JPS62205043A - 9, 10-dihydro-phenanthrene derivative and manufacture - 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 novel 9,10-dihydrofena/tren bait conductors, particularly 9,10-dihydro-nanthrene derivatives, processes for their preparation and pharmaceutical compositions containing them. , relating to the proboscis.

The compounds of the present invention have the general formula 0): 8s R1 [wherein R1 is a) carboxy; b) esterified carboxy; hydrogen or 01-C6 alkyl, or 14a and Rb, together with the nitrogen atom bonded to them, may optionally form another heterozygote selected from oxygen, sulfur, and nitrogen (however, this additional nitrogen atom may contain a water-based atom or a a C6 alkyl, pyridyl or phenyl group), or
1-C6 alkyl, A is a 02-C6 alkylene group, and Ra and Rb are as defined above; R2, R3, R
4 and R5 are each the same or different and are hydrogen;
halogen, 01-C6 alkyl, 03-C4 alkenyloxy or 01-C6 alkoxy, and R1
is -COOH, -COOCH3, -COOC2H5, -
R if CONH2 or -CON(CH5)2
2, at least one of R3, R4 and R5 is other than hydrogen] and a pharmaceutically acceptable salt form thereof.

The present invention also provides suitable carriers and/or diluents, and (I5 as a component of formula (1): in which R1 is: a) carboxy; b) esterified carboxy; different from hydrogen or C1-C6 alkyl, or Ra and Fib together with the nitrogen atom to which they are attached optionally further heteroatoms selected from oxygen, sulfur and nitrogen (but this addition hydrogen atom or CI-06 alkyl,
pyridyl or phenyl group), A is a C26 alkylene group, and Ra and Rb are as defined above; R2,
Each of RlI, R4 and R5 is the same or different and represents hydrogen, halogen, 01-C6 alkyl, 03-C
4 alkenyloxy- or C1-06 alkoxy] or a pharmaceutically acceptable composition thereof.

The present invention also includes within its scope isomers, stereoisomers and optical isomers of the compounds of formula (1) and mixtures thereof;
and all possible substitute products and metabolic precursors or biological precursors.

The halogen atom is preferably chlorine or bromine.

Alkyl, alkylene, alkenyloxy and alkoxy groups are branched! 1ilk'! Or it can be the basis of Zhizhen.

A C1-06 alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, S-butyl or t-butyl, preferably methyl or ethyl.

The C3<4 alkenyloxy group is preferably allyloxy.

C1<6 alkoxy groups are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy, preferably methoxy, ethoxy or propoxy. Alkylene group A includes C2-06 alkylidene, with C2-04 alkylene chains being preferred. Ra
and Rb together with the nitrogen atom to which they are bonded form a saturated heteromonary, this is e.g. It can be a 5- or 6-membered heterocyclic ring, where if the heterocyclic ring is piperazine, it is unsubstituted or t! can be substituted, preferably with O1-C4 alkyl, pyridyl or phenyl.

When R1 is an esterified carboxy group, it is preferably a -COXFLy group [wherein or -0- or -8- and R7 is unsubstituted (where R
a and Rt) are as defined above), more preferably -COXR'7 group [wherein X is as defined above and R17 is not yet (but R'a and R'
t) are each independently hydrogen or 01-C4 alkyl, or R'a and R'b together with the nitrogen atom to which they are attached represent pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine. , where this bi is a ``replacement'' or ``c''.
1-c 4 alkyl, pyridyl or phenyl) by! It is a C1-C4 alkyl group which is highly favored.

The esterified carboxy group is particularly preferred, and R″a and R″b are each independently hydrogen or C1
<4 alkyl or together with the nitrogen atoms bonded thereto form pyrrolidine, morpholine or piperazine, where piperazine is optionally 01
~C4 alkyl or pyridyl).

The substituent pyridyl which can be attached to either the piperazine chain or the alkyl chain is 2-13- or 4-pyridyl, preferably 2-pyridyl.

Pharmaceutically acceptable salts of compounds of the formula (2) include inorganic acids such as salt or sulfuric acid, or organic acids such as citric acid, w
5 relatives, malic acid, maleic acid, mantelic acid, 7 malgt
or methanesulfonic acid, or an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide or aluminum hydroxide, or an alkali gold W4 or alkaline earth metal carbonate or bicarbonate, or an organic base typically Organic amines such as lysine, triethylamine, brocaine, dibenzylamine, N-benzyl-β-
Includes salts formed with phenethylamine, N,N'-dibenzyl-ethylenediamine, dihydroabiethylamine, N-ethyl-piperidine, jetanolamine, N-methyl-glucamine, or tris-hydroxymethyl-aminomethane. be done.

As stated above, the scope of the present invention also includes pharmaceutically acceptable bioprecursors (also known as prodrugs) of compounds of formula (1), i.e. even those having a formula different from formula (1) above. However, it also includes compounds that are directly or indirectly converted into the compound of formula (1) in vivo when administered to humans.

Preferred compounds of the present invention are those in which R1 is a/) of the formula -COXR'7, where X is -0- or -
8- and R'7 is unsubstituted, or pyridine R'k) is independently hydrogen or 01-C4 alkyl, or R'a and R'b are bonded thereto. Together with the nitrogen atom, pyrrolidine, piperidine,
constitutes morpholine, thiomorpholine or piperazine, where the base is unsubstituted or
j -04 alkyl, which may be substituted by pyridyl or phenyl), and A, R'a and R'b is as defined above) and each of R2, R3, R4 and R5 is independently hydrogen, chlorine, bromine, 01-C4 alkyl or C1<4 alkoxy, and R1 is -COOCH3 or -COO
When it is C2H5, it is a compound of formula (1) in which at least one of R2, R3, R4 and R5 is other than hydrogen, and a pharmaceutically acceptable salt thereof.

