阅读说明：本技术 治疗肺纤维化的方法 (Methods of treating pulmonary fibrosis ) 是由 L·巴特 于 2018-12-28 设计创作，主要内容包括：本发明提供使用芳基哌嗪衍生物治疗肺纤维化的方法。该方法包括向有此需要的肺纤维化患者施用有效量的式I化合物的步骤,该式I化合物是一种芳基哌嗪衍生物。<Image he="345" wi="700" file="DDA0002654266800000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides methods of treating pulmonary fibrosis using arylpiperazine derivatives. The method comprises the step of administering to a patient with pulmonary fibrosis in need thereof an effective amount of a compound of formula I, which is an aryl piperazine derivative.)

1. A method of treating pulmonary fibrosis in a subject, the method comprising administering to a subject with pulmonary fibrosis an effective amount of a compound of formula I,

or a pharmaceutically acceptable salt, isomer, racemate, or mixture of diastereomers thereof, wherein,

a is-O- (CH)₂)_n-or NH-C (O) - (CH)₂)_n-n is an integer from 1 to 7; and

R¹and R²Independently is H, halogen, or hydrocarbonoxy;

R³，R⁴，R⁶，R⁷and R⁸Is hydrogen, and R¹，R²，R³，R⁴，R⁶，R⁷And R⁸And A is optionally substituted²H (deuterium) substitution.

2. The method of claim 1, wherein A is-O- (CH)₂)₄-。

3. The method of claim 1, wherein R¹And R²Is chlorine.

4. The method of claim 1, wherein R¹Is H, and R²Is methoxy.

5. The method of any one of claims 1-4, wherein the compound is in the form of a hydrochloride salt.

6. The method of claim 1, wherein the compound is

7. The method of claim 1, wherein the compound is administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent.

8. The method of claim 1, wherein the compound is administered orally.

9. The method of claim 1, wherein the method treats idiopathic pulmonary fibrosis.

10. The method of claim 1, treating pulmonary fibrosis in a subject with Chronic Obstructive Pulmonary Disease (COPD).

11. The method of claim 1, treating pulmonary fibrosis in a subject having Sickle Cell Disease (SCD).

12. The method of claim 1, treating pulmonary fibrosis in a subject with scleroderma.

13. The method of claim 1, which treats pulmonary fibrosis in a subject having lung cancer.

Technical Field

The present invention relates to methods of treating pulmonary fibrosis using aryl piperazine derivatives.

Background

Pulmonary Fibrosis (PF) is a progressive respiratory disorder (disorder) characterized by scarring and thickening of the pulmonary lining, resulting in an irreversible loss of the ability to deliver and exchange oxygen. As the lung tissue becomes scarred, it becomes stiffer, making it more difficult for the lungs to expand and contract. When this occurs, less oxygen is transferred to the bloodstream, making breathing more difficult. As the PF deteriorates, individuals become progressively more debilitating and breathe briefly, and this damage ultimately leads to death. If the cause of PF cannot be clearly identified, the condition is termed Idiopathic Pulmonary Fibrosis (IPF).

IPF is a chronic disease that destroys small spaces (interpatient spaces) in the lungs, and is the most common type of diffuse parenchymal lung disease. It is increasingly understood that IPF is the result of irreversible fibroplasia and an abnormal wound healing cascade (cascade). The course of pulmonary fibrosis and the severity of symptoms can vary significantly among individuals. Major signs (sign) and symptoms of PF include shortness of breath (dyspnea), dry cough, fatigue, unexplained weight loss, muscle and joint pain, and finger or toe tip widening and rounding (clubbing). Complications (co-morbitides) are common in patients with PF. The most common complications are emphysema (commonly clinically known as CPFE: combined pulmonary fibrosis and emphysema), pulmonary arterial hypertension (PH), venous thromboembolism, lung cancer, gastroesophageal reflux disease (GERD), cardiovascular disease, diabetes, and neuropsychiatric symptoms such as psychosis, depression, anxiety, and cognitive deficits.

The exact prevalence of IPF worldwide is not clear, but the american lung disease association estimates that IPF affects approximately 140,000 americans annually, and approximately 40,000 are lost annually. IPF usually occurs in people aged > 50 (40-70 years) with more men affected than women. Median survival time after initial diagnosis is 2-3 years. About two thirds of IPF patients die within 5 years, with the risk of death increasing with age.

