GB2108108A - Novel 1,4-dihydropyridine derivatives - Google Patents

Novel 1,4-dihydropyridine derivatives Download PDF

Info

Publication number
GB2108108A
GB2108108A GB08223168A GB8223168A GB2108108A GB 2108108 A GB2108108 A GB 2108108A GB 08223168 A GB08223168 A GB 08223168A GB 8223168 A GB8223168 A GB 8223168A GB 2108108 A GB2108108 A GB 2108108A
Authority
GB
United Kingdom
Prior art keywords
dimethyl
dihydro
pyrazolyloxy
carboxylic acid
hexyl ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB08223168A
Other versions
GB2108108B (en
Inventor
Kamibayashi Masato
Tsuchiya Shinji
Hiratsuka Kozo
Tsuchiya Susumu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tokyo Tanabe Co Ltd
Original Assignee
Tokyo Tanabe Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP12521681A external-priority patent/JPS5826882A/en
Priority claimed from JP57013398A external-priority patent/JPS58131982A/en
Application filed by Tokyo Tanabe Co Ltd filed Critical Tokyo Tanabe Co Ltd
Publication of GB2108108A publication Critical patent/GB2108108A/en
Application granted granted Critical
Publication of GB2108108B publication Critical patent/GB2108108B/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Novel 1,4-dihydropyridine derivatives of the formula [I] are provided: <IMAGE> wherein R<1> represents a C1-4 alkyl group or a C3-6 alkoxyalkyl group, R<2> represents hydrogen or halogen, R<3> is either nitro when R<2> is hydrogen, or halogen when R<2> is halogen, R<4> represents a C1-8 alkyl group, a pyridyl group, a phenethyl group, an unsubstituted benzyl group, a substituted benzyl group having one or more suitable substituents, an unsubstituted phenyl group, or a substituted phenyl group having one or more suitable substituents, and A represents an unsubstituted hexamethylene group or a substituted hexamethylene group having one or two C1-3 alkyl groups. The 1,4- dihydropyridine derivatives have vasodilating and hypotensive activity which is kept for a long period, and are useful in the treatment of cardiovascular disease and hypertension.

