JPS62223170A - Use of dihydropyridinylcarboxylic acid amide having arylpyperadinylalkyl component useful for drug and ester - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION The present invention has three dicarboxylic acid groups or carboxamide functionalities attached to a lupiberazinial alkylene moiety.

4, which has calcium antagonistic properties and is useful in the treatment of cardiovascular diseases.
An important body of prior art involving the -aryl-1,4-dihydropyridine series of compounds has been developed in the last decade.

These calcium-blocking effects mediate vasodilation, making these compounds useful in the treatment of angina and hypertension. These structures are represented by nifedipine (21), +1 chemically 4-(2'-nitrophenyl)2,6-dimethyl-3,5-dicarpomethoxy-1,4-dihydropyridine. Nifedipine and some related 4-aryl 1,4-dihydropyridines are the subject of U.S. Pat. No. 3,485,847 (issued Dec. 23, 1969).

Subsequently, other substituents were incorporated into the dihydropyridine moiety at various ring positions via a number of chemical bonding groups.
A number of patents have been granted encompassing dihydropyridines.

The purpose of the present invention was to design a therapeutic agent that combines α,-adrenergic-blocking 11 and calcium-blocking effects in a single molecule structure using medicinal chemistry techniques. Scientific rationale suggests that such drugs provide a powerful and effective treatment for vasospastic circulatory disease.

The technology related to the series of compounds of the present invention has the following structural formula (2
), in which R2, R4, R5 and R6 can be any of the many substituents previously defined in the dihydroviridine literature, but 1. Particular attention is paid to the definition of the substituent structure attached to the 3-position of the 4-dihydropyridine ring. To the inventor's knowledge, aryl or hetarylopiperazinyl moieties have heretofore been used in 1,4-dihydrohydroxy:lysine rings as carboxylic acid amide or ester functional groups in the 3-position of the ring. It was not incorporated through all. In the inventor's judgment,
The most relevant art disclosed is to Bossert et al., September 16, 1975 and August 1976, respectively.
.

U.S. Patent No. 3,905.97, a divisional patent issued to
No. 0 and U.S. Pat. No. 3,974,275. The compounds disclosed and claimed in these patents have the above structure (2
) has the following structure (2a) as the 3-substituent side chain moiety, l-pe.

This same 3-substituent side chain (2a) was also disclosed in US Pat. No. 4,393,070 to Sato et al. (issued July 1983).

European Patent Application No. 88,903 (published September 21, 1983) has the following structure (2b), where n is O-5, Z is aryl or hedoaryl, and R is lower 1,4-dihydropyridines having a 3-carboxylic acid ester group (which is alkyl, alkoxycarbonyl or alkanoylamino) are disclosed. The key point of the novelty disclosed as an antihypertensive drug is that “α of the cyclic aminoalkyl ester moiety in the side chain
- is based on Z in that the presence of an aromatic ring or aromatic heterocycle in the - position results in increased and significantly longer availability.

Somewhat less related European Patent Application No. 63,365 (19
(published on October 27, 1982) has a 3-carboxylic acid ester group containing a piperidine ring (3): (wherein n is O-3 and R5 is arylalkyl or acyl). ~dihydropyridine is disclosed.

Additionally, 1,4-dihydropyridine compounds are disclosed having an arylpiperazine system attached to the 2-position of the dihydropyridine ring via an alkyl or alkoxyalkyl chain. Aritomi et al.
Chem, Pharm, Bull, ), 29(11)
, 3163-71 (1980) discloses compounds having the group (4) in the 2-position of the ring: l-, where n=2 and R is alkyl, aryl or arylalkyl. are doing. As an example, the compound (4a
): (4a) is specifically disclosed.

European Patent Application No. 60.674 (published on September 22, 1982) describes the structure (5): (wherein Y is an ethylene or propylene chain and R5
is 01-C4 alkyl, aryl, arylalkyl, etc.) Antiischemic and antihypertensive drugs are disclosed.

These compounds are easily distinguished structurally from the compounds of the present invention by ring position 1 and the attached functionality.

That is, the compound of the present invention has alkyl, ra=-.
2. Contains a ring or hedoarylpiperazine moiety which occupies the α-position bonded to the carboxylic acid ester group or carboxylic acid amide function in the 3-position of the ring.

All of the above compounds promote their therapeutic utility in accordance with common theories of their biological mechanisms due to their inherent ability to act as calcium channel blockers. Essentially, the compounds of the invention can be distinguished from the compounds of the prior art both on the basis of their molecular structure and also on the basis of their biological action.

The present compounds have blocking properties of both calcium channels and alpha-adrenergic action, thereby increasing the usefulness of these compounds in the treatment of hypertensive and ischemic diseases. The compounds were also found to have useful effects in inhibiting certain functions of platelets. Nothing in the prior art anticipates or suggests the compounds of the present invention.

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds of the formula (1): )I (2) and acid addition salts of these substances. In the above structure, the symbols R2, R4, R5,1? '
, X, Y and Z have the following meanings. R2 and R
″′ is independently selected from lower alkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, or dialkylaminoalkyl, and may be the same or different.Lower alkyl means 01-C4 alkyl, and alkoxyalkyl is an oxygen atom 01 connected by
~C4 alkylene chain and C8-C4 alkyl group; similarly alkylaminoalkyl and dialkylaminoalkyl are secondary (-NH-') or tertiary (-N-)
A lower alkyl group connected by an amino group and CI to C4
R4 represents an alkylene chain; cycloalkyl of 5 to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, hetaryl such as furanyl, indolyl, methylthiopyridyl, chenyl, benzoxadiazolyl, benzothiadiazolyl, etc.; phenyl, naphthyl, or acetamino, lower alkyl, lower alkoxy,
Aryl means phenyl substituted with substituents including cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, methylsulfonyl, and the like. R5 is RZ or Y is a low m(auto-,)alkylene chain--Murshigom #mo or tmwm jaw, and Z is unsubstituted or lower alkyl, lower alkoxy, cyano, halo and tri- phenyl, pyridinyl or pyrimidinyl substituted with one or more substituents selected from fluoromethyl.

