DE2451117A1 - THERAPEUTICALLY EFFECTIVE COMPOUNDS - Google Patents

Description

DR. BERG DIPL.-ING. STAP ^
DIPL.-ING. SCHWABE DR. DR. 3ANDMAIR

PATENTAHWÄLTE

8 MUNICH 86, POST BOX 86 02 45

Dr. Berg Dipl.-Ing. Slapf and Partner, 8 Munich 86, P.O. Box 860245

Lawyer File No. 25 490

Your sign
Your ref.

Our mark Ourrer. 35

The Boots Company Ltd.
Nottingham / Great Britain

8 MUNICH 80 λ ι / Τ

Mauerkircherstraße 45 2 8. ^ M

Therapeutically effective compounds.

Addendum to patent (patent registration P 23 55 394.8)

The invention relates to new compounds having therapeutic properties and to therapeutic ones Preparations containing such compounds.

The present invention provides compounds of Formula I.

(D

NO

V / bu

Telegrams: BERGSTAPFPATENT Munich TELEX: 0524560 BERGd

Banks: Bayerische Vereinsbank Munich 453100
Hypo-Bank Munich 3892623
Post check Munich 65343-808

509821/1037

or their enol or enthiol forms of the formula la

H / CH ₂ Q

N-Ar
: (la)

.N

XZ
in which Q is COOH, CH ₂ OH or COORg, where Rg is a

Is ester-forming group, X is oxygen or sulfur, R is hydrogen or alkyl, Z is hydrogen or Is acyl, Ar is aryl and ring J is substituted, or pharmaceutically acceptable salts with inorganic or organic bases of those compounds that are acids. Ar is preferably in the ortho positions unsubstituted at the point of attachment to the phthalazine ring.

The ring J is preferably through the remainder (G) - like defined below - substituted.

The compounds of the invention have valuable diuretic and saluretic properties in mammals. Accordingly, the invention also provides a method for inducing diuresis and saluresis Mammals resulting from the administration of a pharmaceutically acceptable and effective amount of any of the above described connection to mammals exists.

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The invention also provides a therapeutic preparation which contains a compound of the invention in the Mixture with a pharmaceutically acceptable diluent or carrier.

Preferred compounds are those of the formula II

(ID

n _:

or their enol or Enthio! forms of the formula Ha

(Ha)

in which Q, X, R and Z have the above meaning, η is 1-4, each G can be identical or different and fluorine and / or chlorine and / or bromine and / or iodine and / or nitro and / or amino and / or substituted Amino, such as dialkylamino and especially dirnethylamino, and / or cyano and / or alkyl, such as those with 1-4 carbon atoms and in particular methyl, ethyl,

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and isopropyl, and / or substituted alkyl, such as haloalkyl, especially trifluoromethyl, and / or alkoxy, such as one with 1-4 carbon atoms and in particular methoxy, and / or substituted alkoxy, such as Aralkoxy, especially benzyloxy, and / or alkylthio, such as one with 1-4 carbon atoms and in particular Methylthio, and / or alkylsulfonyl, such as mesyl, and / or alkylsulfinyl, such as methylsulfinyl, and / or Hydroxy and / or aryl, such as phenyl, and / or aroyl, such as benzoyl, and R 1, R 1 and R 1 - can be identical or different be and hydrogen and / or fluorine and / or chlorine and / or bromine and / or iodine and / or nitro and / or Nitroso and / or cyano and / or isocyano and / or amino and / or substituted amino, such as alkylamino, dialkylamino, Arylamino, acylamino, hydroxyamino, arylidenamino, alkylidenamino, ureido, carbazoylamino, hydrazino, Thioureido, thiocarbazoylamino, alkylsulfinylamino, alkoxycarbonylamino and sulfamoylamino, and / or sulfonamido, such as alkyl, substituted alkyl and arylsulfonamido, and / or alkyl such as one having 1-7 carbon atoms and in particular methyl, ethyl, propyl, isopropyl and tert-butyl, and / or substituted alkyl, such as haloalkyl, especially trifluoromethyl, and / or Aralkyl, such as benzyl, and / or hydroxyalkyl, such as hydroxypropyl, and / or alkoxyalkyl, such as methoxymethyl, and / or Cycloalkyl, such as cyclohexyl and / or substituted cycloalkyl, and / or alkenyl, such as allyl, and / or aryl,

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such as phenyl, and / or substituted phenyl, such as tolyl, Alkoxyphenyl and halophenyl, and / or cycloalkenyl, such as cyclohexenyl, and / or alkoxy, such as with 1-4 carbon atoms and especially methoxy, Ethoxy, n-propoxy, isopropoxy and butoxy, and / or substituted alkoxy, such as dialkylaminoalkoxy and Aralkoxy, and / or alkenyloxy, such as allyloxy and butenyloxy, and / or cycloalkyloxy, such as cyclohexyloxy, and / or cycloalkenyloxy, such as cyclohexenyloxy, and / or acyloxy, such as acetoxy, and / or alkylthio, such as with 1-4 carbon atoms and in particular methylthio, ethylthio and propylthio, and / or substituted alkylthio, such as haloalkylthio, especially trifluoromethylthio, and / or aralkylthio and / or alkenylthio and / or Cycloalkylthio and / or cycloalkenylthio and / or arylthio, such as phenylthio, and / or alkylsulfonyl, such as mesyl, and / or alkylsulfinyl, such as methylsulfinyl, and / or Acyl, such as acetyl and propionyl, and / or substituted acyl, in particular haloacyl, such as trifluoroacetyl, and / or Aroyl, such as benzoyl, and / or heteroaroyl, such as 2-thenoyl, and / or hydroxy, and / or mercapto and / or carbamoyl, and / or thiocarbamoyl and / or sulfamoyl and / or substituted SuIfamoyl, such as dialkylsulfamoyl, in particular Dimethylsulfamoyl and diethylsulfamoyl, and / or substituted and unsubstituted heterocyclic rings, such as 2-, 3- and 4-pyridyl, piperidino, morpholino, thiamorpholino, Pyrrolin-1-yl, pyrrolidin-1-yl, 1-pyrrolyl,

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2-thienyl, 2-thiazolyl, 2-oxopiperidino, 5-oxopyrazolidinyl, optionally N-alkylated and 2-oxopyrrolidin-1-yl. Rg and R ^ can also together form part of a carbocyclic or heterocyclic ring fused to the benzene ring, which rings are substituted may be, for example with one or more lower alkyl radicals.

If G, Rg, R ^ j or R _{5 is} substituted amino, the nitrogen of the amino group can be mono- or disubstituted, at least one of the substituents preferably being an alkyl, such as methyl, ethyl or isopropyl, or an alkoxy radical, such as methoxy . Where the substituent on the substituted amino group is itself an amino group or is one which contains further amino groups, such as ureido, the further amino groups can also be mono- or disubstituted, usually alkyl-substituted, such as methyl-substituted.