Despite numerous advances that have been made in recent years, particularly in connection with the molecular genetics and cell biology of Pulmonary Fibrosis (PF), PThe pathogenesis of F has not been completely elucidated to date. The development of pulmonary fibrosis is caused by the damage and destruction of epithelial or endothelial cells during normal wound healing (Wynn 2011). The morphological hallmarks of pulmonary fibrosis are alveolar fibrosis, vascular fibrosis, blood clotting and clotting (blood clotting), pulmonary inflammation and respiratory resistance (Wynn 2011). Serotonin (5-HT) and key serotonin receptors have been reported to play key roles in the pathobiology of PF. Elevated serotonin levels in epithelial and endothelial cells of PF patients and serotonin 5-HT are reported_2A，5-HT_2BAnd 5-HT₇Expression of the receptor. Reported 5-HT_2AReceptor modulation regulates blood coagulation and coagulation, proliferation and vasodilation. Reported 5-HT_2BReceptor modulation plays a central role in the regulation of fibrosis and proliferation, while 5-HT₇Receptors have been reported to modulate inflammatory cytokines and chemokines (Lofdhal 2016, man 2013, and Dees 2011).

Despite the increasing understanding of the pathobiology of Pulmonary Fibrosis (PF), the prognosis of patients remains poor. PF is irreversible and there is currently no therapy available to prevent or significantly slow disease progression. In general, treatment strategies for PFs aim to improve quality of life (i.e., alleviate signs/symptoms of disease) or attempt to limit further inflammation and scar formation. Anti-inflammatory agents, including corticosteroids and cytotoxic agents, have also been used, although there is no evidence of their benefit to long-term survival. Pirfenidone (pirfenidone) and nintedanib (nintedanib) are two FDA-approved drugs for IPF management. Both pirfenidone and nintedanib have been reported to reduce fibrotic tissue in the lungs of patients with pulmonary fibrosis to some extent, but treatment is far from optimal. There is an urgent need for more effective and tolerable next generation therapies or treatments that can significantly delay the progression of pulmonary fibrosis, even if they do not provide a cure and improve the patient's overall quality of life (QOL).

Brief description of the drawings

Figure 1 depicts a schedule of various treatments for animals during the bleomycin-induced IPF study.

FIG. 2 shows the survival curves of Sham (Sham), BLM induced and treated animals from days 1-10 (A) and from days 11-21 (B), and body weight (C). BLM: bleomycin; false processing: vehicle and non-induced animals were used. P < 0.05BLM + Veh; compared to the dummy process. P < 0.05; compared to BLM + Veh.

Fig. 3 shows the hemodynamic and cardiac parameters (a-C) and systemic arterial pressure (D-F) measured on day 21. BLM: bleomycin; false processing: vehicle and non-induced animals were used. P < 0.05BLM + Veh; compared to the dummy process. # P < 0.05; compared to BLM + Veh. # P is less than 0.05; compared to BLM + Veh.

Figure 4 shows respiratory resistance (a) and pulmonary hydroxyproline (B) measured on day 21. BLM: bleomycin; false processing: vehicle and non-induced animals were used. P < 0.05, BLM + Veh; compared to the dummy process. P < 0.001; compared to the dummy process. # P < 0.05; compared to BLM + Veh. # P is less than 0.01; compared to BLM + Veh.

Figure 5 shows parameters reflecting pulmonary edema at day 21, including lung weight (a), BALF cell count (B), and BALF total protein (C). BALF: bronchoalveolar lavage; BLM: bleomycin; false processing: vehicle and non-induced animals were used. P < 0.01, BLM + Veh; compared to the dummy process. P < 0.001; compared to the dummy process. # P < 0.05; compared to BLM + Veh.

Figure 6 shows the morphological changes shown by H & E staining and Ashcroft scores (a, C). Masson trichrome staining (B, D) induced in rats by BLM on day 21 reflects collagen deposition. BLM: bleomycin; false processing: vehicle and non-induced animals were used. BLM + RP5063 (all animals). P < 0.001; compared to the dummy process. # P < 0.001; compared to BLM + Veh.

Fig. 7 shows the effect of BLM induction on blood oxygen saturation (a) and blood lactate level (B) measured on day 21. BLM: bleomycin; false processing: vehicle and non-induced animals were used. P < 0.01; compared to the dummy process. # P < 0.05; compared to BLM + Veh. # P is less than 0.01; compared to BLM + Veh.