Preferred compounds of the invention are those in which R2 and R6 are lower alkyl, R4 is nitrophenyl, and R5 is
or NH, and has a structure of formula (2) in which Y is 02-C, alkylene, t*, and Z is substituted phenyl. Most preferred compounds of the invention are R2 and R& are methyl and R4 is 2- or 3-nitrophenyl;
It has a structure of formula I in which R5 is a methyl or pyrene chain and Z is a 2-substituted phenyl ring, preferably 0-methoxyphenyl.

The compounds of the invention can exist as optical isomers, and racemic mixtures of these isomers as well as the individual optical isomers themselves are within the scope of the invention.

Racemic mixtures can be resolved into their individual isomers by well-known methods, eg, by resolving diastereomeric salts formed with optically active acids and then converting back to optically active bases.

As mentioned above, the present invention also relates to pharmaceutically acceptable non-toxic salts of these basic compounds. Such salts include organic and inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, maleic acid, sorbic acid, aconite acid, salicylic acid, phthalic acid, embonic acid (em
bonic acid), etentic acid, etc.

The compounds of the present invention can be prepared by applying haunches (
It can be produced by the following process using a modification of the Ilantzch synthesis reaction.

In particular, the present invention employs a modified Hauntzsch method for preparing compounds of formula I according to the reaction scheme below. The general reaction process and many of the necessary intermediate compounds were previously described in U.S. Pat. No. 4,414.
No. 213, which patent is incorporated herein by reference.

General method for preparing a compound of formula: -Intershell formula: (I) In the above -intershell formula, R4 and X are as defined in Formula I. R' can be R2 or R6 in formula (2). The preparation of compounds of formula (1) by the -intershell process generally involves heating both type (1) and type (2) intermediate compounds either undiluted or in the presence of various reaction-inert a-containing solvents. Suitable solvents include, but are not limited to, benzenetoluene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, ethanol, propatool, and the like. A suitable reaction temperature is about 6ON150°C. No catalyst or condensing agent is usually required. Intermediate enamine ester or amide IVc is produced from intermediate ① by Hantzsch type reaction conditions (NIIaOAc/alcohol).

Intermediate (1) (defined below) is usually not isolated and can be reacted directly with compound (2). Intermediate acyl cinnamate compounds of structure (1) are generally prepared by using known Knoevenagel condensation reaction conditions. Generally, a suitable substituted aldehyde and 1.
When condensed with a 3-dicarbonyl compound, ■ is produced.

A preferred variation of the general scheme is shown in the following reaction scheme.

I+1IO1+ [fi”
O11 scheme 2 (X scheme 3 (X-0, R rah (IV a ) summary NH) (II[a) (1,X=NH) R2, R4, R5, R6, X, Y in these above schemes
and Z are as defined in Formula I.

According to Scheme I, a chloroalkanol (Vl) or an arylpiperazinyl alkanol (V) is added to Meldrun+'s acid as shown in Scheme 4.
(The Merck rndex+ 10th edition, 563
5, p. 828 (1983)) or by treatment with diketene under modified Hantzsch condensation conditions (ammonium acetate L/
When reaction is carried out with cinnamate intermediate (IIIb), 2(
The desired product of 1) or the chloroalkyl ester compound (■) shown in Scheme IA is formed. Intermediate compound (■
) is reacted with a frugal arylpiperazine (■) or an arylpiperazine alkyl alcohol or amine (IX) to form 3 of various embodiments of formula (1) shown in Scheme LA.
- Carboxylic acid ester compounds can be produced.

The dihydropyridine product CI> obtained by the method outlined in Scheme 1 is isolated by chromatography in reasonable yields.

Synthesis Scheme 2 shows an example of the reaction used to obtain a product of Formula 1 of the 3-carboxylic acid amide subclass.

In Scheme 2, aminoalkylpiperazine (■, prepared by the well-known Gabriel synthesis from the corresponding Rubiperazine (■) and chloroalkylimide)
Treatment of with diketene or the appropriate alkanoyl acetyl halide yields the intermediate acetoamide (XI), which is converted to the cinnamate amide (I[
Ia). As shown, intermediate compound 11r
Applying the general reaction to a and rVb yields the desired product of X-NH.

Scheme 3 shows symmetric dihydropyridines (i.e. 3- and 5-
- The route used for the synthesis of carboxylic acid ester groups (in which the carboxylic acid ester groups are the same) is shown. As shown, intermediate compound ■a (prepared from Inc. under Hauntzsch reaction conditions) has the appropriate R'
The desired compound I is obtained through a condensation reaction with CHO.

Other (1) and XI reaction intermediates used in the preparation of the compounds included in the present invention can be prepared according to the following synthetic schemes or by modifications thereof obvious to those skilled in the chemical arts.

Scheme 4 (R2 and/or Rh are alkyl) Scheme 4
For more details, see Y, Oikawa et al., Jie, Org, Kem,
(J, Org, Chew,), Dish, 2087 (1
978).

Scheme 5 (Rg and/or R6 are alkyl-X-alkyl.) XV XrV (X-0 or N7/+/kyl)
The structural moiety represented by "alkyl" is a standard 〇- or N-protection 1! in organic synthesis! ! If so, its removal generally yields an intermediate where R2 or R6 is an alkanol or alkylamino as defined above.

-C, XIV is a cold (0
°) prepared by treating the solution with lithium diisopropylamide and then introducing the alkali metal salt of the X-alkyl reagent. Examples of this reagent are sodium methoxide, sodium ethoxide, 2-phenylethyl ethoxide, sodium phenoxide, lithium methylamide,
These include lithium dimethylamide and lithium methylphenylamide. The reaction medium is an inert organic liquid, preferably tetrahydrofuran or tetrahydrofuran-DM.
It's SO. XIVO isolation and purification is achieved by chromatography on silica gel.

