JPS5920241A - Preventive therapy for theileriosis - 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 The present invention relates to compounds and preparations for the treatment and prevention of (theileriosiθ) and methods for producing their (E compounds).

Theisiliosis is a disease caused by protozoa of the genus Thθ11θria. In cattle, T. Parva (pa
rva), causing substantial damage mainly in Central and East Africa and the Middle East. In sheep, T. h
irci and T. ouis and is ubiquitous in the Middle East. Infected ticks transmit these protozoa to mammalian hosts.

When Hinoba bulb cells are infected, they immediately begin to divide, contrary to their normal function. The death occurs due to the release of reproducing substances from the destructive bulb, and the harmful effects of the parasite itself, which in turn infect the live worms with red blood cells and mites, which then infect the animal in the evening.

In the field, there are no known effective treatments for Taiciliasis. Compounds with anti-Theilerial activity are known, but are toxic to the host. They are used to treat Theileria infection. The only drug ever used to treat cattle and sheep is oxytetracycline (Terram7Cin). . 1968 Academic Pre
Published by Weinman D. and Ristic M.
．． Edited by S. F.

Infectious Blood by Barnett
Diseases of Manand Animals
s, Vol. According to No. 11, this compound has a very limited effect even if administered before infection is established, but it is ineffective once infection has established. often,
The anaplasma infection was misdiagnosed and the patient was diagnosed with Taiciliasis, and as a result, oxytetracycline was administered.
Often administered in large doses, reaching almost toxic levels. Tire 1: What appears to be an apparent recovery from anaplasmosis is actually just a recovery from anaplasmosis and bacterial infection.

British Patent/I6155 3424 describes 2-hydroxy-6-cyclohexylalkyl and 2-hydroxy-3-cyclohexyl-1,4-naphthoquinone derivatives useful in the prevention and treatment of taiciliasis. The latter, namely 2-hydroxy-6-cyclohexyl-1,4-1-phthoquinone, was subsequently found to be by far the most effective compound, especially against infections of T., parV&.

European patent application/l67 8,1 0 1,4 2
6 refers to 6-hydroxy-1,4-naphthoquinone in which the 2-position substituent is the 03-12 cycloalkyl ring, which optionally has a substituent such as a C1-4 alkyl group, especially a methyl group. mentioned. However, a specific compound having a substituent is not described, nor is it described at which position on the cycloalkyl ring the cycloalkyl ring should be substituted.

The compounds of formula (I) below are described in our patent application UK481
31206, certain 2-monosubstituted-6-hydroxy-1
．． 4-naphthoquinone synthesis σ) Recorded as 11JI form vl
It was done. It has now been discovered that the compounds of (1) below also exhibit high and advantageous fluoroactivity against the Theileria species and, in contrast to the compounds of the British Patent <g1553424,
T. 'annulat-a infections were found to be particularly effective. As a result, it is possible to produce therapeutic compounds for Kikui and to treat infected animals with these biological diseases.

One feature of the present invention is that compounds having the formula (wherein R is an alkyl group having from 1 to 10 carbon atoms), their [sigma] tautomers, or their sigma tautomers, or as drugs thereof, Provide entertainment.

As a result of tautomerism, the acidic hydrogen of the 6-hydroxy group is donated to the adjacent oxo group, but it is believed that formula (1) represents a more stable state. Since the hydroxy group in the formula is capable of forming salts with suitable salts, pharmaceutically acceptable salts of the compound include salts of alkali metals such as sodium or potassium and organic bases such as ethanolamine, jetanolamine and N- There is a salt with methylglucamine.

As will also be understood, compounds of formula (1) can exist as cis or trans isomers and the cyclohexyl ring covers both naphthoquinone-methylene residues and mixtures thereof in any proportion. do.

Note that in the unsubstituted 1,4-nattoquinone ring, the 2 and 6 positions are the same, so place the cyclohexyl substituent or hydroxyl group at the 2 position. For convenience, compounds will be referred to in general positions herein.

In the compound of formula (1), it is appropriate that R is a straight button-shaped 01-4 alkyl group. Preferred groups are methyl or ethyl.

The compound of formula (T') can be prepared by any known method for preparing compounds having similar structures.

For example, a compound of formula (1) may be modified from a compound of formula (It) in which R is as defined by 6-hydroxy-1,
It can be prepared by standard literature methods, converting to 4-naphthoquinone. Compounds of formula (It) may be prepared from compounds of formula (HA) by Fr1e8 rearrangement.