Description

SPECIFICATION Novel 1,4-dihydropyridine derivatives The present invention relates to novel 1,4-dihydropyridine derivatives having hypotensive activity.
Heretofore, there have been known, as 1,4-dihydropyridine derivatives, 4-(2-nitrophenyl)-2,6- dimethyl-1 ,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (U.S. Patent 3,644,627; hereinafter referred to as Nifedipine), 4-(3-nitrophenyl)-2,6-dimethyl-1 ,4-dihydropyridine-3,5-dicarboxylic acid 3methyl ester 5-p-(N-benzyl-N-methylamino)ethyl ester hydrochloride (Japanese Patent Publication No.
45075/1980; hereinafter referred to as Nicardipine) etc. which are useful as therapeutic agents for improving the coronary circulation or the cerebral circulation.
However, it has been reported based on an animal test that the vasodilating effect and the hypotensive effect resulting from said effect of these compounds disappear within a short period of time, such as 30 40 minutes or so, at the effective intravenous dosage at which they become significant, for example, 10 Mg/kg, and also that these compounds have an effect to increase the heart rate which means that they increase the burden on the function of the heart; in other words, they also have a kind of side effect (Arzneimittel-Forschung, Vol. 22, No. 1, p. 33, 1972; ibid., Vol. 26, No. 12, p.
2172, 1976; Toho Igakukai Zasshi, Vol. 26, No. 2, p. 48, 1972). Therefore, when these compounds are to be employed as remedies for hypertension, cardiovascular diseases etc. which require continuous use of drug for a prolonged period of time, the improvement of the preparation, for example, by making it slow-releasing etc., frequent administration, or use in combination with other drugs, is needed.
The present invention relates to 1,4-dihydropyridine derivatives which possess a long-lasting hypotensive effect resulting from the vasodilating effect and have a very low tendency to change the heart rate.
According to the present invention, there are provided 1 ,4-dihydropyridine derivatives of the following general formula [I]:
wherein R' represents an alkyl group having from 1 to 4 carbon atoms or an alkoxyalkyl group having from 3 to 6 carbon atoms, R2 represents a hydrogen atom or a halogen atom, R3 represents either a nitro group when R2 is a hydrogen atom or a halogen atom when R2 is a halogen atom, R4 represents an alkyl group having from 1 to 8 carbon atoms, a pyridyl group, a phenethyl group, a benzyl group which may optionally be substituted by at least one member selected from the group consisting of a lower alkyl group, a lower alkoxy group, a methylenedioxy group and a halogen atom or a phenyl group which may optionally be substituted by at least one member selected from 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 benzoylamino group, a methylenedioxy group and a halogen atom, and A represents a hexamethylene group which may optionally be substituted by one or two alkyl groups having from 1 to 3 carbon atoms.
The derivatives of the present invention [I] also include the tautomers of the following general formula [ll]:
wherein R1, R2, R3, R4 and A are as defined above, as well as the optical isomers due to the asymmetric carbon atom at the 4-position of the 1,4-dihydropyridine ring.
In the definition of the general formula [I], the term "lower alkyl" means either of methyl, ethyl or propyl, and the term "halogen atom" means either atom of fluorine, chlorine, bromine or iodine, unless otherwise stated. And, of course, the terms "alkyl" and "alkoxyalkyl" include those of both straight chains and branched chains.
The derivatives of the present invention [I] may be produced by any of the processes described hereinbelow.
[Process 1] The derivatives of the present invention [I] may be produced by reacting 1.0 mole of a benzylideneacetoacetate derivative of the following general formula [III]:
wherein R2 and R3 are as defined above, and R5 represents R' as defined above or a substituted pyrazolyloxyhexyl group of the following general formula [IV]:
wherein A and R4 are as defined above, with 1.0-2.0 mole, preferably 1.0 mole, of an enaminocarboxylate derivative of the following general formula [V]::
wherein R6 represents R1 as defined above or a substituted pyrazolyloxyhexyl group of the above general formula [IV], with a proviso that when R5 is R1, R6 is then a substituted pyrazolyloxyhexyl group [IV], and when R5 is a substituted pyrazolyloxyhexyl group [IV], R8 is then R1, in the presence or absence of a reaction solvent at a reaction temperature of 5--2000C, preferably 50-1 500 C. Preferred as the reaction solvent are aicohols such as methanol, ethanol, isopropanol, butanol etc., diois such as ethylene glycol, propylene glycol etc., cellosolves such as methyl cellosolve, ethyl cellosolve, propyl cellosolve etc., nitrobenzene, N,N-dimethylacetamide, N,N-dimethylformamide, hexamethylphosphoric triamide, acetic acid, water and a mixture of two or more thereof. In the above Process 1, according to the necessity, an appropriate amount of e.g. molecular sieves, piperidine, diethylamine, triethylamine, N,N-dimethylaniline, N,N-diethylaniline etc. may be employed as a reaction accelerator.
[Process 2] The derivatives of the present invention [I] may also be produced by reacting 1.0 mole of a benzaldehyde derivative of the following general formula [VI]:
wherein R2 and R3 are as defined above, with 1.0-2.0 mole, preferably 1.0 mole, of an enaminocarboxylate derivative of the above general formula [V] and 1.0-2.0 mole, preferably 1.0 mole, of an acetoacetate derivative of the following general formula [VII]:
wherein R5 is as defined above, in the presence or absence of a reaction solvent at a reaction temperature of 5--200"C, preferably 50-1 500 C. As the reaction solvent and the optionally employed reaction accelerator, those described in Process 1 may be employed.
[Process 3] Further, the derivatives of the present invention [I] may also be produced by reacting 1.0 mole of a benzylideneacetoacetate derivative of the above general formula [Ill] with 1.0 mole of an acetoacetate derivative of the following general formula [VIII]:
wherein R6 is as defined above and 1.0 mole or more, preferably 1.0-3.0 mole, of ammonia in the presence or absence of a reaction solvent at a reaction temperature of 5--2000C, preferably 50 1 500 C. As the reaction solvent and the optionally employed reaction accelerator, those described in Process 1 may be employed.
[Process 4] Furthermore, the derivatives of the present invention [I] may also be produced by reacting 1.0 mole of a dihydropyridine derivative of the following general formula [IX]:
wherein R1, R2, R3 and A are as defined above, and R7 represents a halogen atom,a mesyloxy group, a tosyloxy group or a benzenesulfonyloxy group, with 1.0-6.0 moles, preferably 1.0-2.0 mole, of a pyrazolone derivative of the following general formula [X]::
wherein R4 is as defined above in the presence of an an anionizing reagent and, according to the necessity, an alkali metal iodide in a reaction solvent at a reaction temperature of 0-1 800 C, preferably 1 5-1 000C. The reaction of this Process 4 advantageously proceeds by reacting first the pyrazolone derivative [X] with the anionizing agent, and adding to the resultant reaction mixture the dihydropyridine derivative [IX] and also, according to the necessity, the alkali metal iodide.
Suitable as the anionizing reagent are alkaline metals such as metallic sodium, metallic potassium etc., alkaline earth metals such as metallic calcium, metallic magnesium etc., alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride etc., carbonates such as sodium carbonate, potassium carbonate etc., sodium or potassium alkoxides with alcohols such as methanol, ethanol, propanol, butanol etc., tertiary amines such as triethylamine, pyridine, N,N-dimethylaniline etc.
When a sodium or potassium alkoxide is employed as the anionizing reagent, it is advantageous to remove as much as possible alcohol produced in the course of the reaction. In the present process, the amount of the anionizing reagent, when said reagent is other than tertiary amine, is suitably such that it falls within 1.0-6.0 mole, preferably 1 1.0--2.0 mole, and further that, within such a limit, it is always equimolar to or less than that of the pyrazolone derivative [X]. On the other hand, where a tertiary amine is employed, it is suitably 1.0 mole or more. The alkali metal iodide promotes the reaction of the present process where a dihydropyridine derivative in which R7 in the above general formula [IX] is a halogen atom other than iodine atom is employed.
Suitable as the reaction solvent is dimethylsulfoxide, N,N-dimethylacetamide, N,Ndimethylformamide, pyridine, dioxane, hexamethylphosphoric triamide, N-methylmorpholine, 1,2dimethoxyethane or a mixture of two or more thereof.
Furthermore, in Process 4, a compound of the following general formula [Xl]:
wherein R', R2, R3, R4 and A are as defined above, may also be produced as a by-product, the compound having long-lasting hypotensive effect and vasodilating effect.
[Processes for producing main starting materials in Processes 1--4] The acetoacetate derivatives of the above general formulae [VII] and [VIII] may be produced by using diketene and an alcohol of the following general formula [XII]: R1-OH [Xll] wherein R' is as defined above, or a pyrazolyloxy hexanol derivative of the following general formula [XIII]:
wherein R4 and A are as defined above, by a process according to the known processes for producing acetoacetate derivatives, for example, the process described in the Journal of the Chemical Society, Vol. 97, p.1978(1910).
Secondly, the enaminocarboxylate derivative of the above general formula [V] may be produced by using the acetoacetate derivative [Vlil] and ammonia by a process according to the known processes for producing enaminocarboxylate derivatives, for example, the process described in the Journal of the American Chemical Society, Vol. 67, p.1017(1945).
Further, the benzylideneacetoacetate derivative of the above general formula [III] may be produced by using the benzaldehyde derivative [VI] and the acetoacetate derivative [VII] by a process according to the known processes for producing benzylideneacetoacetate derivatives, for example, the process described in Organic Synthesis Collective Volume, Vol. 4, p. 408 (1963).
While in the above Processes 1 4, the explanation has been made by referring the amount of each starting compound employed to as the unit amount, i.e. 1.0 mole, for convenience sake, it is needless to say that said amount employed may be freely established as long as the relative molar ratio between the respective compounds is within the specified limit.
The derivatives of the present invention [I] produced by Processes 1 4 may be purified by such purifying methods as extraction with an appropriate solvent, column chromatography using alumina, silica gel, ion exchange resin etc. as a carrier, crystallization by concentration etc., fractional precipitation, recrystallization, or an appropriate combination of these.
Test examples of the pharmacological activity of representative compounds, of the derivatives of the present invention [I], which have been produced by the above-described processes are given below.
[Hypotensive effect] The test was carried out using groups of 5-6 adult dogs in each group and measuring the heart rate and the blood pressure at the right femoral artery as well as the duration of the hypotensive effect after injecting 3 yg/kg or 10 yglkg of each compound to the femoral vein. The dogs used had been anesthetized beforehand by intravenous administration of 30 mg/kg of sodium pentobarbital. The measuring instruments were a pressure transducer MPU-0.5 and a pulse rate tachometer RT-2 (both manufactured by Nippon Koden Co.), and the recording apparatus was a pen oscillograph WI-380 (manufactured by Nippon Koden Co.). The duration was obtained by measuring the time from when the effect manifested to when it died out. Administration of each compound was carried out by injecting each compound dissolved in 10% polyethylene glycol aqueous solution into the femoral vein.
The results are as set forth in Table 1. The heart rate and the hypotensive effect are expressed as the increase or decrease of the heart rate (per minute) and the difference in mean blood pressure, respectively, before and after administration of each compound, and the duration is expressed in the unit of minutes. In addition, these effects of Nifedipine and Nicardipine measured by the present inventors are also set forth in the same table.
Table 1 Hypotensive effect Dosage Heart rate Mean blood ressure Duration Compound glkgi.v. #heart rate/min.#S.E. #mmHg#S.E. min.#S.E.
Nicardipine 3 5.1#0.6 -20.1#1.4 19.0#1.3 10 9.0#1.2 -43.0#3.9 40.6#3.3 Nicardipine 3 19.0#3.5 -13.3#2.5 20.1#5.0 10 23.0#4.5 -23.5#2.8 32.5#6.9 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 0.8#0.4 -14.5#1.3 46.5#2.8 methoxycarbonylpyridine-5-carboxylic acid 10 1.0#2.6 -24.3#1.8 103.6#4.3 6-(5-methyl-3-pyrazolyloxy)hexyi ester (Example 1) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 -1.2#1.9 -18.6#1.2 73.5#5.3 methoxycarbonylpyridine-5-carboxylic acid 6- 10 -3.6#1.0 -29.1#2.4 180 or longer (5-isopropyl-3-pyrazolyloxy)hexyl ester (eExample 3) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 3.2#0.8 -14.9#1.4 53.5#5.2 ethoxycarbonylpyridine-5-carboxylic acid 6- 10 6.1#3.5 -27.4#2.7 141.0#6.7 (5-methyl-3-pyrazoiyloxy)hexyl ester (Exampie 4) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.4#1.7 -12.5#2.8 43.4#3.2 isopropoxycarbonylpyridine-5-carboxylic acid 10 2.2#1.6 -25.7#2.6 136.2#5.3 6-(5-methyl-3-pyrazolyloxy)hexyl ester (Example 7) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.3#1.2 -15.5#1.6 57.4#3.3 (2-methoxyethoxycarbonyl)pyridine-5-carboxylic 10 3.4#1.8 -25.9#2.1 127.3#3.7 acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester (Example 10) 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3- 3 3.8#1.0 -16.1#1.7 51.5#3.1 methoxycanbonylpyridine-5-carboxylic acid 6- 10 7.3#2.1 -27.9#1.4 110.9#2.6 (5-methyl-3-pyrazolyloxy)hexyl ester (Exampie 12) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 2.8#1.3 -13.1#1.6 117.6#3.9 ethoxycarbonylpyridine-5-carboxylic acid 6- 10 5.8#1.7 -26.6#2.2 180 or longer (5-isopropyl-3-pyrazolyloxy)hexyl ester (Example 14) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.7#1.6 -14.6#2.6 6.71#3.8 isopropoxycarbonylpyridine-5-carboxylic acid 10 3.5#1.4 -26.1#2.3 161.0#2.1 6-(5-isopropyl-3-pyrazolyioxy)hexyl ester (Example 16) Table 1 Hypotensive effect Dosage Heart rate Mean blood ressure Duration Compound glkgi.v. #heart rate/min.#S.E. #mmHg#S.E. min.#S.E.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 -3.0#2.5 -17.5#2.2 86.6#6.7 methoxycarbonylpyridine-5-carboxylic acid 6- 10 -7.2#3.8 -27.2#3.1 180 or longer (5-methyl-3-pyrazolyloxy)hexyi ester (Example 18) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 -3.7#1.3 -18.1#2.9 73.2#4.2 (2-normalpropoxyethoxycarbonyl)pyridine-5- 10 -6.5#2.5 -30.6#3.2 180 or longer carboxylic acid 6-(5-ethyl-3-pyrazolyloxy) hexyl ester (Example 21) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 2.4#1.3 -15.0#2.0 48.9#3.1 (2-normalpropoxyethoxycarbonyl)pyridine-5- 10 3.6#1.4 -29.2#2.1 91.2#5.8 carboxylic acid 6-(5-ethyl-3-pyrazolyloxy) hexyl ester (Example 23) 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3- 3 2.7#1.8 -19.1#2.0 82.0#3.1 isopropoxycarbonylpyridine-5-carboxylic acid 10 7.9#2.8 -31.4#3.3 180 or loger 6-(5-isopropyl-3-pyrazolyioxy)hexyl ester (Example 28) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 -3.5#2.4 -17.1#2.8 82.5#3.9 methoxycanbonylpyridine-5-carboxylic acid 6- 10 -8.2#1.6 -28.8#2.4 163.2#4.3 (5-methyl-3-pyrazolyloxy)hexyl ester (Exampie 33) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.7#1.1 -15.6#2.8 73.5#5.3 normalpropoxycarbonylpyridine-5-carboxylic acid 10 3.9#1.0 -29.0#3.0 180 or longer 6-(5-methyl-3-pyrazolyloxy)hexyi ester (Example 35) 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3- 3 5.8#3.7 -24.3#1.4 149.1#1.4 methoxycanbonylpyridine-5-carboxylic acid 6- 10 8.2#1.7 -39.4#2.0 180 or longer (5-methyl-3-pyrazolyloxy)hexyl ester (Exampie 37) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 -6.0#3.2 -19.6#3.7 98.3#6.2 methoxycanbonylpyridine-5-carboxylic acid 6- 10 -11.0#2.9 -31.8#3.4 180 or longer (5-methyl-3-pyrazolyloxy)hexyl ester (Exampie 39) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 4.8#2.1 -13.0#3.6 44.1#3.6 methoxycanbonylpyridine-5-carboxylic acid 6- 10 7.5#3.6 -23.3#2.9 108.6#4.5 (5-methyl-3-pyrazolyloxy)hexyl ester (Exampie 40) Table 1 Hypotensive effect Dosage Heart rate Mean blood ressure Duration Compound glkgi.v.