Figure 8 shows BALF cytokine levels at day 21: MIP1 (a); MCP1 (B); IL6 (C); IP10 (D); and rantes (e). BLM: bleomycin; false processing: vehicle and non-induced animals were used. P < 0.05; compared to the dummy process. P < 0.001; compared to the dummy process. # P < 0.05; compared to BLM + Veh. # P is less than 0.01; compared to BLM + Veh. # P < 0.001; compared to BLM + Veh.

Detailed Description

Definition of

"alkyl" or "hydrocarbyl" refers to a saturated, branched or straight chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical hydrocarbyl groups include, but are not limited to, methyl; an ethyl group; propyl, such as prop-1-yl, prop-2-yl, prop-1-yl; butyl, e.g., but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, cyclobut-1-yl, and the like. Preferably, the hydrocarbyl group contains 1 to 20 carbon atoms, more preferably, 1 to 10, or 1 to 6, or 1 to 4 carbon atoms.

"alkenyl" refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent olefin. The group may be in either the cis or trans configuration relative to the double bond. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, for example prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, prop-1-en-1-yl, prop-2-en-1-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl and the like; and the like.

"alkynyl" refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl and the like; butynyl groups such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like; and so on.

"acyl" refers to the group-C (O) R, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

"acylamino" refers to "amide" as defined herein.

"hydrocarbylamino" refers to the group-NHR, where R is hydrocarbyl, as defined herein, or cycloalkyl, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like.

"hydrocarbyloxy" means a group-OR, wherein R is hydrocarbyl, OR cycloalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

"hydrocarbyloxycarbonyl" refers to the group-C (O) -hydrocarbyloxy, wherein hydrocarbyloxy is as defined herein.

"Alkylsulfonyl" refers to the group-S (O)₂R, wherein R is hydrocarbyl, or cycloalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

"Hydrocarbylsulphinyl" refers to the group-S (O) R, wherein R is hydrocarbyl or cycloalkyl as defined herein, optionally substituted by one or more substituents as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

"hydrocarbylthio" means a group-SR where R is hydrocarbyl or cycloalkyl as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

"amide" or "acylamino" refers to the group-NR 'C (O) R ", wherein R' and R" are each independently hydrogen, hydrocarbyl, cyclohydrocarbyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein. Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonyl-amino, benzoylamino, benzylcarbonylamino and the like.

"amino" refers to the group-NH₂。

"aryl" refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene (aceanthrylene), acenaphthylene (acenaphthylene), acephenanthrylene (acephenanthrylene), anthracene (anthrylene), azulene (azulene), benzene,

(chrysene), coronene (coronene), fluoranthene (fluoranthene), fluorine (fluorrine), hexacene (hexacene), naphthotetrabenzene (hexaphene), benazolin (hexalene), xanthene (hexalene), asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indane (indacene), indene (indene), naphthalene, octacene (octacene), octaphene (octaphene), ovalene (ovalene), penta-2, 4-diene, pentacene (pentacene), pentalene (pentalene), pentaphene (pentaphene), perylene (perylene), phenalene (phenalene), phenanthrene (picene), heptalene (plelene), pyrene (pyrene), triphenylene (triphenylene), triphenylene (perylene), triphenylene (triphenylene, etc. Preferably, the aryl group contains 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms.

"aromatic hydrocarbon radical" refers to an acyclic hydrocarbon radical in which a hydrogen atom (typically terminal or sp) is bonded to a carbon atom³Carbon atom) is substituted with an aryl group. Typical aromatic hydrocarbon groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, naphthylbenzyl, 2-naphthylphenyleth-1-yl, and the like. Preferably, the aromatic hydrocarbon group is (C)₆-C₃₀) Aryl radicals, e.g. the hydrocarbon part of an aryl radical being (C)₁-C₁₀) And the aryl moiety is (C)₆-C₂₀) More preferably, the aromatic hydrocarbon group is (C)₆-C₂₀) Aryl radicals, e.g. the hydrocarbon part of an aryl radical being (C)₁-C₈) And the aryl moiety is (C)₆-C₁₂)。

"Aryloxyalkyl" refers to a group-O-aralkyl, wherein the aralkyl is as defined herein, optionally substituted with one or more substituents as defined herein.