Alternatively, a compound of formula (I) can be combined with the corresponding 6-chloro-9-1 of formula (III), exactly 6-chloro-*&! The 3-zolome analogs (or halogens, R being as defined above) can be converted to 6-hydroxy-substituted compounds by alkaline thawing, e.g., with alkali metal hydroxides in a suitable medium. For example, it has been found convenient to use potassium hydroxide in an aqueous methanol medium. The starting 6-halogen derivative is substituted or unsubstituted 2-cyclohexylmethylphenol as suggested by Fiereer, L., Am.

Ohem, Soa, 194 L 3165)
4a, 5, 7.7a-, correspondingly substituted by
Tetrahydro-2-cyclohexylmethyl-1,4-f
(Obtained from futoquinone by oxidation and halogenation.

In yet another method, formula (1) can be applied to 6 of a compound of formula (IV) 1 (wherein R is as defined above).
It can be produced by introducing a hydroxyl group into the position.

Thus, for example, a compound of formula (1) may be halogenated (ie, chlorinated or brominated) to form a compound of formula (IID) above, which is then converted into a metal compound of formula (1) above.

The compound of formula (IV) is epoxidized to give a compound of formula (V) cH3, which is treated with, for example, a dilute base or a dilute acid solution @
It can be hydrolyzed in a liquid to form a compound of formula (1).

Compounds of formula (rV) can also be subjected to 'rhte1e acetylation by reaction with an acylating agent (e.g. acetic anhydride) in the presence of an oxidizing agent (e.g. perchloric acid) to form compounds of formula (■a). 5ru. The compound of the formula (Via) is converted to the formula (Via) by melting the ice.
Vlb), these are e.g.
The compound of formula (I) is converted into the compound of formula (I) by oxidation in a manner similar to that described in NIC Reaction, Vol. 19, p. 222.

Suitable oxidizing agents include, for example, ferric chloride-mineral acids or chromic acids.

R1 R10H3 In the method described above, the stereochemistry of the final product is determined by that of the starting materials. That is, it produces a stereochemically pure compound.

A further advantageous alternative is to combine the compound of formula (1) with a compound of () 1 in which R1 is a chlorine or bromine atom, or a hydroxy, acetoxy or alkoxy group. , and the resulting 2-cyclohexylmethyl group-substituted condensate, if desired. inside, other than hydroxy group
It can also be produced by hydrolyzing one group to form a fluoryl group.

A preferred donor compound is a correspondingly IF-converted cyclohexyl acetic acid which undergoes oxidative decarboxylation.

For example, persulfuric acid with catalysts such as silver ions is used for this purpose (Jacobson N, et al., Anna
len.

1972.763, 135 and Acta Ohem.

8cand, 1973 r 27 + 3211
) Preferably, when using persulfuric acid under these conditions, 1,4-naphthoquinone in which R1 is substituted with a group other than a hydroxy group is used. Conveniently, ammonium persulfate can be used as the oxidizing agent and the catalyst is silver nitrate.

The main coupling reaction is followed by hydrolysis, if necessary, to yield hydroxyl groups. Alkaline conditions are usually advantageous for ice melting.

An example of a cyclohexylmethyl donor compound that itself has a peroxide group is a suitably substituted cyclohexylmethylalkanoyl peroxide, as suggested in U.S. Pat.

Donation of the cyclohexyl free radical by spontaneous release from the donor compound can be accomplished using, for example, tricyclohexylmethyl-borane. Such reagents may be prepared by reacting cycloalkenes with borane dimethyl sulfide. It is convenient to carry out the reaction in a solvent such as tetrahyrofurane. The 2-substituted-1;4-naphthoquinones required in some of the above reaction schemes may be prepared by known synthetic methods in the literature. For example, F1θS
or.

L,,J,Am,-Ohem,Soc,,19
4 B, 5 L65 or similar methods.

Furthermore, cyclohexyl-donating compounds include correspondingly substituted cyclohexylcarboxylic acids. In that case,
As will be clear to those skilled in the art, an additional step of reduction of the alkene is required after the condensation to provide compounds of formula (1).

It is natural that the above process gives a mixture of cis and trans isomers.

When a single compound of the cis or trans isomer of formula (1) is required, the isomerically pure starting compound is used in the above reaction in which no isomerization occurs. In particular, stereospecific pure carboxylic acids are used in the last method above. If a mixture of isomers occurs, the mixture may be separated by physical means.

Such methods are known in the art, such as fractional crystallization and chromatographic separation.

Yet another feature of the invention is to provide compounds of formula (■).

(wherein R is as defined above and R1 is as defined above or is a benzyloxy group) These compounds are useful as intermediates in the above synthesis. Compounds having as Rl a group that is readily hydrolyzed to a hydroxyl group in vivo can be used as therapeutics, such as as prodrugs in formulations. Acetyl or benzoyl groups undergo such lysis and can therefore be used for long-term 1N1 acting glycerol lengths of active compounds.

