KR20020087045A - Agent for treating hepatitis c - Google Patents

Agent for treating hepatitis c Download PDF

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KR20020087045A
KR20020087045A KR1020027005739A KR20027005739A KR20020087045A KR 20020087045 A KR20020087045 A KR 20020087045A KR 1020027005739 A KR1020027005739 A KR 1020027005739A KR 20027005739 A KR20027005739 A KR 20027005739A KR 20020087045 A KR20020087045 A KR 20020087045A
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ukline
ifn
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바실 노비키
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    • A—HUMAN NECESSITIES
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    • A61K31/66—Phosphorus compounds
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    • A61K38/19—Cytokines; Lymphokines; Interferons
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    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

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Abstract

본 발명은, C형 간염 치료용 의약을 제조하기 위한 켈리도늄 마주스 L.의 알칼로이드와 티오아인산 트리아지리디드의 반응 생성물의 용도에 관한 것이다.The present invention relates to the use of a reaction product of an alkaloid of kelidonium majus L. and a thiophosphorous triazideide for the manufacture of a medicament for the treatment of hepatitis C.

Description

Ｃ형 간염 치료제{AGENT FOR TREATING HEPATITIS C}Hepatitis C treatment agent {AGENT FOR TREATING HEPATITIS C}

"C형 간염"이란 것은, 다소 최근에 조사된 질병을 지칭한다. 오랫동안, 이 질병은 외관으로 보기에 특정한 실질적인 차이를 보유하고 있음에도 불구하고, 지금까지 알려진 질병인 A형 간염 및 B형 간염과 유사한 증상을 일으키는 질병으로만 공지되어 왔다. 따라서, 이 질병은 오랫동안 "비A비B형 간염(hepatitis non-A non-B)"이라는 말로 특징되어 왔다."Hepatitis C" refers to a rather recently investigated disease. For a long time, the disease has only been known to cause symptoms similar to hepatitis A and hepatitis B, which have been known so far, despite having certain substantial differences in appearance. Thus, the disease has long been characterized by the words "hepatitis non-A non-B."

C형 간염은 특히 미개발국에서 널리 확산되는 질병이다; 전세계에는 약 1억 7천만명(즉, HIV 감염자의 약 4배)이 C형 간염에 감염된 것으로 추정된다.Hepatitis C is a widespread disease, especially in developing countries; It is estimated that about 170 million people worldwide (ie about four times as many people with HIV) are infected with hepatitis C.

한편, C형 간염 바이러스가 플라비바이러스(flavivirus)의 일종인 것이 발견될 수 있었고, 전세계는 이 질병을 예방하거나 치료하기 위한 약제를 개발하는데 온 힘을 기울여 왔다.On the other hand, hepatitis C virus could be found to be a type of flavivirus, and the whole world has been devoted to developing drugs for preventing or treating the disease.

오스트리아 특허 출원서 제 377 988호 및 354 644호에는 알칼로이드의 신규한 인 유도체 및 티오아인산의 알칼로이드 유도체의 신규한 염의 제조방법이 각각 개시되어 있다. 이러한 화합물은 약리학적 활성을 보유하며, 세포증식 억제제로서사용할 수 있다.Austrian patent applications Nos. 377 988 and 354 644 disclose methods for the preparation of novel salts of alkaloids and novel salts of alkaloid derivatives of thiophosphoric acid, respectively. Such compounds possess pharmacological activity and can be used as cell proliferation inhibitors.

본 발명은 C형 간염 치료용 의약 제조를 위한 알칼로이드의 인 유도체의 용도에 관한 것이다.The present invention relates to the use of alkaloid phosphorus derivatives for the manufacture of a medicament for the treatment of hepatitis C.

놀랍게도, 상기 특허 출원서에 기재된 물질 중에서 특히 켈리도늄 마주스 L.(Chelidonium majus L.)의 알칼로이드와 티오아인산 트리아지리디드의 반응 생성물을 C형 간염을 치료하는데 사용할 수 있으며, 이러한 약제를 사용하여 우수한 결과를 달성할 수 있다는 사실을 새로이 발견하였다.Surprisingly, among the substances described in the patent application, the reaction products of alkaloids of helidonium majus L. and thiophosphorous triazideide can be used to treat hepatitis C, using such agents We have newly discovered that good results can be achieved.

따라서, 본 발명은 C형 간염 치료용 의약을 제조하기 위한 켈리도늄 마주스 L.의 알칼로이드와 티오아인산 트리아지리디드의 반응 생성물의 용도에 관한 것이다.Accordingly, the present invention relates to the use of a reaction product of an alkaloid of kelidonium majus L. and a thiophosphorous triazideide for the manufacture of a medicament for the treatment of hepatitis C.

이하에서, 상기 반응 생성물을 간단히 "우크라인(Ukrain)"이라고 명명할 것이며, 이 우크라인의 주요 성분은 하기 화학식으로 표시된다:In the following, the reaction product will be simply referred to as "Ukrain", the main component of which is represented by the formula:

인터페론-알파와 혼합시킨 우크라인에 대한 시험과, 우크라인을 단독으로 사용한 시험을 실시하였다. 이하에서, 이 일련의 2가지 시험에 대해서 설명할 것이다.The test for ukline mixed with interferon-alpha and a test using ukline alone were performed. In the following, this series of two tests will be described.

1. 인터페론-알파 및 우크라인의 용도1. Use of interferon-alpha and ukline

방법Way

재조합 인간 인터페론-알파2b(IFN) 및 우크라인[오스트리아에 소재한 "노비키 팔마(Nowicky Pharma)"사 제품인 켈리도늄 마주스 L.-알칼로이드 및 티오아인산 트리아지리디드의 반-합성 화합물, NSC-631570]의 효과를 전류 적정법으로 혈중 티올-디술파이드비(SH/SS)를 측정함으로써 시험관내에서 시험하였다(러시아 연방 특허 제 N 99108889호). 40 CHC 환자들에 대해서 시험하였다. IFN은, 20, 50, 100, 200, 400, 600, 1000U/㎖ 혈액의 투여량에서, 그리고 우크라인은 0.05, 0.1, 0.2, 0.5, 1.0 및 2.0㎍/㎖ 혈액의 투여량에서 시험하였다. 주당 3회로 투여하는 개별적인 최적 IFN-투여량(3 경우의 HCV-페노타입 1a를 포함하고 있는 6명의 환자에게 1회 주사당 0.5 내지 2.0MU) 및 이틀에 한번 투여하는 우크라인 투여량(2 HCV 1b 경우를 포함하고 있는 4명의 환자에게 1회 주사당 0.25 내지 2.5mg)을 사용하여 임상 파일롯 시험을 하기 위해서, 시험된 CHC 환자중 10명을 선택하였다.Semi-synthetic compound of recombinant human interferon-alpha 2b (IFN) and Ukline [Kellydonium Mazu's L.-alkaloid and thiophosphorous triazideide, NSC- from "Nowicky Pharma, Austria" 631570] was tested in vitro by measuring blood thiol-disulfide ratio (SH / SS) by current titration (Russian Federal Patent No. 9999889). 40 CHC patients were tested. IFN was tested at doses of 20, 50, 100, 200, 400, 600, 1000 U / ml blood, and ukline at doses of 0.05, 0.1, 0.2, 0.5, 1.0 and 2.0 μg / ml blood. Individual optimal IFN-dose administered three times per week (0.5 to 2.0 MU per injection in six patients with three HCV-phenotype 1a) and ukline dose administered once every two days (2 HCV) Ten of the CHC patients tested were selected for clinical pilot testing using 0.25 to 2.5 mg per injection in 4 patients including the 1b case.

결과result

두 조성물에 대한 반응이 상이하였다는 것이 증명되었다: 모든 환자의 52.5%가 IFN에, 그리고 73.1%가 우크라인에 민감하게 반응하였는데, 조성물 영향하에서SH/SS비가 증가하는 것은 포지티브 효과로 추정되는 반면, 이들이 감소하는 것은 네거티브 효과로 추정되었다. 일부 환자에서는 1회 투여로 포지티브 효과를 보이지만, 다른 환자들은 2회 이상을 투여해야 했다. IFN에 대한 최적 생물학적 응답이 400, 200 및 100U/㎖ 혈액의 투여량에서 매우 자주 관찰되었고, 우크라인에 대해서는 0.5, 0.1 및 0.2㎍/㎖ 혈액에서 관찰되었다. 생체내에 주사한 경우에 3.0 내지 5.0MU 투여량에 대응하는 600 내지 1000U/㎖의 표준 치료학적 IFN 투여량은, 상기 경우중의 0 내지 18.2%로만 SN/SS 시스템에 대한 포지티브 효과를 나타내는 반면 63.6 내지 81.8%의 네거티브 효과를 나타내었는데, 이것은 CHC 중에서 IFN이 불량한 효능을 나타내고, IFN-치료법을 시행하는 중에 부작용이 빈발하게 발생하는 것에 대한 이유중 하나이다. 모든 CHC 환자의 거의 절반이 4가지 경우의 입증된 HCV-페노타입 1b를 포함하는 IFN(47.5%)에 내성을 나타내었다. IFN 또는 우크라인을 사용하여 개별적으로 치료한지 한달 후에, 개별적인 IFN을 투여한지 석달 후에, 그리고 개별적인 우크라인을 투여한지 3주 후에, 10명의 환자중 9명이 PCA:3으로 HCV-RNA 네거티브였다. 어떠한 심각한 부작용도 발견되지 않았으며, 모든 환자를 계속적으로 치료하였다.It was demonstrated that the response to both compositions was different: 52.5% of all patients responded sensitively to IFN and 73.1% to ukline, while increasing the SH / SS ratio under the effect of the composition is estimated to be a positive effect. However, these decreases were estimated to be negative effects. In some patients, one dose showed a positive effect, while others had to be given two or more doses. Optimal biological responses to IFN were observed very frequently at doses of 400, 200 and 100 U / ml blood and 0.5, 0.1 and 0.2 μg / ml blood for ukline. Standard therapeutic IFN doses of 600-1000 U / ml, corresponding to 3.0-5.0 MU doses when injected in vivo, show a positive effect on the SN / SS system with only 0-18.2% in this case, while 63.6 Negative effects of from 81.8% were shown, which is one of the reasons for the poor efficacy of IFN in CHC and the frequent occurrence of side effects during IFN-therapy. Nearly half of all CHC patients were resistant to IFN (47.5%), including four cases of proven HCV-phenotype 1b. One month after being individually treated with IFN or Ukline, three months after individual IFN and three weeks after individual Ukline, 9 of 10 patients were HCV-RNA negative with PCA: 3. No serious side effects were found and all patients were treated continuously.

논의Argument

수득된 상기 데이터를 기초로, 본 발명자는 IFN 또는 우크라인을 특정의 최적 투여량을 사용하여 치료함으로써 입증할 수 있는 환자, 여기에 반응하지 않는 환자, 그리고 상이한 의약으로 치료해야만 하는 환자에 대한 예비 치료법의 선택 방법을 제공할 수 있다. 개별적인 치료법에 의해서, CHC 치료법의 효능이 증강되고, 부작용 횟수도 감소할 뿐만 아니라, 보다 비용적으로 효율적인 치료법(예를 들어, IFN 치료법에 대해서는, 3 내지 5배)이 정립될 것이다.Based on the data obtained, the inventors preliminary for patients who can be demonstrated by treating IFNs or uklines using specific optimal dosages, patients who do not respond to them, and patients who have to be treated with different medications. A method of selecting a therapy may be provided. Individual therapies will enhance the efficacy of the CHC therapy, reduce the number of side effects, as well as establish more cost-effective therapies (eg, 3-5 times for IFN therapy).

2. 우크라인 단독으로의 용도2. Use of ukline alone

방법Way

우크라인[오스트리아에 소재한 "노비키 팔마"사 제품인 켈리도늄 마주스 L.-알칼로이드 및 티오아인산 트리아지리디드의 반-합성 화합물, NSC-631570]의 효과를 전류 적정법으로 혈중 티올-디술파이드비(SH/SS)를 측정함으로써 시험관내에서 시험하였다(러시아 연방 특허 제 N99108889). 26 CHC 환자들에 대해서 시험하였다. 우크라인을, 0.05, 0.1, 0.2, 0.5, 1.0 및 2.0㎍/㎖ 혈액의 투여량에서 시험하였다. 이틀에 한번의 우크라인 개별적인 최적 투여량(0.25 내지 2.5mg/주입물)을 사용하여 임상 파일롯 시험을 하기 위해서, 4명의 CHC 환자(2명은 치료하지 않은 환자이고, 2명은 인터페론-알파로 치료하였으나 완쾌되지 않은, 입증된 HCV-페노타입 1b를 앓고 있는 환자)를 선택하였다.The thiol-disulfide ratio in blood was analyzed by the current titration method with the effect of Ukrain [Semi-synthetic compound of Kelidonium Mazu L.-alkaloid and thiophosphorous triazideide, NSC-631570 from "Noviki Palma" of Austria] It was tested in vitro by measuring (SH / SS) (Russian Federal Patent No. N99108889). 26 CHC patients were tested. Uklines were tested at doses of 0.05, 0.1, 0.2, 0.5, 1.0 and 2.0 μg / ml blood. Four CHC patients (two untreated and two treated with interferon-alpha) to conduct a clinical pilot test using a single optimal dose of ukline (0.25-2.5 mg / injection) every other day Patients with unproven, proven HCV-phenotype 1b) were selected.

결과result

우크라인에 대한 반응은 상이하였다는 것이 증명되었다: 모든 환자의 73.1%가 이 조성물에 민감하게 반응하는 반면, 동일한 군의 CHC 환자에 있어서는 인터페론 알파2b(IFN)에 대한 민감도가 예를 들어 46.2%로 상당히 감소되었다. IFN 내성이 있는 CHC 환자 군내에서는 우크라인에 대한 감도가 거의 동일(71.4%)하였으며, 또한 HCV-페노타입 1b로 감염된 모든 4 CHS 환자들은 시험관내에서의 우크라인에대해서 민감하였다. 0.5, 0.1 및 0.2㎍/㎖ 혈액의 우크라인 투여량에 대한 최적 생물학적 응답이 자주 관찰되었다. 10 우크라인 주사 후의 임상 시험에서, 본 발명자는 포지티브한 임상적, 생화학적(모든 4가지 경우에서 ALT가 감소함) 및 세균학적 응답(PCR HCV-RNA가 HCV-1b가 있는 하나의 경우를 포함한 3가지 경우에서 네거티브함)을 이미 확인할 수 있었다. 2가지 경우에 있어서, 우크라인 치료법(ALT가 3배 넘게 감소한 HCV-1b가 있는 다른 하나의 경우를 포함함)을 도입한 후에 ALT 증가보다 먼저 ALT가 감소되었다. 우크라인 치료법을 실시한 후에, 혈청학적인 SH/SS비가 생화학적이고 세균학적인 응답이 있는 세가지 경우에서 증가된 반면, 세균학적 응답이 없는 경우에서는 감소되었으며, 어떠한 부작용도 확인되지 않았다. 이러한 4명의 환자를 계속적으로 치료하였다.Responses to uklines have been demonstrated to be different: 73.1% of all patients are sensitive to this composition, while sensitivity to interferon alpha 2b (IFN) is, for example, 46.2% in the same group of CHC patients. Was significantly reduced. In the group of patients with IFN-resistant CHC, the sensitivity to ukline was nearly the same (71.4%), and all 4 CHS patients infected with HCV-phenotype 1b were sensitive to ukline in vitro. Optimal biological responses to ukline doses of 0.5, 0.1 and 0.2 μg / ml blood were frequently observed. In clinical trials after 10 ukline injections, we found positive clinical, biochemical (reduced ALT in all four cases) and bacteriological responses (including one case where PCR HCV-RNA has HCV-1b). Negative in three cases). In two cases, ALT was reduced prior to ALT increase after the introduction of ukline therapy (including the other case with HCV-1b with an ALT reduced by more than threefold). After the ukline treatment, serological SH / SS ratio was increased in three cases with biochemical and bacteriological responses, while in the absence of bacteriological response, no side effects were identified. These four patients were treated continuously.

논의Argument

CHC 환자의 우크라인에 대한 고감도를 시험관내에서 측정(IFN에 비해서 1.58배 더 높음)하였는데, 우크라인 및 IFN 사이에 어떠한 교차 내성도 없었다. 심지어 HCV-페노타입 1b에 감염된 환자조차도 생체 및 시험관내 모두에서 우크라인에 대해 민감하게 반응하였다. 우크라인에 의한 CHC의 개별적인 치료법은 치료하지 않은 환자 뿐만 아니라, IFN을 단독으로 또는 리바비린(Rivavirin)과 함께 사용한 후에 치료를 중단하고 있거나 내성이 있는 환자에 모두에 대해서도 효과가 있는 것으로 보였다. 얻어진 이러한 결과를 기초로 해서, 본 발명자는 CHC 환자에 대한 우크라인의 특정한 임상 시험을 설정할 수 있다.High sensitivity to ukline in CHC patients was measured in vitro (1.58 fold higher than IFN), with no cross resistance between ukline and IFN. Even patients infected with HCV-phenotype 1b responded sensitively to uklines both in vivo and in vitro. Individual treatment of CHC with ukrains has been shown to be effective both in untreated patients, as well as in patients who are discontinued or resistant to treatment after using IFN alone or in combination with Rivavirin. Based on these results obtained, we can establish specific clinical trials of uklines for CHC patients.

바람직하게는, 본 발명에 따라 제조된 의약은 사용된 알칼로이드 인산 유도체 및 이것의 염의 수용액으로 이루어지거나, 임의적으로 공지된 추가의 보조제를 함께 포함하기도 한다. 바람직하게는, 본 발명에 따른 의약은 예를 들어 복강내 투여, 근육내 투여 또는 정맥내 투여로 투여되며, 치료할 질병의 중증도 및 환자 상태에 따라서 투여량이 결정된다.Preferably, the medicaments prepared according to the invention consist of an aqueous solution of the alkaloid phosphate derivatives used and their salts, or optionally together with additional auxiliaries known. Preferably, the medicament according to the invention is administered for example by intraperitoneal administration, intramuscular administration or intravenous administration, depending on the severity of the disease to be treated and the patient's condition.

그러나, 경우에 따라 적당한 투여량을 결정하기 위해, 당업자의 전문적인 지식 범위내에서 치료법을 수행할 수 있다.However, in some cases, to determine the appropriate dosage, therapies may be carried out within the skill of one of ordinary skill in the art.

Claims (2)

C형 간염 치료용 의약을 제조하기 위한, 켈리도늄 마주스 L.의 알칼로이드와 티오아인산 트리아지리디드의 반응 생성물의 용도.Use of the reaction product of the alkaloid of kelidonium majus L. and thiophosphorous triazideide for the manufacture of a medicament for the treatment of hepatitis C. 제 1항에 있어서, 반응 생성물이 특히 인터페론-알파와 같은 다른 활성 물질과 병용되는 것을 특징으로 하는 용도.2. Use according to claim 1, characterized in that the reaction product is used in combination with other active substances, in particular interferon-alpha.
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