JPS5862112A - Biological therapy - 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 therapeutic methods. Sulfonylurinellll
Many anti-diabetic drugs such as 1lII can effectively lower blood clots, but they can also be used to treat cataracts and neurological diseases.

6 U.S. Pat.
585, 14.117, 230, 11d, 1
5G, No. 714, No. 4127.445 and 1ii
No. 421 to No. 667 suggest that various aldose reductase inhibitors are useful in this regard. Such compounds include aldoses such as glucose and galactose, sorbitol and galactitol. The harmful effects of polyols on inhibiting the enzymatic reduction to different 'polyols, such as KjP, in the affected organs of the body! For example, inhibition of glucose reduction may reduce the accumulation of glucose in the lens and retina of diabetic cataracts (D) and in the peripheral nerves of diabetic neuropathies.
Preventing the osmotically traumatic accumulation of sorbitol in the kidneys of IjI disease.A variety of bis- and bis-chromones, penzodipane, and pitsquinolinones have prophylactic antiallergic properties. - It is known that Surprisingly, it has now been discovered that these compounds may be used in the prophylactic or therapeutic treatment of cataracts, retinopathy, kidney disease, vascular disease, and neurological diseases in patients with chronic urine disease. f14
According to the ``Diseases'', diabetes mellitus is used to treat cataracts, retinopathy, neurological diseases, vascular diseases, or kidney diseases associated with galactosemia (hereinafter collectively referred to as ``diseases'') either prophylactically or oleaginously. At the same time, iodine, optionally substituted -
The alkoxy group contains at least two substituents on the benzene product! bilan-4-one-2-carboxylic acid or a pharmaceutically acceptable derivative thereof, and preferred 11. < is an active ingredient with sodium cromoglycate-like activity that may cause such a condition or 1IAJ! A method is provided comprising administering the drug to a susceptible patient.

When benzopyran-4-one-2-carboxylic acid has two or more substituents on the benzene group,
Adjacent pairs of these substituents may be fused to form a third term, e.g. jointly chain -COCH-0 (COOH
)-NR11- or II2 chain-COCH=C(C
! 0OH)-0-1 formation.

Compounds with sodium chromoglycate-like activity inhibit the release of pharmacological mediators resulting from the in vivo binding of certain types of antibodies and specific antigens, such as reactive antibodies and specific antigens. [UK Patent No. 1292.401 specification (
Example 27) See section "Passive dermal anaphylaxis test in rats").

Compounds with sodium cromoglycate-like activity are characterized by the following biological tests and results.

Compounds are first tested in a passive cutaneous anatsuiraxy test in rats. If the compound does not show significant inhibition of allergy development in this test at an intravenous (i, p,) or intravenous (1, ma) dose of 2 oq/Kg of Wta, its activity is generally too low. KaiA ( D Other well-known biological tests may be employed.

A particular group of active ingredients are chromone-2-carboxylic acids, and suitable derivatives thereof, such as those described in British Patent No. 156B, 24
No. 5, No. 1144905, No. t2sO,087 and German Patent No. 2.553.688. Other active ingredients are Belgian patents 86122 and 8879.757.
This is a pyranoquinolinone described in each specification of the No.

Particularly preferred are British Patent Nos. 1,144.905 and 1230.087 and West German Patent No. 2.5.
53.6B8 These are chromones and chromone-like compounds described in each specification. For details, see formula■,■,
hydrogen, V or V (wherein R1 is hydrogen, hydroxy or hydroxylamine, R2 and R3 may be the same or different and each represents hydrogen, an alkyl group having 2 to 6 carbon atoms) , R5, R8, R? and R
The latter two of lo may be the same or different,
each alkyl, R6, R7, R12 and R
ts/d, which may be the same or different, each hydrogen.

hydroxy or alkoxy having 1 to 6 carbon atoms], 2 is a single bond or a group -0XO-
Deru! is alkylene having 2 to 6 carbon atoms optionally substituted by 10H), Y#1
-NRll- or -〇-, R11 is hydrogen or alkyl, and Rtati hydrogen, hydroxy, or iodine, provided that if R1, R2, and R1 are all hydrogen, then R14 is not hydrogen or hydroxy) or any pharmaceutically acceptable derivative thereof having i.

Pharmaceutically acceptable derivatives of benzobylan-4-one-2-carboxylic acid include pharmaceutically acceptable derivatives of the 2-carboxylic acid group, esters and ions.

