CN112656791A

CN112656791A - Compound for treating maple syrup urine disease

Info

Publication number: CN112656791A
Application number: CN202110139143.0A
Authority: CN
Inventors: 洪楠方
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-02-01
Filing date: 2021-02-01
Publication date: 2021-04-16

Abstract

The invention discloses an application of an ammonia derivative in preparation of a medicine for treating maple syrup urine disease, and relates to the field of medicines. The compound has a general formula of H₂N-G, and can generate nucleophilic addition reaction with plasma alpha ketonic acid to generate a product with a carbon-nitrogen double bond structure; wherein G is NHR OR OR. The compound of the invention can directly remove the branched-chain alpha keto acid accumulated in the body of a patient and obviously improve the maple sugarSymptoms of the urinary diseases, easy taking, quick absorption, small toxicity, little side effect, low price and easy popularization.

Description

Compound for treating maple syrup urine disease

Technical Field

The invention relates to the field of medicines, and in particular relates to application of an ammonia derivative in preparation of a medicine for treating maple syrup urine disease.

Background

Maple syrup urine disease is also called branched-chain alpha-ketoacid dehydrogenase deficiency, because of the congenital deficiency of alpha-ketoacid dehydrogenase (BCKD), normal branched-chain alpha-ketoacid in vivo cannot be metabolized and discharged out of the body, and accumulates in vivo, causing a series of symptoms. Specifically, the main branched chain amino acids in the human body under normal conditions: leucine, isoleucine, valine, and the like are degraded and metabolized to α -keto acid (KIC), α -keto- β -methylvaleric acid (KMV), and α -ketoisovaleric acid (KIV), respectively, by the action of in vivo branched chain amino acid transaminase (BCAT). The further metabolism of these 3 ketoacids requires the participation of the branched-chain ketoacid dehydrogenase complex (BCKD), which, if the BCKD activity is deficient, leads to an increase in the concentration of branched-chain amino acids in the blood and excretion from the urine, resulting in a distinctive odor; the 3 ketoacids are accumulated in the body, and the 3 ketoacids are toxic substances to the nervous system of the human body, so that a series of symptoms of the maple syrup urine disease are caused, and the maple syrup urine disease is an autosomal recessive inherited dysbolism disease.

Maple syrup urine disease is particularly prominent in the infant population and infants with this disease may appear normal at birth. Within three to four days, however, symptoms may appear, which may include loss of appetite, dysphoria, and sweet urine. The increase in the amino acid content of urine produces an odor that reminds of maple syrup. This is the cause of Maple Syrup Urine Disease (MSUD). If left untreated, the condition usually worsens and babies seizures, enter a coma and die within the first few months of life. The clinical manifestations of the disease are extremely heterogeneous, and the disease is difficult to diagnose from asymptomatic to severe clinical manifestations; meanwhile, because of autosomal recessive inheritance, family history cannot be predicted for prevention and treatment. Therefore, the disease is sudden and difficult to prevent. The treatment of maple syrup urine disease is currently receiving a great deal of attention, and the current methods used in the medical community to treat maple syrup urine disease are generally as follows:

1. diet control, namely controlling the concentration of amino acid in a body, but the patient needs to restrict diet for the whole life, which brings limitation and inconvenience to the life of the patient;

2. the administration of a large dose of vitamin B1 (thiamine) and intravenous high-energy nutrition, thiamine pyrophosphate can keep the BCKD complex stable, so that the tolerance of a patient to branched chain amino acid is increased, but the method needs to be continued to a hospital for medical treatment, and the long-term intravenous infusion of the high-energy nutrition, vitamin B1 and the like not only bring inconvenience to the normal working life of the patient, but also aggravate the pain of the patient;

3. dialysis treatment to remove a large amount of leucine accumulated in blood, and the method also needs to be continued to a hospital for medical treatment, so that the economic burden and the psychological burden of patients are increased;

4. liver transplantation, which results in a significant increase in branched-chain 2-oxoacid dehydrogenase activity, involves significant expense, surgical risks and outcomes.

Therefore, the current methods for treating maple syrup urine disease are all deficient and do not facilitate optimal treatment of the patient. In view of the current situation, the present application starts from the onset symptoms and mechanisms, designs and researches a group of new drugs capable of directly removing branched-chain alpha keto acid accumulated in the body of a patient, and obviously improves maple syrup urine disease symptoms.

Disclosure of Invention

The invention aims to provide application of an ammonia derivative in preparing a medicament for treating maple syrup urine disease, which can directly remove branched-chain alpha keto acid accumulated in a patient body and obviously improve maple syrup urine disease symptoms.

