JPH0426654A - Isocarbacycline derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is formula II (R<61> to R<63> are H or 1-10C alkyl) or formula III (R<71> to R<73> are H or 1-10C alkyl; R<74> is H, 1-10C alkyl, phenyl, etc.); R<2> and R<3> are H, tri-1-7C hydrocarbon silyl or a group capable of forming acetal bond or ester bond together with O atom of OH; R<4> is H, CH3 or vinyl; R<5> is 1-10C alkyl which may contain O, 3-10C alkenyl, 3-10C alkynyl, phenyl which may be replaced, phenoxy which may be replaced, etc.) and salt thereof. EXAMPLE:9(O)-Methano-# <6(9alpha)>-prostaglandin I1 carboxymethyl ester. USE:A remedy for lesion of organ and liver reduced in action such as blood pressure lowering action, blood planet aggregation suppressing action, etc. PREPARATION:Isocarbacyclin carboxylic acids expressed by formula IV is subjected to condensation through dehydration with hydroxyacids expressed by formula V or amino acids expressed by formula VI to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to novel isocarbacyclines, a method for producing the same, and a therapeutic agent for organ disorders containing the same as an active ingredient.

More specifically, novel isocarbacyclines useful as therapeutic agents for organ disorders, and isocarbacycline carboxylic acids and hydroxy acids or amino acids are subjected to a dehydration condensation reaction, followed by deprotection and/or salt formation reactions as necessary. The present invention particularly relates to a method for producing the isocarbacyclines and a therapeutic agent for organ disorders containing the isocarbacyclines.

<Prior art> Prostaglandins have a variety of physiological effects such as strong platelet aggregation inhibiting action, blood pressure lowering action, gastric acid secretion inhibiting action, smooth muscle contraction action, and diuretic action, and they can cause peripheral circulation disorders, myocardial infarction, It is a useful substance for the treatment or prevention of angina pectoris, arteriosclerosis, hypertension, gastric ulcer, duodenal ulcer, induction of labor, abortion, etc.

Recently, it has been found that some of these prostaglandins have a so-called cytoprotective effect that protects cells in living tissues. This cell-protective effect exists on all cells in the body, and for example, the therapeutic effect on gastric ulcers, the reduction of myocardial infarct lesions, and the preventive effect on lung damage caused by endotoxin shock are derived from this cell-protective effect. It is said that there are (Ayumi of Medicine, Volume 125).

(See page 250, 1983). It is also known that prostaglandins exhibit a cytoprotective effect on hepatocytes. For example, structurally modified forms of P G E 2
A certain 16.16-dimethyl-PGE2 was reported to prevent carbon tetrachloride-induced and galactosamine-induced hepatocyte necrosis in rats [).
Folia Hist.

Chemical et Cytochemical,
Volume 18, page 311.

1980; and Gastroenterology (Gast
PGE2 and its structurally modified derivatives (15-methyl PGE2, 16.16-
Regarding the hepatocellular protective effect of dimethyl-PGE2, etc.,
It is also described in US Pat. No. 4,374,856. Also, 6-oxo-P G E 1'! Regarding the cytoprotective effect of modified fj derivatives, Japanese Patent Application Laid-Open No. 58-1645
No. 12, and JP-A-58-203911.

Furthermore, prostacyclin (PG I 2 >) has been reported to have a protective effect on cat liver tissue in hypoxic conditions [American Journal of Physiology (Amer, J., Physiol.).

238, p. 176, 1980]. Also,
Prostacyclin derivatives such as 6,9α-nitrilo PGI□ have also been reported to have hepatocellular protective effects (JP-A-58-164512, JP-A-5820391).
(Refer to each publication No. 1). Furthermore, it has been reported that the carbacycline derivative iloprost and the cyanoprostacyclin class nileprost have protective effects on the liver, pancreas, and kidneys (see Japanese Patent Publication No. 61-502819).

Recently, prostaglandins have also been used in the field of organ transplantation due to their strong cell-protecting effects (
Kazuo Ota, "Modern Medicine" Volume 18.

2693-2697, 1986). In other words, prostaglandins are used in organ preservation to protect the organs extracted from the donor during organ transplants, minimize damage to the organs, and preserve them in good condition until the time of transplant surgery. There is. For example, natural prostacyclin (
PGI2) has been reported to be effective in preserving the liver and kidneys (M, Monden).

et al Ann, Surg, vol. 19
6. p38.1982; J, W.

Bradley, et al., Transplan
t, Proc, vol, 15p424.1983)
L, OP-414, a prostacyclin derivative
83 is effective for kidney preservation (MTobimatSu
, et al., Transplant, Proc.
, vol. 17pi461.1985) and that prostaglandins are effective in suppressing rejection reactions during organ transplantation due to their strong cytoprotective effects (Kazuo Ota, ``Modern Medicine'' above). .

By the way, natural prostacyclin is a local hormone produced mainly in the inner walls of arteries in living bodies, and is an important factor that regulates cell functions in living bodies through its powerful physiological activities, such as platelet aggregation inhibitory activity and vasodilatory activity. Taking advantage of this fact, attempts are being made to directly provide this substance as a medicine [P.J. Lewis, J.O.G. Lewis, J.
,0. Grady et al., Clinical Pharmacology of Prostacyclin
Pharmacology of Prostacycli
n)”, Raven Press, N, Y,,
(1981), natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, so it is easily deactivated under neutral or acidic conditions, and although it is a preferred compound as a pharmaceutical due to its chemical instability. do not have. For this reason, chemically stable synthetic prostacyclin derivatives that have the same physiological activity as natural prostacyclin have been intensively investigated [Synthesis
is), 1984, p. 449]. By replacing the oxygen atom at position 69 of prostacyclin with a methine group (-CH-), the present inventors have developed prostacyclin 9<0
)-methanoΔ6 (9(1+-prostaglandins 1
(Isocarbacyclines) were not successfully synthesized (see JP-A-59-210044). This derivative has a strong organ protective effect and 1m organ damage suppressing effect (see Japanese Patent Application No. 63-69845, etc.), as well as a strong platelet aggregation inhibiting effect comparable to natural prostacyclin and a blood pressure lowering effect. To clarify that it has activity, please refer to Japanese Patent Application Laid-open Nos. 59-210044 and 61-197518, etc.).

By the way, when prostaglandins are used as pharmaceuticals, various effects that prostaglandins generally have, such as blood pressure lowering effect, platelet aggregation inhibiting effect, and smooth muscle contracting effect, may act as side effects and give unfavorable results. It is known that there are many Therefore, many attempts have been made to separate the main effects and side effects and reduce the side effects.

