JPH0477465A - New aminoalkanesulfonic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula [R<1> is H or protecting group of amino; R<2> is H or, together with R<3>, forms trimethylene or hydroxytrimethylene; R<3> is (protected group) carboxyalkyl or (protected group) aminoalkyl; X is sulfo, acetylthio or mesyloxyl and salts thereof. EXAMPLE:2-((S)-Benzyloxycarbonylpyrrolidinyl)methyl ethanethioate. USE:A medicine having strengthening and protective action on cardiac muscles. PREPARATION:For example, OH group in a compound expressed by the formula (X is OH) is activated with triphenylphosphine and diethyl azocarboxylat, etc., in a suitable solvent and then allowed so react with thioacetic acid to provide a thioate derivative, which is subsequently sulfonated by oxidation with performic acid, etc., to afford the objective compound expressed by the formula (X is sulfo group).

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel aminoalkanesulfonic acid derivative that has the effect of strengthening and protecting myocardium.

(Prior Art) Cardiomyocytes maintain homeostasis of calcium ions and the like through the cardiomyocyte membrane. If there is a disorder in this cell membrane function or if excessive calcium ions are loaded into the cell due to some cause such as drugs (Ca”□-over-1oa
d) Myocardial cells are damaged, resulting in lesions called cardiomyopathy or causing myocardial necrosis.

If the isolated myocardium is perfused briefly with a calcium-free solution and then reperfused with a calcium-containing solution, myocardial contracture, loss of electrical activity, cell destruction, and outflow of intracellular enzymes are caused. This phenomenon is called the calcium paradox, and the above-mentioned Ca'overload is thought to play an important role in the mechanism of its occurrence. Ca”-overloa is one of the factors that cause myocardial damage.
d is suggested. Although the calcium paradox ultimately causes irreversible changes in the myocardium, it has been reported that, for example, calcium antagonists can alleviate this damage.

The present inventors have completed the present invention by discovering that the aminoalkanesulfonic acid derivatives of the present invention have excellent myocardial strengthening and protecting effects against myocardial damage caused by Ca''-overload and the like.

(Problems to be Solved by the Invention) An object of the present invention is to provide a novel aminoalkanesulfone #1 derivative useful as a medicine and a synthetic intermediate thereof.

(Means for Solving the Present Invention) The compound of the present invention is a novel aminoalkanesulfonic acid derivative represented by the following general formula (1).

In the formula r, R1 represents hydrogen or a protecting group for an amino group, and R"
4 together with hydrogen or Ry represents trimethylene or hydroxytrimethylene, R3 represents a carboxyalkyl group which may have a protecting group, an aminoalkyl group which may have a protecting group, or together with Rt represents trimethylene or hydroxytrimethylene, X represents a sulfo group, an acetylthio group or a mesyloxy group. ] In the above general formula (1), as the protecting group for the amino group represented by R1, the usual protective groups used in the field of peptide synthetic chemistry can be used, such as t-butoxycarbonyl, t-pentoxy Lower alkoxycarbonyl groups such as carbonyl groups, benzyloxycarbonyl groups having substituents such as hensyloxycarbonyl groups, o-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxyhensyloxycarbonyl groups, tosyl groups , trityl group, formyl group, phthaloyl group, 0-nitrophenylsulfenyl group, 9-fluorenylmethyloxycarbonyl group, and the like.

R1 is bonded with hydrogen or R3 and jointly represents trimethylene or hydroxytrimethylene, and R'' is a carboxyalkyl group that may have a protecting group or an aminoalkyl group that may have a protecting group, preferably a protected Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, L-butyl, pentyl, isopentyl, neo-pentyl, which has a carboxyl group that may have a group or an amino group that may have a protecting group. t-
It represents a linear or branched C1-C5 alkyl group such as a pentyl group, or trimethylene or hydroxytrimethylene covalent with R2, and X represents a sulfo group, an acetylthio group, or a mesyloxy group.

As the protecting group for the amino group in R3, the same amino group-protecting group as in R1 above can be used, and as the protecting group for the carboxyl group, a carboxyl-protecting group used in ordinary peptide synthesis, ie, hensyloxy Aralkyloxy or 4-pyrisiloxy having a substituent such as p-methocinobenzyloxy and the like can be mentioned.