Suitable salts include ammonium salts, alkali metal salts (e.g. sodium, potassium and lithium salts) and alkaline earth metals (e.g. calcium or magnesium salts), and salts with suitable radicals such as hydroxyl. salts with amines, salts with lower alkyl amines such as methylamine or ethylamine, salts with substituted lower alkyl amines such as hydroxy-substituted alkylamines such as tri(hydroxymethyl)-methylamine;
Alternatively, simple monomer-containing multi-accumulative compounds such as salts with biridine or morpholine are included. Suitable esters include simple lower alkyl esters, such as ethyl ester, alcohols containing basic groups, such as those derived from di-lower alkyl71-substituted alkanols.
esters such as -(diethyl 1))-ethyl ester, and acyloxy lower alkyl esters such as piparoyloxymethyl ester, or bis-esters derived from polyhydroxy compounds such as ly-(1
droxy-lower alkyl) ester, f'1lJjf his-2-o middle two pro/zono1. Pharmaceutically acceptable addition salts of basic esters, including S-diyl esters, such as salts, hydrobromide salts, oxalates, and rFi7 malates, are also used. The esters may be prepared by conventional methods such as esterification, transesterification or by reacting the acid or its salt with a suitable metal compound having a good leaving group. The amines V may be unsubstituted or, for example, 7- or 1-04-alkyl and can be prepared in a conventional manner, for example by reacting an ester of the corresponding acid with ammonia or a suitable amine. ] can be manufactured. Preferably, the sodium salt is used.
The method of the present invention is applicable to cataracts, retinopathy, and kidney disease.

It can be used in the prophylactic and therapeutic treatment of chronic complications of diabetes, such as vascular and neurological diseases, and the in vivo enzymatic reduction of harmful aldoses associated with diabetes, galactosemia, etc. They can be administered to patients in need of treatment by a variety of conventional routes of administration, such as orally, intravenously, intramuscularly, subcutaneously, topically, ophthalmically (as drops into the abdomen) and intraperitoneally).
can be administered. Administration may also be by intranasal or oral inhalation. To prepare a suitable composition, the active ingredient is processed with inorganic or organic pharmaceutically acceptable adjuvants or excipients. Examples of such adjuvants KFi
The following can be mentioned.

Tablets, capsules and dragees contain microcrystalline cellulose,
The herbal medicine contains natural oils, %/% hydrogenated oils or waxes; The composition for inhalation is crude lactose. The active ingredient is (LOI)
~1° mass average diameter of an electrochron (mass media
It is preferable to have a form having a n diameter. The compositions of the invention may also contain suitable preservatives, stabilizing and wetting agents, solubilizing agents, sweetening agents, and coloring and flavoring agents.
M may also be prescribed. Compositions adapted to be taken orally and to release their contents in the gastrointestinal tract are preferred.

Preferably each of R1 to RIJIC (if they contain carbon) contains from 1 to 6 and preferably from 1 to 4 carbon atoms.Specific compounds used as active ingredients include: , 1,3-bis-(2-carboxychromon-5-yloxy)-pro/4-en-2-ol, 1,5-his-(2-carboxychromon-6-yloxy)-pro/cen-2- All, 1,5-bis-
(2-carboxychromon-7-yloxy>-fropan-2-ol.

-15-bis-(2-carboxychromon-7-yloxy)-hantane.

6.7.8.9-Tetrahyvlow-5-hydroxy-4-
Okino 10-propyl-4H-naphtho[2,5-b
) pyran-2-carboxylic acid, 4,6-thioxo-10-
Propyl-4H,6H-pyrano (S, 2-g)”
? Nolino 2.8-dicarboxylic acid, 4.6-dioxo-10-propyl-4H,4H-benzo(s,2-g)pyran-2,8-dicarboxylic acid, 5-(2-hydroxypropoxy)-chromone- 2-Carboxylic acid, 5-(2-hydroxypropoxy)-8-propyl-chromone-2-carvone #I! , 6.8- Sea JIE
i-thiyl-chloro-2-carboxylic acid, 5-eYadt-6,8-diethyl-2-carboxylic acid,
carboxylic acid.

6.7,8. ? -tetrahydro-4-okyne-10-propyl-4H-naphtho(2,5-b)pyran-2-carboxylic acid.

1.3-bis-(2-carboxy-5-hydroxy-7
-yloxy)-pro/(n-2-ol-8-propyl-7-(3-(4-acetyl-5-hydroxy-2-propylphenoxy)-2-hydroxypropoxy;]-4-okine-4H-1- Benzopyran-2-
carboxylic acid.