For example, attempts have been made to convert the carboxylic acid moiety at position 1 of 6-kedo PGE
2-277352).

<Disclosure of the Invention> The present inventors synthesized a hydroxyacetic ester of the 1-position carboxylic acid of isocarbacycline and an amino acid amide, and examined the biological activity of such isocarbacycline. Surprisingly, the inventors found that it strongly inhibited organ damage. The present invention was achieved based on the discovery that, while it has a certain effect, it has reduced effects such as blood pressure lowering effect and platelet aggregation inhibiting effect, and has an ideal medicinal efficacy profile as a therapeutic agent for organ disorders. It is. That is, the present invention provides a nontoxic salt of the following formula [I]R3.

'R, 74 or different, represents a hydrogen atom or an alkyl group of C to CIO. Examples of alkyl groups of C□ to C1° include methyl, ethyl, n-propyl, 1so-propyl, n
-butyl, 1so-butyl, sec~butyl, sec-
Butyl, low pentyl, n-hexyl.

Examples include linear or branched groups such as 3-methylbutyl, 4-methylpentyl, -octyl, and n-decyl groups. Among these, R”R63 is a hydrogen atom,
R62 is a hydrogen atom or a methyl group.

Ethyl group, 1so-isopropyl group, isobutyl group 7
1R72 R71, R72, and R73 are the same or different and represent a hydrogen atom or an alkyl group of C to C1o.

As the alkyl group of C□ to C1o, the above-mentioned ones (R
”, R62, R63), but
Hydrogen atoms are preferred as R71, R72, and R73.

R" is a hydrogen atom; an alkyl group of C□ to C1o; a phenyl group; and a phenyl group or a phenol group.

It represents a C3-C, alkyl group that is not substituted with a hydroxyl group, mercapto group, methylthio group, carboxyl group, amine group, guanidino group, imidazole group, indole group, etc.

Note that R'l and R74 may be combined to form a ring. C
As the 1-C1° alkyl group, those mentioned above (R'
1. In the case of R62, R63), examples include methyl group and ethyl group.

1so-propyl group, 1so-butyl group, 5ec-
Butyl group etc. are preferred. Phenyl group, phenol group.

Examples of C-C5 alkyl groups that are not substituted with hydroxyl group, mercapto group, methylthio group, carboxyl group, amino group, guanidino group, imidazole group, indole group, etc. include methyl group, ethyl group, n-propyl group, n-butyl group. basis,
n-pentyl group.

Examples include 1so-propyl group and igo-butyl group, with methyl group and ethyl group being preferred. Among these, examples of R'' include a hydrogen atom, a methyl group, and is.

A butyl group and a benzyl group are particularly preferred. Also RIR”R
72 -N-C*-COOR73 The carbon marked with the main symbol may be an asymmetric carbon, and in this case, the configuration of this carbon is 0 body,
This includes the L-configuration and mixtures thereof in arbitrary proportions, but the -1 configuration of the natural amino acid is preferred.

R2 and R3 are the same or different and are hydrogen atoms.

It is a tri(C1-C7) hydrocarbon silyl group, or a group that forms an acecool bond or an ester bond with an oxygen atom of an acid group.

Examples of the hydrocarbon silyl group include tri(C1-C4)alkylsilyl such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl, and di(C,-C4)alkyl such as dimethylphenylsilyl. Preferred examples include diphenyl(Ct-C4)alkylsilyl such as phenylsilyl, t-butyldiphenylsilyl, 1-rephenylsilyl, and tribenzylsilyl. Particularly preferred is t-butyldimethylsilyl group.

Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl, 1-ethoxyethyl,
2-methoxy-2-propyl 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl 12-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[ 3,1,0]hex-4-yl group. Among these, 2-tetrahydropyranyl group is particularly preferred.

Examples of groups that form an ester bond with the oxygen atom of a hydroxyl group include a formyl group and an acetyl group.

Propionyl group, butanoyl group, pentanoyl group, etc. (
Ct~.C6) Alkanoyl group; Substituted or unsubstituted benzoyl groups such as benzoyl group and tolyl group can be mentioned. Acetyl group and benzoyl group are particularly preferred.

Among these, a hydrogen atom is particularly preferable as R2 or R3.

R4 does not represent a hydrogen atom, methyl group or vinyl group,
A hydrogen atom and a methyl group are preferred.

In the above formula [I], R5 is a straight-chain or branched C3-C1o alkyl group which may contain an oxygen atom; a straight-chain or branched C5-CIO alkenyl group; a straight-chain or branched C3-Coo alkynyl group group; optionally substituted C3-C1o cycloalkyl group; optionally substituted phenyl group: optionally substituted phenoxy group;
or an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C
3-CtO represents a straight-chain or branched C-C5 alkyl group substituted with a cycloalkyl group.

Straight chain or branched chain C3~ which may contain an oxygen atom
C1° alkyl groups include 2-methoxyethyl, 2-ethoxyethyl, propyl, and butyl.

pentyl, hexyl 1 heptyl, octyl, decyl, 1
-Methylpentyl, 1--methylhexyl.

1.1-dimethylpentyl, 2-methylpentyl.

Examples include 2-methylhexyl, 5-methylhexyl, 2,5 dimethylhexyl, etc., preferably butyl, pentyl, hexyl, (R)- or (S)- or (R8)-1-methylpentyl, (R ) or (S)
- or (R3)-2-methylhexyl group.

C3-CIO alkenyl groups include 2-butenyl group, 2
-benzonyl group, 3-pentenyl group, 2hexenyl group,
4-hexenyl group 72-methyl 4-hexenyl group, 2.
Examples include 6-dimethyl-5-heptenyl group.

The C3-CIO alkynyl group is 2-butynyl.

2-pentynyl, 3-pentynyl, 2-hexynyl, 4
-hexynyl, 2-octynyl, 5-decynyl, 1-methyl-3-pentynyl, 1-methyl3-hexynyl, 2
-Methyl-4-hexynyl group and the like.

Examples of the optionally substituted C3-C1o cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, (C1-C5) alkylcyclopentyl group 1 (C1-C4) Examples include an alkylcyclohexyl group, a dimethylcyclopentyl group, a dimethylcyclohexyl group, a chlorocyclopentyl group, a bromocyclohexyl group, an iodocyclopentyl group, a fluorocyclohexyl group, and preferably a cyclopentyl group and a cyclohexyl group.