#heart rate/min.#S.E. #mmHg#S.E. min.#S.E.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 2.8#1.7 -20.2#3.7 139.1#4.3 methoxycarbonylpyridine-5-carboxylic acid 6- 10 6.1#3.5 -36.4#3.1 180 or longer (5-hexyl-3-pyrazolyloxy)hexyl ester (Example 42) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.7#1.3 -14.7#1.7 64.4#3.7 (2-isopropoxyethoxycarbonyl)pyridine-5- 10 4.9#1.4 -26.5#2.3 152.1#4.3 carboxylic acid 6-(5-methyl-3-pyrazoloxy) hexyl ester (Example 47) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 4.3#0.8 -12.9#2.1 151.0#5.9 methoxycarbonylpyridine-5-carboxylic acid 6- 10 9.2#1.2 -27.0#2.6 180 or longer (5-phenyl-3-pyrazolyioxy)hexyl ester (Example 49) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 4.1#1.7 -13.2#2.2 50.3#3.8 methoxycarbonylpyridine-5-carboxylic acid 6- 10 8.5#2.4 -22.6#1.9 103.5#4.9 (5-m-fluorophenyl-3-pyrazolyloxylhexyl ester (Example 50) 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3- 3 2.9#1.3 -14.5#1.6 113.2#7.5 methoxycarbonylpyridine-5-carboxylic acid 6- 10 9.8#2.9 -25.9#2.4 180 or longer (5-p-phenyl-3-pyrazolyloxylhexyl ester (Example 51) 1,4-Dihydro-2,6-dimethyl-4-(3-nitropheanyl)-3- 3 7.3#1.6 -14.7#1.8 63.5#3.8 methoxycarbonylpyridine-5-carboxylic acid 6- 10 13.6#2.8 -25.2#1.7 115.6#5.7 (4-phenyl-3-pyrazolyloxy)hexyl ester (Example 57) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 -2.0#1.3 -14.2#2.6 87.3#4.6 methoxycarbonylpyridine-5-carboxylic acid 6- 10 -7.0#1.8 -20.9#2.7 180 or longer (5-0-chlorophenyl-3-pyrazolyloxy)hexyl ester (Example 58) 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3- 3 -5.6#.25 -21.7#2.1 136.3#9.2 methoxycarbonylpyrldine-5-carboxylic acid 6- 10 -10.1#3.0 -37.8#3.2 180 or longer (5-0-chlorophenyl-3-pyrazolyloxy)hexyl ester (Example 59) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.5#0.3 -10.9#1.4 102.4#7.5 normalpropoxycarbonylpyridine-5-carboxylic acid 10 -4.1#2.7 -18.6#2.3 159.6#4.8 6-[5-(2,4-dichlorophenyl)-3-pyrazolyloxy]hexyl ester (Example 65) Table 1 (contd.) Hypotensive effect Dosage Heart rate Mean blood ressure Duration Compound glkgi.v. #heart rate/min.#S.E. #mmHg#S.E. min.#S.E.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 2.0#1.1 -15.7#1.8 34.0#3.6 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 2.8#1.9 -25.3#2.7 89.5#3.8 0-methoxyphenyl-3-pyrazolyloxy)hexyl ester (Example 67) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 4.2#1.8 -16.6#1.6 146.6#4.3 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 9.5#2.7 -28.2#2.4 180 or longer 0-nitrophenyl-3-pyrazolyloxy)-3,4-dimethylhexyl ester (Example 76) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 10.3#2.3 -14.6#1.3 52.1#2.0 isobutoxycarbonylpyridine-5-carboxylic acid 6- 10 16.4#4.3 -22.4#2.1 82.5#4.8 (5-m-fluorophenyl-3-pyrazolyloxy)hexyl ester (Example 80) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 8.8#3.6 -19.5#1.4 124.4#7.4 (2-isobutoxyethoxycarbonyl)pyridine-5-carboxylic 10 10.3#3.3 -29.9#2.2 180 or longer acid 6-(5-m-fluorophenyl-3-pyrazolyloxy)hexyl ester (Example 81) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 0.00#.0 -12.6#2.0 124.4#7.4 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 -2.31#.1 -21.0#2.1 180 or longer 0-tolyl-3-pyrazolyloxy) hexyl ester (Example 83) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.00#.3 -13.8#1.7 102.8#4.7 (2-isopropoxyethoxycarbonyl)pyridine-5- 10 -2.00#.8 -25.2#2.0 165.0#6.5 carboxylic acid 6-(5-0-tolyl-3-pyrazolyloxy) hexyl ester (Example 84) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 5.82#.6 -12.9#1.6 60.8#2.9 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 8.93#.4 -21.4#1.9 96.3#4.3 m-cyanophenyl-3-pyrazolyloxy)hexyl ester (Example 87) 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3- 3 7.74#.8 -20.1#1.3 160.2#7.7 methoxycarbonylpyridine-5-carboxylic acid 6-[5- 10 12.15#.3 -32.5#2.7 180 or longer (0-trifluoromethylphenyl)-3-pyrazolyloxy]hexyl ester (Example 89) Table 1 (contd.) Hypotensive effect Dosage Heart rate Mean blood ressure Duration Compound glkgi.v. #heart rate/min.#S.E. #mmHg#S.E. min.#S.E.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 2.4#0.8 -23.6#2.1 48.5#2.4 methoxycarbonylpyridine-5-carboxylic acid 6-[5- 10 7.8#3.1 -44.3#3.4 93.7#5.8 (2-pyridyl)-3-pyrazolyloxy]hexyl ester (Example 91) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.5#2.4 -14.3#1.8 132.8#9.3 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 -3.0#4.2 -22.6#2.7 180 or longer benzyl-3-pyrazolyloxy)hexyl ester (Example 94) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 0.0#0.0 -14.5#1.6 76.8#2.8 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 -1.0#2.0 -25.0#2.3 137.2#4.1 p-chlorophenyl-3-pyrazolyloxy)hexyl ester (Example 96) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 0.0#0.0 -13.8#1.8 78.6#3.6 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 -1.0#0.8 -24.3#2.2 129.0#5.0 p-chlorophenyl-3-pyrazolyloxy)thexyl ester (Example 97) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.8#0.9 -13.5#2.4 58.6#3.5 methoxycarbonylpyridine-5-carboxylic acid 6-[5- 10 2.4#1.2 -23.7#2.6 104.3#5.2 (3,4-methylenedioxyphenyl)-3-pyrazolyloxy]hexyl ester (Example 98) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 3 1.5#0.8 -14.5#1.5 124.7#7.3 3-methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 3.1#1.2 -22.8#2.1 180 or longer phenyl-3-pyrozolyloxy)hexyl ester (Example 100) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 2.0#42 -17.2#2.2 98.6#3.8 ethoxycarbonylpyridine-5-carboxylic acid 6-[5- 10 -5.3#1.8 -26.7#2.4 180 or longer 0-chiorophenyl-3-pyrozolyloxy)hexyl ester (Example 101) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 1.2#0.8 -13.2#1.7 51.2#2.9 methoxycarbonylpyridine-5-carboxylic acid 6-[5- 10 -1.5#2.9 -24.8#2.3 106.8#3.5 (p-N-acetylaminophenyl)-3-pyrazolyloxy]hexyl ester (Example 110) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- 3 9.3#3.7 -19.5#2.1 98.2#6.2 methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 15.7#2.3 -31.2#2.7 156.1#5.7 phenyl-3-pyrazolyloxy)hexyl ester (Example 113) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 3 1.5#0.8 -12.4#1.7 80.1#4.2 3-methoxycarbonylpyridine-5-carboxylic acid 6-(5- 10 2.6#1.3 -25.6#2.3 145.2#4.6 p-methoxyphenyl-3-pyrozolyloxy)hexyl ester (Example 117) As is clear from Table 1, it is observed with each compound that a hypotensive effect is retained for from about 1.5 hours in even the shortest case to as long as 3 hours or longer in the longer cases at an amount equivalent to the dosage, for example, 10 yg/kg, and that the change in heart rate is slight.
In the test separately conducted on the hypotensive effect on the vertebral artery, each compound was observed to have a long-lasting vasodilating effect. Further, in the toxicity test, it was confirmed that each compound is of only a low degree of toxicity. Therefore, the derivatives of the present invention [I] are useful as drugs for treating hypertension.
The present invention is more particularly described by the following Examples.
Example 1 0.24 g (10 mmole) of sodium hydride was suspended in 10 ml of dimethylsulfoxide, to which was added gradually 1.00 g (10 mmole) of 3-methyl-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added dropwise 30 ml of a solution of 5.87 g (10 mmole) of 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in dimethylsulfoxide, and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was poured into 200 ml of ice water, and the separated product was extracted with 100 ml of chloroform. This chloroform solution was washed with 50 ml of water 5 times, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a brown oily residual liquid.This residual liquid was purified by silica gel column chromatography using a mixed solution of benzene -- ethyl acetate (the ratio by volume of 1:1) as an eluent to obtain 3.20 g (yield 62.4%) of a pale yellow powder of the 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3methoxycarbonylpyridine-5-carboxylic acid 6-( 5-methyl-3-pyrazolyloxy)hexyl ester.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1520,1340,1220,1118.
PMR Spectrum (CDCI3+D2O) S: 1.10-1.19 (8H, m), 2.20 (3H, s), 2.33 (6H, s), 3.60 (3H, s), 4.00 (4H, t), 5.02 (1 H, s), 5.37 (1 H, s), 7.00-8.10 (4H, m).
Analysis for C26H32N407: Calcd. (%): C, 60.93 H, 6.29 N, 10.93 Found (%): C, 61.13 H, 6.43 N, 10.75 Procedures similar to the above were repeated, except that the 3-methyl-5-pyrazolone and the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6tosyioxyhexyl ester were replaced by the corresponding compounds and further the sodium hydride was replaced, depending on the necessity, by other appropriate anionizing reagents, to obtain the compounds 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)- ,6-diisopropylhexyl ester Aspect: Pale yellow powder IR Spectrum (CHCl3) cm-1: 3490, 3460, 2940, 1690, 1520, 1340.
PMR Spectrum (CDCI3) S: 3.60 (3H,s),5.10 (1H,s), 5.40 (1H,s).
Analysis for C32H44N4O7: Calcd. (%): C, 64.41 H, 7.43; N, 9.39 Found (%): C, 64.81 H, 7.76 N, 9.05 Example 3 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5 isopropyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm~': 3490, 3460, 2940, 1690, 1520, 1340, 1220.
PMR Spectrum (CDCI3+D20) S: [1.00--1.90 (8H, m) and 1.20 (6H, d); total 1 4H], 2.30 (6H, s), 2.55-3.00 (1 H, m), 3.57 (3H, s), 4.00 (4H, t), 5.01 H, s), 5.38 (1 H, s), 7.05-8.07 (4H, m).
Analysis for C28H36N4O7: Calcd. (%): 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)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-( 5methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3470, 2980, 2940, 1695, 1520.
PMR Spectrum (CDCl3+D2O) #: 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 ( 1 H, s), 5.35 (1 H, s), 7.15-8.07 (4H, m).
Analysis for C27H34N4O7: Calcd. (%): C, 61.58 H, 6.51 N, 10.64 Found (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1520, 1340.
PMR Spectrum (CDCl3+D2O)#: 0.65-1.95 (21 H, m), 2.30 (6H, s), 2.553.00 (1 H, m), 3.80-4.21 (6H, m), 5.09 (1 H, s), 5.38 (1 H, s), 7.02-8.07 (4H, m).
Analysis for C31H42N407: Calcd. (%): C, 63.90 H, 7.27 N, 9.62 Found (%): C, 64.27 H, 7.58 N, 9.90 Example 6 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5 hexyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490,3460,1685,1340.
PMR Spectrum (CDCI3+D20) #: 0.55-2.00 (22H, m), [2.30 (6H, s) and 2.30-2.70 (2H); total 8H], 3.80-4.23 (6H, m), 5.10 (1 H, s), 5.37 (1 H, s), 7.02-8.05 (4H, m).
Analysis for C32H44N407: Calcd. (%): 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)-3-isopropoxycarbonylpyridine-5-carboxylic acid 6 (5-methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1520, 1340, 1220.
PMR Spectrum (CDCI3+D20) #: [1.10 (3H, d), 1.25 (3H, d) and 1.00-1.95 (8H, m); total 1 4H], 2.20 (3H, s), 2.30 (6H, s), 3.97 (4H, t), [4.60-5.05 (1 H, m) and 5.00 (1 H, s); total 2H], 5.00 (1 H, s), 5.37 ( 1 H, s), 7.05-8.07 (4H, m).
Analysis for C28H36N4O7: Calcd. (%): C, 62.21 H, 6.71 N, 10.36 Found (%): C, 62.40 H, 6.92 N, 10.44 Example 8 1 ,4-Di hydro-2,6-dimethyl-4-(3-nitrophenyl)-3-isopropoxycarbonylpyridine-5-carboxylic acid 6 (5-octyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
RSpectrum(CHCl3)cm-1: 3490, 3460, 1690, 1520, 1340.
PMR Spectrum (CDCl3)#: 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 (1H,m), 5.10 (1H,s).
Analysis for C35H50N4O7: Calcd. (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1340, 1220.
PMR Spectrum (CDCI3+D20) S: [0.77 (6H, dd), 1.20 (6H, d) and 1.00-2.00 (9H, m); total 21 H], 2.30 (6H, s), 2.50-3.07 (1 H, m), [3.67 (2H, d) and 3.53-4.13 (4H, m); total 6H], 5.03 (1 H, s), 5.33 (1 H, s), 7.05- 8.07 (4H, m).
Analysis for C31H42N4O7: Calcd. (%): C, 63.90 H, 7.27 N, 9.62 Found (%): C, 64.35 H, 7.51 N, 9.42 Example 10 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(2-methoxyethoxyCa rbonyl)pyridine-5-carboxylic acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1340.
PMR Spectrum (CDCI3) S: 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 (1 H, s), 5.40 (1 H, s), 6.93 (1 H, s), 7.07-8.16 (4H, m), 8.83 (1 H, broad).
Analysis for C26H36N407: Calcd. (%): 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-5carboxylic acid 6-(5-octyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3)cm-1: 3490, 3460, 1690, 1520, 1340.
PMR Spectrum (CDCl3+D2O) S: 0.57-2.00 (29H, m), 2.30 (6H, s), 2.30-2.70 (2H), 3.2(&num;4.45 (9H, m), 5.10 (1H s), 5.38 (1 H, s), 7.05-8.07 (4H, m).
Analysis for C37H54N406: Calcd. (%): 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-carboxylic acid 6-(5methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490,3455, 1685, 1515, 1345.
PMR Spectrum (CDC13+D20) S: 1.10-2.00 (8H, m), 2.04-2.40 (9H), 3.55 (3H, s),3.76-4.16 (4H), 5.37 (1 H, s), 5.67 (1 H, s), 6.92-7.70 (4H, m).
Analysis for C26H32N4O7: Calcd. (%): C, 60.93 H, 6.29 N, 10.93 Found (%): C, 60.85 H, 6.43 N, 10.86 Example 13 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-(2-isopropoxyethoxycarbonyl)pyridine-5carboxylic acid 6-(5-methyl-3-pyrazolyl oxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3485, 3460, 1690, 1520.
PMR Spectrum (CDC13+D20) #: [1.13 (6H, d) and 0.90-1.95 (8H, m); total 1 4H], 2.05-2.41 (9H), 3.22-4.48 (9H, m), 5.40 (1H,s),5.70 (1H,s),6.93-7.70 (4H,m).
Analysis for C30H40N4O8: Calcd. (%): C, 61.63 H, 6.90 N, 9.58 Found (%): C, 61.96 H, 7.06 N, 9.89 Example 14 To 1 5 ml of a suspension of 0.36 9 (1 5 mmole) of sodium hydride in N,N-dimethylformamide was added gradually 2.52 g (20 mmole) of 3-isopropyl-5-pyrazolone with stirring at room temperature, and the mixture was allowed to stand until evolution of hydrogen ceased. To this solution was added dropwise 15 ml of a solution of 6.01 g (10 mmole) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3ethoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in N,N-dimethylformamide, and the mixture was stirred at 70 C for 2 hours.The resulting reaction mixture was poured into 200 ml of ice water, the separated product was extracted with 100 ml of ethyl acetate, and this ethyl acetate solution was washed with 50 ml of water twice, 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 impurities-free fractions in the fixed phase were eluted with a mixed solution of chloroform-methanol (the ratio by volume of 160:1), and the eluate was conentrated to dryness under reduced pressure to obtain 2.55 g (yield 46.0%) of a pale yellow powder of the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5isopopyl-3-pyrazolyloxy)hexyl ester.
IR Spectrum (CHCI3) cm-1: 3490, 3465, 2940, 1690, 1520.
PMR Spectrum (CDCI3+D20) S: [1.21 (6H, d), 1.00--2.00 (11 H, m); total 1 7H], 2.30 (6H, s), 2.56-3.00 (1 H), 3.7-4.27 (6H, m), 5.00 (1 H, s), 5.37 (1 H, s), 7.00-8.07 (4H, m).
Analysis for C29H38N407: Calcd. (%): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 63.10 H, 7.07 N, 9.82 Procedures similar to similar to the above were repeated, except that the 3-isopropyl-5-pyrazolone and the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6tosyloxyhexyl ester were replaced by the corresponding compounds, and further the sodium hydride or other anionizing reagents or the solvent was appropriately chosen and used, to obtain the compounds in Examples 1 5-38 below.
Example 15 1 ,4-Di hydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-( 5normalbutyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490,3460,2940,1690,1525.
PMR Spectrum (CDCl3) S: 0.68-1.11 (3H),[1.22 (3H,t) and 1.05-2.00 (12H,m); total 15H],2.30 (6H,s),2.30 2.75 (2H), 3.83-4.21 (6H,m),5.01 (1H,s), 5.35 (1H,s),6.80 (1H,s),7.05-8.10 (4H,m), 8.92 (1H, broad).
Analysis for C30H40N4O7: Calcd. (%): 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-isopropoxyca rbonylpyridine-5-carboxylic acid 6 ( 5-isopropyl-3-pyrazolyloxy) hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3490,3465,2940,1690,1520.
PMR Spectrum (CDCI3+D2O) (5: 0.91-1.86 (20H, m), 2.30 (6H, s), 2.53-3.13 (1 H, m), 3.804.1 7 (4H, m), [4.63-5.10 ( 1 H, m) and 5.00 (1 H, s); total 2H], 5.38 (1 H, s), 7.13-8.07 (4H, m).
Analysis for C30H40N4O7: Calcd. (%): C, 63.36 H, 7.09 N, 9.85 Found (%): C, 63.45 H, 7.28 N, 9.98 Example 17 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-isobutoxycarbonylpyridine-5-carboxylic acid 6-(5 methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3490,3460,2970,2940,1690,1340.
PMR Spectrum (CDCI3+D2O) (5: 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 3 (4H); total 6H], 5.02 (1 H, s), 5.32 (1 H, s), 7.00-8.06 (4H, m).
Analysis for C29H38N4O7: Calcd. (%): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 63.15 H, 7.26 N, 10.41 Example 18 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-isobutoxycarbonylpyidine-5-carboxylic acid 6-(5 ethyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3465, 2940, 1695, 1520, 1340, 1220, 1120.
PMR Spectrum (CDCl3+D2O)#: 0.78 (6H, dd), [1.20 (3H, t) and 1.00-2.09 (9H, m); total 1 2H], 2.30 (6H, s), 2.53 (2H, q), [3.70 (2H, d) and 3.52-4.14 (4H, m); total 6H], 5.00 ( 1 H, s), 5.30 ( 1 H, s), 7.00-8.10 (4H, m).
Analysis for Ca0H40N4O7: Calcd. (%): C, 63.36 H, 7.09 N, 9.85 Found (%): 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-normalbutyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3495, 3460, 2940, 1690, 1525, 1340, 1220.
PMR Spectrum (CDC13+D20) #: 0.67-1.08 (3 H), 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 (1 H, s), 5.40 (1 H, s), 7.05-8.10 (4H, m).
Analysis for C31H42N4O8: Calcd. (%): C, 62.19 H, 7.07 N, 9.36 Found (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1520, 1340.
PMR Spectrum (CDCI3+D2O) #: [0.83-2.00 (8H, m) and 1.23 (6H, d); total 1 4H], 1.23 (6H, d), 2.33 (6H, s), 2.50-3.13 (1 H, m), 3.30 (3H, s), 3.51 (2H, t), 3.70-4.27 (6H, m), 5.07 (1 H, s), 5.43 (1 H, s), 7.10- 8.13 (4H, m).
Analysis for C30H40N4O8: Calcd. (%): 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-nitrophenyli-3-(2-normalpropoxyethoxywarbonyl)pyridine-5- carboxylic acid 6-(5-ethyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3495,3460,1687,1458,1342.
PMR Spectrum (CDCI3) #: 0.86 (3H, t), [1.20 (3H, t) and 1.00-1.90 (1 OH, m); total 1 3H], 2.30 (6H, s), 2.57 (2H, q), 3.21-3.73 (4H, m), 3.73-4.29 (6H, m), 5.07 (1 H, s), 5.40 (1 H, s), 6.80 (1 H, s).
Analysis for C31H42N408: Calcd. (%): 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-normalpropoxyethoxycarbonyl)pyridine-5carboxylic acid 6-(5-isopropyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3490, 3460, 1690, 1460, 1340.
PMR Spectrum (CDCl3)#: 0.86 (3H, t), [1.20 (6H, d) and 1.00-1.90 (1 OH, m); total 1 6H], 2.30 (6H, s), 2.55-3.05 (1 H, m), 3.20-3.73 (4H, m), 3.73-4.30 (6H, m), 5.05 (1 H, s), 5.38 (1 H, s), 6.75 (1 H, s).
Analysis for C32H44N4O8: Calcd. (%): C, 62.73 H, 7.24 N, 9.14 Found (%): C, 63.14 H, 7.65 N, 9.38 Example 23 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(2-isobutoxyethoxyearbonyl)pyridine-5-carboxylic acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3490,3460,3000,2950,2860,1690,1515.
