an atmosphere. Depending on the reaction conditions and starting materials, this new compound can be liberated.
or in the form of their salts, which are also
within the scope of the present invention, and this new compound or
salts are also available in their hemi-, mono-, sesqui- or po-
It can be in the form of rehydrate. The acid addition salt of this new compound is
Methods known per se, e.g. alkali metal hydroxides
, such as carbonates or bicarbonates or ion exchangers.
By treatment with basic agents. It can be converted into the free compound. On the other hand, obtained
The free base can be combined with an organic or inorganic acid, e.g.
Acid addition salts can be produced; the production of such salts
In particular, the production of pharmaceutically acceptable non-toxic salts should be
A suitable acid is used for the preparation. The salt of this new compound with the ffi group can be prepared by a method known per se.
Acidic agents such as dilute mineral acids (e.g. hydrochloric acid or sulfuric acid) or organic acids (e.g. acetic acid)
, or by treatment with an acidic ion exchanger
, can be converted to the free carboxylic acid. these
by reaction with a base (e.g. an inorganic or organic base)
can in turn generate the corresponding salts, especially for pharmaceutical purposes.
An acceptable non-toxic base, such as those mentioned above, may be used.
It will be done. These and other salts, especially the acid addition salts of this new compound
, for example oxalate or perchlorate can also
For purification of free bases, convert the free bases into salts and
The salt is separated, then purified, and then the base is extracted from the salt again.
It can be used by liberating it. Depending on the starting materials and the selection method, this new compound can be
May be in optical enantiomer or racemic form;
If these have at least two asymmetric carbon atoms
If so, it may also be in the form of a racemic mixture. starting material
Quality can also be used in the form of certain optical objects.
Ru. The resulting racemic mixture has two stereoisomers (diastereoisomers).
racemic isomer) using known methods such as chromatography.
By roughy and/or fractional crystallization, diastereo
Separation based on physical-chemical differences between isomers
can be done. The racemate obtained can be prepared by methods known per se, e.g. optical
suitable microorganisms by recrystallization from a solvent active in
or racemate and salt by treatment with
The optically active substance produced, for example, the acid 17〈is1''1
111 thus obtained
For example, a mixture of
The Vi detached enantiomer, which can be M-agglutinated by the action of the drug, is obtained from it.
Diastereoisomer 1! to be separated into
can be separated more easily. Especially river 1. ) optics
Examples of physically active acids include tartaric acid D and L
Together, g0.0°-(p-1 luoyl)-tartaric acid,
Malic acid, mandelic acid, camphor sulfonic acid, glu, tamic acid
, aspartic acid or quinic acid. Optically active bases that are particularly used include, for example,
optically active amines, e.g.
Acid ester, (-)-brucine, (+)-quinidine, (
-)-quinine, (+)-cinchonine, (+)-dihydro
Abethylamine, (+)- or (-)-eph
I can give you a drink. The activity of two normal bodies is large
If possible, it can be advantageously isolated. The present invention also relates to a process form, and the process
obtained as an intermediate at any stage of the process, depending on the form
using the compound as a starting material and then proceeding with the remaining process steps.
shall be carried out or discontinued at any stage,
or the process in which the starting materials are
is produced, or in the process, the reaction
something is in one form of its salt, as the case may be
. In order to carry out the reaction according to the invention, special mention is made at the outset.
It is possible to use the starting materials which lead to the group of end products described and in particular the end products described or indicated.
It's advantageous. Starting materials are known or even new
, in a manner known per se - as described above, e.g.
For example, similar to the method described in the examples,
I can do that. The present invention also provides novel starting materials, in particular those mentioned above.
Formula TI (wherein R and n have the meanings in Formula 1)
, n represents 1, R is in the 3- or 6-position, but
Particularly present at the 5-position, lower alkoxy-lower alkyl (
For example, 2-methoxyethyl), or phenyl-low
represents a class alkyl (e.g. benzyl) or
and if n is 1, R has 2 to 7 carbon atoms.
lower alkyl (e.g. ethyl, n-propyl or n-
-butyl), and if n is 1, lower alkyl
R at the 4-position as kill has 3 to 7 carbon atoms;
and represents, for example, n-propyl or n-butyl.
starting materials (with the further proviso that
salts, especially pharmaceutically acceptable, non-toxic acid additions of 11
1, and 44 methods for producing them. The present invention also provides that by this method
This invention relates to novel intermediates obtained and methods for producing them. The present invention also provides compounds of formula (1) or such compounds
Pharmaceutically acceptable salts of
in the control area, especially in the form of compounds with pharmacological action.
Regarding the use of. These are preventive measures for hypertonia and
and/or in a method for therapeutic treatment.
Preference is given to using it in the form of a preparation. alone or used
of the active ingredient administered in combination with carriers and additives.
Dosage depends on the species, age and individual condition being treated, as well as
Depends on administration method. antihypertensive compound per day
The entire dose may be administered in one or more doses, preferably in up to four doses.
However, for mammals weighing 70 kg, no symptoms are observed.
Preferably according to the type of case, individual condition and age.
is 150 to 750 mg. The present invention also contains the active ingredient in a pharmacologically effective amount.
Regarding pharmacological preparations, this pharmacological preparation koji may be used in some cases.
For example, enteral administration 1, e.g. oral administration, or parenteral administration.
and suitable for inorganic or organic or solid
or a pharmaceutically acceptable carrier which may be a liquid.
(Jl is used. Therefore, the active ingredient may be mixed with a diluent such as lactose, dextrose, etc.)
strose, saccharose, mannitol, sorbitol,
cellulose and/or glycerin; and/or
lubricants such as silica, talc, stearic acid or
its salts (e.g. magnesium stearic vinegar or
calcium thearate); and/or polyethylene
Tablets or gelatin capsules containing with glycol
is used. Tablets may also contain a binder 1 such as silicate magnet.
aluminum, starch (e.g. corn
, wheat, rice or arrowroot starch), gelatin
, tragacanth, methylcellulose, sodium carpo
methyl cellulose and/or polyvinyl pylori
and, if desired, a disintegrant, e.g. starch.
N, agar, alginic acid or one of them! (for example,
sodium alginate) and/or effervescent mixture
, or containing adsorbents, colorants, flavorings and sweeteners.
You can also Introducing novel pharmacologically active compounds into the intestinal tract.
Use in the form of preparations for external administration or in the form of infusions
is also possible. Such solutions are preferably isotonic
liquid aqueous solution or suspension containing the active ingredient, e.g.
Alone or together with carriers, e.g. mannitol,
If so, it is possible to manufacture them before use.
Ru. Pharmacological preparations may also be sterile and/or
may contain additives such as preservatives, stabilizers, wetting agents and/or
or emulsifiers, solubilizers, salts for adjusting osmotic pressure and/or
Buffers may also be included. Pharmacological preparations of the invention
may contain other pharmacologically active substances, if desired.
However, methods known per se, e.g.
manufactured by granulation, sugar refining, melting or freeze-drying processes.
and contains about 0.1% to 100% of the active ingredient.
Contains about 1% to about 50% of lyophilized
In some cases, it may contain up to 100%14,7. The following examples will serve to illustrate the invention;
Temperature is expressed in °C. After adding 1.5 g of palladium-supported carbon catalyst (5%),
N-(benzyloxycarbonyl) in Tanol 150 Pengwen
)-L-glutamic acid 5-[? 12-(5-n-buty)
-2-pyridyl)-hydrazide]-1-benzyl es
A solution of 15.1 g of hydrogen was passed through the solution until hydrogen was completely absorbed.
Hydrogenation was carried out under standard conditions. This suspension was mixed with methanol.
Diluted, heated and then filtered using a filter. The filtrate was concentrated in a rotary evaporator to a low concentration and injected into
Thoroughly stirred with propatool and then filtered. This residue
The residue was recrystallized from methanol and dried under high vacuum.
L-glutamic acid 5-( with melting point 155-157°
N2-(5-n-butyl-2-pyridyl)-hydrazide
1 hemihydrate was obtained. [α120: +27°±
1' (c=0.5-1% in methanol). This starting material can be produced as follows. 48 2-hydra in dry tetrahydrofuran 175+al
A solution of 6.9 g of dino-5-n-butyl-pyridine was added to a water bath.
Cooled on top. N-(benzyl-oxycarbonate) without stirring.
(rubonyl)-L-glutamic acid l-benzyl ester 5
-(N-hydroxysuccinimide)-ester 19.
Add 8g in portions and continue stirring at 0° for a further 2 hours.
I did it. The solvent was removed in a rotary evaporator and the residue was
Chlorinated on silica gel using ethyl acetate as eluent.
When applied to matoography, N-(benzyl
oxycarbonyl)-L-glutamic acid 5-[N2-(
5-n-butyl-2-pyridyl)-hydrazide 1-1-
The benzyl ester is obtained in the form of an oil and is kept in that form.
It was further used in the next operation. Dimethylformamide 5I while stirring at room temperature! l
A solution of 0.53 g of acetic anhydride in
Monoglutamic acid 5- in 20mu of chillformamide
[N2-(5-n-butyl-2-pyridyl)-hydrazi
] 1.47 g and anhydrous sodium carbonate 1.33 g.
It was added dropwise to the cloudy liquid. Stirring was continued for a further 15 hours at room temperature and then
The whole is then filtered using a filter and then rotary evaporator.
The solvent was removed from the filtrate in a vacuum. Remove remaining colored foam
Chloroform/methanol/ammonia on silica gel
Chromatography using a solvent mixture of (5:3:l)
- I put it on. Combine the main fractions and remove the solvent in a rotary evaporator.
I left. To produce ammonia salt, the residue is
Dissolve in methanolic ammonia and evaporate the solution.
and then recrystallize the product from Improper Tools.
Then, N-7 cetyl-monoglutamic acid 5- (N2
-(5-n-butyl-2-pyridyl)-hydrazide 11
7.
m, p, 147-149°; 20° [α], +28° ± 10, (c = 0.5-1% meta
in alcohol); methylene chloride/methanol/W NH40
Rff white in H (5:3:1) system = 0.76° support
After adding 0.5 g of Upalladium-supported carbon catalyst 1 (5%),
N-acetyl-glutamine in methanol 50 intestines
Acid 5-[N2-(5-n-butyl-2-pyridyl)-h
Add a solution of 2.7 g of drazide]-1-benzyl ester to water.