Examples of substituted amino groups are methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, trimethylammonio, anilino, benzylamino, N-methylformamido, N-methylacetamido, methanesulfonamido, N-methylmethanesulfonamido, N-methyl-p-toluenesulfonamido and N- ¹ , N'-diethylhydrazino.

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Examples of fused ring systems are as follows.

Unless otherwise shown, these are on the 2-nitrogen of the phthalazine ring in either the 5- or 6-position (in the case of 9-membered bicyclic Ring systems and usually in the 5-position) or in the 6- or 7-position (in the case of 10-membered bicyclic Ring systems). The first four of these systems are particularly preferred.

R.

R.

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R.

R-

^ N ' R,

R.

R,

8 ^R

24511Ϊ7

NO.

R.

^ 9 R ^

^ N

-N

R.

R.

R.

R.

R,

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R.

10

¹ IO

R_, Rg, Rg and R are identical or different and are hydrogen or lower alkyl such as methyl.

Particularly preferred systems are as follows

and

R ₅ is preferably hydrogen. R- is preferably not hydrogen. R can be alkyl with, for example, 1-7 carbon atoms, preferably 1-3 carbon atoms and in particular methyl or ethyl. However, it is generally preferred that R is hydrogen - except when one or more of the radicals R 1, R 4 and R _{5 is} a substituted or unsubstituted amino group. 0 is common

509821/1037 " ^l0 ~

lent COOH, but - if it is C00R, R _g is preferably an alkyl group such as methyl or ethyl, although other ester-forming may also be suitable groups, for example, alkyloxyalkyl, acyloxyalkyl groups such as pivaloyloxymethyl and 6-indanyl. X is preferably oxygen, η is preferably 1 or 2, and most preferably 1, in which case G is preferably in the 7-position.

Particularly preferred groups that G can be are methyl, ethyl and methoxy and isopropyl, fluorine, chlorine and bromine.

A particularly preferred group of compounds are those in which R 1 is hydrogen, η is 1 and G is itself is in the 7-position, Q is carboxy, X is oxygen, R * is hydrogen and R ^ is not hydrogen or Rj and R ^ together form part of a heterocyclic ring which is fused with the benzene ring, as well as salts thereof.

Particularly preferred from this group of compounds are those in which G is chlorine, fluorine, methyl, ethyl, isopropyl or methoxy and - if R (or Z) is hydrogen - R _{3 is} nitro, trifluoromethyl, methylthio, chlorine or bromine or R ^ and R ^ together with the benzene ring to which they are attached, benzothiazol-5-yl, 1,2,3-benzo-

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thiadiazol-5-yl or 1,2-benzoisothiazol-5-yl and - if R is methyl - R _{3 is} Ν, Ν-dimethylamino.

The preferred compounds of the present invention can be prepared by a method as follows Levels includes:.

(a) Reacting 2-naphthol-1-sulfonic acid of the formula III

(G)

III

or a salt of it,

in the. G and η have the meaning above, with a Compound of formula IIIa

HIa

in which R ^, R- and R, - have the above meaning, R2 Is hydrogen, iodine, bromine or chlorine and Y is the anion of a mineral acid,

(b) treating the product of (a) with a weak base,

(c) treating the product of (b) with an alkali metal hydroxide, which is followed by acidification in order to obtain a compound of the formula IV

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H _v CH ₂ COOH

IV

SO.

to obtain,

(d) if necessary, modification of at least one of the radicals G, R.3, R ^ or Rj- and / or - if R _{2 is} iodine, bromine or chlorine - its conversion into hydrogen and / or conversion of the 1-acetic acid group into a hydroxyethyl group ,

(e) treating the product of (c) or (d) with an aqueous acid or an alcoholic acid to to obtain a compound of formula II in which R is hydrogen and X is oxygen,

(f) in the event that R is iodine, bromine or chlorine, its Conversion to hydrogen,

(?) if necessary modification of at least one of the residues Q, X, Z, G, R, Ro, R4 or R, - in the product obtained

of (e) or (f), and
(h) optionally forming a pharmaceutically acceptable salt with an inorganic or organic base of a compound that is an acid.

Steps (e) to (h) do not always have to be carried out in the order given. So both

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For example, in some cases where the radical R _{2 is} halogen, this can be converted into hydrogen after modification of one or more radicals G, R ^, R4, Rc or -Q, or even simultaneously, for example if such a modification includes a hydrogenation step . It may also be desirable to carry out steps (d) and (e) simultaneously, for example the conversion of the 1-acetic acid group to a hydroxyethyl group can be carried out at the same time as the hydrolysis of the 4-sulfonate group.

It should also be noted that it is not necessary to isolate the products of a stage before proceeding to next stage is passed.

The compounds of formula III and their salts are new and can be prepared by sulfonation of the substituted 2-naphthol, such as by treatment with concentrated sulfuric acid, usually at a low temperature can be prepared preferably from -10 to +10 ⁰ C. The sulfonate salts can then be obtained by treating the sulfonic acid so obtained with an inorganic salt such as sodium chloride.

Without wishing to be bound by any theory, it is believed that the reaction used to make the compounds Formula II proceeds in the following manner;

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R.

OH +

" ^R 5

'i stage (a)

Stage (b)

Stage (c)

CH = CHCOO "

C = N-NH

soö

Stage (c) _v

continuation

- 15 -

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(G)

Stage (s)

(if (d) is omitted)

Step (a) is generally conducted at a temperature below 6O ⁰ C, preferably between -20 to + 5O ⁰ C, for example -10 to + 1O ⁰ C is performed. The salt is preferably an alkali metal salt such as sodium salt, and Y i ^st preferably Cl.

Step (b) is generally conducted at a temperature between -20 and +20 ⁰ C, for example -10 to +10 ⁰ C performed. The weak base is generally an alkali metal carbonate or ammonium carbonate, and it is preferably sodium carbonate. The duration of the reaction depends mainly on the nature of the substituents in the compounds of the formula II. Such compounds in which at least one of the radicals Rj »RoΛ R. or R _{5 is} an electron-withdrawing substituent, such as halogen and trifluoromethyl, generally require

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only a short reaction time, for example 1-30 minutes. These compounds, in which at least one of the radicals R-, R ₃ , R ₄ or R ^ is an electron-donating substituent, for example alkyl, generally require a longer reaction time, for example half a hour to 24, preferably 1 to 6 hours.

Step (c) is generally conducted at a temperature between -20 and +50 ⁰ C, for example -5 to +30 ⁰ C is performed. The alkali metal hydroxide is generally sodium hydroxide. The duration of the reaction is generally between 1 and 24 hours.