In order to achieve the purpose, the technical scheme of the invention is as follows:

firstly, the invention provides a compound of general formula H₂The N-G compound can generate nucleophilic addition reaction with alpha keto acid in plasma to generate product with carbon-nitrogen double bond structure.

Wherein G is NHR OR OR, and R is a substituent.

The reaction general formula of the nucleophilic addition reaction is as follows:

the medicine for treating maple syrup urine disease comprises an effective dose, and the general formula is H₂A compound of N-G and a pharmaceutically acceptable carrier, wherein G is NHR OR OR, R is a substituent group, and the effective dose is 15-50 mg/kg.

Preferably, R is selected from:

any one of the above.

Further preferably, the compound is selected from:

still further preferably, the compound is selected from:

most preferably, the compound is

Isoniazid is selected as the optimal drug, because isoniazid has good water solubility, easy absorption by oral administration, high selectivity, little side effect and little toxicity, can well achieve the treatment effect, and simultaneously has low price, thereby being beneficial to popularization in poor areas.

The medicine for treating maple syrup urine disease comprises the compound and a pharmaceutically acceptable carrier, wherein the effective dose of the compound is 15-50 mg/kg.

Preferably, the dosage form of the medicine is selected from any one of oral preparation, injection, nasal spray, sublingual tablet, inhalant and implant; further preferred is an oral preparation.

The oral dosage form is selected from any one of tablet, oral liquid, suspension, capsule, granule, pill, powder, dripping pill, syrup, mixture, distillate, effervescent, paste, emulsion and tea.

The pharmaceutically acceptable carrier is selected from any one or combination of an antibacterial agent, an antioxidant, a preservative, a stabilizer, a flavoring agent or an aromatizing agent.

Compared with the prior art, the invention has the following beneficial effects:

the compound of the invention can directly remove the branched-chain alpha-keto acid accumulated in the body of a patient, obviously improve the symptoms of maple syrup urine disease, and simultaneously has the advantages of easy administration, quick absorption, small toxicity, less side effect, low price and contribution to popularization.

Drawings

FIG. 1 is a structural diagram of a reaction product A obtained by reacting alpha keto acid with isoniazid in plasma;

FIG. 2 is a structural diagram of a reaction product B obtained by reacting alpha keto acid with isoniazid in plasma;

FIG. 3 is a structural diagram of a reaction product C obtained by reacting alpha-keto acid with isoniazid in plasma.

Detailed Description

The present invention will be further explained with reference to specific examples in order to make the technical means, the technical features, the technical objectives and the effects of the present invention easier to understand, but the following examples are only preferred embodiments of the present invention, and not all embodiments of the present invention. In the interest of clarity, not all features of an actual implementation are described. In the following description, well-known functions or constructions are not described in detail since they would obscure the invention in unnecessary detail. It will of course be appreciated that in the development of any such actual embodiment, numerous implementation-specific details must be set forth in order to achieve the developer's specific goals. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.

The experimental methods in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Example 1 therapeutic Effect of Isoniazid on MSUD model mice

Isoniazid structural formula is:

1.1 30 maple diabetes model mice (iMSUD mice) of 25g were selected as subjects and divided into 3 groups of 10 mice each for testing. The group 1 is a control group, the stomach of which is infused with 20mg/kg of physiological saline, the group 2 is infused with VitaminB 120 mg/kg, and the group 3 is infused with 20mg/kg of isoniazid. After the culture in the same environment and continuous administration for 3 days, the amount of alpha-ketonic acid in the serum of the isoniazid mice is obviously lower than that of other two groups (P <0.01), and the survival rate of the isoniazid mice is also obviously improved (P < 0.01).

1.2 is different from 1.1 in that 15mg/kg of isoniazid is infused into the stomach of the group 3, after 3 days of continuous administration, the amount of alpha-keto acid in the serum of the mice in the isoniazid group is obviously lower than that in the other two groups (P <0.05), and the survival rate of the mice in the isoniazid group is also obviously improved (P < 0.01).

1.3 is different from 1.1 in that 50mg/kg of isoniazid is infused into the stomach of the group 3, after 3 days of continuous administration, the amount of alpha-keto acid in the serum of the mice in the isoniazid group is obviously lower than that in the other two groups (P <0.01), and the survival rate of the mice in the isoniazid group is also obviously improved (P < 0.05).

Example 2 therapeutic Effect of phenelzine on MSUD model mice

The structural formula of the phenethyl hydrazine is as follows:

30 of 25g maple syrup urine disease model mice (iMSUD mice) were selected as subjects and divided into 3 groups of 10 mice each for in vivo testing. The group 1 is control group with 25mg/kg of intragastric saline, the group 2 with intragastric Vitamin B125 mg/kg, and the group 3 with intragastric phenelzine 25 mg/kg. The mice in the phenethyl hydrazine group have obviously lower alpha keto acid amount in serum than other two groups (P <0.01) after being placed in the same environment for culture and continuously administrated for 3 days, and the survival rate of the mice in the phenethyl hydrazine group is also obviously improved (P < 0.05).

