DE3230400A1 - NEW 1,4-DIHYDROPYRIDINE DERIVATIVES - Google Patents

Description

The present invention relates to new 1,4-dihydropyridine derivatives with antihypertensive effects.

So far, the 1,4-dihydropyridine derivatives are 4- (2-nitrophenyl) -2,6-dimethnyl'-1,4-dihydropyridine ~ 3,5-dicarboxylic acid dimethyl ester (US-PS 3,644,627, hereinafter referred to as "Nifedipine"), 4- (3-nitrophenyl) ~ 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5- - (N-benzyl-N-methylamino) ethyl ester hydrochloride (Japanese Patent Publication No. 45075/1980, hereinafter referred to as "Nicardipine") etc. have been known as therapeutic Means to improve coronary or cerebral circulation are suitable.

However, it has been reported on the basis of an animal experiment that the vasodilatory effect and the antihypertensive effect which result from the said effect of this compound can be achieved in a short period of time, e.g. In 30-40 minutes or so at an effective intravenous dose at which these compounds are significantly effective, e.g. B. 10 g / kg, disappear, and that these compounds also have an effect on increasing the heartbeat or the heart rate ("heart rate"), which is to be understood as a factor for the increase in the load on the heart function, so one Type of side effect may be (Drug Research, Vol. 22, No. 1, p. 33, 1972; ibid., BoI. 26, No. 12, p. 2172, 1976; Toho Igakukai Zasshi, Vol. 26, No. 2, p. 48, 1972). Therefore, when these compounds are used as agents for hypertension, cardiovascular disease, etc., requiring continued use of the drug for a long period of time, improvement of the preparation, e.g. B. by giving him the property of slow drug delivery zsw. requires regular administration or use with other drugs.

The invention relates to 1,4-dihydropyridine derivatives, which have a long have lasting antihypertensive effects due to the vasodilatory Effect, and have very little ability change the heartbeat or heart rate.

The invention provides 1,4-hydropyridine derivatives of the following general ones Formula (I) available:

-p -R "

Il

G-C

c'-O-A-

(D

• iOi-j.! -. , < an alkyl group with 1 to 4 carbon atoms or an alkoxyal

2 represents a kyi ^ group with 3 to 6 carbon atoms, R a water atom or represents a.-iaiogenatom, R entu / eder represents a nitro group,

2 2

w-er.n i <is a hydrogen atom, or represents a halogen atom, u / enn R

4th
c-in Haglcgenatom, R is an alkyl group with 1 to 8 carbon atoms, a ^ yricyl group, a phenylethyl group, a benzyl group, which may optionally be substituted by at least one member of the group, soft from a lower alkyl group, a lower alkoxy group, a Hjtnylenciioxygruppe and a halogen atom, or a phenyl group which can be substituted by at least one member of a group Kanr ... which consists of a lower alkyl group, a lower alkoxy group, ϊ-te. · rifluoromethyl group, a nitro group, a cyano group, a. ^ inegruppo, a mono-lower-alkylamino group, a di-lower-alkylarrano group, an acetylamino group, a benzoylamino group, a methylenedioxy group and a halogen atom, and A represents a hexamethylene group which is optionally substituted by an alkyl group or two al- ^ yl groups having 1 to 3 carbon atoms can be.

7.U the derivatives of the invention (I) also include the tautomers of the follow the aiJfjüiiu; ιηΐ'π luimoi ''. ! 's

R-o-c-

—C - 0 - A - 0

(II)

12 3 4
in which H, R, R, R and Λ have the meaning given above, as well as the optical isomers possible due to the asymmetric carbon atom in the 4-position of the 1,4-dihydropyridine ring.

In the definition of the general formula (I), under the term "lower Alkyl "to understand methyl, ethyl or propyl and the term" halogen atom "to understand the fluorine, chlorine, bromine or iodine atom, if it is not otherwise stated. Include the terms "alkyl" and "alkoxyalkyl" of course, both such groups with straight chains and such groups with branched chains.

The derivatives of the invention (I) can be prepared according to any of those described below Process are produced.

(Method 1)

The derivatives of the invention (I) can be prepared by reacting 1.0 mole of benzylidene acetoacetate derivative of the following general formula (III)

R -Γ \ Ί / ^ COCH

CH = C (III)

^x ₃

2 3 5

in which R and R have the meanings given above and R have the meanings given above R has the meaning or represents a substituted pyrazolyloxyhexyl group of the following general formula (IV),

C.
NH
= L _R 4 (IV)

wherein A and R have the meanings given above, with 1.0-2.0 mol, preferably with 1.0 mole of an enamine carboxylate derivative of the following general Formula (V)

CH., - C = CH - C - OR ⁰ (V)

Ml 0

/1

where R has the practice unijtMjfibunu Hodoutuny of R or a substituted one Pyrazolyloxyhexylgrgppö of the above general formula (IV) represents, with with the proviso that when R is R, then R is a substituted pyrazolyloxy

hexyl group (IV), R is then R ¹ , in the presence or absence of a reaction solvent at a temperature of 5-200 C, preferably 50-150 ° C. As the reaction solvent, alcohols, such as. Example, methanol, ethanol, Iaopropanol, butanol, etc., diols, such as. B. ethylene glycol, propylene glycol, etc., Ä'thylenglykoläther such. B. ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, etc., nitrobenzene, Ν, Ν-dimethylacetamide, N, N-dimethylformamide, hexamethylphosphoraic acid triamide, acetic acid, water and a mixture of two or more of these solvents are preferred. In the above procedure 1, an appropriate amount of molecular sieves, peperidine, diethylamine, triethylamine, Ν, Ν-dimethylaniline, N, -diethylaniline, etc. can be used as the reaction accelerator, depending on the requirements.

(Method 2)

The derivatives of the invention can also be obtained by reacting 1.0 mole of one

Benzaldehyde derivative of the following general formula (VI)

CHO

(VI)

2 3

wherein K and R have the meanings given above, with 1.0-2.0 mol, preferably with 1.0 mole of an enaminocarboxylate derivative of the above general Formula (V) and 1.0-2.0 mol, preferably 1.0 mol, of an acetoacetate derivative of the following general formula (VII)

CHp - C - CH ₀ - C - OR ⁵

0 0 (VII)

wherein R has the meaning given above, in the presence or absence of a HouUUonol / inuiitjuiii »η niu btu oinor induction temperature of 5 - 200 ° C, vor / uyaweiüu vor »!> u - IMJ '' C, has been filled. All reaction solvents and ala optionally using / u reduction accelerators can be those in substances described in method 1 are used.

(Method 3)

The derivatives of the invention (I) can further also by reacting 1.0 Mol of a benzylidene acetoacetate derivative of the above general formula (III) with 1.0 mole of an acetoacetate derivative of the following general formula (VIII)

- 5 -

CH,

-C-U Ü

CH,

- C

- OFTEN

(VIII)

wherein R has the meaning given above, and 1.0 mol or more, preferably 1.0 moles - 3.0 moles of ammonia in the presence or absence of a reaction solvent at a reaction temperature of 5-200 ° C, preferably 50-150 ° C, are prepared. As a reaction solvent and as an optional reaction accelerator to be used, those in the process 1 are used.

(Method 4)

The derivatives of the invention (I) can furthermore also by reacting 1.0 mole of a dihydropyridine derivative represented by the following general formula (IX)

(IX)

12 3 7

wherein R, R, R and A have the meaning given above and R is a halogen atom, a mesyloxy group, a tosyloxy group or a bezolsulfonyloxy group means with 1.0 mole - 6.0 moles, preferably with 1.0 mole - 2.0 moles, of a pyrazolone derivative of the following general formula (X)

(X) 4
wherein H dio otjon aiujiujtrbono Uudeutuny hut, in the presence of an anionisie -.-

renden fteagena and jv nor don Lrf'urdernisaen an alkali iodide in a reaction solvent at a reaction temperature of 0-180 C, preferably 15-100 ° C, are produced.

The implementation of this process 4 proceeds advantageously by reacting first the pyrazolone derivative 3 (X) with the anionizing agent and adding the dihydropyridine derivative (IX) and also, depending on the requirements of the alkali iodide, to the reaction mixture obtained. Ais anionizing reagent are alkali metals, such as. B. metallic sodium, metallic potassium usu /., Alkaline earth metals such. B. metallic calcium, metallic magnesium, etc., alkali hydrides such. B. sodium hydride, potassium hydride, lithium hydride, etc., carbonates, such as. B. sodium carbonate, potassium carbonate, etc., sodium or potassium alkoxides with alcohols, such as. B. methanol, ethanol, propanol, butanol, etc., tertiary amines, such as. B. triethylamine, pyridine, Ν, Ν-dimethylaniline, etc., suitable. When a sodium or potassium alkoxide is used as the anionizing agent, it is advantageous to remove as much as possible of the alcohol formed in the course of the reaction. In this method, the amount of the anionizing agent other than a terminal amine is suitably so much as to be in the range of 1.0 mol - 6.0 mol, preferably 1.0 mol - 2.0 Moles, and that furthermore, within such a limit, it is always equimolar to the proportion of the pyrazolone derivative (X) or less. On the other hand, when a tertiary amine is used, it is suitably 1.0 mol or more. The alkali iodide promotes reaction in this process when a dihydropyridine derivative is used in which R is in the ob:
Halogen atom is different from the iodine atom.

in which R in the above general formula (IX) is used

The reaction solvent is dimethyl sulfoxide, Ν, Ν-dimethylacetamide, N, N-dimethylformamide, pyridine, dioxane, Hexamethylphosphoreäuretriaraid, N-Methylmorphoiin, 1,2-Dimethoxyethane or a mixture of two or more of these solvents are suitable.

In the case of method 4, ' also a combination of the following general ones Formula (XI)

U ι ι. ■ ·. R ² P. Il
- O - C ! ■ R ³ J * ϋ R ¹ V Il
C. H ₃ C | l : ι

(XI)

12 3 4

wherein R, R, R, R and A have the meaning given above, as a by-product and this compound has long-lasting antihypertensive and vasodilatory effects.

(Procedure for the formation of the main starting materials in procedures 1-4)

The acetoacetate derivatives of the above general formulas (VII) and (VIII) can using diketene and an alcohol of the following general Formula (XII)

R * - OH (XII)

has given meaning, or derivatives of the following general formula (XIII)

wherein R has the meaning given above, or a pyrazolyloxyhexanol

HO-A- 0- e NH

= / R ⁴ (XIII)

wherein R and A are as defined above, by a process according to the known processes for the preparation of acetoacetate derivatives, such as z. After that in the Journal of the Chemical Society, Vol. 97, p. 1978 (1910) described processes.

Second, the enaminocarboxylate derivative of the above general formula (V) using the acetaacetate derivative (VIII) and ammonia according to a process according to the known processes for the formation of enaminocarboxylate derivatives, such as D. according to that in the Journal of the American-Chemical Society, Vol. 67, '), 10! 7 (J'M!>) Buuehriubenen process.

The benzylidene acetoacetate derivative represented by the above general formula (III) can using the benzaldehyde derivative (VI) and the acetoacetate derivative (VII) by a method according to the known methods for the formation of Benzylidene acetoacetate derivatives, such as. B. after that in Organic Synthesis Collective Volume, Vol. 4, p. 408 (1963).

In Procedures 1-4 above, the amount of each Au3 gang compound used was determined specified in such a way that it is a unit quantity,

d. H. 1.0 mole, acted for simplicity. There is no need for calibration mentions that this quantity used is freely determined can be provided that the relative molar ratio between the relevant Connections is within the specified limit.

The derivatives of the invention (I) prepared by processes 1-4 can by means of a purification process such as extraction with a suitable solvent, column chromatography using clay, Silica gel, ion exchange resin zsw. as a carrier, crystallization through Concentrating, etc., fractional precipitation, recrystallization or by means of a suitable combination of these methods.

The following are test examples for the pharmacological activity of typical compounds which belong to the derivatives of the invention (I) and which have been prepared by the processes described above are given. (Blood pressure lowering effect)

The test was carried out using groups of 5-6 adult dogs in each group and measuring the heartbeat or the heart rate and the blood pressure in the right femoral artery as well as the duration of the antihypertensive effect after injection of 3 / ug / kg or 10 / ug / kg of each Connection performed in the leg vein. The dogs used were previously anesthetized by intravenous administration of 30 mg / kg sodium pentobarbital been. The measuring instruments were a pressure transducer MPU-0.5 and a pulse rate ta'chometer RT-2 (both manufactured by Nippon Koden Co.) and the recording device was a WI-300 writing oscilloscope (manufactured by Nippon Koden Co.). The duration was determined by measuring the time from which the effect was clearly shown in itself to the point in time at which the effect ceased. Each connection was made by injection the respective 10 Joigen aqueous polyethylene glycol solution of the compound administered into the leg vein.

The results are given in Table 1. The heartbeat or the Heart rate and the antihypertensive effect are expressed as an increase or decrease. take the heartbeat (per minute) and the difference in mean blood pressure given before and after administration of each compound and the duration is given in units of minutes. In addition, the relevant, from

of the Applicant's measured effects of "Nifedipine" and "Nicardipine" in given in the same table.

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"Nifedipine"

"Nicardipine"

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-CS-methyl-3-pyrazolyloxy) hexyl ester (Example 1)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-δ-CS-isopropyl-3-pyrazolyloxy) hexyl ester (Example 3)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine - ^ - carboxylic acid-o-CS-methyl-3-pyrazolyloxy) hexyl ester (Example 4)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isopropoxycarbonylpyridine-S-carboxylic acid-o-oCS-methyl-3-pyrazolyloxy) hexyl ester (Example 7)

Table 1

Dosage heartbeat

-ug / kg
IV

antihypertensive effect mean blood pressure _ duration

10

10

10

10

3
10

3
10

Heartbeat / min + s.e.

5.1 + 0.6 9.0 + 1.2

19.0 + 3.5 23.0 + 4.5

0.8 + 0.4

1.0 + 2.6

-1.2 + 1.9 -3.6 + 1.0

3.2 + 0.8

6.1 + 3.5

1.4 + 1.7 2.2 + 1.6

mm Hg + s.e.

-20.1 + 1.4 -43.0 + 3.9

-13.3 + 2.5 -23.5 + 2.8

-14.5 + 1.3 -24.3 + 1.8

-18.6 + 1.2 -29.1 + 2.4

-14.9 + 1.4 ■ 27.4 + 2.7

-12.5 + 2.8 -25.7 + 2.6

mm + s.e.

19.0 + 1.3 40.6 + 3.3

20.1 + 5.0 32.5 + 6.9

46.5 + 2.8 103.6 + 4.3

X ··

73.5 +5.3 180 or longer

53.5 + 5.2

141.0 + 6.7

43.4 + 3.2 136.2 + 5.3

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1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (α-methoxyethoxycarbonyl-pyridine-S-carboxylic acid-δ- (5-methyl-3-pyrazolyloxy) hexyl ester (Example 10)

1,3-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-iS-methyl-3-pyra2olyloxy) hexyl ester (Example 12)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-S-carboxylic acid-o-iS-isopropyl-3-pyrazolyloxy) hexyl ester (Example 14)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isopropoxycarbonylpyridine-S-carboxylic acid-o-tS-isopropyl-3-pyrazolyloxy) hexyl ester (Example 16)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isobutoxycarbonylpyridine-S-carboxylic acid-o-iS-ethyl-3-pyrazolyloxy) hexyl ester (Example 18)

Table 1 (continued)

Dosage heartbeat antihypertensive effect

mean blood pressure duration

, µg / kg heartbeat / mm Hg + s.e. min + s.e, i.v. min + s.e.

3
10 1.3
3.4 +1 +1 1.8 -15.5
-25.9 +1 +1 1.6 57.4
127.3 +
+ + 3.3
3.7 I. * # »
Λ # »
y * 9 longer S 1 i
· * »Λ
a »*
ft * 9
»Ϊ
»9»
t ■ *
»A · 3 3.8 + 1.0 -16.1 + 1.7 51.5 + + 3.1 * \
I. J * * δ: ■ j
j
*
> 3.8 10 7.3 + 2.1 -27.9 + 1.4 110.9 + 2.6 >
* * 2.1 3 2.8 + 1.3 -13.1 + 1.6 117.6 + + 3.9 ■ 4k>
> » CO 10 5.8 + 1.7 -26.6 + 2.2 180 or 180 or 6.7 OO 3 1.7 + 1.6 -14.6 + 2.6 67.1 CD 10 3.5 + 1.4 -26.1 + 2.3 161.0 3 -3.0 + 2.5 -17.5 + 2.2 86.6 10 -7.2 + 3.8 -27.2 + 3.1 longer

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Table 1 (continued) Dosage heartbeat

/ Ug / kg
iV

Heartbeat / min + s.e.

antihypertensive effect mean blood pressure duration mm Hg + s.e. min + s.e.