Hydrogenated under normal conditions until absorption of element is complete
. The catalyst is filtered off and the filtrate is then freed from the solvent in a rotary evaporator.
I left. The residue was purified with chloroform/methanol on silica gel.
Clean with a solvent mixture of 1:1/ammonia (5:3:1).
romatographed. Combine the main fractions and then dissolve
The medium was removed. The residue is used for the production of ammonium salts.
Dissolves in excess methanolic ammonia and dissolves by evaporation.
Concentrate the liquid and then recycle the product from the Improper Tool.
When crystallized, N-acetyl-glutamic acid 5-IN
2-(5-n-butyl-2-pyridyl)-hydrazide J
An ammonium salt of m, p, 147-1 was obtained.
49°; [αl Otsu 0: +29°± 1', (cJ,
5-1% in methanol). This starting material can be produced as follows. : 2-hydrazino in 60aJl of dry tetrahydrofuran
-5-n-butylpyridine dihydrochloric acid 1fi3.17g suspension
The suspension was cooled to 5° and then, with stirring, first
Tylamine 4.2 seconds, then after 5 minutes one acetyl 5
l -L-glutamic acid 1-benzyl ester 5-(N-hyperoxygenate)
Add 5.0 g of droxysuccinimide)-ester.
Ta. The mixture was then stirred at room temperature for 15 h and triethyl alcohol was added.
Min hydrochloride was filtered off and then concentrated in a rotary evaporator at 30-40%
The solvent was removed on a bath at a temperature of °C. slightly greenish
The residue was purified on silica gel with a chloroform/methanol mixture.
(95:5). N-Acetyl- obtained from the main fraction in the form of a colorless foam
-Glutamic acid 5-[N2-(5-n-butyl-2-
pyridyl)-hydrazide 1-1-benzyl ester is
The form of methylene chloride/
Rf using silica gel in methanol (9:1) system
Value = 0.29゜ 1 group 1 nitriethylamine 5.9㎜, dried tetrahydrofuran
2-hydrazino-5-n-butylpyri in 2101
Added to a solution of 7.0 g of gin: followed by stirring at room temperature.
3-sulfa in 120% tetrahydrofuran
Moyl-4-chlorobenzoyl chloride lo, 8g solution 5
2 for 1 hour, then at this temperature for another 2 hours 30
The mixture was stirred for several minutes. Triethylamine hydrochloride is filtered out,
30 (1 mJL) of aqueous 2N acetic acid was then added to this mixture while stirring.
Added to filtrate. The formed crystals are filtered, dried and
Recrystallization was performed twice from ethyl acetate, but the final recrystallization
At this time, 2.5 μm of glacial acetic acid was added to the solvent. When the precipitate is filtered and dried, N2-(5-n-butyl
-2-pyridyl)-3-sulfamoyl-4-chloro
Benzoic acid hydrazide acetate is obtained, with a melting point of 142
It was -144°. Mitate 1 Utoluene 40■ Suspension of sodium hydride 3.2g in exchange
Add toluene + 2-hydrochloride to the suspension over 15 minutes.
Solution of 10.0 g of dorazino-5-n-butylpyridine
of toluene over 10 minutes.
0 to which a solution of 9.2 g of picolinate ethyl ester was added.
Next, carefully heat the whole thing at 40° for 30 minutes until it reaches the maximum temperature.
(at first an exothermic reaction), then 2 more times under reflux while boiling.
It was heated for 30 minutes. After cooling, the reaction mixture was
Extraction with 0+JL of 2N Jig acid 1111. ,water
Wash the acidic phase with ether and dilute with sodium hydroxide solution.
The mixture was made alkaline with ether and thoroughly extracted with ether. After drying the ether solution, a 5N solution of hydrogen chloride in ether
Add the solution to it until 9% of the strong acidic reaction and the precipitate
was filtered off and then recrystallized from ethanol; N2-
(5-n-butyl-2-pyridyl)-picolinic acid hydra
Jidoni 11! The acid salt is obtained in the form of slightly yellowish crystals.
The melting point was IH-191' (decomposed). 1 unit of toluene was cooled, stirred, and flowing with a nitrogen stream.
A solution of 6.5 g of chloroformic acid ethyl ester in 1 sentence is 1
Over 5 minutes, the 2-hydride in toluene 10(la+Q)
Add an oval to a solution of 8.55 g of radino-5-n-butylpyridine.
added. The reaction product was separated as an oil as the bottom layer. To complete the reaction, the mixture was heated under reflux for an additional 2 hours.
heated and then concentrated to dryness by evaporation; the resinous residue was
Water 250 Somi and 4 N 11! In a mixture of acids IOw statement
The opaque solution was washed with 100 μg of ether.
Purified. The reaction product was dissolved in 4N sodium carbonate solution 25
The aqueous layer is made alkaline using mJJ.
(salt), (is liberated in the form of ether 100+++Q)
This ether solution was extracted with tritrium sulfate.
After drying and evaporation to dryness, the crude product is
I let go. The crude product was dissolved in ether loOmJJ and anhydrous ether.
Dissolved in a mixture of 50mM alcohol and 5N in ether
1 hl of hydrogen tetrahydride solution was added;
Ru-N2-(5-n-butyl-2-pyridyl)-hydra
Gin was obtained as monohydrochloride in the form of colorless crystals, but
The points are 133-135° (from ethanol/ether)
Met. 1. Cook for 30 minutes while cooling and stirring vigorously.
Then, a solution of 2.5 g of acetic anhydride in 20 mQ of ether was prepared.
, 2-hydrazino-5-n-butylene in 40 ml of ether
Added to a solution of 4.0 g of lupyridine. Show the whole thing for 3 hours
After standing, diluted with ether 50+en,
5N hydrogen chloride solution in ether? , stir 3 ml of the solution.
Disinfect with stirring and cooling, then filter off the formed precipitate with suction and recrystallize from ethanol/ether.
did. N2-(5-n-butyl-2-pyridyl)-N-
Acetate hydracite was slightly colored as 1111 acid salt.
It is obtained in crystalline form and its melting point is 211-212°.
Ta. Practical example: 3.2 g of sodium hydride in 40 tsl of L-toluene
The suspension was added to the 2-
Dissolution of 111.0g of hydrazino-5-n-butylpyridine
Add the solution, then add 20 sodas of toluene over 10 minutes.
Add a solution of 11.7 g of fusaric acid ethyl ester,
The mixture was then heated at 60° for 1 hour and then
The mixture was heated under reflux for an additional 2 hours while the mixture was allowed to cool. After cooling,
The reaction mixture was extracted with 200 μl of 2N hydrochloric acid,
Wash the aqueous-acidic phase with water and remove the aqueous phase with concentrated sodium hydroxide.
Make alkaline using a solution and thoroughly extract with ether.
, the ether solution was then dried over sodium sulfate,
Evaporated to dryness. Dissolve the residue in 2001 anhydrous ether.
, a 5N solution of hydrogen chloride in ether.
The precipitate formed was filtered off with suction and then recrystallized from ethanol.
N2-(5-n-butyl-2-pyridyl)-N-
Fusaric acid hydrazide has a slightly yellow color as a dihydrochloride.
It is obtained in the form of needle-shaped crystals with a melting point of 175° (decomposition
)Met. In the presence of 2.3 g of Shimuso A Eupalladium-supported carbon catalyst (5%),
Obtained according to example 3 in 120 ml of anhydrous methanol
N-acetyl-thi-glutamic acid 5-(N2-(5-n
-butyl-2-pyridyl)-hydrazide]-1-ben
A solution of 11.5 g of diester was stirred at room temperature for 24 hours.
Ta. The catalyst is filtered off, then the filtrate is concentrated in a rotary evaporator and then
Next, the residue was chlorophotted on silica gel (FLUKA80).
Chromatography using a mixture of lumen/methanol (95:5)
I applied it to the graph. N-acetyl-L-glutamic acid
5-[N2-(5-n-butyl-2-pyridyl)-hyper
Drazide 1-1-methyl ester is obtained and methylene chloride
using silica gel in a methanol/methanol (9:1) system.
The Rf value was 0.23. 1K': Explanation 1. There is no example 1
In a manner similar to that described in Section 9, suitable starting materials
and reaction conditions to form the following compounds of formula I or
It is also possible to prepare 111 of: a) N-acetyl-thi-glutamic acid 5- rN2-
(5-n-butyl-2-pyridyl)-hydrazide 1-!
-ethyl ester is the N-acetic acid obtained in Example 3.
Chyl-shi-glutamic acid 5-[N2-(5-n-butyl
-2-pyridyl)-hydrazide 1-1-benzyl ester
of palladium with excess absolute ethanol and palladium 4i1 charcoal
Transesterification was carried out at room temperature in the presence of a basic catalyst (5%).
, then treated and over-treated as described in Example 9.
The residue obtained by evaporating the excess ethanol is converted into silica gel.
(FLUKA EIO) Chromatography with J2?
methylene chloride/methanol
J value using silica gel in 8:1 system = 0.2
5. b) N-acetyl-thi-glutamic acid 5-(N2-(
5-n-butyl-2-pyridyl)-hydrazide]-1-
(2,2-dimethylpropyl)-ester Example 3
N-acetyl-thi-glutamic acid 5-[
N2-(5-n-butyl-2-pyridyl)-hydrazide
]-1-benzyl ester was dissolved in excess of anhydrous 2,2-dimethyl
Chill propatool and palladium supported carbon catalyst (5%)
The transesterification is carried out at room temperature in the presence of
Treat as described in Example 9, excess 2.2-di
The residue obtained by evaporating methylpropateol is converted into silica
Chromatography on gel (FLUKA 60)
methylene chloride/methanol (
Rf value using silica gel in 9:l) system = 0.2
8. c) N-acetyl-glutamic acid 5-[N2-(
5-n-butyl-2-pyridyl)-hydrazide]-1-
The n-butyl ester is the N-butyl ester obtained in Example 3.