The compounds of formula (1) have extreme activity against protozoa of the genus Theileria and can be used for the treatment and/or prevention of theisiliosis in cattle and sheep. In particular, these compounds are effective against T. annulata infections.

The amount of a compound of formula (1) required for use in the treatment or prevention of Theileria infection depends not only on the type of active compound;
Varies with nature of infection and route of administration.

As used herein, the term "effective amount, dosage, or unit" refers to a predetermined dose of a compound that is sufficiently effective against Theillria microorganisms. To serve or achieve prophylaxis or treatment, certain preparations may contain several times the dosage required by one animal.

Initial dose for cows weighing 400 kg is 0.2 to 1
0 g, conveniently from 0.2 to 2.5 g, and for small animals or sheep from 50rn9 to 1.0 g or preferably from about 0.1 to [J, an amount of active compound of 5 g, but with further dosages. You can increase it.

Although the compounds of formula (1) can be administered as raw materials for anti-Theileriosis agents, it is advantageous to use the active ingredient as a therapeutic preparation.

Therapeutic preparations containing a compound of formula (1) may take the form of a sealed container, or a molded tablet with ingredients such as excipients, or a composition. Advantageously, the preparation is in unit dosage form or a sterile, encapsulated formulation.

Preparations containing compounds of formula (1) may be administered by injection (subcutaneously or preferably intramuscularly), intravenously or orally in conjunction with a suitable carrier. Sterile injectable formulations may be formulated with preferably organic carriers. The carrier may contain bacteriostatic agents, antioxidants, buffering solutes to render the preparation isotonic with the substrate, thickening agents, suspending agents or other pharmaceutically acceptable additives.

Formulations for injection may be placed in unit-dose containers, such as ampoules, single-use injection devices, or in multi-dose forms, such as bottles, from which appropriate quantities may be dispensed.

Formulations for oral administration may contain as carrier solids for the formation of tablets, pastes, granules or powders, or may contain liquids for suspension or dissolution. They may include diluents, binders, dispersants, surfactants, lubricants, chemicals, colorants, bath media, thickeners, suspending agents or other pharmaceutically acceptable additives. .

These products are available in unit-dose or multi-dose form or as additives to foods. Compounds of formula (1) can also be used as monkeys) to allow animals to receive preventive treatment in the field. formula(
The compounds of 1) may also contain up to 10% by weight of the active compound in a suitable carrier such as dimethyl sulfoxide. It is also used in the formulation for li injection.

Yet another feature of the invention is to provide a packaged composition for protecting and treating mammals against Tyciliasis. This includes preparations as defined above, together with indications for their use for protecting and treating diseases.

For therapeutic purposes, the compound of formula (1) or a salt thereof may be given in relatively large amounts, sometimes when the animal's body temperature is elevated and schithoontia appears, or at the time of late pathology.

The administration is then repeated daily for several days, for example 5 days. The total dose over this treatment period is preferably from 0.5 to 501119k, more preferably from 0.5 to 10/k.
g and most preferably a dosage of 1 to 5 μg/kg. As an alternative treatment, administered once or twice daily,
A total of 1° administration may be required.

For preventive treatment, for example when it is suspected that an animal has been infected, a compound of formula (1) may be administered at 1 dose on the first day.
from 5 to 9 days per week, and then repeat the same administration once weekly for up to 5 doses. Depending on the risk of infection,
0.2 to 5 μ/k19 may be administered per week. The period of prophylaxis can range from 4 to 20 or 120 days. Alternatively, the compound may be injected under the skin in a pellet with a relatively insoluble carrier in addition to a slow-release implant. As the pellet dissolves,
The active ingredient is released slowly over a period of, say, April.
A low level of prophylaxis is maintained, such as with the second dose.

In yet another aspect, a method of prophylactically or therapeutically treating bovine or ovine taiciliasis is provided. In this method, a compound of formula (i) or a pharmaceutically acceptable effective amount thereof is administered prophylactically or therapeutically to an animal infected with or likely to be infected with a pathogenic Theileri species. Administer directly. In particular, the method of treatment is accomplished using preparations or compositions containing compounds as defined above.

Furthermore, another feature of the treatment as defined above is the administration of a vaccine containing one or more live Theileria species or strains that act as effective antigens. To produce a vaccine for this purpose, Th
ejyleria species such as T, parVa(pa
rva ) and T, parva (lawrenc
ei ) (Radley, D. E., et al. (1975),
VeterinaryParallif;010g7
+ 51 60 ) of ground mites or other infected material (e.g. suspensions of cultured mammalian cells infected with Theileria or cultured mite cells or Theileria
It can be prepared from salivary tissues infected with Ia or their products or exudates. Conveniently, the dosage of said active compound will be 0.5 to 5 Tn97 of the host animal.
The vaccine should be administered from the vaccine injection port until 7 or 14 days after vaccination.

