CN104370852B - A kind of thiazolidone compound and the application in the disorderly relative disease medicine of preparation treatment iron thereof - Google Patents

Abstract

The invention discloses a kind of thiazolidone compound, its chemical structure is as shown in general formula (I).The invention also discloses the application of described thiazolidone compound in preparation treatment thalassemia medicine.Experiment confirms, the expression of hepcidin in the effective irritation cell of described thiazolidone compound energy under the concentration of 10 μMs, 6hr is exposed respectively horizontally through the dosage of 30mg/kg animal, 24hr, 48hr equally can the effectively expression of hepcidin in induced liver, and effectively reduce the level of serum levels of iron simultaneously, this thiazolidone compound energy is good is as can be seen here target spot with hepcidin, reduce the iron level in serum, be expected to the medicine becoming potential treatment and alleviate the disorderly relative disease of iron, there is potential applicability in clinical practice and economic development value widely.

Description

A thiazolidinone compound and its application in the preparation of medicines for treating diseases related to iron disorders

technical field

The invention relates to thiazolidinone derivatives and applications thereof, in particular to a novel thiazolidinone compound and its application in the preparation of medicines for treating diseases related to iron disorders; it belongs to the field of medicinal chemistry.

Background technique

Iron is an essential trace element for the body, and it is widely involved in the physiological processes of the body, such as electron transfer, DNA replication, DNA repair, etc. In some diseases, such as β-thalassemia, hereditary hemochromatosis, hepatitis C, alcoholic liver disease, renal hyperfunction, etc., are accompanied by high serum iron levels and low hepcidin expression levels symptom.

β-thalassemia is a kind of disease that seriously threatens human health. It has a high incidence in my country, especially in Guangdong, Guangxi, Guizhou, Hainan and other provinces, and frequently occurs in Southeast Asia and countries around the Mediterranean Sea abroad. β-thalassemia is a type of hemolytic anemia in which the lack of β-globin chain synthesis due to the deletion of the β-globin gene eventually leads to red blood cell deficiency and anemia.

With the in-depth research on the pathogenesis and pathological process of thalassemia, the current clinical treatment for β-thalassemia mainly includes: blood transfusion to increase hemoglobin; iron chelation to excrete excess iron from urine and feces; and Hematopoietic stem cell transplantation, etc. There are two main types of chemotherapies:

(1) α-peptide chain synthesis inhibitors: This type of drugs mainly reduces the synthesis of hemoglobin by inhibiting the synthesis of -amino-levulinase. Such inhibitors mainly include isoniazid.

(2) γ-peptide chain gene activators: This type of drug activates the γ-peptide chain gene that has been turned off by the patient, allowing the γ-peptide chain to replace the β-peptide chain, thereby playing a functional compensation role. Such activator drugs mainly include 5-azacytidine, hydroxyurea, and butyrates.

Hereditary hemochromatosis is a type of hereditary disease in which gene mutations lead to iron deposition in organs, which is mainly manifested as iron load in parenchymal cells, eventually leading to organ dysfunction. Because the mutations of different genes mainly include six types, among which HHI (HFE), HHIIA (HFE2), HHIIB (HAMP), HHIII (TFR2), HHIIV (FPN) all have similar mechanisms, that is, the expression of hepcidin is too low and Difficulty regulating ferreportin. Current treatments for hereditary hemochromatosis mainly include phlebotomy and iron dechelation agents.

Similarly, studies of hepatitis C and alcoholic liver disease have both found symptoms of low serum hepcidin levels. Therefore, the low expression of hepcidin is shown in such diseases, which suggests that hepcidin is a potential target for the treatment of such diseases, and the corresponding symptoms can be alleviated by effectively increasing the expression of hepcidin.

New medicines for the treatment of iron disorders and other diseases are constantly emerging, but they all have corresponding defects. For many severe patients, the current treatment method is accompanied by many complications and side effects, such as unstable curative effect, bone marrow suppression caused by long-term medication, etc. The result is unbearable for patients, so there is an urgent need for research and development with high efficacy and high safety. Drugs for the treatment of diseases related to iron disorders mentioned above.

Contents of the invention

In view of clinical needs, the purpose of the present invention is to provide a novel thiazolidinone compound and its application in the preparation of drugs for treating diseases related to iron disorders, especially the application in the preparation of drugs for treating thalassemia.