Representative examples of the active ingredients of the compound W of the present invention or the pharmaceutical composition of the present invention are as follows.

9.10-dihydro-phenanthrene-9-carboxylic acid; 9.10-dihydro-7enanthrene-9-carvone #
2-NUN-dimethylamino-etherester; 9.10-dihydro-phenanthrene-9-carboxylic acid 2-N,N-dimethylamino-ethylthioester; 9.10-dihydro-7enanthrene-9-carvone M
, 5- N,N-dimethylamino-probyl ester; 9t10-dihydro-phenanthrene-9-carboxylic acid 2- N,N-diethylamino-ethyl ester; 9.10-'; hydro-7enanthrene-9-carvone r112-morpholino -Ethyl ester; 9.10-dihydro-7-enanthrene-9-carboy1g2- (pyrrolicin-1-yl)-ethyl ester; 9.10-dihydro-7-enanthrene-9-9-N-(2-
N,N-dimethylamino-ethyl)-carboxamide; 9.10-';hydrophenanthrene-9-N-methyl-N-(2-N,N-dimethylamino-ethyl)
-carboxamide; 9.10-dihydro-7enanthrene-9-N-(3-
N,N-dimethylamino-propyl)-carboxamide; 9.10-dihydro-phenanthrene-9-carboxylic acid 2-(2-pyridyl)-ethyl ester; 9.10-dihydro-9-[4-(2-pyridyl) )-Piperazine-1
-yl]-carbonyl-phenanthrene; and their salts which are pharmaceutically Ff.

Compounds of formula (1) and pharmaceutically Wf-treated salts thereof may be prepared by the following method, namely: (wherein R1,
or B) a compound of formula (III): (wherein R1, R2, R5, R4 and R5 are as defined above) or a salt thereof; or C).
Formula (■): A compound of formula (1) in which R2, RlS, R4 and R5 are as defined above is reacted with C, -Cl, alkyl alcohol or 01-C6 alkylthiol.
) (wherein R1 is c , -c 6 alkoxycarbonyl or 01-C6 alkylthiocarbonyl), or D) The above fixed compound of formula (N) is hydrolyzed to form a compound of formula (凰) (where R1 is either carbamoyl or a free carboxy group depending on the reaction conditions) and/or, if desired, a compound of formula (I) Converting to a compound of formula (1) and/or
converting the compound of formula (1), if desired, into a pharmaceutically acceptable salt thereof; and/or converting the salt of the compound of formula (0), if desired, into the free compound; and/or If desired, the isomer mixture of the compound of formula (1) is separated into individual isomers.

The production of the compound of formula (1) and its salt by this method includes B
1 is -COOH, -COOCHx, -COOC2H5
, -CONH2 or 100N(CH3)2 and R2
, Rs 2 , R4 and R5 all constitute a part of the present invention, except for compounds and salts thereof.

The salts of the compounds of formula (II) can be, for example, alkali metal salts or alkaline earth metal salts, the sodium or potassium salts being preferred.

For example, reduction of the compound of formula (11) or a salt thereof can be carried out using OC
by treatment with sodium or aluminum amalgam in a solvent such as an aqueous lower alkyl alcohol, aqueous dioxane, aqueous tetrahydrofuran, or an aqueous ether at a temperature ranging from In particular, reduction of compounds of formula (1) in which R1 is carboxy is carried out using aqueous NaOH or KOHO at room temperature.
This can be done by treating a sodium hydroxide amalgam.

Alternatively to the above method, the reduction of compound 111J of formula (n) may be carried out by treatment with lithium or sodium in reconstituted ammonia.

The compound of formula (Ill) may be in the cis or trans form or a mixture thereof.

The speed ratio of the compound of formula (lit) is, for example, from OC to about 6D.
It can be carried out by irradiation with a 500 nm light in a solvent such as benzene, lower alkyl alcohols, water and mixtures thereof under an inert atmosphere at a temperature in the range of 100 to 200 ℃.

The reaction of a compound of formula (fV) with a C1<6 alkyl alcohol or a C1-06 alkyl thiol can be carried out in a conventional manner, for example in the presence of an M* medium such as H2SO4, HCt or p-toluenesulfonic acid, from about fL temperature range.

Hydrolysis of compounds of formula (■) to obtain compounds of formula (1) in which R1 is carbamoyl is carried out according to well-known methods, e.g.
treated with 5% H2SO4 or from about 600 to about 10
It can be carried out by heating with water in the presence of a copper bed as catalyst under an inert atmosphere at a temperature of 0°C.

Alternatively, hydrolysis of the compound of formula (IV) to obtain a compound of formula (1) in which R1 is a free carboxy group can be carried out according to known methods, e.g. , C1<2 alkoxyethanol, cl-c4 alkyl alcohol or mixtures thereof, with a basic reagent preferably aqueous NaOH or K
This can be done by treatment with OH followed by acidification.