Cetyl-glutamic acid 5- (N2- (5-n-
Butyl-2-pyridyl)-hydrazide]-1-benzyl
The ester was treated with excess anhydrous n-butanol and palladium
Ester at a temperature of 40-50° in the presence of a supported carbon catalyst
The catalyst is filtered off and the filtrate is concentrated in a rotary evaporator.
59 and then syringe the residue as described in Example 9.
Chromatography with 1 liter of Lycagel (FLUKA 80)
Obtained by applying: methylene chloride/methanol
Rf value using silica gel in Le (9:1) system = 0
．． 27. d) N-acetyl-glutamic acid 5- [N2-
(5-n-butyl-2-pyridyl)-hydrazide 1-1
-amide is monoglutamic acid obtained according to Example 1
5-[N2-(5-n-butyl-2-pyridyl)-hydro
Radide monohydrate is dissolved in excess methanol etc.
By reacting at room temperature in the presence of xylcarbodiimide, (
N-benzyloxy-carbonyl)-L-glutamic acid
5-[N2-(5-n-butyl-2-pyridyl)-hydro
radido]-1-methyl ester, followed by the formation of the latter
, excess ammonia dissolved in methanol and a closed container
The reaction was allowed to proceed for 5 hours at room temperature in a vessel, and then the reaction mixture was worked up.
L-glutamic acid 5-[N2-(5-n-butylene)
Generates 1-1-amide (2-pyridyl)-hydrazide
and the latter was subsequently treated with acetic anhydride in dimethylformamide.
, reacted for 60 15 hours at room temperature in the presence of anhydrous sodium carbonate and then as described in Example 2.
and work-up and then chromatography of the residue.
Obtained by multiplying; methylene chloride/methanol
R'f value using silica gel in (9:1) system = 0.
15゜e) N-propionyl-L-glutamic acid 5-[N
2-(5-n-butyl-2-pyridyl)-hydrazide]
is L-glutamic acid 5-[N2 obtained in Example 1
-(5-n-butyl-2-pyridyl)-hydrazide 1
dihydrate, anhydrous propion in dimethylformamide
acid and 200 hours at room temperature in the presence of anhydrous sodium carbonate.
react and then as described in Example 2.
treatment and then chromatography of the residue on silica gel.
-obtained by further processing the main fraction;
1N methylene/methanol/conc. NH40H (5:3:
1) The Rr value in the system is = 0.78. f) N-pivaloyl-shi-glutamic acid 5-(N2-
(5-n-butyl-2-pyridyl)-hydrazide 1 is
, monoglutamic acid 5- [N2
-(5-n-butyl-2-pyridyl)-hydrazide 1
dihydrate with pivalic anhydride in dimethylformamide.
, at a temperature of 40-50° in the presence of anhydrous sodium carbonate.
react for 200 hours and then react as described in Example 2.
After treatment, the residue was chromatographed on silica gel 1-.
I decided to apply it to matography and process another 1 mm portion.
Obtained from: methylene 11/methanol/conc. NH
The Rf value in the 40H (5:3:1) system is = 0.80;
g) N-benzoyl-thi-glutamic acid 5-[N2
-(5-++ -butyl-2-pyridyl)-hydrazide
l is L-glutamic acid 5-[N
2-(5-n-butyl-2-pyridyl)-hydrazide 1
Hemihydrate, benzoic anhydride in dimethylformamide
and a temperature of 40-50° in the presence of anhydrous sodium carbonate.
for 25 hours and then as described in Example 2.
After treatment, clean the residue with silica gel.
chromatography and further processing of the main fraction.
Obtained from; methylene 10ide/methanol/conc. NH4
The Rf value in the 0H (5:3:I) system is = 0.79. h) N-7 cetyl monoglutamic acid 5-[N2-(
5-Methyl-2-pyridyl)-hydrazide 1 is
Dorazino-5-methyl-pyridine was dissolved in anhydrous tetrahydrochloride.
N-(benzyloxycarbonyl)-L-g in furan
Rutamic acid 1-benzyl ester 5-(N-hydroxy
succinimide)-ester for 2 hours at 0°.
, evaporate the solvent and run on silica gel using acetic acid ethyl acetate as eluent.
The residue was chromatographed using chiller and then
The main fraction was then worked up to give (N-benzyloxycarbohydrate)
Nyl[N2-(5-methyl-2-pyridyl)-hydrazide]
-1-benzyl ester and subsequently convert the latter into methane
Palladium-supported carbon catalyst (5%)
obtained after debenzylation and treatment in the presence of
Monoglutamic acid 5-[N2-(5-methyl-2-p
Lysyl)-hydrazide 1 was recrystallized from methanol and then
acetic anhydride in dimethylformamide and carbonic anhydride.
By reacting at room temperature for 15 hours in the presence of sodium.
After N-acetylation, evaporate the solvent and transfer onto silica gel.
and chloroform/methanol/ammonia (5:3:l
) chromatography of the residue using a mixture of
Then 163. is obtained by working up the main fraction: methylene chloride
/methanol/concentrated Ml (R in 40H (5:3:I) system
f value = 0.70. i) N-benzoyl-1,-glutamic acid 5-[N2
-(5-methyl-2-pyridyl)-hydrazide l is the actual
1,-glutamic acid 5-[N2 obtained according to example h)
-(5-methyl-2-pyridyl)-hydrazide
Benzoic anhydride in chillformamide and anhydrous sodium carbonate
The reaction was carried out for 200 hours at room temperature in the presence of
Then add chloroform/methanol/anhydride to the silica gel.
Chromatograph the residue using a mixture of Monia (5:3:l).
by processing the main fraction and then working up the main fraction.
obtained by: methylene chloride/methanol 4/conc.
R value for H(5:3:1) leg = 0.73. j) N-7 cetyl-L-glutamic acid 5-[N2-(
5-benzyl-2-pyridyl)-hydrazide 1 is 2-
Hydrazino-5-benzylpyridine is converted into anhydrous tetrahydride.
N-(benzyloxycarbonyltamine) in Lofuran
l-benzyl ester 5-(N-hydroxysuccini
(mido)-ester for 2 h at 0°, evaporated the solvent, and run on silica gel with vinegar as eluent.
Chromatograph the residue using ethyl acid
, then the main fraction was worked up to give (N-benzyloxycarbonate)
(benyl)-L-glutamic acid 5-(N2-(5-ben
Zyl-2-pyridyl)-hydrazide]-1-benzyle
ster and subsequently the latter by hydrogen in methanol.
Deventing was carried out in the presence of palladium-supported carbon catalyst (5%).
The monoglutamic acid obtained after zylation and post-treatment
5-[N2-(5-benzyl-2-pyridyl)-h
Drazide] was recrystallized from methanol, and the latter was then di-crystallized.
Acetic anhydride in methylformamide and anhydrous sodium carbonate
N- by reacting for 15 hours at room temperature in the presence of
Acetylate, evaporate the solvent, and chloroform on silica gel.
Mixture of form/methanol/ammonia (5:3:1)
The residue is chromatographed using a
Obtained by post-treatment of the fraction; methylene chloride/
Rf value in methanol/concentrated NH40H (5:3:1) system
= o. et; k) N-acetyl-thi-glutamic acid 5-[N2-(
5-phenyl-2-pyridyl)-hydrazide l is 2-
Hydrazino-5-phenyl-pyridine was converted into anhydrous tetrahydrogen.
N-(benzyloxycarbonyl)-L in Dorofuran
-Glutamic acid! -benzyl ester 5-(N-hydro
xysuccinimide)-ester and incubate at 0° for 2 hours.
evaporate the solvent and run on silica gel using vinegar as eluent.
Chromatograph the residue using ethyl acid
, then the main fraction was worked up to give (N-benzyloxycarbonate)
5-[N2-(5-phenyl)-L-glutamic acid
Nyl-2-pyridyl)-hydrazide 1-1-benzyle
ster and subsequently the latter by hydrogen in methanol.
Develation was carried out in the presence of a palladium-40 carbon catalyst (5%).
The glutamate obtained after oxidation and post-treatment
Minic acid 5-[N2-(5-phenyl-2-pyridyl)-
Hydrazide 1 was recrystallized from methanol and then the latter
, acetic anhydride in dimethylformamide and anhydrous sodium carbonate
By reacting at room temperature for 15 hours in the presence of
N-acetylation, evaporation of solvent, silica gel-1-
chloroform/methanol/ammonia (5:3:1)
Chromatograph the residue using a mixture of ). It is then obtained by working up the main fraction:
In tyrene/methanol/concentrated NH40H (5:3:1) system
Rff direct = 0.7θ; dan) N-acetyl-glutamic acid 5-[N2-(5
-(2-oxo-n-butyl)-2-pyridyl)-hydro
Radizide J is 2-hydrazino-5-(2-oxo-n-
butyl)-pyridine in anhydrous tetrahydrofuran with N
-(benzyloxycarbonyl)-L-glutamic acid 1
-benzyl ester 5-(N-hydroxysuccinimide)
d)-ester at 0° and evaporate the solvent.
and eluted with ethyl acetate on silica gel.
The residue is chromatographed, and the main fraction is then chromatographed.
After treatment, (N-benzyloxycarbonyl)-1,
-Glutamic acid 5-[N2-(5-(2-oxo-n-
Butyl-2-pyridyl)-hydrazide]-1-benzyl
to form an ester and subsequently convert the latter into hydrogen in methanol.
Devetting was performed in the presence of palladium-supported carbon catalyst (5%).
The glutamate obtained after oxidation and post-treatment
Minic acid 5-[N2-(5-(2-oxo-n-butyl))
-67 2-pyridyl)-hydrazide 1 in methanol/ethanol
1 crystallization from the mixture, and the latter was then converted into dimethyl fluoride.
Presence of acetic anhydride and anhydrous sodium carbonate in Lumamide
N-acetyl by reacting at room temperature for 15 h under
and evaporate the solvent. Chloroform/methanol/ammonia on silica gel
Chromatograph the residue using a mixture of (5:3:1)
by subjecting the main fraction to
: Methylene chloride/methanol/concentrated NH4011 (5
:3+1) system R ((fi = 0.71; m)
N-acetyl-glutamic acid 5-[N2-(5-a
cetyl-2-pyridyl)-hydrazide l is 2-hydra
Dino-5-acetylpyridine was diluted with anhydrous TeI.Rahydrof.
