Compound for regulating NMDA receptor activity, pharmaceutical composition and application thereof
阅读说明：本技术 一种调节nmda受体活性的化合物、其药物组合物及用途 (Compound for regulating NMDA receptor activity, pharmaceutical composition and application thereof ) 是由 顾为 于 2019-04-09 设计创作，主要内容包括：本发明属于医药化工领域,涉及调节NMDA受体活性的化合物、其药物组合物及用途。具体地,本发明涉及式I所示的化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物。本发明还涉及包含式I化合物的药物组合物和药盒产品,以及式I化合物在制备治疗和/或预防抑郁症、焦虑症、脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛或精神分裂症的药物中的用途。NH-2-P1-P2-P3-P4-COR 式I。(The invention belongs to the field of pharmaceutical chemicals, and relates to a compound for regulating NMDA receptor activity, a pharmaceutical composition and application thereof. In particular toThe invention relates to a compound shown as a formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof. The invention also relates to a pharmaceutical composition and a kit product containing the compound of the formula I, and application of the compound of the formula I in preparing a medicament for treating and/or preventing depression, anxiety, cerebral apoplexy, Huntington's disease, Alzheimer disease, neuralgia or schizophrenia. NH (NH) 2 -P1-P2-P3-P4-COR formula I.)
1. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof,
NH2-P1-P2-P3-P4-COR
formula I
Wherein the content of the first and second substances,
NH2-P1 is selected fromWherein the dotted lines all represent the attachment site to P2;
p2 is selected fromWherein the wavy lines all represent the same as NH2-the linkage site of P1, the dotted lines each indicating a linkage site to P3;
p3 is selected fromWherein the wavy lines all represent the attachment site to P2 and the dashed lines all represent the attachment site to P4;
wherein, for P2 and P3,
R1are all independently selected from C1-C5Alkyl radicals andwherein R is11、R12And R13Independently selected from H, halogen, C1-3Alkoxy and C1-3Alkyl, and n is 0, 1, 2, 3, 4, 5 or 6;
P4-CO-is selected fromWherein the wavy lines all represent the attachment site to P3 and the dashed lines all represent the attachment site to R;
r is selected from OR2And NR3R4Wherein R is2、R3And R4Are independently selected fromFrom hydrogen, C1-C6Alkyl and the following substituents:
wherein the dotted lines all indicate the attachment site to P4, R21、R22And R23Independently selected from H, OH and OCH3，R31、R32And R33Independently selected from H and C1-C3An alkyl group;
and when P2 and P3 are simultaneouslyWhen R is2Is other than C1-C6Alkyl and R3And R4Not hydrogen at the same time.
2. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, according to claim 1, characterized by any one of the following (1) to (4):
(1)NH2-P1 isAnd P4-CO-is
(2)NH2-P1 isAnd P4-CO-is
(3)NH2-P1 isAnd P4-CO-isOr
(4)NH2-P1 isAnd P4-CO-is
3. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, according to any one of claims 1 to 2, characterized by any one of the following 1) to 9):
1) p2 isAnd P3 is
2) P2 isAnd P3 is
3) P2 isAnd P3 is
4) P2 isAnd P3 is
5) P2 isAnd P3 is
6) P2 isAnd P3 is
7) P2 isAnd P3 is
8) P2 isAnd P3 isOr
9)
P2 is selected fromAnd is
P3 is selected from
4. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, according to any one of claims 1 to 3, wherein,
R1are all independently selected from C1-C5An alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a 2-pentyl group, an isopentyl group, or a neopentyl group;
or
R1Are all independently selected fromSuch as phenyl or benzyl.
5. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, according to any one of claims 1 to 4, wherein:
r is OR2Wherein R is2Selected from hydrogen, C1-C6Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, or 3-hexyl) and the following substituents:
wherein the dotted lines all represent the attachment site to P4; or
R is selected from NR3R4Wherein R is3And R4Each independently selected from hydrogen and C1-C6Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl or 3-hexyl)) And the following substituents:
wherein the dotted lines all represent the attachment site to P4;
and when P2 and P3 are simultaneouslyWhen R is3And R4Not hydrogen at the same time.
6. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as claimed in any one of claims 1 to 5, wherein the compound of formula I is selected from:
3- (L-threonyl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-threoninamide;
3- (L-seryl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-threonine amide;
3- (L-threonyl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-serine amide;
3- (L-seryl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-serine amide;
3- (L-threonyl-L-prolyl) -thiazolidine- (4R) -carbonyl-L-threonine amide;
3- (L-seryl-L-prolyl) -thiazolidine- (4R) -carbonyl-L-threonine amide;
3- (L-threonyl-L-prolyl) -thiazolidine- (4R) -carbonyl-L-serine amide;
3- (L-seryl-L-prolyl) -thiazolidine- (4R) -carbonyl-L-serine amide;
3- (3-L-threonyl-thiazolidine- (4R) -carbonyl-) -thiazolidine- (4R) -carbonyl-L-threonine amide;
3- (3-L-seryl-thiazolidine- (4R) -carbonyl-) -thiazolidine- (4R) -carbonyl-L-threonine amide;
3- (3-L-threonyl-thiazolidine- (4R) -carbonyl-) -thiazolidine- (4R) -carbonyl-L-serinamide;
3- (L-threonyl) -2, 2-dimethylthiazolidine- (4R) -carbonyl-L-prolyl-L-threoninamide;
3- (L-threonyl-L-prolyl) -2, 2-dimethylthiazolidine- (4R) -carbonyl-L-threonine amide;
3- (L-seryl-L-prolyl) -2, 2-dimethylthiazolidine- (4R) -carbonyl-L-threonine amide;
3- (L-threonyl-L-prolyl) -2, 2-dimethylthiazolidine- (4R) -carbonyl-L-serine amide;
3- (L-threonyl-L-prolyl) -2-methylthiazolidine-4 (R) -carbonyl-L-threoninamide;
3- (L-threonyl-L-prolyl) -2-ethylthiazolidine-4 (R) -carbonyl-L-threoamide;
3- (L-threonyl-L-prolyl) -2-isopropylthiazolidine-4 (R) -carbonyl-L-threoamide;
3- (L-threonyl-L-prolyl) -2-benzylthiazolidine-4 (R) -carbonyl-L-threoamide;
3- (L-threonyl-L-prolyl) -2-phenylthiazolidine-4 (R) -carbonyl-L-threoamide;
3- (L-threonyl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-threonine methyl ester;
3- (L-threonyl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-threonyl methylamine;
3- (L-threonyl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-threonine ethyl ester;
3- (L-threonyl) -thiazolidine- (4R) -carbonyl-L-prolyl-L-threonine isopropyl ester;
L-threonyl-L-prolyl-L-threonyl-L-menthyl ester;
L-threonyl-L-prolyl-L-threonyl- (+) -2-camphanol ester;
2-acetamido-pyrrolidone- (4S) -hydroxy-L-threonyl-L-prolyl-L-threonine acid ester;
7-ethyl-theophylline-hydroxy-L-threonyl-L-prolyl-L-
Threonine esters;
7-propyl-theophylline-hydroxy-L-threonyl-L-prolyl-L-
Threonine esters;
L-threonyl-L-prolyl-L-threonyl-memantine;
L-threonyl-L-prolyl-L-threonyl-amantadine;
L-threonyl-L-prolyl-L-threonyl-dopamine; and
1- ((2- (7-methoxy-naphthalen-1-yl) ethyl) amino-L-threonyl-L-prolyl-L-threonine amide.
7. A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as claimed in any one of claims 1 to 6, wherein the solvate is a hydrate.