The first treatment thus consists of administration of a combination product which releases the antigen immediately, followed by administration of the active compound for 7 days or more. Following the first dose, 0
．． 5 to 5 meters? /kg weekly for 10 weeks.

Example A: Preparation of 4-t-alkylcyclohexanecarboxylic acid The carboxylic acid used in subsequent examples was prepared as follows.

1J4-t-butylcyclohexane-1-carboxylic acid,
4-t-Butylcyclohexyl acetic acid, and its pure cis and trans isomers, are available commercially or in the literature (J. Amer, Ohem.

Sac, 1970, 92.2800 and references therein).

1r-4-t-pentylcyclohexyl-1-callus-
4-t-pentylcyclohexyl-1-carboxylic acid was produced as follows.

Production of xyl-1-carboxylic acid 4-t-pentylcyclohexanone (49,2F)?
Dissolved in ether (200ml) and added sodium cyanide (24,46y) and water (30ml). The mixture was cooled to 0° C. and concentrated hydrochloric acid was added over 71 hours while stirring vigorously. The mixture was stirred for an additional 6 hours and left overnight. The mixture was washed with saturated sodium metabisulfite solution (2 x 200 ml) and the ether layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 54.0 y of cyanohydrin as a pale yellow oil.

Cyanohydrin (54, Of) was converted to anhydrous pyridine (70
mg) and anhydrous benzene (70 ml) and heated to 0°C.
Cool and stir. A solution containing phosphoryl chloride (90t, 4) in pyridine (83v) was added over 45 minutes. During this time, the temperature was maintained at 0°C.

The reaction mixture was heated to reflux for an additional 60 minutes. The mixture was allowed to cool, poured onto ice, stirred for 30 minutes, extracted with ether, washed with water, dried with sodium sulfate, evaporated to dryness under reduced pressure,
4-t-pentylcyclohex-1-en-1-nitrile. 48.41 and oily. 1-4-t-pentylcyclohex-1-ene-1-nitrile (48, Of )
'&, potassium hydroxide (23,3F) 'ax' solution contained in water (64 mg) and ethanol (,15
0-/) was added to the mixture.

The mixture was heated to reflux for 72 hours, cooled on ice, and diluted with water (175+
alV) and acidified with concentrated hydrochloric acid. The precipitated colorless solid was filtered out, washed with water, and dried. The solid material was distributed between ethyl acetate and sodium hydroxide (2N), and the base layer was acidified with concentrated hydrochloric acid.

The resulting colorless solid was collected, washed with water, dried, and 4-t-
Pentylcyclohex-1-ene-1-carboxylic acid, 5
C4-t-pentylcyclohex-1-ene-1-carboxylic acid (33,51), melting point 123-1256C, was dissolved in ethanol (275m) and 10% palladium on charcoal. (1,OF) added,
The mixture was hydrogenated at 10 atmospheres to absorb the theoretical amount of hydrogen. //l! The colorless filtrate was evaporated to dryness under reduced pressure to obtain 4-t-pentylcyclohexyl-1-carboxylic acid. 27. OP (cis/trans mixture)
.

Preparation of 1-carboxylic acid A cis/trans mixed acid (12F, prepared by method a) was heated in a steam bath in the presence of concentrated sulfuric acid (60d) for 16 hours. The reaction mixture was cooled and poured into ice, producing a black solid. Remove the solids, knead with light petroleum (40-60℃),
Most of the solid beggars were dissolved. Petroleum extract is treated with charcoal powder,
Evaporation to dryness under reduced pressure gave 1-carboxylic acid. 5.7F,
Melting point 92-100℃, 95-9 from NMR spectrum
7% pure trans isomer.

Example 1 Preparation of 2-() lance-(4-t-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone A, 1-) lance-(4-t-butylcyclohexyl)
-Production of acetic acid 4-t-butylcyclohexane-1-carboxylic acid (50
y, mixture of cis and trans isomers), potassium hydroxide (150y) and ethylene glycol (500y)
ml) '11 It was heated under reflux.

The reaction mixture was poured onto crushed ice (2000F) and acidified with concentrated hydrochloric acid to remove the resulting white color. The mixed product was dissolved in ethyl acetate, the aqueous layer was removed, and the organic layer was dried over magnesium nitrate. The solvent χ was distilled off under reduced pressure to give a white solid Z. When this was reconstituted from toluene, 1-trans-(4-t-butylcyclohexyl)-carboxylic acid (30.9F, melting point 172-174°C) was obtained.