"Aryloxycarbonyl" refers to the group-C (O) -O-aryl, wherein aryl is as defined herein, optionally substituted with one or more substituents as defined herein.

"carbamoyl" refers to the group-C (O) NRR where each R group is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein.

"carbamate" refers to a group-NR 'c (o) OR "wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to, methylcarbamate (-NHC (O) OCH)₃) Ethyl carbamate (-NHC (O) OCH)₂CH₃) Benzyl carbamate (-NHC (O) OCH)₂C₆H₅) And the like.

"carbonate" refers to the group-OC (O) OR, wherein R is hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein. Representative examples include, but are not limited to, methyl carbonate (-C (O) OCH₃) Cyclohexyl carbonate (-C (O) OC₆H₁₁) Phenyl carbonate (-C (O) OC₆H₅) Benzyl carbonate (-C (O) OCH)₂C₆H₅) And the like.

"carboxy" refers to the group-C (O) OH.

"cyano" refers to the group-CN.

"cycloalkyl" refers to a substituted or unsubstituted cyclic hydrocarbyl group. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In a preferred embodiment, the cycloalkyl group is (C)₃-C₁₀) A cyclic hydrocarbon group, more preferably (C)₃-C₇) A cyclic hydrocarbon group.

"Cycloheteroalkyl" refers to a saturated or unsaturated cyclic hydrocarbon radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatoms. Typical heteroatoms substituted for carbon atoms include, but are not limited to, N, P, O, S, Si, and the like. Where a particular saturation level is to be achieved, the term "cycloheteroalkyl" or "cycloheteroalkenyl" is used. Typical cyclic heterocarbyl groups include, but are not limited to, groups derived from epoxides, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrolidines, quinuclidines, and the like.

"halogen" means fluorine, chlorine, bromine, or iodine.

"heteroaryl" refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from: acridine, indolylene, carbazole, carboline, chromane (chromane), chromene (chromene), chromane, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, piperidine, phenanthridine, phenanthroline, phenazine, phthalazine, piperidine, purine, pyrola, pyrolazine, pyrolazole, pyridazine, pyrolidine, pyrimidine, pyrollidine, pyrolazine, quinazoline (quinazoline), quinoline (quinoline), quinolizine (quinolizine), quinoxaline (quinoxaline), tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene (xanthene), and the like. Preferably, the heteroaryl group is a 5-20 membered heteroaryl group, with a 5-10 membered heteroaryl group being particularly preferred. Preferred heteroaryl groups are those derived from: thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazoline.

"Heteroaryloxycarbonyl" refers to the group-C (O) -OR, wherein R is heteroaryl as defined, optionally substituted with one OR more substituents as defined herein.

"Heteroarylalkyl" refers to an acyclic hydrocarbyl group in which one of the carbon-bonded hydrogen atoms (typically terminal or sp) is bonded³Carbon atom) is substituted with heteroaryl. Preferably, the heteroarylalkyl group is a heteroarylalkyl of 6-30 membered carbon atoms, e.g., the hydrocarbon portion of the heteroarylalkyl is 1-10 membered and the heteroaryl portion is a 5-20 membered heteroaryl, more preferably 6-20 membered heteroarylalkyl, e.g., the hydrocarbon portion of the heteroarylalkyl is 1-8 membered and the heteroaryl portion is a 5-12 membered heteroaryl.

"hydroxy" refers to the group-OH.

"oxo" refers to a divalent group ═ O.

"pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like); or with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2, 2, 2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like); or (2) salts, formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or a complex with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.).

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or carrier with which the compound of the invention is administered.

"phosphate" refers to the group-OP (O) (OR '), wherein R ' and R ' are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"phosphate ester" refers to the group-P (O) (OR ') (OR "), wherein R' and R" are each independently hydrogen, hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"prevent" or "prevention" refers to a reduced risk of developing a disease or disorder (i.e., causing at least one clinical symptom of the disease not to develop in a patient who may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

"racemate" refers to an equimolar mixture of enantiomers of a chiral molecule.

