CN107226833A - A kind of CYP11B, CYP17 and or CYP21 inhibitor salt type compound - Google Patents

Abstract

There is provided herein formula A CYP11B, CYP17 and or CYP21 inhibitor compound, for treating Androgen-dependent type disease, illness and the purposes of symptom.

Description

A kind of CYP11B, CYP17 and or CYP21 inhibitor salt type compound

Technical field

The invention provides it is a kind of for CYP11B, CYP17 and or CYP21 inhibitor compound salt or its pharmaceutical composition, by oral administration or note Method of administration is penetrated, as treating Androgen-dependent type disease, illness and the purposes of symptom.Invention further describes the synthesis of the new compound Method.

Technical background

Cancer is the important burden of human health, and estimation accounts for the 13% of annual whole death tolls.Particularly, several frequently seen cancer and disease It is related all to the hormone signal conduction of male sex hormone, such as prostate cancer, breast cancer, soft nest cancer, many capsule Soft nests disease.Wherein, prostate cancer is people The distinctive disease of class, is one of most common malignant tumour of male in America and Europe, in the U.S., prostate-cancer incidence accounts for the 1st, and the death rate is only second to lung Cancer.Asian countries's prostate-cancer incidences such as China, Japan, India have growth trend far below America and Europe.

Since nineteen forties, androgen deprivation therapy has become the treatment standard of patients with prostate cancer.Most of patient uses up Pipe has carried out androgen-deprivation, finally still undergoes disease progression.For many years, the disease it is relatively late be referred to as " Hormone-refractory prostate cancer " or " androgen independent prostate cancer ".Understood later, the prostate cancer that the several years occurs after androgen deprivation therapy still relies on androgen. The prostate gland cancer cell of survival obtains the ability for introducing low-level circulation androgen (being expressed by adrenal gland), becomes to these low-level testosterones It is more sensitive, the synthesis testosterone actually in prostate gland cancer cell itself.The prostate cancer in this stage is referred to as " the intractable prostate of castration now Cancer " or CRPC.

It has been proved that androgen plays an important role in the development, growth and progress of prostate cancer.Two kinds of important androgens are testis sterone With dihydro-testosterone sterone.The testis sterone of testis synthesis about 90%, remaining 10% is synthesized by adrenal gland.Testis sterone enters by the enzyme sterol for concentrating on prostate One step is converted into more effective androgen DHT.

Because prostate cancer is usually Androgen-dependent type, therefore surgery or pharmacology castrating reduction androgen are produced as mainly controlling for this indication Treatment scheme.Androgen-deprivation has been used for advanced prostate cancer and the therapy of metastatic prostate cancer.But orchiectomy reduces the androgen production of testis It is raw, but have no effect on the generation of androgen in adrenal gland.CYP17 is related to the key intermediate of androgen biosynthesis, therefore its pharmacology has been suppressed to The treatment of prospect, wherein testis, adrenal gland and peripheral androgen biosynthesis will be reduced, therefore CYP17 is suppressed to important prostate cancer and ground Study carefully direction.

Clinically CPY17 inhibitor medicaments, such as Abiraterone acetate is in Nikkei U.S. FDA approval listing April 28 in 2011, with sprinkling Buddhist nun's pine combination treatment castration prostate cancer.Abiraterone targeted inhibition regulation androgen generation enzyme CYO17 activity, reduces the generation of androgen, So as to alleviate the growth of tumour.

CYP21 and CYP11B1 is that vital two kinds of enzymes are synthesized to cortisol, and the excessive generation of cortisol, has involved storehouse Xing Shi Disease group.Storehouse Xing Shi diseases group refers to the long-term form of expression induced exposed to excessive glucocorticoid, and it can be caused by a variety of causes.Spontaneous storehouse Xing Shi Disease group can be caused by each reason, and all reasons have in common that the long-term excessive secretion cortisol of adrenal gland.

The short-term and long-term consequence of hypercortisolism requires the necessary normalization of Determination of cortisol, and surgery ethanol pituitary adenoma still represents a line and controlled Treat, in the case of surgery failure, then radiotherapy.The safely and effectively medicine of two cortisol blocker excess generations still lacks, and drug therapy is not For main therapeutic scheme.

On drug therapy direction, to block CYP21 and CYP11B1 as rational treatment strategies.There are some medicines to be used for storehouse Xing Shi diseases Group, the medicine includes first than ketone, ketoconazole, methylbenzyl rice ester and mitotane.Although these medicines clinically have a significant curative effect, effect due to a lack of Block the active efficiency of CYP11B1 and be restricted.

Provided herein is abiraterone analog, it has drug effect more preferable than abiraterone, while having good dissolubility, beneficial to oral absorption Or for injecting, with very high clinical value.

The content of the invention

The present invention provides compound shown in a kind of chemical constitution Formula X.