Compounds of formula (1) can also be converted into other compounds of formula O) by known methods, as mentioned above. for example,
The compound of formula (1), in which R1 is an esterified carboxy group, can be prepared using, for example, sodium hydroxide or potassium hydroxide, in a solvent such as water or a lower Hh II/J group alcohol, from room temperature to about 1500 ml. By basic hydrolysis and subsequent acidification operating at a range of temperatures, an alternative formula (1) in which R1 is a free carboxy group
can be converted into a compound of or, for example, water, or t
It may also be carried out by acid cutting in a solvent such as a mixture of aliphatic alcohols and water or dioxane and water at temperatures ranging from room temperature to 11 current temperatures. The reaction may also be carried out, for example, by treatment with a lithium halide, preferably lithium bromide, in a suitable solvent such as dimethylsulfoxide, hexamethylphosphorotriamide or dimethylformamide, preferably dimethylformamide, at a temperature above 50C. You can also do that.

Furthermore, for example, the formula (
The conversion of a compound of formula (1) to another compound of formula (1) in which R1 is an esterified carboxy group having the formula -COXR7, where X and R7 are as in the above-mentioned table, can be carried out for example by a) in the absence of a solvent or in an inert organic solvent such as benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride or In tetrahydrofuran, for example, the desired acid chloride such as oxalyl chloride, thionyl chloride, PCl5, PCLs 1 f= is POCl2
b) converting the obtained halocarbonyl derivative to R7-XH (wherein R7 and X are as defined above). ) in a solvent which may be the same alcohol or an inert solvent such as benzene, toluene, etc. at a temperature in the range from about OC to about 600 ℃, if desired in the presence of a base such as triethylamine. The reaction is carried out in xylene, dioxane, dichloroethane, methylene chloride or tetrahydrofuran.

Furthermore, compounds of formula (1), for example where R1 is a free carboxy group, may be prepared by combining reactive derivatives of such carboxylic acids, such as acyl halides, preferably chlorides or mixed anhydrides, with the formula HNRaRb or HN(R6)-A -NR
R1 is -CONRaRb or 100N by reacting with an amine having aRb (A%Ra, Rb and R9 are as defined above), respectively.
R6-A-NRaRb group (A %Ra %Rb
and R6 are as defined above). This reaction can be carried out in the presence of a suitable basic reagent such as triethylamine, if desired, in the range of from about OC to about 1000 Dioxane, at a temperature of
Tetrahydrofuran, dichloromethane, chloroform or pen.

It can be carried out in an organic solvent such as zene.

The optional salt formation of the compounds of formula (1) and the conversion of the salts into the free compounds and the separation of isomeric mixtures into the individual isomers can also be carried out by customary methods.

For example, separation of optical isomers involves salt formation with an optically active base or compound, followed by fractional crystallization of the diastereoisomeric salt, followed by optically active isomer! ! 1! Alternatively, it can be carried out by recovering the bases respectively.

The compound of formula (U) is, for example, the Pschorr of the compound of formula (V): J [wherein R1, R2, R3, R4 and B5 are as defined above]
This can be done by cyclization.

Cyclization of compounds of formula (V) is described, for example, in rJ, Med.

Chem, J, 21.395 (1978).

The compound of formula (lft) in which R1 is carboxy is, for example, an aldehyde of formula (Vr); [wherein R2 and B3 are as defined above] and a compound of formula (■): [wherein R4 and R5 are as defined above] with arylacetic acid.

The threshold reaction between an aldehyde of formula (Vl) and a compound of formula (■) is described, for example, in D-Med, Chem, J 21
e 395 (1978), for example, by heating to reflux in acetic anhydride in the presence of triethylalmon.

Compounds of formula (2) in which R1 is not carboxy can be prepared, for example, by starting from the corresponding compounds of formula (1) in which R1 is carboxy and according to synthetic methods well known in the art. From the compound, R1 is b
), C) and d) can be produced according to the methods described above for the conversion of 20) to other compounds.

The compound of formula (IV) is, for example, formula (■): [wherein R2
, Rs, Ra and R5 are as defined above] by chemical transformation of the compound of formula (ill) according to the same experimental conditions as described above for the cyclization of the compound of formula (ill).

The compound of formula (V) is a compound of formula (■); 'QJ [wherein R1, R2, R3, R4 and R5 are as defined above], for example, by 5net2. 37 in 2H20 and acetic acid
% HCl and reduction.

The compound of formula (■) can be prepared, for example, by combining the aldehyde of formula (Vl) and the compound of formula (X): [wherein R4 and R5 are as defined above] in ethanol at a temperature of from room temperature to about 1,000 °C. , methanol, dioxane, dimethylformamide in the presence of a basic condensing agent such as sodium ethoxide, sodium methoxide, sodium hydride.

The compound of formula (■) can be prepared, for example, by heating the aldehyde of formula (M): [in which R2 and R3 are as defined above] with the acid of formula (■), and then preparing the compound of formula (III). can be produced according to the synthesis method described above.

Compounds of formulas (Vl), (Vl), (X) and (XI) can be obtained by synthetic methods well known in the art. If there are groups in the novel compounds of the present invention and their intermediates that require protection before being subjected to the above-mentioned reactions, they may be protected prior to the reaction being carried out according to methods well known in organic chemistry. However, the theory can be confirmed.

The compounds and pharmaceutical compositions of the invention possess immunomodulatory and antiviral activity.

Their immunomodulatory activity may be due to the intraperitoneal route (i, p
-) suboptimal ovine red blood cell cells (8R
BC) by its ability to alter antibody responses fermented in mice.

