JPS60208917A - Use of prostaglandin for ards and organ insufficiency treatment or prevention - 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]

FIELD OF THE INVENTION The invention relates to the use of prostaglandins in the treatment and prevention of ARDS and multiple organ failure. BACKGROUND OF THE INVENTION The present invention provides novel uses for known compounds. In particular, the invention is useful in treating patients with ARD S (Acute Respiratory Disorder Syndrome, also known as Adult Respiratory Disorder Syndrome) due to shock, trauma or sepsis and in preventing death due to multisystem damage in this disease. provide a method. ARDS is considered to be a symptom associated with pulmonary embolism due to microaggregation of platelets and/or leukocytes. This syndrome and its associated multiple organ failure are associated with shock,
It is the cause of death other than brain death in the majority of patients resuscitated from trauma and sepsis or other severe symptoms listed below. Pulmonary artery insufficiency is characterized by low arterial oxygen concentrations, disproportionate ventilation perfusion, poor pulmonary adaptation, and, in some cases, increased vascular resistance in the pulmonary arteries. In addition to damage to the lungs, damage to other organs also accompanies shock, trauma, and sepsis. The overall mortality rate for patients with ARDS or other severe organ failure following shock, trauma or sepsis exceeds 50%. Currently used treatments for ARDS focus on treating its causes, shock, trauma, and sepsis. Rapid shock resuscitation, rapid bleeding control, early initiation of mechanical ventilation with volume ventilators, and
In this case, Swan-Ganz
) Large-volume intravascular infusions using a pulmonary artery catheter can help treat shock. Fixation of fractures, removal of dead or devitalized tissue. Drainage glands, sealing of gastrointestinal tract holes, diversion of the gastrointestinal tract near the injury, and administration of antibiotics all help prevent the adverse effects of tissue trauma or infection. However, only a few specific treatments are available to treat ARD S or other organ failure once it has occurred. If a patient has severe ARDS, heparin administration therapy can be tried to reduce intravascular clots and emboli to the lung tissue. However, heparin further increases the risk of bleeding in patients undergoing severe trauma. According to the method disclosed in the unknown specification, ARDS and other organ failures following shock, trauma or sepsis can be treated without this type of risk. The invention also relates to a method for treating patients at risk of developing failure of vital organs (lungs, liver, kidneys, gastrointestinal tract, brain or heart) due to abnormal, traumatic or septic events. These severe cataclysmic events have been widely described for ARDS, some of which are listed in Table 1 below. These are situations that endanger the patient to be treated according to the invention due to vital organ failure. Similar to ARDS, other vital organ failures include the liver, kidneys,
It may be associated with embolism and/or deposition of platelets and/or leukocytes in the gastrointestinal tract, brain or heart. Liver and renal failure is usually first noticed by the appearance of pathological levels of certain cellular products (eg, bilirubin and creatinine) in the blood. Insufficiency of the gastrointestinal tract includes bleeding in the gastrointestinal tract. Brain dysfunction can present with disorientation. Cardiac dysfunction may manifest as depressive insufficiency with decreased cardiac apparatus and high end-diastolic U-ventricular pressure. Bilirubin level greater than 5 m1% and 2!1
Taleatinine levels of 1 g% or higher indicate liver or kidney failure. Gastrointestinal bleeding requiring blood transfusion indicates insufficiency of the gastrointestinal tract. Severe disorientation to people, time, or place indicates brain dysfunction. 3.3g/min/7
Less than 7i 0) -L>! The HA index indicates heart failure with a right atrial pressure of 8 to 11 g or more or a left atrial pressure of 15 to 11 g or more. 1llll at the end of expiration). The group of patients to be treated with the prostaglandins of the present invention include signs of organ failure diagnosed as described above (respiratory disorders caused by severe events as shown in Table 1, platelet or white blood cell levels in vital organs). patients with emboli and/or deposits, high blood levels of bilirubin or creatinine, gastrointestinal bleeding, disorientation, decreased splenic index, etc.) or due to acute severe events as listed in Table 1. Includes patients who are at high risk. These hazardous conditions are generally well known to those skilled in the art and include the following: (1) A septic or traumatic attack that causes the patient to require ventilatory support (this is a sign of terminal lung failure) (2) Peritonitis (31 lung contusions or major thoracic trauma (4) non-thoracic trauma) Major trauma (5) Hand requiring more than 6 units of blood during or before or after surgery (6) Second- or third-degree burns involving more than 30% of the patient's body (7) Trauma or significant fat emboli resulting from surgery (8) Hemorrhagic or septic shock + 91 - IL'genic or anaphylactic shock () Severe viral, bacterial or fungal pneumonia (11) Oxygen (0°50% or more) ), smoke and inhalation of nitrous oxide (for long periods of time) (2) inhalation of gastric contents into the lungs (3) drug overdose (5) infectious intraluminal coagulation (5) drowning (Fresh water or seawater) - (]6) Cryitis or uremia (]7)・Patients requiring long-term U-lung bypass (]8
) patients whose heart has stopped for an extended period of time (more than 3 minutes); (19) air or amniotic fluid emboli; and (m) any patient requiring a large blood transfusion of 6 units or more. "Clinical Prediction of Respiratory Disorder Syndrome" American Journal of Surgery (P.
epe, et al. 1C11nical Pre
directorsof Adult Re5pirato
ry Distress 5yndrane”. Anerican Journal of Surge
ry, ) 144:124 (1982). The prostaglandin used in the present invention is a derivative of brostanic acid. A conventional nomenclature system has been developed to classify prostaglandins by substituents on the cyclopentane ring. N.A. Nelson, Journal of Medicinal Chemistry (N.A., Nejson, J.
Our own of Medicinal Cbani
[Bergstram et al., Ph.
armcol, Rev.) 20:1 (1968) and the references cited therein. As used herein, the term prostaglandin analog retains the characteristic characteristic properties of prostaglandins;
Refers to compounds structurally related to prostaglandins, especially those containing a cyclopentane or similar cycloalkane ring and a pair of side chains attached to adjacent carbon atoms of the ring. See Bergestrom et al., supra. Various structural variations of prostaglandins are known for producing useful prostaglandin analogs. Many of these structural variations are described in the US patents listed below. Prior literature Prostaglandin E (PGE), PGE2 and ]
] PGI2 is known as a derivative of brostanic acid. PGE], its lower alkyl esters, salts and amides are known as useful pharmaceuticals. l) G E for the treatment or prevention of peripheral vascular disease by non-intra-arterial administration
] and the use of its alkyl esters, salts and amides are described in US Patent No. 4]03026. U.S. Pat. No. 4,116,988 describes various uses of l) G E 1 . They have smooth muscle thorns
Antilipidolytic activity; stimulation of epidermal proliferation and keratinization; treatment of nasal congestion = treatment of bronchial asthma; bronchitis; bronchiectasis; pneumonia and emphysema; blood products, blood substitutes and artificial extracorporeal circulation and extraction The use of soil as an additive to other liquids used in the first stream of treated body parts and the induction of moxibustion in female animals is included. PGI2 is also known as prostacyclin, and its pharmaceutically acceptable salts, esters, and amides exhibit useful pharmacological activity. U.S. Pat. Nos. 4,158,667 and 4, which disclose their use as platelet aggregation inhibitors.