N-(benzyloxycarbonyl)-L-glue in the run
Tamamine 1-benzyl ester 5-(N-hydroxys
react with succinimide)-ester for 2 hours at Oo,
Evaporate the solvent and use silica gel I-acetic acid as eluent.
The residue was chromatographed using chiller and then
The main fraction was post-treated to give (N-benzyloxycarbonyl)
)-L-glutamic acid 5-IN2-68 (5-acetyl-2-pyridyl)-hydrazide 1-1-
to produce the benzyl ester and subsequently dissolve the latter in methanol.
of hydrogen in the presence of palladium-supported carbon catalyst (5%)
Obtained after debenzylation and post-treatment under
Monoglutamic acid 5-[N2-(5-acetyl-2-pyrylate)
Zyl)-hydrazide 1 was recrystallized from methanol and then
the latter with acetic anhydride in dimethylformamide and anhydrous
React at room temperature for 15 hours in the presence of sodium carbonate.
After N-acetylation and evaporation of the solvent, the silicage
Chloroborum/methanol/ammonia (5:3)
: Chromatography of the residue using the mixture of 1)
and then by working up the main fraction; salt
Methylene chloride/methanol/conc. NH40H (5:3:1)
Ilf value in the system = Q, f (5. n) N-acetyl-glutamic acid-5[N2-(
5-n-butyl-2-pyridyl)-hydrazide]-1-
(pivaloyloxymethyl)-ester in Example 3
N-acetyl-glutamine obtained as an intermediate from
5-[N2-(5-n-butyl-2-pyridyl)-
Neutralize with hydrazide and sodium hydroxide and evaporate to dryness.
The sodium obtained by
Pihelic acid iodomethyl ester in lumamide and 0-
The reaction was carried out at a temperature of 50°, followed by stirring at room temperature for 17 hours.
, the reaction mixture was concentrated under high vacuum and extracted with ethyl acetate.
Then, the solvent was evaporated and the resulting residue was dissolved in methylene chloride.
Chromatography using a 9:1 /methanol mixture
Obtained by applying methylene chloride/methanol
Rg4f using silica gel in Le (0:1) system
j = 0.2B; Compound shown in h)-n)
by a method similar to that used for the production of the corresponding medium.
It is also possible to prepare the following compounds via intermediate steps:
o) N-acetyl-1,-glutamic acid 5-[N2
-(3-n-butyl-2-pyridyl)-hydrazide 1 is
, 2-hydrazino-3-n-butyl-pyridine, N-
(benzyloxycarbonyl)-L-glutamic acid 1-
Benzyl ester 5-(N-hydroxysuccinimide
)-ester to form (N-benzyloxycarboxylate)
5-[N2-(3-n-butyl)-L-glutamic acid
(Tyl-2-pyridyl)-hydrazide 1-1-benzyle
ster and debenzylates the latter to produce L-glutamic acid.
5-[N2-(3-n-butyl-2-pyridyl)
- producing hydrazide 1 and then acetylating the latter
Obtained by producing the above-mentioned N-acetyl compound
methylene chloride/methanol/conc. NH40H (5:3
:1) Rf value in system = 0.78; p) N-acetyl-glutamic acid 5-[N2-
(4-n-butyl-2-pyridyl)-hydrazide 1 is
2-hydrazino-4-n-butyl-pyridine is converted into N-(
benzyloxycarbonyl)-L-glutamic acid l-be
ester 5-(N-hydroxysuccinimide)
- ester, (N-benzyloxycarboxylic acid)
5-[N2-(4-n-butyl)-L-glutamic acid
-2-pyridyl)-hydrazide]-1-benzyl es
and debenzylation of the latter to form monoglutamine.
Acid 5-[N2-(4-n-butyl-2-pyridyl)-
hydrazide] and then acetylates the latter to -
Obtained by producing the above-mentioned N-acetyl compound
methylene chloride/methanol,/conc. NH40H (5:
71 Rf value in the 3:l) system = 0.77; q) N-7 cetyl monoglutamic acid 5-(N2-(
B-n-butyl-2-pyridyl)-hydrazide 1 is 2
-hydrazino-6-n-butyl-pyridine, N-(base)
l-benzyloxycarbonyl)-L-glutamic acid
Dyl ester 5-(N-hydroxysuccinimide)-
React with ester to form (N-benzyloxycarbonyl)
5-[N2-(8-n-butyl)-L-glutamic acid
-2-pyridyl)-hydrazide]-]-benzyl ester
by debenzylation of the latter], -glutamine
Acid 5- (N2-(B-n-butyl-2-pyridyl)
- producing hydrazide 1 and then acetylating the latter
Obtained by producing the above-mentioned N-acetyl compound
Ru: It1 methhidimethylene/methanol/1N11
40113: Rf value in l) system = 0.77; r) L-alanyl-[82-(5-n-butyl-2-
pyridyl)-hydrazide 1 is 2-hydrazino-5-n
-butylpyridine with -alanine methyl ester,
Heating under nitrogen atmosphere in benzene for 2 hours under reflux.
The solvent was evaporated, the residue was dissolved in 72 ml of toluene and washed with water, and the organic phase was extracted with 2N hydrochloric acid.
Then wash the aqueous acid solution with ether and dilute with concentrated sodium hydroxide.
solution into this aqueous phase until a strong alkaline reaction is obtained.
The mixture was then extracted with ether and the ether
Wash the solution with water. A 5N solution of hydrogen chloride in ether was prepared using sodium sulfate.
A strong acidic reaction occurs in the ether solution that has been dried and smoked.
is added until obtained, then obtained in the form of white crystals.
1alanyl-[N2-(5-Tl-butyl-2-pyri)
obtained by separating the hydrochloride salt into hydrazide
methylene chloride/methanol/conc. NH4OH (5:
3: Ri value of free base in 1) system = 0.92. s) L-alanyl-[N2-(8-n-butyl-2-
pyridyl)-hydrazide 1 is 2-hydrazino-8-n
-Butylpyridine is reacted with -alanine methyl ester.
and then processed as described in r) and then
Araniru [N2-(
6-n-butyl-2-pyridyl)-hydrazide hydrochloride
obtained by separating methylene chloride/meta/
-Jl//eNII401f (5:3: I) series
Teno'! 771!11 III group Rf (ff=0.9
0. t) N-acetyl-shi-alanyl-[N2-(5-n
-butyl-2-pyridyl)-hydrazide 1 according to r)
L-alanine-IN2-(5-n-butyl-
2-pyridyl)-hydrazide 1-dihydrochloride was subjected to concentrated hydroxidation.
reacted with a sulfur solution and then obtained in this way.
The resulting base was mixed with acetic anhydride in dimethylformamide,
React for 10 hours at room temperature in the presence of anhydrous sodium carbonate.
, evaporate the solvent under reduced pressure and take up the residue in ether.
, this ether solution was washed with water and 5 N in ether
A strong acidic reaction is applied to the hydrogen dihydride solution to its ether solution.
until a reaction is obtained, then obtained in the form of white crystals.
N-acetyl-L-alanyl-[N2-(5-n-butyl)
Separate methyl-2-pyridyl)-hydrazide monohydrochloride
Obtained by; methylene chloride/methanol/concentrated N
■401 (free l!# in (5:3:I) system, Rf of base
Value = 0.85. u) N-acetyl-7-ranyl(N2-(13-
n-butyl-2-pyridyl)-hydrazide 1 is S)
L-alanyl-[N2-(6-n-butyl) obtained from
-2-pyridyl)-hydrazide with concentrated sodium hydroxide
reacted with lium solution and then obtained in this way
The base is converted to acetic anhydride in a manner similar to that described in S).
and treat the reaction mixture with white crystals.
N-acetyl-L-alanyl-[N2-(8
-n-butyl-2-pyridyl)-hydrazide J hydrochloride
Obtained by separating: methylene chloride/methanol
Rf of free base in Le/concentrated NH40H (5:3:1) system
Value=0.83. v) L-alanyl-[N2-(5
-n-butyl-2-pyridyl)-hydrazide] dihydrochloride
obtained by treating with concentrated sodium hydroxide solution
From the free base obtained, similarly to t), with the corresponding acid anhydride,
The reaction yields the following compound in the form of its hydrochloride:
can be made: N-propionyl-mono-alanyl [N2-
(5-n-butyl-2-pyridyl)-hydrazide];
Methylene chloride/methanol/WNH40H (5:3:1
) system with Rf value of free base = 0.85. w) N-benzoyl-7-ranyl[N2-(B-
Methyl-275-pyridyl)-hydrazide l is 2-hydrazino-6-
Methylpyridine is reduced with L-alanine methyl ester.
Heating under nitrogen atmosphere in flowing benzene for 3 hours
React further, evaporate the solvent, and dissolve the residue in toluene.
The organic phase was extracted with 2N hydrochloric acid and washed with water.
Wash the acidic solution with ether and dilute it with concentrated sodium hydroxide solution.
liquid is added to this aqueous phase until a strong alkaline reaction is obtained.
The mixture was then extracted with ether and the ether solution was
Wash the liquid with water and remove the 5N hydrogen chloride solution in ether with sulfuric acid.
The ether solution, which had been dried with sodium chloride,
Add to the solution until a strong acidic reaction is obtained, then white crystals form.
17 Ranyl [N2-(8-methyl) obtained in the form of crystals
-2-pyridyl)-hydrazide to separate the ffi acid salt,
The resulting aqueous solution of dihydrochloride was dissolved in concentrated sodium hydroxide solution.
The liquid is treated until a strong alkaline reaction is obtained, and the free #
The base is extracted by shaking with ether and this ether is
The solution was washed with water, dried over sodium sulfate,
The solvent was then evaporated and the di-alanyl-[N2-(8-
The residue consisting of methyl-2-pyridyl76-hydrazide 1 was dissolved in dimethylforma
Benzoic anhydride in the presence of anhydrous sodium carbonate
for 24 hours at room temperature and then work up the reaction mixture.