2 as an antigen to 10 female CD-1 strain 79s per #1.
X106SRBC were injected intraperitoneally. The compounds and compositions tested were administered at two doses, 2 hours prior to challenge.
That is, 1 dose was administered intraperitoneally to 9 bodies in 50 and 5119/.

Control group mice received 5RBC and saline instead of the compound. After 68 days, mice were sacrificed and antibody titers in serum against 5RBC were determined by Williams C.A.
Methods in Immunology and
Immunochemistry J, C, A, Will
iams and M, W.

Chase, published by Academic Press;
Vol. 11.152 (1977),
It was measured.

The antiviral activity of the compounds and pharmaceutical compositions of the invention has been evaluated, for example, against influenza in mice.
bent.

Influenza virus AP in # of cp-1 macus
Intranasal infection with R8 strain was performed. Test compounds and compositions were administered by various routes such as intraperitoneally, subcutaneously or orally.

The efficacy of test compounds and compositions against influenza virus was evaluated based on the number of H lesions in drug-treated animals and control groups.

Because of their high therapeutic index, the compounds and pharmaceutical compositions of the invention can be safely used in medicine.

For example, the approximate LD of compounds of the invention and active ingredients in pharmaceutical compositions of the invention in mice.
so) was generally greater than V to 800 I1g/g when administered orally in increasing doses and measured 7 days after treatment. The compounds of formula (1) and pharmaceutical compositions of the present invention are useful in the treatment of transplant reactions, such as transplant reactions of the shogumi, bone marrow, skin and endocrine glands.

Other pathological areas where the immunomodulatory properties of these compounds and systemic compositions are therapeutically effective are neoplastic diseases, a#i and viral acute and 1! ! infections, and diseases characterized by immunological imbalances, such as congenital or acquired immunodeficiency and autoimmune diseases. This last category includes rheumatoid arthritis 1, systemic lupus erythematosus, and glomerular VM! Inflammation, vasculitis and blood diseases are treated. ■"
The treatment methods for the clinical syndrome of the disease must be adapted to the four symptoms of the disease.

In transplant and infectious diseases, the time of manifestation and clinical course are generally known, whereas the signs of immunological disorders are unknown and the clinical course is generally long and complex.

Therefore, therapeutic doses must be determined for each individual clinical case, taking into account the dependence on the route of administration.

For all conditions that require such compounds,
Oral administration is generally used.

For prevention of rejection and treatment of acute infections, parenteral routes, such as injections or infusions, are preferred. Oral or parenteral routes, such as intramuscular or subcutaneous routes, are preferred for hair removal.

For these purposes, the active ingredients of the compounds and pharmaceutical compositions of the invention may be administered, for example, at a dosage of about 0.5 to about 10% per day.
Can be administered orally in the range of +y/9 body weight.

For example, active compounds in the range of about 0.2 to about 5 my/K4 body weight can be used for parenteral administration.

Of course, these dosage regimens can be adjusted to obtain the optimal therapeutic response.

As mentioned above, the present invention comprises a compound of formula (1) in a pharmaceutically acceptable excipient (often a carrier or diluent).
Also included are systematic compositions containing the same.

The pharmaceutical acids of the invention are usually prepared according to conventional methods and administered in a pharmaceutically suitable form, e.g. solid oral forms are prepared together with the activated compound along with diluents such as lactose, dextrose, sucrose, etc. Cellulose, corn starch and potato starch, lubricants such as silica, Merck, stearin, magnesium or calcium, and/or polyethylene glycol, binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone. , disintegrants such as starch, alginic acid, alginates, sodium starch glycolate, effervescent mixtures, dyes, sweeteners, humectants such as lecithin, polysorbate, lauryl sulfate, and generally pharmaceutical It may contain non-toxic and pharmacologically inactive substances used in the formulation. Such pharmaceutical preparations can be manufactured by known methods, such as mixing, granulating, tabletting, dragee-coating or coating methods. Dispersions for oral administration can be prepared, for example, syrups, emulsions and suspensions.

Syrups may contain as carriers, for example sucrose, sucrose and glycerin and/or mannitol and/or sorbitol; in particular, syrups administered to diabetic patients may contain as carriers substances which are not metabolized to glucose or which are not metabolized to glucose, such as sorbitol. It can contain only substances that are poorly metabolized to glucose.

Suspensions and emulsions can be prepared using carriers such as natural gums,
It may contain agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol L.

Suspensions or solutions for intramuscular injection can be prepared by combining the active compound with a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, water, and a suitable stimulant if desired. It may contain a large amount of lidocaine.

Solutions for intravenous injection or infusion can be enriched with, for example, sterile water as a carrier, or preferably they can be in the form of sterile aqueous isotonic saline solutions.

The herbal medicine may contain the active ingredient together with a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The invention is illustrated by the following 5AM examples2; however, the invention is not limited thereto.

Example 1 To a suspension of sodium 7enanthrene-9-carboxylate ri (15t) in refluxing liquid ammonia, sodium metal (3,67r) was added in small pieces with stirring over the course of one hour. The deep red mixture obtained at this stage was stirred for a further 2 hours and then the ammonia was carefully evaporated. The residue was heated with ethanol (20 mt) and then dissolved in water (20 mt). Add this solution to 6
Acidified to 1 with 7% HC2 and extracted the precipitate with ether. Evaporation of the organic solution to dryness gave a gummy residue which was crystallized from CH2C42/n-hexane to give 9.10-dihydro-phenanthrene-
10.4F of 9-carboxylic acid was obtained.

m, p, 118-120C.