"substituted" refers to groups in which one or more hydrogen atoms are each independently substituted with the same or different substituents. Typical substituents include, but are not limited to, -X, -R⁵⁴，-O^-，＝O，-OR⁵⁴，-SR⁵⁴，-S，＝S，-NR⁵⁴R⁵⁵，＝NR⁵⁴，-CX₃，-CF₃，-CN，-OCN，-SCN，-NO，-NO₂，＝N₂，-N₃，-S(O)₂O^-，-S(O)₂OH，-S(O)₂OR⁵⁴，-OS(O)₂O³¹，-OS(O)₂R⁵⁴，-P(O)(O-)₂，-P(O)(OR¹⁴)(O³¹)，-OP(O)(OR⁵⁴)(OR⁵⁵)，-C(O)R⁵⁴，-C(S)R⁵⁴，-C(O)OR⁵⁴，-C(O)NR⁵⁴R⁵⁵，-C(O)O^-，-C(S)OR⁵⁴，-NR⁵⁶C(O)NR⁵⁴R⁵⁵，-NR⁵⁶C(S)NR⁵⁴R⁵⁵，-NR⁵⁷C(NR⁵⁶)NR⁵⁴R⁵⁵and-C (NR)⁵⁶)NR⁵⁴R⁵⁵Wherein each X is independently halogen; r⁵⁴，R⁵⁵，R⁵⁶And R⁵⁷Each independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR⁵⁸R⁵⁹，-C(O)R⁵⁸or-S (O)₂R⁵⁸Or optionally R⁵⁸And R⁵⁹Taken together with the atoms to which they are attached to form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R⁵⁸And R⁵⁹Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl.

"sulfate" refers to the group-OS (O) OR, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"sulfonamide" refers to the group-S (O) NR ' R "wherein R ' and R" are independently hydrogen, hydrocarbyl, cyclohydrocarbyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, optionally substituted with one or more substituents as defined herein, or optionally R ' and R "together with the atoms to which they are both attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. Representative examples include, but are not limited to, azetidinyl (azetidinyl), pyrollidinyl, piperidinyl, morpholinyl, 4- (NR' ") -piperazinyl, or imidazolyl, wherein said groups may be optionally substituted with one or more substituents as defined herein. R' "is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein.

"sulfonate" refers to the group-S (O) OR, wherein R is hydrogen, hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one OR more substituents as defined herein.

"thio" means a group-SH.

"thioether" means a radical-SR, wherein R is hydrocarbyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein, optionally substituted with one or more substituents as defined herein.

In one embodiment, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to ameliorating at least one physical parameter that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.

"therapeutically effective amount" refers to an amount of a compound that, when administered to a patient to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and the severity and age of the patient to be treated, body weight, and the like, and can be determined by one of skill in the art without undue experimentation.

The present invention relates to a method of treating pulmonary fibrosis.

Compounds useful in the invention

Compounds of formula (I) are useful in the present invention:

wherein:

a is-O- (CH)₂)_n-，-(CH₂)_n-，-S-(CH₂)_n-，-S(O)(O)-(CH₂)_n-，-NH-(CH₂)_n-，-CH₂-O-(CH₂)_n-，-(CH₂)_n-O-CH₂-CH₂-，-CH₂-S-(CH₂)_n-，-(CH₂)_n-S-CH₂-CH₂-，-CH₂-S(O)(O)-(CH₂)_n-，-(CH₂)_n-S(O)(O)-CH₂-CH₂-，-O-C(O)-(CH₂)_n-，-S-C(O)-(CH₂)_n-，-NH-C(O)-(CH₂)_n-，-CH₂-C(O)-O-(CH₂)_n-，-CH₂-C(O)-NH-(CH₂)_n-，-CH₂-C(O)-S-(CH₂)_n-，-(CH₂)_n-C(O)-O-CH₂-CH₂-，-(CH₂)_n-C(O)-NH-CH₂-CH₂-，-(CH₂)_n-C(O)-S-CH₂-CH₂-，-CH₂-O-C(O)-(CH₂)_n-，-CH₂-NH-C(O)-(CH₂)_n-，-CH₂-S-C(O)-(CH₂)_n-，-(CH₂)_n-O-C(O)-CH₂-CH₂-，(CH₂)_n-NH-C(O)-CH₂-CH₂-, or (CH)₂)_n-S-C(O)-CH₂-CH₂-, where n is an integer from 1 to 7, preferably n is from 2 to 5, for example n is 4;