Among the compounds of the present invention, particularly preferred compounds are as follows.

・2-pyrrolidinyl methanesulfonic acid ・2-(4-hydroxypyrrolidinyl) methanesulfonic acid ・3-amino-4-sulfobutyric acid ・4-amino-5-sulfopentanoic acid ・2,6-diamithexane Sulfonic acid/2,5-diaminopentanesulfonic acid The aminoalkanesulfonic acid derivatives of the present invention include pharmaceutically acceptable salts thereof, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, boric acid, Formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-)luenesulfonic acid, naphthalene Acid addition salts with acids such as sulfonic acid and sulfanilic acid, or sodium,
Examples include salts with alkali metals such as potassium, alkaline earth metals such as calcium and barium, other metals such as aluminum, and salts with ammonium and organic amines.

Further, the compound of the present invention includes its metal complex compounds, such as complex compounds with zinc, nickel, cobalt, steel, iron, etc.

These salts and metal complex compounds can be produced from the free aminoalkanesulfone #I derivative of the present invention by known methods, or can be converted into each other.

When optical isomers exist in the compound of the present invention,
The present invention includes both of them.

Next, an example of a method for producing the compound of the present invention will be described.

As a raw material, a compound in which X in the general formula (1) is a hydroxyl group can be used. This amino alcohol compound is converted into a thioate by activating the hydroxyl group of the raw material with a reaction reagent such as triphenylphosphine and diethylazocarboxylate in a suitable solvent such as tetrahydrofuran that does not inhibit the reaction, and then reacting it with thioacetic acid. can do.

Furthermore, after mesylating an aminoalcohol compound, it can also be thioated. For example, by reacting methanesulfonic acid chloride in the presence of a base such as triethylamine in a suitable solvent that does not inhibit the reaction such as methylene chloride. Mesylation can be carried out, and then thioate can be obtained by reacting potassium thioacetate in a suitable solvent that does not inhibit the reaction, such as dimethylformamide.

The compound of the present invention in which X in general formula (I) is a sulfo group can be obtained by sulfonating the thioate compound synthesized in this manner by oxidation with performic acid or the like.

In the above-mentioned sulfonation, mesylation, and thioate formation, it is preferable to protect amino groups, hydroxyl groups, etc. that do not participate in the reaction of the starting material with protecting groups used in ordinary peptide synthesis, etc.; however, depending on the type of reaction, In some cases, protection may not be necessary. Regarding the removal of the protecting group, a preferable deprotection reaction can be applied depending on the type of protecting group, but common methods such as catalytic reduction and acid decomposition used in peptide synthesis chemistry may be used.

When performic acid oxidation reaction is used as a sulfonation method, deprotection reaction can be performed simultaneously with performic acid oxidation when t-butoxycarbonyl etc. is used as a protecting group, and the deprotection reaction can be performed at the same time as performic acid oxidation reaction. In some cases, the diprotecting group can be removed during a reaction in which excess peroxide is reduced with palladium-carbon or the like after performic acid oxidation, which is preferable because the operation is simple.

The obtained compound of the present invention is purified by conventional means such as chromatography and recrystallization, and subjected to elemental analysis, melting point, IR,
Identification was performed by NMR, UV, mass spectra, etc.

Note that the specific optical rotation was measured using sodium D&I.

Examples of the manufacturing method of the present invention are shown below.

(Example) Example 1゜(1) Under an argon atmosphere, 11.8 g of N-benzyloxycarbonyl-prolinol and 13.9 g of triphenylphosphine were dissolved in 150 m of tetrahydrofuran solution and cooled in a water bath. Then, 8.4 d of diethyl azodicarboxylate and 3.87 d of thioacetic acid were sequentially added. After stirring for 2 hours under water cooling and 20 hours at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11.96 g of 2-((S)
-1-benzyloxycarbonylpyrrolidinyl) methylethanethioate was obtained as an oil.

[α) ”: -48,1” (C=1.0.CH
CL3) NMR (DMSo-d, ): δ=1.63
4.67 (ILmL 1.701.81 (Illll)
, 1.82-1.97 (2H, m), 2.32 &
2.34 (3B, 5x2), 2.95-3.07 (
IH, m), 3.11-3.23 (IH.

m), 3.25-3.41 (28, 餠), 3.87
-3.98(I)l,s)5.06 and 5.11
(2H, ABq, J-12Hz), 7.28-7.4
1(5H, m) The following compound was obtained in the same manner.