Niso, 10-, which produced the following compound by a similar process
dihydro-6-methyl-phenanthrene-9-carboxylic acid; 9.10-') hydro-6-methoxy-phenanthrene-9-carboxylic acid; 9.10-dihydro-6-methoxy-phenanthrene-9-carboxylic acid; and 9.10-dihydro-5,6-dimethoxy-phenanthrene-9-carboxylic acid.

Example 2 α-Phenyl-Cinnamon # dissolved in methanol (1t)
1 (0,5f) at 300 n under argon at room temperature for 20 h.
It was irradiated with m lamp. After evaporating the solvent to dryness under vacuum, the residue was crystallized from CH2C22/n-hexane to give 9
,10-dihydrophenanthrene-9-carboxylic acid0
．． 42f was obtained. m-p, 118-120C0 The following compound was manufactured by the same process.

9.10-dihydro-5-methyl-phenanthrene-9
-carboxylic acid; 9.10-dihydro-6-medoxy-7enanthrene-9-carboxylic acid; 9.10-dihydro-6-methoxy-phenanthrene-9-carboxylic acid; and 9.10-dihydroCm -5,6-dimethoxy -phenanthrene-9-carboxylic acid.

'iX, Example 3 9-cyano-9 in 2-methoxyethanol (20m)
, 10-dihydro-phenanthrene (5t) in water (2-
) and the solution was heated to reflux under nitrogen for 10 hours. After cooling, the solution was diluted with ice water (150d) and extracted with ethyl acetate. The organic layer was removed and the aqueous phase was acidified with 37*HCl to 1. The precipitate was filtered and washed with water until it became neutral, yielding 9,10-dihydro-7enanthrene-9-carvone [(4,8F). m, p.

117-119°C.

The following compounds were produced by similar steps.

9.10-dihydro-3-methyl-phenanthrene-9
-Carboxylic acid; 9.10-dihydro-3-methoxy-phenanthrene-
9-carboxylic acid.

Example 4 9-cyano-9,10-u hydro-phenanthrene (3
,01), n-propyl alcohol (1,811!g)
OjD: p-) Leuene sulfonic acid monohydrate < 2.8
51) was refluxed with stirring under argon for 6 hours. After cooling, the reaction mixture was diluted with ice water (50 mg) and washed.
Extraction was performed using ethyl n-acid. The extract was diluted with 10% Na
Washed with 2COs solution and then water and dried over sodium sulfate. This solution is evaporated to dryness under vacuum.9.
n of 10-dihydro-phenanthrene-9-carboxylic acid
-Propyl ester 2.4f was obtained as a pale yellow oil.

The following compounds were produced by similar steps.

9.10-'; hydrophenanthrene-9-carvone as narrow ethyl ester iPj and 9.10-dihydro-3-methoxy-phenanthrene-
9-Carvone is ethyl ester.

Example 5 9-cyano-9,1 in 851 H2SO4 (30d)
〇-Dihydro-7enanthrene (5,5?) was refluxed at 800 °C for 3 hours under argon. The solution was cooled and 300 ice cubes were poured on top. The precipitate of 9,10-dihydro-phenanthrene-9-carboxamide was filtered and washed with water until neutral. 2.8tSm, p, 226~8c
.

The following compound was obtained by a similar process.

9.10-uhydro-6-methyl-phenanthrene-9
-carboxamide; 9.10-dihydro-6-methoxy-phenanthrene-9-carboxamide strand Llo-:) hydro-6-methoxy-phenanthrene-9-carboxamide; and 9.10-dihydroC1-5,6-dimethoxy-phenanthrene -9-carboxamide.

*mExample 6 9.10-dihydro-phenanthrene-9-carvone f
f(4,!M) was suspended in thionyl chloride (50m) and kept at room temperature overnight. This solution was evaporated under vacuum. The residue from M was dissolved in 100 d of anhydrous dichloromethane and the resulting solution was added dropwise into a solution of morpholine (4,4 d) in 100 d of dichloromethane at 0.15°C.

After 1 hour the solution was washed with water, dried over sodium sulfate and concentrated to dryness under vacuum to give 9.10-dihydro-9.
-morpholinocarbonyl-7enanthrene 4.22 was obtained.

The following compounds were produced by similar steps.

9.10-dihydro-9-(pyrrolidin-1-yl)-
Carbonyl-phenanthrene; 9.10-dihydro-9-(4-methyl-piperazine-
1-yl)-carbonyl-phenanthrene and 9.10-dihydro-9-(4-(2-pyridyl)-piperazin-1-yl)-carbonyl-phenanthrene.

Example 7 9.10-dihydro-7enanthrene-9-carvone*
(3,2f) in thionyl chloride (30rnl) with M
After being kept at room temperature for 20 hours, the solution was evaporated under vacuum. The crude residue was dissolved in 80° of benzene and the resulting solution was added dropwise to a solution of N,N,N'-trimethylenediamine (1,4 m) in 80° of benzene at room temperature. After 60+ the solution was washed with water, dried over sodium sulfate and concentrated to dryness under vacuum to give 9,10-dihydro-
Phenanthrene-9-CN-(2-N,N-dimethylaminoethyl)-N-methylcoucarboxamide was obtained as a colorless oil.

The following compounds were produced by similar steps.