2.21-dicarboxy-5,5',7.7'-tetramethoxy-8,8'-bicromonyl, 2.22-dicarboxy-7,7'-dimethoxy8
．． 8'-bicromonyl, 7-! I-Docromone-2-carboxylic acid, and 7-HyVroxy13-ii-Bichromone-2-carboxylic acid, and pharmaceutically acceptable salts thereof, such as the sodium salt. This will of course vary depending on the condition being treated, its severity and its location. The dosage administered will also vary with the mode of administration and the particular compound employed--but generally from about 0.1 #4000
It is appropriate for the daily dose of the drug to be administered in divided doses, e.g. 15 to 50 minutes before meals; generally the medication is given four times a day, three times before meals and once before bedtime. However, in some circumstances it is possible to administer up to 10 times a day. 1,3-bis-(2-carboxychromone-5) at a dosage of 10 MN or more
It is preferable to use pan-2-ol, a conductor of 10 pan-2-ol (10-yloxy), which is one of the active ingredients in chronic diabetic complications and aldose.
The ability to control f# elementary reduction is determined by a number of semi-biological and pharmacological tests. These include (1) determination of the ability of isolated aldose-reducing compounds to suppress the activity of (z)-sorbitol in the sciatic nerve of acutely administered streptocytocin-treated (i.e. diabetic) rats; (8) Measurement of the ability to reverse the already elevated fluvitol levels in the sciatic nerve and lens of chronic streptocytosine-induced diabetic rats; (4) Acute galactose (6) Determination of the ability to halt or suppress galactitol formation in the lens of hyperemic rats; and (6) Determination of the ability to delay cataract formation and reduce the severity of lens opacity in chronic galactosemic rats. The invention is illustrated by, but is not limited to, the following example: EXAMPLE A Reduction #Element Inhibition Activity According to the procedure described in U.S. Pat. No. 4,821,483. and Hayman M.'s ``Journal of Biological Studies'' (
Journal of Biological
Chemistry) J Vol. 240 No. 877 (1)
The ability to reduce or inhibit the activity of aldose reductase based on the procedure described in 945)
The active ingredients listed above are tested. The substrate used is a partially purified aldose-reducing compound obtained from the crystalline lens of the crystalline lens.The drug was tested at 10-4 M in the ninth stage to determine the degree of inhibition of enzyme activity compared to untreated controls. Then, AI is tested on different rails to measure IC5Q4 straight.

Example B Suppression of Sorbitol Accumulation The active ingredients described above were administered to streptocytosine to reduce or suppress sorbitol accumulation in the sciatic nerve of diabetic (i.e. diabetic) rats by procedures substantially as described in US Pat. The ability to do things will also be tested.

In the current study, the amount of sorbitol accumulation in sciatica MiK #'i is measured 27 hours after the induction of diabetes. The compound was administered at 4.8 following administration of streptocytosine.
and at 24 hours at a dose level equivalent to 'I11. The results obtained with this method are expressed as the percent inhibition obtained by the test compound compared to a control that was not sham administered with any compound (i.e., in untreated animals, sorbitol levels are normally 1 y of tissue). Approximately 5
Tissue 1 during the 27 hour test period from 0 to 100 mmol
f per j) rises to a height of 400 f remol).

Example C Human placenta aldose orphan #raw placenta IKIIt-25 mm of pH 44 + phosphate buffer 2
Homogenize using t and 17. Centrifuge for 30 minutes at OOOF and then transfer the effluent to Con A'-8sspharose 4B.
A human placenta homogenate solution is prepared by flowing down the iy Clam Pharmacia product.

Column preparation 4-carboxybenzaldehyde2. 15j' of M-Sepharose 4B, previously swollen in 2005 g of α5m sodium chloride and washed on a glass filter with 3 L of distilled water, is added to 100 μl of a dioquinane-water (1!1) solution containing OF. - 1-Ethyl-5-(5-dimethylaponopropyl)-carbosioid hydrochloride 1881 dissolved in 105 g of water is added dropwise to this slurry. The mixture quickly becomes turbid and an additional 30°C of tetrahydrofuran is added. The mixture is placed on a shaker at room temperature while the pH is maintained below 5.0 for the first hour. After 72 hours, the clear mixture was dioxane-water (
1 Step 1) Wash the mixture twice with 250 liters of water and 2 tons of water. 1 Then wash with 250 sd of pH 4 buffer. End〕
The bound Sepharose is washed with pH&2 (standard) buffer and loaded into a Pharmacia 1v40 column.

Preparation of human placental aldose reductase To 1,500 d of placenta solution, add 125 μl of sugar alcohol and 1.1,000 sd of saturated ammonium sulfate solution.