The main technical idea of the present invention is: in view of the fact that most of the drugs currently used for treating iron disorders have certain side effects. Blood transfusion can easily cause infection, hemolysis, iron load, etc.; compounds targeting γ-peptide chain and α-peptide chain can easily cause liver damage, gastrointestinal tract reactions, inhibit bone marrow proliferation, etc.; deferoxamine can cause hearing impairment, etc.

The above-mentioned β-thalassemia, hereditary hemochromatosis, hepatitis C, alcoholic liver disease and other diseases all show the phenomenon of insufficient expression of hepcidin. Therefore, it is urgent to develop drugs that target hepcidin and can effectively stimulate hepcidin expression. Hepcidin is a kind of short peptide produced in the liver (ChristinaH.Park.Hepcidin, aurinaryantimicrobialpeptidesythesizedintheliver.ThejournalofBio.Chem.2001276(11):7806-7810), which can specifically bind to ferroportin and degrade it , thereby regulating intracellular iron levels (ElizabetaNemeth.Hepcidinregulatescellularironeffluxbybindingtoferroportinandinducingitsinternalization.Science306:2090-2093). Therefore, the present invention takes hepcidin as a target (GardenghiS.Hepcidina satherapeutictooltolimitironoverloadandimproveanemiainβ-thalassemicmice.JClinInvest.2010120(12):4466-4477), by regulating the expression level of hepcidin in the liver, indirectly regulating the level of serum iron to alleviate excessive iron disorders. Iron load on the body.

The present invention utilizes the methods of combinatorial chemistry, molecular biology and medicinal chemistry, takes hepcidin as the main screening target, uses human liver cell line (SMMC-7721) as the carrier, and transfers the hepcidin promoter and luciferase gene through in vitro A new class of thiazolidinone derivatives that can effectively regulate hepcidin was obtained by using high-throughput screening in vitro, expression of endogenous mRNA in cells, and animal exposure experiments.

The thiazolidinone compound of the present invention has a chemical structure as shown in general formula (I):

in:

R ₁ , R ₂ and R ₃ are each independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ unsaturated hydrocarbon group, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 5-7 membered heteroaralkyl, substituted or unsubstituted 5 -7 membered heterocyclyl;

The aryl in the above-mentioned aryl or aralkyl is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl;

The above-mentioned 5-7 membered heteroaryl or 5-7 membered heterocyclic group contains 1-3 heteroatoms of oxygen, sulfur and nitrogen, and is optionally substituted by phenyl and/or one or more substituents; Wherein the substituent is selected from halogen, C ₁ -C ₆ straight chain or branched saturated or unsaturated hydrocarbon group, cyano group, nitro group, amino group, carbamoyl group, sulfamoyl group, hydroxyl group, hydroxymethyl group, ureido group, Thiourea, N-(C ₁ -C ₆ alkyl) amino, N,N-(C ₁ -C ₆ alkyl) 2 amino, trifluoromethyl, trifluoromethoxy, carboxyl, C ₁ -C ₆ alkoxy, mercapto, C ₁ -C ₆ acyl, C ₁ -C ₆ alkanoyloxy, C ₁ -C ₆ alkanoylamino, N-(C ₁ -C ₆ alkyl) ureido, N-( C ₁ -C ₆ alkyl)thioureido, C ₁ -C ₆ alkoxycarbonyl, N-(C ₁ -C ₆ alkyl)sulfamoyl, N,N-(C ₁ -C ₆ alkyl) 2 sulfamoyl, C ₁ -C ₆ alkyl sulfonylamino, N-(C ₁ -C ₆ alkyl) carbamoyl, N,N-(C ₁ -C ₆ alkyl) 2 carbamoyl, benzyl group, benzyloxycarbonyl, benzoyl and phenylsulfonyl.

A further preferred mode is: in the general formula (I), R ₁ and R ₂ are each independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl groups, substituted or unsubstituted C ₁ -C ₆ unsaturated hydrocarbon groups , substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 5-7 membered heteroaralkyl; in general formula (I), R ₃ is independent is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ unsaturated hydrocarbon group, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted aryl substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 5-7 membered heteroaralkyl, substituted or unsubstituted 5-7 membered heterocyclic group;

Wherein: the above-mentioned aryl or the aryl in the aralkyl is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; the above-mentioned 5-7 membered heteroaryl contains 1-3 oxygen, sulfur, Heteroatoms of nitrogen, and optionally substituted by phenyl and/or one or more substituents; wherein the substituents are selected from halogen, C ₁ -C ₆ linear or branched saturated or unsaturated hydrocarbon groups, Cyano, nitro, amino, carbamoyl, sulfamoyl, hydroxyl, methylol, ureido, thiourea, N-(C ₁ -C ₆ alkyl)amino, N,N-(C ₁ - C ₆ alkyl) 2 amino, trifluoromethyl, trifluoromethoxy, carboxyl, C ₁ -C ₆ alkoxy, mercapto, C ₁ -C ₆ acyl, C ₁ -C ₆ alkanoyloxy, C ₁ -C ₆ alkanoylamino, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.