Examples of substituents for the optionally substituted phenyl group and the optionally substituted phenoxy group include halogen atoms,
Hydroxy group, C2-C7 acyloxy group, 01-C4 alkyl group optionally substituted with halogen atom, C1-C4 alkoxy group optionally substituted with halogen atom, nitrile group, carboxyl group or (C1-C6) Preferred are alkoxycarbonyl groups and the like. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the C2-C7 acyloxy group include acetoxy and propionyloxy.

Mention may be made of n-butyryloxy, 1so-butyryloxy, nvaleryloxy, 1so-valeryloxy, caproyloxy, enantyloxy or benzoyloxy. C optionally substituted with halogen
Examples of the 1-C4 alkyl group include methyl, ethyl, n-propyl, and 1so-propyl.

[1-Butyl, chloromethyl, dichloromethyl, trifluoromethyl, etc. can be mentioned as preferred. Preferred examples of the C1-C4 alkoxy group which may be substituted with halogen include methoxy, ethoxy, n-propoxy, 1so-profoxyph n-butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy, etc. . (C engineering ~ C
6) Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group or substituted phenoxy group can have 1 to 3, preferably 1 substituent as described above.

An optionally substituted phenyl group.

An optionally substituted phenoxy group, an optionally substituted phenyl group among linear or branched C1-C5 alkyl groups substituted with an optionally substituted C3-CIO cycloalkyl group, As the phenoxy group which may be substituted, the above-mentioned ones can be mentioned directly. As the C3-C1o cycloalkyl group, the above-mentioned ones can be preferably mentioned as they are, and as for the substituents, the same ones as those of the above-mentioned substituted phenyl group and substituted phenoxy group can be mentioned. Straight chain or branched chain C1
~C5 alkyl groups include methyl and ethyl.

Examples include propyl, 1so-propyl, butyl, 1so-butyl, 5ee-butyl, t-butyl, pentyl, and the like, and the substituent may be bonded to any position thereof.

Among these, *2 is preferably butyl, pentyl, ], methylpentyl, 2-methylhexyl, 1-cyclopentyl, cyclohexyl, etc.

In the above formula [I], n represents O or 1. n=
In the case of o, either the natural configuration at the 15th position represented by the following formula [I-1] or the non-natural configuration at the 15th position represented by the following formula [Ni2] is one or any proportion thereof. represents a mixture.

Among these, the natural configuration at position 15 represented by the above formula [E-11] is preferred. In the case of n”-1, (R
)-configuration, (S)-configuration and mixtures thereof in any proportion.

8 of isocarbacyclines represented by the above formula [E]
The configuration at positions 9, 11, and 12 is a useful stereoisomer because it is a natural prosfcyclin type, but
The present invention includes stereoisomers having different steric configurations at each position, or mixtures thereof in arbitrary proportions.

In the present invention, when R63 or R'3 of R1 in the isocarbacycline represented by the above formula [E] is a hydrogen atom,
Contains its non-toxic salts. Non-toxic salts include all pharmacologically acceptable salts, including alkali metal salts such as sodium salts, potassium salts, and lithium salts;
di- or trivalent metal cation salts such as calcium salts, magnesium salts, zinc salts, aluminum salts, ammonium salts;

Methylammonium salt, dimethylammonium salt.

trimethylammonium salt, benzylammonium salt,
Ammonium salts such as phenethyl ammonium salt 1 mol polynium salt, monoethanol ammonium salt, and dicyclohexylammonium salt are mentioned. Among these, sodium salt and potassium salt.

Calcium salts are preferred.

Preferred specific examples of the novel isocarbacyclines represented by the above formula provided by the present invention include the compounds shown below.