8. A pharmaceutical composition comprising an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as claimed in any one of claims 1 to 7;
optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
9. The pharmaceutical composition of claim 8, further comprising one or more selected from the group consisting of a 5-hydroxytryptamine reuptake inhibitor, a 5-hydroxytryptamine-norepinephrine reuptake inhibitor, mirtazapine, bupropion, vilazodone, vortioxetine;
preferably, the 5-hydroxytryptamine reuptake inhibitor is one or more selected from citalopram, sertraline, paroxetine and fluoxetine;
preferably, the 5-hydroxytryptamine-norepinephrine reuptake inhibitor is one or more selected from duloxetine, graphanetacin, norgraphanetacin, and milnacipran.
10. The pharmaceutical composition of claim 8, further comprising one or more selected from the group consisting of benzodiazepines, carisoprodol, and tylosin;
preferably, the benzodiazepine is one or more selected from the group consisting of chlordiazepoxide, diazepam, lorazepam and estazolam.
11. A kit product comprising an individually packaged pharmaceutical formulation 1 and an individually packaged pharmaceutical formulation 2, wherein:
the pharmaceutical formulation 1 comprises an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as claimed in any one of claims 1 to 7;
said pharmaceutical formulation 2 comprises one or more selected from the group consisting of a 5-hydroxytryptamine reuptake inhibitor, a 5-hydroxytryptamine-norepinephrine reuptake inhibitor, mirtazapine, bupropion, vilazodone, vortioxetine, or said pharmaceutical formulation 2 comprises one or more selected from the group consisting of benzodiazepines, carisoprodol, and tylosin;
optionally, the pharmaceutical preparation 1 and/or the pharmaceutical preparation 2 further comprise one or more pharmaceutically acceptable excipients;
preferably, the 5-hydroxytryptamine reuptake inhibitor is one or more selected from citalopram, sertraline, paroxetine and fluoxetine;
preferably, the 5-hydroxytryptamine-norepinephrine reuptake inhibitor is one or more selected from duloxetine, graphanetacin, norgraphanetacin, and milnacipran;
preferably, the benzodiazepine is one or more selected from the group consisting of chlordiazepoxide, diazepam, lorazepam and estazolam.
12. Use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof, as claimed in any one of claims 1 to 7, for the manufacture of a medicament for the treatment and/or prophylaxis of depression, anxiety, stroke, huntington's disease, alzheimer's disease, neuralgia or schizophrenia.
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a compound for regulating NMDA receptor activity, a pharmaceutical composition and application thereof. In particular, the present invention relates to compounds having enhanced potency in the modulation of NMDA receptor activity and the use of such compounds for the prevention/treatment of depression, anxiety, stress, learning and cognitive deficits, neuropathic pain and other disorders.
Background
At present, the incidence rate and the harmfulness of depression are increasing day by day, but the treatment medicine of the depression cannot completely meet the clinical requirement. The anti-depression agents on the market mainly comprise selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) and 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs), and the anti-depression agents taking 5-hydroxytryptamine as a core mechanism have a plurality of defects, including slow effect taking, more adverse reactions, more non-response patients (refractory depression patients) and the like. Clinically, there is a strong need for antidepressants with new mechanism and new characteristics.
N-methyl-D-aspartate (NMDA) receptors play an important role in a variety of central activities, such as learning, memory, emotion, cognition, pain sensation, and the like. Over-activation of NMDA receptors can lead to stroke, Huntington's disease, Alzheimer's disease, neuralgia, schizophrenia, depression, etc. (NMDA receptors in neural system diseases. neuropharmacology, 2013, 74: 69-75).
Antidepressants targeting NMDA receptors are a hot spot in the current drug development (NMDA receptors as drug targets. Nature Neuroscience,2002, 5: 1039-. Esketamine and Rapasatinel have strong advantages in the aspects of quick response, more response to refractory depression patients and the like. However, Esketamine is at risk for addiction, induction of dissociations, and mania; rapasinetel cannot be taken orally, and intravenous administration is necessary in clinical application. This severely limits the clinical utility of the above compounds.
There is a need to develop new drugs against NMDA receptors, especially orally available drugs.