The compounds of this invention have been shown to have some useful pharmacological properties. For in vitro screening, target various smooth muscle systems such as the rat dorsal aorta and hilum.

Calcium activity in the pulse and trachea, and j
α-Binding Affinity Measured in Rat Heart and Brain
Power was golden. In general, preferred compounds of the invention;
has a potency similar to that of the reference compound nifedipine (
It had calcium influx pathway blocking activity. α-bond 1
Activity was greater for this compound than for nifedipine, with most members of this series having one or two orders of magnitude greater potency.

Fluctuation studies involving ganglionic blockade, a response to anesthetized rats, showed that α-adrenergic receptor blockade was a pharmacological consequence of α-binding. The procedure is explained by Deitchman (
Jie tchman) et al.

Pharmacol, Methods (J, Pharmacol, M
methods), 3.311-321 (1980)
It is described in.

In vivo tests included nerve H blockade, angiotensin-■ vasodilation results in supported rats, and spontaneous voluntary blood pressure rats (
Antihypertensive screening in SHR or DOCA rats was conducted. In general, vasodilation results for this series corresponded to calcium-blocking activity. Anti-hypertensive screening data showed that good calcium-5 and alpha-adrenergic blocking activity cooperated to produce a very impressive anti-hypertensive effect.

BMY20064, BIIY, which is also a preferred compound for vines
20064 was administered orally to both normotensive and spontaneously hypertensive conscious rats. Doses of 1 and 10 mg/Kg produced 25 and 53 mmHg, respectively, in the normotensive rat group.
and induced maximum mean arterial blood pressure reductions of 34 and 100 wings in the spontaneously hypertensive rat group, respectively. These mean arterial blood pressure responses observed in both groups were rapid in onset (10 minutes) and significant mean arterial blood pressure persisted for more than 4 hours after the higher dose of BMY20064.

Additionally, BMY20064 and nifedipine were tested in anesthetic Pegle to determine their comparative acute hemodynamic effects. The two compounds showed similar efficacy and hemodynamic profiles in this characteristic hemodynamic model.

The specific tests used to evaluate the compounds of the invention were conducted according to the following procedure, or with slight modifications.

Evidence that these compounds have a specific blocking effect on calcium ion channels is shown when maintained at 1,37°C and at 9°C.
The results were obtained from an in vitro study consisting of a typical longitudinal smooth muscle strip of a Mormoa (Mormor) suspended in a bath containing Quirode's solution aerated with 5% 0□-5% CO□.

Tissues were allowed to equilibrate for 60 minutes before the start of all tests.

A single response to carbachol is obtained and used as the control maximum for all tests. Tissues are re-equilibrated and washed with Tyrode's solution every 15 minutes between consecutive doses. Tissues are exposed to the antagonist for 10 minutes before the addition of carbachol to investigate the effects of the compounds. For all tests, simply test one antagonist at any one concentration in any given Mi tissue. The result is a 50% reduction in muscle response.
It is expressed as the molar concentration of inhibiting antagonist. Calcium antagonism generally suppresses the contraction coupling in vascular smooth muscle.

As such, drugs of this type usually cause vasodilation. Tests of selected compounds of the present invention on ganglionic blockade, angiotensin-supported rat model (Deitman
chman) et al., Jie, Pharmacol, Methods (J,
Pharmacol, Methods), 3.311~
321 (1980)) showed vasodilation with a concomitant decrease in blood pressure.

Additionally, selected compounds of the invention were tested in vitro and in vivo in laboratory tests developed to predict the potential of drugs to protect cardiac tissue from ischemic damage. These tests use the known relationship between the gradual depletion of high-energy phosphates and the development of lethal cell damage in ischemic myocardium. The results of these screening tests indicate that the selected compounds have strong anti-ischemic effects.

Indicates that it has.

Finally, the compounds of the invention exhibit effective inhibition of various aspects of platelet function. These changes are not related to the calcium blocking effect of the compound. This is evidenced by Table 1, which shows the comparative efficacy of BMY20064 and two reference calcium influx blockers, nifedipine and verapamil.

+1'(CO) As shown in Table 1, there is little similarity in the effects on platelet function between BMY20064 and the control compound.

Summarizing the above discussion of biological activity, the present compounds have cardiovascular properties that make them particularly suitable for use in hypertension and ischemia. Accordingly, another aspect of the invention involves the systemic administration to the mammal of an effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof to treat hypertension or ischemia in a mammal in need thereof. Regarding how to improve. Based on animal studies, the effective oral dose can be expected to be about 1-2 mg/kg, and the effective parenteral dose is lower, about 0.05 mg/kg.
It can be expected to be in the range of ~1 mg/kg body weight.

However, for clinical applications, dosing and administration regimens should be carefully adjusted on a case-by-case basis using sound professional judgment and taking into account the age, weight and physical condition of the patient, the route of administration, and the nature and condition of the disease. It is.

-) W, the compounds of the invention are administered in the same manner as for the reference drug nifedipine, with an oral daily dose of about 5 to about 50 m
g, preferably 10-20 mB administered 1-3 times a day. In some cases a sufficient therapeutic effect may be obtained with lower doses, while in other cases higher doses may be necessary.

The term systemic administration used refers to oral, rectal and parenteral (ie intramuscular, intravenous and subcutaneous) routes. It is generally recognized that when the compounds of this invention are administered orally, which is the preferred route, a larger amount of active drug is required to produce an effect similar to a lower amount given parenterally. Good morning.

Good clinical experience indicates that the compounds are preferably administered at concentration levels that produce effective antihypertensive and/or antiischemic effects without causing harmful or undesirable side effects.