See No. 338325. 6a-carbaprostacyclin (carbacycline) and its 9-β-methyl derivatives are disclosed in U.S. Pat. Nos. 4,238,414 and 442, respectively.
No. 0632. A large number of other prostaglandins and their analogs are also known. That is, PGE1 is US Patent No. 30693
I) GE2 is described in U.S. Patent No. 35
No. 98858. PGE2 esters are described in US Pat. Nos. 3,795,697 and 3,611,216. 2°-Impropylidene compounds are described in JP-A-52-97946. Other prostaglandin analogs are also available in U.S. Pat.
639463.36912] 6.3706789,3
725454.3726909.3728382.37
59978.3776938.3776939.379
5697.3804879.3804889.3804
890.38] 2] 72.38] 2] 79, 38
] 3433, 3836578, 3839409. 3
849487. 3852337, 3855270, 3
8809]2.38889]6,3890372.38
94062, 392986], 3929862.395
93] 9.3962293, 3968] 40, 3969
376, 3969377, 3969380.3974]
89, 3974] 95, 3987084, 399886
7.3998869, 4005] 33, 4017535
% 4032576, 4057564, 4060534
% 406789], 4069386, 408]47
], 4082783.4084063.4098805
, 4] 03098, 4] ] 9666, 4] 28
577, 4] 30584, 4130720, 4130
72], 4]39564, 4158667, 4]71
460, 4] 76236.4] 97257, 4205
]78, 4220796, 3903] 31, 39547
4], 4187381.39729]7.40525
] 2.38.23 ] 80, 4] 07] 91.41
47879 and 4]65436. pGE-induced reversal of e/JX vascular permeability increases in sheep has also been observed. Staub, N.C. “Pulmonary Edema: Physiological Approaches to Treatment” Chest (Staub,
N, C, “Pulrmnary Ederm:
Pbysiologic Approaches to
P14anagcment” (hest), V
ol, 74. PP, 559-64, November 1978. Increased pulmonary microvascular permeability is associated with respiratory failure in endotoxin-induced lung injury in sheep. "Prostacyclin Infusion Reduces Lung Injury" Journal of Surgical Research (Sm1th, Micbael E, et al.
l,, ”Proscagrandin E]an
d Prostacycline Infusion D
``Ecrease Lung Injury'', Jou
rnal of Surgical Research
) Volume 32, No. 3, pp. 283-288 (1982, 3
See month. Additionally, many cases have been reported in which endotoxin-induced lung damage appears to be the same as that observed clinically in sepsis. Pulmonary and systemic damage associated with endotoxin injection is associated with PGE 1 and PG J 2
It has been reported that injection of “The Role of Prostacyclin in Acute Pulmonary Artery Microvascular Injury” Diemling R.H., Annals New York Academy of Sciences (“Role of Prostacyclin”)
Prostacyclins in Acute Pu
lmonaryMicrovascular Inj
ury”, Demling, Rol-1, Ann
alsNew York Academy of 5c
), vol. 384, pp. 517-534 (19
See 1982). PGE reduces microvascular permeability
All studies reported prior to the present invention regarding the use of 1 or P Gl 2 involve treatment of animals with endotoxin-induced lung injury. In most of the studies, endotoxin-induced lung damage was induced in sheep by injecting them with E. coli endotoxin;
and l'GI2, respectively,] OU n g/kg,
Infused over 7 minutes and at a rate of 10 ng/kg/min. Diemling et al., [Effect of prostacyclin on endotoxin-induced lung injury Hassage x +) (E
ing et al, ”-1he 11.ffec
cof Prostacycline 1nfusio
n on Endotoxin-InducedLu
ng Injury”, Surgery) + 89
See Vol. 2, pp. 257-263 (February 198). Ogletree, M.L. et al., “Reduction of pulmonary transvascular penetration by PGE1 during induction of endotoxin hyperpermeability in sheep” Clinical Research (0g1etree, M.L.
, et al. ”PGEIReduces Lung -1'ran
svascular filtration Durin
g Endotoxin Induced 1-1-1
i Permability 1nSheep”, C1
1nical Re5ereh) Volume 27, No. 2, 4
Page 02A] April 979 Hata Teru. Diemling et al., “Effect of prostacyclin infusion on endotoxin-induced lung injury,” Surgery, St. Louis (Denning
, et al, ”-1he Ef[ect of
I'rostacycloinfusion on
Endotoxin-Induced Lung I
St. Louis),
Vol. 89, No. 2, pp. 257-263 (February 198)
reference. Rofln, C.T., et al., "Mechanism of the protective effect of prostaglandin E and F2a in endotoxic shock in dogs," European Journal of Pharmacology (Rofln, G, -1', e
tal, ”Mechanismofprot
Active Effects of Prostag
landinE]andF2a1n” Can1ne
Endotoxin 5hock”, Europe
eanJournal of Phannacolog
y)% No. 24, pp. 86S-95 (1973). The survival rate of a beagle suffering from hemorrhagic shock is PGE.
Improved by injection of 1. Machido 5, “Comparison of corticosteroids and prostagranges in the treatment of hemorrhagic shock,” Annals of Surgery (Mi
Chied. et al,, “CjrrW parison of
C1orcicosteroid and1'lost
aglandines in treaunent o
f llanorrbagicSbock”, A
nnals of Surgery), vol. 190, 6
No. 735-39 (December 1979). 1)G
12 has been experimentally reported to be helpful in increasing survival rates after trauma. For example, Lefer et al., “Beneficial Actions of Prostaglandins in Traumatic Shock.”
ostaglandins in1'raurmt i
e 5hock”, Prostaglandins
)+17:76]~7. 19796 photos. Burino et al., “PG for endotoxin-induced pulmonary dysfunction.