A further preferred mode is: in the general formula (I), R ₁ and R ₂ are each independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ unsaturated Hydrocarbyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 5-7 membered heteroaralkyl; R in general formula (I) ₃ for hydrogen.

The most preferred thiazolidinone compound in the present invention is 2,2-R ₁ disubstituted phenylimino-5R ₂ substituted phenylmethylene-4-thiazolidinone compound.

Wherein: the most preferred specific compound of the above-mentioned thiazolidinone compound is a compound of the following structural formula:

The preparation method of the above-mentioned 2,2-R ₁ disubstituted phenylimino-5R ₂ substituted phenylmethylene-4-thiazolidinone compounds

When R ₃ =H, it can be prepared as follows:

a. Reaction of amine R ₁ -NH ₂ (1) with ammonium thiocyanate NH ₄ SCN (2) to generate corresponding NR ₁ substituent thiourea (3);

bN-R ₁ substituent thiourea (3) reacts with ethyl chloroacetate (4) to generate the corresponding 2-R ₁ substituent imino-4-thiazolidinone (5);

c. The 2-R ₁ substituent imino-4-thiazolidinone (5) reacts with the aldehyde R ₂ -CHO (6) to generate the corresponding 2-R ₁ substituent imino-5-R ₂ Methylene-4-thiazolidinones (7);

The chemical reaction formula for the preparation of the above 2,2-R ₁ disubstituted phenylimino-5R ₂ substituted phenylmethylene-4-thiazolidinone compounds is as follows:

The application of the thiazolidinone compound of the present invention in the preparation of drugs for inducing the expression of hepcidin in the liver.

Application of the thiazolidinone compound described in the present invention in the preparation of medicaments for treating thalassemia.

Wherein: the thiazolidinone compound is preferably 2,2-R ₁ disubstituted phenylimino-5R ₂ substituted phenylmethylene-4-thiazolidinone compound. Most preferred are the above-mentioned compounds numbered 76#, 186#, 268#, 277#.

The invention provides a pharmaceutical preparation for treating iron disorders, characterized in that: the preparation contains an effective amount of 2,2-R ₁ disubstituted phenylimino-5R ₂ substituted phenylmethylene-4- Thiazolidinone compound and pharmaceutically acceptable carrier. Among them, the 2,2-R ₁ disubstituted phenylimino-5R ₂ substituted phenylmethylene-4-thiazolidinone compounds are preferably the above-mentioned numbered 76#, 186#, 268#, 277# compound of.

Experiments have proved that the thiazolidinone compound of the present invention can effectively regulate the expression of hepcidin at a concentration of 10 μM, and at the same time effectively reduce the level of serum iron, and has no toxic effect on cells. By screening the thiazolidinone compounds of the present invention, it was found that many thiazolidine compounds of the present invention, especially the above-mentioned compounds numbered 76#, 186#, 268#, and 277#, could induce hepcidin in the mouse liver. Enhanced expression, and effective reduction of serum iron levels.

The invention discloses a novel thiazolidinone compound and its application in the preparation of medicines for treating iron disorder-related diseases, especially the application in the preparation of medicines for treating thalassemia. It has been confirmed by in vitro/in vivo experimental analysis that the thiazolidinone compounds provided by the present invention can better target hepcidin and reduce iron levels in serum, and are expected to become potential drugs for treating and alleviating iron disorder-related diseases, and have a wide range of clinical application prospects and economic development value.

Description of drawings

Figure 1: No. 76#, 78#, 96#, 128#, 186#, 1251#, 252#, 254#, 268#, 277# exposed to SMMC-7721 cell line at a concentration of 10M, all of which can induce cells Expression of hepcidin within.

Figure 2: After exposure to BALB/C mice with numbers 76#, 186#, 268#, and 277# at a concentration of 30 mg/kg, the expression of hepcidin in the liver was induced.