Step (e) is generally carried out at a temperature, for example from 20 to 200 ° C, preferably from 50 to 120 ° C, carried out and, if desired, under reflux. The acid is usually a mineral acid, for example hydrochloric acid. The reaction time is usually at least half an hour, for example 1-6 hours.

When the acid is used in conjunction with an alcohol, the acid may be anhydrous, for example Hydrogen chloride gas contained in the alcohol, for example Methanol or ethanol is dissolved. The product obtained is then one in which Q is COORg.

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Compounds in which R is alkyl are generally used obtained by alkylating the compounds in which R is hydrogen.

Suitable alkylating agents are alkyl halides, such as methyl or ethyl iodide or propyl bromide, and dialkyl sulfates, such as dimethyl or diethyl sulfate. The alkylation is preferably carried out in the presence of a base, for example an alkali metal hydroxide. In the event that it is desired to obtain the acid, the acidification, for example with hydrochloric acid, can be carried out. When an alkyl halide is used, the reaction is generally carried out on a metal derivative which can be preformed, for example using a metal hydride, for example sodium hydride. The alkylation may for example at a temperature of 0 to 200 ⁰ C, a Lö ^ ngsmittels, such as tetrahydrofuran or diglyme, preferably carried out in the presence.

To obtain compounds in which X is sulfur it is usually necessary to sulfurize the compound in which X is oxygen. This can be done with a sulfurizing agent such as phosphorus pentasulfide. This reaction can be carried out at a temperature of 20-100 ^° C., for example.

- 18-509821 / 1037

The compound of formula II is generally before Sulfurization converted into an ester. If the free Acid is required, this can then be taken from the sulfu— rated esters can be obtained by hydrolysis.

If R _{2 is} a halogen radical, it is replaced by oxygen, generally by hydrogenation in a manner known per se, for example using a Palladium charcoal catalyst, preferably in the presence of a salt of a weak acid, for example sodium acetate.

Examples of modifications to one or more of the radicals G, R ₃ , R ₄ and R ₅ that can be carried out are the following, where the radicals shown are examples of G - where applicable - and for the radicals R ₃ , 3 ^ » and Rg can be. A particularly useful modification is the reductive alkylation of a nitro or amino group. Examples are given under c, d, f xmä tj.

^a> ~ ^ΒΓ) metal cyanide _CN

b) -NO _o H ₉ / Pd charcoal _{v MU}

ί __Z ^ -WH ₂

C) -NO ₀ HCHO w _XT "

'2 - ^ -NMe ~

H ₂ / Pd charcoal

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509821/1037;

-NO ₂ - j.y - CH ₃ CHO / ArSO ₂ Cl ■ X -TtfK-hh 245111 7th d) -NH- H ₂ / Pd charcoal * tL HCHO s. -NMe- e) -NH ₀ KOH v ^Δ HCHO -NMe- f) -NH ₂ - H ₂ / Pd charcoal -NH ₂ - CH ₃ CHO > -NH & th HCHO G.) H ₂ / Pd charcoal -NHSO ₂ Me H ₉ / Pd wood
money H) MeSO-Cl -NHSO ₂ Ar Me ₂ SO ₄ i) K ₂ CO ₃ } -N (Me)
SO ₂ Me Me ₂ SO ₄ -N (Me) -
SO ₂ Ar K ₂ CO ₃ >

(Ar = Ph or p-tolyl)

1) NaN0 ₂ / HCl

j) -NH ₂ : - ■ - ^ -or

^{2) HBF} 4 (R = Me or Äth)

3) RAW

NaN0 ₂ / HCl

2) SnCl ₂

₂ /
k) -NH ₉ ^ -NHNH ₉

AcOH MeI

1) -NH ₉ } -NHCOMe ^ -N (Me) COMe

Close

PhCHO H ₉ Pt m) -NH ₂ > -N = CHPh ) NHCH ₂ Ph

PhCOCH ₂ SO ₂ Cl

n) -NH-> -NHSO ₉ CH ₉ COPh

^{Z Z Δ} - 20 -

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ο) -SR

H ₂ O ₂

H ₂ O ₂
-SOR - ^ " ^S0 2 ^R

(R = Me or Äth)

NaBH,

ρ) -COalkyl

q) -NH, +

MeO

A- -CH (OH) alkyl

MeO

In some cases fused rings can be obtained by appropriate modification of R, and R ^, so that they cyclize to form the fused ring. Examples of such implementations are following:

r)

R ¹ - ^ rCO

R ¹¹ CH,

-NHN = C-CH ₂ R "

R ¹

acid

R ¹ and R "= alkyl

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• N .;

NaNO, acid

t)

u)

O = Cl 2 ι

O =

NH,

(from s)

/ ^NH 2 '/ \\ R' COOH

\ 7- ^NH 2

(from s)

v)

- SH

S-CH COR "

R ¹

- 22 -

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NHCSR ■

Br.

NH,

—NHCSNH.

Br,

. N

S NH.

Cl .SH

NO

NO,

SH

NH ₂ }

// \\ Glycerin "Λ ⁷ V-NH ₀

H ₂ SO ₄ PhNO ₀

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The conversion of compounds in which Q is COOH to those in which Q is CH ^ OH can be done in a number of ways. When R is alkyl, the Compound into a mixed anhydride, for example by reaction with an ester of a haloformic acid, usually ethyl chloroformate, in the presence of a tertiary Amine, for example triethylamine, can be carried out. The mixed anhydride is then with, for example Sodium borohydride reduced. If the remainder in the 4-position of the phthalazine nucleus is a hydroxy or Is mercapto group, it may first be necessary to carry out the procedure, for example by acylation, usually acetylation, or by treatment with an agent such as Benζylchlorformat to form the Protect 4-benzyloxycarbonyloxy compound. The protecting group can then by conventional means, for example by hydrolysis in the case of the acetyl group or hydrogenation in the case of the benzyloxycarbonyl group. When R is hydrogen or alkyl, can alternatively acids in the corresponding acid chloride, for example by reaction with thionyl chloride, which then can be reduced, for example using lithium aluminum tri-tert-butoxyhydride being transformed. When compounds are converted in which the group is in the 4-position of the phthalazine nucleus is a sulfonate, for example the compounds of the formula IV, the procedure used is generally

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mean in the formation and reduction of the mixed anhydride.

Salts of acids can be obtained by reacting the acids with organic and inorganic bases.

O- or S-acylated derivatives can be obtained by the compounds in which R is hydrogen are treated with an acylating agent, for example acetyl chloride, or Acetic anhydride.

If desired, compounds in which Q is C ^ OH, conventionally oxidized to give compounds in which Q is COOH. Connections in which Q COORg can also be hydrolyzed in a conventional manner to give compounds in which Q is COOH, or salts of such compounds.