Effects of E] and Ibuprofen - Biochemistry and Electron Microscopy Q■ Investigation" Silk Shock (Breen et
al,,” The Effects of PGEl
and Ibuprofen on 1ndocoxi
n-Induced Pu1nnary Dy5f
unction: A BiochemicaJan
dElection Microscope 5tu
dy”, C1rc, 5hock), 9, (21
, 197 (1982) H.B.Tschitman et al., [Treatment of pulmonary failure in surgical patients. , e
t aJ,. “-1he Management of Cardi
orespiratory failure in su
RGICAL PATIENTS”, Advance
es in Surgery. Ed, LD, McLean), 15 volumes (198
3 years) pp. 123-156; and Leffer, “The Role of Prostaglandins and Thromboxane in Shock Conditions,” Handbook of Shock and Drown 7.
(Lefer, “Role of Prostag
landins and'1hrCXTi)oxane
s in 5hock 5tates, ”1hnd
book of Shock and Traum),
VoJ, l: Ba5ic Science, NewYo
rk) 198-3. B. L. Appel and D. V. C. Shoemaker (P, L, Appel and W, C, S
``Symposium on Clinical Therapeutic Drugs - 21st Symposium J ('lhe 5)q
rposiLfnSyllabus forthe C
r1tical Care Medicine + 2
[St. 1lanodyna+nic and Oxyg
en 'l'transport Effects of
Pr@staglandine E]in 1%tie
ncs with Adult Respiratory
Distress 5ynd+o+ne, Cr1
tical (areMedicine), vol. 12,
No. 6, pp. 528-529, 1984, in five patients with A R]) S after severe surgery.
It is reported that he has been enrolled in the school. It is noteworthy that while improvements in lung function were reported in each patient, they were accompanied by medical problems, including death or vital organ failure in three patients. SUMMARY OF THE INVENTION The present invention relates, in particular, to the treatment of ARDS or organ failure in a human, comprising systemically administering an effective layer of P G E J -like plastaglandins to a human having or susceptible to said ARDS or organ failure. A method for treating or preventing organ failure (from systemically administering a blPGel-like prostaglandin to a human suffering from a condition selected from the group consisting of shock, trauma, sepsis or a combination thereof) and [cl[ll] P G E l of sufficient amount to effectively treat or prevent ARDS or multiple organ failure in an adult human for at least 7 days.
and (11) a pharmaceutically acceptable carrier.
or to provide a pharmaceutical unit dosage form for treating or preventing organ failure. f DR day 1-)':! (Z17 tl=?(:T;
-Yo 4 ry 7 J // = Njinga formula [■] (
(See Structural Formula Table below) or N] is -
0JNR53SO2R51 is a pharmaceutically acceptable salt thereof. In formula [1], N1 is (Al-COOR], k] is +a+hydrogen fbl /: alkyl fcl of prime number 1 to]2 prime number 3
~30 cycloalkyl [d + aralkyl of prime number 7 to 16 let unsubstituted or], phenyl substituted with 2 or 3 chloro or alkyl of 1 to 4 carbon atoms, whose para position is fll-N old CO-25 +ill -GO-R26 fllll-0-CO-R54 or [1vl -CIJ -N'N1 (phenyl substituted with -CONH2 (R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl or -NH2
, R26 is methyl, phenyl, -N)12 or methoxy and R54 is phenyl or acetamide) or (gl pharmaceutically acceptable cation IBI-CH20H (q-COL4.L4 is ta1 formula: NR5].R52 noamino (R5 ]OyobiR
52 is (+7 hydrogen (11) alkyl having 1 to 12 carbon atoms (il+l/J prime number 3 to]0 cycloalkyl (1v)
Carbon number 7~] 2 aralkyl group unsubstituted or 1.2 or 3 chloro, carbon number J~
4 alkyl, alkoxy having 1 to 4 carbon atoms, hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl having 2 to 5 carbon atoms or nitro (vll carboxyalkyl having 2 to 5 carbon atoms (viD)
Carbamoyl alkyl with leg prime number 2 to 5 &iil carbon number 2
~5 cyanoalkyl fl
4 alkoxy, hydroxy, hydroxyalkyl, alkoxycarbonyl having 2 to 5 prime numbers or nitro-substituted benzoyl alkyl having 7 to 1 carbon atoms, fxil unsubstituted or ], 2 or 3 chloros,
Pyridyl substituted with alkyl having 1 to 3 carbon atoms or alkoxy having 1 to 3 carbon atoms 1x10 unsubstituted or pyridyl alkyl substituted with 1.2 or 3 chloro or alkyl having 1 to 3 carbon atoms [Hydroxyalkyl finely divided prime number of 1 to 4] ~
4 dihydroxyalkyl 4 Trihydroxyalkyl having 1 to 4 carbon atoms, where both k5] and 5□ are hydrogen or Almoto Relais I version σ) - 6 r voice l → soup shi) - fbl Pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrodine or 3.4- unsubstituted or substituted with 1 or 2 alkyl having 1 to 2 carbon atoms
cycloamino selected from the group consisting of didehydropiperidinyl iC1 carbonylamino of the formula NR53COR5 (R53 is hydrogen or alkyl having 1 to 4 carbon atoms, R
5] is the above-mentioned group other than hydrogen) tdi formula: NRsa S 02Rs] sulfonylamino (R51 and R53 are the above (same as C1tC1)
(ej-CH2NL2L3 (L2 and L3 are the same or different and are hydrogen or alkyl having 1 to 4 carbon atoms)
or its pharmaceutically acceptable salt (fl-Co2R. (gl-C)1201((ltl-CONR5R6 mountain-CH2N R5R6 or [jl-CONH5O2CH3 M+H-cis f-Z+ trans-CHyoCH4CH,
j --(CH2)n-1-(Cji-12)n-]
-]CF2-5-■-C1-12)3-Q-12, trans-(CI(2)m-Ci-1=CI-1,-,-C
116-1-(G-12), -1-CF2- or -
■-(Q-12) 3-C) 2-Ll is α-〇17β-H, =CH2 or oxo is hydrogen, hydroxy or methyl E] is trans-C1 (=C1(-, -0 Mouth 2-CF
12- or -c=c- Q] is 2 to α-OI7β-, α-R2:β-OH or OxoA] is 1-13 to α-17β-, α-CI-+3:
β-1ζ α-H: β-crosspiece α-F: β-F or α-C
I”13:7 to β-CH3 is (al-(C:1-12)P-CI-13[blcis-
ClowC1-1-C1-12-CD3((1-((:口2)2-C三C口tdl-(0口2)3-CH=C(Di3)27: Tahalel -C(R3R4 ) -(Cl-12) g-C
2 for H2R14 is hydrogen or methyl 1 (3 and 4 are the same or different, hydrogen or methylmethyl or ethyl R34 is hydrogen or alkyl having 1 to 4 carbon atoms g is] ~ 4