fJ) 9(○)-Methano-Δ6 (9a)-Prostaglandin ■1 Carboxymethyl ester (isocarbacycline carboxymethyl ester>+2) 20-
Methyl-9(○)-methano-86 (9) Proscugrandin ■1 Carboxymethyl ester <3116-Methyl-9(O)-methano-Δ6 (9(
1) Prostaglandin 11 power! Levoxymethyl ester (4116,16-dimethyl-9(0)-methanoΔ6(
9(1)-Prostaglandin ■1 carboxymethyl ester <5117-methyl-9(0)-methano-Δ6 C9a
) ~ Prostaglandin ■, force l and boxymethyl lres two chill (6) 17.20-dimethyl-9(0)-methanol-Δ
6 (9y)-Prostaglandin ■] Carboxymethyl ester (7) ((17R) of 61 (8) ((17S) of 61 + 9) 15-methyl-9(O) ~ methanol Δ6 (9
') Prostaglandin ■1 carboxymethyl ester (10) 17.18-dehydro-9(O)-methano-
Δ6 (9a)-Prostaglandin ■, carboxymethyl ester (11) 20-impropylidene-17-methyl-9
(0)-MechnoΔ6 (9(1)-Prostaglandin
-Methyl 9(O)-methano-Δ6(9")-prostaglandin ■1 carboxymethyl ester (13) 18.18.19.19-tetrahydro-1
6,20-dimethyl-9(O)-methano-Δ6 (9a
)-Prostaglandin ■1 carboxymethyl ester (14) +3), (12), (13> of (16S)
) of (15) (3), (12), (13) (
16R> Integral (16) 1617.18, 19.20-
Pentanol-15-cyclopentyl-9(O)-methano-Δ6 (9(11-prostaglandin 11-ruboxymethyl ester (17) 16.17.18.19.2
0-Pentano-15-cyclohexyl-9(O)-methano-Δ6<9a)-prostaglandin 11-ruboxymethyl ester (18) 17.18,19.20-tetratrue 16-<p-fluorophenoxy)- 9 (0
〉-methanoΔ6 (9(11-prostaglandin 11 carboxymethyl ester (19) 17.18,19.20-tetratrue 16
-cyclohexyl-9(0>-methano-Δ6(9″)-
Prostaglandin 11 carboxymethyl ester (
20) 15-deoxy-16-hydroxy-9(O)
-Methanol Δ6391-Prostaglandin 11 calphoxymethyl ester 21) 15-deoxy-16-hydroxy-16-
Methyl-9(○)-methano-Δ6(9“〉-prostaglandin■, phosphoroxymethyl ester (22)
(21) (16S) integral (23) (21) (16R) integral <24+ 17.18, 19.20 - Tetra True 15
-deoxy16-cyclopentyl-16-hydroxy-
16-Methyl-9(O)-methano-Δ6(9a'-prostaglandin ■1 carboxymethyl ester <251
15-deoxy-16-hydroxy-6-vinyl-9〈O)-methano-Δ639''〉-prostaglandin ■1 carboxymethyl ester (26+ 15-deoxy-16-hydroxy-16.20 dimethyl-9 (0
)-Methano-△6 (9(1)-Prostaglandin 1
1 Carboxymethyl ester 27+ 15-deoxy-16-hydroxy-16 20 20 Trimethyl-16-vinyl-9(O)-methanoΔ6 (9ff)
-Prostaglandin ■1 carboxymethyl ester (28) 15-deoxy-16-hydroxy-161
8 dimethyl-9〈0) to methanol△6 (9(11-prostaglandine 1 carboxymethyl ester (29
) 15-deoxy-16-hydroxy-16-methyl-18-oxa-9(0)-methano-Δ6(9″) prostaglandin 11 carboxymethyl ester (30+ 17.18,19.20-tetratrue 15
-thioxy16-hydroxy-16-methyl-16-phenyl9(0)-methano-Δ6 (9(1)-prostaglandin ■1 carboxymethyl ester (31) 17,18,19.20-tetratrue 15
-deoxy16-cyclohexyl-16-hydroxy-
16-methyl-9<0)-methano-Δ6 (9(11-
Prostaglandin ■1 carboxymethyl ester (3
2) 17,18,19.20-tetratrue 15-deoxy 16-(2-butylcyclopentyl>-16-hydroxyl 16-methyl-9(0)-methanoΔ6 (9
')-Prostaglandin ■1 carboxymethyl ester<33) 18.19.20-trinor-15-deoxy-16hydroxy-17-phenyl-9(0)-methanoΔ6 (9(1)-prostaglandin 11 carboxy Methyl ester (341 18.19.20 -triblue 15-deoxy-16hydroxy-17-phenoxy-16-pinyl-9(0)-methano-Δ6+9″)-prostaglandin 11 carboxymethyl nisdel+351 20-true 15 -deoxy-19-cyclohexyl-16-hydroxy-16-methyl-9 (○)
Methanol-Δ6 (911)-prostaglandin ■1 carboxymethyl ester <36) (241-(35) (16S) integral (37
) (24) to (35) (16R) integrated (38)
The esters of (1) to (37) are not carboxymethyl esters and are 1-carboxymethyl esters The esters of (391 <1) to (37) are not carboxymethyl esters and are 1-carboxymethyl esters Compound (40) which is lexoxy 3-methylbutyl ester Compound (40) <1) to (37) whose ester is not carboxymethyl ester but 1-carboxytyl ester <411 (1) to (37) A compound in which the ester of is not carboxymethyl ester but 1-carboxy-1-methyl ester<42>9(0)-methano-Δ6<9")-prostaglandin IIL-leucineamide (isocarbacycline) Leucinamide> +43+ 20-methyl-9(0)-methano-Δ6 (
9(1) Prostaglandin IIL-Leucinamide (
44116-Methyl-9(O)-methano-Δ6〈9“)
-Prostaglandin■□L-leucineamide<45+
16.16-Simethyl-9(0)-methanoΔ6(9a
)-Prostaglandin IIL-Leucinamide+46+ 17-Methyl-9(O)-Methano-Δ6 (
9a) Prostaglandin IzL-Leucinamide <4
7117.20-dimethyl-9(0〉-methanoΔ6 (
9111-Prostaglandin IIL-Leucinamide (48) <47) (17R) unitary (49) (47) <173) unitary (50) 15-Methyl-9(○)-methano-Δ6 (
9 (11 Prostaglandin IzL-Leucinamide (
51) 17.18-dehydro-9(○)-methanoΔ6
39")-Prostaglandin 11L-Leucinamide<52+ 20-Isopropylidene-17-Methyl-9
(0)-Metanor Δ6 <91+1-Prostaglandin IIL-Leucinamide (53) 18.18.19.19-Tetradehydro-
16-Methyl 9(○)-Methano-Δ6(9″)-Prostaglandin E□-Leucinamide (54) 18.i8,19.19-Tetradehydro-
1620-dimethyl-9(O)-methano-Δ6 (9f
f)-Prostaglandin 1. L-leucinamide <55+ <44+, (53), (16 of (54)
S) Integral (56) <44), (53), <54+
(16R) Integral (57) 16.17.18,19.
20-penktrue 15-cyclopentyl-9(O)-
Methano-Δ6(9a)-prostaglandin IIL-leucineamide (58116,17,18,19,20-
Pentanol-15-cyclohexyl-9(O〉-methano-Δ6(9σ)-prostaglandin-ethyl-leucinamide (59) 17.18,19.20-tetratrue-16-(γ-fluorophenoxy)-9( 0)-methanoΔ6 (9″)-prostaglandin ■, L-leucineamide (60) 17,18.19.20-tetratrue16
-cyclohexyl-9(0)-methano-Δ6 (9(1
)-Prostaglandin L-leucinamide (61) 15-deoxy-16-hydroxy-9〈O
〉Methanol-Δ6 (91+1-prostaglandin A1
■--Leucinamide (62) 15-deoxy-16-hydroxy-16-
Methyl-9(0)-Methano-Δ6 (9711-Prostaglandin IIL-Leucinamide (631(62)<163) Integral<641(62)(16R)+65+ 17.18,19.20-Tetra True 15
-deoxy16-cyclopentyl-16-hydroxy-
16-Methyl-9(0)-methano-Δ6 (9a>-Prostaglandin IIL-Leucinamide (66) 15-deoxy-16-hydroxy-16-
Vinyl-9(0)-methano-86 (9711-prostaglandin 1.L-leucinamide (67115-deoxy-16-hydroxy-16,2
0dimethyl-9<0>-methano-Δ639'>-prostaglandin IIL-leucinamide (68) 15
-deoxy-16-hydroxy-16,20,20trimethyl-16-vinyl-9<O>-methanoΔ6 (9(
1)-Prostaglandin ■, L-leucineamide (69) 15-deoxy-16-hydroxy-46,
18dimethyl-9(0)-methano-Δ6 (9(1)-
Prostaglandin ■IL-Leucinamide (70)
15-deoxy-16-hydroxy-16-methyl-1
8-oxa-9(0)-methano-Δ6 (9111 prostaglandin l1L-leucineamide (71) 17
．． 18.19.20-tetratrue 15-deoxy 16
-Hydroxyl 16-methyl-16-phenyl 9 (○)
-methano-Δ6 (9(11-prostaglandin II)
L-Leucinamide (72) 17.18,19.20-Tetra True 15
-deoxy16-cyclohexyl-16-hydroxy-
16-Methyl-9(O)-methano-Δ6(9·)-prostaglandinItL-leucinamide+73) 17,18,19.20-tetratrue15
-deoxy16-(2-butylcyclopentyl)-16
-Hydroxy-16-methyl-9(0)-methanoΔ6
(9al-Prostaglandin IIL-Leucinamide (74) 18.19.20-) Reflu 15-deoxy-16hydroxy-17-phenyl-9(O)-methanoΔ6 (9(11-Prostaglandin 1.L- Leucinamide (75) 1g, 19.20-)Tunoru-15-deoxy-16-hydroxy-17-phenoxy-16-pinyl-9(0)-methano-Δ6(9aゝ-Prostaglandin IIL-Leucinamide (76) 20 -True 15-deoxy-19-cyclohexyl-16-hydroxy-16-methyl-9(0)methano-Δ6 (9(11-prostaglandin) IL-leucinamide (77) (24)-(35 ) of (15S) integrated (78
) (24) to (35) (15R,) integral (79)
Compound (80) in which the amide of (38) to (78) is L-alanine amide instead of L-leucine amide (38
) to (78), the amide is not L-leucinamide but glycinamide (81) +38) to (78), the amide is not L-leucinamide but monoisoleucinamide (81)
82) <Compounds in which the amides of 381 to (78) are monophenylalanine amide instead of L-leucine amide (Compounds (84) in which the amides of 831(38) to (78) are monotyrosine amide instead of L-leucine amide
(Compounds in which the amide of 381 to (78) is monoprolinamide instead of L-leucinamide <85) (3
Compounds (86) (381-(
Compounds in which the amide of 78) is monocysteinamide instead of L-leucineamide +87) (38) to (78)
) Compound (88) in which the amide of (38) to (78) is mono-histidine amide instead of L-leucine amide Compound (891 (38) to (78)) in which the amide in (38) to (78) is monotryptophan amide instead of L-leucine amide Compounds in which the amide of is monovalinamide instead of 1-leucineamide (901
Compound (91) (3
Compound (92) in which the amide of 81 to (78) is not L-leucinamide but monoglutamic acid amide (92) <38
) to (78) are monoaspartic acid amide instead of L-leucine amide (931 (Compounds 381 to (78) are not L-lysine amide but L-lysine amide <94)
Compounds in which the amide in (38) to (78) is L-argininamide rather than L-leucineamide +95) +
Compounds (96) in which the amides of 38) to (78) are not L-leucinamide but N-carboxymethyl-N-methylamide (96) The amides of <38) to (94) are not L-amino acid amide but D-amino acid Compounds that are amides (97
) Compound 98) (38) to (94) in which the amides are not L-amino acid amide but DL-amino acid amide
Sodium salt of 1-(97) 99) (1-(97)
Potassium salt of 100) (1) to (97) Lesium salt 101 Aluminum salt of (1) to 97) 102 1
) to (97) ammonium salt 103+ Methyl ester of 11 to 97 1041 Ethyl ester of 97 1051 to isopropyl ester of (97) 106 1
) to (97) t-butyl ester 1071 to (97 hexyl ester 108) 1) to 97) decyl ester 109) (
11-(1081 of 11.15-(Manaha16)-diacetate (10)(11-(108) of ICl3 (or 1
6)-dibengueate (11) (1)-(108) 11-acetate + 12
) (1) to (108) 11-benzoate + 13) (
1) to (108) 11.15 (or 16)-bis L-butyldimethylsilyl ether (+14) (1) to (108> 11.15 < or 16)-bis-tetrahydropyranyl ether (1151 (1) ~(108+ 1l-t-butyldimethylsilyl ether fl16) fl) ~(108) 11-1-butyldimethylsilyl ether-15 (or 16)-trimethylsilyl ether (117) Mirror image of (1) ~ (116) body (118)
(1) to (116) 8th, 9th, 11th, 12th, 1
Examples include, but are not limited to, a stereotactic form at the 5th position (mana is at the 16th position).