For treatment, the compounds are generally given as a pharmaceutical composition comprising an effective anti-hypertensive and/or anti-ischemic amount of a compound of formula ■ or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. . Pharmaceutical compositions for carrying out such treatments may be administered in large or small amounts, e.g.
5% of at least one compound of the invention in combination with a pharmaceutical carrier, the carrier comprising one or more non-toxic, inert and pharmaceutically acceptable solid, semi-solid or liquid diluents; Includes fillers and formulation aids. Such pharmaceutical compositions are preferably in dosage unit form, i.e., physically separate units containing a predetermined amount of drug corresponding to a fraction or multiple of a dose calculated to produce the desired therapeutic response. It is. Dosage unit: 2.
3.4 or more servings, or 1/dose of a serving
2.1/3f or 1/4 may be included. One dose is preferably an amount sufficient to produce the desired therapeutic effect when administered in one application of one or more dosage units, usually once, twice, or three times daily, according to a scheduled dosage regimen. Full, half, 1/3 or 1 daily dose administered once or 4 times
Contains /4 amount. Other therapeutic agents may also be present. Pharmaceutical compositions providing from about 1 to 50 mg of active ingredient per dose are preferred, conveniently in the form of tablets, troches, capsules,
Produced as powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions. Preferred oral compositions are in the form of tablets or capsules and contain binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers (
such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycerin), lubricants (such as magnesium stearate, talc, polyethylene glycol or silica), disintegrants (such as starch) and wetting agents (such as sodium 991 mononitrate). It may contain the usual excipients. Solutions or suspensions of compounds of Formula I with conventional pharmaceutical vehicles are employed in parenteral compositions, such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injection. Desired transparency for parenteral use,
Such compositions are stable and compatible, with 0.1 to 10 tffi% of the active compound dissolved in a vehicle consisting of water or polyhydric aliphatic alcohols such as glycerin, propylene glycol and polyethylene glycol or mixtures thereof. It is obtained by Polyethylene glycols are soluble in both water and liquids and consist of a mixture of non-volatile, normally liquid polyethylene glycols having molecular weights of about 200 to 1.500.

The compounds constituting this invention and their method of preparation will become more fully apparent from a consideration of the following examples. These examples are given for illustrative purposes only and should not be construed as limiting the invention in scope or scope. All temperatures are in °C unless otherwise specified.

Nuclear magnetic resonance (NMR) spectral characteristics were determined using Hyakuba Hayabusa (p
Chemical shifts (δ) in pm) are shown. The relative areas shown for various shifts in the proton NMR spectral data correspond to the number of hydrogen atoms of a particular functional group in the molecule. The nature of the shift with respect to multiplicity is Broad-multiplicity '4
yS (bs), - doublet (S), multi-Ti line (m), doublet (d), doublet of doublets (dd) or quartet (q
). Terms used: DMS O-di
(Shuuterodimethyl sulfoxide), CDCβ, (
the other is commonly used. In the description of the infrared (IR) spectrum source, only the absorption wave number (cm-') having a functional group identification value is shown. Potassium bromide (KBr) was used as a diluent in the IR measurement.

Elemental analysis is given as fffffi%.

Synthesis of Intermediate A1 Intermediate Example 1 of Formula (■) Oikawa et al., J, Org, Chem
A solution of 75 g (0,403 mol) of 2-chloroethanol and 200 ml of 2-chloroethanol was heated at 125° C. for 5 hours. After cooling the dark solution to room temperature, excess 2-chloroethanol was removed in vacuo and the resulting residue was distilled to yield product 4.
9.4 g (74%) obtained as a clear liquid, boiling point 8
0-85℃/0.4mm.

Example 2 Acetoacetic acid 3-chloropropyl 3-chloropropatur (47.3 g, 0.50 mol) and a catalytic amount of triethylamine were added to diketene 4 at 65°C.
2 g (0.50 mol) were added dropwise.

After the addition was complete, the reaction mixture was stirred for an additional hour at 65°C. Distillation of the residue yields 72.9 g (82
%) was obtained as a transparent liquid, boiling point 78-85℃/
150mm).

Other intermediates of formula (2) can be prepared by modifications of the above examples and will be within the knowledge of those skilled in the art of organic chemical synthesis.

3-nitrobenzaldehyde 151g (1,00mol)
, 116 g (1,00 mol) of methyl acetoacetate, 10 mj of glacial acetic acid? , 4 ml of piperidine and 400 ml of benzene
1 l of the solution was refluxed for 2 hours, during which time 21 m2 of water was removed in a Dean-Stark trap. The dark yellow solution solidified upon cooling to room temperature. Filtration followed by washing with ether gave 180 g of product as a yellow solid.

An additional 23g of product was obtained from the filtrate, totaling 203g.
(82%) of the product was obtained, melting point 145-146°C (
Literature value melting point 158°C, Meyer et al., Arzneim, - Forsch/DragResearch (Arzne
im, -Forsch/Drug Research)
, 31.407 (1981)).

Example 4 2-((3-nitrophenyl)methylene]-3-oxobutane ethyl This compound was prepared on a molar scale by the method described in Example 3 using methyl acetoacetate in place of the methyl ester. From ethanol. Recrystallization yields 182 g of product (
69%) was obtained as a yellow solid, melting point 103-10
6°C (literature value melting point 10°C; Ruhema
nn), Jie, Kem.

Hook, (J, Chem, Soc,), 83.
717 (1903)).

Other examples of Formula (1) prepared using the above procedure are listed in Table 2.

Gostopan R・ 22 m-chlorophenyl 23 m-trifluoromethylphenyl 24 p-hydroquine-m m; trophenyl 25 0-methquinophenyl 26 m-methoxyphenyl 27 p-hydroxy-m-methoxyphenyl 28 p-acetamidophenyl 29 m-Methylsulfonylphenyl 30 m-trifluoromethylsulfonylphenyl 31 0-chloro-m-nitrophenyl 32 o-nitrophenyl 33 m-nitrophenyl 34 m-nitrophenyl 35 m-nitrophenyl 36 m-nitrophenyl 37 2,3-dichlorophenyl 38 2,3-dichlorophenyl 39 4-benzoxanoazolyl 40 4-benzothiadiazolyl 41 3-(2-methylthiobilinonyl) 1 弗 tun fusion R5 ('C/ 0.1 .m
m) ('C)ethyl 120
-123-ethyl 1
00-110 Ethyl - -ethyl -ethyl
140- Ethyl! 10-1
12 ethyl - -ethyl - -ethyl
− −Ethyl
− −Methyl
− −Methyl
145-146n-propyl
- -2-chloroethyl
- 68-763-chloropropyl - -methyl
− −Methoquinethyl
- -Methyl
- -Ethyl -
-Methyl-
The preparation of this intermediate and other v-type intermediates is described by Wu et al., J.D. Met, Kem. (J. Med. Chem.
), 12, 876 (1969). 1
-(2-methoxyphenyl)piperazine (10.0 g.

