CN117263922A - Heterocyclic compounds as AT2R agonists - Google Patents
Heterocyclic compounds as AT2R agonists Download PDFInfo
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- CN117263922A CN117263922A CN202310742702.6A CN202310742702A CN117263922A CN 117263922 A CN117263922 A CN 117263922A CN 202310742702 A CN202310742702 A CN 202310742702A CN 117263922 A CN117263922 A CN 117263922A
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- Prior art keywords
- alkyl
- cycloalkyl
- ring
- compound
- substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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Abstract
The present invention provides heterocyclic compounds of formula I, tautomers, stereoisomers, hydrates and solvates thereofPharmaceutically acceptable salts or prodrugs; the compounds are useful as agonists of the AT2 receptor,
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an angiotensin II (AngII) type 2 receptor (AT 2R) agonist.
Background
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) refers to abnormal repair of alveolar epithelial cells following injury, resulting in transformation of pulmonary fibroblast proliferation to myofibroblasts, hypersecretion of extracellular matrix, collagen deposition, changes in alveolar structure, and eventual fibrosis. Its pathogenesis is not completely understood, and current research is believed to be closely related to oxidative stress, inflammatory response, and regulation of the renin-angiotensin-aldosterone system (RAAS) by body fluids. The RAAS system is currently believed to play an important role in the progression of pulmonary fibrosis, and Angiotensin converting enzyme (Angiotensin converting enzyme, ACE) can hydrolyze Angiotensin I (Angiotenin I, ang I) to Angiotensin II (Ang II), which plays an important role in the development and progression of various inflammatory processes.
In humans, two major classes of AngII receptors have been identified, designated AngII type 1 receptor (AT 1 receptor) and AngII type 2 receptor (AT 2 receptor), respectively. Ang ii has been shown to regulate blood pressure, body fluids and electrolyte homeostasis in a number of organs, including the kidneys, adrenal glands, heart, blood vessels, brain, gastrointestinal tract and reproductive organs. The effect of Ang ii is regulated by the balance of AT1R and AT2R expression of two G Protein Coupled Receptors (GPCRs). AT1R is expressed in the whole life cycle and is mainly responsible for regulating blood pressure, and a blocker thereof is widely used as a blood pressure reducing medicament clinically, and the AT1R controls most of AngII physiological effects. AT2R is mainly expressed in embryonic tissues, and is related to blood pressure regulation, nerve growth, pain control and myocardial regeneration, and drugs targeting AT2R can improve cardiovascular functions, relieve neuropathic pain and the like. However, in pathological conditions, the expression of AT2R is markedly elevated, such as vascular injury, wound healing and heart failure.
Several studies in adult individuals appear to confirm the following facts: in the modulation of response following Ang ii stimulation, AT2 receptor activation has an opposite effect to AT1 receptor modulation.
The AT2 receptor has been shown to be involved in the inhibition of apoptosis and cell proliferation. Recently, it has been shown that AT2 receptor agonists may be useful in the treatment and/or prevention of digestive tract diseases such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339).
There remains a need for potent and/or selective AT2 receptor agonists, which are expected to be useful in the above-mentioned diseases.
Disclosure of Invention
The object of the present invention is to provide a heterocyclic compound as an AT2 receptor agonist, which has a structure as shown in the first aspect of the present invention, which is useful for preparing a medicament, a pharmaceutical composition or a formulation for treating and/or preventing a disease or a disorder associated with AT2R, and the use thereof; or treating and/or preventing a disease or disorder associated with AT 2R.
In a first aspect of the invention, there is provided a heterocyclic compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
wherein ring E is a 7-11 membered saturated or partially saturated spiro ring;
re is selected from halogen, hydroxy, cyano, amino, oxo (= O), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the Re is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
n is 0, 1, 2, 3 or 4;
when Re is 2, 3 or 4, the Re is the same or different;
L is C which is unsubstituted or substituted by one or more substituents 1 -C 6 Alkyl, each substituent being independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o);
ring B is selected from benzene ring or 5-6 membered heteroaromatic ring;
m is selected from 0, 1, 2, 3 or 4;
R 1 and R is 3 Each independently selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the R is 1 And R is 3 Each independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
R 2 selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 3 -C 7 cycloalkyl-C 1 -C 6 An alkyl group;
z is selected from O or NR 4 ；
R 4 Selected from hydrogen or C 1 -C 3 An alkyl group;
R 6 selected from hydrogen, halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the R is 6 Independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are plural substituents, the substituents may be the same or different.
In a second aspect of the invention, the invention provides a compound which is a compound of formula II, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula II:
Wherein ring E is a 7-11 membered saturated or unsaturated spiro ring;
re is selected from halogen, hydroxy, cyano, amino, oxo (= O), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl; the Re is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
when Re is 2, 3 or 4, the Re is the same or different;
l is C which is unsubstituted or substituted by one or more substituents 1 -C 6 Alkyl, each substituent being independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o);
ring B is selected from benzene ring or 5-6 membered heteroaromatic ring;
m and n are each independently selected from 0, 1, 2, 3 or 4;
R 3 each independently selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl; the R is 3 Each independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are plural substituents, the substituents may be the same or different.