b is O, S (O), or NR⁵(ii) a And is

R¹，R²，R³，R⁴，R⁵，R⁶，R⁷And R⁸Each independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyclicA hydrocarbyl group, a substituted cycloalkyl group, a cycloheteroalkyl group, a substituted cycloheteroalkyl group, a heteroaryl group, a substituted heteroaryl group, a heteroarylhydrocarbyl group, a substituted heteroarylhydrocarbyl group, an acyloxycarbonyl group, an acyloxytetraoxycarbonyl group, an acyloxytetraoxycarbonylamino group, an acyloxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an alkoxycarbonylhydrocarbyloxycarbonylamino group, an alkoxycarbonylhydrocarbyloxyamino group, an alkylsulfinyl group, an alkylsulfonyl group, an alkylthio group, an amino group, an alkylamino group, an aralkylamino group, a dihydrocarbylamino group, an aralkyloxy group, an aryloxycarbonylhydrocarbyloxy group, an aryloxycarbonylhydrocarbylamino group, an aryloxycarbonylhydrocarbyloxy group, a carboxyl group, a carbamoyl group, a carbamate group, a carbonate group, a cyano group, a halogen, a heteroaryloxycarbonyl group, a hydroxyl group, a phosphate group, a phosphonate group, a sulfate group, a sulfonate group, or a sulfonamide, wherein R is¹，R²，R³，R⁴，R⁵，R⁶，R⁷And R⁸And A may be optionally substituted with an isotope, including but not limited to²H (deuterium) is added to the reaction mixture,³h (tritium) is introduced into the reaction chamber,¹³C，³⁶Cl，¹⁸F，¹⁵N，¹⁷O，¹⁸O，³¹P，³²p, and³⁵s; preference is given to²H (deuterium);

or a pharmaceutically acceptable salt, racemate or diastereomeric mixture thereof.

In one aspect of the invention, A is-O- (CH)₂)_n-。

In one aspect of the invention, A is- (CH)₂)_n-。

In another aspect of the invention, A is-S- (CH)₂)_n-，-CH₂-O-(CH₂)_n-，-(CH₂)_n-O-CH₂-CH₂-，-CH₂-S-(CH₂)_n-, or- (CH)₂)_n-S-CH₂-CH₂-; preferably, A is-O- (CH)₂)_n-。

In another aspect of the invention, A is-NH-C (O) - (CH)₂)_n-，-CH₂-NH-C(O)-(CH₂)_n-，-CH₂-C(O)-NH-(CH₂)_n-or- (CH)₂)_n-C(O)-NH-CH₂-CH₂-。

In another aspect of the invention, B is O.

In another aspect of the invention, R³，R⁴，R⁶，R⁶And R⁸Is H.

In a preferred embodiment, A is-O- (CH)₂)_n-or-NH-C (O) - (CH)₂)_n-，n＝2-5。

In a preferred embodiment, B is O.

In a preferred embodiment, R³，R⁴，R⁶，R⁶And R⁸Is H.

In a preferred embodiment, R¹And R²Each independently is H, halogen (e.g., chloro), halohydrocarbyl, or hydrocarbyloxy (e.g., methoxy or ethoxy); halogen or hydrocarbonoxy radicals are preferred.

Preferred compounds of formula I include, for example, the following compounds A-D and their hydrochloride salts.

6- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butoxy) -2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one (brilaroxazine, or Compound A);

6- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butoxy) -2H-benzo [ B ] [1, 4] oxazin-3 (-4H) -one (Compound B);

the compounds useful in the present invention further relate to enantiomerically separated compounds of formula I. The isolated enantiomeric forms of the compounds of formula I are substantially free of one another (i.e., enantiomeric excess). In other words, the "R" form of a compound is substantially free of the "S" form of the compound, and thus the "R" form is in enantiomeric excess. In contrast, the "S" form of a compound is substantially free of the "R" form of the compound, and thus the "S" form is in enantiomeric excess. In one embodiment of the invention, the isolated enantiomeric compound is at least about 80% enantiomeric excess. Thus, for example, the compound is in at least about 90% enantiomeric excess, preferably at least about 95% enantiomeric excess, more preferably at least about 97% enantiomeric excess, or even more preferably at least 99% or greater than 99% enantiomeric excess.

The compounds of formula I may be synthesized according to U.S. patent No. 8,188,076, which is incorporated herein in its entirety.