Dissolve this 1-trans-(7I+, -t-7" methylcyclohexylnocarboxylic acid (35P)'& anhydrous ether (250rig), and add this solution to hydrogenated IJ
Thiumium aluminum (7,3F)'Y was added slowly to the solution in anhydrous ether (200IIIt) to maintain a gentle reflux. After the addition was complete, the mixture was heated to reflux for an additional 1.5 hours.

The reaction mixture was then cooled in a water bath and treated with water-cooled hydrochloric acid (2N,
Add 200 liters of water, divide the water layer into 7, and add ether (100 liters).
Wash with m), combine with ether extract and dilute hydroxide)
Wash with IJum, water, dry over magnesium sulfate, and remove the solvent under reduced pressure.

It gave a 28F colorless oil. The above 1-trans-<4
-t-butyl-cyclohexyrune-methanol (28,
9') Dissolved in dry acetonitrile (330ml), added anhydrous lithium bromide (28,,7y) and chlorotrimethylsilane (44,5,P)'Y, the mixture was
The mixture was heated under M flow for 0 hours. The reaction mixture was allowed to cool, and the solvent was distilled off under reduced pressure. The residue was dissolved in ether and water (100
+t/J, 10 t Sodium bicarbonate (100 t/J, water (
100 m/), dried with Mg5U4, and the solvent was distilled off under reduced pressure. The crude product was subjected to column chromatography, and
15.5 jl of oily 1-trans-<4-t-'butylcyclohexylnomethane bromide was obtained.

The above bromide (15F'), sodium cyanide (4,8,3
In addition to step y), it was kept at room temperature for one night or so. The crude reaction mixture was diluted with water (250 tl) and extracted with ether (2 x 20
0d) did. Combine the organic layers and wash with water 6×100m1
Then, dry Mg, 8 (J4), remove the solvent under reduced pressure,
1-trans-(4-t-butylcyclohesyl)methanenitrile (10.5 fl) was obtained as a colorless liquid.

1-trans-(4-t-butylcyclohexyl)
-Methane uni 1, linol, (10!I
1) Lamb (20y),
Ethanol (200FIe) and alcohol (50ml
) ``a terror'' Heated and refluxed for 5 hours.
) and extracted with ethyl acetate (100F).The aqueous layer was made acidic with hydrochloric acid and extracted with ethyl acetate (2 x 10.
0m1) 'L, to. Combine the organic layer and wash with water 20
0 ml), MgE+04 dried C solvent was distilled off under reduced pressure, the residue was kneaded with cold water, and 1-trans-(4-
tert-Butylcyclohexyl]-vinyl acid (9,5y, melting point 96-95°C).

B, Preparation of 2-() lance-(4-t-butylcyclohexyl)megl]-6-hydroxy-1,4-naphthoquinone 2-chloro-1,4-naphthoquinone (960 g), 1-
) lance-(4-t-putino-2-cyclohexyl) vinegar e
< 990719, J, Amer, as above
Chern.

Soc, 1970, 92.2800) and silver nitrate (250"!)) in acetonitrile (9-) was vigorously stirred and refluxed to give persulfuric acid 'an-i = A < 5. .Oy ) w water (12,
The solution contained in e) was added dropwise over the course of 1 hour. The mixture was allowed to flow for an additional hour, cooled on ice, and the resulting yellow solid was collected and washed with water. The solid was extracted with 7 hot ethyl acetate and cooled to give 2-() lance-(4-sheptylcyclohexyl)-methyl)-3-10-1,4-naphthoquinone. MA 154-156”On NMR
The spectrum showed structure Z of 2-[trans-(4-t-butycyclohexyl)methyl-3-chloro-1,4-naphthoquinone. It was also shown that it is 100% trans isomer. Melting point is 154-156°C.

A solution containing ``1'' of chlorquinone (6y) obtained as above in ``1'' dimethoxyecune (60 ml) and water (60 yd) was heated to reflux, and potassium hydroxide (
6,0! ) '2 Water (60ml) Etc included'f
The f'f solution v2i was added dropwise over a period of 10 minutes.