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl-3- (2-normalpropoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) -hexyl ester (Example 21)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-isobutoxyethoxycarbonyl) pyridine-5-carbonic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester (Example 23)

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-isopropoxycarbonylpyridine-S-carboxylic acid-o-iS-normalbutyl-3-pyrazolyloxy) hexyl ester (Example 28)

1,4-Dihyro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-CS-normalbutyl-3-pyrazolyloxy) hexyl ester (Example 33)

10

10

3
10

10

-3.7 + 1.3 -6.5 + 2.5

2.4 + 1.3 3.6 + 1.4

2.7 + 1.8 7.9 + 2.8

-3.5 + 2.4 -8.2 + 1.6

-18.1 + 2.9 -30.6 + 3.2

-15.0 + 2.0 -29.2 + 2.1

-19.1 + 2.0 -31.4 + 3.3

-17.1 + 2.8 -28.8 + 2.4

73.2 + 4.2 180 or longer * .. «?,

% I c * ♦ *

Xt

48.9 + 3.1 i ^ «« .. i «

91.2 + 5.8 ^ V "'.

82.0 + 3.1 180 or longer

82.5 + 3.9 163.2 + 4.3

CO

TNJ)

OO CD 4> CD CD

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1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-normalpropoxycarbonylpyridine-S-carboxylic acid o- (5-isopropyl-3-pyrazolyloxy) hexyl ester (Example 35)

1,4-Dihydro-2,6 ~ dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-octyl-3-pyrazolyloxy) hexyl ester (Example 37

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -J- methoxycarbonylpyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester (Example 39)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-iS-methyl-3-pyrazolyloxy) hexyl ester (Example 40)

1,4-Dihydro-2, o-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-S-carboxylic acid-o-iS-hexyl-3-pyrazolyloxy) hexyl ester (Example 42)

Table 1 (continued)

Dosage heartbeat antihypertensive effect

mean blood pressure duration

, µg / kg heartbeat / mm Hg + s.e. min + s.e. i.v. min + s.e.

3 1.7 + 1.1 -15.6 + 2.8 73, 5 + 5 ', 3 > »* 10 3.9 + 1.0 -29.0 + 3.0 180 or longer I «U39 3 5.8 ± ³ » ⁷ -24.3 + 1.4 149, 1 + 1 »4, »* T »
> 10 8.2 + ¹ ^ ⁷ -39.4 + 2.0 180 or longer 3
10 -6.0
-11.0 + 3.2
+ 2.9 -19.6 +
-31.8 + 3.7
3.4 98
180 3 + 6
or , 2
longer *
■ * * ·
* # »
* a
* i * 9
»· Ν
4 * 9 3 4.8 + 2.1 -13.0 + 3.6 44, 1 + 3 , 6 10 7.5 + 3.6 -23.3 + 2.9 108 6 + 4 , 5 N) 3 2.8 + 1.7 -20.2 + 3.7 139 1 + 4 , 3 CO
O 10 6.1 + 3.5 -36.4 + 3.1 180 or longer

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Table 1 (continued) Dosage heartbeat

/ µg / kg

I.V.

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ~ 3- (Z-isopropoxyethoxycarbony-dpyridine-S-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester (Example 47)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-S-carboxylic acid-o-iS-phenyl-3-pyrazolyloxy) hexyl ester (Example 49)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-S-carboxylic acid o- (5-mfluorophenyl-3-pyrazolyloxy) hexyl ester (Example 50)

1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-6- (5-phenyl-3-pyrazolyloxy) hexyl ester (Example 51)

Heartbeat / min + s.e.

antihypertensive effect mean blood pressure duration mm Hg + s.e,

1.7 + 1.3 4.9 + 1.4

4.3 + 0.8 9.2 + 1.2

4.1 + 1.7 8.5 + 2.4

2.9 + 1.3

9.8 + 2.9

-14.7 + 1.7 -26.5 + 2.3

-12.9 + 2.1 -27.0 + 2.6

-13.2 + 2.2 -22.6 + 1.9

-14.5 + 1.6 -25.9 + 2.4

min + s.e.

64.4 + 3.7 152.1 + 4.3

151.0 + 5.9 180 or longer

50.3 + 3.8 103.5 + 4.9

113.2 + 7.5 180 or longer

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-5-carboxylic acid 6- (4-phenyl-3-pyrazolyloxy) hexyl ester (Example 57)

7.3 + 1.6 13.6 + 2.8

-14.7 + 1.8 -25.2 + 1.7

63.5 + 3.8 115.6 + 5.7

OO

CD

C3

link

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-S-carboxylic acid-o-CS-chlorophenyl-3-pyrazolyloxy) hexyl ester
(Example 58)

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-CS-ochlorophenyl-3-pyrazolyloxy) hexyl ester
(Example 59)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-normalpropoxycarbonylpyridine-S-carboxylic acid-o-5- (2,4-dichlorophenyl) -3-pyrazolyloxy hexyl ester (example 65)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-iS-omethoxyphenyl-3-pyrazolyloxy) hexyl ester
(Example 67)

Table 1 (continued)
Dosage heartbeat

antihypertensive effect mean blood pressure duration

µg / kg heartbeat / mm Hg + s.e. min + s.e. min + s.e.

3 -2 , 0 + 1, 3 -14 , 2 + 2, 6th 87 * »A
4.6 ^% "" · ' 9.2 ■. ; _ _; _ 10 -7 , 0 + If 8th -20 , 9 + 2, 7th 180 or longer
ι *
a ♦ »* s?
I ι * S ί ' longer " * 3 -5 , 6 + 2, 5 -21 , 7 + 2, 1 136 , 3 + 10 -10 ,1 + 3, 0 -37 ,8th + 3, 2 180 odei * * *
4 «I.
7.5 * ·: 4.8 Γ '. · ⁵ 3 1 , 5 + O, 3 -10 , 9 + 1, 4th 102 > ⁴ i 10 -4 ,1 + 2, 7th -18 + 2, 3 159 , 6 +

2.0 + 1.1
2.8 + 1.9

-15.7 + 1.8 -25.3 + 2.7

34, = + 3.6 89.5 + 3.8

link

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-δ-iS-onitrophenyl-3-pyrazolyloxy) -3,4-dimethylhexyl ester (Example 76)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isobutoxycarbonylpyridine-S-carboxylic acid-o-CS-mfluorophenyl-3-pyrazolyloxy) hexyl ester (Example 80)

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- ^ -isobutoxyethoxycarbony-dpyridine-S-carboxylic acid 6- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester (Example 81)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-otolyl-3-pyrazolyloxy) hexyl ester (Example 83)

1,4-Dihydro-2,6-dimethyl ~ 4- (3-nitrophenyl) -3 - (^ - isopropoxyethoxycarbonyl / pyridine-S-carboxylic acid 6- (5-o-tolyl-3-pyrazolylocy) hexyl ester (Example 84)

Table 1 (continued) Dosage heartbeat

.ug / kg

I.V.

3 10

Heartbeat / min + s.e.

4.2 + 1.8
9.5 + 2.7

antihypertensive effect mean blood pressure duration mm Hg + s.e. min + s.e.

-16.6 + 1.6 -28.2 + 2.4

146.6 + 4.3 180 or longer

3 10 , 3 + 2 , 3 -14 , 6 + 1 , 3 52.1 + 2 + 4 , 0 iy fce («ί
«Crc
* t
* _fc * C
O ^ C ft * 10 16 , 4 + 4th , 3 -22 , 4 + 2 ,1 82.5 + 4 + 6 ,8th ' <* C «· 3 8th ,8th + 3 , 6 -19 , 5 + 1 , 4 57.2 + 4 , 6 «Et
# fc «
e ε ε 10 10 , 3 + 3 , 3 -29 , 9 + 2 , 2 98.0 + 5 , 2 3 0 , 0 + 0 , 0 -12 , 6 + 2 , 0 124.4 + 7 , 4 ro 10 -2 , 3 + 1 ,1 -21 , 0 + 2 ,1 180 or longer CD CD 3 1 , 0 + 0 , 3 -13 ,8th + 1 , 7 102.8 , 7 10 -2 , 0 + 0 ,8th -25 , 2 + 2 , 0 165.0 , 5

link

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-S-carboxylic acid-o - ^ - mcyanophenyl-3-pyrazolyloxy) hexyl ester (Example 87)

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl-3-methoxycarbonylpyridine-S-carboxylic acid-o-5- (o-trifluoromethylphenyl) -3-pyrazolyloxy hexyl ester (example 89)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid o-5- (2-pyridyl) -3-pyrazolyloxy) hexyl ester (Example 91)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o- iS -benzyl-3-pyrazolyloxy) hexyl ester (Example 94)

Table 1 (continued

Dosage heartbeat antihypertensive effect

mean blood pressure duration

yUg / kg heartbeat / mm Hg + s.e. min + s.e. i.v. min + s.e.

5.8 + 2.6

8.9 + 3.4

7.7 + 4.8 12.1 + 5.3

2.4 + 0.8 7.8 + 3.1

1.5 + 2.4 3.0 + 4.2

-12.9 + 1.6 -21.4 + 1.9

-20.1 + 1.3 -32.5 + 2.7

-23.6 + 2.1 -44.3 + 3.4

-14.3 + 1.8 -22.6 + 2.7

60.8 + 2.9 96.3 + 4.3

160.2 + 7.7 180 or longer

48.5 + 2.4 I, 93.7 + 5.8

132.8 + 9.3

180 or longer | \ j

■ tr ff

link

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o - ^ - pchlorphenyl-3-pyrazolyloxy) hexyl ester (Example 96)

1,4-Dihydo-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-δ-iS-pmethoxyphenyl-3-pyrazolylocy) hexyl ester (Example 97)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-δ-5- (3,4-methylenedioxyphenyl) -3-pyrazolyloxy hexyl ester (example 98)

1,4-Dihydro-2, o-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid-6- (5- phenyl-3-pyrazolyloxy) hexyl ester (Example 100)

.V.

Table 1 (continued) Dosage heartbeat

Heartbeat / min + s.e.

0.0 + 0.0 -1.0 + 2.0

antihypertensive effect mean blood pressure duration mm Hg + s.e. min + s.e.

-14.5 + 1.6 -25.0 + 2.3

76.8 + 2.8 137.2 + 4.1

3 -ι, 0 + 0.0 -13 ,8th + 1, 8th 78 , 6 + 3 »6 TS
I cr 10 0 + 0.8 -24 , 3 + 2, 2 129 , 0 + 5 , 0
tea*
t C
* C β * 1, 3 2, 8th + 0.9 -13 , 5 + 2, 4th 58 , 6 + 3 »5: ·· γ 10 1, 4th + 1.2 -23 , 7 + 2, 6th 104 , 3 + 5 • * *
, 2: * .. · 3 3, 5 + 0.8 -14 , 5 + 1, 5 124 , 7 + 7 , 3 10 1 + 1.2 -22 ,8th + 2, 1 180 or longer ^; CO

link

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-S-carboxylic acid-o-iS-ochlorophenyl-3-pyrazolyloxy) hexyl ester (Example 101)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-δ-5- (p-N-acetylaminophenyl) -3-pyrazolyloxy hexyl ester (example 110)

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-S-carboxylic acid-o-IIJ-pheyl-3-pyrazolyloxy) hexyl ester. (Example 113)

1,4-Dihydro-2, o-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-methoxyphenyl-3- pyrazolyloxy) hexyl ester (Example 117)

Table 1 (continued)

Dosage heartbeat antihypertensive effect

mean blood pressure duration

■ µg / kg heartbeat / mm Hg + s, e. min + s.e. i.v. min + s.e.

2.0 + 4.2 -5.3 + 1.8

1.2 + 0.8 -1.5 + 2.9

9.3 + 3.7 15.7 + 2.3

1.5 + 0.8

2.6 + 1.3

-17.2 + 2.2 -26.7 + 2.4

-13.2 + 1.7 -24.8 + 2.3

-19.5 + 2.1 -31.2 + 2.7

-12.4 + 1.7 -25.6 + 2.3

98.6 + 3.8 180 or longer

51.2 + 2.9 106.8 + 3.5

98.2 + 6.2 156.1 + 5.7

80.1 + 4.2 145.2 + 4.6

323040Q

As can be seen from Table 1, it is found for each connection been found to have an antihypertensive effect from about 1.5 hours in the shortest case to as long as 3 hours or longer in the is retained for longer cases, whereby the respective value of the dosage, from Z. B. 10 / Ug / kg, is equivalent, and that the change in heartbeat is low. In a separately carried out test to determine the antihypertensive effect on the vertebral artery, it was a long-lasting one vasodilatory effect noted for each compound. In the toxicity test It has also been confirmed that each compound has a low level of toxicity. The derivatives of the invention (I) are therefore useful as medicaments suitable for the treatment of high blood pressure.

The invention is described in more detail in the following examples.

example 1

0.24 g (IGmMoI) sodium hydride suspended in 10 ml dimethyl sulfoxide, and it was then gradually added 1.00 g (10 mmol) of 3-methyl-5-pyrazolone added with stirring at room temperature. After the hydrogen evolution has ended 30 ml of a solution of 5.37 g (10 mmol) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid o-tosyloxyhexyl ester in dimethyl sulfoxide, and the mixture was stirred at room temperature for 2 hours. That obtained reaction mixture was poured into 200 ml of ice water, and the deposited Product was extracted with 100 ml of chloroform. This chloroform solution was washed five times with 50 ml of water, over anhydrous sodium sulfite dried and then concentrated under reduced pressure to obtain a brown oily residual liquid. This sest liquid would by means of silica gel column chromatography using a solvent mixture of benzene and ethyl acetate (in a volume ratio of IeI) purified as the eluent, after which 3.20 g (yield 62.4? Ό) of one light yellow powder of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-iS-methyl ^ -pyrazolyloxyJhexyl ester were obtained.

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1690, 1520, 1340, 1220, 1118

PMR spectrum (CDCl ₃ + D

1.10 - 1.19 (8H, m), 2.20 (3H, s), 2.33 (6H, s), 3.60 (3H, s), 4.00 (4H, t), 5.02 (IH, s), 5.37 (IH, s), 7.00 - 8.10 (4H, m)

Analysis for ^C ₂ 6 ^H 32 ^N 4 ° 7 ^:

Calculated (%) -. C, 60.93 H, 6.29 N, 10.93 Found (%) ι C, 61.13 H, 6.43 N, 10.75

Procedures similar to the above procedure were carried out using the exception that the 2-methyl-5-pyrazolone and the l ^ -dihydro ^ jö-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester have been replaced by the corresponding compounds and also the sodium hydride, depending on the requirements, by other suitable anionizing agents Reagents was replaced to obtain the compounds given in Examples 2-13 below.

Example 2

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) 3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) -1,6-diisopropylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, '1690, 1520, 1340

PMR spectrum (CDCl ₃ ) S :

3.60 (3H, s), 5.10 (IH, s), 5.40 (IH, s)

Analysis for C ₃₂ H ₄₄ N ₄ O ₇ :

Calculated (%): C, 64.41 H, 7.43 N, 9.39 Found (SQ: C, 64.81 H, 7.76 N, 9.05

Example 3

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbanylpyridine-S-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester

;; ' 32304

E.g.