PMR Spectrum (CDCI3) S: 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 (1H, s), 5.36 (1H, s).
Analysis for C31H42N4O8: Calcd. (%): 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-methoxyethoxycarbonyl)pyridine-5-carboxylic acid 6-(5-methyl-3-pyrazolyloxy)-2,5-dimethylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3)cm-1: 3490,3455,1685,1515,1345.
PMR Spectrum (CDCI3) S: 0.55-1.95 (1 2H, m), 2.04-2.41 (9H), 3.32 (3H, s), 3.50 (2H, t), 3.82-4.20 (6H, m), 5.38 (1 H, s), 5.70 (1 H, s).
Analysis for C30H40N4O8: Calcd. (%): C, 61.63 H, 6.90 N, 9.58 Found (%): C, 61.92 H, 7.34 N, 9.77 Example 25 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-(methoxycarbonylpyridine-5-carboxylic acid 6-(5ethyl-3-pyrazolyloxy)- 1 ,6-dimethylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCi3) cm-1: 3490, 3455, 1680, 1520, 1345.
PMR Spectrum (CDCI3) S: 0.85-1.90 (1 7H, m), 2.23 (3H, s), 2.30 (3H, s), 2.56 (2H, q), 3.57 (3H, s), 5.40 (1 H, s), 5.73 (1 H, s).
Analysis for C29H38N4O7: Calcd. (%): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 62.98 H, 7.05 N, 10.40 Example 26 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-(methoxycarbonylpyridine-5-carboxylic acid 6-(5isopropyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 1685, 1520, 1340.
PMR Spectrum (CDCl3) #: [1.00-1.90 (8H, m) and 1.20 (6H, d); total 1 4H], 2.21 (3H, s), 2.27 (3H, s), 2.55-3.00 (1 H, m), 3.55 (3H, s), 3.76- 4.15 (4H), 5.38 (1 H, s), 5.72 (1 H, s).
Analysis for C28H36N4O7: Calcd. (%): C, 62.21 H, 6.71 N, 10.36 Found (%): C, 62.60 H, 6.98 N, 10.75 Example 27 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-(ethoxycarbonylpyridine-5-carboxylic acid 6-(5methyl-3-pyrazolyloxy)-2,5-diisopropylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3490,3460,1685,1520,1345.
PMR Spectrum (CDCI3) S: 0.57-2.00 (23H, m), 2.04-2.50 (9H), 3.78-4.22 (6H, m), 5.37 (1 H, s), 5.70 (1 H, s).
Analysis for C33H46N4O7: Calcd. (%): C, 64.89 H, 7.59 N, 9.17 Found (%): C, 65.26 H, 7.95 N, 9.01 Example 28 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-isopropoxycarbonylpyridine-5-carboxylic acid 6 (5-norma Ibutyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3)cm-1: 3490, 3455, 1 685, 1345.
PMR Spectrum (CDCI3) S: 2.20 (3H, s), 2.25 (3H, s), 2.30-2.70 (2H), 3.80-4.20 (6H, m), 4.55-5.05 (1 H, m), 5.40 (1H, s), 5.70 (1H, s).
Analysis for C3,H42N407: Calcd. (%): C, 63.90 H, 7.27 N, 9.62 Found (%): C, 63.99 H, 7.46 N, 9.68 Example 29 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5methyl-3-pyrazolyloxy)- 1 ,6-diethylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3485,1685,1520.
PMR Spectrum (CDCI3) #: 0.58-1.95 ( 1 8H, m), 2.04-2.40 (9H, m), 3.60 (3H, s), 5.40 (1 H, s), 5.70(1 H, s).
Analysis for C30H40N407: Calcd. (%): C, 63.36 H, 7.09 N, 9.85 Found (%): C, 63.75 H, 7.42 N, 9.98 Example 30 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-etoxycarbonylpyridine-5-carboxylic acid 6-(5isopropyl-3-pyrazolyioxy)- 1 ,6-dimethylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 1690, 1520, 1342.
PMR Spectrum (CDCI3) (5: 0.65-2.00 (23H, m), 2.30 (6H, s),2.56-3.00 (1 H, m), 4.00 (2H, t), 5.10 (1 H, s), 5.40 (1H,s).
Analysis for C3,H42N407: Calcd. (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3485,3455,1685,1220.
PMR Spectrum (CDCI3) #: 3.32 (3H, s), 3.50 (2H, t), 3.70-4.32 (6H, m), 5.40 (1 H, s), 5.70 (1 H, s).
Analysis for C29H38N4O8: Calcd. (%): 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-( 5ethyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3)cm-1: 3490, 3460, 2940, 1695, 1520, 1340.
PMR Spectrum (CDCI3) #: 2.33 (6H, s), 2.56 (2H, q), 3.80-4.25 (6H, m), 5.00 ( 1 H, s), 5.40 ( 1 H, s), 6.71(1 H, s).
Analysis for C28H36N4O7: Calcd. (%): C, 62.21 H, 6.71 N, 10.36 Found (%): C, 62.60 H, 6.33 N, 10.12 Example 33 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl )-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5normalbutyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1520, 1340, 1220.
PMR Spectrum (CDCI3+D2O) #: 0.70-1.10 (3H), 1.10-2.00 (1 2H, m), 2.30 (6H, s), 2.30-2.70 (2H), 3.57 (3H, s), 3.70-4.17 (4H), 5.00 (1H,s), 5.34 (1H,s), 7.02-8.10 (4H, m).
Analysis for C29H38N407: Calcd. (%): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 62.97 H, 6.76 N, 10.21 Example 34 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl-4-(3-nitrophenyl)-3-norma Ipropoxycarbonylpyridine-5-carboxylic acid 6-(5-ethyl-1-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder IR Spectrum (CHCI3) cm-1: 3490,3460,2940,1690.
PMR Spectrum (CDCI3) S: 2.30 (6H, s), 2.55 (2H), 3.83-4.22 (6H, m), 5.00 (1 H, s), 5.35 (1 H, s), 6.64 (1 H, s).
Analysis for C29H38N4O7: Calcd. (%): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 63.14 H, 6.76 N, 10.41 Example 35 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-normalpropoxycarbonylpyridine-5-carboxylic acid 6-( 5-isopropyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
@R Spectrum (CHCl3)cm-1: 3490,3465,2940,1690,1520.
PMR Spectrum (CDCI3) (5: 2.30 (6H, s), 2.50-3.00 (1 H, m), 3.834.25 (6H, m), 5.01(1 H, s), 5.40 (1 H, s), 6.81(1 H, s).
Analysis for C30H40N407: Calcd. (%): C, 63.36 H, 7.09 N, 9.85 Found (%): C, 63.47 H, 7.18 N, 9.68 Example 36 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-(ethoxycarbonylpyridine-5-carboxylic acid 6-(5ethyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3455,1685.
PMR Spectrum (CDCI3) #: 2.20 (3H, s), 2.27 (3H, s), 2.56 (2H, q), 3.80-4.20 (6H, m), 5.40 (1 H, s), 5.70 (1 H, s).
Analysis for C28H36N407: Calcd. (%): C, 62.21 H, 6.71 N, 10.36 Found (%): 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-(5octyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCIa) cm-1: 3485, 3455, 1690.
PMR Spectrum (CDCI3) #: 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 (1H,s),5.70 (1H,2).
Analysis for C33H46N4O7: Calcd. (%): C, 64.90 H, 7.59 H, 9.17 Found (%): C, 64.78 H, 7.71 H, 9.36 Example 38 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(methoxycarbonylpyridine-5-carboxylic acid 6-(5methyl-3-pyrazolyloxy)-5,5-dimethyl hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490,3460,1690,1520.
PMR Spectrum (CDCI3) a: 0.64-1.95 (1 2H, m), 2.20 (3H, s), 2.30 (6H, s), 3.60 (3H, s), 3.80-4.23 (4H, m), 5.10 ( 1 H, s), 5.40 (1 H, s).
Analysis for C28H36N4O7: Calcd. (%): C, 62.21 H, 6.71 N, 10.36 Found (%): C, 62.58 H, 6.99 N, 10.15 Example 39 0.72 g (30 mmole) of sodium hydride was suspended in 60 ml of N,N-dimethylformamide, to which was added gradually 5.60 g (50 mmole) of 3-ethyl-5-pyrazolone with stirring at room temperature, and the mixture was allowed to stand until evolution of hydrogen ceased. To this solution was added dropwise 40 ml of a solution of 4.91 g (10 mmole) of 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-chlorohexyl ester in N,Ndimethylformamide, the mixture was heated at 90-1 000C 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 resulting separated product was extracted with 100 ml of ethyl acetate, and this was washed with water, dried, and concentrated under reduced pressure to obtain a brown oily residual liquid. This residual liquid was purified by subjecting to silica gel column chromatography using a mixed solution of chloroform-ethanol (the ratio by volyme of 20:1) as an eluent to obtain 1.79 g (yield 34.0%) of a pale yellow powder of the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5carboxylic acid 6-(5-ethyl-3-pyrazolyloxy)hexyl ester.
IR Spectrum (CHCI3) cm-1: 3490, 3465, 2940, 1690, 1520.
PMR Spectrum (CDCI3+D2O) (5: [1.20 (3H, t), 1.00--1.89 (8H, m), total 11 H], 2.33 (6H, s), 2.56 (2H, q), 3.60 (3H, s), 4.00 (4H, t), 5.05 ( 1 H, s), 5.40 (1H, s), 7.07-8.08 (4H, m).
Analysis for C27H34N4O7: Caicd. (%): C, 61.58 H, 6.51 N, 10.64 Found (%): C, 61.74 H, 6.80 N, 10.42 Procedures similar to the above were repeated, except that the 3-ethyl-5-pyrazolone and the 1,4dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-chlorohexyl ester were replaced by the corresponding compounds, and further the sodium hydride or toher anionizing reagents or the solvent was appropriately chosen and used, to obtain the compounds in Examples 40 47 below.
Example 40 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5methyl-3-pyrazolyloxy)-1-methylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490,3460,1690,1520.
PMR Spectrum (CDCl3)#: 0.92-1.95 (1 1 H, m), 2.20 (3H, s), 2.27 (6H, s), 3.60 (3H, s), 3.80-4.18 (2H, t), 4.60- 5.06 (1 H, m), 5.09 (1 H, s), 5.38 (1 H, s).
Analysis for C27H34N4O7: Calcd. (%): C, 61.58 H, 6.51 N, 10.64 Found (%): 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-(5isopropyl-3-pyrazolyloxy)-1-methylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm~l: 3490, 3460, 2940, 1690, 1520.
PMR Spectrum (CDCI3) (5: 0.95-1.95 (1 7H, m), 2.30 (6H, s), 2.55-3.00 (1 H, m), 3.57 (3H, s), 3.75-4.23 (2H), 4.50--5.16 (1 H, m), 5.38 (1 H, s), 5.69 (1 H, s).
Analysis for C29H38N4O7: Calcd. (%): C,62.80 H,6.91 N, 10.10 Found (%): C, 62.99 H, 7.30 N, 10.39 Example 42 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5hexyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) mc-1: 3490, 3460, 1690, 1340, 1220.
PMR Spectrum (CDCI3+D2O) #: 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 (1H,s), 5.38 (1H,s), 7.02-8.09 (4H, m).
Analysis for C31H42N4O7: Calcd. (%): C, 63.90 H, 7.27 N, 9.62 Found (%): C, 63.81 H, 7.48 N, 9.83 Example 43 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5 ethyl-3-pyrazolyloxy)-5-methylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3455, 1690.
PMR Spectrum (CDCI3+D20) #: 0.66-1.95 (1 6H, m), 2.21 (3H, s), 2.28 (3H, s), 2.56 (2H, q), 3.83-4.20 (6H, m), 5.40 ( 1 H, s), 5.70(1 H, s), 6.93-7.70 (4H, m).
Analysis for C29H38N4O7: Calcd. (%): 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-normalpoxycarbonylpyridine-5-carboxylic acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3465, 2940, 1695, 1520.
PMR Spectrum (CDCI3) S: 0.90 (3H, t), 1.00-2.00 (1 OH, m), 2.18 (3H, s), 2.30 (6H, s), 3.80-4.25 (6H, m), 5.00 (1 H, s), 5.40 (1H,s).
Analysis for C28H3eN407: Calcd. (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490,3465,2940,1695,1520.
PMR Spectrum (CDCl3) #: 1.00-2.00 (17H, m), 2.33 (6H, s), 2.56 (2H, q), 3.80-4.15 (4H), 4.60-5.00 (1 H, m), 5.03 (1H, s), 5.40 (1H, s), 6.30 (1H, s).
Analysis for C29HasN4O7: Calcd. (%): C, 62.80 H, 6.91 N, 10.10 Found (%): C, 62.98 H, 7.05 N, 10.45 Example 46 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(2-methoxyethoxywarbonyl)pyridine-5-carboxylic acid 6-(5-ethyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3490, 3460, 2940, 1690, 1340.
PMR Spectrum (CDCl3) #: 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 (1H,s), 5.40 (1H,s), 6.80 (1H,s).
Analysis for C29H38N4O8: Calcd. (%): C, 61.04 H, 6.71 N, 9.82 Found (%): C, 61.43 H, 6.98 N, 9.61 Example 47 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(2-isopropoxyethoxywarbonyl)pyridine-5- carboxylic acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3495,3460,1490,1520,1455.
PMR Spectrum (CDCI3) S: 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 (1 H, s), 5.37 ( 1 H, s).
Analysis for C30H40N4O8: Calcd. (%): 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 mmole) of sodium hydride in N,N-dimethylformamide was added gradually 2.00 g (20 mmole) of 3-methyl-5-pyrazolone with stirring at room temperature, and the mixture was allowed to stand until evolution of hydrogen ceased. To this solution was added dropwise a solution of 5.87 g (10 mmole) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester dissolved in 1 5 ml of N,Ndimethylformamide. After completion of the addition, the mixture was stirred at 1 000C for an hour, 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 subjecting to silica gel column chromatography. The substances adsorbed onto the fixed phase were monitored by thin layer chromatography and carefully eluted using a mixed solution of benzeneethyl acetate (the ratio by volume of 1:1), to obtain two kinds of eluted fractions, each containing a single substance different from each other. The first eluted fraction was concentrated to dryness under reduced pressure to obtain 2.95 g (yield 57.5%) of a pale yellow powder of 1 ,4-dihydro-2,6-dimethyl4-(3-nitrophenyl)-3-methoxyca rbonylpyridine-5-carboxylic acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester.
Analysis for C26H32N40,: Calcd. (%): C, 60.93 H, 6.29 N, 10.93 Found (%): C, 61.20 H, 6.41 N, 10.69 Both IR and PMR spectra agreed with those obtained in Example 1.
Thereafter, the later eluted fraction was concentrated to dryness under reduced pressure to obtain 0.49 g (yield 7.8%) of a pale yellow oil of 1 14-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- methoxycarbonylpyridine-5-carboxyl ic acid 6-(3-hydroxy-5-methyl- 1 -pyrazolyl)hexyl ester.
IR Spectrum (CHCI3) cm~1: 3460,2490,1690,1520, 1340,1220.
PMR Spectrum (CDCI3+D2O) (5: 1.00--1.90 (8H, m), 2.13 (3H, s), 3.60 (3H, s), 3.73 (2H, t), 3.96 (2H, t), 5.00 (1 H, s), 5.17 (1 H, s), 7.00-8.10 (4H, m).
Analysis for C26H32N4O7: Calcd. (%): C, 60.93 H, 6.29 N, 10.93 Found (%): C, 61.18 H, 6.42 N, 10.73 Example 49 4.98 g (20 mmole) of methyl 3-nitrobenzylideneacetoacetate, 6.86 g (20 mmoie) of 3aminocrotonic acid 6-(5-phenyl-3-pyrazolyloxy)hexyl ester and 7 ml of ethanol were mixed and heated at reflux for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain a yellow oily residue. This oily residue was chromatographed on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 1 60:1) as an eluent and the eluate fractions containing the intended compound were concentrated under reduced pressure to obtain a yellow oil, to which was added 10 ml of ethanol, and the mixture was allowed to stand overnight, when pale yellow crystals separated.These crystals were filtered off, and recrystallized from ethanol to obtain 7.35 g (yield 64.0%) of pale yellow crystals of the 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- methoxyca rbonylpyridine-5-carboxylic acid 6-( 5-phenyl-3-pyrazolyloxy)hexyl ester.
Melting point: 151-1 530C.
IR Spectrum (CHCI3) cm~1: 3500,3460,1695,1520, 1345.
PMR Spectrum (CDCI,)G: 0.95-1.90 (8H, m), 2.31 (6H, s), 3.59 (3H, s), 3.80-4.23 (4H, m), 5.05 (1 H, s), 5.89 (1 H, s), 6.78 (1H, s), 7.038.25 (10H, m).
Example 50 4.98 g (20 mmole) of methyl 3-nitrobenzylideneacetoacetate, 7.23 g (20 mmole) of 3aminocrotonic acid 6-(5-m4luornphenyl-3-pyrazolyloxy)hexyl ester and 10 ml of isopropanol were mixed and heated at reflux for 3 hours. This reaction mixture was concentrated under reduced pressure to obtain a yellow oily residue. This oil was purified by chromatography on a silica gel column using a mixed solution of benzene-ethyl acetate (the ratio by volume of 3:1) as an eluent to obtain eluate fractions containing the intended compound, which were concentrated to dryness under reduced pressure to obtain 6.52 g (yield 55.0%) of the 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- methoxycarbonylpyridine-5-carboxylic acid 6-(5-m-fluorophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1693,1520,1345.
PMR Spectrum (CDCI3+D2O) #: 1.00-1.90 (8H,m),2.33 (6H,s),3.57 (3H,s),3.76-4.21 (4H,m),5.04 (1H,s),5.87 (1H, s),7.00-8.10 (8H,m).
Analysis for C3,H33FN407: Calcd. (%): C, 62.83 H, 5.61 N, 9.45 Found (%): C, 62.91 H, 5.83 N, 9.26 The compounds in Examples 51-95 below were producted similar procedures as in the above Example 50 except that the starting materials, the reaction solvent and other conditions were appropriately changed.
Example 51 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5phenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 198-201 0C (from toluene).
IR Spectrum (KBr) cm-1: 3320,2950,1690,1520,1350,1210.
PMR Spectrum (DMSO-ds)#: 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 (1 H, s), 6.04 (1 H, s), 6.96-7.81 (9H, m), 8.84 (1 H, s).
Analysis for C31H34N407: Calcd. (%): C, 64.80 H, 5.96 N, 9.75 Found (%): C, 64.67 H, 6.09 N, 9.59 Example 52 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5pheyl-3-pyrazolyloxy)-1,6-dimethylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3465,1693,1522,1345.
PMR Spectrum (CDCI3) #: 0.81-2.00 (1 4H, m), 2.30 (6H, s), 3.56 (3H, s), 5.04 (1 H, s), 5.89 (1 H, s), 6.89 (1 H, s).
Analysis for C33H38N4O7: Calcd. (%): C, 65.77 H, 6.36 N, 9.30 Found (%): C, 65.83 H, 6.70 N, 9.13 Example 53 1 ,4-Dihyd ro-2,6-di methyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5phenyl-3-pyrazolyloxy)-6-isopropylhexyl ester.
Aspect: Pale yellow oil.
IR Spectrum (CHCl3) cm-1: 3500,3460,1690,1520,1345.
PMR Spectrum (CDCl3)#: 2.28 (6H, s, 2,6-dimethyl group on dihydropyridine ring), 3.56 (3H, s, methyl ester), 3.97 (2H, t), 5.06 ( 1 H, s), 5.89 ( 1 H, s), 6.85 ( 1 H, broad).
Analysis for C34H40N407: Calcd. (%): 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)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5phenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3465,1695,1522,1350.
PMR Spectrum (DMSO-ds)#: 0.95-1.90 (1 1 H, m), 2.22 (3H, s), 2.28 (3H, s), 3.71-4.23 (6H, m), 5.52 ( 1 H, s), 6.04 (1H,s).
Analysis for C32H36N4O7: Calcd. (%): C, 65.29 H, 6.16 N, 9.52 Found (%): C, 65.49 H, 6.03 N, 9.37 Example 55 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-isoporopoxycarbonylpyridine-5-carboxylic acid 6 (5-phenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 1 57-1 600C (from toluene).
IR Spectrum (CHCI3) cm-': 3500, 3460, 1693, 1520, 1345.
PMR Spectrum (CDCl3) S: 0.95-1.90 (1 4H, m), 2.32 (6H, s), 3.76- 4.23 (4H, m), 4.61-5.07 (1 H, m), 5.05 (1 H, s), 5.89 (1 H, s), 6.80 (1 H, broad).
Analysis for C33H38N4O7: Calcd. (%): C, 65.77 H, 6.36 N, 9.30 Found (%): 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.
Aspect: Pale yellow crystals.
