EP0477195A1 - Composes du type suramine et steroides angiostatiques inhibiteurs de l'angiogenese - Google Patents

Composes du type suramine et steroides angiostatiques inhibiteurs de l'angiogenese

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Publication number
EP0477195A1
EP0477195A1 EP90907622A EP90907622A EP0477195A1 EP 0477195 A1 EP0477195 A1 EP 0477195A1 EP 90907622 A EP90907622 A EP 90907622A EP 90907622 A EP90907622 A EP 90907622A EP 0477195 A1 EP0477195 A1 EP 0477195A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydroxy
fluoro
dihydroxy
dione
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP90907622A
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German (de)
English (en)
Inventor
Paul A. Aristoff
Mark A. Mitchell
John W. Wilks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0477195A1 publication Critical patent/EP0477195A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention is a method of treating angiogenesis in mammals who have a need for the same which utilizes suramin or suramin-type compounds and an angiostatic steroid.
  • Conditions in which this combination may be used are diseases of neovascularization such as cancer, diabetes and arthritis.
  • Angiogenesis is the development of blood vessels which typically would lead to a vascular bed capable of sustaining viable tissue. Angiogenesis is a necessary process in the establishment of embryonic tissue and development of a viable embryo. Similarly, angiogenesis is a necessary step in the establishment and development of tumor tissue as well as certain inflammatory conditions. The inhibition of angiogenesis would be useful in the control of embryogenesis, inflammatory conditions, and tumor growth, as well as numerous other conditions.
  • Heparin is presently used with inhibitors of angiogenesis, especially angiostatic steroids to treat diseases involving neovascularization, see Biochem. Pharmacol. 34, 905 (1985) and Annals of Surgery 206, 374 (1987).
  • the heparin potentiates the angiogenesisinhibiting activity of other drugs, for example of collagen biosynthesis inhibitors such as L-azetidine carboxylic acid.
  • the problem with using heparin is that the efficacy of each preparation/batch of heparin differs due to the chemical heterogeneity of the heparin molecules.
  • ⁇ -Cyclodextrin tetradecasulfate is known to be a substitute for heparin in anti-angiogenesis treatments containing angiostatic steroids, see Science 243, 1490 (1989).
  • Fibroblast growth factor is one of a number of known angiogenic growth factors. See, J. Cell Physiol. 132, 143 (1987).
  • US Patent 4,599,331 discloses 20-substituted ⁇ 1,4 -16-methyl steroids which did not have a ⁇ 9 (11) double bond which are useful as antiangiogenics.
  • US Patent 4 , 771 , 042 discloses 21-hydroxy steroids which are useful in the inhibition of angiogenesis involving the co-administration of steroids with heparin or heparin fragments.
  • R 10 is ⁇ -R 10-5 : ⁇ -R 10-6 and R 5 is ⁇ -R 5-5 : ⁇ -R 5-6 , where R 10-6 is -CH 3 , one of R 5-5 and R 5-6 is -H and the other of R 5-5 and R 5-6 taken with R 10-5 is -CH 2 -CR 2 -CR 3 -CH 2 - where R 2 and R 3 are as defined above;
  • R 6 is ⁇ -R 6 - 1 : ⁇ -R 6 - 2 where one of R 6-1 and R 6-2 is -H and the other of R 6-1 and R 6-2 is -H, -F, -Cl, -Br and -CH 3 ;
  • R 7 is ⁇ -R 7 - 1 : ⁇ -R 7 - 2 where one of R 7-1 and R 7-2 is -H and the other of R 7-1 and R 7-2 is -H or -CH 3 ;
  • R 17 is C 1 -C 20 alkyl, C 1 -C 10 fluoroalkyl containing from 1-23 -F atoms, C 1 -C 6 alkoxy, (C 1 -C 8 )alkylamino(C ⁇ -Cg)alkyl, (C 5 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkyl optionally substituted with 1-3 -CH 3 , -F, -Cl, -OH, -OCH 3 , -OC 2 H 5 and -NH 2 , C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, (C 3 -C 8 )cycloalkyl(C 2 -C 10 ) alkenyl;
  • X is -O- or -S-;
  • R 21 is C 1 -C 10 alkyl optionally substituted with 1 to 10 -F, -Cl or -Br,
  • R 21-1 is C 1 -C1 0 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 2 -C 10 alkenyl containing 1 thru 4 double bonds optionally substituted with -OH, -F, -Cl or -Br,
  • n 1 is 0 or 1 and phenyl is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OCH 3 , -OC 2 H 5 , C 1 -C 4 alkyl, -NH 2 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or -NO 2 ,
  • R 21-2 and R 21-3 are tne same or different and are -H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, - ⁇ , -CE 2 - ⁇ and where R 21-2 and R 21-3 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidine, 1-piperidine, 1-piperazine and 1-morpholine.
  • the present invention involves a method of treating angiogenesis in a warm blooded mammal who is In need of such treatment which comprises administration of an angiogenic inhibiting amount of a combination of a suramin-type compound and an angiostatic steroid.
  • the mammal be a human.
  • Suramin-type compounds are compounds which mimic the anti-angiogenic action of suramin and which augment the activity of angiostatic steroids.
  • Suramin and the suramin-type compounds are known to those skilled in the art. It is preferred that the suramin-type compound be selected from the group consisting of
  • the suramin-type compound be suramin and 4,4'-bis[[4-(o-hydroxyanilino)-6-(m-sulfoanilino)-s-triazin-2-yl]amino]-2,2'stilbenedisulfonic acid. It is even more preferred that the suramin-type compound be suramin.
  • Angiostatic steroids refer to those steroids which prevent the process of angiogenesis/neovascularization, or cause the regression of new vasculature which results from angiogenic stimuli.
  • Angiostatic steroids refer to, and include, the known 20-substituted steroids of formula (I) see US Patent 4,599, 331, the known 21-hydroxy steroids of formula (II) see US Patent 4,771,042, the known C 11 -functionalized steroids of formula (III) see International Patent Publication WO87/02672, the following known steroids 6 ⁇ -fluoro17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione 21- acetate, 6 ⁇ -fluoro-17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione, 6 ⁇ -fluoro-17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione 21-phosphonooxy and pharmaceutically
  • the ⁇ 9(11) -etianic esters (IV) are prepared by methods known to those skilled in the art from steroid starting material known to those skilled in the art, see CHART B.
  • the starting materials for preparation of the ⁇ 9(11) -etianic esters (IV) are the corresponding 17 ⁇ ,21-dihydroxy steroids (V).
  • These compounds are oxidized by known procedures to remove C21 and produce a steroid where C 20 is substituted with -X-H where X is -O- or -S-, rather than -CH 2 -OH.
  • the oxidation reaction is performed with an aqueous solution of an oxidizing agent such as periodate. It is preferred to use an excess of the oxidizing agent (about 2 equivalents).
  • the carboxylic acid product (VI) is isolated and ean be purified by recrystallization as is known to those skilled in the art.
  • the carboxylic acids (VI) are esterified at C 17 by reaction with the an anhydride of the desired corresponding 17-esters (VII).
  • the anhydride is of the formula R 17 -CO-O-CO-R 17 as is known to those skilled in the art, see US Patent 4,599,331.