2-((S)-4-benzyloxy-1-t-butoxycarbonylpyrrolidinyl)methylethanethioate Ca
) t4: 50.0@(C・1.4.CHC]
+) NMR (DMSO-dri: δ=1.40 an
d 1.43 (9H, 5x2) 1.64-1.78 (l
tl, @), 2.05-2.18 (Ill, m),
2.33 (3H, s), 3.03-3.19 (18
, m), 3.21-3.33 (2B, m).

3.48-3.63 (IH, m), 3.93-4.
04 (IH, m), 4.054.10 (IN, w)
, 4.40-4.49(2)1. s), 7.2
4-7.36 (5B, m) Benzyl (S) -3-(t-butoxycarbonyl)amino-4 acetylthiobutyrate Melting point: Oil Ca) ”: +6.1” (C=1.0.C )
ICIs) NMR (CDC13): δ=1.43(
911, s), 2.34 (3H, s).

2.61 (IH, dd, J=6.16Hz), 2.6
7 (IH, dd, J=6°16Hz), 3.12 (I
N, dd, J=7.14Hz), 3.16 (ILdd
, J=6.14Hz), 4.05-4.15(IH,
w+).

5.08-5.15 (11, br, side), 5
．． 09 (211, s).

7.30-7.39(5)1. a+) t-Mesyl (S)-5-acetylthio-4-hensyloxycarbonylaminopentanoate (α)” knee 17.5° (C=1.0. CHCL3
) NMR (CDCI+): δ=1.42 (98,s
), 1.68-1.89 (2) 1. ■), 2.24
-2.37 (2H, s), 2.31 (38, s) 3.
04 (III, dd, J=7.14Hz), 3.09
(Ill, dd, J=5°14Hz), 3.77-
3.87 (1B, m), 4.86 (IH, d, J=
9Hz).

5.06 and 5.10 (20, ABq, J=12
．． 5Hz).

7.28-7.38 (5N, *) (S)-2,6-di(t-butoxycarbonyl)aminohexylethanethioate Melting point: 92-93°C [α]” 18.1@( C=1.0.CHCh
) NMR (CDCIs): δ=1.43 (9B, s
), 1.44 (9H, s).

1.30-1.60 (68, m), 2.35 (31 (
, s), 2.98 (IH, dd.

J=7.13.5Hz), 3.05-3.14(3H
,s), 3.67-3.76(Ill,m), 4
．． 57(II(,d,J=8Hz amideL4.
55-4.64 (IH, br, side) (2) 24
A fort M solution was prepared by stirring 240 m of 30% hydrogen peroxide solution and 240 m of 98% formic acid at room temperature for 1 hour. This was cooled in a water bath and 11.0 g of the above product was dissolved in formic acid (4
0d) was added dropwise over 30 minutes. After stirring for 2 hours under water cooling and 20 hours at room temperature, 5 g of 10% palladium on carbon was added to decompose excess peroxide. Further palladium-carbon was added and stirred under hydrogen atmosphere for 10 hours.

After filtering off the catalyst, the filtrate was distilled off under reduced pressure to give 5.78
g of 2-((S)-pyrrolidinyl)methanesulfone v
! (Compound 1) was obtained as white crystals.

Melting point: 307-308°C (decomposition) [α)”:
+33.4° (C=1.0.H,O) Elemental analysis:
Cs H+ + N Ox S 0% N%
N% Calculated value: 36.35 6.71 8.48 Actual value: 36.43 6.94 8.37HM
R(0,2N Na0DHt-BuOD, δ=1.
23 ppm): δ=1.45 (1B, ddd, J
=8.8.9.5.13Hz), 1.671.83(
2H, m), 2.20 (1B, ddd, J=5.
7. 8. 13Hz) 2.78 (II, ddd, J=
7.8.10Hz), 2.89(11,ddd.

J=6.7.10)1z), 3.01((18,dd
, 6.5.14Hz) 3.04 (IH, dd, J=6.
5.14Hz), 3.23-3.40 (IH, m) The following compounds were obtained in the same manner.