Disclosure of Invention
The present inventors have made intensive studies and creative efforts to obtain a compound represented by formula I. The present inventors have surprisingly found that compounds of formula I, or a pharmaceutically acceptable salt, solvate or mixture thereof, are agonists, particularly partial agonists, of the NMDA receptor and have a high degree of affinity for the NMDA receptor; reflected on an animal model, can quickly, effectively and durably prevent and treat the depression and anxiety states of the animal model.
The following invention is thus provided:
one aspect of the present invention relates to a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof,
NH2-P1-P2-P3-P4-COR
formula I
Wherein the content of the first and second substances,
NH2-P1 is selected fromWherein the dotted lines all represent the attachment site to P2;
p2 is selected fromWherein the wavy lines all represent the same as NH2-the linkage site of P1, the dotted lines each indicating a linkage site to P3;
p3 is selected fromWherein the wavy lines all represent the attachment site to P2 and the dashed lines all represent the attachment site to P4;
wherein, for P2 and P3,
R1are all independently selected from C1-C5Alkyl radicals andwherein R is11、R12And R13Independently selected from H, halogen, nitro, C1-3Alkoxy and C1-3Alkyl, and n is 0, 1, 2 or 3;
P4-CO-is selected fromWherein the wavy lines all represent the attachment site to P3 and the dashed lines all represent the attachment site to R;
r is selected from OR2And NR3R4Wherein R is2、R3And R4Each independently selected from hydrogen and C1-C6Alkyl and the following substituents:
wherein the dotted lines all indicate the attachment site to P4, R21、R22And R23Independently selected from H, OH and OCH3，R31、R32And R33Independently selected from H and C1-C3An alkyl group;
and when P2 and P3 are simultaneouslyWhen R is2Is other than C1-C6Alkyl and R3And R4Not hydrogen at the same time.
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, is characterized by any one of the following (1) to (4):
(1)NH2-P1 isAnd P4-CO-is
(2)NH2-P1 isAnd P4-CO-is
(3)NH2-P1 isAnd P4-CO-isOr
(4)NH2-P1 isAnd P4-CO-is
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, is characterized by any one of items 1) to 9) below:
1) p2 isAnd P3 is
2) P2 isAnd P3 is
3) P2 isAnd P3 is
4) P2 isAnd P3 is
5) P2 isAnd P3 is
6) P2 isAnd P3 is
7) P2 isAnd P3 is
8) P2 isAnd P3 isOr
9)
P2 is selected fromAnd is
P3 is selected from
Any one of the above items (1) to (4) may be combined with any one of the above items 1) to 9). In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, is NH2When P1 and P4-CO are selected from any one of items (1) to (4) above, and P2 and P3 are selected from any one of items 1) to 9) above, it will be understood by those skilled in the art that there are a total of 36 (4 × 9) specific embodiments, which are within the scope of the present invention.
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, wherein,
R1are all independently selected from C1-C5An alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a 2-pentyl group, an isopentyl group, or a neopentyl group;
or
R1Are all independently selected fromSuch as phenyl or benzyl.
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, wherein:
r is OR2Wherein R is2Selected from hydrogen, C1-C6Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and isobutyl,Pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl or 3-hexyl) and the following substituents:
wherein the dotted lines all represent the attachment site to P4;
or
R is selected from NR3R4Wherein R is3And R4Each independently selected from hydrogen and C1-C6Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, or 3-hexyl) and the following substituents:
wherein the dotted lines all represent the attachment site to P4;
and when P2 and P3 are simultaneouslyWhen R is3And R4Not hydrogen at the same time.
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, wherein the compound of formula I is selected from the compounds shown in table 1 below.
Table 1: example compounds of the invention
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, wherein the solvate is a hydrate.
Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as described in any one of the present inventions;
optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
A pharmaceutical composition as described in some embodiments of the invention, further comprising one or more selected from the group consisting of a 5-hydroxytryptamine reuptake inhibitor, a 5-hydroxytryptamine-norepinephrine reuptake inhibitor, mirtazapine, bupropion, vilazone, vortioxetine;
preferably, the 5-hydroxytryptamine reuptake inhibitor is one or more selected from citalopram, sertraline, paroxetine and fluoxetine;
preferably, the 5-hydroxytryptamine-norepinephrine reuptake inhibitor is one or more selected from duloxetine, graphanetacin, norgraphanetacin, and milnacipran.
A pharmaceutical composition as described in some embodiments of the invention, further comprising one or more selected from the group consisting of benzodiazepines, carisoprodol, and tylosin;
preferably, the benzodiazepine is one or more selected from the group consisting of chlordiazepoxide, diazepam, lorazepam and estazolam.
Yet another aspect of the invention relates to a kit product comprising an individually packaged pharmaceutical formulation 1 and an individually packaged pharmaceutical formulation 2, wherein:
the pharmaceutical formulation 1 comprises an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as described in any one of the present inventions;
said pharmaceutical formulation 2 comprises one or more selected from the group consisting of a 5-hydroxytryptamine reuptake inhibitor, a 5-hydroxytryptamine-norepinephrine reuptake inhibitor, mirtazapine, bupropion, vilazodone, vortioxetine, or said pharmaceutical formulation 2 comprises one or more selected from the group consisting of benzodiazepines, carisoprodol, and tylosin;
optionally, the pharmaceutical preparation 1 and/or the pharmaceutical preparation 2 further comprise one or more pharmaceutically acceptable excipients;
preferably, the 5-hydroxytryptamine reuptake inhibitor is one or more selected from citalopram, sertraline, paroxetine and fluoxetine;
preferably, the 5-hydroxytryptamine-norepinephrine reuptake inhibitor is one or more selected from duloxetine, graphanetacin, norgraphanetacin, and milnacipran;
preferably, the benzodiazepine is one or more selected from the group consisting of chlordiazepoxide, diazepam, lorazepam and estazolam.
A further aspect of the present invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof, as defined in any one of the preceding aspects, for the manufacture of a medicament for the treatment and/or prophylaxis of depression, anxiety, stroke, huntington's disease, alzheimer's disease, neuralgia or schizophrenia.
A further aspect of the present invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as described in any one of the present invention, for the manufacture of a medicament for modulating (e.g. up-regulating or down-regulating) the activity of an NMDA receptor (e.g. a human NMDA receptor) in vivo or in vitro.
Yet another aspect of the present invention relates to a method for the treatment and/or prevention of depression, anxiety, stroke, huntington's disease, alzheimer's disease, neuralgia or schizophrenia, comprising the step of administering to a subject in need thereof an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof or a solvate thereof, as defined in any of the present invention.
Yet another aspect of the present invention relates to a method of modulating (e.g., up-regulating or down-regulating) the activity of an NMDA receptor (e.g., a human NMDA receptor) in vivo or in vitro comprising the step of administering to a subject, a mammalian cell, or an NMDA receptor solution an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as described in any one of the present invention.
In some embodiments of the invention, the compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, is used for the treatment and/or prevention of depression, anxiety, stroke, huntington's disease, alzheimer's disease, neuralgia or schizophrenia.
A compound of formula I, a pharmaceutically acceptable salt or ester thereof, a stereoisomer thereof, or a solvate thereof, as described in some embodiments of the invention, is used to modulate (e.g., up-or down-regulate) NMDA receptor (e.g., human NMDA receptor) activity in vivo or in vitro.
Some terms related to the present invention are explained below.
In the present invention, the term "C1-C6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl and the like; c1-C5Alkyl and C1-C3Alkyl groups are similarly understood.
The term "metabolic stability" refers herein to the ability of a compound to enter and stably exist in the body as a proto-drug without being metabolized to other structural forms.
The pharmaceutical compositions of the invention generally contain 0.1 to 90% by weight of a compound of the formula I and/or a physiologically acceptable salt thereof. The pharmaceutical compositions may be prepared according to methods known in the art. For this purpose, the compounds of the formula I and/or stereoisomers can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or auxiliaries in a suitable administration form or dosage form for human use.