52, 1 mmol), 3-chloropropatol (4.2
5g, 45.0 mmol), potassium carbonate fine powder (6.2
1 g, 45 mmol) and 75 ml of acetonitrile was refluxed for 23 hours. After cooling to room temperature, water 2
00ml was added and the resulting mixture was extracted with methylene chloride. Combine the remaining parts and wash with water and brine,
It was then dried over magnesium sulfate. Filtration and removal of volatiles in vacuo yielded 11.7 g of crude alcohol product.
was gotten. Recrystallization from acetonitrile gives product 9
．． 4g (72%) was obtained, which was a white solid.
Melting point 94-95°C.

D. Intermediate of formula (1) Example 43 1,4-dihydro-2.6-dimethyl-4-(3-nitrophenyl)-3.5-pyridinedicarvone 2-chloroethyl ammonium methylacetate (3.85 g, 50. 0 mmol) of the acetoacetate prepared in Example 1 (8.0 mmol).
25 g, 50.0 mmol) and 50 ml of absolute ethanol
and refluxed under nitrogen for 1 hour. Then the cinnamate ester intermediate product prepared in Example 3 (1 2
．． 5 g'- 0.0 mmol) was added and the resulting yellow solution was refluxed for a further 12 hours. After cooling to room temperature,
The solvent was removed in vacuo and the residue was recrystallized from ethanol to give the product as a yellow solid, mp 129-1.
31°C (literature value melting point 130°C, Iwanami et al., Chem.Pharm.Pur, (Chem.

Pharm. Bull. ), 2 7, 1426 (
(1979)).

Example 44 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic 73-chloropropylmethyl Prepared in Examples 2 and 3 according to the method described in Example 43 Example 45 1.4-Dihydro-2 Preparation of the Subject Intermediate Using the Intermediate and the Product was Obtained as a Yellow Solid in 99% Yield on a 50 mmol Scale, Melting Point 125-130 °C0 Product Example 45 1.4-Dihydro-2 ,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid (2-(
4-(2-Methoxyphenyl)-niza 3 length box (9) 17L ≦ "jll" Intermediate prepared in Example 43 (1,98 g, 5, OO mmol), 1 -(2-
methoxyphenyl)piperazine (1,05 g, 5.5 mmol), triethylamine (0,61 g, 6.04 mmol) and tetrahydrofuran 25 m! 1 solution was refluxed for 36 hours under nitrogen flow. After removing the volatiles in vacuo, the residue was dissolved in 2-propanol and 1
0% aqueous HCβ (V:V) 50mI! was added and the solution was heated on a steam bath for 15 minutes. After extraction with methylene chloride, the combined portions were washed with water and brine, dried over magnesium sulfate, filtered, and dried in vacuo to give a brown oil. Crystallization of the oil from ethanol:ether gave 1.7 g (55%) of the product as a light brown solid, mp 159-160°C (decomposition).

Elemental analysis: Calculated value (CzqHzMaOt・21(Cj
!・0.71(,0) :C,54,76; H,5,
93; N, 8.81° Measured value: C, 54,87° H, 6,21; N, 8.78° NMR (DMSO-d,): 2.36 (3, s);
2.45 (3, s); 3.45 (10, m); 3
．． 62 (3, s); 3.87 (3, s); 4.55
(2, m); 5.09 (1, s); 7.08 (4, m
); 7.70 (2, m); 8.06 (2, m); 8
．． 45 (2, bs); 9.60 (1, bs).

IR (KBr): 755. 1015. 1100
．． 1120. 1215°1350, 1485.15
30.1650.1700.2450.3360cm-
'.

Example 46 1,4-dihydro-2,6-dimethyl-4-(3-di
・Lophenyl)-3,5-pyridinedicarboxylic acid 2-
(4-Phenyl-1-piperazinyl)ethyl methyl Using a procedure similar to that described in Example 44, a solution of dihydropyridine intermediate ■ and phenylpiperazine was refluxed in acetonitrile using potassium carbonate as the acid acceptor. did. After forming the hydrochloride salt and crystallizing from acetonitrile-isopropyl ether, the product was obtained in 15% yield as a yellow solid, mp 201-204°C.

Elemental analysis, calculated values (Czalh□N40b・lIC1)
:C, 60, 37; ) I, 5.97; N, 10
．． 06° Measured value: C, 60, 48; 11.6.1
1; L 10.30°N gate R (DMSO-db):
2.32 (3, s): 2.40 (3, s); 3.
21 (6, m); 3.44 (4, m); 3.60 (
3,s); 4.4&(2,m);5.04(1,s)
; 6.92 (3, m); 7.2B (2, m); 7
．． 64 (2, m); 8.01 (2, n+L 9.40 (
1, bs); 11.65 (1, bs).

IR(KBr): 695.755.1100.11
20.1215.1350°1480, 1525. 1
670. 1700.2430.3280, cm-
'.

Example 47 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-C
4-(2-Methoxyphenyl)-1-piperazinyl]propyl methyl Mizuguchi Dihydropyridine intermediate prepared in Example 44 (8,
A 50ml solution of 1-(2-methoxyphenyl)piperazine (4.1g, 20mmol), triethylamine (6g) and a catalytic amount of potassium iodide in acetonitrile was refluxed for 48 hours. After removing the volatiles in vacuo, the residue was triturated in acetonitrile to give 3.5 g (17%) of the product as a yellow solid, mp 70-75°C.