X is pharmaceutically acceptable acid；

When X is n member acid, Y is 1 to n integer.

Such as claim 1, it is characterised in that acceptable salt includes phosphate, sulfate, borate, carbonate, bicarbonate, formic acid Salt, acetate, propionate, benzoate, pyridine carboxylic acid salt, fumarate, malate, maleate, matrimony vine hydrochlorate, succinate, Mesylate, tosilate, fluoroform sulphonate, tetrafluoroborate, hexafluoro borate, hydrochloride, hydrogen bromide salt or iodate hydrogen salt.

Above-claimed cpd or its pharmaceutically acceptable salt and more than one pharmaceutically acceptable filler, adhesive, disintegrant, lubricants.

Above-claimed cpd or composition, with one or more kinds of pharmaceutically acceptable solvents.

Above-mentioned to state pharmaceutical composition, the composition can be the liquid forms such as tablet, capsule, granule, oral liquid or injection.

It is a kind of suppress CYP11B, CYP17 and or CYP21 enzymes method, it include above-mentioned compound or pharmaceutical composition and CYP11B, CYP17 and or CYP21 enzymes contact.

Compound or pharmaceutical composition in summary treatment Androgen-dependent type illness application, such as prostate cancer, benign prostatauxe, Prostate intraepithelial neoplasia sample lesion, hirsutism, acne, androgenetic alopecia, polycystic ovary disease.Wherein the Androgen-dependent type illness is prostate Cancer.

The present invention method that also offer prepares chemical structural formula A, is added dropwise acid in D4A ethyl acetate solution, and stirring and crystallizing obtains synthesizing road Line is as follows：

Embodiment

The present invention is illustrated below with reference to embodiment, embodiments of the invention are merely to illustrate technical scheme, and non-limiting The essence of invention.

Example one：34.7g objects are added in 500ml ethyl acetate, after dissolving completely, 7ml concentrated hydrochloric acid is added dropwise, stirs at room temperature Crystallization obtains the 30g products being dried under reduced pressure after off-white powder, filtering.

Example two：34.7g objects are added in 500ml ethyl acetate, after dissolving completely, 10ml concentrated hydrobromic acid are added dropwise, at room temperature Stirring and crystallizing obtains the 35g products being dried under reduced pressure after off-white powder, filtering.

Example three：34.7g objects are added in 500ml ethyl acetate, after dissolving completely, the 9.8g concentrated sulfuric acid is added dropwise, stirs at room temperature Mix the 37g products that crystallization obtains being dried under reduced pressure after off-white powder, filtering.

Example four：34.7g objects are added in 200ml methanol, after dissolving completely, the methanol that 13.8g fumaric acid and 100ml is added dropwise is molten Liquid, at room temperature stirring and crystallizing obtain the 36g products being dried under reduced pressure after off-white powder, filtering.

Claims (8)

1. a kind of formula A compound

X is pharmaceutically acceptable acid；

When X is n members acid or its acid group, Y is 1 to n integer.

2. such as claim 1, it is characterised in that acceptable acid include phosphoric acid, sulfuric acid, boric acid, carbonic acid, formic acid, acetic acid, propionic acid, It is benzoic acid, pyridine carboxylic acid, fumaric acid, malic acid, maleic acid, matrimony vine acid, butanedioic acid, methanesulfonic acid, ethylsulfonic acid, right Toluenesulfonic acid, trifluoromethanesulfonic acid, tetrafluoro boric acid, hexafluoro boric acid, hydrochloric acid, hydrogen bromide salt or hydrogen iodide.

3. a kind of pharmaceutical composition, it is characterised in that comprising compound described in claim 1 and claim 2 or its is pharmaceutically acceptable Salt and more than one pharmaceutically acceptable filler, adhesive, disintegrant, lubricants.

4. a kind of pharmaceutical composition, it is characterised in that compound shown in chemical structural formula A described in claim 1 and claim 2 or its Pharmaceutically acceptable salt, with one or more kinds of pharmaceutically acceptable solvents.

5. such as claim 3 and claim 4 described pharmaceutical composition, it is characterised in that the composition can be tablet, capsule, The liquid forms such as granule, oral liquid or injection.

6. it is a kind of suppress CYP11B, CYP17 and or CYP21 enzymes method, it includes the compound or medicine described in claim 1-5 Composition and CYP11B, CYP17 and or CYP21 enzymes contact.

7. compound or pharmaceutical composition as described in claim 1-5 are in the application for the treatment of Androgen-dependent type illness, such as prostate cancer, Benign prostatauxe, prostate intraepithelial neoplasia sample lesion, hirsutism, acne, androgenetic alopecia, polycystic ovary disease.

8. such as claim 7, the wherein Androgen-dependent type illness is prostate cancer.