It is therefore to be understood that compounds of the invention can be prepared by a process in which a compound of the formula VI or VIa

(G ₁ )

l'n

or

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VI

- 25 -

(G ₁ )

l'n

- 25 -

H .

Via

in which A is the radical O as defined above or a Remainder that can be converted into Q, G- ^ the remainder G as above or is a residue convertible to G, Ar ^ ' Is aryl, T is the radical XZ as defined above or SO3 and R and Z are as defined above is to at least one or more radicals A, G- ^, Ar ^, To modify R, X, T or Z in order to obtain a new compound according to the invention.

Examples of radicals that can be converted into Q are an aldehyde group, which can be oxidized to give COOH or a cyano or carbamoyl group which hydrolyzes can be to give COOH.

It should be noted that - since the compounds according to the invention have an asymmetric carbon atom - they are usually in the form of a racemic mixture. The redemption of such Racemate can be carried out by conventional means and the optically active stereoisomers separated make up part of the present invention,

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The therapeutic effectiveness of the compounds according to the invention can be determined in various ways by administering the drug to the animal and the amount of sodium ions excreted Urine after a period of time (usually expressed as milliequivalents of sodium ions per kilogram of body weight of the animal). The drug was administered orally to rats as a suspension in distilled water, containing 0.25% hydroxyethyl cellulose administered and the amount of sodium ions in the urine will match the amount of control rats given the same amount of fluid given without drugs. In this experiment, 4-hydroxy-7-methyl-2- (3-methylthiophenyl) -1,2-dihydrophthalazine-1-acetic acid promoted (or in its "keto" form, 7-methyl-2- (3-methylthiophenyl) -4-oxo-l, 2,3,4-tetrahydrophthalazine-l-acetic acid) the sodium ion loss and had an effectiveness, based on sodium ion diuresis, that was better than which was from Frusemid.

The compounds can be administered in a conventional manner, for example orally, rectally or parenterally, preferably administered orally. The optimal dose rate depends, among other things, on the route of administration and the treatment conditions but is normally in the range of 0.003 to 100, for example 0.1 to 100 mg / kg / day. The unit dose can be from 0.1 to 500 mg, for example

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Vary 3 to 500 mg. For oral administration the dose rate is preferably 0.1 mg to 2 g, for example 3 mg to 2 g per subject per day.

To facilitate administration, the compounds are preferably used as therapeutic preparations formulated containing the active compound together with pharmaceutical carriers for the manufacture of preparations for oral, rectal or parenteral administration. These preparations contain preferably 0.1-90% by weight of a compound according to the invention.

Preferred preparations according to the invention are preparations for oral administration and these are the conventional pharmaceutical forms for such administration, such as tablets, Capsules, lozenges, powders, effervescent grains, syrups and aqueous and oily suspensions. The one in the making The carriers used for these preparations are the carriers known to pharmacists. So are typical Carrier in the manufacture of tablets disintegrants, for example corn starch and lubricants such as magnesium stearate. In the production of Capsules, standard gelatin capsules can be used, which contain the active ingredient alone or with a Mixed diluents included. The liquid ones

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Preparations may contain water and sucrose as carriers to create syrups, water, dispersants and suspending agents such as sodium carboxymethyl cellulose to create aqueous suspensions, and a non-toxic oil such as a vegetable oil,
e.g., peanut oil, and a suspending agent to create oily suspensions.

Other preparations according to the invention are preparations for rectal administration and these are
the conventional pharmaceutical forms for such administration, such as suppositories with fatty glyceride or polyethylene glycol bases.

Preparations for parenteral administration are the conventional pharmaceutical forms for one such administration, for example a sterile solution of the sodium salt in water.

In some formulations it may be useful to present the compounds of the invention in the form of particles
very small size, such as those obtained in vortex energy milling, such as micronization, to use.

The active compounds can be used with other therapeutic

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table agents such as other diuretic agents, particularly those that stimulate potassium ion excretion reduce, for example amiloride, spironolactone or triamterene, and antihypertensive agents, Agents such as reserpine and adrenergic neuron blocking agents such as guanethidine or methyldopa mixed or used with them. The connections can additionally or alternatively with a potassium salt, such as potassium chloride, mixed in or used with it to prevent the excessive To replace potassium loss that may occur with the use of the diuretic compound. In general the potassium salt is enterically coated.

The following examples illustrate the invention. Parts and percentages are parts by weight and percentages by weight if nothing

otherwise is said. The following abbreviations are used in the examples:

TPA = 1,2,3,4-tetrahydrophthalazine-1-acetic acid TPAE = 1,2,3,4-tetrahydrophthalazine-1-acetate DPA = 1,2-dihydrophthalazine-1-acetic acid DPAE = 1,2-dihydrophthalazine-1-acetate IMS = industrial methylated fuel

The products of the examples gave satisfactory results Elemental analyzes.

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example 1

6-Bromo-2-naphthol (44 g) was added in portions to concentrated sulfuric acid cooled to ^{0 ° C. with stirring.} When the mixture solidified, it was left at room temperature overnight. Water (250 ml) was added and the mixture stirred and filtered. Sodium chloride (40 g) was added to the filtrate with stirring, the mixture was allowed to stand overnight and then filtered. The solid that was collected was washed with saturated brine (350 ml), dried and extracted with boiling absolute ethanol. The extract was filtered, the ethanol evaporated and the residue stirred with ether (500 ml) for 2 hours. The mixture was filtered to leave sodium 6-bromo-2-naphthol-isulfonate. A portion (6.3 g) of this was filtered into water (250 ml) and cooled. This was then then slowly added to a diazonium salt which was prepared by slowly adding ice-cold aqueous sodium nitrite (1.7 g in 5 ml of water) to a cooled solution of m-trifluoromethylaniline (3.22 g) in

concentrated hydrochloric acid (8 ml) and

became

Water (30 ml) given. T ~ A yellow precipitate formed which was filtered off, washed with cold saturated brine (250 ml) and with cold water (100 ml) was made into a paste. The paste was

^{cooled to 0} ° C. and sodium carbonate with stirring

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(6 g) added. After 1 1/2 minutes it became cold aqueous Sodium hydroxide (12 g in 30 ml of water) was added and the mixture was - after becoming a red solution - Stirred on an ice bath for 3 hours and then overnight at room temperature, Das Mixture was acidified to pH 2-3 with concentrated hydrochloric acid and then with saturated brought to pH 8 aqueous sodium carbonate. The mixture was filtered and the filtrate with concentrated Hydrochloric acid acidified to pH 1 while stirring. The solid was filtered off and dissolved in warm water (250 ml) and the solution refluxed for 2 hours. During this time it was concentrated hydrochloric acid (15 ml) added. The mixture was then cooled, the solid filtered off and from a 2: 1 mixture of Acetic acid and water recrystallized to give 7-bromo-4-hydroxy-2- (3-trifluoromethylphenyl) -DPA to obtain. Mp = 217 to 219 ° C.