9.10-dihydro-phenanthrene-9-N-methyl-carboxamide; 9.10-dihydro-phenanthrene-9-N-ethyl-carboxamide; 9.10-dihydro-phenanthrene-9-N-(2-
N,N-dimethylaminoethyl)-carboxamide; 9.10-dihydro-7enanthrene-9-N-(5-
N,N-dimethylaminopropyl)-carboxamide; 9.10-dihydro-6-methyl-phenanthrene-9
-(N-(2-N,N-dimethylaminoethyl)-N-
Methylcoucarboxamide; 9.10-dihydro-3-methoxy-phenanthrene-9-(N-(2-N,N-dimethylaminoethyl)-N
-Methylcoucarboxamide; 9110-dihydro-6
-methoxy-phenanthrene-9-(N-(2-N,N
-dimethylaminoethyl)-N-methylcoucarboxamide; and 9.10-dihydro-3,6-dimethoxy-phenanthrene-9-CN-(2-NlN-dimethylaminoethyl)-N-methylcoucarboxamide.

Example 8 9.10-9 Hydro-7 Enanthrene-9-carboxylic acid (:l) was reacted with thionyl chloride (5,39) for 20 hours at room temperature, and then the solution was evaporated to dryness under vacuum. The residue was dissolved in inpropyl ether (40m) and 2-dimethylaminoethanol (2f) dissolved in inpropyl ether (401nt) and dioxane (15+d)! : Reaction was carried out for 3 hours by presentation. The solution was diluted with water (100 g), the organic phase was separated, washed with water and then evaporated to dryness under vacuum to give 2-N,N-u methyl 9,10-dihydro-phenanthrene-9-carboxylic acid. 1.7 t of aminoethyl ester was obtained as a colorless oil. n21℃=1.5861, NMR (CDCl2)
δp, p, m,: 2.18 (s) (6H, CR2
), 248), 5.95 (t) (IH, C-9 proton), 4.150) (2H.

C00C) (2-), 7.50 (m) (6H, c-1
, C-2, c-, 5, C-6, C-7 and C-S protons), 7.78 (m) (2H, C-4 and C-5
Proton) The following compounds were produced by the same process.

9eIG-'; Hydrophenanthrene-9-carvone #R2-N, N-diethylaminoethyl ester; 9.10-dihydro-phenanthrene-9-carvone f
i 5- N,N-dimethylaminopropyl ester; 9.10-dihydro-phenanthrene-9-carboxylic acid 2-morphodinoethyl ester; 9.10-') hydro-phenanthrene-9-carboxylic acid 2-(pyrrolidine −
1-yl)-ethyl ester; 9elQ-') hydro-phenanthrene-9-carvone [2-N,N-dimethylamine ethyl thioester; 9+10-', ;hydro-7enanthrene-9-carvone 1! [! 2-(2-pyridyl)-ethyl ester; 9
．． 10-dihydro-3-methyl-phenanthrene-9-
Carboxylic acid 2-N,N-dimethylaminoethyl ester; 9*10-u human o-3-methoxy-7 enanthrene-9-carboxylic acid 2-N,N-dimethylaminoethyl ester; 9.10-dihydro-6- Medoxy 7-enanthrene-9-carvone 1: R2-N,N-dimethylaminoethyl ester; and 9,10-dihydro-5,6-dimethoxy-phenanthrene-9-carvone@'l-N,N-dimethylaminoethyl ester.

Example 9 9.10-Dihydro-phenanthrene-9-carboxylic acid (1,6f) was suspended in thionyl chloride (5t) and kept at room temperature for 20 hours. The solution was evaporated to dryness under vacuum and the residue was treated with absolute ethanol (20m) at 500 for 6 hours. The bath was evaporated to dryness under vacuum and the residue was dissolved in ethyl acetate. The organic phase was washed with water until neutral and evaporated to dryness under Makabe.9.
1.42 of 10-dihydro-7ena/tren-9-carboxylic acid ethyl ester was obtained as an oil.

The following compounds were produced by similar steps.

9.10-dihydro-phenanthrene-9-carboxylic acid methyl ester; 9.10-dihydro-3-methyl-7enanthrene-9
-Carboxylic acid ethyl ester; 9.10-dihydro-3-methoxy-phenanthrene-
9-carboxylic acid ethyl ester; and 9.10-dihydro-6-medoxyphenanthrene-9-carboxylic acid ethyl ester.

Example 10 9.10-dihydro-7enanthrene-9-carvone M
(1,8r) in 0.5 N ethanol 8:NaOH(
16-). The solution was evaporated to dryness under vacuum and the residue was diluted with acetone (10-Omj). The precipitate was filtered to obtain 1.62 of 9,10-dihydro-phenanthrene-9-carboxylic acid sodium salt. m, p
, 230C (decomposition).

The following compounds were produced by similar steps.

9.10-'; Hydro-3-methyl-phenanthrene-
9-Carboxylic acid sodium salt; 9.10-dihydro-3-methoxy-phenanthrene-
9-carboxylic acid sodium salt; 9.10-dihydro-6-methoxy-phenanthrene-9-carboxylic acid sodium salt; and 9.10-dihydro-3,6-simethoxy-7enanthrene-9-carboxylic acid sodium salt.

Example 11 9.10-Dihydro-7enanthrene-9-(N-(2-dimethylaminoether)-N-methyl]-carboxamide (1,1t) in isopropyl ether (25m/)
) was added a stoichiometric solution of gaseous HCl in inpropyl ether (50 g). The precipitate was filtered and washed with isopropyl ether to give 9,10-dihydro-phenanthrene-9-1:N-(2-N,N-dimethylaminoethyl)-N-methyltucarboxami,
Hydrochloride 1? was gotten. m, p, 175c (decomposition).