The novel isocarbacyclines of the present invention represented by the above formula [I] include isocarbacycline carboxylic acids represented by the following formula [11] and the following formula [I] R"C-COOR63'...II] Formula In the formula, R631 represents a hydrogen atom or a C1 to C1° alkyl group, and R'' and R62 are as defined above.

It is produced by dehydration condensation reaction with hydroxy acids represented by the following formula [IV] or amino acids represented by the following formula [IV], and optionally subjected to deprotection and/or salt formation reaction.

For the above dehydration condensation reaction, any reaction that produces an ester or amide by dehydration condensation of a carboxylic acid and an alcohol or an amine can be used. (See Chapter 5-7, etc.)

For example, in an ether solvent such as tetrahydrofuran or diethyl ether, or in a salt or hydrocarbon solvent such as dichloromethane or chloroform, in the presence of a basic reagent such as triethylamine, N-methylmorpholine, or 4-dimethylaminopyridine, Vivaloi An acid anhydride is prepared by reacting an acid chloride such as lechloride or isobutyl chlorocaponate with a compound of formula [II] at 50'C20°C for 10 minutes to several hours, and the reaction solution is added with a compound of formula [I]. Adding hydroxy acids or amino acids of formula [IV], -20'
This is achieved by further reacting at C to 50 C for 1 to 5 hours. At this time, the yield can be improved by adding an organic polar solvent such as hexamethylphosphoric triamide or dimethylformamide to the reaction system in the latter stage. In addition, when carrying out this reaction, R2], R'' in the above formula [I[] is not a hydrogen atom, but forms an acetal bond or an ester bond with a tri(C1-C7) hydrocarbon silyl group or an oxygen atom of a hydroxyl group. Groups that do are preferred.

The thus obtained isocarbacyclines can be subjected to a deprotection reaction and/or a salt formation reaction, if necessary.

When the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group (deprotection reaction), for example, acetic acid, p-)luenesulfonic acid, pyridiniuno\p-1" luene can be removed (deprotection reaction). Using sulfonate, cation exchange resin, etc. as a catalyst, for example, water, methanol 1 ethanol, or tetrahydrofuran', ethyl ether 7 dioxane in which water, methanol, ethanol, etc. coexist.
This reaction is preferably carried out using acetone, acetonitrile, or the like as a reaction solvent. The reaction temperature is usually -78°C to +5
It is carried out for about 10 minutes to 3 days at a temperature range of 0°C. When the protecting group is a tri(C1-C7) hydrocarbon group, the reaction is carried out in the above-mentioned reaction solvent at the same temperature using an acid such as acetic acid p-toluenesulfonic acid or pyridinium p-toluenesulfonate as a catalyst, or Using a fluorine-based reagent such as tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, fluorinated pyridine, etc., and using tetrahydrofuran, ethyl needle, dioxane, acetone, acetonitrile, etc. as a reaction solvent at the same temperature as above. It is suitably carried out by carrying out the same period of time. When the protecting group is a group that forms an ester bond with the oxygen atom of a hydroxyl group, for example, an aqueous solution or a water-alcohol mixed solution of sodium hydroxide, potassium hydroxide, calcium hydroxide.