An integer m is an integer from 3 to 5, n is an integer from 5 to 7, and P is an integer from 1 to 6. The above divalent substituents (e.g. Ll, Q] and AI
), these divalent substituents are α-ki:β-Rj
, Ri means a divalent substituent having an α configuration with respect to the plane of the C8-C1□ cyclopentane ring, while Rj means a 2rdli substituent having a β configuration with respect to the layer plane. Therefore, when Ll is defined as α-014:β-11, the hydroxy of L1 means the α configuration, and the hydrogen substituent means the β configuration. As used herein, the term alkyl refers to straight or branched chain; for example, alkyl having 1 to 3 carbon atoms includes methyl, ethyl, propyl and inpropyl. q] has a methyl substituent, the compounds all have a methyl substituent,
It is called a 15-methyl compound. Furthermore, 91 groups are β
When having a hydroxy group in the configuration, such compounds are referred to as 5-shrimp compounds. Therefore, in the present specification, as the E1 group -(cit
2) Brostanglacine compounds having 2- or -C;
．． It is called 14-didehydration. Straight chain - (0 mouth 2), C113 [P is the same as above]
and P is ], 2.4 or 5. The compounds are 19.20-dinol, 20-nor,
It is called a 20-methyl or 20-ethyl compound. R
7 is a branch tl -C(It31'-4)-(0 mouth 2
) g-012R34 and g is 4 or 5 and the unbranched portion of the chain is at least n-butyl, then such compounds are 7-1 8-1 9- or 20 −
Alkyl, or 17.17-117.18.17.
19, 17.20.18.18.18.19-118.
20% 19.19- or 19.20-dialkyl compound, for example 1g is 5(]-methylpentyl)
If 17.20-diR7 is cis-C)1=c)
i-CH2Cl-13, the compound is cis-1
It is called a 7,18-didehydro compound. R7 is -(CH2) 3-C)i=C(C1(3) 2
, the compound is referred to as a 20-impropylidene compound. When N1 is -COL4, the compound is referred to herein as an amide. Additionally, when N is -GOORl, the compounds are referred to herein as prostaglandin esters and salts. The amide in Specification 1 (i.e., N1 - OL4
example)

[This includes the following: (]) Formula; Amides in which N, 51 and 52 are alkylamino include methylamide, ethylamide, n-propylamide, n-butylamide, n-pentylamide, n-hexylamide, n-hebutylamide, n-octylamide. , n-nonylamide, n-decylamide-n-undecylamide and n-dodecylamide and their isomers. Examples of such amides include dimethylamide, diethylamide, di-n-propylamide, di-n-butylamide, methylethylamide, methylpropylamide, methylbutylamide, ethylpropylamide, ethylbutylamide and propylbutyl. Amides are included. Within the scope of cycloalkylamino are cyclopropylamide, cyclobutylamide, cyclopentylamide, 2,3
-dimethylcyclopentylamide, 2.2-dimethylcyclopentylamide, 2-methylcyclopentylamide, 3-tert-butylcyclopentylamide, cyclohexylamide 54-ter(-butylcyclohexylamide, 3-isopropylcyclohexylamide, 2
．． 2-dimethylcyclohexylamide, cyclohebutylamide, cyclooctylamide, cyclononylamide,
Cyclodecylamide, N-methyl-N-cyclobutyramide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclo\xylamide, N-ethyl-N-
Included are cyclopentylamide and N-ethylhexylamide. Aralkylamides include benzylamide, 2-phenylethylamide and N-methyl-
Included is N-benzylamide. Substituted phenylamides include P-chloroanilide, m-chloroanilide, 2.4
-dichloroanilide, 2.4.6-trichloroanilide, m-nitroanilide, P-nitroanilide, P-methoxyanilide, 3,4-dimethoxyanilide, 3.4
．． 5-trimethoxyanilide, P-human; roxymethylanilide, P-methylanilide, m-methylanilide,
P-ethylanilide, [-butylanilide, P-carboxyanilide, P-methoxycarbonylanilide, P-
Included are carboxyanilides and υ-hydroxyanilides. Carboxyalkylamides include carboxyethylamide, carboxypropylamide, carboxymethylamide and carboxybutyramide. Carbamoylmethylamide,
Included are carbamoylethylamide, carbamoylpropylamide and carbamoylbutyramide. Cyanoalkylamides include cyanomethylamide, cyanoethylamide, cyanopropylamide and cyanobutyramide. Acetylalkylamides include acetylmethylamide, acetylethylamide, acetylpropylamide and acetylbutyramide. Benzoylalkylamide includes benzoylmethylamide, benzoylethylamide, benzoylpropylamide, and yohypenzoylbutyramide. Substituted benzoylalkylamides include P-chlorobenzoylalkylamide, p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide, 2.4-dichlorobenzoylmethylamide%2.4.6-trichlorobenzoylethylamide , tn-nitrobenzoylmethylamide, P-nitrobenzoylmethylamide, P-
Methoxybenzoylmethylamide, 2,4-dimethoxybenzoylmethylamide, 3,4.5-) Rimethoxybenzoylmethylamide Kn-I-; -Methylbenzoylmethylamide, P-ethylbenzoylmethylamide, L-butylbenzoylmethylamide, P-carboxybenzoylmethylamide, m-
Methoxycarbonylbenzoylmethylamide, O-carboxybenzoylmethylamide, θ-hydroxybenzoylmethylamide, P-chlorobenzoylethylamide, m-chlorobenzoylethylamide, 2.4-dichlorobenzoylethylamide, 2.4.6 = trichloro benzoylethylamide, m-nitrobenzoylethylamide 1', p-=trobenzoylethylamide, m-
Methoxybenzoylethylamide, P-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide, 3,4.5-)methoxybenzoylethylamide, P-hydroxymethylbenzoylethylamide, P-methylbency! Reethyl reamide, In-methylbenzoylethylamide, P-ethylbenzoylethylamide, [-butylbenzoylmethylamide, p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide, O-carboxybenzoylethylamide, shun-hydroxy Benzoylethylamide, P-chlorobenzoyl bunalamide, In-[J
Lopenzoylpropylamide %2.4-dichlorobenzoylpropylamide, 2.4.6-)! I Chlorobenzoylpropylamide 1. lll-Nitrobenzoylpropylamide, P-Nitrobenzoylpropylamide, p-methoxybenzoylpropylamide% 2
．． 4-dimethoxybenzoylpropylamide, 3.4.