The following compounds were produced using similar steps.

9.10-dihydro-phenanthrene-9-N-(2-
9.10-dihydro-6-methyl-phenanthrene-9
-[N-methyl-N-(2-N,N-dimethylaminoethyl)]-carboxamide salt modification: and 9.10-dihydro-6-methoxy-phenanthrene-9-[N-(2-N,N -dimethylaminoethyl)-N
- Methyltwocarboxamide hydrochloride.

Formulation Examples Formulation 1: Tablets (50 ■) Tablets, each quadruple 1150Q and containing 50 ml of active ingredient, were prepared as follows.

Composition (per 10,000 tablets) 9.10-9hydro-phenanthrene-9-carboxylic acid 500f lactose
710? corn starch
238g talcum powder
66? Magnesium stearate
1699.10-'; Hydro-7 enanthrene-9-carboxylic acid, lactose and half the corn starch were mixed and then the mixture was passed through a sieve with 0.5 wm openings. Cornstarch (18t) was suspended in warm water (180mj). The resulting paste was used for granulating the powder bed. Dry the granules and sieve size 1
．． Grind on a 4 m sieve, then add the rest of the starch, Merck and magnesium stearate, mix carefully and form into tablets using 8 m+ diameter bunches.

Intramuscular injection of AIJ 27 in sterile water or sterile standard saline (2-5-) at 9.10
-dihydro-phenanthrene-9-carboxylic acid 2-N
lN-dimethylamino-ethyl ester hydrochloride 50-1
An injectable pharmaceutical composition was prepared by dissolving 001g.

In a similar manner, injectable pharmaceutical compositions containing the compounds described in the previous examples were prepared.

Applicants for the crash license: Farmitalia Calguchi, Elva Nchieta, Bel Atsuioji and two others

Claims (1)