, N-benzoyl-L-alanyl-[N2-(8-method)
(2-pyridyl)-hydrazide]
Obtained from; methylene chloride/methanol/conc. NH40
Rf value in H (5:3:1) system = 0.80. Tablets each containing 2hg of active substance and having the following composition:
was produced by a conventional method: Wheat starch 80 mg Lactose 50 mg Colloidal silica 5 mg Talc 9 mg Magnesium stearate 11 g 45 mg
-n-butyl-2-pyridyl)-hydrazide 1 ammo
Nium salts as part of wheat starch, lactose and colloidal
Mixed with silica and then sieved the mixture. Another portion of wheat starch was placed on a water bath with 5 times the amount of water.
form into a paste and then mix the powdered mixture with this paste.
The mixture was kneaded to form a slightly plastic material. This plastic material is passed through a sieve with a mesh width of about 3 mm.
The dry granular material obtained is sieved again.
I got it. Wheat starch residue, talc and magnesium stearate
Cium is then mixed and this mixture is compressed to give each
A tablet with a weight of 145 g and a breakout notch was formed.
did. Each of the supporting soils is a tablet containing l-g of active substance and having the following composition:
was produced by a conventional method: Group 1-'L-Unit Wheat Flour 60II 1g Lactose 50mg Colloidal Silica 5+ng Talc L+ng Magnesium Stearate 1mg 12B+++, g

[-1] U-L-glutamic acid 5-[N2-(5-n-butyl-2-
Pyridyl)-hydrazide J hemihydrate was mixed with a portion of wheat starch, lactose and colloidal silica, and the mixture was then sieved. A further portion of the wheat starch was formed into a paste on a water bath with 5 times the strength of water, and the powdered mixture was then kneaded with this paste to form a slightly plastic material. The plastic material was sieved with a mesh width of approximately 3 mm, then dried and the resulting dry granular material was sieved again. The remainder of the wheat starch, talc, and 79 Mg stearate were then mixed and the mixture was compressed to form tablets each having a landing and break notch of 126-g. Tablets containing the active substance 10B each and having the following composition were prepared in a conventional manner: hydrazide acetate talc 2QO+ig colloidal silica 50B 1--] The two active ingredients were thoroughly mixed with talc and colloidal silica;
The mixture was passed through a sieve with a mesh width of approximately 0.5+sm and llfllg portions were filled into appropriately sized hard gelatin capsules. Ammonium of N-acetyl-glutamic acid 5-[N2-(5-n-butyl-2-pyridyl)-hydrazide] j15. A sterile solution of Og
ral ampules were filled into 80 ampules, each of which contained 5 ml of solution.
It contains 5 mg of active ingredient in m4. Actual example 1 N2-(5-n-butyl-2-pyridyl)-3-sulfamoyl-4-chlorobenzoic acid hydrazide acetate 3
．． 82g was dissolved in distilled water to make a volume of 18100mM. 5. Sterile solution. (I filled it into a 1m ampoule, but
Each ampoule contains 1 mg of active ingredient. In place of the compounds used as active ingredients in Examples 11 to 15, the following compounds or their pharmaceutically acceptable, non-toxic acid addition salts were prepared into tablets, sugar-coated tablets, It can also be used as an active ingredient in capsules and the like. ; N2-(5-n-butyl-2-pyridyl)-picolinic acid hydrazide, N-ethoxycarbonyl-N2-(5-n
-butyl-2-pyridyl)-hydrazide, N2-(5
-n-butyl-2-pyridyl)-N-acetic acid hydrazide or N2-(5-n-butyl-2-pyridyl)-N-fusaric acid hydrazide, N-acetyl-glutamic acid 5
- [N2-(5-n-butyl-2-pyridyl)-hydrazide]-1-methyl ester or a compound of formula I mentioned in Example 10 or a salt thereof, especially a pharmaceutically acceptable, toxic No acid addition salts.

Claims (1)

[Claims] (1) General formula (1): [In the formula, R represents an optionally substituted aliphatic or aromatic hydrocarbon group, this represents an acyl group, and n is an integer of 1 to 4. However, when n represents a number from 2 to 4, the group R is the same -
or different, may be attached at any possible position on the pyridine ring] in its racemic mixture, racemate, optical antipode or salt, especially in its pharmaceutically acceptable non-toxic acid addition salt. Pharmaceutical preparations containing in form. (2) n represents an integer of 1 to 4, and R is an optionally substituted lower alkyl group, lower alkenyl group, or lower alkynyl group, or a monocyclic or bicyclic carbon homocyclic or heterocyclic group; Represents an aromatic hydrocarbon group, and ^C is the formula -
〇(=O) R+ (wherein R1 represents an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group), or a carbonic acid moddiester or monoamide. Compounds of the general formula (1) according to claim 1 representing groups in the form of racemic mixtures, racemic compounds, optical antipodes or salts thereof, particularly in the form of pharmaceutically acceptable non-toxic acid addition salts. Pharmaceutical formulations. (3) n represents an integer of 1 to 4, R is a lower alkyl group,
optionally etherified or esterified hydroxy-lower alkyl groups, such as hydroxy-lower alkyl groups, lower alkoxy-lower alkyl groups or halo-lower alkyl groups, or optionally substituted, e.g. lower-fulkylated or acylated amino-lower alkyl group,
For example, amino lower alkyl group, N-lower alkylamino-lower alkyl group, N,N-di-lower alkylamino-lower alkyl group, lower alkanoylamino-lower alkyl group, or (+(alkoxycarbonylamino-lower alkyl group) , or an optionally esterified or amidated carboxy group, such as a carboxy group,
lower alkyl groups substituted with oxycarbonyl groups or optionally substituted carbamoyl groups, such as carboxy-lower alkyl groups, lower alkoxycarbonyl-lower alkyl groups, carbamoyl-lower alkyl groups, oxo-lower alkyl groups, and A cyano-lower alkyl group, or an optionally substituted aryl-lower alkyl group (an aryl group is a monocyclic aromatic hydrocarbon group,
For example, a phenyl group, or a bicyclic aromatic hydrocarbon group, such as a 1- or 2-naphthyl group, or a partially saturated naphthyl group, such as a 1,2,3,4-tetrahydro-5
- a naphthyl group, and the substituent is a lower alkyl group, a hydroxy group and/or a halogen, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a lower alkenyloxy group,
or optionally lower alkylated or acylated amino-lower alkyl groups, such as mono- or di-lower alkylamino-lower alkyl groups or lower alkanoylamino-lower alkyl groups, optionally esterified carboxy groups, e.g. Carboxy or lower alkoxycarbonyl groups, amidated carboxy groups, such as optionally substituted carbamoyl groups, such as carbamoyl groups, N-lower alkylcarbamoyl groups or N,N-di-lower alkylcarbamoyl groups, cyano groups, nitro groups or an acylated amino group, such as an amine group, a lower alkylamino group, a lower alkoxycarbonylamino group, a lower alkylamino group or a di-lower alkylamino group, and 1 to 3 such substituents may be present. ,
(which may be the same or different), or R and a group ^
The group R1 contained in C is in each case an aryl group, such as a phenyl group, a 1- or 2-naphthyl group or a partially saturated naphthyl group, such as 1,2,3,4-tetrahydro-
5-naphthyl group, or preferably has 5 or 6 ring members and is bonded to the pyridyl group via a ring carbon atom, with oxygen, sulfur or nitrogen atoms as ring members and optionally 1 to 3 a group containing additional nitrogen atoms (which may be at least partially hydrogenated and in which case substituted with an oxo group; the second ring in the bicyclic heterocyclic group is a fused benzene ring) ), and especially pyridyl groups, such as 2-13- or 4-pyridyl groups, or dihydroxo-pyridinyl groups, such as 1,6-dihydro-6-oxo-2-pyridinyl groups, pyridazinyl groups, such as 3-pyridazinyl groups. , a pyrazinyl group, such as a 2-pyrazinyl group, a pyrimidinyl group, such as a 2-14- or 5-pyrimidinyl group, or a dihydro-oxo-pyrimidinyl group, such as 3,4-dihydro-4-oxo-2-
pyrimidinyl group, furyl group, e.g. 2- or 3-furyl group, pyryl group, e.g. 2- or 3-pyryl group,
chenyl groups, such as 2- or 3-chenyl groups, oxacylyl groups, such as 2- or &; -thiadiazol-3- or 5-yl or 1,25-thiadiazol-3-yl, imidazolyl, such as imidazol-2- or -4-yl, pyrazolyl, such as 3- or 4-pyrazolyl; , triazolyl group,
For example, 1,2,3-triazol-4-yl group or 1,
2.4-) lyazol-3-yl group, tetrazolyl group,
For example, tetrazol-5-yl groups and indolyl groups, such as indol-4-yl groups, quinolinyl groups, such as 2
-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzimidazolyl, e.g. 2-benzimidazolyl, benzofuranyl, e.g. 4- or 5
- represents a benzofuranyl group, a benzothenyl group, such as a 4- or 5-benzochenyl group or a naphthyridinyl group, such as a 1,8-naphthyridin-2-yl group, such aryl groups being particularly and one or more, preferably up to four, optionally substituted lower alkyl groups, such as lower alkyl groups, optionally etherified or esterified hydroxy-lower alkyl groups, such as hydroxy-lower alkyl groups, lower alkoxy-lower alkyl groups or halo-lower alkyl groups, or optionally substituted, e.g. lower alkylated or acylated, amino-lower alkyl groups, such as amino-lower alkyl groups, N-
Lower alkylamino-lower alkyl group, N, N-di-lower alkylamino-lower alkyl group, lower alkanoylamino-lower alkyl group or lower alkoxycarbonylamino-lower alkyl group, [lower alkenyl group or lower alkynyl group, optionally etherified or esterified hydroxy or mercapto groups, such as hydroxy groups, lower alkoxy groups, phenyl-lower alkoxy groups, halogens, mercapto groups, lower alkylthio groups, phenyl-lower alkylthio groups, or optionally etherified or Lower alkoxy groups substituted with esterified hydroxy groups or mercapto groups or acyl groups, such as lower alkoxy groups, phenyl-lower alkoxy groups, hydroxy-lower alkoxy groups, lower alkoxy-lower alkoxy groups, lower alkylthio-lower alkoxy groups , halo lower alkoxy group, lower alkanoyl-lower alkoxy group, or lower alkenyloxy group,
lower alkynyloxy groups, lower alkylthio groups, acyl groups such as lower alkanoyl groups, optionally esterified carboxy groups such as carboxy groups or lower alkoxycarbonyl groups, amidated carboxy groups such as optionally substituted carbamoyl groups, e.g. Carbamoyl group, N-lower alkylcarbamoyl group or N, N-
di-lower alkylcarbamoyl groups, cyano groups, nitro groups or optionally substituted, e.g. acylated amino groups,
For example, a group selected from a lower alkanoylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonyl group, a sulfamoyl group, an optionally substituted ureido group and an amine group, an N-lower alkylamino group or an N,N-di-lower alkylamino group. It may be substituted with a substituent such that the group R1 contained in the radical is i! (class alkyl group, lower alkenyl group, lower alkynyl group, phenyl-lower alkyl group, phenyl-(1 (class alkenyl group, phenyl-lower arginyl) table, tI'i cyclic or polycyclic cycloalkyl group, e.g. cyclo represents an alkyl group, each group optionally an etherified or esterified hydroxyl, such as a hydroxyl group, a lower alkoxy group and/or a halogen, an optionally substituted, for example a lower alkylated or acylated amino group; For example, an amino group, an N-lower alkylamino group, an N,N-di-lower alkylamino group, a lower alkanoylamino group, and/or a:
1. Carboxy groups optionally modified with functional groups, such as carboxy groups, esterified carboxy groups, such as optionally substituted lower alkoxycarbonyl groups, optionally substituted carbamoyl groups, or monocyano groups, substituted The group R1 can be substituted at any suitable position for substitution.