In a third aspect of the invention, the invention provides a compound which is a compound of formula III, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula III:
Wherein the dotted line represents a single bond or a double bond;
re is selected from halogen, hydroxy, cyano, amino, oxo (= O), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl; the Re is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
when Re is 2, 3 or 4, the Re is the same or different;
l is C which is unsubstituted or substituted by one or more substituents 1 -C 6 Alkyl, each substituent being independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o);
ring B is selected from benzene ring or 5-6 membered heteroaromatic ring;
m and n are selected from 0, 1, 2, 3 or 4;
R 1 and R is 3 Selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl; the R is 1 And R is 3 Substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
R 2 selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 3 -C 7 cycloalkyl-C 1 -C 6 An alkyl group;
z is selected from O or NR 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 4 Selected from hydrogen or C 1 -C 3 An alkyl group;
R 6 is hydrogen or is selected from halogen, hydroxy, cyano, amino, oxo (= O), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl; the R is 6 Independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are plural substituents, the substituents may be the same or different.
When n is 0, the compound of formula III has the structure:
when n is not 0, the structure of the compound shown in the formula III is as follows:
in the present invention, the definition of certain substituents in the compounds of formula I, II or III may be as follows, and the definitions of the substituents not mentioned are as described in any of the schemes above.
In a preferred embodiment of the invention, the building blocksHaving the structure->
In a preferred embodiment of the invention, ring E 1 Each independently is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl.
In a preferred embodiment of the invention Y 1 Each independently is N or CRe.
In a preferred embodiment of the invention Y 2 Each independently is NRe or C (Re) 2 。
In a preferred embodiment of the inventionIn embodiments, theHas the structure of
Ring E 1 Each independently is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
Y 1 Each independently is N or CRe;
Y 2 each independently is NRe or C (Re) 2 ；
Re is defined as in the first aspect of the invention.
In a preferred embodiment of the present invention, it is a compound of formula II-A or formula II-B or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula II-A or formula II-B,
wherein ring E 1 Each independently is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
Y 1 each independently is N or CRe;
Y 2 each independently is NRe or C (Re) 2 ；
Re is defined as in the first aspect of the invention.
In a preferred embodiment of the invention, the ring E 1 Is 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
the 4-7 membered heterocycloalkyl has 1, 2, 3 or 4 heteroatoms selected from N, O or S; when the hetero atom is plural, the hetero atoms are the same or different;
preferably, the heterocycloalkyl group contains at most one O or S.
In a preferred embodiment of the invention, the 3-7 membered cycloalkyl is selected from: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane.
In a preferred embodiment of the present invention, the 4-7 membered heterocycloalkyl is selected from: cyclopropane containing 1, 2, 3 or 4 heteroatoms, cyclobutane containing 1, 2, 3 or 4 heteroatoms, cyclopentane containing 1, 2, 3 or 4 heteroatoms, cyclohexane containing 1, 2, 3 or 4 heteroatoms or cycloheptane containing 1, 2, 3 or 4 heteroatoms, wherein the heteroatoms are selected from at least one of N, O or S.
In a preferred embodiment of the present invention, the 4-7 membered heterocycloalkyl is selected from: oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, tetrahydrothiopyran.
In a preferred embodiment of the invention, the ring E 1 Selected from:
in a preferred embodiment of the present invention,has the structure of
In a preferred embodiment of the invention, each Re is independently selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when Re is plural, the Re is the same or different; the Re is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are plural substituents, the substituents may be the same or different.
In a preferred embodiment of the invention, the Re's are each independently selected from F, cl, br, I, oxo (=O), C 1 -C 6 Alkyl or C 3 -C 7 Cycloalkyl groups.
In a preferred embodiment of the invention, the Re's are each independently selected from oxo (=O) or C 1 -C 3 An alkyl group.
In a preferred embodiment of the invention, L is C which is unsubstituted or substituted by 1 to 3 substituents 1 -C 3 An alkyl group; the substituents are independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o).
In a preferred embodiment of the invention L is C 1 -C 3 Alkyl, quilt C 1 -C 6 Alkyl substituted C 1 -C 3 An alkyl group.
In a preferred embodiment of the invention, L is-CH 2 -or-CH (CH) 3 )-。
In a preferred embodiment of the invention, the ring B is selected from benzene rings or 5-6 membered heteroaromatic rings having 1 or 2 heteroatoms which are N.
In a preferred embodiment of the present invention, the ring B is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring.
In a preferred embodiment of the present invention, the R 3 Selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl; the R is 3 Independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are plural substituents, the substituents may be the same or different.
In a preferred embodiment of the invention, R 3 Selected from halogen,Cyano, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 An alkoxy group.
The "alkyl group substituted with halogen" is simply referred to as "haloalkyl".
In a preferred embodiment of the invention, R 3 Each independently selected from F, cl, cyano, methyl, methoxy, halomethyl, cyclopropyl.
In a preferred embodiment of the invention, re is selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when Re is plural, the Re is the same or different;
the Re is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
preferably, re is selected from F, cl, br, I, oxo (=o), C 1 -C 6 Alkyl or C 3 -C 7 Cycloalkyl;
preferably, re is selected from oxo (=o) or C 1 -C 3 An alkyl group.