Appearance: light yellow powder

IR spectrum (CHCl,) cm " ¹ :

3490, 3460, 2940, 1690, 1520, 1340, 1220

PMR spectrum (CDCl ₃ + D ₂ O) δ :

1.00-1.90 (8H, m) and 1.20 (6H, d); total 14H, 2.30 (6H, s), 2.55 - 3.00 (IH, m), 3.57 (3H, s), 4.00 (4H, t), 5.01 (IH, a), 5.38 (IH, s), 7.05 - 8.07 (4H, m)

Analysis for C, _D H ,, N.0_:

Calculated (Si): C, 62.21 H, 6.71 N, 10.36 Found (%): C, 62.35 H, 6 82 N, 10.35

Example 4

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - ethoxycarbonylpyridine-S-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3470, 2980, 2940, 1695, 1520

PMR spectrum (CDCl ₃ "+ D ₂ O) 6: 1.07-1.87 (8H, m), 1.22 (3H, t), 2.18 (3H, s), 2.30 (6H , s), 3.80 - 4.23 (6H, m), 5.00 (IH, s), 5.35 (IH, s), 7.15 - 8.07 (4H, m)

Analysis for C ₂₇ H ₃₄ N ₄ O ₇ :

Calculated (%): C, 61.58 H, 6.51 N, 10.64 Found (%) t C, 61.71 H, 6.49 N, 10.49

Example 5

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) -3,4-dimethylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1690, 1520, 1340

PMR spectrum (CDCl ₃ + D ₂ O) δ:

0.65 - 1.95 (21H, m), 2.30 (6H, s), 2.55 - 3.00 (IH, m),

3.80-4.21 (6H, m), 5.09 (IH, s), 5.38 (IH, s), 7.02-8.07 (4H, m)

Analysis for C ₃₁ H, ₂ NO:

Calculated (%); C, 63.90 H, 7.27 N, 9.62 Found (? I): C, 64.27 H, 7.58 N, 9.90

Example 6

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-hexyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :
3490, 3460, 1685, 1340

PMR spectrum (CDCl ₃ + D ₂ O):

0.55-2.00 (22H ₁ Tm), 2.30 (6H, s) and 2.30-2.70 (2H $ total 8H, 3.80-4.23 (OH, m), 5, 10 (IH, s), 5.37 (IH, s) 7.02 - 8.05 (4H, m)

Analysis for ^ ο ^ λ λ ^N 4 ° 7 ^:

Calculated (%): C, 64.41 H, 7.43 N, 9.39 Found (.%) '. C, 64.89 H, 7.22 N, 9.68

Example 7

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - isopropoxycarbonylpyridine-S-, 6- (5-methyl-3-pyrazolyloxy) hexyl carboxylate

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm ":

3490, 3460, 2940, 1520, 1430, 1220

PMR spectrum (CDCl ₃ + D ₂ O):

1.10 (3H, d), 1.25 (3H, d) and 1.00-1.95 (8H, m); total 14H, 2.20 (3H, s), 2.30 (6H, s), 3.97 (4H, t), 4.60-5.05 (IH, m) and 5.00 (IH, s); total 2H, 5.00 (IH, s), 5.37 (IH, s), 7.05 - 8.07 (4H, m)

Analysis for C ₇₉ HI ₆ NO ₇ :

Calculated (? £): C, 62.21 H, 6.71 N, 10.36 Found (Si): C, 62.40 H, 6.92 N, 10.44

Example 8

1,4-Dihydro ~ 2, o-dimethyl-4- (3-nitrophenyl) ^ - isopropoxycarbonylpyridine-S-carboxylic acid 6- (5-octyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 1690, 1520, 1340

PMR spectrum (CDCl ₃ ) O:

0.55-2.03 (29H, m "), 2.30 (6H, s), 2.30-2.70 (2H), 3.70-4.23 (4H, m"), 4.60 - 5.05 (IH, m), 5.10 (IH, a)

Analysis for C ₃₅ H ₅₀ N ₄ O ₇ :

Calculated (A): C, 65.81 H, 7.89 N, 8.77 Found (%): C, 65.98 H, 8.05 N, 8.36

Example 9

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isobutoxycarbonylpyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1340, 1220,

PMR spectrum (CDCl ₃ + D _£ 0) 6 :

0.77 (6H, d), 1.20 (6H, d) and 1.00-2.00 (9H, m); a total of 21H, 2.30 (6H, s), 2.50-3.07 (IH, m), 3.67 (2H, d) and 3.53-4.13 (4H, m); total 6H, 5.03 (IH, s), 5.33 (IH, s), 7.05 - 8.07 (4H, m)

Analysis for C ,, H ₄₂ NO ₇ :

Calculated (£): C, 63.90 H, 7.27 N, 9.62 Found (%): C, 64.35 H, 7.51 N, 9.42

Example 10

1,4-Dihydro-2, o-dimethyl-4- (3-nitrophenyl) 3- (2-methoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1690, 1340

PMR spectrum (CDCl ₃ ) 6:

1.00 - 2.00 (8H, m), 2.20 (3H, s), 2.33 (6H, s), 3.32 (3H, s),

3.50 (2H, t), 3.73-4.34 (6H, m), 5.07 (IH, s), 5.40 (IH, s),

6.93 (IH, s), 7.07 - 8.16 (4H, m), 8.83 (IH, broad)

Analysis for C ₂₈ H ₃₆ N ₄ O ₇ :

Calculated (? "'): C, 60.42 H, 6.52 N, 10.07 Found (%): C, -60.51 H, 6.71 N, 10.26

Example 11

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-isopropoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-octyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

- 26 -

IR spectrum ₃

3490, 3560, 1690, 1520, 1340

PMR spectrum (CDCl ₃ + D ₂ O) δ:

0.57-2.00 (29H, m), 2.30 (6H, s), 2.30-2.70 (2H),

3.20-4.45 (9H, m), 5.10 (IH, a), 5.38 (IH, a), 7.05-8.07 (4H ₁ Mi)

Analysis for ^c x-yrJ4.0 _Q :

Calculated (%) t C, 65.08 H, 7.97 N, 8.21 Found (%): C, 65.49 H, 8.28 N, 8.02

Example 12

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carbon3 acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3455, 1685, 1515, 1345

PMR spectrum (CDCl ₃ + 0 _£ 0) 6 :

1.10 - 2.00 (8H, m), 2.04 - 2.40 (9H), 3.55 (3H, s),

3.76-4.16 (4H), 5.37 (IH, s) 5.07 (IH, s), 6.92-7.70 (4H, m)

Analysis for ^C ₂ 6 ^H 32 ^N 4 ° 7 ^:

Calculated (%): C, 60.93 H, 6.29 N, 10.93 Found (Sa) i C, 60.85 H, 6.43 N, 10.86

Example 13

1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3- (2-isopropoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :
3485, 3460, 1690, 1520

PMR spectrum (CDCl

_{3 2}

1.13 (6H, d) and 0.90-1.95 (8H, m) j total of 14 H, 2.05-2.41 (9H), 3.22-4.48 (9H, m), 5.40 (IH, s) 5.70 (IH, s), 6.93 - 7.70 (4H, m)

Analysis for ^C 30 ^H 40 ^N 4 ° 8 J 6th , 90 N , 9 , 58 Calculated \ 'O)% C, 61 , 63 H, 7th , 06 N , 9 , 89 Found C, 61 , 96 H, 14th example

To 15 ml of a suspension of 0.36 g (15 mmoles) of sodium hydride in N, N-dimethylformamide was gradually added 2.52 g (20 mmoles) of 3-isopropyl-5-pyrazolone with stirring at room temperature, and the mixture became left to stand until the evolution of hydrogen ceased. 15 ml of a solution of 6.01 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-4-4 (3-nitrophenyl) 3-ethoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester were added dropwise to this solution N, N-dimethylformamide was added, and the mixture was stirred at 70 ° C. for 2 hours. The obtained reaction mixture was poured into 200 ml of ice water, the deposited product was extracted with 100 ml of stylacetate, and this ethyl acetate solution was washed twice with 50 ml of water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain an oily residual liquid. This liquid was subjected to column chromatography using silica gel, the impurity-free fractions in the stationary phase were eluted with a mixed solvent of chloroform-methanol (in a volume ratio of 160: 1), and the eluate was dried to dryness under reduced pressure concentrated, whereby 2.55 g (yield 46.0 %) of a pale yellow powder of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carbonic acid-6- (5 -isopropol-3-pyrazolyloxy) hexyl ester.

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3465, 2940, 1690, 1520

PMR spectrum (CDCl ₃ + d ' ₂ O) 6:

1.21 (6H, d), 1.00 - 2.00 (llH, m) j total 17 H,

3230Λ00

2.30 (6H, s), 2.56-3.00 (IH), 3.7-4.27 (6H, m), 5.00 (IH, s), 5.37 (IH, s), 7.00 - 8.07 (4H, m)

Analysis for C 29 H ₃₈ N 4 ° 7 * H, 6th , 91 N, 10 , 10 Calculated {% ): C , 62 , 80 H, 7th , 70 N, 9 , 82 Found (P ): C , 63 , 10

Procedures similar to the above procedure were carried out using the exception that the 3-IsOPrOPyI-S-PyTaZOlOn and the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid-6-tosyloxy- hexyl ester were replaced by the corresponding compounds and also the sodium hydride or other anionizing reagents or the solvent appropriately selected and used to obtain the compounds given in Examples 15-38 below.

Example 15

1,4-Dihydro-2 _> 6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-normalbutyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder IR spectrum (CHCl, cm:

3490, 3460, 2940, 1690, 1525

PMR spectrum

0.68-1.11 (3H), 1.22 (3H, t) and 1.05-2.00 (12H, m); a total of 15H, 2.30 (6H, s), 2.30-2.75 (2H), 3.83-4.21 (6H, m), 5.01 (IH, s), 5.35 (IH, s), 6.80 (IH, s), 7.05 - 8.10 (4H, m), 8.92 (IH, broad)

Analysis for C _3n H ₄₀ N ₄ O ₇ :

Calculated (? = '): C, 63.36 H, 7.09 N, 9.85 Found (%): C, 63.81 H, 7.48 N, 9.71

Example 16

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isopropoxycarbonylpyridine-5-carboxylic acid 6- (5-iaopropyl-3.pyrazolyloxy) hexyl ester

- 29 -

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3465, 2940, 1690, 1520

PMR spectrum (CDCl, + D "0) δ : 0.91-1.86 (2OH, m), 2.30 (6H, s), 2.53-3.13 (IH, m),

3.80-4.17 (4H, m), 4.63-5.10 (IH, m) and 5.00 (IH, s) 5 total 2H,

5.38 (IH, s), 7.13-8.07. (4M)

Analysis for C ₃₀ H _4n N ₄ O ₇ : Calculated (8): C, 63.36 H, 7.09 N, 9.85 Found (SS): C, 63.45 H, 7.28 N, 9, 98

Example 17

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isobutaxycarbqnylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3460, 2970, 2940, 1690, 1340

PMR spectrum (CDCl ₃ + D ₂ O) S : 0.77 (6H, dd), 1.00 - 2.07 (9H, m), 2.12 (3H, s), 2.23 (6H, s), 3.70 (2H, d) and 3.70-4.13 (4H); total 6H, 5.02 (IH, s), 5.32 (IH, s), 7.00 - 8.06 (4M)

Analysis for C ₂₉ H ₃₈ N ₄ O ₇ : Calculated (%); C, 62.80 H, 6.91 N, 10.10 Found (JS): C, 63.15 H, 7.26 N, 10.41

Example 18

1,4-Dihydro-2, o-dimethyl-4- (3-nitrophenyl) ^ - isobutoxycarbonylpyridine-S-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester

- 30 -

3230Α00

Appearance: light yellow powder

IR spectrum ₃

3490, 3465, 2940, 1695, 1520, 1340, 1220, 1120

PMR spectrum (CDCl ₃ + O ₂ O) 6:

0.78 (6H, dd), 1.20 (3H, t) and 1.00-2.09 (9H, m); a total of 12 H, 2.30 (6H, s), 2.53 (2H, q), 3.70 (2H, d) and 3.52-4.14 (4H, m); total 6H, 5.00 (IH, s), 5.30 (IH, s), 7.00 - 8.10 (4H, m),

Analysis for ^c % q ^ aq ^ a ° -7 ^:

Calculated (%) i C, 63.36 H, 7.09 N, 9.85 Found (58): C, 63.54 H, 7.23 N, 9.68

Example 19

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-methoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-normal-butyl-3-pyrazolyloxy) hexyl ester

Appearance; Light yellow powder

IR spectrum (CHCl ₃ ) cm ~:

3495, 3460, 2940, 1690, 1525, 1340, 1220

PMR spectrum (CDCl ₃ * + D ₂ O) & 1

0.67 - 1.08 (3H), 1.08 - 2.00 (12H, m), 2.33 (6H, s) 2.53 (2H, t), 3.30 (3H, s), 3.52 (2H, t), 3.76 - 4.32 (6H, m), 5.07 (IH, s), 5.40 (IH, β), 7.05 - 8.10 (4H, m)

Analysis for C ₃₁ H ₄₂ N ₄ O ₈ :

Calculated (%) ·. C, 62.19 H, 7.07 N, 9.36 Found (a): C, 62.54 H, 7.38 N, 9.02

Example 20

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-methoxyethoxycarbonyl) -pyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1690, 1520, 1340

PMR spectrum (CDCl ₃ + D "O) δ:

0.83-2.00 (8H, m) and 1.23 (6H, d); a total of 14 H, 1.23 (6H, d), 2.33 (6H, s), 2.50-3.13 (IH, m), 3.30 (3H, s), 3.51 (2H, t), 3 .70 - 4.27 (6H, m), 5.07 (IH, s), 5.43 (IH, s), 7.10 - 8.13 (4H, m)

Analysis for C ₃₀ H ₄₀ N ₄ O ₈ :

Calculated (%): C, 61.63 H, 6.90 N, 9.58 Found (? <!): C, 61.99 H, 7.38 N, 9.25

Example 21

1,4-dihydro-2,6 ~ dimethyl-4- (3-nitrophenyl) -3- (2-normalpropoxyethoxyearbonyl) pyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl-8ter

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3495, 3460, 1687, 1458, 1342

PMR spectrum (CDCl ₃ ) ό:

0.86 (3H, t), 1.20 (3H, t) and 1.00-1.90 (1OH, m); total 13 H, '2.30 (6H, s), 2.57 (2H, q), 3.21-3.73 (4H, m), 3.73-4.29 (6H, m),
5.07 (IH, s), 5.40 (IH, s), 6.80 (IH, s)

Analysis for ^C 3i ^H 42 ^N 4 ° 8 ^!