Melting point: 161-1 640C (from ethanol).
IR Spectrum (CHCI3) cm-1: 3500, 3460, 1695, 1520, 1345.
PMR Spectrum (CDCI3+DMSO-d6) #: 1.00-1.87 (8H, m), 2.31 (6H, s), 3.27 (3H, s), 3.31-3.67 (2H, m), 3.734.28 (6H, m), 5.04 (1 H, s), 5.86 (1 H, s), 7.00-8.07 (9H, m).
Analysis for C33H38N408 Calcd. (%): C, 64.07 H, 6.19 N, 9.06 Found (%): C, 64.20 H, 6.27 N, 8.89 Example 57 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(4phenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow powder.
IR Spectrum (CHCl3) cm-': 3500, 3460, 1695, 1520, 1345.
PMR Spectrum (CDCI3) S: 0.96-1.97 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.68-4.20 (4H, m), 5.04 ( 1 H, s), 6.80 ( 1 H, broad), 7.00-8.10 (9H, m).
Analysis for C31H34N407: Calcd. (%): C, 64.80 H, 5.96 N, 9.75 Found (%): 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 6-(5o-chlorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow crystals.
Melting point: 159-1 61 0C (from ethanol).
IR Spectrum (KBr) cm-1: 3360,1700,1520,1340,1207.
PMR Spectrum (DMSO-d6) #: 1.00-1.90 (8H, m), 2.29 (6H, s), 3.53 (3H, s), 3.97 (2H, t), 4,05 (2H, t), 4.99 ( 1 H, s), 6.00 (1 H, s), 7.10-8.05 (8H, m), 8.93 (1 H, s).
Analysis for C31H33CIN407: Calcd. (%): C, 61.13 H, 5.46 N, 9.20 Found (%): C, 61.38 H, 5.61 N, 8.92 Example 59 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5o-chlorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 189-1920C (from ethanol).
IR Spectrum (KBr) cm-': 3450,1685,1522,1350,1210.
PMR Spectrum (DMSO-ds)#: 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 (1 H, s), 6.07 (1 H, s), 7.13-7.77 (8H, m), 8.83 (1 H, broad).
Analysis for C31H33CIN407: Calcd. (%): 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)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5m-chlorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 147-1490C (from ethanol).
IR Spectrum (KBr) cm-1: 3377,2950,1700,1515,1340.
PMR Spectrum (DMSO-d6) S: 0.93-1.86 (8H, m), 2.30 (6H, s), 3.51 (3H, s), 3.67-4.17 (4H, m), 4.95 ( 1 H, s), 6.11(1 H, s), 7.00-7.99 (8H, m).
Analysis for C31H33CIN407: Calcd. (%): C, 61.13 H, 5.46 N, 9.20 Found (%): C, 61.47 H, 5.60 N, 9.02 Example 61 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-pchiorophenyl-3-pyrazolyloxy)-1-methylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHC13) cm-': 3500,3460,1692,1520,1345.
PMR Spectrum (DMSO-d6) #: 0.87-1.96 (14H, m), 2.31 (6H, s),3.72-4.20 (4H, m), 4.53-5.06 (2H, m), 6.07 (1 H, s), 7.05-8.06 (8H, m), 8.94 (1 H, s).
Analysis for C33H37CIN407: Calcd. (%): C, 62.21 H, 5.85 N, 8.79 Found (%): C, 62.37 H, 6.00 N, 8.63 Example 62 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5p-chlorophenyl-3-pyrazolyloxyl)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 1 92-1 940C (from benzene).
IR Spectrum (KBr) cm-1: 3310,1690,1675,1525,1350,1215.
PMR Spectrum (DMSO-d6) #: 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 (1 H, s), 6.09 (1 H, s), 7.06-7.86 (8H, m), 8.83 (1 H, s), 12.20 (1 H, s).
Analysis for C31H33ClN4O7: Calcd. (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500,3465,1695,1522,1345.
PMR Spectrum (DMSO-d6) #: 0.97-1.90 (8H, m), 2.27 (6H, s), 3.54 (3H, s), 4.99 (1 H, s), 6.03 (1 H, s), 7.00-8.05 (7H, m).
Analysis for C31H32CI2N407: Calcd. (%): C, 57.86 H, 5.01 N, 8.71 Found (%): C, 57.64 H, 5.29 N, 8.63 Example 64 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-isopropoxycarbonylpyridine-5-carboxylic acid 6 (5-o-chlorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
@R Spectrum (CHCl3)cm-1: 3500,3465,1695,1520,1345.
PMR Spectrum (DMSO-d8) #: 0.95-1.90 (1 4H, m), 3.80-4.21 (4H, m), 4.57-5.05 (1 H, m), 5.51(1 H, s), 6.00 ( 1 H, s), 7.00-8.03 (8H, m).
Analysis for C33H37CIN407: Calcd. (%): C, 62.21 H, 5.85 N, 8.79 Found (%): C, 62.07 H, 5.92 N, 8.59 Example 65 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-normalpropoxycarrbonylpyridine-5-carboxylic ic acid 6-[5-(2.4-dichlorophenyl)-3-pyrazolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500,3460,1695,1520,1345.
PMR Spectrum (CDCI3) #: 1.02--2.00 (10H, m), 2.31(6H, s), 3.78--4.23 (6H, m), 5.05 (1H, s), 6.01(1H, s).
Analysis for C33H36CI2N407: Calcd. (%): C, 59.02 H, 5.40 N, 8.34 Found (%): C, 58.71 H, 5.22 N, 8.50 Example 66 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (3,4-dichlorophenyl)-3-pyrazolyloxy] hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-': 3500, 3463, 1695, 1520, 1345.
PMR Spectrum (CDCI3) #: 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 (1 H, s).
Analysis for C31H32CI2N407: Calcd. (%): C, 57.86 H, 5.01 N, 8.71 Found (%): C, 57.69 H, 5.08 N, 8.54 Example 67 1 ,4-Dihydro-2,6-di methyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5o-methoxyphenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 1 54-1 560C (from ethanol).
IR Spectrum (CHCI3) cm-': 3380, 2950, 1690, 1520, 1345.
PMR Spectrum (DMSO-ds)#: 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 ( 1 H, s), 6.03 (1 H, s), 6.73-8.00 (8H, m), 8.80 ( 1 H, broad).
Analysis for C32H36N4o8: Calcd. (%): C, 63.56 H, 6.00 N, 9.27 Found (%): C, 63.70 H, 6.27 N, 9.11 Example 68 1 ,4-Dihydro-2,6-di methyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5-o-methoxyphenyl-3-pyrazolyloxy)hexyl ester.
Aspect: White powder.
IR Spectrum (CHCI3) cm-': 3500, 3467, 1690, 1460.
PMR Spectrum (DMSO-d6) #: 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 ( 1 H, s), 6.03 ( 1 H, s), 6.73-8.05 (7H, m), 8.73 (1 H, s).
Analysis for C32H35Ci2N3o6: Calcd. (%): C, 61.15 H, 5.61 N, 6.69 Found (%): C, 61.18 H, 5.87 N, 6.54 Example 69 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-normalpropoxyethoxycarbonylpyridine-5carboxylic acid 6-( 5-o-methoxyphenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500, 3460, 1690, 1520, 1345.
PMR Spectrum (CDCI3+DMSO-d8) S: 0.89 (3H, t), 1.00-2.00 (1 OH, m), 2.30 (6H, s), 3.18-3.75 (4H, m), 3.75-4.25 (6H, m), 3.87 (3H, s), 5.04(1 H, s), 5.95 (1 H, s), 6.70-8.17 (8H, m).
Analysis for C36H44N4O: Calcd. (%): C, 63.89 H, 6.55 N, 8.28 Found (%): C, 63.98 H, 6.32 N, 8.41 Example 70 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5m-methoxyphenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500,3460,1690,1520,1345.
PMR Spectrum (DMSO-d6) S: 0.95-1.90 (8H, m), 2.21 (3H, s), 2.28 (3H, s), 3.43 (3H, s), 3.75-4.23 (4H, m), 3.82 (3H, s), 5.51 (1H, s), 5.96 (1H, s), 6.70-8.07 (8H, m).
Analysis for C32H36N4O8: Calcd. (%): C, 63.56 H, 6.00 N, 9.27 Found (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1522,1345.
PMR Spectrum (DMSO-d6) S: [1.06 (3H, d), 1.20 (3H, d) and 0.95-1.90 (8H, m); total 1 4H], 2.31 (6H, s), 3.72 (3H, s), 3.73-4.21 (4H, m), 4.58-5.03 ( 1 H, m), 5.02 (1 H, s), 5.97 (1 H, s), 6.93 (2H, d), 7.23- 8.03 (6H,m),8.91 (1H,s),12.05 (1H,s).
Analysis for C34H40N408: Calcd. (%): C, 64.54 H, 6.37 N, 8.86 Found (%): 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 acid 6-[5 (2,3-dimethoxyphenyl)-3-pyrazolyloxy] hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1693,1522,1345.
PMR Spectrum (CDCI3) S: 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 (1 H, s), 5.93 (1 H, s), 6.30 (1 H, s), 6.65-8.13 (7H, m).
Analysis for C33H38N409: Calcd. (%): C, 62.45 H, 6.04 N, 8.83 Found (%): C, 62.53 H, 6.27 N, 8.55 Example 73 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (3,4-dimethoxyphenyl)-3-pyrazolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1520,1345.
PMR Spectrum (CDCI3) S: 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 ( 1 H, s), 5.85 (1H,s).
Analysis for C33H38N4O9.
Calcd. (%): C, 62.45 H, 6.04 N, 8.83 Found (%): C, 62.54 H, 6.18 N, 8.62 Example 74 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-[5 (3,4-methylenedioxyphenyl)-3-pyrazolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500,3465,1695,1520,1345.
PMR Spectrum (DMSO-d6) S: 0.89-1.90 (8H,m),1.16 (3H,t),2.28 (6H,s),3.73-4.23 (6H,m),4.97 (1H,s), 5.95 (3H, s),6.74-8.04(7H,m),8.97 (1H,broad),11.90 (1H,broad).
Analysis for C33H36N409 Calcd. (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500, 3460, 1692, 1521, 1345.
PMR Spectrum (CDCl3) S: 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 (1 H, s), 5.83 (1H, s), 6.50 (1 H, s), 6.75 (2H, s), 7.10-8.13 (4H, m).
Analysis for C34H40N4O10: Calcd. (%): C, 61.44 H, 6.07 N, 8.43 Found (%): C, 61.21 H, 6.00 N, 8.56 Example 76 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5o-nitrophenyl-3-pyrazolyloxy)-3,4-dimethylhexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500, 3460, 1693, 1520, 1345.
PMR Spectrum (DMSO-d6) S: 2.28 (6H, s), 3.53 (3H, s), 3.754.21 (4H, m), 5.01(1 H, s).
Analysis for C33H37N509: Calcd. (%): C, 61.20 H, 5.76 N, 10.81 Found (%): C, 61.53 H, 5.77 N, 10.60 Example 77 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5m-nitrophyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow crystals.
Melting point: 96-99"C (from ethanol).
IR Spectrum (KBr) cm-': 3440, 1690, 1520, 1342, 1210.
PMR Spectrum (DMSO-d6) S: 1.00-1.90 (8H,m),2,26 (6H,s),3.56 (3H,s),3.70-4.22 (4H,m),4.97 (1H,s),6.27 (1H, s),7.25-8.52 (8H,m),8.78 (1H,s).
Analysis for C31H33N509: Calcd. (%): C, 60.09 H, 5.37 N, 11.30 Found (%): C, 60.03 H, 5.48 N, 11.11 Example 78 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-isopropoxycarbonylpyridine-5-carboxylic acid 65-m-nitropheyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow powder.
IR Spectrum (CHCI3) cm-': 3500,3463,2950,1696,1520.
PMR Spectrum (DMSO-d6) S: [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 (1 H, m), 4.99 ( 1 H, s), 6.27 (1 H, s), 7.25-8.50 (8H, m).
Analysis for C33H37N5O9: Calcd. (%): C, 61.20 H, 5.76 N, 10.81 Found (%): C, 61.26 H, 5.97 N, 10.63 Example 79 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5o-fluorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow glassy solid.
IR Spectrum (CHCl3) cm-': 3500, 3460, 1695, 1520, 1345.
PMR Spectrum (CDCI3) S: 1.00-1.90 (8H, m), 2.30 (6H, s), 3.57 (3H, s), 3.73-4.21 (4H, m), 5.05 (1 H, s), 5.86 (1 H, s).
Analysis for C31H33FN4O7: Calcd. (%): C, 62.83 H, 5.61 N, 9.45 Found (%): C, 62.94 H, 5.56 N, 9.62 Example 80 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-isobutoxycarbonylpyridine-5-ca rboxylic acid 6-( 5m-fluorophenyl-3-pyrazolyloxy) hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-': 3500,3460,1695,1520,1345.
PMR Spectrum (CDCI3) #: 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 (1 H, s), 5.85 (1 H, s), 6.30 (1 H, s), 7.00-8.13 (8H, m).
Analysis for C34H39FN4O7: Calcd. (%): C, 64.34 H, 6.19 N, 8.83 Found (%): C, 64.08 H, 6.24 N, 8.99 Example 81 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(2-isobutoxycarbonylpyridine-5-carboxylic acid 6-(5-m-fluorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-': 3500,3460,1695,1520,1345.
PMR Spectrum (CDCI3) #: 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 (1H,s),5.88 (1H,s),7.02-8.13 (8H,m).
Analysis for C38H43FN4O8: Calcd. (%): 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-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5p-fl uorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1520,1345.
PMR Spectrum (CDCl3+D2O)#: 1.00-1.90 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.73-4.21 (4H, m), 5.03 (1 H, s), 6.90- 8.10 (8H, m).
Analysis for C3,H33FN407: Calcd. (%): C, 62.83 H, 5.61 N, 9.45 Found (%): C, 62.92 H, 5.48 N, 9.46 Example 83 1 ,4-Dihydro-2,6-di methyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5o-tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 135-1 370C (from isopropanol).
iR Spectrum (KBr) cm-1: 3360,2950,1702,1520,1342,1210.
PMR Spectrum (DMSO-d6) #: 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 (1H, s), 5.87 (1 H, s), 7.00-8.05 (8H, m).
Analysis for C32H36N407: Calcd. (%): C, 65.29 H, 6.16 N, 9.52 Found (%): C, 65.38 H, 6.31 N, 9.27 Example 84 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-(2-isopropoxyethoxywarbonyl)pyridine-5- carboxylic acid 6-(5-o-tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1520,1345.
PMR Spectrum (CDCI3) #: [0.94-1.90 (8H,m)and 1.13 (6H,d);total 14H],2.30 (6H,s),2.34 (3H,s),3.21-4.31 (9H),m),5.04 (1H,s),5.72 (1H,s),6.48 (1H,s),7.05-8.05 (8H,m).
Analysis for C36H44N4O8: Calcd. (%): C, 65.44 H, 6.71 N, 8.48 Found (%): C, 65.60 H, 6.85 N, 8.31 Example 85 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5o-tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow powder.
IR Spectrum (CHCl3) cm-1: 3500, 3460, 1693, 1522, 1345.
PMR Spectrum (DMSO-d8) S: 0.95-1.97 (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 (1H,s),5.85 (1H,s),6.96-8.10 (8H,m),8.90 (1H,broad).
Analysis for C32H38N4O7: Calcd. (%): 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)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5o-cyanophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500, 3460, 2230, 1696, 1520, 1345.
PMR Spectrum (DMSO-d8) #: 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 ( 1 H, s).
Analysis for C32H33NsO7: Calcd. (%): 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)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5m-cyanophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500, 3460, 2227, 1695, 1520, 1345.
PMR Spectrum (CDCl3) (5: 1.00-1.95 (8H,m),2.30 (6H.s).3.57 (3H,s),3.75-4.22 (4H,m),5.06 (1H,s),6.12 (1H, s).
Analysis for C32H33NsO7: Calcd. (%): C, 64.10 H, 5.55 N, 11.68 Found (%): C, 63.87 H, 5.71 N, 11.49 Example 88 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5p-cyanopyenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500, 3460, 2230, 1695, 1520, 1345.
PMR Spectrum (CDCI3) S: 1.00-1.92 (8H,m),2.30 (6H,s),3.57 (3H,s),3.75-4.21 (4H,m),5.03 (1H,s),5.82 (1H, s),6.10 (1H,8),7.07-8.10 (8H,m).
Analysis for C32H33N5O7: Calcd. (%): C, 64.10 H, 5.55 N, 11.68 Found (%): C, 63.94 H, 5.80 N, 11.57 Example 89 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (o-trifluoromethylphenyl)-3-pyrazolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1696,1520,1345.
PMR Spectrum (CDCl3) #: 0.96-1.90 (8H, m), 2.30 (6H, s), 3.55 (3H, s), 3.76-4.27 (4H, m), 5.73 ( 1 H, s).
Analysis for C32H33F3N4O7: Calcd. (%): C, 59.81 H, 5.18 N, 8.72 Found (%): C, 59.80 H, 5.34 N, 8.60 Example 90 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (m-trifl uoromethylphenyl)-3-pa razolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1520,1345.
PMR Spectrum (CDCl3) #: 0.93-1.90 (8H, m), 2.31 (6H, s), 3.56 (3H, s), 3.75-4.28 (4H, m), 5.75 ( 1 H, s).
Analysis for C32H33F3N4O7: Calcd. (%): C, 59.81 H, 5.18 N, 8.72 Found (%): C, 59.97 H, 5.32 N, 8.47 Example 91 1 ,4-Di hydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridi ne-5-carboxylic acid 6-[5 (2-pyridyl)-3-pyrazolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-': 3500,3460,1695,1520,1345.
PMR Spectrum (CDCl3) #: 0.97-2.00 (8H, m), 2.30 (6H, s), 3.57 (3H, s), 3.73-4.22 (4H, m), 5.03 (1 H, s), 6.01(1 H, s).
Analysis for C30H33N507: Calcd. (%): C, 62.60 H, 5.78 N, 12.17 Found (%): C, 62.26 H, 5.83 N, 12.36 Example 92 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (3-pyridyl)-3-pyrazolyloxy] hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500, 3460, 1694, 1520, 1345.
PMR Spectrum (CDCl3) S: 1.00-2.00 (8H, m), 2.30 (6H, s), 3.58 (3H, s),3.78-4.32 (4H, m), 5.03 (1 H, s), 5.90 (1 H, s), 7.00-8.10 (8H, m), 8.17-8.53 (1 H, m), 8.75 (1 H, s).
Analysis for C30H33N5O7: Calcd. (%): C, 62.60 H, 5.78 N, 12.17 Found (%): 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.
Aspect: Pale yellow crystals.
Melting point: 1 65-1 680C (from ethanol).
IR Spectrum (CHCI3) cm-': 3500,3465,1695,1523,1345.
PMR Spectrum (DMSO-d6) #: 1.00-1.92 (8H, m), 2.30 (6H, s), 3.56 (3H, s), 3.77-4.24 (4H, m), 5.01(1 H, s), 6.36 (1 H, s), 7.05-8.15 (6H, m), 8.48-8.74 (2H, m).
Analysis for C30H33N507: Calcd. (%): C, 62.60 H, 5.78 N, 12.17 Found (%): C, 62.57 H, 5.99 N, 12.25 Example 94 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5benzyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow oil.
IR Spectrum (CHCl3) cm-1: 3500, 3460, 1693, 1520, 1345.
PMR Spectrum (CDCl3) S: 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 ( 1 H, s), 5.42 (1 H, s), 6.62 (1 H, s), 7.00-8.40 (1 OH, m).
Analysis for C32H38N407: Calcd. (%): C, 65.29 H, 6.16 N, 9.52 Found (%): C, 65.07 H, 6.33 N, 9.50 Example 95 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5o-chlorobenzyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow oil.
IR Spectrum (CHCI3) cm-1: 3500, 3460, 1693, 1522, 1345.
PMR Spectrum (CDCI3+D20) S: 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 (1H, s),5.43 (1H,s),6.90-8.10 (8H,m).
Analysis for C32H3sCIN407: Calcd. (%): C, 61.68 H, 5.66 N, 8.99 Found (%): C, 61.60 H, 5.78 N, 9.14 Example 96 4.98 9 (20 mmole) of methyl 3-nitrobenzylideneacetoacetate, 7.55 g (20 mmol) of 3aminocrotonic acid 6-(5-p-chlorophenyl-3-pyrazolyloxy)hexyl ester and 10 ml of ethanol were mixed and heated at reflux for 6 hours. This reaction mixture was concentrated under reduced pressure to obtain a yellow oily residue, which, after adding 2 ml of ethyl acetate, was stirred overnight. Then, the separated crystals were filtered off, and recrystallized from isopropanol to obtain 8.65 g (yield 71.0%) of pale yellow crystals of the 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine 5-carboxylic acid 6-(5-p-chlorophenyl-3-pyrazolyloxy)hexyl ester.
Melting point: 187-188 C.
IR Spectrum (KBr) cm-': 3380,1705,1690,1515,1345.
PMR Spectrum (DMSO-d6) S: 1.00--1.91 (8H, m), 2.31 (6H, s), 3.52 (3H, s), 3.77-4.20 (4H, m), 4.97 (1 H, s), 6.07 (1 H, s), 7.058.06 (8H, m), 8.94 (1 H, s).