or may contain one or more, especially up to three, different substituents, and may also contain lower alkoxycarbonyl groups, unsubstituted or substituted hydroxyl groups, such as free or etherified hydroxy groups, such as lower Alkoxy groups, or unsubstituted or substituted amino groups, such as amino groups, lower alkylamino groups, and especially di-substituted amino groups, such as di-lower alkylamino groups, N-lower alkyl-N-phenyl-lower alkylamino groups, or optionally a lower alkylene amino group interrupted by oxygen, sulfur or unsubstituted or substituted, e.g. a lower alkyl group, or phenyl, unsubstituted or substituted, e.g. a lower alkyl group, a lower alkoxy group and/or substituted with a halogen; lower alkoxycarbonyl groups containing groups, and N-unsubstituted or N-mono- or N,N-di-substituted carbamoyl groups, such as lower alkylcarbamoyl groups, di-lower alkylcarbamoyl groups, or optionally lower alkylene moieties containing oxygen, sulfur; Alternatively, the compound of general formula H) according to claim 1 representing a nitrogen-blocked N,N-lower alkylenecarbamoyl group substituted with an unsubstituted or substituted, for example, a lower alkyl group, can be used as a racemic mixture or racemic compound thereof. Pharmaceutical formulations comprising the compound, optical diagonal or salt, especially in the form of a pharmaceutically acceptable non-toxic acid fζJ salt. (4) n represents 1 or 2, and R is a lower alkyl group, such as a methyl group, a lower alkoxy-lower alkyl group, such as a 2-methoxyethyl group, a halo lower alkyl group, such as a 1-lifluoromethyl group, or a lower Alkanoylamino-represents a lower alkyl group, e.g. acetylaminomethyl, R4 in the group Ac represents a phenyl or pyridyl group, each optionally a lower alkyl group, e.g. a methyl group, a lower alkoxy-lower alkyl group, e.g. 2- methoxyethyl group, halo lower alkyl group such as trifluoromethyl group, lower alkanoylamino-lower alkyl group such as 2-acetylaminomethyl group, hydroxy group,
Lower alkoxy groups, such as methoxy groups, lower alkoxy-lower alkoxy groups, such as 2-ethoxyethoxy groups,
substituted with halogen, a lower alkoxycarbonyl group, such as an ethoxycarbonyl group, a carbamoyl group, a cyano group, an amino group, or a lower alkanoylamino group, such as an acetylamino group, or a sulfamoyl group, or R
7 is optionally a lower alkoxy group, such as a methoxy group,
an amino group, a lower alkanoylamino group such as an acetylamino group, a carboxy group, an optionally substituted lower alkoxycarbonyl group such as an ethoxycarbonyl group or a 2- or preferably 1-(lower alkylcarbonyloxy)-lower alkoxycarbonyl group or It can represent a lower alkyl group substituted with a carbamoyl group, such as an ethyl group or an n-propyl group, or it can also represent a lower alkoxycarbonyl group, such as an ethoxycarbonyl group or an unsubstituted carbamoyl group, or a lower alkoxy group, such as a methoxy group or an amino group. The compound of the general formula (I) according to claim 1, which represents a carbamoyl group substituted with a group, is prepared as a racemic mixture, racemate, optical antipode or salt thereof, especially a pharmaceutically acceptable non-toxic compound. Pharmaceutical preparations containing in the form of acid addition salts. (5) n represents 1, R represents a lower alkyl group, such as a methyl group, a lower alkoxy-lower alkyl group, such as a 2-methoxyethyl group, or a halo lower alkyl group, such as a trifluoromethyl group; R1 represents a phenyl group or a pyridyl group, each optionally a lower alkyl group such as a methyl group, a lower alkoxy-lower alkyl group such as a 2-methoxyethyl group, a halo lower alkyl group such as a trifluoromethyl group, a hydroxy group, substituted with a lower alkoxy group, such as a methoxy group, a lower alkoxy-lower alkoxy group, such as a 2-ethoxyethoxy group, a halogen, a lower alkoxycarbonyl group, such as an ethoxycarbonyl group, a carbamoyl group, a cyano group, an amino group or a sulfamoyl group; or R1 is optionally a lower alkoxy group, such as a methoxy group, an amino group, a lower alkanoyl group, such as a cetylamino group, and a carboxy group, or an optionally substituted lower alkoxycarbonyl group, such as an ethoxycarbonyl group, or a 2- or preferably represents a lower alkyl group substituted with a 1-(lower alkylcarbonyloxy)-lower alkoxycarbonyl group or a carbamoyl group, such as an ethyl group or an n-propyl group, or further represents a lower alkoxycarbonyl group, e.g. The compound of the general formula (1) according to claim 1, which represents an ethoxycarbonyl group or a carbamoyl group, is prepared as a racemic mixture, a racemic compound, an optical diagonal or a salt thereof, particularly an addition with a pharmaceutically acceptable non-toxic acid. Pharmaceutical preparations containing in the form of salts. (6) represents n months, and R is a lower alkyl group, such as a methyl group, or a lower alkoxy-lower alkyl group, such as 2
- methoxyethyl group, R1 in the base film is optionally a lower alkyl group, such as a methyl group, a halo lower alkyl group, such as a trifluoromethyl group, a hydroxy group, a lower alkoxy group, such as a methoxy group, a halogen, a carbamoyl group, phenyl groups substituted with cyano and/or sulfamoyl groups, or optionally amino groups, lower alkanoylamino groups, such as acetylamino groups, and carboxy groups or optionally substituted lower alkoxycarbonyl groups, such as lower alkoxycarbonyl groups, For example, an ethoxycarbonyl group or a 2- or 6-year old, preferably 1-(
(lower alkylcarbonyloxy) - represents a lower alkyl group substituted by a lower alkoxycarbonyl group, such as an ethyl group, n-propyl group or n-butyl group, or AC further represents a lower alkoxycarbonyl group, such as an ethoxycarbonyl group Compounds of the general formula (H) according to claim 1 are prepared as racemic mixtures, racemic compounds, optical antipodes or salts thereof, particularly in the form of pharmaceutically acceptable non-toxic acid addition salts or in the presence of acidic groups. (7) General formula (I): /4\ [wherein R is an optionally substituted aliphatic or aromatic carbon] represents a hydrogen group, Ac represents an acyl group, n represents an integer of 1 to 4, and when n represents a number of 2 to 4, the group R is the same -
Alternatively, R as a lower alkyl group bonded to the 3-position may be bonded to any possible position of the pyridine ring, but when n is 1 and the bladder represents an acedel group, R as a lower alkyl group bonded to the 3-position.