Elemental analysis, calculated value (CiolhJnOt'0.5HzO
): C, 62, 81; ) l, 6.50: N,
9.77° Measured value: C, 62,50; H, 6,41;
N, 9.43°NMR (DMSO-da): 1.72 (2, m);
2.30 (6, s); 2.40 (6, m); 2.
92 (4, m); 3.56 (3, s); 3.77 (
3,s): 4.02(2,m); 5.02(1,s
); 6.87 (4, m): 7.59 (2, m)
; 8.00 (2, m); 9.01 (1, bs).

IR (Br): 750.1100,1120,1
215,1240,1350゜1500.1530.1
685.1700.3400 cmli.

Example 48 1,4-dihydro-5-((2-(4-(2-methoxyphenyl)-1-piperazinyl]ethyl]amino]carbonyl)-2,6-dimethyl-4-(3-nitrophenyl) -Methyl diketene 3-pyridinecarboxylate (1.85 g, 22.0 mmol) was mixed with ■-
(2-aminoethyl)-4-(2-methoxyphenyl)
Piperazine (4.7 g, 22 mmol; manufactured by Maru (
Mull) et al., J., Met., Pharm.

Chem, (J, Med, Pharm, Chem
, ), 5.944 (1962)) in 20 ml of absolute ethanol at 0°C. After the addition was complete, the solution was allowed to warm to room temperature and stirred for 30 minutes.

Concentration in vacuo gave 5.5 g of the crude acetoamide intermediate as a clear oil, which was used without further purification.

3-nitrobenzaldehyde (2.25 g, 15 mmol), acetamide intermediate, 5 drops of glacial acetic acid and piperidine 3? In Xun's benzene 25mβ? Tanebena gel condensation was achieved by refluxing the 8 liquid for several hours. After flash chromatography (5% methanol:chloroform) 4.35 g (44%) of product were obtained as a yellow oil.

Portion of yellow oil (3.5 g, 7.7 mmol), 3
-Methyl aminocrotonate (3.9 g, 7.8 mmol) and 40 ml of 2-propatol were refluxed overnight (18 hours). Concentration in vacuo yielded 3.5 g of yellow gum. Flash chromatography (2% methanol:chloroform; 3% methanol:chloroform; then 4% methanol:chloroform) yields 0.73 of the product.
g (17%) was obtained as a yellow foam, melting point 83.
~88℃.

Elemental analysis, calculated value CCzqHx, N5Oh・0.2C1
lCl:l) :C, 61,15; H, 6,19;
N, 12.21, Measured value: C, 61,08;
H, 6, 18; N, 11.93°NMRc
cDc13)7 2.30 (6,s); 2.54 (
61m); 3.01 (4, m); 3.3'2 (2,
m); 3.63 (3, s); 3.85 (3, s)
; 4.96 (1, s); t3.16 (1, bs);
6.26 (1, bs): 6.92 (4, m); 7.3
8 (1, m); 7.68 (1, m); 8.05 (
2, m).

fR(K[lr): 750. 1110.1240
．． 1350.1500°1530, 1625. 16
60 cm-'.

Example 49 1.4-dihydro-5-(((3-(4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino)
Carbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarbon7methyl This compound was prepared as in Example 48, but with Wu
Others, J, Med, Che
m, ), 12.876 (1969) using the starting aminopropyl biverazine. The desired product was isolated as a yellow foam, mp 70-80.
℃.

Elemental analysis, calculated value (CZ.) l! '1NsO&・0.4
CHCA, ) :C, 59,72; I+, 6.1
7; N, 11.45° Measured value: C, 59, 54;
H, 6, 17; N, 11.38°NMR (
CDC1*): 1.65 (2, m); 2.17
(3,s); 2.31(3,s); 2.52(
6, m); 3.00 (4, m): 3.3B (2
, m); 3.53 (3, s); 3.85 (3,
s); 4.99 (1, s); 5.90 (1, b
s); 6.89 (5, m); 7.52 (2, m);
8.03 (2, m).

IR (KBr): 750. 1115. 1230
．． 1240. 1350°1500, 1530.16
25. and 1680 cm-'.

Example 50 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- and lysinedicarboxylic acid his(3
-(4-(Methoxyphenyl)-Nizatogon Yokokonizuki and Buta Deaf Eiken-=1 S*-------Piperazine intermediate 2 produced in Example 42 (5,00g, 20. diketene (1.68 g,
20.0 mmol) was added slowly. After the addition is complete, add 5QmA of absolute ethanol, ammonium acetate (1,
20 g, 16 mmol) and 3-nitrobenzaldehyde (1.58 g, 10.4 mmol) were added and the resulting solution was refluxed for 17 hours. After cooling to room temperature, the reaction was concentrated in vacuo to yield 8.5 g of a dark yellow oil.

The oil was extracted with methylene chloride and 10% aqueous H(
1! Washed with 2 portions (V:V) and concentrated the organic layer to yield a yellow solid. Recrystallization from ethanol-ethyl ether gave 2.95 g (35%) of the product as a yellow solid, mp 155-175°C (decomposed).

Elemental analysis, calculated values (C4Js4N&Oi・2HCg・0
．． 511□0): C, 59,72; H, 6,64;
N, 9.72; ++to, 1.04° Measured value:
C, 59,67; H, 6,90: N, 9.54
;H2O.

1.04°NMR (D?l5O-di): 2.18 (4, m)
; 2.38 (6, s); 3.18 (12, m);
3.44 (8, m); 3.79 (6, s): 4.0
8 (4, m); 5.00 (1, s); 6.93 (8,
m); 7.70 (2, m); 8.02 (2, m):
9,46 (1, bs).

rR(KBr): 750.1120.1215.1
250.1350°1515, 1550.1665.1
710,2640. and 3400 cm-'.