The term "effective amount" refers to a dose that achieves treatment, prevention, alleviation and/or amelioration of a disease or disorder described herein in a subject.
The term "subject" can refer to a patient or other animal, particularly a mammal, e.g., a human, dog, monkey, cow, horse, etc., that receives a composition of the invention to treat, prevent, ameliorate, and/or alleviate a disease or disorder described herein.
The term "disease and/or disorder" refers to a physical condition of the subject that is associated with the disease and/or disorder of the present invention. The term "pharmaceutically acceptable" refers herein to: the compound or composition is compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or with the human or mammal with which the disease or condition is to be prevented or treated.
The term "subject" or "patient" in this application includes humans and mammals.
The term "adjuvant" refers herein to an excipient or vehicle used to administer a compound, including, but not limited to, diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, coating materials, and the like. Adjuvants are generally described in "Remington's Pharmaceutical Sciences" by e.w. martin. Examples of adjuvants include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyeicosateyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, and the like.
The term "solvate" refers herein to a complex formed by combining a compound of formula I, or a pharmaceutically acceptable salt thereof, and a solvent. It is to be understood that any solvate of a compound of formula I used in the treatment of a disease or condition described herein, while potentially offering different properties (including pharmacokinetic properties), upon absorption into a subject, results in a compound of formula I such that the use of the compound of formula I encompasses the use of any solvate of the compound of formula I, respectively.
The term "hydrate" refers to the case where the solvent in the above term "solvate" is water.
It is further understood that the compound of formula I, or a pharmaceutically acceptable salt thereof, may be isolated in the form of a solvate, and thus any such solvate is included within the scope of the present invention. For example, a compound of formula I or a pharmaceutically acceptable salt thereof may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
The term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M.Berge et al, "Pharmaceutical Salts", J.pharm.Sci.1977,66, 1-19. Among them, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, or the like; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, diglucosic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, succinic acid, and the like, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, etc. For example, HCl (or hydrochloric acid), HBr (or hydrobromic acid solution), methanesulfonic acid, sulfuric acid, tartaric acid, or fumaric acid can be used to form pharmaceutically acceptable salts with compounds of formula I.
The compounds of the present invention may be formulated into pharmaceutical preparations, including dosage forms suitable for oral administration, dosage forms suitable for parenteral injection (e.g., intravenous, subcutaneous injection) (e.g., as solutions), dosage forms suitable for topical administration (e.g., as ointments, patches, or creams), and dosage forms suitable for rectal administration (e.g., as suppositories), and the like.
The pharmaceutical preparations of the present invention may be administered once or more times daily in different dosages depending on the disease to be treated and the patient and the route of administration. For example, a daily dosage of a compound of the invention may be about 0.1-10mg/kg body weight for oral administration.
The dosage of the compound of the present invention, its pharmaceutically acceptable salt, solvate thereof, or N-oxide thereof, or the pharmaceutical composition of the present invention to be administered depends on many factors, such as the nature and severity of the tumor to be treated or adjunctive treatment, the sex, age, body weight and individual response of the patient or animal, the specific compound used, the route of administration and the number of administrations, and the like. The above dosage may be administered in a single dosage form or divided into several, e.g., two, three, four dosage forms.
The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The compounds according to the invention may be effective in the prevention and/or treatment of various diseases or conditions described herein.
Advantageous effects of the invention
The compound of formula I or pharmaceutically acceptable salt, solvate or mixture thereof can be used for preventing/treating depression and/or anxiety.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Specific synthetic methods for the P2/P3 fragment are shown in preparation examples 1-8 below.