has 2 to 7 carbon atoms, further n is 1, and Ac
represents a benzoyl group, R as a lower alkyl group bonded to the 3-14-15- or 6-position has 2 to 7 carbon atoms], a racemic mixture, a racemic compound or New compounds in the form of optical enantiomers. (8) n represents an integer of 1 to 4, and R is an optionally substituted lower alkyl group, lower alkenyl group, or lower alkynyl group, or a monocyclic or bicyclic carbon homocyclic or heterocyclic group; Represents an aromatic hydrocarbon group, and has the formula -c
(-o) -R1 (wherein R1 represents an optionally substituted aliphatic, cycloaliphatic, aromatic or aromatic) I)i aliphatic hydrocarbon group; or may represent a moddiester or monoamide group, but when n is 1 and 肚 represents an acetyl group, R as a lower alkyl group bonded to the 3-position may have 2 to 7 carbon atoms. and furthermore, when n is 1 and Ac represents a benzoyl group, R as a lower alkyl group bonded to the 3-14-15- or 6-position has 2 to 7 carbon atoms. A new compound in the form of a racemic mixture, racemate compound or optical diagonal, represented by the general formula 〇) according to claim 7. (9) n represents an integer of 1 to 4, R is a lower alkyl group,
optionally etherified or esterified hydroxy-lower alkyl groups, e.g. hydroxy-lower alkyl groups, lower alkoxy-lower alkyl groups or halo-lower alkyl groups, or optionally substituted, e.g. lower alkylated or acylated amino-lower alkyl group,
For example, an amino lower alkyl group, an N-lower alkylamino-lower alkyl group or a N,N-di-lower alkylamino-lower alkyl group, a lower alkanoylamino-lower alkyl group or a lower alkoxycarbonylamino-lower alkyl group, or optionally an ester. carboxy or amidated carboxy groups, such as carboxy groups, ethoxycarbonyl groups or optionally substituted carbamoyl groups, such as lower alkyl groups substituted with carbamoyl groups, such as carboxy-lower alkyl groups, lower alkoxycarbonyl-lower alkyl groups; , carbamoyl-lower alkyl, oxo-lower alkyl and cyano-lower alkyl, or optionally substituted aryl-lower alkyl, where aryl is a monocyclic aromatic hydrocarbon group, such as phenyl, or Cyclic aromatic hydrocarbon groups, such as 1- or 2-naphthyl groups or partially saturated naphthyl groups, such as 1,2,3,4-tetrahydro-5-
It is a naphthyl group, and the substituent is a lower alkyl group, a hydroxy group and/or a halogen, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, or optionally a lower Alkylated or acylated amino-lower alkyl groups, such as mono- or di-lower alkylamino-lower alkyl groups or lower alkanoylamino-lower alkyl groups, optionally esterified carboxy groups, such as carboxy groups or lower alkoxycarbonyl groups. groups, amidated carboxy groups, such as optionally substituted carbamoyl groups, e.g. evacarbamoyl groups,
N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, cyano, nitro or optionally acylated amino groups, such as amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylamino or di-lower alkylamino group, in which 1 to 3 such substituents may be present and may be the same or different, or R and the group R1 included in the pronunciation are each an aryl group. , such as a phenyl group, a 1- or 2-naphthyl group or a partially saturated leaf-thyl group, such as a 1.2,3.4-Te1lahydro5
- a naphthyl group, or preferably has 5 or 6 ring members and is attached to a pyridyl group via a ring carbon atom;
Groups containing as ring members oxygen, sulfur or nitrogen atoms and optionally 1 to 3 additional nitrogen atoms (which may be at least partially hydrogenated and in which case substituted with oxo groups, bicyclic the second ring in a heterocyclic radical of the formula may be a fused benzene ring), and especially a pyridyl group, such as a 2-13- or 4-pyridyl group, or a dihydroxo-pyridinyl group, such as a 1,6- a dihydro-6-oxo-2-pyridinyl group, a pyridazinyl group, e.g. 3-pyridazinyl, a pyrazinyl group, e.g. 3.4-dihydro-4-oxo-2-pyrimidinyl group, furyl group, e.g. 2- or 3-furyl group, pyryl group, e.g. 2- or 3-pyryl group, chenyl group, e.g. 2- or 3-chenyl group , oxasilyl groups, such as 2- or 4-oxasilyl groups, thiazolyl groups, such as 2-14- or 5-thiazolyl groups, thiadiazolyl groups, such as 1,2,4-thiadiazole-3
- or 5-yl group or 1,2°5-thiadiazol-3-yl group, imidazolyl group, e.g. imidazole-
2- or -4-yl group, pyrazolyl group, e.g. 3-
or 4-pyrazolyl group, triazolyl group, e.g. 1
, 2.3-1-riazol-4-yl group, or 1,2.
4-triazol-3-yl, tetrazolyl, e.g. tetrazol-5-yl, and indolyl, e.g. indol-4-yl, quinolinyl, e.g. 2-
Quinolinyl group, isoquinolinyl group, e.g. 1-isoquinolinyl group, benzimidazolyl group, e.g. 2-benzimidazolyl group, benzofuranyl group, e.g. 4- or 5-
A benzofuranyl group, a benzothenyl group, such as a 4- or 5-benzochenyl group, or a naphthyridinyl group, such as l. 8-naphthyridin-2-yl, such aryl groups may be present in particular on ring carbon atoms, but also on secondary nitrogen atoms of the ring, and may contain one or more, preferably up to four , optionally substituted lower alkyl groups, such as lower alkyl groups, optionally etherified or esterified hydroxy-lower alkyl groups, such as hydroxy-lower alkyl groups, lower alkoxy-lower alkyl groups or halo lower alkyl groups, or Optionally substituted, e.g. lower alkylated or acylated amino-lower alkyl groups, such as amino-lower alkyl groups, N-lower alkylamino-lower alkyl groups, N, N-di-lower alkylamino-lower alkyl groups, lower alkanoyl Amino-lower alkyl or lower alkoxycarbonylamino-lower alkyl, or lower alkenyl or lower alkynyl, optionally etherified or esterified hydroxy or mercapto groups, such as hydroxy, lower alkoxy, phenyl-lower Alkoxy group, halogen, mercapto group, lower alkylthio group,
a phenyl-lower alkylthio group, or a lower alkoxy group optionally substituted with an etherified or esterified hydroxy group or a mercapto group or an acyl group;
For example, lower alkoxy group, phenyl-lower alkoxy group, hydroxy-lower alkoxy group, lower alkoxy-lower alkoxy group, lower alkylthio lower alkoxy group,
halo lower alkoxy group or lower alkanoyl-lower alkoxy group, or lower alkenyloxy group, lower alkynyloxy group, 4+(-level alkylthio group, 7-syl group, e.g. lower alkanoyl group, optionally esterified carboxy group, e.g. carboxy group) or lower alkoxycarbonyl groups, amidated carboxy groups, such as optionally substituted carbamoyl groups, such as carbamoyl groups,
An N-lower alkylcarbamoyl group or an N,N-di-lower alkylcarbamoyl group, a cyano group, a cyano group, or an optionally acylated amino group, such as an acylated amino group, e.g. (selected from an alkanoylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonyl group, a sulfamoyl group, an optionally substituted ureido group and an amino group, an N-lower alkylamino group or an N,N-di-lower alkylamino group) may be substituted with a W substituent, and the group R1 included in the pronunciation is a lower alkyl group, a lower alkenyl L(ill alkynyl group, a phenyl-(!() class alkyl group, a phenyl-lower alkenyl group, a phenyl-lower alkynyl group) , represents a monocyclic or polycyclic cycloalkyl group, for example a cycloalkyl group, each group optionally containing an etherified or esterified hydroxy group, such as a hydroxy group, a lower alkoxy group and/or a halogen, optionally substituted, For example, lower alkylated or acylated amino groups, such as amino groups, N-lower alkylamino groups or N,N-di-lower alkylamino groups,
Substituted with a lower alkanoylamino group and/or a carboxy group optionally modified with a functional group, such as a carboxy group, an esterified carboxy group, such as an optionally substituted lower alkoxycarbonyl group, an optionally substituted carbamoyl group or a cyano group The substituted group R1 may contain one or more, in particular up to three, the same or different substituents at any position suitable for substitution, and ^C furthermore represents a lower alkoxycarbonyl group, an unsubstituted or substituted hydroxy groups, such as free or etherified hydroxy groups, such as lower alkoxy groups, or unsubstituted or substituted amino groups, such as amino groups, lower alkylamino groups,
and especially di-substituted amino groups, such as di-lower alkylamino groups, N-lower alkyl-N-phenyl-lower alkylamino groups, or optionally interrupted by nitrogen substituted with oxygen, sulfur or unsubstituted or substituted, e.g. lower alkyl groups. unsubstituted or substituted lower alkoxycarbonyl groups, including unsubstituted or substituted phenyl groups, such as lower alkyl groups, lower alkoxy groups and/or halogen-substituted phenyl groups, and N-unsubstituted or N-mono- or N,N-di-substituted carbamoyl group, e.g. lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, or optionally the lower alkylene moiety is interrupted with oxygen, sulfur or nitrogen which is unsubstituted or substituted, e.g. lower alkyl group N,N- may represent a lower alkylenecarbamoyl group, but when n is 1 and the bladder represents an acetyl group, R as a lower alkyl group bonded to the 3-position may represent a 2 to 7 carbon represents an atom, for example, an ethyl group, n-propyl group, or n-butyl group, and when n represents 1 and ^C represents a benzoyl group, 3-1
R as a lower alkyl group bonded in the 4-15- or 6-position represents 2 to 7 carbon atoms, for example the above-mentioned ethyl, n-propyl or n-butyl group; A novel compound of the general formula (1) according to item 7 in the form of a racemic mixture, a racemic compound or an optical enantiomer. (10) n represents 1 or 2, and R is a lower alkyl group, such as a methyl group, a lower alkoxy-lower alkyl group, such as a 2-methoxyethyl group, a halo lower alkyl group, such as a trifluoromethyl group, or a lower alkanoylamino group. - represents a lower alkyl group, for example an acetylaminomethyl group, R1 in the group Ac represents a phenyl or pyridyl group, in each case optionally a lower alkyl group, such as a methyl group, lower alkoxy - a lower alkyl group, for example 2-methoxy Ethyl group, halo lower alkyl group such as trifluoromethyl group, lower alkanoylamino-lower alkyl group such as 2-acetylaminoethyl group, hydroxy group, lower alkoxy group such as methoxy group, lower alkoxy-lower alkoxy group such as 2 - substituted with an ethoxyethoxyalkoxycarbonyl group, such as an ethoxycarbonyl group, a carbamoyl group, a cyano group, an amino group, or a lower alkanoylamino group, such as an acetylamino group, or a sulfamoyl group, or R1 is optionally substituted with a lower alkoxy group, For example, a methoxy group, an amino group, a lower alkanoylamino group, such as an acetylamino group, a carboxy group, an optionally substituted lower alkoxycarbonyl group, such as a 1-oxycarbonyl group or a 2- or 1-(lower alkylcarbonyloxy)-lower alkoxy It can represent a lower alkyl group substituted with a carbonyl or carbamoyl group, such as an ethyl group or a n-propyl group, or it can also represent a lower alkoxycarbonyl group, such as an ethoxycarbonyl group or an unsubstituted carbamoyl group or a lower alkoxy group, such as a methoxy group. may represent a carbamoyl group substituted with a group or an amino group, but when n is 1