5-trimethoxybenzoylpropylamide, P-hydroxymethylbenzoylpropylamide, P-methylbenzoylpropylamide, nl-methylbenzoylpropylamide, P-ethylbenzoylpropylamide,
t”-butylbenzoylpropylamide, ■)-carboxybenzoylpropylamide, m-methoxybenzoylpropylamide, 0-carboxybenzoylpropylamide, 0-hydroxybenzoylpropylamide, P-chlorobenzoylbunalamide, ■1- Chlorobenzoylbutyramide, 2,4-dichlorobenzoylbutyramide, 2.4.6-trichlorobenzoylbutyramide, m-nitrobenzoylbutyramide,
P-nitrobenzoylbutyramide, P-methoxybenzoylbutyramide, 2,4-dimethoxybenzoylbutyramide, 3,4.5-trimethoxybenzoylbutyramide, P-hydroxymethylbenzoylbutyramide, P-methylbenzoylbutyramide, m-Methylbenzoylbutyramide, P-ethylbenzoylbutyramide, [-butylbenzoylbutyramide, P-carboxybenzoylbutyramide, m-methoxycarbonylbenzoylbutyramide, and -carboxybenzoylbutyramide and d-hydroxybenzoylbutyramide Included. Pyridylamide includes α-pyridylamide, β-pyridylamide and l-pyridylamide. Substituted pyridylamide has 4-methyl-α-
Pyridylamide, 4-methyl-β-pyridylamide, 4
-chloro-α-pyridylamiij and 4-chloro-β
-Pyridylamide is included. Pyridylalkylamide (C)Amides include α-pyridylmethylamide and β-pyridylmethylamide.
-pyridylmethylamide, l-pyridylmethylamide,
α-pyridylethylamide, β-pyridylethylamide, γ-pyridylethylamide, α-pyridylpropylamide, β-pyridylpropylamide, γ-pyridylpropylamide. Included are α-pyridylbutyramide, β-pyridylbutyramide and γ-pyridylbutyramide. Substituted pyridylalkylamides include 4-methyl-α-pyridylmethylamide, 4-methyl-β-pyridylmethylamide, 4-chloro-α-pyridylmethylamide, 4-chloro-β-pyridylmethylamide, 4-methyl -α-pyridylpropylamide, 4-methyl-β-pyridylpropylamide, 4-chloro-α-pyridylpropylamide, 4
-Chloro-β-pyridylpropylamide, 4-methyl
-α-pyridylbutyramide, 4-methyl-β-pyridylbutyramide, 4-chloro-α-T II S5 no I+
d millet 1177ze V set 1 and A-ka 110-8-←0
Included are lysyl butyramide. Hydroxy dialkylamides include hydroxymethylamide, β-hydroxyethylamide, β-hydroxypropylamide, l-hydroxypropylamide, ]-(hydroxymethylpropylamide, 1-(hydroxymethyl)propylamide,
2-(Hydroxymethyl)propylamide and α,α
-dimethylhydroxyethylamide. Dihydroalkylamides include dihydroxymethylamide, β
J-') Hydroxypropylamide, 1-(hydroxymethyl)-2-hydroxymethylamide. Included are βlrldiedroxybutyramide, β,δ-dihydroxybutyramide, l,δ-dihydroxybutyramide and ], ]-bis(hydroxymethyl)ethylamide. Trihydroxyalkylamides include tris(hydroxymethyl)methylamide and 1,3-dihydroxy-2-hydroxymethylpropylamide. (21Amides containing a cycloamino group as mentioned above include pyrrolidylamide, piperidylamide morpholinylamide, hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and (3) Formula ?-NR53C1) Carbonylamino-containing amides of R51 include methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide, and benzylcarbonylamide. +41 type? Amides containing sulfonylamino of N, R53SUR5 include methylsulfonylamide, ethylsulfonylamide, phenylsulfonylamide F, p-tolylsulfonylamide and benzylsulfonylamide. Examples of alkyl having 1 to J2 carbon atoms are methyl, ethyl, furovyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and their isomers. Examples of cycloalkyl having 3 to 10 carbon atoms including alkyl-substituted cycloalkyl are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-
Diethylcyclopropyl, 2-butylcyclobutyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl%21314-)! J Ethylcyclobutyl, cyclopentyl, 2.2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert
-butylcyclopentyl, cyclohexyl, 4-ter
They are t-butylcyclohexyl, 3-inpropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Examples of aralkyl having 7 to 12 carbon atoms are benzyl, 2-phenylethyl, ]-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(
]-naphthylethyl) and 1-(2-naphthylmethyl).]Examples of phenyl substituted with ~3 chloros or alkyl having 1 to 4 leg primes LLp-chlorophenyl, m-chlorophenyl, 2+4-dichlorophenyl , 2.4.6-
) dichlorophenyl, p-)lyl, m-tolyl so-
tert9, P-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4'-chloro-
2-methylphenyl 2°4-dichloro-o-3-methylphenyl. Examples of C4-C7 cycloalkyl unsubstituted or substituted with C1-C4 alkyl are cyclobutyl, "-propylcyclobutyl, ]-butylcyclobutyl, ]-pentylcyclobutyl, 2-methylcyclobutyl. , 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 2.3.4-1-ethylcyclobutyl, cyclohentyl, 2 +2-') methylcyclopentyl, 3-nitylcyclopentyl, 3-propyl Cyclohentyl, 3-butylcyclopentyl, 3-te
rt-Butylcyclopentyl, l-methyl-3-propylcyclopentyl, 2-methyl-3-propylcyclohentyl, 2-methyl-4-propylcyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-inpropylcyclohexyl, 4-methyl cyclohexyl, 4
-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 4-cert-butylcyclohexyl%2゜6-dimethylcyclohexyl, 2.