The synthetic routes of preparation examples 1 to 3 are shown below:
preparation example 1: synthesis of L-thiazolanoic acid
Dissolving 12.1g (0.1mol) of L-cysteine in 60mL of hot water, slowly pouring into 10mL of 36% formaldehyde water solution, shaking uniformly, standing overnight, filtering the precipitated crystals the next day, and recrystallizing with ethanol and water to obtain 12.8g of needle-like white crystals with the yield of 96.2%.
Preparation example 2: synthesis of L-thiazolecarboxylic acid methyl ester hydrochloride
Dissolving L-thiazolealkanoic acid 13.3g (0.1mol) in anhydrous methanol 100ml, introducing hydrogen chloride gas until the raw materials are completely dissolved, continuously introducing the gas for more than 2h, and stirring overnight after the gas introduction is finished. The next day the solvent was evaporated down under reduced pressure, the residue was dissolved in methanol and evaporated down again, repeated 2 times to carry away hydrogen chloride gas. The solvent was evaporated to dryness to give a crude product, which was recrystallized from methanol-ether in 91% yield.
Preparation example 3: synthesis of N-tert-butyloxycarbonyl-L-thiazolanoic acid
In an ice bath, 0.10mol of L-thiazolealkanoic acid was dissolved in 50mL of a 2N aqueous solution (0.10mol) of sodium hydroxide, and a mixed solution of 24.4g (0.11mol) of t-butoxycarbonyl acid anhydride and 50mL of acetone was slowly dropped under stirring, and stirring was continued for 2 hours after the addition was completed. Adding 200mL of water to dilute the reaction solution, extracting with ethyl acetate for 3 times, and using 80mL of ethyl acetate each time; the organic phase was discarded. Adjusting the pH value of the water phase to 2 by using 1mol/L hydrochloric acid under ice bath, and extracting for 3 times by using ethyl acetate, wherein 80mL of ethyl acetate is used for each time; the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure, and recrystallized from petroleum ether and ethyl acetate to give white crystals with a yield of 88%.
The synthetic routes for preparation examples 4-5 are as follows:
preparation example 4: synthesis of 2, 2-dimethyl-L-thiazolanoic acid methyl ester
3.5g L-cysteine methyl ester hydrochloride (20mmol) and 40ml acetone are mixed and refluxed for 10 minutes, 10ml methanol is added to completely dissolve the solid in the system, the mixture is continuously refluxed for 0.5h, cooled and crystallized, mother liquor is concentrated and continuously crystallized to obtain colorless crystals of 2, 2-dimethyl-L-thiazolinecarboxylic acid methyl ester hydrochloride, and the yield is 94%.
Preparation example 5: synthesis of N-tert-butyloxycarbonyl-2, 2-dimethyl-L-thiazolanoic acid
4.03g (19mmol) of methyl 2, 2-dimethyl-L-thiazolecarboxylate hydrochloride and 1.92g of triethylamine are mixed and dissolved in 20ml of dichloromethane, 4.15g (19mmol) of t-butyloxycarbonyl anhydride dissolved in 20ml of dichloromethane are added dropwise with stirring, after reaction for 3h at room temperature, the mixture is washed successively with 20ml of 10% citric acid and 20ml of water, after spin-drying, the mixture is dissolved in 25ml of methanol, adding 25ml of 2N sodium hydroxide aqueous solution, reacting for 4 hours at room temperature, reducing pressure to remove methanol as much as possible, diluting with water to 50ml, washing away excessive tert-butoxycarbonyl acid anhydride with 20ml of multiplied by 3 ethyl ether, adjusting the pH value to 2 with 1mol/L hydrochloric acid under phase ice bath, separating out a large amount of white solid, filtering and washing with water to obtain N-tert-butoxycarbonyl-2, 2-dimethyl-L-thiazoloic acid with the yield of 86%.
Preparation example 6: synthesis of 2-alkyl substituted-L-thiazolic acid methyl ester
Wherein R is methyl, ethyl, isopropyl and the like.