In a preferred embodiment of the invention, the L is C which is unsubstituted or substituted by one or more substituents 1 -C 3 An alkyl group; the substituents are independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o);
preferably L is C 1 -C 3 Alkyl, quilt C 1 -C 6 Alkyl substituted C 1 -C 3 An alkyl group;
more preferably, L is-CH 2 -or-CH (CH) 3 )-。
In a preferred embodiment of the invention, the ring B is selected from benzene rings or 5-6 membered heteroaromatic rings having 1 or 2 heteroatoms which are N;
preferably, the ring B is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring.
In a preferred embodiment of the present invention, the R 3 Selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the R is 3 Independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
preferably, R 3 Selected from halogen, cyano, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 An alkoxy group;
more preferably, R 3 Selected from F, cl, cyano, methyl, methoxy, halomethyl, cyclopropyl.
In a preferred embodiment of the invention, R 1 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 An alkyl group.
In a preferred embodiment of the invention, R 1 Selected from C 1 -C 6 An alkyl group.
In a preferred embodiment of the invention, R 1 Is isobutyl.
In a preferred embodiment of the invention, R 2 Selected from C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group.
In a preferred embodiment of the invention, R 2 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl.
In a preferred embodiment of the invention, R 2 Is butyl.
In a preferred embodiment of the invention Z is selected from O, -NH-or-NC 1 -C 3 Alkyl-.
In a preferred embodiment of the invention, Z is selected from O.
In a preferred embodiment of the invention, R 6 Selected from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl;
in a preferred embodiment of the invention, R 6 Is hydrogen, halogen or C 1 -C 3 An alkyl group;
in a preferred embodiment of the invention, R 6 Is hydrogen.
In a preferred embodiment of the invention, R 1 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 An alkyl group;
preferably, R 1 Selected from C 1 -C 6 An alkyl group;
more preferably, R 1 Is isobutyl.
In a preferred embodiment of the invention, R 2 Selected from C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group;
preferably, R 2 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl;
more preferably, R 2 Is butyl.
In a preferred embodiment of the invention Z is selected from O, -NH-or-NC 1 -C 3 Alkyl-;
preferably, Z is selected from-NH-.
In a preferred embodiment of the invention, R 6 Is hydrogen or is selected from halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl;
preferably, R 6 Is hydrogen, halogen or C 1 -C 3 An alkyl group;
more preferably, R 6 Is hydrogen.
In a preferred embodiment of the present invention, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the compound comprises:
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, formula II or formula III, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first, second or third aspects; and pharmaceutically acceptable carriers and/or adjuvants.
In a fifth aspect of the invention, the use of a compound of formula I, formula II or formula III, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first, second or third aspects, or a pharmaceutical composition as described in the fourth aspect, comprises:
as AT2 receptor agonists;
and/or preparing a medicament for preventing and/or treating diseases with insufficient endogenous production of Ang II;
and/or for the preparation of a medicament for the prophylaxis and/or treatment of a disease in which an increased action of Ang II is desired or required;
and/or preparing a medicament, pharmaceutical composition or formulation as an AT2 receptor agonist, and/or preventing and/or treating a disease in which AT2 receptor is expressed and which is desired or necessary to stimulate.
In a fifth aspect of the present invention, the present invention provides the use of a compound according to the first, second or third aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the fourth aspect, for the manufacture of a medicament for the prevention and/or treatment of a disease caused by endogenous deficiency of Ang ii; and/or increasing the expression of Ang ii in vivo.
In a sixth aspect of the invention, the invention provides the use of a compound according to the first, second or third aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the fourth aspect, as an AT2 receptor agonist.
In a seventh aspect of the invention, the invention provides the use of a compound according to the first, second or third aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the fourth aspect, for the manufacture of a medicament for increasing expression of AT2 receptors in vivo or increasing activity of AT2 receptors in vivo.
In an eighth aspect of the invention, the invention provides the use of a compound according to the first, second or third aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for the treatment or prophylaxis of a disease in which AT2 receptor expression is desired or necessary.
There is provided a compound of formula I, formula II or formula III, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first, second or third aspects, or a pharmaceutical composition according to the fourth aspect, which is intended for use in the treatment of diseases of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive system or Central Nervous System (CNS).
Gastrointestinal disorders that should be mentioned include esophagitis, barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease (e.g., hepatitis), cholecystitis, multiple organ failure, sepsis. Other gastrointestinal disorders that should be mentioned include xerostomia, gastritis, gastric retention tumor, gastric hyperacidity, biliary tract disease, coeliac disease, crohn's disease, ulcerative colitis, diarrhea, constipation, acute angina, dysphagia, nausea, vomiting and Sjogren's syndrome.
Respiratory diseases that should be mentioned include inflammatory diseases such as asthma, obstructive pulmonary disease (e.g. chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, adult respiratory distress syndrome and idiopathic pulmonary fibrosis.
Kidney diseases which should be mentioned include renal failure, nephritis and renal hypertension.
Eye diseases that should be mentioned include diabetic retinopathy, retinopathy of prematurity and retinal microvasculature.