and when Ac represents an acedel group, R as a lower alkyl group bonded to the 3-position represents 2 to 7 carbon atoms, such as an ethyl group, n-propyl group or n-butyl group. and furthermore, when n represents 1 and vesical represents a benzoyl group, R as a lower alkyl group bonded to the 3-, 4-, 5- or 6-position represents 2 to 7 carbon atoms. ,
For example, the general formula (1) according to claim 7, which does not represent the above-mentioned ethyl group, n-propyl group or n-butyl group,
New compounds in the form of racemic mixtures, racemates or optical antipodes. (I I)n represents 1 and R is a lower alkyl group, such as a methyl group, a lower alkoxy-lower alkyl group, such as 2
- represents a methoxyethyl group, or a halo lower alkyl group, such as a trifluoromethyl group, R1 in the base film represents a phenyl group or a pyridyl group, each optionally a lower alkyl group, such as a methyl group, a lower alkoxy-lower alkyl group , such as 2-methoxyethyl group, halo lower alkyl group, such as trifluoromethyl group, hydroxy group,
Lower alkoxy groups, such as methoxy groups, lower alkoxy-lower alkoxy groups, such as 2-ethoxyethoxy groups,
is substituted with halogen, a lower alkoxycarbonyl group, such as an ethoxycarbonyl group, a carbamoyl group, a cyano group, an amino group or a sulfamoyl group, or R is optionally substituted with a lower alkoxy group, such as a methoxy group, an amino group, a lower alkanoylamino group , for example an acetylamino group and a carboxy group or an optionally substituted lower alkoxycarbonyl group, such as an ethoxycarbonyl group or a 2- or preferably 1-(lower alkylcarbonyloxy)-lower alkoxycarbonyl group or a lower substituted with a carbamoyl group. It may represent an alkyl group, such as an ethyl group or an n-propyl group, or it may further represent a lower alkoxycarbonyl group, such as an ethoxycarbonyl group or a carbamoyl group, but if the vesicle represents an acetyl group, R as a lower alkyl group bonded to the 3-position represents 2 to 7 carbon atoms, for example ethyl group, n
- represents a propyl group or n-butyl group, and when Ac represents a benzoyl group, R as a lower alkyl group bonded to the 3-, 4-, 5-, or 6-position has 2 to 7 carbon atoms. racemic mixture, racemic compound or optical antipode form of the general formula (I) according to claim 7, which represents an atom, for example the aforementioned ethyl group, n-propyl group or n-butyl group; new compound. (12) n represents 1, R represents a lower alkyl group, such as a methyl group, or a lower alkoxy-lower alkyl group, such as a 2-methoxyethyl group, and R1 in the group Ac is optionally a lower alkyl group, such as methyl groups, halo lower alkyl groups, such as trifluoromethyl groups, hydroxy groups,
phenyl groups substituted with lower alkoxy groups, such as methoxy groups, halogens, carbamoyl groups, cyano groups and/or sulfamoyl groups, or optionally amino groups, lower alkanoylamino groups, such as acetylamino groups, and carboxy groups or optionally substituted lower alkoxycarbonyl groups such as lower alkoxycarbonyl groups such as ethoxycarbonyl groups or 2- or preferably 1-
(Lower alkylcarbonyloxy) - represents a lower alkyl group substituted by a lower alkoxycarbonyl group, such as an ethyl group, n-propyl group or n-butyl group, or furthermore represents a lower alkoxycarbonyl group, such as an ethoxycarbonyl group. However, when the bladder represents an acedel group, R as a lower alkyl group bonded to the 3-position represents 2 to 7 (11i1 carbon atoms, such as an ethyl group, a n-propyl group, or represents an n-butyl group, and furthermore, when the bladder represents a benzoyl group, R as a lower alkyl group bonded to the 3-14-15- or 6-position is 2-7
(IF, represents a carbon atom of l, for example, the above-mentioned ethyl group,
A novel compound in the form of a racemic mixture, a racemic compound or an optical antipode, which does not represent an n-propyl group or an n-butyl group and has the general formula → according to claim 7. (13) n represents 1, R is a lower alkyl group, for example n
-butyl group, or a lower alkoxy-lower alkyl group, such as a 3-methoxy-〇-propyl group, and R1 in C of claim 8 is preferably an amino group or especially Lower alkanoylamino groups, such as acetylamino and carboxy groups, lower alkoxycarbonyl groups, such as ethoxycarbonyl groups, 2- or preferably 1-(lower alkylcarbonyloxy)-lower alkoxycarbonyl groups, such as pivaloylcarbonyloxymethoxycarbonyl or a lower alkyl group substituted with a carbamoyl group, such as an ethyl group or an n-propyl group.
Novel compounds or salts thereof in the form of racemic mixtures, racemic compounds or optical antipodes. (14,) n represents 1 and R is a lower alkyl group bonded to the 5-position, such as n-butyl group, or lower alkoxy-
R1 in the membrane according to claim 8 represents a lower alkyl group, for example, a 3-methoxy-n-propyl group, and R1 is ω
- position is an amino group or especially a lower alkanoylamino group, such as an acetylamino group and a carboxy group, a lower alkoxycarbonyl group, such as an ethoxycarbonyl group or a 1-
(Lower alkylcarbonyloxy) - A novel compound or group of general formula (1) according to claim 7 representing an n-propyl group substituted with a lower alkoxycarbonyl group, for example a pivaloylcarbonyloxymethoxycarbonyl group. A compound in which R7 has the above definition in an optically active form, especially in the I2-form, or a salt thereof. (15) L-glutamic acid 5- (N2- (5-n-
butyl-2-pyridyl)-hydrazide] hemihydrate. (16) N-acetyl-■7-glutamic acid 5-(N2
-(5-n-butyl-2-pyridyl)-hydrazide]. (17) N2 (5-n-butyl-2-pyridyl)-3
-Sulfamoyl-4-chlorobenzoic acid hydrazide. (1B) N-acetyl-■,-glutamic acid 5-(N'
-(5-n-butyl-2-pyridyl)-hydrazide]
The compound according to claim 7, which is a 1-methyl ester. (19) The compound according to claim 7, which is N2 (5-n-butyl-2-pyridyl)-picolinic acid hydrazide. (20) The compound according to claim 7, which is N-ethoxycarbonyl-N"-(5-n-butyl-2-pyridyl)-hydrazine. (21) N2 (5-n-butyl-2- pyridyl)-N
- The compound according to claim 7, which is acetic acid hydracite. '(22)N' -(5-n-butyl-2-pyridyl)
-N-fusaric acid hydrazide Claim 7
Compounds described in Section. (23) The compound according to claim 7, which is the compound of general formula (1) listed in Example 10. (2. A salt of a compound according to claims 7 to 23. (2. A pharmaceutically acceptable non-toxic acid addition salt of a compound according to claims 7 to 23). (26) Claims 7 to 16 having an acidic group
Salts of the compounds described in Section 1 with pharmaceutically acceptable non-toxic bases. (2. Pharmaceutical preparations containing the novel compounds described in Claims 7 to 23, 25 and 26). (28) Claims 1. Objects according to items 1 to 23 and 25 and 26. (29) Claims 1 to 23 as pharmaceutical preparations or new compounds having pharmacological activity, particularly in the kidney and coronary blood vessel regions. The object described in paragraphs 23, 25, and 26. (30) Claims 1 to 23 as an antihypertensive agent
Items 25 and 26. (31) A compound of general formula (1) in which 80 represents a pyridylcarbonyl group, as a substance having anti-leukemic activity. (32) Use of the compounds described in claims 7 to 23 and 25In and 26 for the manufacture of pharmaceutical preparations. (33) A pharmaceutical preparation characterized in that the compound according to claims 1 to 23, 25 and 26 is processed, optionally with the addition of an auxiliary agent, to form a pharmaceutical preparation. manufacturing method. (34) General formula (I): /\ , when n represents a number from 2 to 4, the groups R are the same or different and may be bonded to any possible position in the pyridine ring. ■): /\',, / is reacted with a compound of the general formula (■): HOOC-R+ (nT) or a reactive derivative of such a carboxylic acid or a modiester or monoamide of carbonic acid. , Matana J b) General formula (■): /\ [In the formula, X1 and Xl each represent hydrogen or a substituent that can be substituted with hydrogen, or Xl and Xl are both substituted with two hydrogen atoms. and/or the group R and the functional groups present in the membrane are optionally present in a protected form, but at least one of the groups X1 and Xl represents something other than hydrogen, or At least X, and Xl together represent a divalent group which can be substituted with two hydrogen atoms, or at least the group R and/or the functional group present in the membrane are present in a protected form or a salt thereof in which a group XI, Xl, or a combination of Xl and remove the protecting group attached to
or C) general formula (Ha): /\c in which X represents a suitable leaving group] is substituted with hydrogen, or
■): to react with a compound of H2N NHAc (■), or d) to produce a compound of general formula (I) where n represents 1 and R represents a monocyclic or bicyclic heteroaryl group, General formula (■): /\',, / [In the formula, the hydro-4-cy group and/or the amino group are protected with a protecting group, and R2 is a mono-Ti or bicyclic heteroaryl group R
[representing a substituent capable of forming]] to form a monocyclic or bicyclic heteroaryl group R, simultaneously or subsequently removing the protecting group and substituting with hydrogen, and optionally, forming the general formula The compound (T) can be changed into a different compound of general formula H) and/or if necessary, the racemic mixture formed can be converted into a racemic compound or the formed racemic compound can be converted into an optical enantiomer. An acylated hydrazine compound characterized in that the resulting free compound of the general formula → is separated into a salt, or the resulting salt is converted into a free compound or a different salt, if necessary. manufacturing method. (35) A compound obtained by the method according to claim 34. (36) General formula (■): /ゝ・, \, / [In the formula, R and n have the definitions given in the general formula (1), in particular, n represents 1, and R represents 3- or 6- or especially in the 5-position, lower alkoxy-lower alkyl groups, e.g. 2-
represents a methoxyethyl group, or a phenyl-lower alkyl group, such as a benzyl group, or if n is 1 R
represents a lower alkyl group having 2 to 7 carbon atoms, such as an ethyl group, n-propyl group or n-butyl group;
having 3 to 7 carbon atoms, for example representing n-propyl or n-butyl groups, or salts thereof, especially pharmaceutically acceptable non-toxic acid addition salts. (Margin below)