After refluxing for an additional 15 minutes, the mixture was rapidly cooled to room temperature and acidified with acetic acid. The resulting bright yellow solid Y was collected, washed with water, and dried to obtain 2-[)lans-(4-t-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone. Melting point: 180-182 °C - Naphthoquinone is treated with 1-cis-(4-t-butylcyclohexyl)-acetic acid, and the resulting chloroquinone is hydrolyzed to form 2-[cis-4-t-butylcyclohexyl]
methyl)-3-hydroxy-1,4-naphthoquinone was obtained. Melting point 124-125'00 2-()trans-(4'-t-<butylcyclohexyl)methyl)-1-hydroxy-1,4-naphthoquinone A, 1-trans(4-t, -<butylcyclohexyl)methyl Preparation of cyclohexylene acetic acid Trans-t-pentylcyclohexane-1-carboxylic acid (8,02), dichloromethane (34,7 ml) and thionyl chloride (17,77 fl) were stirred at room temperature for 22 hours. The reaction mixture was evaporated under reduced pressure to a black residue. This is distilled under reduced pressure and trans-t-
Pentylcyclohexane-1-carboxylic acid Rola ``1
I got it. 7.0510i'a point 107-110°/0
, 5 n, a 11g0-Arsenic acid chloride was added dropwise to a solution containing diazomethane ether at 0°C over 60 minutes, and the solution was cooled to 7. *Leave it overnight.

For medical use, excess solvent was distilled off to obtain the corresponding diazoketone. The yellow oil (6-81) was mixed with octopus 8-water methanol (
A solution containing silver benzoate (0,45%) and triethylamine (7 vJ) was added with stirring. The solution was heated under reflux for 1 hour, allowed to cool, the charcoal powder was evaporated, and the furnace liquid was evaporated to dryness under reduced pressure. The residue was distilled to obtain trans-t-pengelcyclohexylmelal acetate. Boiling 494-100'C70, 2mm)]
g, ) >Nosu-1,'-”' 7N/Chlohequinlumedyl acetate (5,6y) ' was dissolved in methanol (11 mg), and sodium hydroxide (1,0
81) Add a solution containing 1 salt layer to 2 water (5 ffg),
'The reaction mixture 1 was stirred overnight at a cold temperature. The reaction mixture was diluted with water (50 mlV) and extracted with ether. The aqueous phase was acidified with warm hydrochloric acid and extracted with ether. The ether extract was dried over magnesium chloride and evaporated under reduced pressure to form an oil. 1-trans-(4-t-pentylcyclohexane) acid resistance (obtained 2,O), B, 2-[trans(4/-t-pentylcyclohexylmethyl)-3-hydroxy-1,4-naphthoquinone Production of 2-chloro-1,4-naphthoquino/'(0,95y),
1-) U, :/Sue (4-1 nipentylcyclohexyl) -D'5m (1,OS') Oyohinitrate m*J
4 (,0,1751) care ten toni one lil (1,5,I+/) Vko 3” ff
Cut the kelp in half, heat to reflux, and add ammonium persulfate (1,7
J') A solution containing 1-dihydride in 2-water (6 ml) was added over 1 hour. The mixture was heated at reflux for 1 hour, cooled with water and extracted with ether. The ether extract was washed with water, dried over magnesium sulfate, and evaporated to give 2-[trans-
(4'-t-pentylcyclohexyl)methyl)-3-
Chlor-1,4-naphthoquinone was produced. 700■.

Chlorquinone (700~) Y methanol (2
Dissolve potassium hydroxide (70D 7) in 7ml of potassium hydroxide (70D 7) by heating to reflux for 10 minutes.
Y droplets of the solution contained in the solution were added. After refluxing for an additional 15 minutes, the mixture was immediately cooled to room temperature and acidified with concentrated hydrochloric acid. r
The No. 1 compound was extracted with achloroform and thoroughly washed with water. The organic extract was dried over magnesium silicate and evaporated to an oil under reduced pressure. Chromatographed on silica gel, eluted with toluene, recrystallized with acetonitrile, 2-[trans-
(4'-t-pentylcyclohexyl)methyl]-6-
Hydroxy-1,4-naphthoquinone was obtained. 150 da.

Melting point 132-135°C.

Example 4 2-Ctransyl(4-tert-butylcyclohexyrunmethyl)3-hydroxy-1,4-naphthokyyy, which can be prepared as follows:
April 1 amount - dimethyl sulfoxide 10ni! castor oil
Example 5 with 100 Hayakeibu Water-based & Irrigation 1. Prepared as if it were a liquid.

2-(tra-7s(4-t-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone
1.00 parts by weight Neosy1
16.00 iOkibe Bentonite 3.20
Parts by weight Glycerin 15.00 Parts by weight Sodium benzoin L D 0.3h
M part BeValoia /2
1.00 N Okibe Thymol 0
．． 04 parts by weight 100, OD Example 6 The finely divided grains can be mixed to form a Saldo block.

2-(trans-(4-t-butylcyclohexyl)methyl-6-hydroxy-1,4-naphthoquinone (0,
54 parts by weight) Sodium chloride (99.5 parts by weight) The mixture is pressed into blocks.

