JPS6287568A - Alkoxy and phenoxy alkyl ester of 2,6-dimethyl-4- (2-difluoromethoxyphenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid - 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] (Industrial application field) The present invention relates to organic chemistry, and more particularly.

A new compound, 2,6-dimethyl-Hiro-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-3, which shows depressing and vasodilatory effects, especially in the blood vessels of the heart and brain, and therefore can be used in the medical field. ，! −
Relating to alkoxy and phenoxy-alkyl esters of dicarboxylic acids.

(Prior art) 2.6-cymethyl-3. j-dimethoxycarbonyl-μ
-(cornitrophenyl)-/, preparation of 4 cm dihydropyrine (N1pbedlpin) →
[W, Vater et al., Pharmacology of dimethyl ester of 4A-dihydropyridine-3,j-dicarboxylic acid, 'Hiro-(2'-nitrophenyl)-2,6-dimethyl-/, 4A-dihydropyridine-3,j-dicarboxylic acid. 6-cymethyl-3. ! -Dimethoxycarbonyl-(difluoromethoxycarbonyl-a-(t--)diphenyl in fluoromet)-/.

Hiro-dihydropyridine (USSR Inventor's Certificate No. 704u10, cl, C071) co///ri0, A4
/ K 3//4L4L.

(see 1 and 7) are each well known. The medicinal preparations described above are highly toxic. In addition, nifedibine sometimes causes dizziness and vomiting, and is a light-stable drug.

Also, tips 6-dimethyl-3-methoxycarbonyl-≠=
(3-nitrophenyl)-1-(co(N-benzyl-N
-methylamino)ethoxycarbonyl: l-1,4-dihydropyridine hydrochloride
(pin) regulation) is also known and has vasodilatory activity, especially in cerebral blood vessels [Takenaka T, Usuda S.
,,Nomura T,,Maeno H6,Sado T,,Arzneiynitts
l-Forscbung), /ri71J.

Volume 3, No. 1, No. 2/72-2/71r N4)
.

The abovementioned compounds are characterized by insufficient activity and a very complicated manufacturing process for their preparation.

(Problems to be Solved) The compounds disclosed by the present invention are new and hitherto not described in the literature.

The object of the present invention is to provide a new compound that has both hypotensive and vasodilatory effects and low toxicity.

Means for Solving the Problems The object of the present invention is to provide compounds disclosed herein according to the present invention, ie compounds represented by the following general formula.

6-Simethyl-Hiro-(,X-difluoromethoxyphenyl)-7,u-dihydropyridine-3,! - achieved by alkoxy and phenoxyalkyl esters of dicarboxylic acids.

In the formula, R is C2H40CH15,0gH40C2H
5, C2H4003H7, CgH%0C6) N5, CD
(CH3) ClH2OCH3. (I)
The compounds disclosed herein are pale yellow crystalline materials that are insoluble in water and relatively readily soluble in ethanol, chloroform and other organic solvents. This compound is chemically stable.

Effect: The biological efficacy of the compound under investigation was studied in tests on laboratory animals.

The special effects of the compounds in question (hypertensive and vasodilatory effects) and their acute toxicity were studied here.

Known drugs for high vasodilation and blood pressure lowering: Niadibin [Phenyhydrin (Ph@n1hydin),
] - Nicardibin [Ferdivin (Psrdipi)
n)), and co,6-cymethyl-3. j-dimethoxycarbonyl-μm(2-difluoromethoxyphenyl)-l,a-dihydropyridine was used for comparison.

The above compounds have been tested experimentally on cats, dogs, rats, and mice.

Glucofluoralose (glucochloralos@
) and urethane (intraperitoneal administration of Q and 200 q/K9 respectively), arterial pressure, respiration, and electrocardiogram (ECG) from the normal carotid artery were measured using standard leads ( 5 standard
sad) recorded at n. The compound to be studied was administered intravenously as a solution in dimethylacetamide. All compounds under study were clearly effective in reducing arterial pressure. The results obtained are shown in the table below.

The disclosed compounds are characterized by superior antihypertensive activity compared to those previously known.

Compounds of the invention, namely co,6-dimethyl-3,j-
Bis-(2-propoxyethoxycarbonyl)-Hiro-(
The best efficacy of 2-difluoromethoxyphenyl)"'t"-dihydropyridine is when administered intravenously in cats: o,oooz~o,ooimy/Kp
Even low doses of can cause a decrease in arterial pressure. Nihuedavin and 2°6-dimeteru3. ! -dimethoxycarbonyl-(2-difluoromethoxyphenyl)-/.