Methods of treating pulmonary fibrosis

The present invention relates to a method of treating Pulmonary Fibrosis (PF) and Idiopathic Pulmonary Fibrosis (IPF). If the cause of the PF cannot be unambiguously identified, this case is referred to as IPF. Although the etiology of PF and IPF may be different, the signs and symptoms of PF and IPF are the same, and the present invention is effective in treating PF and IPF regardless of the etiology. The method comprises the step of administering to a patient having pulmonary fibrosis an effective amount of a compound of formula I. The compounds of formula I can reduce fibrosis in the pulmonary arteries (blood vessels leading from the heart to the lungs) or alveoli of a patient and treat pulmonary fibrosis. The treatment may also reduce disease complications such as lung inflammation, shortness of breath, pain crisis (crisis), pneumonia, and increase survival.

In one embodiment, the method treats pulmonary fibrosis in a subject with Chronic Obstructive Pulmonary Disease (COPD), Pulmonary Arterial Hypertension (PAH), Sickle Cell Disease (SCD), scleroderma, or lung cancer.

In one embodiment, the method treats a comorbid psychiatric disorder, such as psychosis, depression, and mood symptoms, in a patient with pulmonary fibrosis. In another embodiment, the method treats anxiety in a patient with pulmonary fibrosis.

When used to treat pulmonary fibrosis, one or more compounds of formula I may be administered to a patient, alone or in combination with other agents. The patient may be an animal, preferably a mammal, more preferably a human.

The compounds of formula I are preferably administered orally. The compounds of formula I may also be administered by any other convenient route, for example, by infusion or bolus (bolus) injection, by absorption through epithelial or intra-mucosal membranes (e.g., oral, rectal and intestinal mucosa, etc.). It may be administered systemically or locally. A variety of delivery systems (e.g., encapsulated in liposomes, microparticles, microcapsules, capsules, etc.) are known to be useful for administering the compounds and/or compositions of the present invention. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ear, nose, eye, or skin. Inhalation or transdermal administration may be preferred for young children.

The compounds of formula I may be delivered by sustained release systems, preferably oral sustained release systems. In one embodiment, a pump may be used (see Langer, supra; Seffon, 1987, CRC Crit. Ref biomed. Eng.14: 201; Saudek et al, 1989, N.Engl. J.Med.321: 574).

In one embodiment, polymeric materials may be used (see "medical applications for controlled release", Langer and Wise (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol Chem.23: 61; also see Levy et al, 1985, Science 228: 190; During et al, 1989, Ann. neurol.25: 351; Howard et al, 1989, J. neurosurg.71: 105). In a preferred embodiment, the polymeric material is for oral sustained release delivery. Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferably hydroxypropylmethylcellulose). Other preferred cellulose ethers have been described in the art (Bamba et al, int.j.pharm., 1979, 2, 307).

In one embodiment, the enteric coated formulation may be used for oral sustained release administration. Preferred coating materials include polymers with pH-dependent solubility (i.e., pH controlled release), polymers with slow or pH-dependent swelling, dissolution or erosion rates (i.e., time controlled release), polymers that are degraded by enzymes (i.e., enzymatic controlled release), and polymers that form a solid layer that is disrupted by an increase in pressure (i.e., pressure controlled release).

In another embodiment, the osmotic delivery system is used for oral sustained release administration (Verma et al, drug Dev. Ind. pharm., 2000, 26: 695-. In a preferred embodiment of the method of the present invention,osmotic delivery systems are used in oral sustained release delivery devices (see, e.g., Theeuwes et al, U.S. Pat. No. 3,845,770; and Theeuwes et al, U.S. Pat. No. 3,916,899).

In yet another embodiment, a controlled release system may be placed in proximity to the target of the compounds and/or compositions of the invention, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, "medical applications for controlled release", supra, vol.2, pp.115-138 (1984)). Also useful are those described in Langer, 1990, Science 249: 1527 and 1533.

The compounds of formula I can be cleaved chemically and/or enzymatically. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal can enzymatically cleave the compounds and/or compositions of the present invention.

Pharmaceutical formulations of the invention

The present invention relates to a pharmaceutical formulation for the treatment of pulmonary fibrosis. The pharmaceutical formulation comprises a therapeutically effective amount of one or more compounds of formula I, preferably in purified form, together with an appropriate amount of a pharmaceutically acceptable carrier. When administered to a patient, the pharmaceutical formulation is preferably sterile. Water is a preferred carrier when the compounds of the invention are administered intravenously. Saline solutions, as well as aqueous dextrose and glycerol solutions, may also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The reagent or pH buffer. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used.