Disorders of the female reproductive system that should be mentioned include disorders of the ovulation mechanism.
Cardiovascular diseases which should be mentioned include hypertension, myocardial hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, re-infarction, ischemic damage, erectile dysfunction and neointimal hyperplasia.
CNS disorders that should be mentioned include cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction.
The compounds of formula I, formula II or formula III, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, as described in the first, second or third aspects, or the pharmaceutical composition of the fourth aspect, may also be used for modulation of growth metabolism and proliferation, for example for the treatment of mastopathy, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcer healing, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer (e.g. gastrointestinal cancer, lung cancer etc.), apoptosis, tumour (in general), proliferative diabetes, nerve damage and organ rejection.
The compounds of formula I, II or III, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical compositions of the fourth aspect of the invention, as described in the first, second or third aspects, are suitable for the therapeutic and/or prophylactic treatment of the aforementioned diseases.
In a further aspect the present invention provides a method of treating a disease in which there is an insufficient endogenous production of Ang II, and/or in which there is a desire or need to increase the effect of Ang II, and/or in which there is a desire or need for AT2 receptor expression and stimulation, which method comprises administering to a person suffering from or susceptible to such a disease a therapeutically effective amount of a compound of formula I, formula II or formula III, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to the first, second or third aspects of the invention, or a pharmaceutical composition according to the fourth aspect.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Terminology and definitions
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combined group definitions and structures of compounds should fall within the scope of the description herein.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 speed." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Unless otherwise indicated, a substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different substituted at each substitutable position.
The term "unsubstituted" means that the specified group does not carry a substituent.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, for example, for compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may have a substituent substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
When describing substituents by conventional formulas written from left to right, the substituents also include right to leftChemically equivalent substituents obtained when writing structural formulae. For example, CH 2 O is equal to OCH 2 . As used herein, representing the attachment site of the group. As used herein, "R 1 "," R1 "and" R 1 "has the same meaning and can be replaced with each other. For R 2 And the like, and the meanings of like definitions are the same.
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.
Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both endpoints of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1, 2, 3, 4, 5, and 6.
In the present application, when the number of substituents is indicated, the term "one or more" refers to one substitution to the maximum number of substitutions possible, i.e. to replace one hydrogen to all hydrogens replaced with substituents. When the number of substituents is indicated, the term "1-4" means 1, 2, 3 or 4 substitutions, i.e. 1, 2, 3 or 4 hydrogens are substituted with a substituent.
In the present application, "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents fully unsaturated with hydrogen, and substituents partially saturated with hydrogen.
In this application, "AT2 receptor" and "AT2R" have the same definition.
In this application, the term "halogen" means fluorine, chlorine, bromine, iodine, alone or as part of other substituents.
In the present application, the term "amino" means-NH, alone or as part of another substituent 2 。
In this application, the term "hydroxy" means-OH, alone or as part of another substituent.
In this application, the term "cyano" means-CN, alone or as part of another substituent.
As used herein, the term "alkyl" alone or as part of another substituent means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, free of unsaturation, having, for example, 1 to 6 carbon atoms, and linked to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl and hexyl. The alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group can also be an isotopic isomer of a naturally abundant alkyl group that is enriched in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
The term "C", alone or as part of another substituent 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylpropylButyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 2-dimethylbutyl, or the like, or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C 1 -C 3 Alkyl "), such as methyl, ethyl, n-propyl or isopropyl.
The term "C", alone or as part of another substituent 1 -C 6 Alkoxy "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms and an oxygen atom composition, or C 1 -C 6 alkyl-O-C 1 -C 6 Alkyl groups are defined herein, and oxygen atoms may be attached to C 1 -C 6 Alkyl groups on either a straight chain or a straight chain carbon atom. Including but not limited to: methoxy (CH) 3 -O-), ethoxy (C) 2 H 5 -O-), propoxy (C) 3 H 7 -O-), butoxy (C) 4 H 9 -O-)。
The term "oxo" when used alone or as part of another substituent means that the two hydrogens on the methylene group are replaced with oxygen, i.e., the methylene group is replaced with a carbonyl group, representing =o.
The term "cycloalkyl" or "carbocyclyl" alone or as part of another substituent refers to a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C m -C n Cycloalkyl "is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C 3 -C 15 Cycloalkyl "refers to a cyclic alkyl group containing 3 to 15,3 to 9,3 to 6, or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "5-8 membered cycloalkyl" contains 5-8 carbon atoms. Including monocyclic, bicyclic, tricyclic, spiro, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl groups. The term "C 3 -C 6 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
"halocycloalkyl" when used alone or as part of another substituent means cycloalkyl as described above wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl are replaced with fluorine, chlorine, bromine or iodine.
The term "4-8 membered heterocycloalkyl", alone or as part of another substituent, refers to a monocyclic saturated heterocycle having a total of 4, 5, 6, 7 or 8 ring atoms and containing one or two identical or different ring heteroatoms or heteroatom-containing groups selected from the group consisting of: n, NH, O, S, SO and SO 2 The heterocycloalkyl group may be attached to the remainder of the molecule through any one carbon atom or (if present) nitrogen atom. The heterocycloalkyl group may be a 4-membered ring such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1, 3-dioxolanyl, thiaclopentyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1-dioxothiaclopentyl, 1, 2-oxazolidinyl, 1, 3-oxazolidinyl or 1, 3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1, 3-dioxanyl, 1, 4-dioxanyl, or 1, 2-oxazalonyl.