Example 51 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 4-C
4-(2-(methoxyphenyl)-1-piperazinyl cobutyl methyl diketene (4.6 g, 0.05
5 mol) to 4-(2-methoxyphenyl)-1-piperazinebutanol (13.2 g, 0.05 mol) (UK Patent No. 803.403, 22 October 1958)
was added dropwise at 100°. The melt was heated at 100° for 20 minutes. The melt was dissolved in 200 ml of ethanol and ammonium acetate (3.5 g, 0.05 mol) was added. The solution was heated under reflux for 2 hours. Om-methyl nitro-2-acetylcinnamate (8.4 g, 0.05 mol) was added and reflux was continued for 17 hours. The solution was concentrated under reduced pressure. The residue was flash chromatographed in CCHCh at 2% M e
OH, on silica gel). Conversion of the product to the hydrochloride salt with ethanolic MCI yields the product 1.55
g (4,7%) was obtained, melting point 110-130°.

Elemental analysis, calculated values (C31HxmNaO9'2HCl
): C, 57, 14: H, 6, 19; N, 8.6
0. Measured value: C, 57, 35; ) 1. 6.3
9; N, 8.51° Other examples of products of the invention are shown in Table 3.

These additional products are made using the procedures described in Examples 45-51.

Table 3 Shikiyu (7) (li (7) t, Kuchimata plastic 52 Me
3-NOzPh Me Me53 Gate e
3-NOzPh R,” Me54 Me 3
-NOzPh Me Me55 Me 3-N
OzPh Me Me56 Me 3-NOz
Ph [t Me57 Me 3-NOxPh
Me Me58 Me, 3-NO, Ph
Me Me59 Me 3-NOtPh
Ri” Me60 Me 3-NOzPh M
eOCIIxCIIx-Me61 Me 2-NO
zPh Me Me62 Me 3-NOzP
h Me Meo -(C11g) s-
2-pyriminonyl 0 - (C11ri 3-
2-pyrimidinyl 0 - (Clb
) x-2(3-CN-pyridyl)0-(
CIlx) s-3-CFxPh0 - (C
1+ri x-2-Mo0I'hO-(CIlg) 5
Nll (C11g) 3-2-MaOI'
hO-(C11g) *0 (C1lx) t-2
-MeOI'hO- (CL) to (C1lx)
z-2neOPhO-(C1h) s-2-McO
Ph O-(CIlz) s-2-Ma01'l+0
-(CIlx)i-3-CIlPhsu10 fresh violet
It, It,, R,
R63Me 3-NOzPh
Mo Ml et al. 4 gates 83
NOxPhRx"Ml 65 Me 3-NOxl'
hMe)
16(i Me 3NOtP
h Me Elementary School 67 Gate e 3-NOzPh
R3"l'L68
Me3-NOzPh
Ml! JCIlzCIb M2
S 9 Cllt011 3-NO
tPh Me
l'L7 0 ClC11zO2,3-
CI Ph MeOCIItCIIz
M17 1 CIIJMe
z 2-NOzPh Et
) L72 Me
4-CallzNtOMe
M173 bit 4-C
il12NzS Me
a74 Me 3-C
NPh [it
M2S MeOCII
3 C, 1lkNS Me
E7 6 MeJCI
I2-NOxPhMe
P-symmetric 3,5-dicarboxylate dihydrobiridinated nX Y
ZO-(C
L) 2-11-FPb:
,Q −(C1+□)! -4-FPh
O-(C1b) 3-2C
FsPhO-(C1lt)2-
2-Mel'hO-(Cllx)s-2-Mel
'l+0 - (C1lx) s-2M
o0I'hO-(C1lt) t-2MePh O-(Cllx)s-3-Cffil'hO-(CIl
g) =-3-MaOPhO-(CHt)s-2-M
eOPh O-(CHtri!-2-Mc01'h 10cII□ O-(C1lt) s-3-CF
tPhLO-(Cllt)z-2Me
OI'hO'-(CIRI#-3-Fl'h; represents a thing.

The resulting physical properties of the products of the examples listed in Table 3 are shown in Table 3.

Additional compounds similar to those defined by Formula J above also possess useful cardiovascular properties; for example, they have blockade of calcium influx and alpha-adrenergic action as well as antihypertensive activity. The significance of such a discovery is already
The compound has been appropriately described. Additional compounds were synthesized as shown in Examples 77 and 78 and are included in the compounds of formula I as well as: R2, R4, R' SRb for the compounds of I'
X and Z are as defined above for compounds of formula (1). However, the definition for Y is extended in Formula I° to include alkylene chains of 2 to 5 carbon atoms and alkylene chains containing sulfur atoms in the chain. The scope of the present invention now extends to include all compounds defined by formula XXI below taken together with compounds of formulas 1 and I. The subject matter of the present invention therefore includes the following formula XXI: or an acid addition salt acceptable to its formulation and/or
The compound represented by the solvent is included, and the symbol R2 in the formula
R4, R', R"SX,, Y and Z have the following meanings: R2 and R6 are independently selected from lower alkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl, and are the same or different; lower alkyl is C, -C,
Alkyl means a C3-C4 alkylene chain and a C,-C4 alkyl group connected by an oxygen atom, and similarly alkylaminoalkyl and dialkylaminoalkyl are secondary (-NH-) or tertiary It shows a class group and a 01-C4 alkylene chain. R4ba5~
cycloalkyl of 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, hetaryl such as furanyl,
Indolyl, methylthiopyridyl, chenyl, benzoxadiazolyl, benzothiadiazolyl, etc.; phenyl, naphthyl, or substituents include acetamino, lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl and aryl meaning phenyl substituted with a substituent including methylsulfonyl. There is R8. Y is an alkylene chain containing 2 to 5 carbon atoms, or an alkyleneoxyalkylene, alkyleneaminoalkylene or alkylenethioalkylene chain. Alkyleneoxyalkylene is 2 linked by oxygen atoms.
02~C, meaning an alkylene chain. Similarly, alkyleneaminoalkylene and alkylenethioalkylene are 02-C linked by Ni+ and S, respectively.
Indicates an alkylene group. Z is phenyl, pyridinyl or pyrimidinyl, unsubstituted or substituted with one or more substituents selected from lower alkyl, lower alkoxy, amino, halo and trifluoromethyl.