Or sodium methoxide, potassium methoxide,
Methanol containing 1 to oxide on sodium.

] This can be carried out by hydrolysis in a nitanol solution.

The carboxyl group-containing compound produced by the above-mentioned hydrolysis reaction is then, if necessary, further subjected to a salt-forming reaction to give the corresponding carboxylate. The salt-forming reaction is known per se, and involves mixing carboxylic acid with a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, etc., or ammonia, trimethylamine, monoethanolamine, morpholine, etc. in a conventional manner. This is done by causing a sum reaction.

The isocarbacycline carboxylic acids represented by the above formula rII, which are the raw materials in the production method of the present invention, can be obtained by a method separately filed by Shikari (see Japanese Patent Application Laid-open No. 63303962, etc.), or by a method described by Yugami, Shibasaki et al. Method (Tetr
aheclron Letters, Volume 25, 50
87 Vege, 1984; J. Chem, Soc.
, Chem, Commu 1984, p. 1602).

The novel isocarbacyclines thus obtained are -R
Prostacyclin-like activity that protects cells, suppresses organ damage, suppresses liver damage, suppresses gastric acid secretion, suppresses platelet aggregation, lowers blood pressure, dilates blood vessels, relaxes smooth muscle, bronchodilator, and diuretics. , and has cancer metastasis suppressing effects. In particular, the novel isocarbacyclines obtained in this way have the same effects as conventional isocarbacyclines, such as cell protection, organ damage suppression, and liver damage suppression, but have antihypertensive effects. , vasodilatory effect, platelet aggregation inhibitory effect, etc. are reduced, and it has a cytoprotective effect.

It is characterized by high selectivity of action, including protection against four organs and inhibition of liver damage.

The compounds of the present invention can be administered to treat or prevent organ disorders such as the liver, kidneys, pancreas, stomach, heart, and lungs, and diseases caused by cell damage.

The compounds of the invention may be used, for example, in patients with toxic liver damage.

Fatty liver, hepatitis, cirrhosis, fulminant hepatitis, hepatic coma, hepatomegaly, obstructive jaundice, parasitic neutral liver disease, liver tumors.

It can be administered for the treatment or prevention of acute or chronic liver diseases such as liver abscess. The compound of the present invention can also be used as an organ-protecting agent in liver preservation during liver transplantation, and as an organ-protecting agent against post-transplant rejection.

Furthermore, the compounds of the present invention can be administered for the treatment or prevention of kidney diseases such as nephritis and diabetic nephropathy, pancreatic diseases such as diabetes, pancreatic inflammation, and organ diseases such as the stomach, heart, and lungs.

When the compounds of the present invention are used for the above purposes, they may be administered orally, rectally, subcutaneously, or intramuscularly.

The drug may be administered parenterally, such as intravenously, intraarterially, or percutaneously, but oral or intravenous administration is preferred.

Licks for oral administration can be in the form of solid or liquid preparations. Examples of solid preparations include tablets, gunpowder,
Available in powder or granule form. In such solid formulations, one or more active substances are present in at least one pharmaceutically acceptable carrier, such as the commonly used sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethylcellulose, and the like. mixed with. Preparation operations are carried out according to conventional methods.
It may also contain additives for formulation other than those mentioned above, such as lubricants such as calcium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration are, for example, emulsions.

Including solutions, cloudy agents, syrups, and xyl agents.

These formulations include commonly used pharmaceutically acceptable carriers such as water or liquid paraffin.

Coconut Oil 1 Fraction Oily bases such as coconut oil, soybean oil, corn oil, etc. can also be used as carriers.

Preparations for oral administration include, for example, solid preparations such as those mentioned above, containing, for example, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol phthalate 1 styrene maleic anhydride copolymer, or methacrylic acid.

It is also possible to formulate an enteric preparation by applying an enteric coating by spraying an organic solvent or an aqueous solution of an enteric substance such as a methyl methacrylate copolymer. Enteric-coated solid preparations such as powders and granules can also be packaged in capsules.

The pharmaceutically acceptable carrier includes other adjuvants, fragrances, stabilizers, or preservatives that are normally used as needed.

Powder-liquid preparations may also be administered in capsules made of an absorbable material such as gelatin.

Solid preparations for rectal administration include suppositories containing one to five or more active substances and prepared by methods known per se.

Formulations for parenteral administration are presented as sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions may be prepared in a pharmaceutically acceptable carrier, such as propyl glycol, polyethylene glycol or a vegetable oil, such as olive oil, or an injectable organic ester, such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, and stabilizers. These solutions, suspensions and emulsions can be passed, for example, through bacteria retention filters.
Sterilization can be achieved by appropriately adding a disinfectant or performing treatments such as irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solution immediately before use.

The compound of the present invention can also be used by forming an inclusion compound with α, β, or γ-cyclodextrin, methylated cyclodextrin, or the like.

Examples of dosage forms for transdermal administration include ointments. These are molded by conventional methods.

When the isocarbacyclines of the present invention are used as an organ protective agent, the degree of symptoms varies depending on the patient's age, gender, body weight, and administration route, but it is usually 1 μg to 10 μg per day for adults.
It can be administered in doses of about mg.

Such a dose may be administered once or several times a day, for example in 2 to 6 divided doses.

<Example> Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 (Compound 1) O (Compound'jfIJii) 17S, 10dimethyl-9(O)-methano-Δ6 (
9″)-Prostaglandin I 11115-bis-t
-Butyldimethylsilyl ether (compound i) 49
2 mg (0.81 mmol) of tetrahydrofuran (5
Cool the solution to -10°C and add N-methylmorpholine (137 μρ; 1.25 mmol), isobutyl chloroformate (162 μρ; 1.25 mmol).
Add and stir at -10°C for 20 minutes. Cooling at -25℃
Hexamethylphosphoric triamide 4m
After stirring for 3 hours, the mixture was acidified by adding water and saturated aqueous K H SO 4 and extracted twice with ethyl acetate.