2-((S)-4-hydroxypyrrolidinyl)methanesulfonic acid (Compound 2) was obtained as white crystals.

Melting point: >330°C (α) ”: +28.1” (C=1.0.Hz
O) Elemental analysis: 0% as CsH+□NO,S
N% N% Calculated value: 33.14 6.12 7.73 Actual measurement W: 32.92 6.42 7.41HM
R(0,2N Na0DHt-BuOD, δ=1.
23 ppm): δ=1.72 (18, ddd, J
=6.10.14Hz), 2.03(18ddt, J
P=6.5.14Hz, Jt=1.5Hz), 2.7
5 (IHddd, J=1.3.11.5Hz), 3
．． 01 (IH, dd, J=7°14Hz), 3.0
8 (IH, dd, J = 6.5. 14) 1z), 3
．． 15(1)1゜dd J=5.5. 11.5Hz
), 3.60-3.68 (IH, m).

4.40-4.45 (IH, m) (S)-3-amino-4-sulfobutyric acid (compound 3) Melting point: 266-267°C (decomposition) (α) ” Knee 4
．． 7° (C=1.0.HzO) NMR (0.2N Na
0D; t-BuOD, δ=1.23 ppm)
: δ=2.28 (1B, dd, J=8.5.15Hz
), 2.41 (18, dd.

J=5.5.15Hz), 2.87(IH, dd, J
=8.5.14Hz).

3.03 (IH, dd, J=3.14Hz), 3.5
7 (IH, ddddJ=3 3.5 5.5.8.5H
z) (S)-4-amino-5-sulfopenconic acid (compound 4) Melting point: 257-258°C (decomposition) [α)
t4: +16.9@(C=1.0.H2O) Elemental analysis: 0% N% as C5H31NOsS
N% Calculated value: 30.45 5,62 7.10 Actual measurement 4! f: 30.30 5.89 6.95
HMR (0,2N NaOD; t-BuOD, δ
=1.23 pPa)'δ-1,97(2H,dt
, Jt=7.5Hz, Jt=7Hz), 2.282.
41 (2H, m), 3.13 (E, dd, J=9.5
．． 15Hz)3.25(1)1. dd, J=3.15H
z), 3.61-3.69 (IH, s+) (S)-2
, 6-diamithexane sulfonate hydrochloride (compound 5) Melting point: 192-194°C [α) ”: +10.4° (C = 1.0. HzO
) NMR (0,2N Na0DHt-BuOD, δ
= 1.23 ppm) : δ = 1.294.62 (
6)1. ■) + 2.74-2.85 (2B, m).

2.82 (IH, dd, J=9.1482), 3.0
3 (18, dd, J=314Hz), 3.19-3.
26 (IH, m) Example 2゜(1) 100 mmol of (S)-2,5-di-t-butoxycarliponylaminopentanol and 11.13
g of triethylamine in methylene chloride solution, add 8.5 m
A methylene chloride solution containing chloromethanesulfonic acid of
It was gradually added dropwise. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 5% aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 31 g of (S).
-2,5 di-t-butoxycarbonylaminopentyl methanesulfonate was obtained as white crystals.

Melting point: 125-126℃ (ff) ”: -17,2” (C=1.0.C
lICl5) Elemental analysis: C++*HstNzO1S
As 0% N% N% Calculated value: 48.47 B, 13 7.06
Actual value: 4B, 76 8.41 7.02H
MR (CDCIs): δ=1.44 (18H,
s), 1.48-1.65 (4H, s+), 3
．． 03 (3H, s), 3.10-3.18 (2H,
m) 3.79-3.90 (18, m), 4.18 (
IH, dd, J=4.5. 10Hz).

4.25 (IH, dd, J=4.5.10Hz),
4.54-4.64 (IHbr), 4.65-4.7
3(1B, br) (2) 7.39 g of the above product was dissolved in dimethylformamide and 2.74 g of potassium thiosulfate was added at room temperature.

After stirring for 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a 5% aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The residual oil obtained by distilling off the solvent under reduced pressure was crystallized from petroleum ether to yield 7.22 g of (S)-2.
, 5-di-t-butoxycarbonylaminopentyl ethanethioate was obtained.