Additional compounds encompassed by Formula I can be prepared by adapting the synthetic methods outlined as Schemes 1-3. In particular, compounds 2f' are obtained by use of the methods given above for compounds 2) or by obvious modifications of these procedures. This is illustrated by the following example.

Example 77 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-(
(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl]thio]phenylmethyldiketene (8.4 g, 100 mmol) was mixed with 2,2-thiodietanol (12
, 2 g, 100 mmol) at 80°. The mixture was heated at 80" for 15 minutes.

The mixture was dissolved in 200 ml of ethanol and ammonium acetate (7.7 g S 100 mmol) was added.

The solution was then heated under reflux for 1 hour. Add methyl 2-[(3-nitrophenyl)methylene-3-oxobutanoate (Example 3.24.9 g, 100 mmol),
Refluxing was continued for 8 hours. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography (2% M in methylene chloride).
Purification by eOH (on silica gel) gives 5 g (21.8%) of the synthetic intermediate compound, whose structure is compound
(Cβ is replaced with W by OH).

This intermediate alkylenethioalkanol compound (4,0
g, 9.2 mmol) and thionyl chloride (1.1 g,
A solution of 9.2 mmol) in 100 mj2 of chloroform solution was heated under reflux for about 1.25 hours. The solution was concentrated under reduced pressure. The residue was dissolved in 300 ml of acetonitrile and 0-methoxyphenylpiperazine (3.5 g, 18 mmol), granulated potassium carbonate (2.5 g, 18 mmol) and sodium iodide crystals were added. The mixture was heated under reflux for 4 days and concentrated under reduced pressure. The residue was purified by flash chromatography (0,5% methanol and 1:4 ethyl acetate-methylene chloride, on silica gel) to give 2.2 g (39,3%) of product, mp 52-63'' .

Elemental analysis, calculated value (C+IHssNaOtS): c
t 60.98:H, 6,27:N, 9.17°
Measured values: C, 60, 61; H, 6, 24; N,
9.46゜Example 78 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- and lysinedicarboxylic acid 5-(
4-(2-methoxyphenyl)-1-piperazinyl]pentylmethyldichloromethane and diketene (3.0 g, 36 mmol) to 1-(5-hydroxypentyl)-4-(2-methoxyphenyl)
Piperazine (10,0 g, 36 mmol, British Patent No. 8
03,403, October 22, 1958) at 85°. After the addition is complete, add 100 ml of absolute ethanol and ammonium acetate (
2.8 g: 36 mmol) was added. After refluxing for 2 hours, methyl 2-((3-nitrophenyl)methylene-3-oxobutanoate (9.0 g, 36 mmol, Example 3)
(manufactured by ) was added and reflux was continued for 17 hours. The solution was concentrated under reduced pressure. The residue was subjected to flash chromatography (1
, 5% methanol and methylene chloride) to give 5.2 g (23.7%) of product, mp 52
~62°.

Elemental analysis, calculated values (C3 Yamayama Ot, 0.2CHHzC1□
): C, 63, 44: H, 6, 68; N, 9.1
9° Measured value: C, 63, 59, H, 6, 73; N,
9.32゜Procedural amendment (method) Showa year, month, day 1, case description 1985 patent application No. 251578
No. 3. Relationship with the amended person case Applicant name: Bristol Myers Company 4, Agent 5, Date of appropriate order: January 27, 1985 (1)
Engraving of pages 1 to 3 of the specification (as attached) (
(no change in content).

(2) "Scheme 1" on page 21 of the same book is corrected to "Formula 1."

(3) "Scheme 2" on page 22 of the same book is corrected to "Formula 2."

(4) "Scheme 3" on the same page of the same book is corrected to "Formula 3."

(5) "Scheme 4" on page 25, line 5 of the same book is corrected to "Formula 11."

(6) Correct "Scheme 5"' in the fourth line of page 26 to "Formula 5."

Claims (4)

[Claims] (1) Formula XXI, ▲There are mathematical formulas, chemical formulas, tables, etc.▼X
XI (wherein R^2 and R^6 are independently selected from lower alkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl; R^4 is cycloalkyl of 5 to 7 carbon atoms; 7-9
bicycloalkenyl of 4 carbon atoms; hetaryl (furanyl, indolyl, methylthiopyridyl, chenyl,
Includes benzoxaneazolyl and benzothiadiazolyl; aryl (phenyl, naphthyl, or independently acetamino, lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl or methylsulfonyl) (including substituted phenyl having a substituent that can be C_5 alkylene chain, Z is phenyl, pyridinyl or pyrimidinyl unsubstituted or substituted with one or more substituents selected from lower alkyl, lower alkoxy, cyano, halo and trifluoromethyl; Phenyl, pyridinyl or pyrimidinyl) A platelet function inhibitor, characterized in that it contains an effective amount of a compound represented by the formula (phenyl, pyridinyl or pyrimidinyl) or a formulation thereof, an acceptable acid addition salt. (2) Claim (1) comprising a dosage of the compound of XXI in the range of about 1-20 mg/kg of mammalian body weight, in a unit dosage form suitable for oral administration to a mammal. The platelet function inhibitor described in Section 1. (3) a dosage of a compound of formula XXI in the range of about 0.05 to 1 mg/kg of mammalian body weight, in a unit dosage form suitable for parenteral administration to a mammal; ) The platelet function inhibitor described in section 2. (4) The claim comprises a dosage of a compound of formula XXI in the range of about 5 to 50 mg, wherein said dosage is in a single dosage form suitable for oral administration to a mammal, administered 1 to 3 times daily. The platelet function inhibitor according to scope item (1).