"haloalkyl", alone or as part of another substituent, is meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v=1 to 3,w =1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
The term "aryl" or "aromatic ring" when used alone or as part of another substituent means a monovalent aromatic carbocyclic ring system containing from 6 to 14, preferably from 6 to 10 carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, and the like.
The term "5-6 membered heteroaryl ring" when used alone or as part of another substituent is interchangeable with a 5-6 membered heteroaryl group "and is understood to be an aromatic ring group having 5 or 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaromatic ring" is understood to mean an aromatic ring group having 5 or 6 ring atoms, and which contains 1 to 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.
"spiro" refers to a group having two linked rings, wherein the two rings share only one single atom (the spiro atom, which is typically a quaternary carbon). The spiro ring may be a carbocycle (all ring atoms are carbon atoms) or a heterocycle (ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S, in addition to carbon atoms). Examples of spiro compounds include, but are not limited to:
spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:
in this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.
The term "amine salt" refers to the product of neutralizing an alkyl primary, secondary or tertiary amine with an acid. The acid includes inorganic or organic acids as described herein.
The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is dextrorotatory.
When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. The absolute configuration of a solid center is represented by wedge-shaped keys and dashed keys.
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The term "solvate" refers to a compound of the invention or a salt thereof that includes a stoichiometric or non-stoichiometric solvent that binds with non-covalent intermolecular forces, and when the solvent is water, is a hydrate.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with radioisotopes, such as deuterium 2 H) Tritium% 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
Advantageous effects
The present inventors have studied extensively and intensively, and have unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof. The invention provides a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, wherein the compound shown in the formula I has a remarkable agonistic effect on AT2R, can prevent or treat diseases or symptoms related to the AT2R, shows excellent pharmacokinetic properties, and has higher safety and pharmaceutical properties.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. Upon a complete understanding of the present invention, experimental methods without specific references in the following examples, generally according to conventional conditions or according to conditions suggested by the manufacturer, may make insubstantial changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of the present invention.
The application has the following definitions:
symbol or unit:
IC 50 : half inhibition concentration, meaning the concentration at which half of the maximum inhibition effect is achieved
M: mol/L, for example n-butyllithium (14.56 mL,29.1mmol,2.5M in n-hexane) means an n-hexane solution of n-butyllithium at a molar concentration of 2.5mol/L
N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution
RT: retention time
Reagent:
DMF: n, N-dimethylformamide
DCM: dichloromethane (dichloromethane)
EA: acetic acid ethyl ester
PE: petroleum ether
TEA: triethylamine
TFA: trifluoroacetic acid
SPhos Pd G3: methane sulphonic acid (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II)
The test method comprises the following steps:
LCMS: liquid chromatography-mass spectrometry
TLC: thin layer chromatography
Intermediate A1: preparation of intermediate A1
6- (4-bromobenzyl) -4, 6-diazaspiro [2.4] heptane-4-en-7-one
The synthetic route for intermediate A1 is shown below:
the first step: synthesis of ethyl 1-isocyanocyanurate
Ethyl 2-isocyanoacetate (10.0 g,88.4 mmol) was dissolved in tetrahydrofuran (100 mL), and sodium hydride (7.78 g,194mmol,60% purity) and 1, 2-dibromoethane (18.3 g,97.2 mmol) were added and reacted at 0℃for 2 hours. The reaction solution was quenched with water (200 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 1-isocyanocyanurate (10.0 g, crude).
And a second step of: synthesis of 6- (4-bromobenzyl) -4, 6-diazaspiro [2.4] heptane-4-en-7-one
Ethyl 1-isocyanatocyclopropate (10.0 g,71.9 mmol) was dissolved in toluene (100 mL), and (4-bromophenyl) methylamine (14.7 g,79.0 mmol) and silver nitrate (2.44 g,14.4 mmol) were added and reacted at 60℃for 2 hours. To the reaction solution was added water (200 mL), followed by extraction with ethyl acetate (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 6- (4-bromobenzyl) -4, 6-diazaspiro [2.4] heptane-4-en-7-one (A1) (3.00 g, yield 14.9%).
LC-MS,M/Z(ESI):278.9[M+H] +
Example 1: preparation of Compound I-1
((5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] hept-4-en-6-yl) methyl) phenyl) thiophen-2-yl) sulfonyl) carbamic acid butyl ester
The synthetic route for the target compound I-1 is shown below:
the first step: synthesis of N- (tert-butyl) -5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] heptane-4-en-6-yl) methyl) phenyl) thiophene-2-sulfonamide
6- (4-bromobenzyl) -4, 6-diazaspiro [2.4] heptane-4-en-7-one (A1) (0.1 g,0.4 mmol) was added to 2mLN, N-dimethylformamide, followed by (2- (N- (tert-butyl) sulfamoyl) -5-isobutylthiophene-3-yl) boronic acid (0.192 g,0.6 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (0.142 g,0.2 mmol), potassium carbonate (0.22 g,1.6 mmol) and heated to 90℃overnight. LCMS showed complete reaction of the starting material, dilution with 5mL of water, extraction with ethyl acetate (10 mL x 2), concentration of the organic phase to dryness, and isolation and purification of the residue on a silica gel column (PE: ea=1:1) gave N- (tert-butyl) -5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] hept-4-en-6-yl) methyl) phenyl) thiophene-2-sulfonamide (1-3) (70 mg, 41.4% yield).