Unlike Hiro-dihydropyridine, one compound of the present invention is
It was found that arterial pressure decreased more markedly at ℃ during diastole than during systole.

For this reason, the tested dosage range (0・ooos −0,/
m9/Kp), the compounds of the present invention and other known compounds can reduce peripheral resistance over a wider range, and can reduce peripheral resistance in a much smaller range. Suppresses contractile force.

The significant hypotensive activity of the compound under consideration was confirmed in experiments on rats anesthetized with intraperitoneally administered urethane (lco0019/Kp).

In addition, this shows that when the compound of the present invention is administered at an ED30 dose, the compound of the present invention decreases the blood pressure response by 3 to 304, and decreases angiotensin.
) has been confirmed to calm the seizure effects caused by

eterninal socii (@tbaninal socii)
In an acute study on anesthetized dogs weighing 7 kg to qKp with intraperitoneal administration of um Although it significantly increased the circulatory rate, it had virtually no effect on systolic arterial pressure.

The compound of the present invention thus administered intravenously at 0,00/■/KP, i.e., 6-cymethyl-J, ! -Bis(2-propoxyethoxycarbonyl)-Hiro-(difluoromethoxyphenyl)-7,Hiro-dihydropyridine increases the circulation rate of the vertebral, carotid and coronary arteries by 0, 10 and 30 respectively. The compound in question is therefore much more effective than nicaldivine, a well-known dilator of cerebral vasculature, in terms of the intensity and duration of the aforementioned effects. The research results obtained are shown in Table 1 below.
Shown below.

Kerr found that the rate of blood flow in the femoral arteries of the dogs tested increased significantly in response to taking the drug, which also caused a decrease in systemic arterial pressure.

In a study of spontaneously hypertensive rats (Sl(R)) given this compound, systolic arterial pressure was observed to fall over a period of 6 hours or longer. The compound of the present invention that showed the most remarkable effect of lowering C and blood pressure was U,A-dimethyl-J.
, j-bis-(2-ethoxyethoxycarbonyl)-μ
2(2-difluoromethoxyphenyl)-1,4-dihydropyridine 26-cymethyl-3. j-bis-(2-propoxyethoxycarbonyl)-g-(2-difluoromethoxyphenyl)-'t''-dihydropyridine, and co,6-cymethyl-J,j-bis-(cofdinoxyethoxycarbonyl)-Hiro- (Cocyfluoromethoxyphenyl)-'t Hiro-dihydropyridine.

The antihypertensive properties produced by the above-mentioned compounds are substantially different from those conferred by nifedibine and are similar to those afforded by 2,6-dimethyl-J,j-bis-(coethoxyethoxycarbonyl)-≠-(2-difluoromethoxyphenyl). −／
, 4A-dihydropyridine, unlike nifedipine, do not cause tachycardia.

A study of the acute toxicity of a compound taken up by albino mice administered intraperitoneally revealed that one compound of the present invention is of low toxicity. Table 3 shows the results obtained from the research.
Shown below. The most effective compound is nifedibine 2,3
On the other hand, the remaining compounds were found to be 13 times less toxic than nifedivine.

Table 3 Acute toxicity of compounds of the invention and comparative known drugs tested in albino mice (administered intraperitoneally) Compounds of the invention with general formula / n = C2H, OCH, //30 (rA5', 2 From/IAI, F) R= C2H,QC2H,2,200(
/l,! ≠ to Kota26) R= C2! H, QC, H7
≠yoO(,3!7 to !Otsu7)R= C2H,QC6
If, 7ri0(t, 3 to//2/, riR= CX1(CH,)CH20CH,2J00(/7
Review from Jt2 Rinifedibin / RiOC
, /416B to 2≠7) difluoromethoxyphenyl) -/l″lage 053 lights (2!Q to h) ginicaldivine fuυ(/Otori, / to 2
Tata, 2j) From these obtained data, the same! It will be appreciated that the compounds of the disclosed invention have many advantages over other known drugs.

It has an excellent and selective vasodilating effect on the vessels supplying blood to the brain and heart, and an excellent blood pressure lowering activity when administered intravenously and orally.

m=Unlike phetdivine, the compounds of the invention do not cause as much tachycardia in unparalyzed animals - from 2.3 to that of phedibine to a lower antecedent, 7
This is critical for a wide range of therapeutic effects.

The compounds of the present invention have the general formula CH,COCH2C00R(
Here, R is C2 horse QC! (,,C2H,QC2H,,
C2H,QC,H7°C2f(,QC6H,,CH(C
H,)CH20CH. ) with 2=difluoromethoxypenzaldehyde and ammonia by a known method by stirring in an organic solvent, preferably ethanol.