  • the 17-esters (VII) are then transformed to the desired ⁇ 9(11) -etianic esters (IV) by esterification procedures (for example with diazoalkyl reagents) well known to those skilled in the art.
  • R 6 is ⁇ -R 6-1 : ⁇ -R 6-2 where R 6-2 is -H and R 6-1 is -H, -F and -CH 3 , it is more preferred that R 6 is -F.
  • R 7 is -H: -H.
  • R 16 is ⁇ -R 16-1 : ⁇ -R 16-2 where one of R 16-1 and R 16-1 -H and the other of R 16-1 and R 16-2 is -CH 3 .
  • R 17 is C 1 -C 4 .
  • angiostatic steroid be ⁇ 9(11) -etianic esters of formula (IV) where
  • R 6 is ⁇ -R 6-1 : ⁇ -R 6-2 where R 6-2 is -H and R 6-1 is -H, -F and -CH 3,
  • R 7 is -H:-H
  • R 16 is c--R 16-1 : ⁇ -R 16-2 where one of R 16-1 and R 16-2 -H and the other of R 16-1 and R 16-2 is -CH 3 ,
  • R 17 is C 1 -C 4 alkyl or -(CF 2 ) n2 -CF 3 where n2 is 0-3,
  • R 21 is C 1 -C 4 alkyl
  • X is -O-
  • R 4 is -H
  • R 6 and R 9 are be the same or different and are -H, -F, -Cl, R 11 Is chosen from the group consisting of hydroxy and keto,
  • R 20 is chosen from the group consisting of methoxy and thiomethyl
  • R 17 is chosen from the group consisting of alkyl groups having less than 6 carbon atoms
  • angiostatic steroid be 6 ⁇ -fluoro-17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione 21-acetate,
  • the method of treating angiogenesis is the treating of diseases of neovascularization.
  • neovascular diseases are selected from the group consisting of solid tumors, diabetes, arthritis, atherosclerosis, neovascularization of the eye, parasitic diseases, psoriasis, abnormal wound healing processes, hypertrophy following surgery, burns, injury, hair growth, ovulation and corpus luteum formation, implantation and embryo development in the uterus. It is more preferred that the neovascular disease is solid tumors, diabetes, arthritis or psoriasis.
  • the suramin-type compounds and angiostatic steroids do not have to be administered in the same pharmaceutical dosage form.
  • the suramin-type compounds are usually administered IV because of their irritation whereas the angiostatic steroids can be administered either orally or parenterally (IM, SQ, IV).
  • the dose of the suramin-type compounds is from about 1 to about 1,000 mg/mVday, preferably from about 5 to about 500 mg/m 2 /day.
  • the suramin-type compound Is given until the appropriate blood level is reached which is about 50 to about 300 ⁇ g/ml, preferably about 250 to about 300 ⁇ g/ml. At that point the administration of the suramin-type compound is stopped as is known to those skilled in the art.
  • the dose of the angiostatic steroids is from about 0.1 to about 100 mg/kg/day, preferably from about 0.1 to about 50 mg/kg/day.
  • angiostatic steroids may be combined with agents other than suramin including sulfated glycosaminoglycans and sulfated polysaccharides, or effective fragments of these molecules.
  • the preferred glycosaminoglycans include heparin and heparan sulfate. Fragments of heparin or heparan sulfate may also be used if they contain a minimum of six saccharide residues; fragments of heparin or heparan sulfate may be prepared from heparin or heparan sulfate isolated from natural sources, or they may be prepared by chemical synthesis.
  • Angiostatic steroids may also be combined with polysaccharides including pentosan polysulphate, cyclodextrins, or other sulfated polysaccharides isolated from natural sources.
  • the preferred polysaccharides are sulfated forms of /S-cyclodextrin Including /3-cyclodextrin tetradecasulfate, pentosan polysulphate, or the polysaccharide-peptidoglycan isolated from Arthrobacter, Journal of Biochemistry 92, 1775 (1982). These polysaccharides may be isolated from natural sources, or prepared by chemical synthesis.
  • Angiostatic steroids may also be used in combination treatments containing compounds which interfere with collagen biosynthesis.
  • Preferred compounds in this group include L-azetidine-2-carboxylic acid, thioproline, and related proline analogs.
  • other inhibitors of basement membrane collagen synthesis such as 8,9- dihydroxy-7-methyl-benzo(b)quinolizinium bromide.
  • the exact route of administration, dose, frequency of administration of both the suramin-type compound and angiostatic steroids depends on the particular treatment of angiogenesis per formed, the severity of the disease, the age, general physical condition, weight, or other clinical abnormaliites, etc., of the particular patient to be treated as is known to those skilled in the art.
  • R i and R j would represent monovalent variable sub- stituents if attached to the formula CH 3 -CH 2 -C(R i ) (R j )H 2 .
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parentheses.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R i and R j are bonded to the preceding carbon atom.
  • C i represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either monovalent or bivalent) at the Cg position.
  • Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion.
  • the cyclic molecular fragment, 4- (ethyl)-1-piperazinyl can be represented by -N -(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C*H 2 .
  • variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
  • R i is defined to consist of two monovalent variable substituents
  • the convention used to define the bivalent variable is of the form " ⁇ -R i-j : ⁇ -R i-k " or some variant thereof.
  • both ⁇ -R i-j and ⁇ -R i-k are attached to the carbon atom to give -C( ⁇ - Ri-j) ( ⁇ -R i-k )-.
  • bivalent variable may be defined as two separate monovalent variable substituents
  • two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable.
  • R i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide.
  • the carbon atom content of variable substituents is indicated in one of two ways.
  • the first method uses a prefix to the entire name of the variable such as "C 1 -C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • C 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
  • the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 - (CH 2 ) n -o- CO- where n is zero, one or two.
  • the carbon atom content of only each portion of the definition is Indicated separately by enclosing the "C i -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
  • this optional convention (C 1 -C 3 )- alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
  • C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.
  • TLC refers to thin-layer chromatography
  • THF refers to tetrahydrofuran
  • ⁇ refers to phenyl (C 6 H 5 ).
  • MS refers to mass spectrometry expressed as m/e or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact.
  • CI refers to chemical ion- Ization.
  • FAB refers to fast atom bombardment.
  • Ether refers to diethyl ether.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • Treating refers to inhibiting and/or preventing.
  • Angiostatic steroids refer to those steroids which prevent the process of angiogenesis/neovascularization, or cause the regression of new vasculature which results from angiogenic stimuli.
  • the ratios of solvents used are volume/volume (v/v).