LC-MS,M/Z(ESI):474.2[M+H] +
And a second step of: synthesis of 5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] heptane-4-en-6-yl) methyl) phenyl) thiophene-2-sulfonamide
N- (tert-butyl) -5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] heptane-4-en-6-yl) methyl) phenyl) thiophene-2-sulfonamide (0.07 g,0.15 mmol) was added to 2mL trifluoroacetic acid and reacted overnight at room temperature. LCMS showed complete reaction of the starting material and concentration to dryness gave 5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] heptane-4-en-6-yl) methyl) phenyl) thiophene-2-sulfonamide (80 mg, 100% yield).
LC-MS,M/Z(ESI):418.1[M+H] +
And a third step of: synthesis of (5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] heptane-4-en-6-yl) methyl) phenyl) thiophen-2-yl) sulfonyl) carbamic acid butyl ester
5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] heptane-4-en-6-yl) methyl) phenyl) thiophene-2-sulfonamide (0.07 g,0.17 mmol) was added to 3mL of dichloromethane, triethylamine (0.1 g,1.0 mmol) and butyl chloroformate (0.05 g,0.33 mmol) were added and the reaction was allowed to proceed overnight at room temperature. LCMS showed complete reaction of the starting material, dilution with 5mL of water, extraction with ethyl acetate (10 mL x 2), concentration of the organic phase to dryness, and isolation and purification of the residue on a silica gel column (PE: ea=1:1) gave butyl ((5-isobutyl-3- (4- ((7-oxo-4, 6-diazaspiro [2.4] hept-4-en-6-yl) methyl) phenyl) thiophen-2-yl) sulfonyl) carbamate (I-1) (4.9 mg, 5.6% yield).
LC-MS,M/Z(ESI):518.2[M+H] +
1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.49(d,2H),7.32(d,2H),6.95(s,1H),4.76(s,2H),3.93(t,2H),2.70(d,2H),1.69-1.66(m,1H),1.49-1.46(m,2H),1.42-1.39(m,2H),1.35-1.32(m,2H),1.19-1.15(m,2H),0.93(d,6H),0.83(t,3H)。
Example 2: preparation of target Compound I-5
(5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptan-6-yl) methyl) phenyl) thiophen-2-yl) sulphonylcarbamic acid butyl ester
The synthetic route for the target compound I-5 is shown below:
the first step: synthesis of N- (4-bromobenzyl) -1- (methylamino) cyclopropane-1-carboxamide
(4-bromophenyl) methylamine (3.20 g,17.1 mmol) and 1- (methylamino) cyclopropane-1-carboxylic acid hydrochloride (2.60 g,17.1 mmol) were dissolved in methylene chloride (30 mL), 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (7.83 g,20.6 mmol) was added, and after the addition, N, N-diisopropylethylamine (8.87 g,68.6 mmol) was added, and the reaction solution was reacted at 20℃for 2 hours. The reaction solution was poured into water (50 mL), extracted three times with ethyl acetate (100 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-1:1) to give N- (4-bromobenzyl) -1- (methylamino) cyclopropane-1-carboxamide (900 mg, 18.5% yield).
LC-MS,M/Z(ESI):283.1[M+H] + .
And a second step of: synthesis of 6- (4-bromobenzyl) -4-methyl-4, 6-diazaspiro [2.4] heptane-5, 7-dione
N- (4-Bromobenzylmethyl) -1- (methylamino) cyclopropane-1-carboxamide (400 mg,1.41 mmol) and di-tert-butyl dicarbonate (463 mg,2.12 mmol) were dissolved in toluene (20 mL) and 4-dimethylaminopyridine (517 mg,4.24 mmol) was added to react at 20℃for 2 hours. The reaction solution was poured into water (50 mL), extracted three times with ethyl acetate (100 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-1:1) to give 6- (4-bromobenzyl) -4-methyl-4, 6-diazaspiro [2.4] heptane-5, 7-dione (389 mg, yield 89.1%).
LC-MS,M/Z(ESI):309.0[M+H] + .
And a third step of: synthesis of N- (tert-butyl) -5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptane-6-yl) methyl) phenyl) thiophene-2-sulfonamide
(2- (N- (tert-butyl) sulfamoyl) -5-isobutyl thiophen-3-yl) boric acid (248 mg, 776. Mu. Mol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), 6- (4-bromophenyl) -4-methyl-4, 6-diazaspiro [2.4] heptane-5, 7-dione (200 mg, 647. Mu. Mol) was added, potassium phosphate (686 mg,3.23 mmol) was further added, and SPhos Pd G3 (111 mg, 129. Mu. Mol) was then reacted under nitrogen at 60℃with stirring for 4 hours. The reaction solution was concentrated to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =50:1-1:1) to give N- (tert-butyl) -5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptan-6-yl) methyl) phenyl) thiophene-2-sulfonamide (300 mg, yield 92.1%).