Examples 2 - 36

In the same way as described in Example 1, the appropriate 2-naphthol and aniline were converted into the corresponding Acetic acid obtained. The compounds obtained are listed in Table I. In some cases was the dilute reaction mixture from the sulfonation of 2-naphthol or a solution of the crude sodium

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naphtholsulfonats with the dxazonium salt solution without Cleaning implemented. In some cases, the neutral and phenolic impurities were also removed from the finished acetic acid by partitioning between a water-insoluble solvent, usually ether, and aqueous sodium hydrogen carbonate removed. The product was then passed out of the aqueous phase Acidification gained.

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Table I.

received connection

cn
CD
CD I. game aniline 2-naphthol co
ro U) 2 3-methylthio 6-bromine » 3 3-nitro 6-bromine S. 4th 3-chlorine 6-bromine -α 5 3-nitro 6-methoxy 6th 3-methylthio 6-methoxy ■ 5 7th 3-nitro 6-tert-butyl 8th 3-Tri fluorine thy I 6-ethyl 9 3-nitro 6-ethyl 10 3-methylthio 6-ethyl 11 3-trifluoromethyl 6-methyl 12th 3-nitro, 6-methyl

^G 2

Fp. ( ⁰ C)

H H H H H H H H H H H

H H H H H H H H H H H

Br H Br H Br H MeO H MeO H Bu ^t H Eth H Eth H Eth H Me H Me H

232-233 U)
U) 245V 228-230 I. 166-168 , 5 217-218 233-235 244-245 202-206 220-222
195-196 219 233-233

Table I (continued)

π _ο 4 _ aniline 3-chlorine 2-naphthol R ₃ received ^G l link ^G 3 Fp. ( ⁰ C) DCl
game 4-chlorine 6-methyl Cl ^R 4 H ^G 2 H 210-211 13th 3-methylthio 6-methyl H H H Me H 215-216 14th 3-bromine 6-methyl MeS Cl H Me H 208-209 15th 3-nitro 6-methyl Br H H Me H 231-232 16 3-methylthio 6-chlorine NO ₂ H H Me H 227-229 17th 3-nitro 6-chlorine MeS H H Cl H 218 18th 3-nitro 6-fluoro NO ₂ H H Cl H £ 242-243 19th 3-nitro 7-fluoro NO ₂ H F. F. H 232-235 ' 20th 3-chlorine 6,7-dichloro NO ₂ H Cl H H 234-235 21 3-trifluoromethyl 6-ethyl Cl H H Cl H 215-220 22nd 3-nitro 6-chlorine CF ₃ H H Eth H 197-198 23 3-trifluoromethyl
3-trifluoromethyl 6-isopropyl NO ₂ H H Cl H 226-227 24 4-methylthio
3-nitro 6-fluoro
7-fluoro CF ₃
CF ₃ H H
F. Pr ¹ H
H ro
123-124 4 ^
cn
228-229 -> 25th
26th 6-methyl
5-chlorine H
N0_ H
H H
H F.
H H
Cl 182-186 - *
230-231 27
28 MeS
H Me
H

Table 1 le I (continued)

game aniline 2-naphthol V R ₄ received connection ^G 2 ^G 3 Fp. ( ⁰ C) 245 29 3-nitro 5,6-dimethyl NO ₂ H ^G l Me Me 268-270 30th 3-nitro 7-ethyl NO ₂ H H H H 138-140 31 3-nitro 5-fluoro NO ₂ H Eth H F. 211-213 32
33 3-fluoro
3-iodine 6-methyl
6-methyl F.
I. H
H H Me
Me H
H 207-209
228-230 in
CD
co
OO 34 3-acetyl 6-methyl CH ₃ CO H H
H Me H 195-196 '
U) 35 3-nitro 6-methylthio NO ₂ H H MeS H 238, 36 4-methyl-3-nitro 6-methyl NO ₂ Me H Me H 138-140 37 3-trifluoroacetyl 6-chlorine CF ₃ CO H H H Cl 130-140 H

Examples 38-47

In the same way as described in Example 1, starting from 1,2,3-benzothiadiazol-5-ylamine and the appropriate naphthol obtained the acids listed in Table II.

• Dai ■ ' / ¹ N Tabel II OH 2-naphthol ^G l H Cc - N
If
/ N
S. M.p. (° C) DC X
game 2 - ^ N>
AJx, 6-methyl H 234 38 XH ₂ COOH 6-chlorine H received * 233 G
G 39 N - - -
κ ¹ 6-fluoro F. G ₂ 254-255 40 7-fluoro H Me 274-275 41 6-isopropyl H Cl 230-231 42 5,6-dimethyl H F. 210-212 43 6-tert-butyl H H link 232-234 44 6-ethyl Cl Pr ¹ G ₃ 235 45 7-chlorine H Me H 265 46 6-benzene But H 164-166 47 Eth H H H PhCO H Me H H H H

This product was obtained in two forms with different IR spectra. Recrystallization from acetic acid gave a product with V__ _v 1710, 1680 cm

Iu α. Χ

509321/1037

- 37-

during the recrystallization from ethyl acetate

Product with Y 1700, 1635 cm " ¹ (KBr compact) resulted in max

Examples 48-50

The product of Example 12 (2.8 g) was dissolved in aqueous potassium hydroxide (6.3 g in 63 ml of water). Dimethyl sulfate (3.2 g) was added and the mixture was stirred at room temperature for half an hour. the Solution was cooled to 0 ° C. and acidified with concentrated hydrochloric acid. The yellow precipitate that is formed, was filtered off and recrystallized from a mixture of acetic acid and water (2: 1) to give 3,7-dimethyl-2- (3-nitrophenyl) -4-oxo-TPA to obtain. Mp: 217-219 ° C (Example 48).

In the same way, the product of Example 39 gave 2- (1,2,3-benzothiadiazol-5-yl) -7-chloro-3-methyl-4-oxo-TPA, Melting point: 260-261 ° C., (Example 49) and the product of Example 36 gave 3,7-dimethyl-2- (4-methyl-3-nitrophenyl) -4-oxo-TPA, M.p .: 2O1-2O2 ° C. (Example 50).

Examples 51-56

The product of Example 48 (19 g) was esterified by reacting with methanol (700 ml) which was concentrated for 6 hours Sulfuric acid (15 ml) at reflux

became

The mixture was evaporated to 150 ml, cooled and poured into ice water. The solid was collected, washed with saturated aqueous sodium

509821/1037 - ₃₈ -

gene carbonate and then washed with water, dried and recrystallized from methanol to Methyl 3,7-dimethyl 1-2- (3-nitrophenyl) -4-oxo TPAE to obtain. M.p .: 179-18O ° C. (Example 51).