Calculated (Jo): C, 62.19 H, 7.07 N, 9.36 Found (%): C, 62.28 H, 7.16 N, 9.50

Example 22

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-normaöpropoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl 8ter

Appearance: light yellow powder

IR spectrum (CHCl,) cm ":

3490, 3460, 1690, 1460, 1340,

PMR spectrum ₃

0.86 (3H, t), 1.20 (6H, d) and 1.00-1.90 (IDH, m); a total of 16 H, 2.30 (6H, s), 2.55-3.05 (IH, m), 3.20-3.73 (4H, m), 3.73-4.30 (6H, m), 5.05 (IH, s) 6.75 (IH, s)

Analysis for ^ ii ^ kt ^ h ^ B *

Calculated (58) s C, 62.73 H, 7.24 N, 9.14 Found (%) i C, 63.14 H, 7.65 N, 9.38

Example 23

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-isobutoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl-8ter

Appearance light yellow powder

IR spectrum (CHCl ₃ ) cm " ^1. ·

3490, 3460, 3000, 2950, 2860, 1690, 1515

PMR spectrum (CDCl ₃ ) "<J:

0.87 (6H, d), 1.13-2.00 (9H, m), 2.19 (3H, s), 2.33 (6H, s), 3.15 (2H, d), 3 , 36-3.73 (2H), 3.83-4.26 (6H, m), 5.03 (IH, s), 5.36 (IH, s)

Analysis for ^^ ι ^ Αο ^ ύΡη '·

Calculated (5S): C, 62.19 H, 7.07 N, 9.36 Found (»): C, 62.33 H, 7.31 N, 9.55

Example 24

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3- (2-methoxyethoxy carbonyl) pyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) -2.5 -dimethylhexyl ester

- 33 -

ρ # «<t

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3455, 1685, 1515, 1345

PMR spectrum ₃ 0.55-1.95 (12H, m), 2.04-2.41 (9H, 3.32 (3H, s), 3.50 (2H, t), 3.82-4 .20 (6H, m), 5.38 (IH, 3), 5.70 (IH, s)

Analysis for C ₃₀ H ₄₀ N ₄ O ₈ : Calculated (%); C, 61.63 H, 6.90 N, 9.58 Found (5S): C, 61.92 H, 7.34 N, 9.77

example

1,4-Dihydro-2, o-dimethyl-4- (2-nitrophenyl) -3-methoxycarbQnylpyridin-5-carboxylic acid-6- (5-ethyl-3-pyrazolyloxy) -l, 6-dimethylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3455, 1680, 1520, 1345

PMR spectrum (CDCl ₃ ) 6%

0.85 - 1.90 (17H, * ra), 2.23 (3H, s), 2.30 (3H, s) 2.56 (2H, q), 3.57 (3H, s), 5.40 (IH, s), 5.73 (IH, s)

Analysis for CogH-jgNLO ^: Calculated (S): C, 62.80 H, 6.91 N, 10.10 Found (K): C, 62.98 H, 7.05 N, 10.40

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) - ^ - methoxyearbonylpyridine-S-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester

β «β #

32304

Appearance: light yellow powder

IR spectrum (CHCl,) cm ": 3490, 3460, 1685, 1520, 1340

PMR spectrum (CDCl ₃ ) O:

1.00-1.90 (8H, m) and 1.20 (6H, d); inagesamt 14 H, 2.21 (3H, s), 2.27 (3H, s), 2.55-3.00 (IH, m), 3.55 (3H, s), 3.76-4.15 (4H), 5.38 (IH, β), 5.72 (IH, s)

Analysis for £ 28 ^ 36 ^ 4 ^ 7 ^! Calculated (%) -. C, 62.21 H, 6.71 N, 10.36 Found (») t C, 62.60 H, 6.98 N, 10.75

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) -2,5-diisopropylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3460, 1685, 1520, 1345

PMR spectrum (CDCl ₃ > d:

0.57-2.00 (23H, m), 2.04-2.50 (9H), 3.78-4.22 (6H, m), 5.37 (IH, a), 5.70 (IH, 8)

Analysis for CZ ₃ H ^ NO ₇ : Calculated (Ji): C, 64.89 H, 7.59 N, 9.17 Found (Si): C, 65.26 H, 7.95 N, 9.01

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) ^ - isopropoxycarbonylpyridine-S-carboxylic acid 6- (5-normalbutyl-3-pyrazolyloxy) hexyl ester

- 35 -

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm ^-1 : 3490, 3455, 1685, 1345

PMR spectrum (CDCl ₃ ) 6:

2.20 (3H, s), 2.25 (3H, s), 2.30-2.70 (2H), 3.80-4.20 (6H, m), 4.55-5.05 ( IH, m), 5.40 (IH, s), 5.70 (IH, s)

Analysis for ^c xi ^ i, 2 ^ ä ⁰ i ^: Calculated (.%) ·. C, 63.90 H, 7.27 N, 9.62 Found (? O '): C, 63.99 H, 7.46 N, 9.68

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) -1,6-diethylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3485, 1685, 1520

PMR spectrum (CDCl ₃ ) δ: 0.58-1.95 (18H ", m), 2.04-2.40 (9H, m), 3.60 (3H, s), 5.40 (IH , s), 5.70 (IH, s)

Analysis for C ₃₀ H _4n N ₄ O ₇ : Calculated (%): C, 63.36 H, 7.09 N, 9.85 Found (%) -. C, 63.75 H, 7.42 N, 9.98

Example

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxy carbonylpyridine-5-carbonic acid 6- (5-isopropyl-3-pyrazolyloxy) 1,6-dimethylhexyl ester

Appearance: light yellow powder

Ύο

IR spectrum (CHCl ₃ ) cm ":

3490, 3460, 1690, 1520, 1342

PMR spectrum (CDCl ₃ ) (S:

0.65 - 2.00 (23H, m), 2.30 (6H, s), 2.56 - 3.00 (IH, m), 4.00 (2H, t, 5.10 (IH, s), 5.40 / IH, s)

Analysis for C, ·, Hz ^ NLO ₇ :

Calculated {%)>. C, 63.90 H, 7.27 N, 9.62 Found (%): C, 64.35 H, 7.65 N, 9.91

Example 31

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3- (2-methoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm:
3485, 3455, 1685, 1220

PMR spectrum (CDCl ₃ ) ö :

3.32 (3Hs,), 3.50 (2H, t), 3.70-4.32 (6H, m), 5.40 (IH, s), 5.70 (IH, s)

Analysis for ^C 29 ^ 38 ^{| yi} 4 ° 8 ^:

Calculated (K) 1 C, 61.04 H, 6.71 N, 9.82 Found (%): C, 61.35 H, 6.40 N, 9.53

Example 32

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1695, 1520, 1340

- 37 -

11th

PMR spectrum ₃

2.33 (6H, s), 2.56 (2H, q), 3.80-4.25 (6H, m), 5.00 (IH, s), 5.40 (IH, s), 6.71 (IH, 3)

Analysis for ^C 2s ^ 36 ^N 4 ° 7 ^:

Calculated (? »'): C, 62.21 H, 6.71 N, 10.36 Found (? Ί) : C, 62.60 H, 6.33 N, 10.12

Example 33

1,4-Dihydro-2,6-dimethyl ~ 4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-normalbutyl-3-pyrazolyloxy) hexyl 3rd

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 1690, 1520, 1340, 1220

PMR spectrum (CDCl ₃ + D ₂ O) ά ι

0.70-1.10 (3H), 1.10-2.00 (12H, m), 2.30 (6H, s), 2.30-2.70 (2H), 3.57 (3H, s), 3.70-4.17 (4H), 5.00 (IH, s), 5.34 (IH, s), 7.02-8.10 (4H, m)

Analysis for ^C 29 ^H 3r ^N 4 ° 7 ^:

Calculated (%): C ', 62.80 H, 6.91 N, 10.10 Found Oi): C, 62.97 H, 6.76 N, 10.21

Example 34

1,4-Dihydro-2,6-dimethyl'-4- (3-nitrophenyl) ^ - normal propoxycarbonylpyridine-S-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :
3490, 3460, -2940, 1690

323040p

»Bold · *» * »(. W» ι

PMR Spectrum (CDCl ₃ ) δ : 2.30 (6H, s), 2.55 (2H), 3.83-4.22 (6H, m), 5.00 (IH, s), 5.35 (IH, s), 6.64 (IH, s)

Analysis for C ₂₉ H, "NO ₇ : Calculated (SS): C, 62.80 H, 6.91 N, 10.10 Found (S): C, 63.14 H, 6.76 N, 10.41

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-normalpropoxycarbonylpyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3465, 2940, 1690, 1520

PMR spectrum (CDCl ₃ ) 6 χ 2.30 (6H, s), 2.50-3.00 (IH, m), 3.83-4.25 (6H, m), 5.01 (IH, s), 5.40 (IH, s), 6.81 (IH, s)

Analysis for C ₃₀ H ₄₀ N ₄ O ₇ : Calculated (%) -. C, 63.36 H, 7.09 N, 9.85 Found (%) x C, 63.47 H, 7.18 N, 9.68

example

1,4-Dihydro-2, o-dimethyl-4- (2-nitrophenyl) ^ - ethoxycarbonylpyridine-S-carboxylic acid-6- (5-ethyl-3-pyrazolyloxy) hexyl third

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3455, 1685

PMR spectrum (CDCl ₃ ) d ":

- 39 -

2.20 (3Η, β), 2.27 (3H, s), 2.56 (2H, q), 3.80-4.20 (6H, m), 5.40 (IH, s), 5.70 (IH, s)

Analysis for ^C 2h ^H 35 ^N 4 ° 7 ^:

Calculated {%) ·. C, 62.21 H, 6.71 N, 10.36 Found (JS): C, 62.46 H, 6.44 N, 10.75

Example 37

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-octyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm:
3485, 3455, 1690

PMR spectrum (CDCl ₃ ) ό:

0.57-2.00 (23H, m), 2.21 (3H, s), 2.28 (3H, s), 2.30-2.70 (2H), 3.56 (3H, s) , 3.76-4.16 (4H, m), 5.40 (IH, s), 5.70 (IH, s)

Analysis for C ₃₃ H- ^ NO ₇ :

Calculated (%) t C, 64.90 H, 7.59 N, 9.17 Found (%): C, 64.78 H, 7.71 N, 9.36

Example 38

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycaΓbonylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) -5,5-dimethylhexyl ester

Appearance: light yellow powder IR spectrum (CHCl ₃ ) cm:

3490, 3460, 1690, 1520 '-

PMR spectrum (CDCl ₃ ) (T:

0.64 - 1.95 (12H, m), 2.20 (3H, s), 2.30 (6H, s), 3.60 (3H, s),

3.80 - 4.23 (4H, m), 5.10 (4H, m), 5.40 (IH, s)

Analysis for C ₀₀ H- ^ INLO- ,:

Calculated (S): C, 62.21 H, 6.71 N, 10.36 Found (S) ζ C, 62.58 H, 6.99 N, 10.15

Example 39

0.72 g (30 mmol) of sodium hydride was suspended in 60 ml of N, N-dimethylformamide, and then gradually added thereto 5.60 g (50 mmol) of 3-ethyl-5-pyrazolone given with stirring at room temperature, and the mixture was until Left to stand for completion of the evolution of hydrogen. To this solution were dropwise 40 ml of a solution of 4.91 g (10 mmol) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid o, chlorhexyl ester given in N, N-dimethylformamide, the mixture was at 90-100 ° C heated for 3 hours and then allowed to stand at room temperature. After cooling, the reaction mixture was poured into 400 ml of ice water, the obtained extracted product extracted with 100 ml of ethyl acetate and this extraction solution then washed with water, dried and reduced under reduced pressure Pressure concentrated to a brown oily residual liquid. This residual liquid was purified by using silica gel column chromatography using a mixed solvent of chloroform-ethanol (im Volume ratio 20: 1) as the eluent, and there were 1.79 g (yield 34.0? Ό) of a light yellow powder of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3 methoxycarbonylpyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester obtain.

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3465, 2940, 1690, 1520

PMR spectrum (CDCl ₃ + D ₂ O) δ :

1.20 (3H, t), 1.00-1.89 (OH, m); total 11 H, 2.33 (6H, s), 2.56 (2H, q), 3.60 (3H, s), 4.00 (4H, t), 5.05 (IH, s), 5.40 (IH, s), 7.07 - 8.00 (4H, m)

Analysis for C ₂₇ H ₃₄ N ₄ U ₇ :

Calculated (S): C, 61.58 H, 6.5.1 N, 10.64

32304OQ

Found (? Ό): C, 61.74 Η, 6.80 N, 10.42

Procedures similar to the above procedure were carried out using the exception that the 3-ethyl-5-pyrazolone and the 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -I-methoxycarbonylpyridine-i-carboxylic acid o-chlorohexyl ester replaced by the appropriate compounds and also the sodium hydride or other anionizing reagents or the solvent has been appropriately selected and used for the purposes described in the following Examples 40-47 to obtain compounds specified.

Example 40

1,2-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) • ^ -methoxycarbonylpyridine-S-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) -l-methylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3460, 1690, 1520

PMR spectrum (CDCl ₃ ) δ :

0.92 - 1.95 (HH, m), 2.20 (3H, s), 2.27 (6H, s), 3.60 (3H, s), 3.80-4.18 (2H, t), 4.60-5.06 (IH, m), 5.09 (IH, s) 5.38 (IH, s)

Analysis for C ₇₇ H, .NO ₇ : Calculated (? Ό): O, 61.58 H, 6.51 N, 10.64 Found (? Ό): C, 61.71 H, 6.79 N, 10 , 85

Example 41

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) -1-methylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3460, 2940, 1690, 1520

PMR spectrum (CDCl ₃ ) O:

0.95-1.95 (17H, m), 2.30 (6H, s), 2.55-3.00 (IH, m), 3.57 (3H, s), 3.75-4.23 (2H), 4.50-5.16 (IH, m), 5.38 (IH, s), 5.69 (IH, s)

Analysis for CjqH-toN.O- ,: Calculated (? I): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 62.99 H, 7.3D N, 10, 39

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -S-methoxycarbonyl-S-carboxylic acid 6- (5-hexyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3460, 1690, 1340, 1220

PMR spectrum (CDCl ₃ + D "0) 6 ι

0.55-2.00 (19H, m), 2.30 (6H, s), 2.30-2.70 (2H), 3.56 (3H, s), 3.73-4.21 ( 4H), 5.04 (IH, s), 5.38 (IH, s), 7.02 - 8.09 (4H, m)

Analysis for C ₃₁ H ^ ₇ NO ₇ : Calculated (%)% C, 63.90 H, 7.27 N, 9.62 Found (%): C, 63.81 H, 7.48 N, 9.83

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) -5-methylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3490, 3455, 1690

PMR spectrum (CDCl ₃ + D ₂ O) <f:

A *

0.66 - 1.95 (16H, m), 2.21 (3H, s), 2.28 (3H, s), 2.56 (2H, q), 3.83-4.20 (6H, m), 5.40 (IH, s), 5.70 (IH, s), 6.93-7.70 (4H, m)

Analysis for ^C 29 ^H 38 ^N 4 ° 7 ^:

Calculated (? Ί): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 63.20 H, 7.25 N, 10.03

Example 44

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-normalpropoxycarbonylpyridine 5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum CHCl ₃ ) cm " ¹ :

3490, 3465, 2940, 1695, 1520

PMR spectrum ₃

0.90 (3H, t), 1.00-2.00 (1OH, m), 2.18 (3H, s), 2.30 (6H, s), 3.80 - 4.25 (6H, m), 5.00 (IH, s), 5.40 (IH, s)

Analysis for C ₂₈ H ₃ ^ NO ₇ :

Calculated (? Ό): C, 62.21 H, 6.71 N, 10.36 Found (? »'): C, 62.52 H, 6.98 N, 10.21

Example 45

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isopropoxycarbonylpyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3465, 2940, 1695, 1520

PMR spectrum ₃

1.00-2.00 (17H, m), 2.33 (6H, s), 2.56 (2H, q), 3.80-4.15 (4H),

4.60 - 5.00 (IH, m), 5.03 (IH, s), 5.40 (IH, s), 6.30 (IH, β)

Analysis for ^ '"Se'W

Calculated (%) ι C, 62.80 H, 6.91 N, 10.10 Found (SS): C, 62.98 H, 7.05 N, 10.45

example

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-methoxyethoxycarbonyl) pyri din-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3490, 3460, 2940, 1690, 1340

PMR spectrum (CDCl ₃ ) ό :

1.20 (3H, t), 1.00-2.00 (8H, m), 2.30 (6H, s), 2.56 (2H, q), 3.30 (3H, s), 3 , 50 (2H, t), 3.73-4.25 (6H, m), 5.04 (IH, s), 5.40 (IH, s), 6.80 (IH, s)

Analysis for ^C ₂ 9 ^H 38 ^N 4 ° 8 ^:

Calculated (S): C, 61.04 H, 6.71 N, 9.82 Found (5S): C, 61.43 H, 6.98 N, 9.61

example

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-isopropoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3495, 3460, 1690, 1520, 1455

PMR spectrum (.C ₃

1.13 (6H, d), 0.83 - 2.00 (8H, m), 2.18 (3H, s), 2.30 (6H, s),

3.23 - 4.50 (9H, m), 5.09 (IH, s), 5.37 (IH, s)

Analysis for C- ^ _n H. _n N ₄ 0 _R :

Calculated Oi) : C, 61.63 H, 6.90 N, 9.58 Found (%): C, 61.85 H, 6.77 N, 9.61

Example 48

To 15 ml of a suspension of 0.36 g (15 mmol) of sodium hydride in N, N-dimethylformamide, 2.00 g (20 mmol) of 3-methyl-5-pyrazolone was gradually added with stirring at room temperature, and the mixture was added Left to stand until the evolution of hydrogen ceases. A solution of 5.87 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester dissolved in was added dropwise to this solution 15 ml of N, N-dimethylformamide are added. After the addition was complete, the mixture was stirred at 100 ° C. for one hour, then the reaction mixture was poured into 200 ml of ice water and extracted with 100 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried and then concentrated under reduced pressure before the product was subjected to silica gel column chromatography. The substances adsorbed on the stationary phase were checked by thin layer chromatography and carefully eluted using a mixed solvent of benzene-ethyl acetate (in a volume ratio of 1: 1), whereby two kinds of eluted fractions were obtained, each containing a single substance, which of the other was different. The first eluted fraction was concentrated to dryness under reduced pressure to give 2.95 g (57.5 % yield) of a light yellow powder of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3 -methoxycarbonylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester.

Analysis for ^C ₂ 6 ^H 32 ^N 4 ° 7 ^:

Calculated (%): C, 60.93 H, 6.29 N, 10.93 Found (? <Q: C, 61.20 H, 6.41 N, 10.69

Both the IR spectrum and the PMR spectrum agreed with the spectra obtained in Example 1.

230400

Thereafter, the fraction eluted later was concentrated to dryness under reduced pressure, and 0.49 g (yield 7.8 %) of a light yellow oil, which was obtained from 1,4-dihydro-2,6 ~ dimethyl-4- ( 3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (3-hydroxy-5-methyl-1-pyrazolyl) ethyl ester.

IR spectrum (CHCl ₃ ) cm ":

3460, 2490, 1690, 1520, 1340, 1220

PMR spectrum (CDCl ₃ + D ₂ O) O:

1.00-1.90 (8H, m), 2.13 (3H, s), 3.60 (3H, s), 3.73 (2H, t), 3.96 (2H, t), 5 .00 (IH, s), 5.17 (IH, s), 7.00 - 8.10 (4H, m)

Analysis for ( '26 3 -2 C. 4 7 ^: 6.29 N, 10 , 93 Calculated (S): C. , 60.93 H, 6.42 N, 10 , 73 Found (Ä): , 61.18 H, 49 example

4.98 g (20 mmoles) of methyl 3-nitrobenzylidene acetoacetate, 6.86 g (20 mmol) 3- aminocrotonic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester and 7 ml Ethanol were mixed and refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure to give a yellow oily Residue was obtained. This oily residue was deposited on a silica gel column using a solvent mixture of chloroform-ethanol (in a volume ratio of 160: 1) was chromatographed as the eluent, and the eluate fractions containing the desired compound were under concentrated under reduced pressure to a yellow oil, to which 10 ml of ethanol were added and the mixture was allowed to stand overnight, during which time yellow crystals separated out. These crystals were filtered off and recrystallized from ethanol, and there were 7.35 g (yield 64.0? ό) of pale yellow crystals of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester obtain.

F .: 151-153 ° C

* ft

IR spectrum (CHCl ₃ ) cm " ¹ :

350G, 3460, 1695, 1520, 1345

PMR spectrum ₃

0.95-1.90 (8H, m), 2.31 (6H, s), 3.59 (3H, s), 3.80-4.23 (4H, m), 5.05 (IH, s), 5.89 (IH, a), 6.78 (lH, s), 7.03 - 8.25 (1OH, m)

Example 50

4.98 g (20 mmoles = 3-nitrobenzylideneacetoacetic acid methyl ester, 7.23 g (20 mmoles) of 3- amine-crotonic acid 6- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester and 10 ml of isopropanol were mixed and refluxed for 3 hours This reaction mixture was concentrated under reduced pressure to a yellow oily residue, and this oil was purified by chromatography on a silica gel column using a mixed solvent of benzene-ethyl acetate (3: 1 by volume) as an eluent to obtain eluate fractions which contained the desired compound, which was concentrated to dryness under reduced pressure, and there were 6.52 g (yield 55.0 %) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methaxycarbonylpyridine ^ -carboxylic acid-ö- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester was obtained as a light yellow powder.

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1693, 1520, 1345

PMR spectrum (CDCl ₃ + 0 _£ 0) 6:

1.00-1.90 (8H, m), 2.33 (6H, s), 3.57 (3H, s), 3.76-4.21 (4H, m), 5.04 (IH, s), 5.87 (IH, s), 7.00 - 8.10 (8H, m)

Analysis for C. 31 33 NO
A. 7 ^: H , 5 , 61 N , 9 , 45 Calculated ( Si): C , 62 , 83 H , 5 , 83 N , 9 , 26 Found ( Ä): C , 62 , 91

The compounds in Examples 51-95 below were prepared according to corresponding Process steps were prepared as in Example 50 above except that the starting materials required for the reaction solvents used and other conditions in a suitable manner

se were changed.

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 198 - 201 ° C (from toluene) IR spectrum (KBr) cm " ¹ :

3320, 2950, 1690, 1520, 1350, 1210

PMR spectrum (DMS0-d ₆ ) S ι

0.90-1.90 (8H, m), 2.23 (3H, s), 2.29 (3H, s), 3.42 (3H, s), 3.89 (2H, t), 4 .00 (2H, t), 5.53 (IH, s), 6.04 (IH, s), 6.96-7.82 (9H, m), 8.84 (IH, s)

Analysis for ^ i ^ aNaUV

Calculated (K): C, 64.80 H, 5.96 N, 9.75 Found (S): C, 64.67 H, 6.09 N, 9.59

Example

I ι ι.

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid-6- (5-phenyl-3-pyrazplyloxy) -1,6-dimethylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3465, 1693, 1522, 1345

PMR spectrum (CDCl ₃ ) Ci:

0.81 - 2.00 (14H, m), 2.30 (6H, s), 3.56 (3H, s), 5.04 (IH, s), 5.89 (IH, s>, 6.89 (IH, s)

Analysis for C ₃₃ H ₃₈ N ₄ U ₇ :

Calculated (S): C, 65.77 H, 6.36 N,?, 30 Found (A): C, 65.83 H, 6.70 N, 9.13

Example 53

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-car 6- (5-phenyl-3-pyrazolyloxy) -6-isopropylhexyl ester

Appearance: light yellow oil

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1690, 1520, 1345

PMR spectrum ₃

2.28 (6H, s, 2,6-dimethyl group on the dihydropyridine ring), 3.56 (3H, s, ethyl ester), 3.97 (2H, t), 5.06 (IH, s), 5.89 (IH, s), 6.85 (IH, broad)

Analysis for C ₃₄ H ₄₀ N ₄ O ₇ :

Calculated («): C, 66.22 H, 6.54 N, 9.08 Found {%) '. C, 66.50 H, 6.73 N, 8.88

Example 54

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) ^ - ethoxycarbonylpyridine-S-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3465, 1695, 1522, 1350

PMR spectrum (DMSO-d ₆ ) (5:

0.95-1.90 (HH, mj, 2.22 (3H, s), 2.28 (3H, s), 3.71-4.23 (6H, m), 5.52 (IH, s), 6.04 (IH, s)

Analysis for C ₃₂ H ₃ -N ₄ O ₇ :

Calculated (%) ι C, 65.29 H, 6.16 N, 9.52 Found (, ⁰ O: C, 65.49 H, 6.03 N., 9.37

Example 55

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - isopropoxycarbonylpyridine-S-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 157 - 160 ° C (from toluene) IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1693, 1520, 1345

PMR spectrum (CDCl ₃ ) 6 :

0.95-1.90 (14H, m), 2.32 (6H, s), 3.76-4.23 (4H, m), 4.61, 5.07 (IH, m), 5.05 (IH, s), 5.89 (IH, s), 6.80 (IH, broad)

Analysis for ^ χ ^ χ <ββη ^χ

Calculated (%) ·. C, 65.77 H, 6.36 N, 9.30 Found (H) t C, 65.55 H, 6.42 N, 9.60

Example 56

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-methoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 161 - 164 ° C (from ethanol) IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ + DMSO-d ₆ ) c5:

1.00-1.87 (8H, m), 2.31 (6H, s), 3.27 (3H, s), 3.31-3.67 (2H, m), 3.73-4.28 (6H, m), 5.04 (IH, a), 5.86 (IH, s), 7.00-8.07 (9H, m)

Analysis for ^c yj ^ _e \ ⁰ Q ''

Calculated (JK) s C, 64.07 W, 6.19 N, 9.06 Found (JB): C, 64.20 H, 6.27 N, 8.89

Example 57

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (4-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum ₃

0.96 - 1.97 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.68 - 4.20 (4H, m), 5.04 (IH, s), 6.80 (IH, broad), 7.00 - 8.10 (9H, m)

Analysis for C ₃₁ H ₃ -N ^ O ₇ :

Calculated (? "'): C, 64.80 H, 5.96 N, 9.75 Found (58): C, 64.93 H, 6.20 N, 9.66

Example 58

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 5- (5-o-chlorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: yellow crystals

F .: 159 - 161 ° C (from ethanol)

IR spectrum (KBr) cm " ¹ :

3360, 1700, 1520, 1340, 1207

PMR spectrum (DMS0-d ₆ ) J:

1.00-1.90 (8H, m), 2.29 (6H, s), 3.53 (3H, s), 3.97 (2H, t), 4.05 (2H, t), 4.99 (IH, s), 6.00 (IH, s,), 7.10 - 8.05 (8H, m), 8.93 (IH, s)

Analysis for C ₃₁ H ₃₃ ClN ₄ O ₇ :

Calculated (%) t C, 61.13 H, 5.46 N, 9.20 Found (SA): C, 61.38 H, 5.61 N, 8.92

Example 59

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) O-methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-chlorophenyl-3-pyrazolyloxy) hexyl ether

Appearance: light yellow crystals F .: 189 - 192 ° C (from ethanol)

IR spectrum (KBr) cm " ¹ :

3450, 1685, 1522, 1350, 1210

PMR spectrum

0.93-1.86 (8H, m), 2.23 (3H, s), 2.30 (3H, s), 3.43 (3H, s), 3.90 (2H, t), 4 .00 (2H, t), 5.55 (IH, s), 6.07 (lH, s), 7.13 - 7.77 (8H, m), 8.83 (IH, broad)

Analysis for C ₃₁ H ₃₃ ClN-O ₇ :

Calculated (%): C, 61.13 H, 5.46 N, 9.20 Found (%): C, 61.21 H, 5.70 N, 8.89

Example 60

1,4 ~ Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid-6- (5-m-chlorophenyl-3-pyrazolyloxy) hexyl-8ter

Appearance: light yellow crystals F .: 147 - 149 ° C (from ethanol)

IR spectrum (KBr) cm " ¹ :

3377, 2950, 1700, 1515, 1340

PMR spectrum (DMS0-d ₆ ) d:

0.93-1.86 (8H, m), 2.30 (6H, s), 3.51 (3H, a), 3.67-4.17 (4H, m), 4.95 (IH, s), 6.11 (IH, s), 7.00 - 7.99 (8H, m)

Analysis for C ₃₁ H ₃₃ ClN Q:

Calculated (%): C, 61.13 H, 5.46 N, 9.20 Found (? Ό): C, 61.47 H, 5.60 N, 9.02

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-p-chlorophenyl-3-pyrazolyloxy) -l-methylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1692, 1520, 1345

PMR spectrum ^

0.87-1.96 (14H, m), 2.31 (6H, s), 3.72-4.20 (4H, m), 4.53-5.06 (2H, m), 6, 07 (IH, s), 7.05 - 8.06 (8H, m), 8.94 (IH, s)

Analysis for C ₃₃ H ₃₇ ClN-O ₇ :

Calculated (? I): C, 62.21 H, 5.85 N, 8.79 Found (%) i C, 62.37 H, 6.00 N, 8.63

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-chlorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 192 - 194 ° C (from benzene)

IR spectrum (KBr) cm ":

3310, 1690, 1675, 1525, 1350, 1215

PMR spectrum ₆

0.95 - 2.00 (8H, m), 2.22 (3H, s), 2.29 (3H, s), 3.43 (3H, s), 3.90 (2H, s), 4.00 (2H, t), 5.53 (IH, s), 6.09 (IH, s), 7.06, 7.86 (8H, m), 8.83 (IH, s), 12.20 (IH, s)

Analysis for C ₃₁ H ₃₃₄₇

Calculated (%); C, 61.13 H, 5.46 N, 9.20 Found (%): C, 61.25 H, 5.70 N, 9.23

Example 63

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (2,6-dichlorophenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3465, 1695, 1522, 1345

PMR spectrum g

0.97 - 1.90 (8H, m), 2.27 (6H, s), 3.54 (3H, s), 4.99 (IH, s), 6.03 (IH, s), 7 ^ 00 - 8.05 (7H, m)

Analysis for C ₃₁ H ₃₂ Cl ₂ N ₄ O ₇ :

Calculated (? I): C, 57.86 H, 5.01 N, 8.71 Found (%) t C, 57.64 H, 5.29 N, 8.63

Example 64

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) ^ - isapropoxycarbonylpyridine-S-carboxylic acid 6- (5-o-chlorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3465, 1695, 1520, 1345

PMR spectrum (DMSO-dJ ό :

0.95 - 1.90 (14H, m), 3.80 - 4.21 (4H, m), 4.57 - 5.05 (lH, m),
5.51 (IH, s), 6.00 (IH, s), 7.00 - 8.03 (8H, m)

Analysis for C ₃₃ H ₃₇ ClN-O ₇ :

Calculated (JS): C, 62.21 H, 5.85 N, 8.79 Found (5S): C, 62.07 H, 5.92 N, 8.59

example

1,4-Dihydro-2, o-dimethyl-4- (3-nitrophenyl) -3-normalpropoxycarbonylpyridine-5-carboxylic acid 6-5- (2,4-dichlorophenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder IR spectrum (CHCl ₃ ) cm ":

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) 6 :

1.02-2.00 (1OH, m), 2.31 (6H, s), 3.78-4.23 (6H, m), 5.05 (IH, s), 6.01 (IH, s)

Analysis for C ₃₃ H ₃₆ Cl ₂ NO ₇ :

Calculated (? "'): C, 59.02 H, 5.40 N, 8.34 Found (%) i C, 58.71 H, 5.22 N, 8.50

example

1, 4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyΓidin-5-carboxylic acid 6-5- (3,4-dichlorophenyl) -3-hexyl pyrazolyloxy

Appearance: light yellow powder IR spectrum (CHCl ₃ ):

3500, 3463, 1695, 1520, 1345

PMR spectrum ₃

0.95-1.90 (8H, m), 2.22 (3H, s), 2.28 (3H, s), 3.53 (3H, s), 3.80-4.23 (4H, m), 5.67 (IH, s)

Analysis for C ₃₁ H ₃₂ Cl ₂ N ₄ O ₇ :

Calculated (%): C, 57.06 H, 5.01 N, 8.71 Found (? Ί): C, 57.69 H, 5.08 N, 8.54

Example 67

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-methoxyphenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 154 - 156 ° C (from ethanol) IR spectrum (CHCl ₃ ) cm " ¹ :

3380, 2950, 1690, 1520, 1345

PMR spectrum (DMS0-d ₆ ) o:

0.90-1.88 (8H, m), 2.30 (6H, s), 3.53 (3H, s), 3.86 (3H, s), 3.38 4.17 (4H, m), 4.95 (IH, a), 6.03 (IH, s), 6.73 - 8.00 (8H, m), 8.80 (IH, wide)

Analysis for C ₃₂ H ₃ ^ N.0 ":

Calculated (%): C, 63.56 H, 6.00 N, 9.27 Found (? Ü): C, 63.70 H, 6.27 N, 9.11

Example 68

1,4-Dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-methoxyphenyl-3-pyrazolyloxy) hexyl ester

Appearance: white powder

- ¥ ί - VA

IR spectrum (CHCl ₃ ) cm " ¹ : 3500, 3467, 1690, 1460,

PMR spectrum (DMSO-dJ ό :

0.85-1.90 (8H, m), 2.24 (6H, s), 3.48 (3H, s), 3.67-4.26 (4H, m), 3.87 (3H, s), 5.30 (IH, s), 6.03 (IH, s), 6.73 - 8.05 (7H, m), 8.73 (IH, s),

Analysis for C ₃₂ H ₃₅ Cl ₂ N ₃ O .: Calculated (JS): C, 61.15 H, 5.61 N, 6.69 Found (SS): C, 61.18 H, 5.87 N, 6.54

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-normalpropoxyethoxycarbonylpyridine-5-carboxylic acid 6- (5-o-methoxyphenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3500, 3460, 1690, 1520, 1345

PMR spectrum (CDCl ₃ + DMS0-d ₆ ) cS:

0.89 (3H, t), 1.00-2.00 (10H, m), 2.30 (6H, s), 3.18-3.75 (4H, m), 3.75-4.25 (6H, m), 3.87 (3H, s), 5.04 (IH, s), 5.95 (IH, s), 6.70, 8.17 (8H, m)

Analysis for C ₃₆ H ₄ ^ N ₄ O ₉ : Calculated (%): C, 63.89 H, 6.55 N, 8.28 Found (.%): C, 63.98 H, 6.32 N, 8.41

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-caΓ-boric acid 6- (5-m-methoxyphenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1690, 1520, 1345

PMR spectrum ₆

0.95 - 1.90 (βΗ, ιη), 2.21 (3H, s), 2.28 (3H, s), 3.43 (3H, s),

3.75-4.23 (4H, m), 3.82 (3H, s), 5.51 (IH, s), 5.96 (IH, s),

6.70 - 8.07 (8H, m)

Analysis for ^ -xo ^ I ^ aPb *

Calculated (S): C, 63.56 H, 6.00 N, 9.27 Found (S): C, 63.48 H, 5.92 N, 9.40

Example 71

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isopropoxycarbonylpyridine 5-carboxylic acid 6- (5-p-methoxyphenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum ₆

1.06 (3H, d), 1.20 (3H, d) and 0.95-1.90 (8H, m); total 14H, 2.31 (6H, s), 3 *, 72 (3H, s), 3.73-4.21 (4H, m), 4.58-5.03 (IH, m), 5, 02 / IH, s), 5.97 (IH, s), 6.9 ^ (2H, d), 7.23 - 8.03 (6H, m), 8.91 (IH, s), 12, 05 (IH, s)

Analysis for C ₃₄ H ₄₀ N ₄ O ₃ :

Calculated (S): 'C, 64.54 H, 6.37 N, 8.86 Found (S): C, 64.63 H, 6.04 N, 8.56

Example 72

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (2,3-dimethoxyphenyl) -3-pyrazolyloxy hexyl ester

• ι »*

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1693, 1522, 1345

PMR spectrum (CDCl ₃ ) 6 :

0.95-2.00 (8H, m), 2.28 (6H, s), 3.59 (3H, s), 3.85 (6H, s), 3.70 4.26 (4H, m ), 5.03 (IH, s), 5.93 (IH, s), 6.30 (IH, s), 6.65-8.13
(7H, ra)

Analysis for ^C 33 ^H 3g ^N 4 ° g ^:

Calculated (5S) 1 C, 62.45 H, 6.04 N, 8.83 Found (SS): C, 62.53 H, 6.27 N, 8.55

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (3,4-dimethoxyphenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) 6:

0.96-1.90 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.70-4.21 (4H, m),, 3.88 (6H, s), 5.05 (IH, s), 5.85 (IH, s)

Analysis for ^c x ^ q ^ a ⁰ ^ '·

Calculated (%): C, 62.45 H, 6.04 N, 8.83 Found (8): C, 62.54 H, 6.18 N, 8.62

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6-5- (3,4-methylenedioxyphenyl) -3-pyrazolyloxy hexyl ester

ti «

4. U *

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm:

3600, 3465, 1695, 1520, 1345

PMR spectrum (DMSO-dg) J ^- :

0.89 - 1.90 (BH, m), 1.16 (3H, t), 2.28 (6H, s), 3.73 - 4.23 (6H, m), 4.97 (IH, s), 5.95 (3H, s), 6.74 - 8.04 (7H, m), 8.97 (IH, broad), 11.90 (IH, wide)

Analysis for ^c ^^ a ° q ^:

Calculated (%): C, 62.65 H, 5.74 N, 8.86 Found (? »'): C, 62.79 H, 5.81 N, 8.59

Example 75

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (3,4,5-trimethoxyphenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm:

3500, 3460, 1692, 1521, 1345

PMR spectrum (CDCl ₃ M:

1.00-1.95 (8H, m), 2.33 (6H, s), 3.61 (3H, s), 3.71-4.22 (4H, m), 3.79 (3H, s), 3.81 (6H, s), 5.03 (IH, s), 5.83 (IH, s), 6.50 (IH, s), 6.75 (2H, s), 7.10 - 8.13 (4H, m)

Analysis for C ₃₄ H ₄₀ N ₄ O ₁₀ :

Calculated (? Ί) ι C, 61.44 H, 6.07 N, 8.43 Found (%) i C, 61.21 H, 6.00 N, 8.56

Example 76

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -J-methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-nitrophenyl-3-pyrazolyloxy) -3,4-dimethylhexyl ester

Appearance: light yellow powder

IR Spectrum Fl (CHCl ₃ ) cm " ¹ :

3500, 3460, 1693, 1520, 1345

PMR spectrum (DMSO-dJd:

2.28 (6H, s), 3.53 (3H, s), 3.75-4.21 (4H, m), 5.01 (IH, s)

Analysis for ^ 3 ¹ SyN ₅ ⁰ O ^:

Calculated (Jo '): C, 61.20 H, 5.76 N, 10.81 Found (%): C, 61.53 H, 5.77 N, 10.60

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -J-methoxycarbonylpyridine-S-carboxylic acid 6- (5-m-nitrophenyl-3-pyrazolyloxy) hexyiester

Appearance: yellow crystals F .: 96 - 99 ° C (from ethanol)

IR spectrum (KBr) cm " ¹ :

3440, 1690, 1520, 1342, 1210

PMR spectrum (DMS0-d ₆ ) d:

1.00-1.90 (8H, m), 2.26 (6H, s), 3.56 (3H, s), 3.70-4.22 (4H, m), 4.97 (IH, s), 6.27 (IH, s), 7.25 - 8.52 (8H, m), 8.78 (IH, s)

Analysis for £ 31 ^H 33 ^N 5 ° ₉ ^:

Calculated (%) i C, 60.09 H, 5.37 N, 11.30 Found (%): C, 60.03 H, 5.48 N, 11.11

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isopropoxycarbonylpyridine-5-carboxylic acid 6- (5-m-nitrophenyl-3-pyrazolyloxy) hexyl ester

Appearance: yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3463, 2950, 1696, 1520

PMR spectrum (DMSO-d,) «i:

1.07 (d), 1.22 (d) and 0.90 - 1.95 (m); total 14H, 2.31 (6H, s), 3.75-4.23 (4H, m), 4.55-5.05 (IH, m), 4.99 (IH, s), 6.27 (IH, s), 7.25 - 8.50 (8H, m)

Analysis for C ₃₃ H ₃₇ N ₅ O ₉ :

Calculated (SS): C, 61.20 H, 5.76 N, 10.81 Found (SS): C, 61.26 H, 5.97 N, 10.63

example

1,4-Dihydro ~ 2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-fluorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow glassy solid substance

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) O:

1.00-1.90 (8H, m), 2.30 (6H, s), 3.57 (3H, s), 3.73-4.21 (4H, m), 5.05 (IH, s), 5.86 (IH, s)

Analysis for C ₃₁ H ₃₃ FN ₄ O ₇ :

Calculated (5S): C, 62.83 H, 5.61 N, 9.45 Found (%): C, 62.94 H, 5.56 N, 9.62

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - isobutoxycarbonylpyridine-S-carboxylic acid 6- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ )

3500, 3460, 1695, 1520, 1345

PMR spectrum ₃

0.80 (6H, dd), 1.00 - 2.05 (9H, m), 2.28 (6H, s), 3.76 (2H, d), 3.74-4.22 (4H, m), 5.03 (IH, s), 5.85 (IH, s), 6.30 (IH, s), 7.00 - 8.13 (8H, m)

Analysis for C ₃₄ H ₃₉ FN ₄ O ₇ :

Calculated (? O: C, 64.34 H, 6.19 N, 8.83 Found (? Ί): C, 64.08 H, 6.24 N, 8.99

Example 81

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-isobutoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) ό :

0.87 (6H, d), 1.05-2.07 (9H, m), 2.28 (6H, s), 3.13 (2H, d), 3.35-3.71 (2H) , 3.77-4.24 (6H, m), 5.03 (IH, s), 5.88 (IH, s), 7.02 - 8.13 (8H, m)

Analysis for ^C 36 ^H 43 ^FN 4 ° q ^:

Calculates {%) '. C, 63.70 H, 6.39 N, 8.25 Found {%) -. C, 63.88 H, 6.62 N, 8.10

Example 82

1,4-Dihydro-2,6-di'methyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-fluorophenyl-3-pyrazolyloxy) hexyl ester

- 6 "

Appearance: light yellow powder IR spectrum (CHCl,) cm ":

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl, + D ₂ O) J:

1.00-1.90 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.73-4.21 (4H, m), 5.03 (IH, s), 6.90 - 8.10 (8H, m)

Analysis for ^] H ₃₃ FN ₄ O ₇ :

Calculated (Sa): C, 62.83 H, 5.61 N, 9.45 Found (Sa): C, 62.92 H, 5.48 N, 9.46

Example 83

1,4-Dihydro-2,6-dimethy1-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-totyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 135 - 137 C (from isopropanol)

IR spectrum (KBr) cm " ¹ )

3360, 2950, 1702, 1520, 1342, 1210

PMR spectrum (DMS0-d ₆ ) o:

1.00 - 1.91 (8H, m), 2.31 (6H, s), 2.35 (3H, s), 3.53 (3H, s), 3.78, 4.22 (4H, m), 4.99 (IH, s), 5.87 (IH, s), 7.00 - 8.05 (8H, m)

Analysis for ^C ₃ 2 ^H 36 ^N 4 ° 7 ^:

Calculated (%): C, 65.29 H, 6.16 N, 9.52 Found (Sa): C, 65.38 H, 6.31 N, 9.27

Example 84

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-isopropoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-o-tolyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) O:

0.94-1.90 (OH, m) and 1.13 (6H, d); total 14H, 2.30 (6H, s), 2.34 (3H, s), 3.21-4.31 (9H, m), 5.04 (IH, s), 5.72 (IH, s), 6.48 (IH, s), 7.05-8.05 (ΒΗ, β), 5.72 (IH, s) 6.48 (IH, s), 7.05-8.05 (8H, m)

Analysis for C ₃₆ H ₄₄ N ₄ O ₃ :

Calculated (JK): C, 65.44 H, 6.71 N, 8.48 Found (»): C, 65.60 H, 6.85 N / 8.31

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-o-tolyl-3-pyrazolyloxy) hexyl-8ter

Appearance: yellow powder

IR spectrum (CHCl ₃ ) cm ": 3500, 3460, 1693, 1522, 1345

PMR spectrum (DMS0-d ₆ ) d:

0.96-1.97 (8H, m), 2.22 (3H, s), 2.29 (3H, s), 2.35 (3H, s), 3.45 (3H, s), 3 , 74-4.22 (4H, m), 5.51 (IH, s), 5.85 (IH, s), 6.96-8.10 (8H, m), 8.90 (IH, broad )

Analysis for C ₃₂ H ₃ ZN ₄ O ₇ : Calculated (%): C, 65.29 H, 6.16 N, 9.52 Found (£): C, 65.03 H, 6.31 N, 9, 49

Example 86
1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) ^ - methoxycarbonylpyridine-S-car-

6- (5-o-cyanophenyl-3-pyrazolyloxy) hexyl ester Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 2230, 1696, 1520, 1345

PMR spectrum (DMS0-d ₆ ) d:

0.96-1.90 (8H, m), 2.20 (3H, s), 2.27 (3H, s), 3.43 (3H, s), 3.75-4.22 (4H, m), 5.52 (IH, s)

> w analysis for C-z ^ H-j-zNcO- ,:

Calculated (? <!): C, 64.10 H, 5.55 N, 11.68 Found (%): C, 63.88 H, 5.67 N, 11.83

Example 87

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-m-cyanophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 2227, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) & :

1.00 - 1.95 (BH, m), 2.30 (6H, s), 3.57 (3H, s), 3.75 - 4.22 (4H, m), 5.06 (IH, β), 6.12 (IH, s)

Analysis for C, "H -, -, N, -O ₇ :

Calculated (%): C, 64.10 H, 5.55 N, 11.68 Found (S): C, 63.87 H, 5.71 N, 11.49

Example 88

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-p -cyanophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum CCHCl ₃ ) cm " ¹ :

3500, 3460, 2230, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) <3:

1.00-1.92 (8H, m), 2.30 (6H, s), 3.57 (3H, s), 3.75-4.21 (4H, m), 5.03 (IH, s), 5.82 (IH, s), 6.10 (IH, s), 7.07 - 8.10 (8H, m)

Analysis for C ₃₂ H ₃₃ N ₅ O ₇ :

Calculated (JS): C, 64.10 H, 5.55 N, 11.68 Found (%): C, 63.94 H, 5.80 N, 11.57

Example 89

1,4-dihydro-2, o-dimethyl-4- (2-nitrophenyl) -O-methoxycarbonylpyridine-S-car 6- 5- (o-trifluoromethylphenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1696, 1520, 1345

PMR spectrum ₃

0.96-1.90 (8H, m), 2.30 (6H, s), 3.55 (3H, s), 3.76-4.27 (4H, m), 5.73 (IH, s)

Analysis for C ₃₂ H ₃₃ F ₃ N ₄ O ₇ :

Calculated (? I): C, 59.81 H, 5.18 N, 8.72 Found (5S) ί C, 59.80 H, 5.34 N, 8.60

Example 90

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6-5- (m-trifluoromethylphenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ):

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ ) J:

0.93-1.90 (8H, m), 2.31 (6H, s), 3.56 (3H, s), 3.75-4.28 (4H, m), 5.75 (IH, 8),

Analysis for C ₃₂ H ₃₃ F-JISLO ₇ :

Calculated (5S): C, 59, BI H, 5.18 N, 8.72 Found (K): C, 59.79 H, 5.32 N, 8.47

example

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-car Bone acid-o-5-2-pyridyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum ₃

0.97 - 2.00 (BH, m), 2.30 (6H, s), 3.57 (3H, s), 3.73 - 4.22 (4H, m), 5.03 (IH, s), 6.01 (IH, s)

Analysis for ^C 3n ^H 33 ^N 5 ° 7 ^:

Calculated (Si): C, 62.60 H, 5.78 N, 12.17 Found (Ji): C, 62.26 H, 5.83 N, 12.36

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6-5- (3-pyridyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1694, 1520, 1345

PMR spectrum (CDCl ₃ ) 6 ι

1.00 - 2.00 (BH, m), 2.30 (6H, s), 3.58 (3H, s), 3.78 - 4.32 (4H, m),

5.03 (lH, s), 5.90 (lH, s), 7.00 - 8.10 (8H, m), 8.17 - 8.53 (IH, m), 8.75 (IH, s)

Analysis for C ₃ QH ^ NLO ₇ :

Calculated (? Ό): C, 62.60 H, 5.78 N, 12.17 Found (%) i C, 62.71 H, 5.80 N, 12.32

Example 93

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (4-pyridyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow crystals F .: 165 - 168 ° C (from ethanol)

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3465, 1695, 1523, 1345

PMR spectrum (DMSO-d ₆ ) c5:

1.00 - 1.92 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.77 - 4.24 (4H, m),

5.01 (IH, s), 6.36 (IH, s), 7.05-8.15 (6H, m), 8.48-8.74 (2H, m).

Analysis for C ₃₀ H ₃₃ N ₅ O ₇ :

Calculated (%): C, 62.60 H, 5.78 N, 12.17 Found (B): C, 62.57 H, 5.99 N, 12.25

Example 94

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-benzyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow oil

IR spectrum (CHCl,) cm:

3500, 3460, 1693, 1520, 1345

PMR spectrum (CDCl ₃ M:

0.97-2.00 (8H, m), 2.31 (6H, s), 3.56 (3H, s), 3.85 (2H, s), 3.74 4.21 (4H, m), 5.08 (IH, s), 5.42 (IH, s), 6.62 (IH, s), 7.00-8.40 (1OH, m)

Analysis for C ^ H ^ NaO ^:

Calculated (%): C, 65.29 H, 6.16 N, 9.52 Found (Si): C, 65.07 H, 6.33 N, 9.50

Example 95

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid ~ 6- (5-o-chlorobenzene-3-pyrazolyloxy) hexyl ester

Appearance: light yellow oil

IR spectrum (CHCl ₃ ) cm:

3500, 3460, 1693, 1522, 1245

PMR spectrum (CDCl ₃ + D ₂ O) ό:

0.95-1.90 (8H, m), 2.30 (6H, s), 3.57 (3H, s), 3.73-4.20 (4H, m), 3.82 (2H, s), 5.07 (IH, s), 5.43 (IH, s), 6.90 - 8.10 (8H, m)

Analysis for C ₃₂ H ₃₅ ClN ₄ O ₇ :

Calculated (%): C, 61.68 H, 5.66 N, 8.99 Found (K): C, 61.60 H, 5.78 N, 9.14

Example 96

4.98 g (20 mmoles) of methyl 3-nitrobenzylidene acetoacetate, 7.55 g (20 mmol) 3-aminocrotonic acid 6- (5-p-chlorophenyl-3-pyrazolyloxy) hexyl-. Ester and 10 ml of ethanol were mixed and refluxed for 6 hours. This reaction mixture was made under reduced pressure concentrated to a yellow oily residue, which after the addition of 2 ml

Ethyl acetate was stirred overnight. Then the deposited crystals were filtered off and recrystallized from isopropanol, and 8.65 g (yield 71.0 %) of light yellow crystals from 1,4-dihydro 2,6-dimethyl-4- (3-nitrophenyl ) -3-methoxycarbanylpyridine-5-carboxylic acid 6- (5-p-chlorophenyl-3-pyrazolyloxy) hexyl ester.

F .: 107-188 ° C

IR spectrum (KBr) cm ":

3380, 1705, 1690, 1515, 1345

PMR spectrum ^

1.00-1.91 (8H, m), 2.31 (6H, s), 3.52 (3H, s), 3.77-4.20 (4H, m), 4.97 (IH, s), 6.07 (IH, s), 7.05 - 8.06 (8H, m), 8.94 (IH, s)

Analysis for C ₃₁ H ₃₃₄₇

Calculated {%) -. C, 61.13 H, 5.46. N, 9.20 Found (? O '): C, 61.33 H, 5.57 N, 9.02

Example 97

1.51 g (10 mmol) 3-nitrobenzaldehyde, 1.15 g (10 mmol) 3-aminocrotonic acid methyl ester, 3.74 g (10 mmol) acetoacetic acid 6- (5-p-methoxyphenyl) -3-pyrazolyloxy) hexyl ester and 20M ethanol were mixed and refluxed for 5 hours. This reaction mixture was concentrated under reduced pressure to a yellow oily residue. This residue was chromatographed on a silica gel column using chloroform as an eluent, and the purified fractions containing the desired compound were concentrated under reduced pressure to give yellow crystals. These crystals were recrystallized from isopropanol, and 1.39 g (yield 23.0 %) of pale yellow crystals of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ -methoxycarbonylpyridine-S- carboxylic acid-ö-iS-p-methoxyphenyl ^ -pyrazolyloxy) hexyl ester obtained.

F .: 160-163 ° C

IR spectrum (KBr) cm ":

3398, 1700, 1508, 1345, 1210

PMR spectrum (DMSO-dg) ύ ι

1.00 - 1.91 (8H, m), 2.31 (6H, s), 3.51 (3H, s), 3.71 (3H, s), 3.78, 4.18 (4H, m), 5.01 (IH, s), 5.97 (IH, s), 6.92 (2H, s), 7.22-8.00 (6H, m), 8.93 (IH, s)

Analysis for ^c j2 ^ 36 ^ h ° 8 ^:

Calculated (K): C, 63.56 H, 6.00 N, 9.27 Found (%): C, 63.68 H, 6.21 N, 9.15

Example 98

0.24 g (10 mmol) of sodium hydride was suspended in 10 ml of N, N-dimethylformamide, and to this suspension was added 2.45 g (12 mmol) of 3- (3,4-methylenedioxyphenyl) -5-pyrazolone with stirring at room temperature given. After the evolution of hydrogen had ceased, 10 ml of a solution of 5.87 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonyl "pyridine-5-" were added dropwise to this solution. 6-tosyloxyhexyl carboxylate was added to Ν, Ν-dimethylformamide, and the mixture was then stirred for one hour and heated to 90 ° C. The resulting reaction mixture was poured into 200 ml of ice water, and the deposited solid matter was filtered off recrystallized from ethyl acetate, and there were 3.21 (yield 51.9 %) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid-6- 5- ( 3,4-methylenedioxyphenyl) -3 ~ pyrazolyloxy hexyl ester.

Appearance: light yellow crystals F .: 167-169 ° C

IR spectrum (KBr) cm " ¹ : 3380, 1694, 1520, 1345

PMR spectrum (DMSO-d _ß ) o:

0.97-1.85 (8H, m), 2.28 (6H, s), 3.52 (3H, s), 3.72-4.18 (4H, m),

>, - .. ■: .. 3230A00 7f

4.96 (IH, s), 5.97 (3H, s), 6.76-8.02 (7H, m), 8.90 (IH, β), 11.97 (IH, s)

Analysis for C ₃₂ H ₃₄ N JJ $

Calculated (S): C, 62.13 H, 5.54 N, 9.06 Found (SS): C, 61.85 H, 5.46 N, 9.29

The compound given in Example 99 below was prepared as in Example 98 except that different starting materials were used.

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-p-nitrophenyl-3-pyrazolyloxy) hexyl ester

Appearance: yellow crystals

F .: 208 - 210 ° C (from acetic acid)

IR spectrum (KBr) cm ": 3425, 1696, 1505, 1340, 1208

PMR spectrum (DMSO-d ₆ ) c5:

1.00-1.90 (ßH.m), 2.29 (6H, s), 3.56 (3H, s>, 3.77-4.23 (4H, m), 4.98 (IH, s), 6.28 (1H, s), 7.38-8.30 (8H, m), 8.86 (IH, s), 12.40 (IH, s)

Analysis for C ₃₁ H ₃₃ N ₅ O ₉ :

Calculated (K): C, 60.09 H, 5.37 N, 11.30 Found (S): C, 60.25 H, 5.54 N, 11.17

Example (process stage i)

33.0 g (0.20 mol) -2,3-dichlorobenzaldehyde, 23.0 g (0.20 mol) 3-aminocrotonic acid methyl ester and 100 ml of ethanol were mixed and for 6 hours on

The product was heated to reflux and the product obtained was chromatographed on a silica gel column, after which 3.47 g (yield 38.0 %) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid ohydroxyhexyl ester was obtained as an oil. 13.7 g (0.03 mol) of this oil were dissolved together with 11.4 g (0.06 mol) of tosyl chloride in 100 ml of chloroform, and 7.1 g (0.09 mol) were then added dropwise to this solution. Pyridine was added with ice cooling and stirring. This mixture was allowed to stand for 2 hours at room temperature, then 100 ml of water was added and stirring was continued for 3 hours. The chloroform layer of the obtained reaction mixture was taken out, washed with 100 ml of 0.02 N sulfuric acid, 100 ml of water and 100 ml of saturated aqueous sodium carbonate solution, successively, and dried over anhydrous sodium sulfate. The solution was concentrated and the residue obtained was chromatographed on a silica gel column using a mixed solvent of chloroform-methanol (in a volume ratio of 150: 1) as an eluent, whereupon 16.3 g (yield 89.0 % ) 1, 4-Dihydro-2, o-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid-o-tosyloxyhexyl ester was obtained. The IR and PMR spectrum of this product were as follows:

IR spectrum (KBr) cm " ¹ :

3340, 1675, 1475, 1345, 1205

PMR spectrum ₃

0.83 - 1.83 (8H, m), 2.23 (6H, s), 2.37 (3H, s), 3.53 (3H, s),

3.73-4.17 (4H, m), 5.36 (IH, s), 6.53 (IH, s), 6.83-7.36 (5H, m);

7.50 - 7.83 (2H, d)

(Process stage ii)

0.51 g (12 mmol) of 55% sodium hydride in mineral oil was added to 10 ml Suspended Ν, Ν-dimethylformamide, including gradually 2.40 g (15 mmol) of 3-phenyl-5-pyrazolone were added with stirring at room temperature. After the evolution of hydrogen ceased, this solution was added dropwise 20 ml of a solution of 6.10 g (10 mmol) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) ~ 3 ~ methoxycarbonylpyridine-5 ~ carboxylic acid 6-tosylhexyl ester, which had been obtained in the above process step i, in

Added Ν, Ν-dimethylformamide, and stirring was continued with heating at 60 C for 4 hours. The resulting reaction mixture was poured into 150 ml of ice water, and the deposited product was extracted with 50 ml of ethyl acetate. This ethyl acetate solution was washed three times with 50 ml of water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to a brown oily residue. This residue was chromatographed on a silica gel column using a mixed solvent of chloroform-methanol as an eluent, and the eluate fractions containing the desired compound were concentrated under reduced pressure to obtain crystals. These crystals were recrystallized from a mixed solvent of benzene-hexane, and 2.63 g (yield 43.9 %) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) ^ - methoxycarbonylpyridine- S-carboxylic acid o- (5-phenyl-3-pyrazolyloxy) hexyl ester was obtained.

Appearance: Colorless crystals. F .: 68-71 ° C

IR spectrum (CHCl ₃ ) cm ": 3499, 3470, 1690, 1460

PMR spectrum (CDCl ₃ + D ₂ 0) .d:

0.93 - 1.90 (üH, m), 2.25 (6H, s), 3.58 (3H, s), 3.74 - 4.25 (4H, m), 5.43 (IH, ö), 5.09 (IH, s), 6.80 - 7.72 (8H, m)

Analysis for C ₃₁ H ₃₃ Cl ₂ N ₃ O ₅ :

Calculated (SA): C, 62.21 H, 5.56 N, 7.02 Found (SS): C, 62.18 H, 5.78 N, 6.77

Example 101

0.24 g (10 mmol) of sodium hydride was suspended in 10 ml of dimethyl sulfoxide, and to this suspension was gradually added 1.95 g (10 mmol) of 3-o-chlorophenyl-5-pyrazolone with stirring at room temperature. After the evolution of hydrogen ceased, this solution was used

10 ml of a solution of 6.01 g (10 mmol) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in dimethyl sulfoxide, and that Stirring was continued with heating at 80 ° C. for one hour. The obtained reaction mixture was poured into 150 ml of ice water, and the deposited product was extracted with 50 ml of chloroform. This chloroform solution was washed four times with 50 ml of water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to a brown oily residue. This residue was purified by chromatography on a silica gel column using a mixed solvent of chloroform-methanol (in a volume ratio of 100: 1) as an eluent, and then purified by chromatography on a silica gel column eluting with a mixed solvent of toluene-ethyl acetate, and the eluate fractions containing the purified desired compound were concentrated to dryness under reduced pressure, whereupon 2.55 g (yield 40.9 %) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid-6- (5-o-chlorophenyl-3-pyrazolyloxy) hexyl ester was obtained as a light yellow powder.

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (DMS0-d ₆ ) d:

0.89 - 1.90 (BH, m), 1.16 (3H, t), 2.27 (6H, a), 3.73 - 4.21 (6H, m), 5.01 (IH, s), 6.01 (IH, s), 7.05 - 8.05 (8H, m), 8.83 (IH, broad), 12.07 (IH, broad)

Analysis for C ₃₂ H ₃₅ ClN ₄ O ₇ :

Calculated ⁽⁰ O: C, 61.68 H, 5.66 N, 8.99 Found (%) ': C, 61.78 H, 5.83 N, 8.84

The compounds in Examples 102-115 below were after prepared the same procedures as in Example 101 above except that the starting materials, the solvent has been or has been appropriately changed for the implementation and other conditions.

Example 102

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid-o- iS -p-trifluoromethylphenyl-J-pyrazolyloxyJhexyl ester

Appearance: light yellow powder IR spectrum (CHCl ₃ ) cm ":

3500, 3460, 1693, 1520, 1345

PMR spectrum g

0.90-1.91 (8H, m), 2.29 (6H, s), 3.51 (3H, s), 3.72-4.20 (4H, m), 5.00 (IH, s)

Analysis for C ₃₂ H ₃₃ F ', NO ₇ :

Calculated (S): C, 59.81 H, 5.18 N, 8.72 Found (%): C, 59.76 H, 5.42 N, 8.59

Example 103

1,4-Dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (4-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: Colorless powder

IR spectrum (CHCl ₃ ) cm " ¹ :
3500, 3460, 1693

PMR spectrum

0.95 - 1.97 (8H, m), 2.27 (6H, s), 3.57 (3H, s), 3.70 - 4.21 (4H, m), 5.44 (IH, s), 6.75 - 7.80 (8H, m)

Analysis for C ₃₁ H ₃₃ Cl ₂ N ₃ O ₅ :

Calculated (%): C, 62.21 H, 5.56 N, 7.02 Found (%): C, 62.33 H, 5.80 N, 7.01

Example 104

• · nt + *

t> W t »* *

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridin-5-oar 6- (5-o-tolyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3463, 1692, 1520, 1345

PMR spectrum (DMS0-d ₆ ) d:

0.90-1.95 (8H, m), 1.17 (3H, t), 2.30 (6H, s), 2.35 (3H, s), 3.74-4.21 (6H, m), 5.00 (IH, s), 5.87 (IH, s), 7.00-8.08 (8H, m), 8.90 (IH, s), 11.83 (IH, broad)

Analysis for C ₃₃ H ₃₈ NO ₇ :

Calculated (? I): C, 65.77 H, 6.36 N, 9.30 Found (? I): C, 65.89 H, 6.40 N, 9.16

example

1,4-Dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-o-tolyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm ":

3500, 3462, 1693, 1520, 1345

PMR spectrum ₆

0.97 - 2.00 (HH, m), 2.22 (3H, s), 2.28 (3H, s), 2.35 (3H, s), 3.72-4.21 (6H, m), 5.53 (IH, s), 5.86 (IH, s), 7.00-8.03 (8H, m), 8.80 (IH, broad)

Analysis for ^C 33 ^H 3g ^N A ° 7 ^:

Calculated (%) -. C, 65.77 H, 6.36 N, 9.30 Found (%): C, 65.93 H, 6.58 N, 9.17

example

³²³⁰⁴⁰ °

1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -J-ethoxycarbonylpyridine-S-car 6- (5 ~ p-chlorophenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3500, 3460, 1692, 1520, 1345

PMR spectrum ^

0.90-2.00 (IIH, m), 2.23 (3H, s), 2.29 (3H, s), 3.72-4.21 (6H, m), 5.53 (IH, s), 6.05 (IH, s), 7.03 - 8.05 (8H, m), 8.90 (IH, s)

Analysis for C ₃₂ H ₃₅₇ Calculated (S): C, 61.68 H, 5.66 N, 8.99 Found (%): C, 61.47 H, 5.75 N, 9.20

example

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-ethoxycarbonylpyridine-5-carboxylic acid 6- (5-p-chlorophenyl-3-pyrazolyloxy) -5-ethylhexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm ": 3500, 3460, 1695, 1522, 1345

PMR spectrum (DMSO-d ^ cf:

2.29 (6H, s), 3.73-4.22 (6H, m), 4.99 (IH, s), 6.07 (IH, s), 7.05 - 8.06 (8H, m), 8.85 (IH, s), 12.24 (IH, s)

Analysis for C ₃₄ H ₃₉ ClN-O ₇ : Calculated (%) : C, 62.71 H, 6.04 N, 8.60 Found (? I): C, 62.99 H, 6.21 N, 8 , 47

Example 108
1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-

5-carboxylic acid 6- (5-p-nitrophenyl-3-pyrazolyloxy) hexyl ester

Appearance: Light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ : 3500, 3468, 1690

PMR spectrum (DMSO-cL) d:

0.95-2.00 (8H, m), 2.25 (6H, s), 3.48 (3H, s), 3.70-4.20 (4H, m), 5.32 (IH, s), 6.26 (IH, s), 6.87 - 8.30 (8H, m), 8.76 (IH, broad)

Analysis for C ,, H ₃₂ CIpN.0 ^: Calculated (%): C, 57.86 H, 5.01 N, 8.71 Found (%) t C, 57.84 H, 5.20 N, 8 , 63

example

1,4-Dihydro-2,6-dimethyl 1-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-methoxyphenyl-3-pyrazolyloxy) hexyl ester

Appearance: yellow powder

IR spectrum (CHCl-j) cm ": 3500, 3465, 1695, 1520, 1345

PMR spectrum (DMS0-d ₆ ) ^:

0.96 - 2.00 (8H, m), 2.23 (3H, s), 2.29 (3H, s), 3.44 (3H, s), 3.73 '(3H, s), 3.73-4.20 (4H, m), 5.53 (IH, s), 5.98 (IH, s), 6.73-8.10 (8H, m), 8.00 (IH, s)

Analysis for ^ -ιι ^ Ιβ ^ ίιΡΰ ^: Calculated (? Ό): C, 63.56 H, 6, OO N, 9.27 Found (%): C, 63.70 H, 6.02 N, 9, 09

Example 110
1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-

carboxylic acid 6- 5- (p-N-acetylaminophenyl) -3-pyrazolyloxy hexyl ester Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 3420, 1695, 1520, 1345

PMR spectrum (CDCl ₃ + D ₂ O) S :

0.95-2.00 (8H, m), 2.13 (3H, s), 2.30 (6H, s), 3.55 (3H, s), 3.74 4.22 (4H, m), 5.07 (lH, s), 5.91 (IH, s), 7.00 - 8.07 (8H, m)

Analysis for ^ 3H ₃₇ N ₅ Og:

Calculated (? «'): C, 62.75 H, 5.90 N, 11.09 Found (! S); C, 62.89 H, 5.74 N, 11.20

Example 111

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-m-tolyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1690, 1520, 1345

PMR spectrum (CDCl ₃ ) β:

0.90-1.92 (8H, m), 2.30 (6H, s), 2.35 (3H, s), 3.57 (3H, s), 3.70 4.21 (4H, m), 5.05 (IH, s), 5.88 (IH, s), 6.90 - 8.07 (8H, m)

Analysis for C _,? H ,, NO- ,:

Calculated (Si): C, 65.29 H, 6.16 N, 9.52 Found (SS): C, 65.33 H, 6.01 N, 9.76

Example 112

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S- ' 6- (5-p-tolyl-3-pyrazolyloxy) hexyl carboxylate

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm:

3500, 3463, 1692, 1521, 1345

PMR spectrum ₃

0.96-1.95 (8H, m), 2.30 (6H, s), 2.34 (3H, s), 3.56 (3H, s), 3.74 4.20 (4H, m), 5.04 (IH, s), 5.88 (IH, s), 6.89 - 8.05 (BH, m)

Analysis for ^C 32 ^H 36 ^N 4 ° 7 ^:

Calculated (%): C, 65.29 H, 6.16 N, 9.52 w. Found (%): C, 65.43 H, 6.31 N, 9.44

Example 113

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -O-ethoxycarbonylpyridine-S-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester

Appearance: light yellow crystals F .: 156 - 159 ° C (from ethanol)

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1693, 1520, 1345

PMR spectrum (CDCl ₃ + D O) S :

0.90-1.90 (8H, m), 1.17 (3H, t), 2.32 (6H, s), 3.72-4.22 (6H, mj, 5.04 (IH, s), 5.87 (IH, s), 6.92 - 8.06 (8H, m)

Analysis for ^C 32 ^{| J |} 3 < ^N 4 ° 7 ^:

Calculated (%): C, 65.29 H, 6.16 N, 9.52 Found (? <Ä): C, 65.32 H, 6.27 N, 9.40

Example 114

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (p-N, N-dimethylaminophenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (CUCl ₃ ) d ":

0.90 - 1.90 (8H, m), 2.30 (6H, s), 2.90 (6H, s), 3.55 (3H, s), 3.71 - 4.20 (4H, m), 5.07 (IH, s)

Analysis for ^c ^^ k ° j ^:

Calculated (%) -. C, 64.17 H, 6.36 N, 11.34 Found (? Ό): C, 64.10 H, 6.54 N, 11.20

Example 115

1,4-Dihydro-2, δ-dimethyl · ^ - (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (m-N -ethylaminophenyl) -3-pyrazolyloxy hexyl ester

Appearance: light yellow powder

IR spectrum (CHCl ₃ ) cm " ¹ :

3500, 3460, 1695, 1520, 1345

PMR spectrum (CDCl ₃ + D ₂ O) j :

0.90-1.97 dlH, m), 2.02 (2H, q), 2.31 (6H, s), 3.56 (3H, s) 3.72 4.20 (4H, m), 5.05 (IH, s), 5.83 (IH-, β)

Analysis for C ₃₃ H ₃ QN ₅ O ₇ :

Calculated (JS): C, 64.17 H, 6.36 N, 11.34 Found (%): C, 64.03 H, 6.47 N, 11.46

Example 116

12.86 g (20 mmol) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-nitrophenyl-3-pyrazolyloxy ) hexyl ester (Example 108) were dissolved in 100 ml of ethanol to this 6 ml of Raney nickel were added to the solution, and the catalytic hydration

tion was carried out at room temperature and normal pressure, with 1350 ml (60 mmol) of hydrogen being absorbed. The Raney nickel was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure to a light yellow oily residue. This residue was purified by chromatography on a silica gel column using a mixed solvent of chloroform-methanol (in a volume ratio of 3: 1) as an eluent, and the fractions containing the desired compound were concentrated under reduced pressure to a light yellow oily residue . This residue was dissolved in ethyl acetate, and then 5 g of activated charcoal was added and stirred well and filtered. The filtrate was concentrated to dryness under reduced pressure, and there was obtained 6.63 g (yield 54.0 %) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine -5-carboxylic acid-6- (5-p-aminophenyl-3-pyrazolyloxy) hexyl ester was obtained as a light yellow powder.

IR spectrum (CHCl ₃ ) cm " ¹ :
3500, 3460, 1695

PMR spectrum (CDCl ₃ + D ₂ O) d :

0.95-1.95 (8H, m), 2.26 (6H, s), 3.58 (3H, s), 3.74-4.21 (4H, m), 5.43 (IH, s), 5.06 (IH, s)

Analysis for C ₃₁ H ₃₄ Cl ₂ N ₄ O ₅ :

Calculated (SS): C, 60.69 H, 5.59 N, 9.13 Found (85): C, 60.55 H, 5.76 N, 9.01

Example 117

To a suspension of 0.262 g of sodium hydride (55% dispersion in Mineral oil) in 10 ml of N, N-dimethylformamide were 1.33 g (7 mmol) of 3-p-methoxyphenyl-5-pyrazolone added in portions while stirring and cooling with ice. To this mixture was added a solution of 3.05 g dropwise (5 mmoles) 1,4-Dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbynylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in 7 ml of N, N-dimethylformamide at 0 to It) C with stirring, and then the mixture heated at 80 C for 3 hours. The reaction mixture obtained was

Poured into ice water, and the precipitate was washed with ethyl acetate extracted. The organic layer was washed with salt water, dried over anhydrous sodium sulfate and then in vacuo up to.einem evaporated oily residue. The residue was purified by silica gel column chromatography purified using a solvent mixture of chloroform-methanol (in a volume ratio of 100: 1) as the eluent, and the fractions containing the desired compound were collected and evaporated to dryness in vacuo, whereby a white crystalline residue was obtained. The residue was recrystallized from a solvent mixture of ethyl acetate - normal hexane, and 1.87 g (yield 59.0 Si) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid-6- (5-p -methoxyphenyl-3-pyrazolyloxy) hexyl ester obtained as colorless needles.

F. 146-148 ° C

IR spectrum (CHCl ₃ ) cm " ¹ : 3500, 3475, 1695, 1615

PMR spectrum (DMSO-dg). i :

0.91 - 1.91 (8H, m), 2.20 (3H, s), 2.23 (3H, s), 3.44 (3H, s),

3.67-4.19 (4H, m), 3.70 (3H, s), 5.25 (IH, s), 5.87 (IH, s),

6.70 - 7.63 (7H, m), 8.64 (IH, broad)

Analysis for C ₃₂ H ₃₅ Cl ₂ N ₃ O ₆ :

Calculated (JS): C, 61.15 H, 5.61 N, 6.69 Found (a): C, 61.30 H, 5.65 N, 6.62

Example 118

1,4-Dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester

Appearance: Colorless powder IR spectrum (CHCl ₃ ) cm " ¹ :

323040Q

3500, 3480, 1690 (protruding edge), 1616

PMR spectrum

1.06 - 1.92 (8H, m), 2.18 (3H, s), 2.27 (6H, s), 3.55 (3H, s), 3.83-4.16 (4H, m), 5.36 (2H, s), 5.86 (IH, broad), 6.87 7.30 (3H, m)

Analysis for ^C 26 ^H 31 ^C1 2 ^N 3 ° 5 ^:

Calculated (K): C, 58.21 H, 5.82 N, 7.83 Found (K): C, 58.45 H, 5.79 N, 7.71

Example 119

1,4-Dihydro-2, o-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester

Appearance: Colorless powder
IR spectrum (CHCl,) cm " ¹ :

3500, 3475, 1690, 1610

PMR spectrum ₃

1.06 - 1.97 (8H, m), 1.23 (6H, d), 2.26 (6H, s), 2.80 (IH, q),

3.56 (3H, s), 3.83-4.20 (4H, m), 5.40 (2H, broad), 5.86

(IH, broad) ", 6.86 - 7.30 (3H, m)

Analysis for C ₂₈ H ₃₅ Cl ₂ N ₃ O ₅ :

Calculated (?;): C, 59.58 H, 6.25 N, 7.44 Found (K): C, 59.72 H, 6.21 N, 7.51

In addition to the above examples, the following compounds were also used made in a similar way:

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-ethoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-p-chlorophenyl-3-pyrazolyloxy) hexyl ester

1,4-dihydro-2,6-dimethyl-4- (2-bromophenyl) -3-methoxycarbonylpyridine-5-

6- (5-phenyl-3-pyrazolyloxy) hexyl carboxylate

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-m -iodophenyl-3-pyrazolyloxy) hexyl ester

1,4-Dihydro-2,6-dimethyl-4- (2,6-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester

1,4-Dihydro-2, o-dimethyl ^ - (3,4-dichlorophenyl) -3-methoxycarbonylpyridine-S-carboxylic acid ^ -CS-phenyl-S-pyrazolyloxy-hexyl ester

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -S-methoxycarbonylpyridine-S-carboxylic acid 6-5- (2,4-dimethylphenyl) -3-pyrazolyloxy hexyl ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6-5- (p-N -benzoylaminophenyl) -3-pyrazolyloxy hexyleater

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -I-methoxycarbonylpyridine-S-carboxylic acid 6-5- (p-N, n-diethylaminophenyl) -3-pyrazolyloxy hexyl ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-ethoxyphenyl-3-pyrazolyloxy) hexyl ester

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - 6- (5-p-niBthoxybenzyl-3-pyrazolyloxy) hexyl carboxylate

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (2,6-dimethylphenyl) -3-pyrazolyloxy hexyl ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid-6- (5- -phenethyl-3-pyrazolyloxy) hexyl ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid-6- (5- -phenethyl-3-pyrazolyloxy) hexyl ester

1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyΓidin-5 carboxylic acid 6 4- (3,4-methylenedioxyphenyl) -3-pyrazolyloxy hexyl ester

1, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-4 ~ (2,6-dimethoxyphenyl) -3-hexyl pyrazolyloxy '

1,4-Dihydro-2, o-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-4- (2,6-dimethylphenyl) -3-pyrazolyloxy hexyl ester

1,4-Dihydro-2, o-dimethyl-4- (3-nitrophenyl) ~ 3-methoxycarbonylpyridine ~ 5-carboxylic acid 6- (4-p-methoxyphenyl-3-pyrazolyloxy) hexyl ester

1,4-Dihydro-2,6-dimethyl 1-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (4-o-chlorophenyl-3-pyrazolyloxy) hexyl ester

1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6-5- (3,4-methylenedioxybenzyl) -3-pyrazolyloxy hexyl ester

Claims (24)

New 1,4-dihydropyridine derivatives Patent claims:
1. 1,4-dihydropyridine derivatives of the following general formula (I): A - 0— \ NH (I) where R is an alkyl group with 1 to 3 carbon atoms or an alcohol represents xyalkyl group having 3 to 6 carbon atoms, R represents a hydrogen atom or represents a halogen atom, R represents either a nitro group 2
if R is a hydrogen atom or a halogen atom, 2 4 and when R is a halogen atom, R is an alkyl group with 1 to 8 carbon atoms, a pyridyl group, a phenylethyl group, a benzyl group, which is optionally substituted by at least one member of the group which consists of a lower alkyl group, a lower alkoxy group, a methylenedioxy group and a halogen atom, or represents a phenyl group which may be substituted by at least one member of the group consisting of a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a nitro group, a cyano group, an amino group, a mono-lower-alkylamino group, a di-lower-alkylamino group, an acetylamino group, a benzoyl- ' amino group, a methylenedioxy group and a halogen atom, and A represents a hexamethylene group which is optionally substituted by one alkyl group or two alkyl groups having 1 to 3 carbon atoms can be. 2. 1,4-dihydropyridine derivative according to claim 1, characterized in that R represents a member of the group consisting of methyl, ethyl, propyl, butyl, 4th
Methoxyethyl and butoxyethyl, R is a member of the group consisting of methyl, ethyl, propyl, hexyl, octyl, phenyl, fluorophenyl, chlorophenyl, 1'olyl, mothoxyphenyl, dichlorophonyl, methylenedioxyphenyl, benzyl and is pyridyl and A is hexamethylene. 3. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester is. 4. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-isopropyl-3-pyrazolyloxy) hexyl ester is. 5. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - ethoxycarbonylpyridine-S-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester is. 6. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2-methoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-methyl-3-pyrazolyloxy) hexyl ester. 7. 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-isobutoxycarbonylpyridine-5-carboxylic acid 6- (5-ethyl-3-pyrazolyloxy) hexyl ester is. 8. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-octyl-3-pyrazolyloxy) hexyl ester is. 9. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-hexyl-3-pyrazolyloxy) hexyl ester is. 10. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester is. 11. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester is. 12. 1,4-dihydropyridine derivative according to claim 2, characterized in that it l, 6-dihydro-2,6-dimethyl-4- (2-nitΓophenyl) 3-methoxycarbonylpyridine-5-carboxylic acid-6- (5-phenyl-3-pyrazolyloxy) hexyl ester is. 13. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,6-dihydro-2,6-dimethyl-4- (3-nitrophenyl) ^ - methoxycarbonylpyridine-S-carboxylic acid 6- (4-phenyl-3-pyrazolyloxy) hexyl ester is. 14. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-26, -dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid-o-CS-o-chlorophenyl ^ -pyrazolyloxy) hexyl ester is. 15. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3nitrophenyl) -S-normalpropoxycarbonylpyridine-5-carboxylic acid 6-5 (2,4-dichlorophenyl) -3-pyrazolyloxy is hexyl ester. 16. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3- (2isobutoxyethoxycarbonyl) pyridine-5-carboxylic acid 6- (5-m-fluorophenyl-3-pyrazolyloxy) hexyl ester. 17. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-o-tolyl-3-pyrazolyloxy) hexyl ester is. 18. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -S-methoxycarbonylpyridine-S-carboxylic acid 6-5- (2-pyridyl) -3-pyrazolyloxy is hexyl ester. 19. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-benzyl-3-pyrazolyloxy) hexyl ester is. 20. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-p-methoxyphenyl-3-pyrazolyloxy) hexyl ester is. 21. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) - ^ - methoxycarbonylpyridine-S-carboxylic acid 6-5- (3,4-methylenedioxyphenyl) -3-pyrazolyloxy is hexyl ester. 22. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4 ~ (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5-phenyl-3-pyrazolyloxy) hexyl ester is. 23. 1,4-dihydropyridine derivative according to claim 2, characterized in that 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-thoxycarbonylpyridine-5-carboxylic acid 6- (5-o-chlorophenyl-3-pyrazolyloxy) hexyl ester is. 24. 1,4-dihydropyridine derivative according to claim 2, characterized in that it 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -3-methoxycarbonylpyridine-5-carboxylic acid 6- (5 ~ p-methoxyphenyl-3-pyrazolyloxy) hexyl ester is.