Figure 3: No. 76#, 186#, 268#, 277# exposed to BALB/C mice at a concentration of 30 mg/kg, effectively reduced serum iron levels.

detailed description

Example 1

Preparation of 2-(2-chlorophenylimino)-5-(4-hydroxy-3-methoxybenzylidene)-1,3-thiazol-4-one

According to the ratio of HCl:H ₂ O (1:4) dubbed hydrochloric acid solution. Weigh 11.4g (150mmol) of ammonium thiocyanate and dissolve it in 50mL of hydrochloric acid solution, add 10.5mL (100mmol) of 3-toluidine, heat to 85°C under stirring conditions, the mixture becomes clear, after 12 hours of reaction, TLC monitors the reaction, After the reaction, the mixture was cooled to room temperature, and a viscous oily liquid appeared, which was extracted with ethyl acetate, and the extract was washed with 10% hydrochloric acid solution, saturated sodium chloride solution, and water successively, and the solvent was evaporated off the extract under reduced pressure to obtain 2-Tolylthiourea.

Add 996mg (6.0mmol) of 2-tolylthiourea and 2479mg (30mmol) of anhydrous sodium acetate into 20mL of ethanol, add 1.28mL (12mmol) of ethyl chloroacetate under stirring conditions, and then heat at 60°C for 6 Hours, TLC detection reaction, after the reaction was cooled to room temperature, precipitation occurred. The reaction solution was filtered, and the solid was washed with ethanol to obtain part of the crude product. The filtrate was distilled under reduced pressure, then extracted with ethyl acetate and water, and the organic phases were combined to obtain more crude product. The crude product was recrystallized from ethyl acetate to give the product 2-(3-tolylimino)-1,3-thiazol-4-one.

Weigh 103 mg (0.5 mmol) of 2-(3-tolylimino)-1,3-thiazol-4-one and dissolve it in 3 mL of ethanol, add 117.6 mg (0.6 mg) of 3,4,5-trimethoxybenzaldehyde mmol), piperidine 100 μL, on a parallel synthesizer, oscillating at a constant temperature of 60°C, and reacting for 24 hours. The reaction is monitored by TLC. After the reaction is completed, it is cooled to room temperature. During the reaction, a large amount of precipitates are formed. After analysis and characterization, the precipitate is the product 2-(3-tolylimino)-5-(3,4,5- Trimethoxybenzylidene)-1,3-thiazol-4-one. Filter, wash with ethyl acetate, ethanol, and petroleum ether in sequence. If no precipitate is formed, evaporate the solvent to dryness, add ethanol (ethyl acetate) or petroleum ether in a ratio of 1:2, shake, and most of the precipitate will appear. After filtering, the filter residue was washed successively with a large amount of ethyl acetate, ethanol, and petroleum ether. Those still without precipitation were separated by silica gel column chromatography, and the developing solution was composed of ethyl acetate and petroleum ether in different proportions.

The product is a yellow powder with a yield of 33.26%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.6 (s, 1H), 7.72 (s, 1H), 7.06 (m, 6H), 3.83 (s, 9H) , 2.34(s,3H).C ₂₀ H ₂₀ N ₂ O ₄ S, ESI-MS: m/z 385.1 (M+1) ⁺ .

Example 2

76#.2-(2-chlorophenyl)-5-(9H-fluorenylbenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 75.5%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.0 (s, 1H), 7.85 (m, 2H), 7.72 (s, 1H), 7.45 (m, 9H) , 4.12(d,2H).C ₂₃ H ₁₅ ClN ₂ OS, ESI-MS: m/z 403.7 (M+1) ⁺ .

Example 3

78#.2-(2-Chlorophenyl)-5-(4-methylthiobenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is orange powder, the yield is 92.6%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.2 (s, 1H), 7.72 (s, 1H), 7.49 (d, 1H), 7.35 (m, 7H) , 2.53(s,3H).C ₁₇ H ₁₃ ClN ₂ OS ₂ , ESI-MS: m/z 360.0 (M+1) ⁺ .

Example 4

96#.2-(4-chloroanilino)-5-(9H fluorenylbenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 74.1%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.0 (s, 1H), 7.85 (m, 2H), 7.72 (s, 1H), 7.46 (m, 7H) , 7.02 (d, 2H), 4.12 (d, 2H). C ₂₃ H ₁₅ ClN ₂ OS, ESI-MS: m/z 403.7 (M+1) ⁺ .

Example 5

128#.2-(3-nitroanilino)-5-(2-chlorobenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 72.8%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.0 (t, 3H), 7.80 (d, 1H), 7.71 (t, 1H), 7.30 (m, 5H) .C ₁₆ H ₁₀ ClN ₃ O ₃ S, ESI-MS: m/z 360.0 (M+1) ⁺ .