Abstract

Le procédé décrit, qui sert à traiter l'angiogénèse chez des mammifères à sang chaud nécessitant un tel traitement, consiste à administrer une quantité inhibitrice de l'angiogénèse d'une combinaison constituée par un composé du type suramine et par un stéroïde angiostatique. Les stéroïdes angiostatiques sont notamment les stéroïdes substitués en position 20 connus de formule (I), les stéroïdes hydroxy en position 21 de formule (II), les stéroïdes fonctionnalisés en position C11 de formule (III) ainsi que les nouveaux esters DELTA9(11)-étianiques de formule (IV), ainsi que divers stéroïdes connus pris séparément.
EP90907622A 1989-06-16 1990-05-17 Composes du type suramine et steroides angiostatiques inhibiteurs de l'angiogenese Ceased EP0477195A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US36693589A 1989-06-16 1989-06-16
US366935 1989-06-16
US48304490A 1990-02-16 1990-02-16
US483044 1990-02-16

Publications (1)

Publication Number Publication Date
EP0477195A1 true EP0477195A1 (fr) 1992-04-01

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EP90907622A Ceased EP0477195A1 (fr) 1989-06-16 1990-05-17 Composes du type suramine et steroides angiostatiques inhibiteurs de l'angiogenese

Country Status (4)

Country Link
EP (1) EP0477195A1 (fr)
JP (1) JPH04506066A (fr)
AU (1) AU5640390A (fr)
WO (1) WO1990015816A1 (fr)

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AU5640390A (en) 1991-01-08
WO1990015816A1 (fr) 1990-12-27

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