2-dimethylcyclohexyl, 26-dimethyl-4-propylcyclohexyl and cycloheptyl. The pharmaceutically acceptable cation R1 includes a pharmaceutically acceptable metal cation, ammonium, amine cation or quaternary ammonium cation. Particularly preferred metal cations are those derived from alkali metals such as lithium, sodium and potassium and alkaline earth metals such as magnesium and calcium, but also cationic forms of bent metals such as aluminum, zinc and iron. Included in the present invention. Pharmaceutically acceptable amine cations are cations derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dibutylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine,
Cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine,
diethylenetriamine, etc., and aliphatic, -cycloaliphatic and araliphatic amines having up to about 18 carbon atoms,
and peterocyclic amines such as piperidine, morpholine, piperazine and their lower alkyl derivatives,
%]-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, etc., as well as amines containing water-soluble or water-affinity groups, e.g. Mono-, di- and triethanolamine, ethyljetanolamine, N-butylethanolamine,
2-Amino-1-phthanol, 2-amino-2-ethyl
1,3-bronoquinone diol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl
) Aminomethane, N-phenylethanolamine, N
-(p-tert-amylphenyl)jetanolamine, glactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephniline, epinephrine, protyrine, and the like. Also useful are amine salts and basic amino acid salts such as arginine and arginine. Examples of suitable pharmaceutically acceptable quaternary ammonium cations are tetra7tylammonium, tetra7tylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like. According to the methods of the invention, a pharmaceutical dosage form of PGE1-like prostaglandin is administered systemically to a human for the treatment or prevention of ARDS or multiple organ failure, such as (-) as used herein. The terms shock, trauma, and sepsis have the meanings commonly used in the art. Shock is generally described as a state of acute circulatory failure due to failure of circulatory control or loss of circulating fluid. It is often characterized by pale skin and cold, moist skin, a weak and rapid drop in blood pressure, decreased breathing, restlessness, agony, and sometimes loss of consciousness.Trauma is generally caused by a wound or injury. It has been said that this can also be the result of surgery. Sepsis is commonly caused by
At the same time, it is said to be a severe bacterial infection with toxic reactions. The term ARDS, as used herein, is well defined in the medical literature, as noted above. This is due to well-known factors, such as those listed above and in Table 1. All these terms are familiar to ordinary physicians. The term “severe vital organ failure” refers to vital organs (intestinal tract,
This means that the function of the brain, liver, kidneys, lungs or heart) is reduced to such an extent that the chances of survival are low. The term "person having or susceptible to vital organ failure" refers to an abnormal situation, such as trauma, sepsis, shock or a dangerous condition of ARDS or vital organ failure as set out above or in Table 1. refers to a person who can experience, is experiencing, or has recently experienced other events that occur. These individuals can be readily determined by an ordinary physician using, for example, these factors and the clinical symptoms described above. The term "unit dosage form" refers to separate unit amounts of prostaglandin and carrier useful for systemic administration in the methods of the invention. The ideal unit dosage form would therefore be one unit containing as its essential component amount the correct amount of prostaglasin suitable for the purposes of the present invention. These unit dosage forms can be packaged in a variety of ways. The prostaglandin can be dissolved or suspended in the carrier, or the prostaglandin and carrier can be combined immediately prior to administration. Thus, the pharmaceutical dosage form of the present invention, tadalandin, for a PGE1-like compound of formula [1), has a molecular weight of about 1 to]
%PGI2.00 ng/at a rate of 9/min. The weight of its salts, esters, amides and stabilized analogs is 0.
The patient is preferably systemically treated at a rate of 1 to 100 ng/ky/min for about 2 to 14 days, respectively, until the patient is out of critical condition or no longer threatened by organ failure. is administered intravenously. The preferred speed is
Each for a period of about 7 days or more, each for 20 to 3
0 ng/ky/min and 2-5 ng/ky/min. PGE, its alkyl esters and salts are well known and readily available compounds. It can be manufactured by methods known in the art. US Pat. No. 3,069,322 discloses such compounds. What is the manufacturing method for the essential substance PGE1, its lower alkyl esters and salts in the US? (No. 3069322
Amides of PGE1 can be prepared by methods known in the art of converting carboxylic acid groups to carboxylic acid amide groups. Such methods are described, for example, in U.S. Pat.
No. 2 [columns 1O and 11]. Other prostaglandins encompassed by the present invention are also known and can be synthesized by the patented methods described in the US patents, particularly in the prior art references cited above. PGI2 and its pharmaceutically acceptable salts, esters and amides are described in US Pat.
It can be produced by the method described in No. 8325. Stabilized analogs thereof are described in US Pat. Nos. 4,238,414 and 4,420,632. The essential substances prostacyclin, its pharmaceutically acceptable salts, and stabilizing analogues are prepared according to the methods of these US patents. Compounds of the invention useful in achieving the objects of the invention include:
Prostaglandins and prostaglandins as effective as PGE 1 in preventing and/or reversing the adverse consequences of trauma, sepsis, shock or other traumatic events as shown in Table 1 under the conditions of the examples. It is a grandin derivative. These compounds are referred to herein as %PGE 1-like compounds because their biological activities are similar. I1 like this? Examples of compounds include PGI2 and its salts,
Included are esters, amides and stabilizing analogs (including carbacyclin and 9β-methylcarbacycline) and prostaglandins of formula [1] described above, particularly the prostaglandins shown below. PGE1 (15s)-35-methyl-PGE] (15R)-15-methyl-PGE 11606-dimethyl-PGE1 2-decarboxy-2-hydroxymethyl-PGE]
PGE2 ]5-keto-PGE2 1606-dimethyl-PGE2 175.20-dimethyl-6-oxy-1) G E
1. Methyl ester 175.20-dimethyl-trans-Δ-2-PGEI
PGE2. N-methanesulfonylamide 9-deoxo-
9-Methylene-16,16-dimethy'・-1'GE2 (155)-15-methyl-PGE2 (15R)-15-methyl-P G h2]1-deoxy-]606-simethyl-P G E211- Deoxy-11αm 16.16-trimethyl-PGE2 6-trimethyl-11-deoxy-11α,16゜]6-trimethyl-P G h2 6-oxo-P G E 2 6-oxy-PGE1 ]]-deoxy-15-methyl- P G E ] GE3 1606-difluoroq P G E 2 and 20-impropylidene-1) GE ] and alkyl esters, pharmaceutically acceptable salts and derivatives thereof. Compounds of the invention may also be used in clathrates (see, e.g., U.S. Pat. No. 4,254,736), triacetin (U.S. Pat. No. 3,966,962) or triacetin/ethanol (see U.S. Pat. No. 4,301,175) formulations, triacetin/silicon dioxide gels ( U.S. Patent Application No. 61300
No. 6, filed May 21, 1984]. PGE] is the most preferred compound of the invention. Pharmaceutical dosage forms for intravenous injection of the PGE 1-like compounds of this invention can be formulated in a conventional manner. Other dosage forms for compounds of the invention are also well known. PGE 1 is also known as alprostadil and is also known as alprostadil.