In the same manner, the product of Example 38 gave methyl 2- (1,2,3-benzothiadiazol-5-yl) -4-hydroxy-7-methyl-DPAE. M.p .: 2O2-2O3 ° C. (Example 52); the product of Example 38 gave methyl 2- (1,2,3-benzothiadiazol-5-yl) -7-chloro-4-hydroxy-DPAE, M.p .: 220-222 ° C (Example 53); the product of Example 50 gave methyl 3,7-dimethyl-2- (4-methyl-3-nitrophenyl) -4-oxo-TPAE, Mp 177-178 ° C (Example 54); the product of Example 45 gave methyl 2- (1,2-benzoisothiazol-5-yl) -4-hydroxy-7-methyl-DPAE, M.p .: 120 ° C (Example 55) and the product of Example 36 gave methyl-4-hydroxy-7-methyl-2- (4-methyl-3-nitrophenyl) -DPAE, M.p .: 188-189 ° C (Example 56).

Example 57

The product of Example 48 (1.4 g) was dissolved in IMS (200 ml), mixed with palladium-charcoal (10% palladium, 0.5 g) and formaldehyde (40%; 1.0 ml) and the mixture with Hydrogen (440 ml) hydrogenated with shaking. The mixture was filtered, evaporated under reduced pressure and the residue at O ⁰ C allowed to stand. White crystals that formed became

- 39 -

509821/1037

filtered off, washed with IMS and recrystallized from IMS and dried in vacuo, and 2- (3-N, N-dimethylaminophenyl) -3,7-dimethyl-4-oxo-TPA obtain. M.p .: 202-2O4 ° C.

Examples 58-60

The product of Example 51 (14 g) was dissolved as' in methanol (1 liter), and at room temperature below Use of a palladium-charcoal catalyst (10%; 1 g) hydrogenated. The mixture was filtered off and the filtrate concentrated and crystals of methyl 2- (3-aminophenyl) -3,7-dimethyl-4-oxo-TPAE obtain. M.p .: 184-185 ° C (Example 58).

In the same way, the product of Example 12 gave 2- (3-aminophenyl) -4-hydroxy-7-methyl-DPA, m.p .: 191 ° C (Example 59) and the product of Example "48 gave 2- (3-aminophenyl) -3 ^ -dimethyl ^ -oxo-TPA, m.p .: 216 bis 217 ° C (example 60).

Example 61

A solution of p-toluenesulfonyl chloride (3.1 g) in Pyridine (11 ml) was added to a solution of the product of Example 58 (5.6 g) in pyridine (33 ml). The mixture was refluxed for 1 hour, cooled and poured onto ice water. The watery Layer was removed and the remaining rubber with

- 40 -

509821/1037

Petroleum ether (boiling point 80-100 ° C.) was stirred. The solid product was filtered off and recrystallized from IMS and methyl-3,7-dimethyl-4-oxo-2- (3-ptoluenesulfonamidophenyl) -TPAE, M.p .: 205-2O6 ° C obtained. This was made with sodium carbonate (3.65 g), dimethyl sulfate (2.5 ml) and acetone mixed and the mixture stirred and refluxed for 2 hours. The acetone was evaporated and the residue treated with a mixture of ethyl acetate and water. The organic Layer was washed with water, dried and evaporated and the product recrystallized from IMS and Methyl-3,7-dimethyl-2- (3-N-methyl-p-toluenesulfonamidophenyD-4-oxo-TPAE, Mp 172-173 ° C obtained. This was dissolved in IMS and treated with aqueous Sodium hydroxide hydrolyzed and then evaporated. The residue was dissolved in water, filtered and acidified and the product filtered, washed with water and recrystallized from aqueous acetic acid and 3,7-dimethyl-2- (3-N-methyl-p-toluenesulfonamidophenyl) -4-oxo-TPA , M.p .: 214-215 ° C.

Example 62

The product from Example 58 (11 g) was refluxed with glacial acetic acid (100 ml) for 18 hours. The mixture was then evaporated to give an oil which was triturated with methanol. The solid product was recrystallized from methanol and methyl 2- (3-acetamido-

- 41-509821 / 1037

phenyl) -3,7-dimethyl-4-oxo-TPAE, m.p .: 224-225 ° C. 3 g of this was dissolved in dioxane (75 ml), sodium hydride (0.6 g) was added and the mixture for 2 hours heated to reflux. It was then cooled and dimethyl sulfate (1.2 ml) added and more Heated under reflux for 4 hours. The mixture was evaporated and the remaining gum washed with water and extracted with dichloromethane. The extract was made with aqueous sodium hydrogen carbonate and water washed, dried, evaporated and the residue was recrystallized from ethyl acetate and methyl-3,7-dimethyl-2- [3- (N-methylacetamido) phenyl] -4-oxo-TPAE, m.p .: 190 ° C.

Example 63

The product of Example 62 was hydrolyzed in the same manner as described in Example 61 and 3,7-dimethyl-2- Qj- (N-methylacetamido) phenyl] -4-oxo-TPA, M.p .: 228-230 ° C obtained.

Example 64

To a cooled solution of the product of Example 48 (5 g) in dry tetrahydrofuran (25 ml) and triethylamine (2 ml) was added dropwise a solution of methyl chloroformate (1.1 ml) in dry tetrahydrofuran (5 ml) added. The (femisch was stirred for 30 minutes at -5 ° C. and then filtered. The filtrate

- 42-

509821/1037

was added dropwise with stirring to a solution of
Added sodium borohydride (1.6 g) in water. That
The mixture was stirred for 3 hours and then acidified with hydrochloric acid (2N; 50 ml). Of the
Solid was extracted with dichloromethane and the extract washed with aqueous sodium hydrogen carbonate, dried and evaporated to give a gum which was triturated with ether. The solid which was separated off was recrystallized from methanol and 3,7-dimethyl-1- (2-hydroxyethyl) -2- (3-nitrophenyl) -4-oxo-1,2,3,4-tetrahydrophthalazine, m.p. : 169-17O ° C obtained.