Analysis for C3rH33CIN40: Calcd. (%): C, 61.13 H, 5.46 N, 9.20 Found (%): C, 61.33 H, 5.57 N, 9.02 Example 97 1.51 g (10 mmole) of 3-nitrobenzaldehyde, 1.15 g (10 mmole) of methyl 3-aminocrotonate, 3.74 g (10 mmole) of acetoacetic acid 6-(5-p-methoxyphenyl-3-pyrazolyloxy)hexyl ester and 20 ml of ethanol were mixed and heated at reflux for 5 hours. This reaction mixture was concentrated under reduced pressure to obtain a yellow oily residue. This residue was chromatographed on a silica gel column using chloroform as an eluent, and the purified fractions containing the intended compound were concentrated under reduced pressure to obtain yellow crystals.These crystals were recrystallized from isopropanol to obtain 1.39 9 (yield 23.0%) of pale yellow crystals of the 1 ,4-dihydro-2,6 dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyddine-5-carboxylic acid 6-(5-p-methoxyphenyl-3pyrazolyloxy)hexyl ester.
Melting point: 1 60-1 630C.
IR Spectrum (KBr) cm-1: 3398, 1700,1508,1345,1210.
PMR Spectrum (DMSO-d6) S: 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(1 H, s), 5.97 ( 1 H, s), 6.92 (2H, d), 7.22-8.00 (6H, m), 8.93 ( 1 H, s).
Analysis for C32H36N408: Calcd. (%): 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 mmoie) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide, to which was added 2.45 g (12 mmole) of 3-(3,4-methylenedioxyphenyl)-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added dropwise 10 ml of a solution of 5.87 g (10 mmole) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3- methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in N,N-dimethylformamide, and the mixture was stirred and heated at 900C for an hour. The resultant reaction mixture was poured into 200 ml of ice water, and the separated solid was filtered off.This solid was recrystallized from ethyl acetate to obtain 3.21 g (yield 51.9%) of the 1 ,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3 methoxycarbonylpyridine-5-carboxylic acid 6-[5-(3,4-methylenedioxyphenyl)-3-pyrazolyloxy] hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 1 67-1 690C.
IR Spectrum (KBr) cm-': 3380,1694,1520,1345.
PMR Spectrum (DMSO-d6) S: 0.97-1.85 (8H, m), 2.28 (6H, s), 3.52 (3H, s), 3.72 4.18 (4H, m), 4.96 (1 H, s), 5.97 (3H, s), 6.76-8.02 (7H, m), 8.90 (1 H, s), 11.97 (1 H, s).
Analysis for C32H34N4O9: Calcd. (%): C, 62.13 H, 5.54 N, 9.06 Found (%): C, 61.85 H, 5.46 N, 9.29 The compound in Example 99 below was produced similarly as in Example 98, except that the starting materials were changed.
Example 99 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5 p-nitrophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow crystals.
Melting point: 208-21 O C (from acetic acid).
IR Spectrum (KBr) cm-1: 3425, 1696, 1505, 1340, 1208.
PMR Spectrum (DMSO-d6) S: 1.00--1.90 (8H, m), 2.29 (6H, s), 3.56 (3H, s), 3.77-4.23 (4H, m), 4.98 (1 H, s), 6.28 (1 H, s), 7.38-8.30 (8H, m), 8.86 ( 1 H, s), 12.40 ( 1 H, s).
Analysis for C31H33N509: Calcd. (%): C, 60.09 H, 5.37 N, 11.30 Found (%): C, 60.25 H, 5.54 N, 11.17 Example 100 (Step i) 35.0 g (0.20 mole) of 2,3-dichlorobenzaldehyde, 23.0 g (0.20 mole) of methyl 3-aminocrotonate, 40.0 g (0.20 mole) of acetoacetic acid 6-hydroxyhexyl ester and 100 ml of ethanol were mixed and heated at reflux for 6 hours, and the resultant product was chromatographed on a silica gel column to obtain 34.7 g (yield 38.0%) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3- methoxycarbonylpyridine-5-carboxylic acid 6-hydroxyhexyl ester as an oil. 13.7 g (0.03 mole) of this oil was dissolved together with 1 1.4 g (0.06 mole) of tosyl chloride in 100 ml of chloroform, to which was added dropwise 7.1 g (0.09 mole) of pyridine under ice cooling with stirring.This mixture was allowed to stand at room temperature for 2 hours, then 100 ml of water was added thereto, and stirring was continued for 3 hours. The chloroform layer of the resultant reaction mixture was separated, washed with 100 ml of 0.02 N sulfuric acid, 100 ml of water and 100 ml of saturated aqueous sodium bicarbonate successively, and dried over anhydrous sodium sulfate. This solution was concentrated, and the resultant residue was chromatographed on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 1 50:1) as an eluent to obtain 16.3 g (yield 89.0%) of 1 ,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6tosyloxyhexyl ester. The IR and PMR spectra of this product were as follows.
IR Spectrum (KBr) cm-1: 3340,1675,1475,1345, 1205.
PMR Spectrum (CDCI3) S: 0.83-1.83 (8H, m), 2.23 (6H, s), 2.37 (3H, s), 3.53 (3H, s), 3.734.17 (4H, m), 5.36 (1 H, s), 6.53 (1 H, s), 6.83-7.36 (5H, m), 7.50-7.83 (2H, d).
(Step ii) 0.51 g (12 mmole) of 55% sodium hydride in mineral oil was suspended in 10 ml of N,Ndimethylformamide, to which was added gradually 2.40 g (15 mmole) of 3-phenyl-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added dropwise 20 ml of a solution of 6.10 g (10 mmole) of the 1 ,4-dihydro-2,6-dimethyl-4-(2,3dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester obtained in the above Step i in N,N-dimethylformamide, and stirring with heating at 600C was continued for 4 hours.
The resultant reaction mixture was poured into 150 ml of ice water, and the separated product was extracted with 50 ml of ethyl acetate. This ethyl acetate solution was washed with 50 mi of water three times, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a brown oily residue. This residue was chromatographed on a silica gel column using a chloroform-methanol mixed solution as an eluent, and the eluate fractions containing the intended compound were concentrated under reduced pressure to obtain crystals. These crystals were recrystallized from a mixed solution of benzene-hexane to obtain 2.63 g (yield 43.9%) of the 1,4dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5phenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Colorless crystals.
Melting point: 68-71 OC.
IR Spectrum (CHCI3) cm-1: 3499, 3470, 1690, 1460.
PMR Spectrum (CDCI3+D2O) b: 0.93-1.90 (8H, m), 2.25 (6H, s), 3.58 (3H, s), 3.74.25 (4H, m), 5.43 (1 H, s), 5.89 (1 H, s), 6.80-7.72 (8H, m).
Analysis for C3,H33CI2N305: Calcd. (%): C, 62.21 H, 5.56 N, 7.02 Found (%): C, 62.18 H, 5.78 N, 6.77 Example 101 0.24 g (10 mmole) of sodium hydride was suspended in 10 ml of dimethylsulfoxide, to which was added gradually 1.95 g (10 mmole) of 3-o-chlorophenyl-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added 10 ml of a solution of 6.01 g (10 mmole) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5carboxylic acid 6-tosyloxyhexyl ester in dimethylsulfoxide, and stirring with heating at 80 C was continued for an hour. The resultant reaction mixture was poured into 150 ml of ice water, and the separated product was extracted with 50 ml of chloroform.This chloroform solution was washed with 50 ml of water 4 times, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily residue. This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 100:1) as an eluent, and further by chromatography on a silica gel column eluting with a toluene-ethyl acetate mixed solution, and the eluate fractions containing the purified intended compound were concentrated to dryness under reduced pressure to obtain 2.55 g (yield 40.9%) of the 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-( 5-o-chlorophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500, 3460, 1695, 1520, 1345.
PMR Spectrum (DMSO-d6) S: 0.89-1.90 (8H,m),1.16 (3H,t),2.27 (6H,s),3.73-4.21 (6H,m),5.01 (1H,s),6.01 (1H, s),7.05-8.05 (8H,m),8.83 (1H,broad),12.07 (1H,broad).
Analysis for C32H35CIN407: Calcd. (%): 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 poduced by similar procedures as in the above Example 101,except that the starting materials,the raction solvent, and other conditions were appropriately changed.
Example 102 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5p-trifluoromethylphenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500, 3460, 1693, 1520, 1345.
PMR Spectrum (DMSO-d6) S: 0.90-1.91 (8H, m), 2.29 (6H, s), 3.51 (3H, s), 3.72-4.20 (4H, m), 5.00 (1 H, s).
Analysis for C32H33F3N4O7: Calcd. (%): 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.
Aspect: Colorless powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1693.
PMR Spectrum (CDCI3) #: 0.95-1.97 (8H, m), 2.27 (6H, s), 3.57 (3H, s), 3.70-4.21 (4H, m), 5.44 (1 H, s),6.75- 7.80 (8H, m).
Analysis for C31H33Cl2N3O5: Calcd. (%): C, 62.21 H, 5.56 N, 7.02 Found (%): C, 62.33 H, 5.80 N, 7.01 Example 104 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-0 tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500,3463,1692,1520,1345.
PMR Spectrum (DMSO-d6) #: 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(1 H, s), 5.87 (1 H, s), 7.00-8.08 (8H, m), 8.90 (1 H, s), 11.83 (1 H, broad).
Analysis for C33H38N407: Calcd. (%): C, 65.77 H, 6.36 N, 9.30 Found (%): C, 65.89 H, 6.40 N, 9.16 Example 105 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-0tolyl-3-pyrazolyloxy)hexyl ester. o-tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500,3462,1693,1520,1345.
PMR Spectrum (DMSO-d6) #: 0.97-2.00 (11 H, m), 2.22 (3H, s), 2.28 (3H, s), 2.35 (3H, s), 3.72-4.21 (6H, m), 5.53 ( 1 H, s), 5.86 ( 1 H, s), 7.00-8.03 (8H, m), 8.80 (1 H, broad).
Analysis for C33H38N4O7: Calcd. (%): C, 65.77 H, 6.36 N, 9.30 Found (%): C, 65.93 H, 6.58 N, 9.17 Example 106 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-pchlorophenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder. IR Spectrum (CHCI3) cm-': 3500,3460,1692,1520.1345.
PMR Spectrum (DMSO-d6) #: 0.90-2.00 (11 H, m), 2.23 (3H, s), 2.29 (3H, s), 3.72-4.21 (6H, m), 5.53 (1 H, s), 6.05 (1 H, s), 7.03-8.05 (8H, m), 8.90 (1 H, s).
Analysis for C32H35C1N4O7: Calcd. (%): C, 61.68 H, 5.66 N, 8.99 Found (%): C, 61.47 H, 5.75 N, 9.20 Example 107 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-pchlorophenyl-3-pyrazolyloxy)-5-ethyl hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1522,1345.
PMR Spectrum (DMSO-d6) #: 2.29 (6H, s), 3.73-4.22 (6H, m), 4.99 ( 1 H, s), 6.07 ( 1 H, s), 7.05-8.06 (8H, m), 8.85 ( 1 H, s), 12.24(1H,s).
Analysis for C34H39CIN4O7: Calcd. (%): C, 62.71 H, 6.04 N, 8.60 Found (%): 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500, 3468, 1690.
PMR Spectrum (DMSO-d6) #: 0.95-2.00 (8H, m), 2.25 (6H, s), 3.48 (3H, s), 3.70-4.20 (4H, m), 5.32 (1 H, s), 6.26 (1 H, s), 6.87-8.30 (8H, m), 8.76 (1H, broad).
Analysis for C31H32ClzN4O7: Calcd. (%): C, 57.86 H, 5.01 N, 8.71 Found (%): C, 57.84 H, 5.20 N, 8.63 Example 109 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5p-methoxyphenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3465,1695,1520,1345.
PMR Spectrum (DMSO-d6) #: 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 (1 H, s), 5.98 (1 H, s), 6.73-8.10 (8H, m), 8.80 (1 H, s).
Analysis for C32H36N408: Calcd. (%): C, 63.56 H, 6.00 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.
Aspect: Pale yellow powder.
IR Spectrum (CHCl3) cm-1: 3500,3460,3420,1695,1520,1345.
PMR Spectrum (CDCI3+D20) #: 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 (1 H, s), 5.91(1 H, s), 7.00-8.07 (8H, m).
Analysis for C33H37N5O8: Calcd. (%): C, 62.75 H, 5.90 N, 11.09 Found (%): 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-( 5m-tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHClg) cm-1: 3500, 3460, 1690, 1520, 1345.
PMR Spectrum (CDCI3) (5: 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 (1 H, s), 5.88 ( 1 H, s), 6.90-8.07 (8H, m).
Analysis for C32H,6N407: Calcd. (%): C, 65.29 H, 6.16 N, 9.52 Found (%): C, 65.33 H, 6.01 N, 9.76 Example 112 1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5p-tolyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500,3463,1692,1521,1345.
PMR Spectrum (CDCI3) S: 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 (1 H, s), 5.88 ( 1 H, s), 6.89-8.05 (8H, m).
Analysis for C32H36N407: Calcd. (%): C, 65.29 H, 6.16 N, 9.52 Found (%): C, 65.43 H, 6.31 N, 9.44 Example 113 1 ,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5 phenyl-3-pyrazolyloxy)hexyl ester.
Aspect: Pale yellow crystals.
Melting point: 156-159 C (from ethanol).
IR Spectrum (CHCI3) cm-': 3500,3460,1693,1520,1345.
PMR Spectrum (CDCI3+D20) S: 0.90-1.90 (8H, m), 1.17 (3H, t), 2.32 (6H, s), 3.72-4.22 (6H, m), 5.04(1 H, s), 5.87 (1 H, s), 6.92-8.06 (8H, m).
Analysis for C32H36N4O7: Calcd. (%): C, 65.29 H, 6.16 N, 9.52 Found (%): 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-dimethyla minophenyl)-3-pyrazolyloxy] hexyi ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500,3460,1695,1520, 1345.
PMR Spectrum (CDCI3) S: 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 (1 H, s).
Analysis for C33H39N5O7: Calcd. (%): C, 64.17 H, 6.36 N, 11.34 Found (%): C, 64.10 H, 6.54 N, 11.20 Example 115 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (m-N-ethylaminophenyl)-3-pyrazolyloxy]hexyl ester.
Aspect: Pale yellow powder.
IR Spectrum (CHCI3) cm-': 3500,3460,1695,1520, 1345.
PMR Spectrum (CDCl3+D2O) S: 0.90-1.97 (11 H, m), 2.02 (2H, q), 2.31 (6H, s), 3.56 (3H, s) s),3.72 4.20 (4H, m), 5.05 (1H,s), 5.83 (1H,s).
Analysis for C33H39N5O7: Calcd. (%): 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 mmole) of 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) was dissolved in 100 ml of ethanol, to which was added 5 ml of Raney nickel, and catalytic hydrogenation was effected at room temperature and atmospheric pressure, thereby 1350 ml (60 mmole) of hydrogen was absorbed. The Raney nickel was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily residue.This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 3:1) as an eluent, and the fractions containing the intended compound were concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was dissolved in ethyl acetate, and after adding 5 g of activated charcoal, stirred well,hand filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 6.63 g (yield 54.0%) of the 1 ,4-dihydro-2,6dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-aminophenyl-3pyrazolyloxy)hexyl ester as a pale yellow powder.
IR Spectrum (CHCI3) cm-1: 3500, 3460, 1 695.
PMR Spectrum (CDCI3+D2O) S: 0.95-1.95 (8H, m), 2.26 (6H, s), 3.58 (3H, s), 3.74-4.21 (4H, m), 5.43 (1 H, s), 5.86 (1 H, s).
Analysis for C3,H34CI2N405: Calcd.(%): C, 60.69 H, 5.59 N, 9.13 Found (%): 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,Ndimethylformamide, 1.33 g (7 mmole) of 3-p-methoxyphenyl-5-pyrazolone was added portionwise with stirring under ice cooling. to the above mixture was added dropwise a solution of 3.05 g (5 mmole) of 1 ,4-Dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in 7 ml of N,N-dimethylformamide at O to 100C with stirring and then the mixture was heated at 800C for 3 hours. The resulting reaction mixture was poured into ice water, and the precipitate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then evaporated in vacuo to obtain an oily residue. The residue was purified by silica gel column chromatography using a mixed solution of chloroform-methanol (the ratio by volume of 100:1) as an eluent, and the fractions containing desired compound were collected and evaporated in vacuo to dryness to give white crystalline residue. The residue was recrystallized from a mixed solution of ethyl acetate-normal hexane to give 1.87 g (yield 59.0%) of 1,4-dihydro 2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5-p- methoxyphenyl-3-pyrazolyloxy)hexyl ester as colorless needles.
Melting point: 146-1 480C.
IR Spectrum (CHCI3) cm-1: 3500,3475,1695,1615.
PMR Spectrum (DMSO-d6) S: 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 ( 1 H, s), 5.87 (1 H, s), 6.70--7.63 (7H, m), 8.64 (1 H, broad).
Analysis for C32H35Cl2N3o6: Calcd. (%): C, 61.15 H, 5.61 N, 6.69 Found (%): 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.
Aspect: Colorless powder.
IR Spectrum (CHCi3) cm-': 3500, 3480, 1695, 1690 (shoulder), 1615.
PMR Spectrum (CDCl3) S: 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 (1 H, broad), 6.87-7.30 (3H, m).
Analysis for C26H3,CI2N305: Calcd. (%): C, 58.21 H, 5.82 N, 7.83 Found (%): C, 58.45 H, 5.79 N, 7.71 Example 119 1,4-Dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5-isopropyl-3-pyrazolyloxy)hexyl ester.
Aspect: Colorless powder.
IR Spectrum (CHCI3) cm-': 3500,3475,1690,1610.
PMR Spectrum (CDCI3) S: 1.06-1.97 (8H, m), 1.23 (6H, d), 2.26 (6H, s), 2.80 (1 H, q), 3.56 (3H, s), 3.83-4.20 (4H, m), 5.40 (2H, broad), 5.86 ( 1 H, broad), 6.86-7.30 (3H, m).
Analysis for C28H35CI2N305: Calcd. (%): C, 59.58 H, 6.25 N, 7.44 Found (%): C, 59.72 H, 6.21 N, 7.51 In addition to the above Examples, the following compounds were also produced similarly.
1 ,4-Di hydro-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-carboxylic acid 6 (5-phenyl-3-pyrazolyloxy)hexyl ester.
1 ,4-Di hydro-2,6-di methyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5m-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-2,6-dimethyl-4-(3,4-dich lorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-phenyl-3-pyrazolyloxy) hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (2,4-dimethylphenyl)-3-pyrazolyloxy]hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (p-N-benzoylaminophenyl)-3-pyrazolyloxy]hexyl ester.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-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-(5p-ethoxyphenyl-3-pyrazolyloxy)hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5p-methoxybenzyl-3-pyrazolyloxy)hexyl ester.
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5 (2,6-di methylphenyl)-3-pyrazolyloxy] hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-n itrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5 cr-phenethyl-3-pyrazolyloxy)hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5 p-phenethyl-3-pyrazolyloxy)hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-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-pyrazolyloxy]hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[4 (2,6-dimethylphenyl)-3-pyrazolyloxy] hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(4 p-methoxyphenyl-3-pyrazolyloxy) hexyl ester.
1 ,4-Dihydro-2,6-dimethyl-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 (26)