Melting point: 95-96°C (α) ” knee 13.4° (C = 1.0. CHCl
3) Elemental analysis: C1, Hx t N z Os S
0% N% N% Calculated value: 54.23 8.57 7.44 Actual value 7 54.33 8.82 7.13 HMR (C
DCIs): δ=1.43(9H,s), 1
．． 45-1.62 (4H, m), 2.35 (3B,
s), 2.99 (IH, dd, J=7°14Hz)
, 3.05-3.15 (38, m), 3.69
-3.76 (18, m).

4.53 (IH, d, J=9Hz), 4.57-4.6
3(IH,br)(3) Using (S)-2,5-di-t-butoxycarbonylaminobentylethanethioate as a starting material, (S) was prepared in the same manner as in Example 1(2).
)-2,5-diaminopentanesulfonate hydrochloride (Compound 6) was obtained.

Melting point: 277-278 'C [α)'': +x2.7@(C=1.0.1(,0
) Elemental analysis: CsH+4NzOsS HCI! 0% N% N% Calculated value: 27.46 6.91 12.81
Actual value: 27.49 6.97 12.86
NMR (0,2N NaOD; t-BuOD, δ=
1.23 ppm): δ=1.50(In, ddd
d, J=6.7.9.14Flz), 1.61 (18
, dddd, J=5.6.9.14Hz), 1.64
-1.78 (2H.

s), 2.87 (IH, dd, J=9.14Hz),
2.93(1)I, ddd.

J=7.7.13Hz), 2.96(IH, ddd,
J=7.7.13Hz).

3.04 (IH, dd, J=3.5.14Hz), 3
．． 25 (18, dddd.

J=3.5.5.7.9Hz) (effect) Next, the pharmacological effects of the compounds of the present invention will be described.

(1) Cardioprotective effect ICR system The fetal heart of a 14th to 16th day pregnant mouse was cut into small pieces, an enzyme solution of 0.06% trypsin and 0.01% collagenase was added, and the mixture was heated at 37°C for 10 minutes. The reaction was performed while shaking for 1 time, and the cells were separated. Eagle's MEM culture solution containing 10% calf serum was added to this and centrifuged, and then the collected cells were redispersed in the culture solution. Since cardiomyocytes have a different adhesion time than fibroblast-like cells, the redispersed cell solution was heated at 37°C.
After removing fibroblasts by incubating for 1 h in 95% air-5% carbon dioxide saturated water vapor conditions, IId
After pre-incubation for 40 to 44 hours, 2×10S to 4×10′ cells were prepared per cell and used for calcium paradox experiments.

The medium was removed and the EGTA medium containing the test drug (Ca ”
After adding 1 d of “free”, heat at 20 to 22°C.
Cells were then incubated in EGTA-free medium (Ca
After washing with ``''-free'', 1mMca'' medium containing the test drug was immediately added, and morphological changes (edema, balloon-like) of the cells were observed 1 minute later.

An example of the results is shown in Table 1.

(Margin below) 1st table Percentage of cells with morphological changes (%) Control 47.4±3.510mM Compound 1 28.5±1.510mM Compound 2 3
8.8 + 2.810mM Compound 3 32.8±
3.810mM Compound 4 33.6±2.510m
M Compound 6 33.7±1.6 (Efficacy) As is clear from the results of the above pharmacological tests, the aminoalkanesulfonic acid derivative of the present invention has an excellent protective effect against morphological changes in myocardium caused by calcium paradox.

As described above, the compound of the present invention has an excellent myocardial protective effect against myocardial damage caused by Ca'overload, etc., and is effective against ischemic heart diseases such as myocardial infarction, angina pectoris, and heart failure, and ischemic conditions during cardiac surgery. It is useful as a drug for treating and preventing myocardial damage associated with myocardial disorders.

Claims (1)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents hydrogen or a protecting group for an amino group, and R
^2 represents trimethylene or hydroxytrimethylene together with hydrogen or R^3, and R^3 represents a carboxyalkyl group which may have a protecting group, an aminoalkyl group which may have a protecting group, or trimethylene together with R^2. or hydroxytrimethylene, and X represents a sulfo group, an acetylthio group, or a mesyloxy group. ] A compound represented by these and its pharmaceutically acceptable salt.