The combined organic layers were washed with saturated saline and dried with Mg5C)a. When the crude product obtained by distilling off the solvent was purified by silica gel column chromatography, ethyl acetate/
n-hexane/acetic acid = 30+70: 597 mg of 173,20-dimethyl-9 (0) in the 0.4 eluate
-Methano-Δ6 (9(1)-Prostaglandin 1.
L-leucinamide 11.15-bis-t-butyldimethylsilyl ether was obtained.

The thus obtained amide silyl ether was added with tetrahydrofurine and stirred at room temperature for 24 hours. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography, and the result was 5% ethanol-ethyl acetate <0.25%.
332 mg (83%) of 1
73,20-9 (0)-methano-Δ6 (9(1)-
Prostaglandin IIL-Leucinamide (Compound I
Get i〉.

NMR (δppm, CDCl3)
:0, 8-1.1(12H), 2.98(I)I,
m) 3, 43 (3H, br: burned out on D20).

3,73<1)1,q,J=7H7),4.16(
IH, m) 4, 58 (IH, m), 5.28 (IH
, s), 5.50 (2H, m).

5, 94 (IH, d, , b8H2; D 2
0 and burnt down).

I R (an-', neat1 3320, 2980, 2950. 2890 2
800-2400. 17251650, 154
5. 1460, 1238, 1160.
1088, 970.

Mass (EI, m/e): 473 (n-
R20), 456, 455, 429 Example 2 R31 (Compound 1') H (Compound ii') In the same manner as in Example 1, obtain the leucinamide of isocarbacycline having the following ω side chain.

Example 3 (Compound III) 17S20 was prepared in the same manner as in Example 1 except that L-phenylalanine was used instead of leucine.
-dimethyl-9(O)-methano-Δ6 (9c)-prostaglandin ILL-phenylalaninamide (yield 75% without obtaining compound iii).

NMR (δppm, CDCl3): 0.8-1
0 (6H), 2.8-3.8 (6H, br) 3.7
3 (LH, q), 4.15 (IH, m), 4.
4-4.9 (1) 1. m) 5.28(1)1. brg)
5.50 (2H, m), 5.95 (IH, d)
7,0-7.4 (5H,br) Example 4 ○R31 (Compound i') H (Compound iii') In the same manner as in Example 3, phenylalanine amide of isocarbacycline having the following ω chain was prepared. Good value.

Example 4 In the same manner as in Example 1, the following amines were used to prepare compound i.
Isocarbacyclines in which the amide part of i) is the amide shown below, and isocarbacyclines in which the amide part of compound ii' is the amide shown below using the amines shown below in the same manner as in Example 2. Obtained.

6 Example 5 (Compounds) (Compound iv) 7S 20-dimethylmethanoΔ6(9a) -Prostaglandin ■1 Bis-t-butyldimethylsilyl ether compound 10g (
1,66 mmo I) of dichloromethane (12 ml)
Melt? Cool overnight to -25°C and add 348μ of triethylamine.
g (2.5 mmol), then pivaloyl chloride 30
8p, Q (2.5 mmol) was added to. 3 at ~25℃
After stirring for 0 minutes, hydroxyacetic acid (glycolic acid) 61
4 mg (8.3 mmol), 2 ml of hexamethylphosphoric triamide, and then 101 g (8.2 mmol) of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 2 hours. The aqueous layer was made slightly acidic by adding saturated aqueous K HS O 4 solution, and then extracted twice with dichloromethane. The combined organic layers were washed with saturated saline and dried over anhydrous MgSO4.

After evaporating the solvent, the obtained f'S@l product was purified by silica gel column chromatography, and 83
1 mg of 17S, 20-dimethyl-9(0)-methano-Δ6 (9')-prostaglandin Ixll, 15
Bis-t-butyldimethylsilyl ether was obtained.

To the total amount of this product, 12 ml of a tetrahydrofuran solution (concentration LM) of tetrabutylammonium fluoride was added, and after stirring at room temperature for 16 hours, the mixture was quenched with a saturated aqueous NH3Cl solution and extracted twice with ethyl acetate.

The combined organic layers were washed with brine, dried over anhydrous MgSO4, and then the solvent was distilled off. The obtained crude product was purified by column chromatography on silica gel, and 513 m
g (yield 71%) of 173.20-dimethyl-9(
0)-Methano-Δ6(9″) ~ Broscugrandin ■1
Carboxymethyl ester (compound iv) was obtained.

NMR (δppm, CDCl3 > : 0.90
(6Hm), 10-1.8 (14H), 1.8-2
．． 6 (9H).

2.8-3.2 (IH, br), 3.76 (IH, q
).

4.0-4.3 (IH, br), 4.60 (2H,
s) 4.8-5.3 (3H, br), 5.28
(IH, brs) 5, 47 (2H, m) I R (cm-1, neat): 3400, 2950. 1745. 1610. 9
67° Example 6 R31 (Compound i') Ql:j31 (Compound iv') In the same manner as in Example 5, the carboxymethyl ester of isocarbacytalin having the following ω chain was obtained.

Example 7 Example 5. And in the same manner as in Example 6, using the following hydroxyacetic acids (compound iv), (compound iv')
An isocarbacycline whose ester moiety was the following ester was obtained.

Example 8 In vitro platelet aggregation inhibitory effect The in vitro platelet aggregation inhibitory effect of the test drug was assayed using rabbits. That is, a 3.8% trisodium citrate solution was collected from the ear vein of a Japanese white male rabbit weighing 2.5 to 3.5 kg at a ratio of 1 part blood to 9 parts blood.
After centrifugation for 10 minutes, set aside the upper layer as PR, P (platelet-rich plasma). The lower part is further 280Or
pm Centrifuge for 10 minutes and remove the upper part, which is divided into two layers.
It was set aside as pp (platelet poor plasma).

The platelet count was adjusted to 6×10 5 /μρ by dilution with PPP.

Add 25μρ of the test drug to the adjusted PRP250μρ and make 3
ADP 1μ after 2 min incubation at 7°C.
M (final) was added and the change in transmittance was recorded using an acribometer. In addition, the test drug was mixed with ethanol at a concentration of 10%.
After dissolving to a concentration of mg/ml, add phosphate buffer (p
Do not use by sequentially diluting with H7, 4).

The aggregation inhibition rate was determined using the following formula.

'f''o: Permeability T of (phosphate buffer added system): The lowest concentration of the drug at which the permeability inhibition rate of the test drug added system exceeds 50% is shown as the IC50 value.

The results are shown in Table 1.

Table 7 As is clear from Table 1, the platelet aggregation inhibiting effect of the above-mentioned isocarbacyclines was significantly lower than that of general isocarbacyclines.