Example 7 The following pastes may be prepared.

2-(trans-(4-t-butylcyclohexyltmethyl)-3-hydroxy-1,4-naphthoquinone
3. ON Okibe Tragacanth Rubber 4. Oi Okibe Bevaloid
35/3 1. ON Okibe Nipag
in "M' [1.1 parts by weight Glycerin 19.0 parts by weight Water 72.9 parts Example 8 Prepare a solution for subcutaneous injection by polymerizing as described above.

Trans-(4-t-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone
4.5 parts by weight Methocel
2. OMi weight part ipag
in “M” 0.1 parts by weight water 96.4
1 part 100.0 Example 9 A solution for intramuscular injection can be prepared by mixing as follows.

2-Ctrans-4-t-butylcyclohexyl)methyl-6-hydroxy-1,4-naphthoquinone

9.5 parts by weight dimethyl sulfoxide
19. ON amount! sorbitan monooleate
4.5ii parts corn oil 6
7.0 parts by weight Example 10 The following pour 1 formulation was prepared.

2-C trans-(4-t-butylcyclohexyl)methyl-6-hydroxy-1,4-naphthoquinone
5 parts by weight N-methyl-pyrrolidone 48.3 parts by weight Tween 80
2 Nit part 5pan 80
4.7 parts by weight Mig17018
12 40 * fit part 00 Example 11 0-Activity R = 0H30 Formula (Effect of compound 11
6-cyclohexyl-1,4-naphthoquinone and comparison are also shown. Cultures of bovine gonorrhea cells infected with T. parva macroschizont crotch were treated with various degrees of 2-[trans-(4-t-butylcyclohexyl)methyl-6-hydroxy-1, 4-naphthoquinone and 2-hydroxy-6-cyclohexyl-1,4-
It was incubated for 48 hours in the presence of naphthoquinone.

The culture was cultured without any other drugs as a control, and the compound was tested in a 4-fold dilution series, and Bl) b 04i1a was added. Each compound was repeated at least twice. j4
jDbO suppresses infection of Sugitzont-infected cells in culture;
During incubation for 48 hours, the 5 C of the untreated control decreased to 1% of the untreated control (1 Da/It). i)'f
', parva 'i'', annuLtaR=C
H.

Example 12 T, parva K sentence 1j Ru in vivo 2 antiquity 2-
[Effect of trans-(4-t-butercyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone,
A comparison is shown with 2-hydroxy-6-cyclo-\xyl-1,4-naphthoquinone, a known anti-Theileria agent.

Purebred Friesian castrated male calves weighing 180-250 Kf and negative for antibodies against T. parva were given T.
stabilize parVa
Inoculated subcutaneously with 1.0 m of 2-[trans-
(4-t-butyl-cyclohexyl)-methyl)-3-
Hydroxyl 1,4-naphthoquinone and a similar formulation of 2-hydroxy-6-cyclohexyl-1.4-naphthoquinone were injected subcutaneously into each group of cows.

The recovery status compared to the control is shown in Table 2.

Table 2 Quinone dosage 2o-7,
5my/Drop crew head weight Z 5 5
Number of animals alive on day 528 0 5
5 Days to treatment a7.4±1.47
5.0+, 0.45 days until death 9.2±1.
46 M-Mild Moderate S-Severe R-Concordance F16 'I', in vivo activity against annulata 115 to 140 to body l @ Jersey calf, T
, H1eear strain of P. annulata was infected by injection of 0.8 ml of stabilizer prepared by dunnization. 12 days after infection, 2-[trans-(4-t
-Butyl cyclohexyl methyl 6-hydroxy 1,4-naphthoquinone (formulation of Example 9) was injected into the neck muscle. Table 6 shows the condition of each group and pair Jrt4 after treatment. .5'lf/'lr 1.25"P
/”p 8 numbers until fever 10 11
12 11 I have had a fever since the treatment started on the 12th day. 0 0 0 4
Four consecutive days of attorney: Asa Tori, Akira, and other four procedural amendments (voluntary), June 31, 1980, Commissioner of the Japan Patent Office, 1, Indication of the case, 1981: l'rKi 1, No. 181200. ,;2
, Name of the invention: Preventive and therapeutic agent for Taiciliasis 3, Participant with Sodeichi 1'l- I7 Applicant 4, Agent 5, Date and month of SodeiE order 8゜ Contents of amendment As shown in the attached sheet (1) Amend the claims as shown in the attached sheet.