The production method is shown below according to the following reaction formula.

(Example) In order to facilitate a further understanding of the present invention, the present invention will be explained in detail by giving examples below.

Example / 211-1 Og (0,/j mol) of methoxyethyl acetoacetate and /co,rig (0,07! mol) of J
Thiammonia water! Dissolve in Oml ethanol 2
Boil for an hour. The mixture was allowed to stand for J hours, after which the precipitate was filtered and dried at room temperature, yielding 2 g (32%) of 2. t-dimethyl-3! −
Bis=(,2-methoxyethoxycarbonyl)-≠-(
2-difluoromethoxyphenyl)-≠-dihydropyridine is obtained. M, p, tag Karari t”c (ethanol!ll) Experimental value, %: Cjl, 2; H4, N j,
IrC22H27N07F2 Theoretical value, CH: Cjg, 0; H6,0; NJ, /CD
Paramagnetic resonance spectrum in Cl, δ: 2.2≠(1,
,4H,! , 6-CH5); J, 2j (a,, 6
H,j, terCH.

); 3. s/(t,, Hiroshi)(, J, j-cr(
2-O, J==jHz) ;u, / 2(t, +
4' HJ, j -COOCH2-, J; Evening Hz
) /yo, 27 (c-y / Ht 4' -H)
T! Jta (b, a,, / H, N-H)
;A, jj (t-z / Ht -0CHF2
+ J = 7! Hz) r A, λ -7,
lA2 p, p, m, (rrl, # HiroH, -C6
H, -).

UV spectrum in ethanol, λmax (10gξ)
:2(8(lfi,/I), 23?(4(,2F
) and 362 nm (JJj).

IR spectrum in Vaseline oil: 17000m-
1 (C=O), 3/Iθcm (NH).

Example: 3413 g (0.2 mol) of ethoxyethyl acetoacetate, /7.2 g (0.7 mol) of cordifluoromethoxybenzaldehyde, 10 ml (0./j mol) of thiammonia water - 1 example/ 30.2g (42,!chi) as a pale yellow crystalline substance by the same method as
2゜6-dimethyl-3. j-Bis-(,2-ethoxyethoxycarbonyl)-≠-(2-difluoromethoxyphenyl)-"t Hiro-dihydrohylysine was obtained.

M, p, / from JJ / co≠℃ (from ethanol) Experimental value, %: C10,3; H6,3; N 2. t ;
C24H51NO□F2 theoretical value 1%: C! ri, 6;
Hip, j; Nλ, PMR spectrum in CDCl, δ, /, /7(t,.

6H, j, j - CH5, J = 7Hz) / Ko, Kota (S,, Otsu H.

Ko, +4l-CH! S); ', ≠Nq-t≠H
, j, j-OCH2-, J=77); 3,1j(
t,,≠H,j, j-13-CH2,J=! 7);
≠, /4t(t,, Hiro H, J, j-C00CH2-,
J=zh ); z, 2g (a, , /H, p-px
); j, t4'(b, a,.

/H,NH); 174 (t,, /H,-0
CHF2. J = 7jrh) i turf, ≠ 2m, d,
(m,,#H,-06H%-)UV spectrum in ethanol, λmax (/gε): 207 (!,,2
j), 23? (Tada33)362 nm (J
Jri).

IR spectrum in Vaseline oil 2/≦5F7ato
t33! Darn (NH) Example 3 37, tg (0.2 mol) of propoxyethyl acetoacetate, i7. ．． 2 g (o, i mol) kodifluoromethoxybenzaldehyde and 10 rnl (0,1
3 mol) 2j% of aqueous ammonia according to the manufacturing method of Example 1, yielding 27.0% as a pale yellow crystalline substance. ≠g(o-
) 2. Otsu-dimethyl-3,! -Bis(λ-propoxyethoxycarbonyl)-μm(2-difluoromethoxyphenyl)-/, 4t-dihydropyridine is obtained. M
, p, ri7karari♂℃ (from ethanol) Experimental value %:
C40,! I; H7,ll; Nu,j-;
C26H,, No7F'2 theoretical value Chi: CjO; H7°/
; N2. PMR spectrum in fCDCI, δ:0
．． liri(t,.

Ah,! ,! -CH,,J=7Hz),'/,J
j-/, 7j(m,.