Example 6

186#.2-(4-hydroxyanilino)-5-(2-hydroxybenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 95.7%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.5 (s, 2H), 7.60 (d, 1H), 7.16 (m, 3H), 7.06 (m, 1H) , 6.96 (m, 1H), 6.80 (m, 3H), 5.35 (s, 2H). C ₁₆ H ₁₂ N ₂ O ₃ S, ESI-MS: m/z 313.1 (M+1) ⁺ .

Example 7

251#.2-(3-fluoroanilino)-5-(3-methoxy4-hydroxybenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 92.7%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.1 (s, 1H), 7.72 (s, 1H), 7.15 (m, 7H), 5.35 (s, 1H) , 3.82(s,3H).C ₁₇ H ₁₃ FN ₂ O ₃ S, ESI-MS: m/z 345.1 (M+1) ⁺ .

Example 8

252#.2-(3-fluoroanilino)-5-(4-methoxybenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is yellow powder, the yield is 44.2%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.6 (s, 1H), 7.72 (s, 1H), 7.03 (m, 8H), 3.83 (s, 3H) .C ₁₇ H ₁₃ FN ₂ O ₂ S, ESI-MS: m/z 329.1 (M+1) ⁺ .

Example 9

254#.2-(3-fluoroanilino)-5-(4-N,N dimethylaminobenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 97.4%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.5 (s, 1H), 7.72 (s, 1H), 7.15 (m, 8H), 3.06 (s, 6H) .C ₁₈ H ₁₆ FN ₃ OS, ESI-MS: m/z 342.2 (M+1) ⁺ .

Example 10

268#.2-(4-fluoroanilino)-5-(4-methylthiobenzylidene)-1,3-thiazol-4-one

The preparation method is similar to the preparation of the compound of Example 1.

The product is a yellow powder with a yield of 89.5%; ¹ HNMR (400MHz, CDCl ₃ ) δ (ppm) = 8.8 (s, 1H), 7.82 (s, 1H), 7.32 (m, 8H), 2.53 (s, 3H) .C ₁₇ H ₁₃ FN ₂ OS ₂ , ESI-MS: m/z 345.1 (M+1) ⁺ .

The structural formulas of the specific compounds involved in the preparation of the products in Examples 1 to 10 are summarized as follows:

Example 11

In vitro/in vivo assays

In vitro experiment: at the cellular level, human hepatoma cell line smmc-7721 was used as the experimental cell line. After exposure to a concentration of 10 μM, the expression level of hepcidin mRNA in cells was observed for 24 hours to evaluate the efficacy of the drug on the cells.

The results are shown in Figure 1. No. 76#, 78#, 96#, 128#, 186#, 1251#, 252#, 254#, 268#, 277# were exposed to the SMMC-7721 cell line at a concentration of 10M, all of which could induce the production of intracellular hepcidin Express.

In vivo experiment: BALB/C was used as an animal model to evaluate the efficacy of the drug after 6hr, 24hr, and 48hr administration.

The results are shown in Figure 2. The numbers 76#, 186#, 268#, and 277# were exposed to BALB/C mice at a concentration of 30 mg/kg to induce the expression of hepcidin in the liver. At the same time, after exposure to BALB/C mice with numbers 76#, 186#, 268#, and 277# at a concentration of 30 mg/kg, the serum iron level was effectively reduced; the results are shown in Figure 3.

The above experiments prove that: the thiazolidinone compound of the present invention can effectively stimulate the expression of intracellular hepcidin at a concentration of 10 μM, and at the animal level, the dose of 30 mg/kg exposed for 6hr, 24hr, and 48hr can also effectively induce hepcidin expression in the liver. The expression of hepcidin in the blood can effectively reduce the level of serum iron at the same time. It can be seen that the thiazolidinone compound can better target hepcidin to reduce the level of iron in the serum, and it is expected to become a potential treatment and relieve iron deficiency. Drugs for disorders-related diseases have broad clinical application prospects and economic development value.

Claims (3)

1. formula 1 or the thiazolidone compound described in formula 2 adjust element (hepcidin) to express application in medicine preparing iron in induced liver, wherein: thiazolidone compound described in formula 1 or formula 2 is the compound of following structural formula:

2. apply as claimed in claim 1, it is characterized in that: the compound of described thiazolidone compound to be structural formula be formula 1.

3. treat a pharmaceutical preparation for iron disorders, it is characterized in that: described preparation is the thiazolidone compound of formula 1 or formula 2 and pharmaceutically acceptable carrier containing the structural formula described in claim 1 of significant quantity.