The active ingredient in rostin (VRPediatric%), which helps maintain the hearing of the ductus arteriosus in newborns. Physician's Desk Reference (P
Hysicians Desk Reference)
See P. 2043 (38th, Ed, 1984). P
GE1(7) sterile solution is most preferred for use in the method of the invention. Similar formulations can be used for other prostaglandins. For the treatment or prevention of ARDS or organ failure,
The pharmaceutical dosage form of PGE 1-like prostaglandin is preferably administered by central venous catheter or through the right heart passage of a Swan-Ganz catheter, and the dosage is
Increase until reaching 00 g/ky/min. Dosage is calculated based on the patient's pre-illness weight. A preferred dosing method begins with an infusion rate of 5 ng/kg/min and increases the dose by 50 g/kg/min every 30 minutes until a 30-day g/ky/min rate is achieved. The prostaglandin is administered for a total of 7 days until the patient is out of danger or threatened with organ failure. Mean systemic arterial pressure 2 below basal level
% 1 to 100 ng/9/ unless decreased by more than 0%
Maintain the infusion rate at 1 min. If the arterial pressure decreases by more than 20%, the infusion rate is reduced until it again reaches a level within 20% of the basal level. Discontinuation of the drug is preferably carried out by reducing the administration to 1.0 ng/kg/min per hour. Also, for other PGE1-like prostagranges, equivalent amounts are used based on the potency of the compound compared to PGE 1 . For the treatment or prevention of ARDS and/or multiple organ failure with PGI2 and its salts, esters, amides and stabilized analogs, from 0.1 to] On/kg/
A similar method is employed, except using a dosage of 2-5 ng/ky/min, preferably %2-5 ng/ky/min. PC, E]-like prostaglandins (1' G 12, including its salts, esters and amides),
The intravenous route is preferable. However, other systemic and non-systemic routes of administration (e.g., orally, rectally, parenterally, including by implant device, intraarterially, transdermally, such as by patch) may also be used. So long as the administration used can achieve similar drug blood levels or equivalent efficacy as the intravenous route, it can be employed. If the Swan-Ganz catheter is on the street, go to the right of the catheter, then follow the living room to the right 1L? The route into the cell is convenient. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Example 13 Gl! : 1 Treatment for Severe Lung Disease"
)G1°]12.5yny is mixed with one 5 ml ampoule of Prostin V.R. Pediatric™ containing D s W or saline 1e to prepare an intravenous solution. This solution or a control solution containing only the carrier without PGEj will be administered in a prospective, randomized, double-blind, placebo-controlled manner to 41 patients suffering from ARDS. PGE1 or control solution was first added to 50
m1 of g/b/min, then 30 ng/kfl/
Increase by 5 ng/ky/min every 30 minutes until reaching a rate of 1 minute. Continue this administration for 7 days or until the patient is out of danger. The survival rate 30 days after discontinuing the injection is shown below. Example 2 Treatment method for severe organ failure due to 1' G E 1 50
1) GE】(30n
g/kg/min for 7 days) or placebo (same volume of saline and same duration) in a double-blind manner. For infusion, the patient requires mechanical ventilation with an inspired oxygen concentration of greater than 40% and a positive endpoint inspiratory pressure of water 5c111. most patients

[70%] have sepsis. P.G.
Of the 26 patients who received E], 17 survived (survival rate 65%), compared to 2 who received a placebo.
Of the 4 patients, only 7 survived (survival rate 29%). The relationship between bilirubin and creatinine levels and survival rates for patients undergoing this experiment is shown in Table 2 below. As can be seen, the survival rate of patients treated with PGE 1 with creatinine and bilirubin levels in the normal range is very high. Creatinine and bilirubin levels are
Each shows renal and hepatic function. Therefore, this data shows that PGE can be used to prevent severe kidney and liver damage and to prevent severe kidney and liver damage in patients at high risk of kidney failure, liver failure and/or death as a result of trauma, sepsis, shock and similar abnormalities. It is shown that it decreases the sex. Example 3 Prevention of Organ Failure with PGE 1 Patients with peritonitis diagnosed at surgery are at very high risk of developing multiple organ failure. The patient has an intravenous line placed to place the tip into a subclavian vein. A solution of PGE 12.511q/l in physiological saline is injected at a rate of 50 g/kg for 7 minutes. Dose 5 ng/ky every 30 minutes at a rate of 30 n
Increase until maximum injection rate of g/ky 1 min is reached. This administration is continued for 7 days to prevent the development of severe organ failure, including ARDS. During this period, peritonitis is controlled using antibiotic therapy and, if necessary, surgical intervention. Example 4 Prevention of Organ Failure with PGE 2 A patient who has been in a motor vehicle accident and sustained severe injuries to his abdominal area, with extensive internal bleeding, should receive appropriate treatment during the period before and immediately after surgical repair of the abdominal injury. A total of 8 units of blood are required to maintain blood volume. This puts the patient at very high risk of developing organ failure. An intravenous line was placed in the supraclavicular vein, and 5 ng/ky of PGE22.5~ in physiological saline Je was added.
Inject at a rate of /min. 50g of this dose every 30 minutes
Increase the rate in increments of /ky/min until a maximum of 30 ng 1ky/min is reached. This administration is continued for 5 days to prevent the occurrence of biological organ dysfunction. Example 5 1) Method for preventing organ failure due to G12 A patient admitted to an intensive care unit with unnatural breathing after surgery inhales stomach contents into the lungs during induction of anesthesia. This results in pulmonary dysfunction. An intravenous line was established and a solution of prostacyclin (PGI2) was added at 2.5
Inject at a rate of ng/ky 1 min. This infusion rate is maintained for 7 days to prevent the occurrence of vital organ (liver, kidney, lung, heart) failure. The patient remains in the intensive care unit (ICU) for an additional two days. Example 6 How to prevent organ failure caused by PGE1 A patient admitted to a hospital emergency room after falling eight stories from a building under construction suffered six shattered ribs and one tibia and numerous bruises. I owe it. Immobilize the shattered tibia and hold and observe the patient. For 5 days, the patient's bilirubin level has increased to 611 g/di and the creatinine level is 2.2-/di. Infusion of pGE1 solution in dextrose was started intravenously in the subclavian vein at a rate of 5 ng/kg in 1 min and 30 n in dextrose over 2 hours.