Claims
1. A 1 ,4-dihydropyridine derivative of the following general formula [I]:
wherein R' represents an alkyl group having from 1 to 4 carbon atoms or an alkoxyalkyl group having from 3 to 6 carbon atoms, R2 represents a hydrogen atom or a halogen atom, R3 represents either a nitro group when R2 is a hydrogen atom or a halogen atom when R2 is a halogen atom, R4 represents an alkyl group having from 1 to 8 carbon atoms, a pyridyl group, a phenethyl group, a benzyl group which may optionally be substituted by at least one member selected from the group consisting of a lower alkyl group, a lower alkoxy group, a methylenedioxy group and a halogen atom or a phenyl group which may optionally be substituted by at least one member selected from 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 benzoylamino group, a methylenedioxy group and a halogen atom, and A represents a hexamethylene group which may optionally be substituted by one or two alkyl groups having from 1 to 3 carbon atoms.
2. A 1 ,4-dihydropyridine derivative according to claim 1, wherein R1 represents one member selected from the group consisting of methyl, ethyl, propyl, butyl, methoxyethyl and butoxyethyl, R4 represents one member selected from the group consisting of methyl, ethyl, propyl, hexyl, octyl, phenyl, fluorophenyl, chlorophenyl, tolyl, methoxyphenyl, dichlorophenyl, methylenedioxyphenyl, benzyl and pyridyl and A is hexamethylene.
3. A 1 4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5-methyl-3-pyrazolyloxy)hexyl ester.
4. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyi)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5-isopropyl-3-pyrazolyioxy)hexyl ester.
5. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-methyl-3-pyrazolyloxy)hexyl ester.
6. A 1,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)-3-(2-methoxyethoxycarbonyl)pyridine-5-carboxylic acid 6-( 5-methyl-3-pyrazolyloxy)hexyl ester.
7. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl )-3-isobutoxycarbonylpyridine- 5-carboxyl ic acid 6-( 5-ethyl-3-pyrazolyioxy)hexyl ester.
8. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(2nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-( 5-octyl-3-pyrazolyloxy)hexyl ester.
9. A 1 4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-hexyl-3-pyrazolyloxy)hexyl ester.
1 0. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-phenyl-3-pyrazolyloxy)hexyl ester.
11. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-m-fluorophenyl-3-pyrazolyloxy)hexyl ester.
12. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(2nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-phenyl-3-pyrazolyloxy)hexyl ester.
13. A 1,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-methoxyca rbonylpyridine-5-carboxylic acid 6-(4-phenyl-3-pyrazolyloxy) hexyl ester.
14. A 1 ,4-dEhydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-3-methoxyca rbonylpyridine-5-ca rboxylic acid 6-(5-o-chlorophenyl-3-pyrazolyloxy)hexyl ester.
1 5. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-3-normalpropoxycarbonylpyridine-S-carboxylic acid 6-[5-(2,4-dichlorophenyl)-3pyrazolyloxy]hexyl ester.
1 6. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-(2-isobutoxyethoxycarbonyl)pyridine-5-carboxylic acid 6-( 5-m-fluorophenyl-3- pyrazolyloxy)hexyl ester.
1 7. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)-3-methoxycarbonylpyridine-S-carboxylic acid 6-( 5-o-tolyl-3-pyrazolyloxy)hexyl ester.
18. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-3-methoxyca rbonyl pyridi ne-5-carboxylic acid 6-[5-(2-pyridyl)-3-pyrazolyloxy] hexyl ester.
19. A 1 4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-benzyl-3-pyrazolyloxy)hexyl ester.
20. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-3-methoxycarbonylpyridine-5-ca rboxylic acid 6-( 5-p-methoxyphenyl-3-pyrazolyloxy)hexyl ester.
21. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-[5-(3,4-methylenedioxyphenyl)-3- pyrazolyloxy]hexyl ester.
22. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4 (2,3-dichlorophenyl)-3-methoxycarbonylpyridine-S-carboxylic acid 5-phenyl-3-pyrazolyloxy)hexyl ester.
23. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4-(3nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-( 5-o-chlorophenyl-3-pyrazolyloxy)hexyl ester.
24. A 1 ,4-dihydropyridine derivative according to claim 2, that is 1 ,4-dihydro-2,6-dimethyl-4 (2,3-dichlorophenyl)-3-methoxycarbonylpyridine-S-carboxylic acid 6-( S-p-methoxyphenyl-3- pyrazolyloxy)hexyl ester.
25. A compound as claimed in claim 1, said compound being the product of any one of the Examples herein.
26. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims and a pharmaceutical carrier.
GB08223168A 1981-08-12 1982-08-11 Novel 1 4-dihydropyridine derivatives Expired GB2108108B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP12521681A JPS5826882A (en) 1981-08-12 1981-08-12 Novel 1-4-dihydropyridine derivative
JP57013398A JPS58131982A (en) 1982-02-01 1982-02-01 Novel 1,4-dihydropyridine derivative

Publications (2)

Publication Number Publication Date
GB2108108A true GB2108108A (en) 1983-05-11
GB2108108B GB2108108B (en) 1985-08-07

Family

ID=26349189

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08223168A Expired GB2108108B (en) 1981-08-12 1982-08-11 Novel 1 4-dihydropyridine derivatives

Country Status (3)

Country Link
DE (1) DE3230400A1 (en)
FR (1) FR2511370B1 (en)
GB (1) GB2108108B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60139688A (en) * 1983-12-28 1985-07-24 Tokyo Tanabe Co Ltd Amorphous dihydropyridine powder pharmaceutical
JPH02288876A (en) * 1989-01-17 1990-11-28 Synphar Lab Inc New-generation 1,4-dihydropyridine derivative

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2218644C3 (en) * 1972-04-18 1982-08-19 Bayer Ag, 5090 Leverkusen Basic esters of 1,4-dihydropyridines, processes for their preparation and their use as pharmaceuticals

Also Published As

Publication number Publication date
DE3230400A1 (en) 1983-03-24
DE3230400C2 (en) 1993-02-25
GB2108108B (en) 1985-08-07
FR2511370B1 (en) 1986-10-24
FR2511370A1 (en) 1983-02-18

Similar Documents

Publication Publication Date Title
EP1080086B1 (en) Dihydropyrimidines
EP0153016B1 (en) Asymmetrical diesters of 1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid
EP0529702B1 (en) Dihydropyridine derivatives, their preparation and their use
HU221810B1 (en) Process for producing amlopidine besylate and the intermediates
US4847379A (en) 3,6-dihydro-1,5(2H)-pyrimidinecarboxylic acid esters
US5100900A (en) Positive inotropically active 4-quinolyl-dihydropyridines and use thereas
CA1322553C (en) Hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds
GB2108108A (en) Novel 1,4-dihydropyridine derivatives
US4418197A (en) 1,4-Dihydropyridine derivatives
US4419518A (en) 1,4-Dihydropyridine derivatives
JPH0259835B2 (en)
EP0063359B1 (en) 1,4-dihydropyridine derivatives and processes for preparing the same
US4567268A (en) Process for preparation of certain tetrahydrofuro[3,4-b]pyridines
HU193785B (en) Process for producing dihydropyridine derivatives
Agamy et al. Enaminones as building blocks in heterocyclic synthesis: a new one pot synthesis of polyfunctional substituted pyridines
JP2640245B2 (en) 1,4-dihydropyridine derivative
US5290939A (en) Process for the manufacture of brofaromine and analogs thereof
DE60002486T2 (en) 1,4-DIHYDROPYRIDINE-5-CARBONIC ACID ESTER DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
JP7447291B2 (en) Method for producing heterocyclic amine derivatives
EP0802193B1 (en) Process for the preparation of substituted pyrimidines
US2916493A (en) Dioxolane derivatives
DE69907769T2 (en) Process for the preparation of 2-sulfonylpyridine derivatives and 2- ((2-pyridyl) methyl) thio) -1H-benzimidazole derivatives
US5693807A (en) Substituted hydroquinone derivatives
US4349675A (en) 4,4-Disubstituted spiro-1,4-dihydropyridines and a process for their production
JPH0220638B2 (en)

Legal Events

Date Code Title Description
PCNP Patent ceased through non-payment of renewal fee

Effective date: 19990811