Example 8 Effect on hepatocyte necrosis induced by carbon tetrachloride (
In vivo) After administering carbon tetrachloride and the test drug to male and female SD rats (6 weeks old, 170-200 g) as described below, the activity of glutamate pyruvate transaminase (GPT), an indicator of liver damage, was measured by ultraviolet absorbance. Determine effectiveness by measuring according to the Rate-Gold Standard Method.

8 to 36 rats were used in each group. The test drug should be dissolved in physiological saline and not administered orally. For all test drugs, 30 minutes before carbon tetrachloride administration and after administration of fractionated carbon tetrachloride.

A total of 5 doses were administered at 2.8 and 18 hours later. Carbon tetrachloride is 0.84ml/1 as a 50% olive oil solution.
It was administered subcutaneously at a rate of 00 g body weight (6670 mg/Kg body weight as carbon tetrachloride). The animals were fasted for about 18 hours before administration of carbon tetrachloride.

Blood was collected from the abdominal aorta of rats under ether anesthesia 24 hours after carbon tetrachloride administration, and the blood was left at room temperature for 1 hour before being incubated for 30 minutes.
After centrifugation at 0 rpm for 15 minutes, the GPT value was measured using the supernatant as a serum sample.

The rate of inhibition by isocarbacyclines of the increase in plasma GPT activity caused by CCl 4 was calculated using the following formula.

Suppression rate of increase in serum GPT activity - As is clear from Table 2, the above-mentioned isocarbacyclines suppressed the increase in GPT activity caused by carbon tetrachloride, and thus were found to have a liver damage suppressing effect.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼(
R^6^1, R^6^2, R^6^3 are the same or different and represent a hydrogen atom or an alkyl group of C_1 to C_1_0)
Or ▲There are mathematical formulas, chemical formulas, tables, etc.▼(R^7^1
^, R^7^2, R^7^3 are the same or different, and represent a hydrogen atom or an alkyl group of C_1 to C_1_0,
^7^4 is a hydrogen atom; an alkyl group of C_1 to C_1_0; a phenyl group; or substituted with a phenyl group, phenol group, hydroxyl group, mercapto group, methylthio group, carboxyl group, amino group, guanino group, imidazole group, indole group, etc. represents a C_1 to C_5 alkyl group. Note that R^7^1 and R^7^4 may be combined to form a ring. ), R^2 and R^3 are the same or different and represent a hydrogen atom, a tri(C_1-C_7) hydrocarbon silyl group, or a group that forms an acetal bond or an ester bond with the oxygen atom of a hydroxyl group, and R^ 4 represents a hydrogen atom, a methyl group, or a vinyl group, and R^5 is a straight or branched chain C_1 that may contain an oxygen atom.
~C_1_0 alkyl group; straight chain or branched chain C_3~
C_1_0 alkenyl group; straight chain or branched chain C_3~
C_1_0 C_3~ which may be substituted with an alkynyl group
C_1_0 cycloalkyl group; optionally substituted phenyl group; optionally substituted phenoxy group; or optionally substituted phenyl group, optionally substituted phenoxy group, or optionally substituted C_3~
C_1_0 represents a straight chain or branched chain C_1 to C_6 alkyl group substituted with a cycloalkyl group, and N is 0
Or represents 1. ] Isocarbacyclines and their non-toxic salts. 2. The isocarbacyclines and their non-toxic salts according to claim 1, wherein R^1 is ▲a mathematical formula, a chemical formula, a table, etc.▼. 3. The isocarbacyclines and nontoxic salts thereof according to claim 1 or 2, wherein R^6^1 and R^6^3 are both hydrogen atoms. 4. The isocarbacyclines and nontoxic salts thereof according to claims 1 to 3, wherein R^6^1, R^6^2, and R^6^3 are all hydrogen atoms. 5. The isocarbacyclines and their non-toxic salts according to claim 1, wherein R^1 is ▲a mathematical formula, a chemical formula, a table, etc.▼. 6. The isocarbacycline and its nontoxic salt according to claim 1 or 5, wherein R^7^1 is a hydrogen atom. 7. The isocarbacyclines and nontoxic salts thereof according to claim 1 or 5 or 6, wherein R^7^2 and R^7^3 are both hydrogen atoms. 8. The isocarbacycline and its nontoxic salt according to claim 1 or 5 to 7, wherein R^7^4 is a hydrogen atom, an isobutyl group, or a phenylmethyl group. 9. Claims 1 to 9, wherein R^2 and R^3 are both hydrogen atoms.
8. Isocarbacyclines and non-toxic salts thereof according to 8. 10.Claim 1, wherein R^4 is a hydrogen atom or a methyl group.
Isocarbacyclines and non-toxic salts thereof according to 9. 11. The isocarbacyclines and nontoxic salts thereof according to claims 1 to 10, wherein R^5 is a butyl group, a pentyl group, a 2-methylhexyl group, a cyclopentyl group, or a cyclohexyl group. 12. The isocarbacyclines and nontoxic salts thereof according to claims 1 to 11, wherein n is 0. 13. The isocarbacyclines and nontoxic salts thereof according to claims 1 to 11, wherein n is 1. 14. The following formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼...[II] [In the formula, R^2^1 and R^3^1 are the same or different, hydrogen atom, tri(C_1~ C_7) Represents a hydrocarbon silyl group or a group that forms an acetal bond or ester bond with the oxygen atom of a hydroxyl group, R^4, R^
5, n is the same as defined above. ] Isocarbacycline carboxylic acids represented by the following formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] [In the formula, R^6^3^1 is a hydrogen atom, or C_1~
Represents an alkyl group of C_1_0, R^6^1, R^6
^2 is the same as the above definition. ] Hydroxy acids represented by the following formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [IV] [In the formula, R^7^3^1 is a hydrogen atom or C_1~C
Represents the alkyl group of _1_0, R^7^1, R^7^
2. R^7^4 is the same as the above definition. ] The following formula [I] ▲Mathematical formulas, chemical formulas, tables, etc. are included▼...[ I ] [In the formula, the definitions of R^1, R^2, R^3, R^4, R^5 and n are the same as the above definitions. ] A method for producing isocarbacyclines and non-toxic salts thereof. 15. A therapeutic agent for organ disorders comprising an effective amount of isocarbacyclines represented by the above formula [I] and non-toxic salts thereof and a pharmaceutically acceptable carrier. 16. A therapeutic agent for liver damage comprising an effective amount of isocarbacyclines represented by the above formula [I] and non-toxic salts thereof and a pharmaceutically acceptable carrier.