After standing for 30 minutes, the solution is centrifuged at 45,000 f for 10 minutes and an additional 250 g of saturated ammonium sulfate solution is added to the stage solution.

After standing for 50 minutes and centrifuging, powdered ammonium sulfate 427f is added under stirring.

The sediment collected after standing and centrifugation (approximately 50-7
ON saturation) is dissolved in a minimum amount of standard buffer and dialyzed twice against 6t of standard buffer.

The resulting solution is stored (by freezing in liquid i1). A small amount of enzyme can be obtained by passing a portion of this solution through the column using a standard buffer and eluting it with a standard buffer having a zero-order 1M sodium chloride gradient.

Preparation weight of rat lens aldose reductase: 125~
Spray Goudry rats with 150 p are asphyxiated with elemental carbon dioxide gas. After the eyeballs are removed, the lens is carefully removed and homogenized in cold distilled water (0.4 d/lens). 10,000 of this homogenate
Centrifuge for 10 minutes at vpm.

Guilford (oixforl) 2400-2 34 Q nm with double vinyl five-minute photometer with automated compensation device
And complement NADPH! The aldose reductase activity of the supernatant is assayed spectrophotometrically by measuring the percent decrease. The reaction mixture contained T)H6,2 in a total volume t0〇
phosphate buffer (approximately 0.1 m), NADPH (o,
104 mm), and DL-glyceraldehyde ('1
0mo). The reference blind contains all of the above compounds except the glyceraldehyde substrate.

Appropriate blinding is used to correct for non-specific reduction of NADPH and any uptake of inhibitor. The inhibition % of each compound is based on fI! and compound at a given concentration by comparing the reaction rate of a solution containing the compound with that of a control solution containing only the substrate, and
The fl value is calculated. The average speed of the control solution is 172 per minute
±o, szng/-. The protein concentration was determined by Bradford (nraarora)'s “Analyt, Bi
och@m, J Vol. 72, pp. 248-254 (1976
) followed the method described by K., and Kalck.
ar)'s equation ["J.

Biol, Chem, J Vol. 167, 461-475.
(1947)] i.e. t 45A286-0.74 A24 (1=N/ml
is measured spectrophotometrically by using

Claims (1)

[Scope of Claims] 1) 11 K-attotherapy for preventive or oil-dynamic treatment of cataract, retinopathy, neurological disease, vascular disease, or kidney disease related to urinary disease or galactosemia. , iodine, an optionally substituted alkoxy group I/& is a benzopyran-4-one-2-carboxylic acid having at least two substituents on top of the benzene, or its pharmaceutically acceptable counterpart. An effective amount of the active ingredient is administered to a person suffering from or suffering from the above-mentioned condition. 2) The method according to claim 1, wherein the active ingredient has sodium chromomelicate-like activity. 3) The active ingredient is of formula I, 1.厘, y is - is V (in the formula R1
is hydrogen, hydroxy or dialkoxy, and sRx and Ri may be the same or different, and each is hydrogen, alkyl having 2 to 6 O bulk atoms, or iodine. ), R4 is hydrogen or hydroxy, Rt%R8, R? and R.I.D.
the latter two being the same or different (and each being alkyl), R6, R7, R1! and R1
! 1 may be the same or different and may be hydrogen, hydroxy or alkoxy with 1 to 6 carbon atoms in JP), 2 may be a single bond or the group -0x
O-, X is alkylene having 2 to 6 carbon atoms, optionally substituted by -O;
is -NR11- or -O-), Rlt is hydrogen or alkyl, and R14 is hydrogen, hydroxy or iodine - provided, however, that when R15R1 and Iku are all hydrogen, Shakasu 4 is hydrogen %L, 4) The method according to claim 1, wherein the active ingredient is It consists of administering the drug orally or by inhalation. 5) The active ingredient is 1,3-bis-(2-carboxyphen-5-(ruoxy)--/dinon-2-ol). 4.6-Sioquinol 10 -Propyl-4H,6H-pyrano[5,2-g)quinoline-2,8-dicarboxylic acid. 4.6-Shioxo-10-propyl-4H,6H-benzo(3,2-g)pyran-2,8-dicarboxylic acid, 5-(2-hydroxyzolopoxy)-8-probylutasemon-2-carboxylic acid ,SuiL 8-propyl-7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy-4-oxo-4H-1--: Nzopyran-2
-Carbon Chestnut. or a pharmaceutically acceptable salt thereof. 6) The method according to claim 8, wherein the active ingredient is administered at a daily dose of 4000 ml.
method fist