7θ 4'H, J, j −+−CHzv J =7 Hl)
/ Ko, 21 (a-* 'H, 2, j-CH,)
; j, j≠(t,,≠H,!,!−α−CH2,J
=71(z); 3. ! J-(t,, !H,j
, J-0CH2QC-, J=j)Lz);Hiroshi,/
! (t,, tLtH,j, j-C00CH2+,
J=j city);! , Koj(a,, /H≠−H);! ,Ico(b,s,, /H,NH); 413-Ct,,
/H, -0CHF.

J=Hx); 6. Turf, 'Aj p, p,
m, (m,, 4tJ -C6Hu-) UV spectrum in ethanol, λmax (/g g); 20
4 (Hiroshi, li), 2Jlr (IA, 30) and 3
62 nm (j, It) IR spectrum in Vaseline oil 2/627 cm-1
(c=o); 6 ml (0
, 02 mol) cothiammonium aqueous solution, according to the production method in Example/, as a pale yellow crystalline substance, 1 g (7
7) of λ, 6-cymethyl-3. ! -Bis-(2-phenoxyethoxycarbonyl)-<z-(J-difluoromethoxyphenyl)-1,4-dihydropyridine is obtained. M, p, 47 to Otsu 2℃ (ethanol) Theoretical value %: C6J, 7; Hj, 7; N2,4A
C, 2H, 1NF20゜Theoretical value: C, niH,
≠;N2. ≠CD CI , PMR spectrum in δ
: Ko, Jr (c,.

tH, 2, Bu-C horse); Hiro, ot (t,,≠H,j,
j-CCH20-J=7); Hiroshi, J4t (t,, da H, J, j-COOCH2-J=!Hz); j,
26 (s,, /H,4(-H); evening, 7z (b
, Hatake, /H,NH); J, Hirof(t,, /
H.

-0CHF2. J=7! kTz); 6.74
-7.37 p, p, m.

(m,, /laH,4L-c6H14- and 3.
r-c6H,) UV spectrum in ethanol, λma
x (/gε): 210 (44, 31), , 2.2
．． 2 (44, JJ'), 23F (4t, 21).

Engineering Paco 7 (7 (3, AI), 277 (3,, r&) b
a4J Otsu ≠ nm (J, ♂3) IR spectrum in vaseline oil: / 702 cm-' (C=O) t 33
00 am-1 (listening) example! 3 hiro, rg (o, 2 mol) l-methoxycobrovir acetoacetate, /7.2 g (0,7 mol)
of 2-difluoromethoxybenzaldehyde and 10ml of
(0.13 mol) and 25% ammonia water in the same manner as in Example/20.3 g (
2. Otsu-dimethyl-3,! - Bisou [(/
-methyl-comethoxy)-ethoxycarzenyl)]-
≠-(2-difluoromethoxyphenyl)-7,4! −
Dihydropyridine (it's daytime.

■ f, p, /≠7 to ℃ (from ethanol) theoretical value %: Cj ri, j; HA, j; N, 2,4 C2, H
,,N07F"2 theoretical value CH: CHri,t; H6,j
; N2. PMR spectrum in CD CI, δ
: To eight! l(d,.

31(,j-COOCHCH,-,,y=7ih)/,
,2(d,,JH,j −C00CCI(v −,J
= 71h) t co, 2j(c,.

4 H? -2t b -CH5) t 3. /ri(s
, t J H, j -0CHs) tj, 2-3. ni r
(m,, !H,j, j-CH2) ; 3.3
3(8,,jH,j-OCH,); IA, 13-
j, /j(m,, JH.

3,! -COOCH-); ! ,22 (a,,/H
, 4A-H);! ;,71(b,m,,/H,NH)
;l,,jko(t,,/H.

-0CHF2. J=7! Hz)t4. Turf, 4
'p, p, m, (1+-tμH,-C6H,-).

UV spectrum in ethanol, λmax (/g: u
07 (g, co2), 27F (fJO), J6J
nrn (j, J'J) IR spectrum in vaseline oil: / 7 (' Oam-1(C=O) r
3210 am (NH) (Effects of the Invention) The compounds of the invention are characterized by an excellent hypotensive effect and do not cause noticeable tachycardia.

In addition, it produces an excellent selective vasodilatory effect on the blood vessels supplying the brain and heart.

Claims (1)

[Claims] 2,6-dimethyl-4-(2-
Alkoxy and phenoxy-alkyl esters of (difluoromethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid. (In the formula, R is C_2H_4OCH_3, C_2H_4
OC_2H_5, C_2H_4OC_3H_7, C_2
H_4OC_6H_5, CH(CH_3)CH_2OC
It is H_3. )