Example 3 therapeutic Effect of carbidopa on MSUD model mice

Carbidopa has the structural formula:

30 of 25g maple syrup urine disease model mice (iMSUD mice) were selected as subjects and divided into 3 groups of 10 mice each for in vivo testing. Group 1 was control group injected with 30mg/kg of saline, group 2 injected with VitaminB 130 mg/kg, group 3 injected with 30mg/kg carbidopa. After the mice are placed in the same environment for culture and continuously dosed for 3 days, the amount of alpha-keto acid in the serum of the mice in the carbidopa group is obviously lower than that of the mice in the other two groups (P <0.01), and the survival rate of the mice in the carbidopa group is also obviously improved (P < 0.05).

Example 4 therapeutic Effect of hydralazine on MSUD model mice

Hydralazine has the structural formula:

30 of 25g maple syrup urine disease model mice (iMSUD mice) were selected as subjects and divided into 3 groups of 10 mice each for in vivo testing. The group 1 is a control group which is perfused with 20mg/kg of gastric saline, the group 2 is perfused with VitaminB 120 mg/kg, and the group 3 is perfused with 15mg/kg of hydralazine. After the mice are placed in the same environment for culture and continuously dosed for 3 days, the amount of alpha-keto acid in the serum of the mice in the hydralazine group is obviously lower than that of the mice in the other two groups (P <0.01), and the survival rate of the mice in the hydralazine group is also obviously improved (P < 0.01).

Example 5 therapeutic Effect of benzyloxyamine hydrochloride on MSUD model mice

The structural formula of the benzyloxy amine hydrochloride is as follows:

30 of 25g maple syrup urine disease model mice (iMSUD mice) were selected as subjects and divided into 3 groups of 10 mice each for in vivo testing. Group 1 was a control group injected with 40mg/kg of saline, group 2 was injected with Vitamin B140 mg/kg, and group 3 was injected with 40mg/kg of benzyloxyamine hydrochloride. The mice in the benzyloxyamine hydrochloride group are cultured in the same environment, and after continuous administration for 3 days, the amount of alpha-keto acid in serum is obviously lower than that in other two groups (P <0.01), and the survival rate of the mice in the benzyloxyamine hydrochloride group is also obviously improved (P < 0.05).

In vitro and in vivo plasma experiments prove that the alpha keto acid and the compounds all have nucleophilic addition reaction in the plasma, and the structure of the reaction product is confirmed by MS.

Taking isoniazid as an example, the reaction formula is:

the structural characteristics of the obtained product are shown in attached figures 1, 2 and 3.

The present invention is not limited to the above-described preferred embodiments, but rather, the present invention is to be construed broadly and cover all modifications, equivalents, and improvements falling within the spirit and scope of the present invention.

Claims

1. A general formula of H₂The application of the N-G compound in the preparation of the medicine for treating maple syrup urine disease is characterized in that the compound can generate nucleophilic addition reaction with alpha keto acid in plasma to generate a product with a carbon-nitrogen double bond structure;

wherein G is NHR OR OR, and R is a substituent.

2. The use of claim 1, wherein the medicament for treating maple syrup urine comprises an effective amount of a compound of formula H₂A compound of N-G and a pharmaceutically acceptable carrier, wherein G is NHR OR OR, R is a substituent group, and the effective dose is 15-50 mg/kg.

3. Use according to claim 1 or 2, wherein R is selected from:

any one of the above.

4. Use according to claim 3, wherein said compound is selected from:

5. the use according to claim 4, wherein said compound is selected from the group consisting of:

6. the use according to claim 5, wherein said compound is

7. A medicament for treating maple syrup urine disease comprising a compound of any one of claims 1 to 6 in an effective amount of 15 to 50 mg/kg; the dosage form of the medicine is selected from any one of oral preparation, injection, nasal spray, sublingual tablet, inhalant and implant.

8. The medicament of claim 7, wherein the medicament is in a dosage form of an oral dosage form.

9. The pharmaceutical composition of claim 8, wherein the oral dosage form is selected from any one of tablet, oral liquid, suspension, capsule, granule, pill, powder, drop pill, syrup, mixture, lotion, effervescent, paste, emulsion, and tea.

10. The medicament of claim 7, wherein the pharmaceutically acceptable carrier is selected from any one or a combination of antibacterial agents, antioxidants, preservatives, stabilizers, flavoring agents or perfuming agents.