Example 65

The product of Example 58 (3g) was made using sodium nitrite and hydrochloric acid
diazotized. Aqueous fluoroboric acid (42%; 24 ml) was added and the yellow precipitate of the diazonium fluoroborate was filtered off, washed with an ether / methanol mixture (4: 1) and then mixed with methanol (50 ml). The mixture was heated to 50 ⁰ C. Nitrogen evolved and the solid dissolved. The red solution was poured into water (200 ml) and the solid that separated was extracted with chloroform. The extract was dried and evaporated and the residue was recrystallized from methanol and methyl 2 (3-methoxyphenyl) -3,7-dimethyl-4-oxo-TPAE, melting point: 120 ° -121 ° C., was obtained. - 43 -

509821/1037

Example 66

The product of Example 58 (1 g) was diazotized and treated with fluoroboric acid as described in Example 65 treated to give the diazonium fluoroborate, which was filtered off and treated with aqueous ice cold fluoroboric acid (10%; 5 ml), ice-cold methanol (10 ml), an ice-cold methanol / ether mixture (1: 1; 10 ml) and ice cold ether (10 ml). The solid was dried in vacuo and then to an ice cold one Solution of potassium carbonate (205 mg) in trifluoroacetic acid (6.3 ml). The mixture was taking 45 minutes Heated to reflux, cooled and poured into water (30 ml). The solid was dissolved in dichloromethane and the solution with aqueous sodium hydroxide (2N; 30 ml) extracted. The extract was treated with charcoal, filtered and the filtrate with hydrochloric acid (5N) acidified. The precipitate was filtered, dried in vacuo and from a mixture of ethyl acetate and Petroleum ether (boiling point 60-80 ° C) recrystallized and 2- (3-hydroxyphenyl) -3,7-dimethy1-4-oxo-TPA, Mp 150-152 ° C obtained.

Example 67

In the same way as that described in Example 48, but when the dimethyl sulfate was replaced by diethyl sulfate, the product of Example 12 was obtained 3-Ethyl-7-methyl-2- (3-nitrophenyl) -4-oxo-TPA, m.p. 232-233 ° C.

- 44 -

509821/1037

Example 68

The product of Example 12 (1 g) was mixed with acetic anhydride (5 ml) and the mixture for one hour heated on a steam bath, excess acetic anhydride was evaporated under reduced pressure and the residue was triturated with petroleum ether (boiling point 40-60 ° C.) and a yellow solid is obtained which recrystallizes from a mixture of ether and petroleum ether (boiling point 40-60 ° C.) to obtain 4-acetoxy-7-methyl-2- (3-nitrophenyl) -DPA, m.p. 204-2O5 ° C.

Example 69

The product of Example 51 (1.5 g) dissolved in xylene (65 ml) was mixed with phosphorus pentasulfide (0.81 g) and the mixture was refluxed for 1 hour and was filtered off. The filtrate was under evaporated under reduced pressure and the residue from petroleum ether (boiling point 80-100 ° C) recrystallized and methyl-3,7-dimethyl-2- (3-nitrophenyl) -4-thioxo-TPAE, Mp: 160-161 ° C obtained.

Example 70

The product of Example 59 (5g) was made using diazotized by sodium nitrite and hydrochloric acid. Mercury bromide (2.3 g) was added and the red precipitate collected, washed with ice water and acetone, dried and converted to hexamethylphosphorus

- 45 -

509821/1037

acid triamide (40 ml).

The mixture was heated to 40 ° C. until the evolution of gas ceased, cooled, poured into water and the resulting solid collected, washed with water and recrystallized from aqueous IMS and 4-Hydroxy-7-methyl-2-phenyl-DPA, m.p .: 223-224 ° C .

- 46 -

509821/1037

Examples 71-74

In the same manner described in Example 1, starting with the appropriate naphthol and aromatic Amine obtained the acids listed in Table III.

Table III

CH ₂ COOH

N-Ar

example

Amine

Compounds obtained from 2-naphthol

Ar

G ₂ m.p. ( ⁰ C)

1,2-benzoisothiazol-5-ylamine 6-methyl

Me 150-200

1,2-benzoisothiazol-5-ylamine 6-chlorine

Benzothiazol-5- 6-ethyl ylamine

Cl 165-170

Eth 229-231

Benzothiazol-5- 6-methyl ylamine

Eth 251-253

- 47-

509821/1037

Example 75

The product of Example 15 (2 g) was dissolved in glacial acetic acid and aqueous hydrogen peroxide (1.4 ml of 100 vol. / Which were diluted with 5 ml) was added. The mixture was stirred at 30 ° C. for 30 minutes, then concentrated by evaporation and diluted with water, filtered and the filtrate left to stand and 4-hydroxy-7-methyl-2- (3-methylsulfinylphenyl) -DPA, Mp 188-191 ° C obtained.

Example 76

In the same manner as Example 75, the product of Example 35 gave 4-hydroxy-7-methylsulfinyl-2- (3-nitrophenyl) -DPA, M.p .: 150-153 ° C.

Example 77

The product of Example 39 (100 mg) was added to a saturated aqueous sodium hydrogen carbonate (100 ml) given and the mixture evaporated to a reduced volume. The solid that crystallized was recrystallized from ethanol and sodium 2- (l, 2,3-benzothiadiazol-5-yl) -7-chloro-4-hydroxy-TPAE, Mp. Above 300 ° C obtained.

Example 78

The following mixture is formed into tablets in a conventional manner. Each tablet contained 2 mg of active

- 48-509821 / 1037

seed component.

Parts

4-Hydroxy-7-methyl-2- (3-methylthiophenyl) -1,2-dihydrophthalazine-1-acetic acid 50

Corn starch 30

Lactose 163

Stearic acid 1

Preparations similar to those described above were made that act as the active ingredient in the final products of Examples 1-14 and 16-77 included.

The substituted 2-naphthol-1-sulfonic acids and their Sodium salts, which are intermediates in the examples, are new compounds.

509821/1037

Example 79

The product of Example 75 was oxidized with more hydrogen peroxide at 100 ° C and 4-hydroxy-7-methyl-2- (3-methylsulfonylphenyl) -DPA obtain. M.p .: 139-145 ° C

Examples 80-81

In the same manner as that described in Example 51, the product of Example 15 gave methyl-4-hydroxy-7-methyl-2- (3-methylthiophenyl) -DPAE, Mp .: 148.5-149 ° C, and the product of Example 71 gave methyl-2- (1,2-benzoisothiazol-5-yl) -DPAE, M.p .: 120-127 ° C

509821/1037

Claims (35)