Increase to g/ky 1 min. Continue this administration for 7 days,
Preventing further organ damage. Table 1 Conditions related to ARDS Table 2 *Abnormality -> 1.5ri/d I N - Number of patients in the experiment Structural formula Table L]

Claims (1)

Claims: (Ill) A pharmaceutical composition for the treatment or prevention of ARDS or multisystem organ failure in humans, characterized by comprising a G E J-like prostaglandin and a pharmaceutically acceptable carrier or diluent. (2) The prostaglandin has one formula: [In the formula, N] is (Al-GOOR], k] is +a+hydrogen [1)l Alkyl having 1 to 12 carbon atoms tC1lSi3 to]0 cyclo Alkyl (dil C7-16 aralkyltel unsubstituted or], phenyl substituted with 2 or 3 chloro or C1-4 alkylffl whose para position is (11N1-1-GO-R25 fill- GO-R26 (Machi-〇-CUR54 or phenyl substituted with (IVI-CM-N-NH-CONI-12) (R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl or -NH2,R2
6 is methyl, phenyl, -NH2 or methoxy and R54 is phenyl or acetamide) or (gl pharmaceutically acceptable cation (111-CI-1201([C)-COL4, L4 is 181 formula: Nk5]・R52 Amino (R51 and R
52' (1) Hydrogen (11j Alkyl with 1 to 2 carbon atoms (Ill) /F cycloalkyl with 3 to 2 O) OVJ
Aralkyl with 7 to 2 carbon atoms (vl unsubstituted or], 2 or 3 chloro, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy, hydroxyalkyl, carboxy, carbon i with 2 to 4 carbon atoms) 5
alkoxycarbonyl or nitro (vl) carboxyalkyl having 2 to 5 carbon atoms (vll
) PR Carbamoyl alkyl with R number 2 to 5 (vllll
) Cyanoalkyl (IX) with carbon i number 2 to 5/i prime number 3
~6 acetylalkyl [x] unsubstituted or], 2 or 3 chloro, alkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms
4 alkoxy, hydroxy A hydroxyalkyl, carboxy, alkoxycarbonyl having 2 to 5 carbon atoms or benzoyl alkyl having 7 to J ] substituted with nitro, lX+) unsubstituted or 2 or 3 chloro, carbon Pyridyl alkyl substituted with alkyl having 1 to 3 carbon atoms or alkoxy having 1 to 3 carbon atoms 1) Unsubstituted or substituted with chloro or alkyl having 1 to 3 carbon atoms 10 Hydroxyalkyl having 1 to 4 carbon atoms W 1 to 4 carbon atoms
4 dihydroxyalkyl (translation) trihydroxyalkyl having 1 to 4 carbon atoms, both R5□ and R5□ cannot be a group other than hydrogen or alkyl] (bl unsubstituted or] or two Cycloamino (C) selected from the group consisting of pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino or 3,4-didehydropiperidinyl substituted with an alkyl having 1 to 2 carbon atoms Formula: N R5a COR5
] carbonylamino (R53 is hydrogen or carbon number 1-
4 alkyl, R5] is the above-mentioned group other than hydrogen) id1 NR53SO2 R51 sulfonylamino (R51 and R53 are the above-mentioned (C1 (same as Cl) (C
) -CH2NL2L3 (L2 and L3 are the same or different and are hydrogen or alkyl having 1 to 4 carbon atoms) or a pharmaceutically acceptable salt thereof when N1 is -C1i2NL2La if) C02R] (gl-CI-12011 [111CON R51'-6 (iH, -GO2NR5R6 Mae C (jl C0N1IS02[jlt3 M1 is cis or trans-(:1-1- to l(-(
C112) m-1 (CI-1C112) (C1(2)
n-1-CF2-1-CO-(C)12)3C)12-
,) Lance-(0 mouth 2) , 11-C)1=C)1-5
-C1i=C1l-(C112)m-]CF2- or -Co-(CH2)3-CI -L is α-011:β
-11% = C 2 or oxo] 1 (8 is hydrogen, hydroxy or methyl 1 et al.)
This is -C Chishi- (21 is α-01l: β-R2, α-R2: β-OH
or oxo z-H:β-H1a-F:β-F or αCH3:β-
CI"t 3 to 7 is (al - (0 mouth 2) P-CH3 + b) cis-C1-1 engineering CH-CH2-CI-13fc
l -(CH2) 2- C”1-C1-1[dl-(
CH2)3-CH=c(CH3)2 or [el-C(
R3R4) -(Cl-12) g-C112R] 2 is hydrogen or methyl, and R4 is the same or different, and hydrogen or methyl k; is hydrogen or alkyl having 1 to 4 carbon atoms g is 1 to 4
The integer m is an integer of 3 to 5, n is an integer of 5 to 7, and P is an integer of 1 to 6] or a pharmaceutically acceptable salt thereof when N1 is -CONR53SO2 is 51. A certain said (
3j the prostaglandin is PGE2 or PGI2,
The pharmaceutical composition according to item (]) above, which is a salt, ester, amide or stabilized derivative thereof. (4) The prostaglandin is PGE]2-decarboxy-2-hydroxymethyl-PGE](155)-15-methyl-PGE. (15R)-1s-methyl-1)GE116.16-dimethyl-13GE] I'GE2 ]5-keto-PGE2 16.16-dimethyl-PGE2 175.20-dimethyl-6-oxo-1)GE], methyl ester 175 .20-dimethyl-trans-Δ-2-1)GE
]1) GE2 N-methanesulfonylamide 9-deoxo-9-methylene-16,16-dimethyl-PGE2 (155)-15-methyl-PGE2 (15R)-15-methyl-PGE2 ]]-deoxy-16,16- Cymethyl-P G E
2]]-deoxy-]]α-16,16-)dimethyl-
P G E 2 6-oxo-]-deoxy-]1α, 16.16-
a prostaglan selected from the group consisting of dolimethyl-PGE2 6-oxy-PGE2 6-oxo-PGE]]-deoxy-]5-methyl-PGE IGE3 16.36-difluoro-PGE2 and 20-impropylidene-PGE] (5) The pharmaceutical composition according to item (4), wherein the prostaglandin is l' G E ]. (6) From injury, sepsis or shock. 1'('J b
A method for reducing the probability of death in humans who are prone to or whose multiorgan failure is progressing, characterized in that it is composed of a 1-like powder, a 1-grain S-gin, and a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition.