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CN-122005558-A - Compound serving as AKR1C3 inhibitor as well as preparation method and application thereof

CN122005558ACN 122005558 ACN122005558 ACN 122005558ACN-122005558-A

Abstract

The invention discloses a compound serving as an AKR1C3 (aldehyde ketone reductase 1C 3) inhibitor, and a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry. The compound has a structure shown in a formula I or pharmaceutically acceptable salt thereof, wherein when R 1 is carboxyl, A is a nitrogen-containing saturated aromatic ring, B is an unsaturated aromatic ring or an unsaturated heterocyclic ring, when R 2 is carboxyl, B is an unsaturated aromatic ring, and A is a condensed ring containing the nitrogen-containing saturated aromatic ring. The piperidine carboxylic acid compound or the benzoic acid compound and the pharmaceutically acceptable salt thereof provided by the invention can selectively inhibit the activity of AKR1C3, have remarkable inhibition effect, achieve the effect of preventing and treating the prostate cancer by inhibiting the final step of androgen production in tumor cells, and can be used for preparing medicaments for treating AKR1C3 related diseases, in particular medicaments for treating the prostate cancer. Formula I.

Inventors

  • ZHENG XUEHUA
  • WU DEYAN
  • YAO ZIQING
  • ZHENG LI
  • LIU HUAN

Assignees

  • 广州医科大学

Dates

Publication Date
20260512
Application Date
20251231

Claims (10)

  1. 1. The application of carboxylic acid compounds in preparing AKR1C3 inhibitors is characterized in that the carboxylic acid compounds have a structure shown in a formula I or pharmaceutically acceptable salts thereof: I is a kind of Wherein when R 1 is carboxyl, A is nitrogen-containing saturated aromatic ring, B is unsaturated aromatic ring or unsaturated heterocyclic ring, R 2 is at least one selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, amino, methanesulfonyl, acetyl, acetamido, trifluoromethyl, trifluoromethoxy, methyl, thienyl, oxazolyl and morpholinyl; When R 2 is carboxyl, B is unsaturated aromatic ring, A is condensed ring containing nitrogen saturated aromatic ring, R 1 is at least one selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, hydroxyl, methyl, methoxy, nitro, carboxymethyl, hydroxymethyl, trifluoromethyl and cyano.
  2. 2. The use according to claim 1, wherein the carboxylic acid compound has a structure represented by formula II or formula III: formula II and formula III Wherein B is selected from at least one of naphthyl, phenyl, indolyl and isoquinolyl, and R 2 is selected from at least one of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, amino, methanesulfonyl, acetyl, acetamido, trifluoromethyl, trifluoromethoxy, methyl, thienyl, oxazolyl and morpholinyl; a is at least one of tetrahydroisoquinoline group, benzomorpholine group and indoline group, and R1 is at least one of hydrogen, fluorine, chlorine, bromine, iodine, amino, hydroxyl, methyl, methoxy, nitro, carboxymethyl, hydroxymethyl, trifluoromethyl and cyano.
  3. 3. The use according to claim 2, wherein when B is naphthyl, R 2 is selected from at least one of hydrogen, bromo, chloro, hydroxy, methoxy, amino.
  4. 4. The use according to claim 2, wherein when B is phenyl, R 2 is at least one selected from hydrogen, fluoro, chloro, bromo, iodo, acetyl, trifluoromethoxy, methyl, thienyl, oxazolyl.
  5. 5. The use according to claim 2, wherein when a is a tetrahydroisoquinoline group, R 1 is selected from at least one of hydrogen, methyl, methoxy, fluoro, chloro, bromo, iodo, hydroxy, nitro, amino, trifluoromethyl, cyano.
  6. 6. Use according to claim 2, wherein when a is an indoline group, R 1 is selected from hydrogen and/or bromine.
  7. 7. The use according to claim 1, wherein the carboxylic acid compound is selected from any one of the following compounds: 。
  8. 8. The application of carboxylic acid compounds or pharmaceutically acceptable salts thereof in preparing medicines for preventing or treating AKR1C3 related diseases is characterized in that the carboxylic acid compounds have a structure shown in a formula I or pharmaceutically acceptable salts thereof: I is a kind of Wherein when R 1 is carboxyl, A is nitrogen-containing saturated aromatic ring, B is unsaturated aromatic ring or unsaturated heterocyclic ring, R 2 is at least one selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, amino, methanesulfonyl, acetyl, acetamido, trifluoromethyl, trifluoromethoxy, methyl, thienyl, oxazolyl and morpholinyl; When R 2 is carboxyl, B is unsaturated aromatic ring, A is condensed ring containing nitrogen saturated aromatic ring, R 1 is at least one selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, hydroxyl, methyl, methoxy, nitro, carboxymethyl, hydroxymethyl, trifluoromethyl and cyano.
  9. 9. The use according to claim 8, wherein the AKR1C3 associated disease is castration-resistant prostate cancer.
  10. 10. The use according to claim 9, wherein the medicament is a reverse tumour resistance medicament.