Pharmaceutical compositions containing the compounds of the present invention may be prepared by conventional mixing, dissolving, granulating, diafiltering, and emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the compounds of the invention into preparations which can be used pharmaceutically. Suitable formulations depend on the chosen route of administration.

The compositions of the present invention may take the form of solutions, suspensions, emulsions, tablets, pills, granules, and capsules, containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other suitable form for use. In one embodiment, the pharmaceutically acceptable carrier is a capsule (see, e.g., Grosswald et al, U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical carriers are described in the art (see remington's pharmaceutical sciences, fischer-tropsch pharmaceutical and scientific college, 17 th edition, 1985). Preferred compositions of the invention are formulated for oral delivery, particularly for oral sustained release administration.

Compositions for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs (elixir). Compositions for oral administration may comprise one or more optional agents, such as sweetening agents, if sugar, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry coloring agents and preservatives, to provide a pharmaceutically palatable preparation. In addition, in the case of tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a prolonged period of time. Selectively permeable membranes surrounding an osmotically active driver compound are also suitable for use with the orally administered compounds of the present invention. In these latter platforms, liquid from the surrounding capsule environment is absorbed by the driving compound, which swells to displace the reagent or reagent composition through the pores. These delivery platforms can provide a substantially zero order delivery profile, as opposed to the sharp profile of immediate release formulations. A time delay material such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions can include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such carriers are preferably pharmaceutical grade.

For oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycol (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers at pH 4 to pH 6 (e.g., acetates, citrates, ascorbates, concentrations from about mM to about 50mM), and the like. In addition, a flavoring agent, a preservative, a coloring agent, a bile salt, acylcarnitine, and the like may be added.

Compositions for administration by other routes are also contemplated. For oral (buccal) administration, the composition may be in the form of tablets, lozenges and the like formulated in a conventional manner. Liquid pharmaceutical formulations suitable for use in nebulizers and liquid spray devices, as well as EHD aerosol devices, generally comprise a compound of the invention and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, such as an alcohol, water, polyethylene glycol or perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of the compounds of the invention. Preferably, the material is a liquid, such as an alcohol, glycol, polyglycol or fatty acid. Other methods of formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611). The compounds of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa, butter or other glycerides. In addition to the formulations described hereinbefore, the compounds of the present invention may also be formulated as long acting formulations (depot). Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

Therapeutic dosage

The amount of the compound of formula I administered depends on, among other factors, the subject being treated, the weight of the subject, the severity of the illness, the mode of administration and the judgment of the prescribing physician. For example, the dose may be delivered in a pharmaceutical composition by a single administration, multiple administrations or controlled release. In one embodiment, the compounds of the present invention are delivered by oral sustained release administration. In one embodiment, the compounds of the invention are administered twice daily, preferably once daily. The dosage may be repeated intermittently, may be provided alone or in combination with other drugs, and may be continued for a period of time necessary to effectively treat the disease state or disorder.

The compound of formula I may be administered in the range of from 0.1mg to 500mg, preferably from 1mg to 100mg per day, for example 5mg, 10mg, 15mg, 20mg, 25mg, 35mg or 50mg per day, and preferably 10mg per day.

Combination therapy

In certain embodiments of the invention, the compounds of the invention may be used in combination therapy with at least one other therapeutic agent. The compound of formula I and the therapeutic agent may act additively or synergistically. In one embodiment, the compound of formula I is administered simultaneously with another therapeutic agent, which may be part of the same composition as the compound of formula I. In another embodiment, a composition comprising a compound of the present invention is administered before or after the administration of another therapeutic agent.

The present invention is effective for treating pulmonary fibrosis. The compound of formula I is serotonin 5-HT_2AReceptor (Compound A, Ki ═ 2.5nM, see example 1), 5-HT_2BReceptor (compound a, Ki ═ 0.19nM, see example 1), and 5-HT₇The receptor (compound a, Ki ═ 2.7nM, see example 1) has strong binding affinity. In addition, the compounds of formula I are useful for dopamine (D2) and serotonin (5-HT)_1A) Exhibit partial agonist activity and are active against serotonin 5-HT₆The receptor exhibits antagonistic activity. Furthermore, the compound of formula I (compound a) showed efficacy in treating pulmonary fibrosis in a bleomycin-induced pulmonary fibrosis rat model (example 2).

The invention is illustrated by the following examples.

Examples