LC-MS,M/Z(ESI):504.1[M+H] + .
Fourth step: synthesis of 5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptane-6-yl) methyl) phenyl) thiophene-2-sulfonamide
N- (tert-butyl) -5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptan-6-yl) methyl) phenyl) thiophene-2-sulfonamide (280 mg, 556. Mu. Mol) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) and reacted at 20℃for 8 hours. The reaction solution was poured into water (10 mL), ph=9 was adjusted with saturated aqueous sodium bicarbonate, then extracted three times with dichloromethane (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =10:1-1:1) to give 5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptane-6-yl) methyl) phenyl) thiophene-2-sulfonamide (230 mg, 92.4% yield).
LC-MS,M/Z(ESI):448.1[M+H] + .
Fifth step: synthesis of butyl (5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptan-6-yl) methyl) phenyl) thiophen-2-yl) sulphonylcarbamate
5-isobutyl-3- (4- ((4-methyl-5, 7-dioxo-4, 6-diazaspiro [2.4] heptan-6-yl) methyl) phenyl) thiophene-2-sulfonamide (100 mg, 223. Mu. Mol) and N, N-diisopropylethylamine (86.6 mg, 670. Mu. Mol) were dissolved in dichloromethane (3 mL), butyl chloroformate (33.6 mg, 246. Mu. Mol) was added, and the reaction was stirred at 0℃for 1 hour. The reaction solution was concentrated, and the resulting mixture was purified by high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: a=water+0.05 volume of formic acid (99%), b=acetonitrile; gradient: 60% -80%,8 minutes) and lyophilized to give butyl (5-isobutyl-3- (4- ((4-methyl-5, 7-dioxaspiro [2.4] heptan-6-yl) methyl) phenyl) thiophen-2-yl) carbamate (60.0 mg, yield 46.6%).
LC-MS,M/Z(ESI):548.2[M+H] + .
1 H NMR(CDCl 3 ,400MHz)δ:7.44(m,4H),7.38(s,1H),6.74(s,1H),4.76(s,2H),4.05(m,2H),2.75(s,3H),2.71(d,2H),1.94(m,1H),1.48-1.55(m,2H),1.41-1.45(m,2H),1.34-1.39(m,2H),1.26(m,2H),0.97-1.01(m,6H),0.89(m,3H).
The following compounds were prepared according to the method described in example 1.
Biological testing
The following test methods may be used.
Test example 1: compounds and AT2R binding assays
According to the experimental instructions of the Angiotenin AT2 Receptor Ligand Binding Assay kit (#C1TT1AT2, cisbio). First 10mM compound stock was diluted in a gradient at 5 Xdilution (10 concentrations each repeated) and 160nL of different concentrations of compound were added to 384 well plates. 40. Mu.L of 1 XTLB was added to each well and shaken at room temperature for 15 minutes. A15 mL centrifuge tube with 5mL of 1 XTLB added was prepared in advance for use. Thawing the frozen labeled cells in a water bath at 37 ℃ for 1-2 minutes, rapidly transferring the thawed cells into the 15mL centrifuge tube, uniformly mixing, and centrifuging at room temperature of 1000g for 5 minutes. The supernatant was removed and 2.7mL of 1 XTLB resuspended cells were added. A new 384 well plate was prepared and 10. Mu.L of the well-mixed cells were added to the corresponding wells according to the assay design. mu.L of a 4 XCompound solution, 5. Mu.L of a 4 XTag-lite red fluorescent labeled ligand, was added to each well. After 1 hour incubation at room temperature, the data were read using the HTRF mode of EnVision. The excitation light intensities of 665nM and 615nM in each well were read separately, the Ratio calculated (ratio=a665 nM/B615 nM), IC50 values calculated using GraphPad Prism8 software, X: logarithmic concentration of compound; y: a665nM/B615nM ratio.
Table 1: compounds with AT2R binding Activity
| Numbering of compounds | AT2R IC50(nM) |
| I-1 | 69.89 |
Conclusion: the test compounds have a stronger binding to AT2R and are highly selective compared to AT1R binding.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (16)
1. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
wherein ring E is a 7-11 membered saturated or partially saturated spiro ring;
re is selected from halogen, hydroxy, cyano, amino, oxo (= O), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the Re is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
n is 0, 1, 2, 3 or 4;
when Re is 2, 3 or 4, the Re is the same or different;
l is C which is unsubstituted or substituted by one or more substituents 1 -C 6 Alkyl, each substituent being independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o);
ring B is selected from benzene ring or 5-6 membered heteroaromatic ring;
m is selected from 0, 1, 2, 3 or 4;
R 1 and R is 3 Each independently selected from halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the R is 1 And R is 3 Each independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are a plurality of substituents, the substituents are the same or different;
R 2 selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, C 3 -C 7 cycloalkyl-C 1 -C 6 An alkyl group;
z is selected from O or NR 4 ；
R 4 Selected from hydrogen or C 1 -C 3 An alkyl group;
R 6 selected from hydrogen or halogen, hydroxy, cyano, amino, oxo (=o), C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, -O-C 3 -C 7 Cycloalkyl;
the R is 6 Independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl; when there are plural substituents, the substituents may be the same or different.
2. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of the following structures:
Wherein ring E, ring B, re, R 3 L, m and n have the definition set forth in claim 1.
3. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of the following structures:
wherein the dotted line represents a single bond or a double bond;
ring B, re, R 1 、R 2 、R 3 、R 6 Z, L, m and n have the definition set forth in claim 1.
4. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1,having the structure->
Ring E 1 Each independently is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
Y 1 each independently is N or CRe;
Y 2 each independently is NRe or C (Re) 2 ；
Re has the definition of claim 1.
5. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 2, wherein the compound is selected from the group consisting of the following structures:
wherein ring E 1 Each independently is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
Y 1 each independently is N or CRe;
Y 2 Each independently is NRe or C (Re) 2 ；
Re has the definition of claim 1.
6. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 4 or 5, wherein ring E 1 Is 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
the 4-7 membered heterocycloalkyl has 1, 2, 3 or 4 heteroatoms selected from N, O or S; when the hetero atom is plural, the hetero atoms are the same or different;
preferably, the heterocycloalkyl group contains at most one O or S
Preferably, the ring E 1 Selected from: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, tetrahydrothiopyran.
7. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 4 or 5, wherein the ring E 1 Selected from:
8. the compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 2, The structure is as follows:
9. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 to 3, wherein Re is selected from F, cl, br, I, oxo (=o), C 1 -C 6 Alkyl or C 3 -C 7 Cycloalkyl;
optionally, each Re is independently selected from oxo (=o) or C 1 -C 3 An alkyl group;
optionally, each Re is independently selected from oxo (=o) or methyl;
optionally, the L is C which is unsubstituted or substituted with 1 to 3 substituents 1 -C 3 Alkyl, wherein the substituents are independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, oxo (=o);
optionally, the L is C 1 -C 3 Alkyl, quilt C 1 -C 6 Alkyl substituted C 1 -C 3 An alkyl group;
optionally, the L is-CH 2 -or-CH (CH) 3 )-；
Optionally, the ring B is selected from a benzene ring or a 5-6 membered heteroaryl ring having 1 or 2 heteroatoms which are N;
optionally, the ring B is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;
optionally, the R 3 Each independently selected from halogen, cyano, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 An alkoxy group;
optionally, the R 3 Each independently selected from F, cl, cyano, methyl, methoxy, halomethyl, cyclopropyl.
10. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 wherein R 1 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 7 Cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 An alkyl group;
optionally, the R 1 Selected from C 1 -C 6 An alkyl group;
optionally, the R 1 Is isobutyl;
optionally, the R 2 Selected from C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group;
optionally, the R 2 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl;
preferably, said R 2 Is butyl;
optionally, Z is selected from O, -NH-or-NC 1 -C 3 Alkyl-;
optionally, Z is O;
optionally, the R 6 Selected from hydrogen, halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl;
optionally, the R 6 Is hydrogen, halogen or C 1 -C 3 An alkyl group;
optionally, the R 6 Is hydrogen.
11. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein the compound comprises:
12. a pharmaceutical composition, the pharmaceutical composition comprising: the compound of any one of claims 1-11, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and pharmaceutically acceptable carriers and/or adjuvants.
13. Use of a compound according to any one of claims 1-11, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or use of a pharmaceutical composition according to claim 12, the use comprising:
as AT2 receptor agonists;
and/or preparing a medicament for preventing and/or treating diseases with insufficient endogenous production of Ang II;
and/or for the preparation of a medicament for the prophylaxis and/or treatment of a disease in which an increased action of Ang II is desired or required;
and/or preparing a medicament, pharmaceutical composition or formulation as an AT2 receptor agonist, and/or preventing and/or treating a disease in which AT2 receptor is expressed and which is desired or necessary to stimulate.
14. The use according to claim 13, wherein the disease is a disease of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive system or central nervous system.
15. The use according to claim 14, the disease is esophagitis, barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia, gastroesophageal reflux, irritable bowel syndrome, inflammatory enteritis, pancreatitis, liver disease, cholecystopathy, multiple organ failure, sepsis, xerostomia, gastritis, gastric retention tumor, gastric hyperacidity, biliary tract disease, abdominal disease, crohn's disease, ulcerative colitis, diarrhea, constipation, acute angina, dysphagia, nausea, emesis, sjogren's syndrome, inflammatory disease, asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, renal failure, nephritis, renal hypertension, diabetic retinopathy, retinopathy of prematurity, retinal microvascular, ovulation mechanism disorder hypertension, myocardial hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, stenosis after balloon dilation, angiogenesis, diabetic complications, microvascular dysfunction, angina, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, re-infarction, ischemic injury, erectile dysfunction, neointimal hyperplasia, cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophic disease, prostatic hyperplasia, autoimmune diseases, psoriasis, obesity, nerve regeneration, ulcers, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer, apoptosis, tumors, proliferative diabetes, nerve damage or organ rejection.
16. The use according to claim 15, wherein the disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.
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