Claims 1. Compounds of formula I (D or their enol or enthiol forms of the formula Ia (Ia) where Q is COOH, CH ₃ OH or COORg, where R _{g is} an ester-forming group, X is oxygen or sulfur, R is hydrogen or alkyl, Z is hydrogen or acyl, Ar is in the ortho positions to the site of the bond to the phthalazine ring is unsubstituted aryl and the ring J is substituted, or a pharmaceutically acceptable salt with an inorganic or organic base of a compound that is an acid. - 50- 509821/1037 2. Compounds according to claim 1 of the formula II (II) or their enol or enthiol forms of the formula Ha , R " (Ha) in which Q, X, R and Z have the meaning given in claim 1, η is 1-4, each G is identical or different can be and fluorine and / or chlorine and / or bromine and / or iodine and / or amino and / or substituted amino and / or nitro and / or cyano and / or alkyl and / or substituted alkyl and / or alkoxy and / or substituted Alkoxy and / or alkylthio and / or alkylsulfonyl and / or and / or aroyl alkylsulfinyl and / or hydroxyY and / or aryl and Rg, R ^ and Rc can be the same or different and are hydrogen and / or fluorine and / or chlorine and / or bromine and / or iodine and / or nitro and / or nitroso and / or cyano and / or Isocyano and / or amino and / or substituted amino and / or alkyl and / or substituted alkyl and / or Cycloalkyl and / or substituted cycloalkyl and / or - 51 - 509821/1 Ü 3 7 sz -SA- substituted cycloalkyl and / or alkenyl and / or aryl and / or cycloalkenyl and / or alkoxy and / or substituted alkoxy and / or alkenyloxy and / or cycloalkyloxy and / or cycloalkenyloxy and / or acyloxy and / or alkylthio and / or substituted alkylthio and / or alkenylthio and / or cycloalkylthio and / or cycloalkenylthio and / or arylthio and / or alkylsulfonyl and / or alkylsulfinyl and / or acyl and / or substituted acyl and / or aroyl and / or heteroaroyl and / or hydroxy and / or mercapto and / or Carbamoyl and / or thiocarbamoyl and / or sulfamoyl and / or substituted sulfamoyl and / or substituted and unsubstituted heterocyclic rings or R, and R * together form part of a carbocyclic or form heterocyclic ring fused to the benzene ring, the rings being substituted can, together with pharmaceutically acceptable salts with inorganic and organic bases of compounds, the acids are. 3. Compounds according to claim 1 or 2, characterized in that Q is COOH. 4. Compounds according to claim 1, 2 or 3, d a characterized in that R or Z Are hydrogen. - 52 - 509821/1 ü 3 7 5. Compounds according to claims 1-4 * characterized in that X is oxygen. 6. Compounds according to claim 2-5, characterized in that R ^ is hydrogen. 7. Compounds according to claim 2-6, characterized in that Rg is no hydrogen is. 8. Compounds according to claim 2-7, characterized in that Rg and / or R ^ Tr i fluorine thy 1 and / or methylthio and / or ethylthio and / or methyl and / or ethyl and / or chlorine and / or iodine and / or bromine and / or methoxy and / or ethoxy and / or isopropoxy and / or acetyl and / or dimethylsulfamoyl and / or diethyl sulfamic acid and / or nitro. 9. Compounds according to claim 2-6, characterized in that Rg and / or R ₄ together with the benzene ring to which they are attached form one of the following radicals and S "" 509821/1037 10. Compounds according to claim 1-3 or 5-10, characterized in that R Is methyl or ethyl. 11. Compounds according to claim 2 or 4 -7, characterized in that Rg and / or R. Ν, Ν-dimethylamino, N-methyl-p-toluenesulfonamido or N-methylacetamido and R are methyl or ethyl. 12. Compounds according to claim 2-11, characterized in that η is 1. 13. Compounds according to claim 12, characterized in that G is in the 7-position is located. 14. Compounds according to claim 2-13, characterized in that G is methyl and / or
Is ethyl and / or methoxy. 15. Compounds according to claim 2-13, characterized in that G isopropyl and / or Is fluorine and / or chlorine and / or bromine. 16. Compounds according to claim 2, characterized
characterized in that R, - is hydrogen, η is and G is in the 7-position, Q is carboxy, - 54 - 509821/1037 X is oxygen, R ^ is hydrogen and R _{3 is} not hydrogen, or R, and R ^ together form the portion of a heterocyclic ring fused to the benzene ring, and salts thereof. 17. Compounds according to claim 16, characterized in that G is chlorine, fluorine, methyl, ethyl, isopropyl or methoxy and - if R or Z is hydrogen - R _{3 is} nitro, trifluoromethyl, methylthio, chlorine or bromine or R ₃ and R - together with the benzene ring to which they are attached, benzothiazol-5-yl, l, 2,3-benzothiadiazol-5-yl or 1,2-benzoisothiazol-5-yl and - when R is methyl - R ₃ Ν , Ν-dimethylamino is. 18. 4-Hydroxy-7-methyl -2- (3-methylthiophenyl) -1,2-dihydrophthalazine-1-acetic acid. 19. 4-Hydroxy-7-methoxy-2- (3-methylthiophenyl) -1,2-dihydrophthalazine-1-acetic acid. 20. 2- (1,2,3-Benzothiadiazol-5-yl) -4-hydroxy-7-methyl-1,2-dihydrophthalazine-1-acetic acid. 21. 2- (1,2-Benzoisothiazol.-5-yl) -4-hydroxy-7-methyl-1,2-dihydrophthalazine-1-acetic acid. - 55 509821/1037 22. 2- (1,2,3-Benzothiadiazol-5-yl) ^ - chloro ^ -hydroxy-1,2-dihydrophthalazine-1-acetic acid. 23. 2- (Benzothiazol-5-yl) -7-ethyl-4-hydroxy-1,2-dihydrophthalazine-1-acetic acid. 24. 2- (Benzothiazol-5-yl) -7-methyl-4-hydroxy-1,2-dihydrophthalazine-1-acetic acid. 25. 2- (1,2-Benzoisothiazol-5-yl) -7-chloro-4-hydroxy-1,2-dihydrophthalazine-1-acetic acid. 26. 4-Hydroxy-7-methyl-2- (3-trifluoromethylphenyl) -1,2-dihydrophthalazine-1-acetic acid. 27. 2- (1,2,3-Benzothiadiazol-5-yl) -7-fluoro-4-hydroxy-1,2-dihydrophthalazine-1-acetic acid. 28. 2- (1,2,3 -Benzothiadiazol-5-yl) -4-hydroxy-7-isopropyl-1,2-dihydrophthalazine-1-acetic acid. 29. 2- (3-N, N-dimethylaminophenyl) -3,7-dimethyl-4-oxo-1,2,3,4-tetrahydrophthalazine-1-acetic acid. 30. Therapeutic preparations which contain a compound according to claim 1 to 29 in admixture with a pharmaceutical contain acceptable diluents. - 56 50982Ί / Ί037 31. Preparations according to claim 30, which are suitable for oral administration and in the form of tablets, Capsules, lozenges, powders, effervescent grains, syrups or aqueous or oily suspensions are present. 32. Preparations according to claim 30, which are suitable for rectal administration and in the form of suppositories are present. 33. Preparations according to claim 30-32, characterized in that they contain 0.1-90% by weight
included in the connection. 34. Preparations according to claims 30-33 in unit dosage form containing 0.1-500 mg of the compound. 35. Preparations according to claim 30-34, which additionally contain one or more diuretics that reduce the excretion of potassium ions depreciate an antihypertensive agent and contain a potassium salt. 509821/1037