[Claims] 1) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is: a) carboxy; b) esterified carboxy; c) ▲mathematical formula, There are chemical formulas, tables, etc. ▼ groups, where Ra
and Rb are the same or different and each of hydrogen or C_
1 to C_6 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached optionally further heteroatoms selected from oxygen, sulfur and nitrogen, provided that this additional nitrogen atom contains a hydrogen atom or C
_1 to C_6 alkyl, pyridyl or phenyl groups) may form a saturated heteromonocyclic ring, or d) ▲ has a mathematical formula, chemical formula, table, etc. ▼ group, with the proviso that R_
6 is hydrogen or C_1-C_6 alkyl, A is a C_2-C_6 alkylene group, and Ra and Rb are as defined above; R
Each of _2, R_3, R_4 and R_5 is the same or different and is hydrogen, halogen, C_1-C_6 alkyl, C_3-C_4 alkenyloxy or C_1-C
_6 alkoxy, and R_1 is -COOH, -
COOCH_3, -COOC_2H_5, -CONH_
2 or -CON(CH_3)_2 if R_2
, R_3, R_4 and R_5 are other than hydrogen] and pharmaceutically acceptable salts thereof. 2) R_1 is a') formula -COXR'7 [wherein X is -O- or -S-
and R'7 is unsubstituted or by pyridyl or ▲ has a mathematical formula, chemical formula, table, etc. ▼ group (provided that R
'a and R'b are each independently hydrogen or C_1~
C_4 alkyl or R'a and R'b together with the nitrogen atom to which they are attached constitute a pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine ring, where the piperazine ring is unsubstituted or b′) ▲ formula, There are chemical formulas, tables, etc.▼Group [in the formula R'
6 is hydrogen or C_1-C_4 alkyl, A is as defined in claim 1, and R'a and R'b are as defined above; R_2, R_3 , R_4 and R_5 are each independently hydrogen, chlorine, bromine, C_1-C_4 alkyl or C_
1 to C_4 alkoxy, and R_1 is -COO
R_ if CH_3 or -COOC_2H_5
2, the formula according to claim 1, wherein at least one of R_3, R_4 and R_5 is other than hydrogen
I) and pharmaceutically acceptable salts thereof. 3) 9,10-dihydro-phenanthrene-9-carboxylic acid 2-N,N-dimethylamino-ethyl ester; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-N,N-dimethylamino-ethyl thioester; 9,10-dihydro-phenanthrene-9-carboxylic acid 3-N,N-dimethylamino-propyl ester; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-N,N-diethylamino-ethyl ester; 9,10 -dihydro-phenanthrene-9-carboxylic acid 2-morpholino-ethyl ester; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-(pyrrolidine-
9,10-dihydro-phenanthrene-9-N-(2-
N,N-dimethylamino-ethyl)-carboxamide; 9,10-dihydro-phenanthrene-9-N-methyl-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,10-dihydro-phenanthrene -9-N-(3-
N,N-dimethylamino-propyl)-carboxamide; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-(2-pyridyl)-ethyl ester; 9,10-dihydro-9-[4-(2-pyridyl) )-piperazin-1-yl]-carbonyl-phenanthrene; and a pharmaceutically acceptable salt thereof. 4) A) Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R_1, R_2, R_3, R_4 and R_5 are as defined in claim 1) or B) Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1, R_2, R_3, R_4 and R_5 are defined in claim 1. or C) formula (IV): ▲Mathematical formula, chemical formula, table, etc.▼(IV) (wherein R_2, R_3, R_4 and R_5 are patented as defined in claim 1).
_1-C_6 alkyl alcohol or C_1-C_6
or D) hydration of a compound of formula (IV) as defined above with an alkylthiol to form a compound of formula (I) where R_1 is C_1-C_6 alkoxycarbonyl or C_1-C_6 alkylthio-carbonyl. Decompose the formula (
I ) compound (where R_1 is either carbamoyl or a free carboxy group depending on the reaction conditions)
and/or, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable compound of formula (I). and/or if desired convert the salt of the compound of formula (I) into the free compound and/or if desired convert the isomer mixture of the compound of formula (I) into the individual A method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises separating into isomers. 5) a suitable carrier and/or diluent and the formula (I) as active ingredient: [wherein R_1 is: a) carboxy; b) esterified carboxy; c) ▲ mathematical formula, chemical formula, table, etc. There is ▼ group, but Ra
and Rb are the same or different and each of hydrogen or C_
1 to C_6 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached optionally further heteroatoms selected from oxygen, sulfur and nitrogen, provided that this additional nitrogen atom contains a hydrogen atom or C
_1 to C_6 alkyl, pyridyl or phenyl groups) may form a saturated heteromonocyclic ring, or d) ▲ has a mathematical formula, chemical formula, table, etc. ▼ group, with the proviso that R_
6 is hydrogen or C_1-C_6 alkyl, A is a C_2-C_6 alkylene group, and Ra and Rb are as defined above; R
Each of _2, R_3, R_4 and R_5 is the same or different and is hydrogen, halogen, C_1-C_6 alkyl, C_3-C_4 alkenyloxy or C_1-C
_6 alkoxy] or a pharmaceutically acceptable salt thereof. 6) Suitable carriers and/or diluents and as active ingredients the following groups: 9,10-dihydro-phenanthrene-9-carboxylic acid; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-N,N- Dimethylamino-ethyl ester; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-N,N-dimethylamino-ethylthioester; 9,10-dihydro-phenanthrene-9-carboxylic acid 3-N,N-dimethylamino -Propyl ester: 9,10-dihydro-phenanthrene-9-carboxylic acid 2-N,N-diethylamino-ethyl ester; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-morpholino-ethyl ester; 9,10- Dihydro-phenanthrene-9-carboxylic acid 2-(pyrrolidine-
9,10-dihydro-phenanthrene-9-N-(2-
N,N-dimethylamino-ethyl)-carboxamide; 9,10-dihydro-phenanthrene-9-N-methyl-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,10-dihydro-phenanthrene -9-N-(3-
N,N-dimethylamino-propyl)-carboxamide; 9,10-dihydro-phenanthrene-9-carboxylic acid 2-(2-pyridyl)-ethyl ester; and 9,10-dihydro-9-[4-(2- A pharmaceutical composition comprising a compound selected from the group consisting of (pyridyl)-piperazin-1-yl]-carbonyl-phenanthrene or a pharmaceutically acceptable salt thereof. 7) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is: a) Carboxy; b) Esterified carboxy; c) ▲There are mathematical formulas, chemical formulas, tables, etc. ▼Group, however, Ra
and Rb are the same or different and each of hydrogen or C_
1 to C_6 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached optionally further heteroatoms selected from oxygen, sulfur and nitrogen, provided that this additional nitrogen atom contains a hydrogen atom or C
_1 to C_6 alkyl, pyridyl or phenyl groups) may form a saturated heteromonocyclic ring, or d) ▲ has a mathematical formula, chemical formula, table, etc. ▼ group, with the proviso that R_
6 is hydrogen or C_1-C_6 alkyl, A is a C_2-C_6 alkylene group, and Ra and Rb are as defined above; R
Each of _2, R_3, R_4 and R_5 is the same or different and is hydrogen, halogen, C_1-C_6 alkyl, C_3-C_4 alkenyloxy or C_1-C
_6 alkoxy] compound or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of a disease characterized by immunological imbalance in a mammal. 8) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is: a) Carboxy; b) Esterified carboxy; c) ▲There are mathematical formulas, chemical formulas, tables, etc. ▼Group, however, Ra
and Rb are the same or different and each of hydrogen or C_
1 to C_6 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached optionally further heteroatoms selected from oxygen, sulfur and nitrogen, provided that this additional nitrogen atom contains a hydrogen atom or C
_1 to C_6 alkyl, pyridyl or phenyl groups) may form a saturated heteromonocyclic ring, or d) ▲ has a mathematical formula, chemical formula, table, etc. ▼ group, with the proviso that R_
6 is hydrogen or C_1-C_6 alkyl, A is a C_2-C_6 alkylene group, and Ra and Rb are as defined above; R
Each of _2, R_3, R_4 and R_5 is the same or different and is hydrogen, halogen, C_1-C_6 alkyl, C_3-C_4 alkenyloxy or C_1-C
_6 alkoxy] or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of bacterial and viral infections in mammals. 9) A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof other than the compound or salt described in claim 3. 10) Compounds of formula (I) or pharmaceuticals according to claim 5 for use in methods of treating the human or animal body by surgery or therapy or for use in diagnostic methods applied to the human or animal body. That salt is acceptable. 11) A compound or salt according to claim 10 for use in the treatment of a disease characterized by immunological imbalance in mammals. 12) A compound or salt according to claim 10 for use in treating bacterial and viral infections in mammals.