(2) In the specification, page 18, lines 8 to 10, "There is a cyclohexyl-providing compound..." is changed to "As a cyclohexyl-providing compound, the corresponding substituted cyclohexenyl carbon zero can also be used. .” is corrected.

(3) In the same book, in the bottom two lines of page 19, ``hydrolyzed in situ'' is corrected to ``hydrolyzed on the spot''.

2. Claims (1) A compound of 1 to 10 represented by formula (1) (wherein R is a C alkyl group) or a pharmaceutically acceptable salt thereof with a carrier acceptable in the veterinary field. Veterinary preparations also included.

(2) The preparation according to claim 1, wherein R in the compound of formula (1) is a straight-chain alkyl group.

(3) The preparation according to any one of claims 1 or 2, wherein R in the compound of formula (I) is a straight-chain a alkyl group of 1 to 4.

(4) The preparation according to any one of claims 1 to 6, wherein R in the compound of formula (1) is methyl.

(5) The preparation according to any one of claims 1 to 6, wherein R in the compound of formula (I) is ethyl.

(6) The preparation according to any one of claims 1 to 5, wherein the compound of formula (1) is in the form of a cis/trans mixture.

(7) The preparation according to claim 6, wherein the isomer ratio of the compound of formula (1) is about 1:1.

(8) A formulation according to any one of claims 1 to 5, wherein the compound of formula (1) is in substantially pure trans isomer form.

(9) A formulation according to any one of claims 1 to 5, wherein the compound of formula (I) is in substantially pure cis isomer form.

(In the formula, R is 01-1o alkyl group) In producing the compound represented by (,1 formula (If) (in the formula, R is as defined above), the compound of (,1 formula (If) (wherein R is as defined above)) or (formula or (C) converting a compound of formula (1v) in which R is as defined above and or is a halogeno group; or hydrolyzing the compound in which R is as defined above or oxidizing the compound in which R is as defined above and R is hydrogen, or (fJ formula (■) where R is as scanned above) with a cyclohexylmethyl donor to optionally convert the group into a hydroxy group, or ( 1) Method for producing the compound.

1U(Q), wherein the substituted cyclohexyl acetic acid containing H3.

02) A compound represented by formula (11) (wherein R is a 0□-1o alkyl group, and R is halogeno, acetoxy, benzyloxy, or a 0□-4 alkoxy group).

Claims (1)

[Claims] (11) A compound having the formula (1) (wherein R is a cl-10 alkyl group) and a pharmaceutically acceptable salt thereof. (2) R is a straight-chain alkyl group; A compound according to item (1) above. (3) The compound described in (1) above, wherein R is a linear cto'4 alkyl group.
Or the compound described in section (2). (4) The compound according to any one of items (1) to (3) above, wherein R is a methyl group. (5) The compound according to any one of items (1) to (3) above, wherein R is an ethyl group. (6) The compound according to any one of the above items (1) to (5) in the form of a cis/trans mixture. (A compound according to item (6) above, in which the ratio of isomers is about 1:1. (8) Any one of items (1) to (5) above, which is essentially in the form of a purely trans isomer. (9) The compound as described in (9) in essentially pure cis isomer form.
The compound according to any one of items 1) to (5). QOI The above (1) used for therapeutic treatment of animals.
) to (9). 01) The compound described in Item 101 above for use in the treatment or prevention of Theileria infection. Q21 The compound described in Item 001 above for use in the treatment or prevention of Theileria infection. Q3) T, annulata or T, par
2. A compound according to item 02 above for the treatment or prevention of infection with P. va (parva). A veterinary formulation comprising a compound of the formula ([) together with a veterinarily acceptable carrier therefor. (15) (a) converting a compound of formula (If) (wherein R is a C1-1° alkyl group), (b) formula (m) (wherein R is 01-10 hydrolyzing a compound of formula (C1 (I
V) converting the compound of formula (V) (in formula 17, R is a 1-1° alkyl group); To oxidize the compound of the formula (Vlb) RICH3 (wherein, R is an 0N-No alkyl group and R1 is hydrogen);
1) react with a cyclohexylmethyl donor containing a compound H3 (wherein R1 is a halogen, a hydroxy group, an acetoxy group or an alkoxy group) and, if desired, R1 is a hydroxy group. (g) Formula (■) (However, in the formula, R is a 01-0゜゛r alkyl group, and R1
A method for producing a compound of formula (1), which comprises converting a compound of formula (1) as defined in formula (1) or a benzyloxy group. The above 0 is a substituted cyclohexyl acetic acid containing a bond.
5) How to define gong. (I7) Formula (~'l1l) (In the formula, R is as defined in any of the above items (1) to (9), and R1 is a halokene, an acetyloxy group, a benzyloxy group, or C1-4 alkoxy group).