Description

Compound serving as AKR1C3 inhibitor as well as preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a compound serving as an AKR1C3 inhibitor, and a preparation method and application thereof. Background Prostate cancer is one of the most common malignant tumors of the male urinary system, and the global incidence is in the prostate of male malignant tumors. The pathogenesis of the androgen is closely related to the continuous activation of an androgen signal pathway, and androgens regulate and control the expression of genes related to cell proliferation, differentiation and survival by binding to Androgen Receptors (AR) in prostate cancer cells, and are core driving factors for the development and the development of tumor. Androgen Deprivation Therapy (ADT) is the standard initial treatment of advanced prostate cancer, with significant delay in tumor progression through surgical castration or drug inhibition of gonadal androgen synthesis. However, most patients develop Castration Resistant Prostate Cancer (CRPC) after 1-3 years of treatment, at which time serum testosterone levels have been reduced to castration levels, but the tumor continues to proliferate. The treatment drugs for CRPC include second generation AR antagonists such as enzalutamide, apatamide, etc. have significant resistance problems. Aldehyde ketone reductase 1C3 (AKR 1C 3) is an important member of the Aldehyde Ketone Reductase (AKR) superfamily, is a cytosolic enzyme dependent on NADPH, is widely expressed in tissues such as liver, adrenal gland, mammary gland, prostate and the like, and has the core function of catalyzing the metabolic conversion of steroid hormone, and particularly plays a key role in the final step of androgen synthesis. Studies have demonstrated that AKR1C3 expression levels are significantly up-regulated in prostate cancer tissue. In CRPC stage, AKR1C3 can catalyze androgen precursor (such as androstenedione and dehydroepiandrosterone) to reduce to active androgen (testosterone and androstenediol) with high efficiency, promote tumor proliferation, and reduce sensitivity of tumor cells to standard therapeutic drugs such as enzalutamide. Thus, AKR1C3 inhibitors have become a hotspot in pharmaceutical chemistry and tumor therapy research. A variety of structurally diverse AKR1C3 inhibitors have been reported, which can be broadly classified into three categories, namely steroidal inhibitors, non-steroidal inhibitors, and natural product-derived inhibitors, depending on their chemical structure and source. However, there have not been compounds successfully employed in clinical practice, which has highlighted that existing inhibitors still have significant shortcomings in terms of potency, selectivity or pharmaceutical properties. In addition, AKR1C3 has a homologous subtype (about 86% of sequence homology) of AKR1C1, but is functionally different. For example, AKR1C1 is expressed in lung and other tissues, and participates in important physiological processes, and inhibition of the important physiological processes possibly brings adverse reaction risks. Therefore, how to design highly selective inhibitors that can accurately distinguish AKR1C3 from AKR1C1 has become critical to push AKRC inhibitors to the clinic. In conclusion, research and development of a new generation of AKR1C3 inhibitors with strong inhibitory activity and excellent subtype selectivity have important scientific significance and clinical value for overcoming CRPC treatment drug resistance and providing new treatment options. Disclosure of Invention In order to solve the above-mentioned problems in the prior art, it is a primary object of the present invention to provide an application of a compound or a pharmaceutically acceptable salt thereof in preparing an AKR1C3 inhibitor. It is still another object of the present invention to provide an application of a compound or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating AKR1C 3-related diseases. In order to achieve the above object, the present invention provides the following technical solutions: Use of a carboxylic acid compound having a structure according to formula I or a pharmaceutically acceptable salt thereof in the preparation of an AKR1C3 inhibitor: I is a kind of Wherein when R 1 is carboxyl, A is nitrogen-containing saturated aromatic ring, B is unsaturated aromatic ring or unsaturated heterocyclic ring, R 2 is at least one selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, amino, methanesulfonyl, acetyl, acetamido, trifluoromethyl, trifluoromethoxy, methyl, thienyl, oxazolyl and morpholinyl; When R 2 is carboxyl, B is unsaturated aromatic ring, A is condensed ring containing nitrogen saturated aromatic ring, R 1 is at least one selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, hydroxyl, methyl,