The synthetic route is shown as follows:
the method comprises the following specific steps:
3.5g L-cysteine methyl ester hydrochloride (20mmol) and 1.96g potassium acetate (20mmol) were dissolved in 60ml methanol in ice bath with stirring, 20mmol aliphatic aldehyde was dissolved in 20ml methanol, and the mixture was dropped into the system and stirred for 5 hours for post-treatment. And (3) spin-drying the solvent, distributing the solvent by using saturated saline water and dichloromethane, drying the organic phase, and then spin-drying to obtain a colorless oily substance which is 2-alkyl substituted-L-thiazolealkanoic acid methyl ester, wherein the yield is 92-96%.
Preparation example 7: synthesis of 2-phenyl-L-thiazolanoic acid methyl ester
The synthetic route is shown as follows:
the method comprises the following specific steps:
2.4g L-cysteine was dissolved in 50ml of ethanol, 2ml of benzaldehyde was added thereto under stirring at room temperature, and stirring was continued for 6 hours, whereby a large amount of white solid was formed. The reaction solution was filtered, and the solid was washed with 20ml × 3 ethanol and dried in a petri dish. And (4) evaporating part of the solvent from the filtrate until a solid is separated out, standing, filtering, washing and drying. 4.0g of 2-phenyl-L-thiazolealkanoic acid was obtained in a yield of 97%.
Dissolving the obtained 4.0g of 2-phenyl-L-thiazolanoic acid in 40ml of methanol, dropwise adding 8ml of thionyl chloride under ice bath, reacting overnight, then spin-drying the reaction solution, adding dichloromethane, and spin-drying twice to obtain 5.0g of light yellow solid with the yield of 96%.
Preparation example 8: synthesis of 2-benzyl-L-thiazolealkanoic acid methyl ester
The synthetic route is shown as follows:
the method comprises the following specific steps:
2.4g L-cysteine was dissolved in 50ml of ethanol, 2ml of phenylacetaldehyde was added thereto under stirring at room temperature, and stirring was continued for 6 hours, whereby a large amount of white solid was formed. The reaction solution was filtered, and the solid was washed with 20ml × 3 ethanol and dried in a petri dish. And (4) evaporating part of the solvent from the filtrate until a solid is separated out, standing, filtering, washing and drying. 4.4g of 2-benzyl-L-thiazolealkanoic acid was obtained in a yield of 94%.
4.4g of the obtained 2-benzyl-L-thiazolealkanoic acid is dissolved in 40ml of methanol, 8ml of thionyl chloride is dropwise added under ice bath, after the reaction is carried out overnight, the reaction solution is dried by spinning, dichloromethane is added for drying by spinning twice, 5.5g of white solid is obtained, and the yield is 95%.
Example A-1: preparation of Compound A-1
The synthetic route is shown as follows:
the method comprises the following specific steps:
(1) synthesis of intermediate 1 (N-tert-butyloxycarbonyl-L-thiazolanoic acid-L-proline methyl ester)：
3.3g (20mmol) of L-proline methyl ester hydrochloride is dissolved in 100ml dichloromethane, 2.0g (20mmol) of triethylamine is added dropwise under ice-bath conditions, after 5 minutes, 2.7g (20mmol) of 4.66g N-tert-butoxycarbonyl-L-thiazolanoic acid (20mmol), 1-hydroxybenzotriazole and 3.8g (20mmol) of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide are added, the temperature naturally rises to room temperature under stirring, and the reaction is monitored by a dot-plate. After the reaction is completed, the reaction solution is rotated and evaporated, ethyl acetate and water are added to the concentrate for dissolving, liquid separation is carried out, and the ethyl acetate layer is sequentially treated with citric acid aqueous solution, saturated sodium bicarbonate solution and saturated sodium bicarbonate solutionAnd sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to a colorless oil. Petroleum ether: purification on a 1:1 column with ethyl acetate gave 4.74g of a colorless clear oil in 68.9% yield.1H-NMR(400MHz,DMSO-d6),δppm:4.77(m,1H,-CH),4.43(m,1H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2),1.37(m,6H,-CH3，-CH3),1.15(m,3H,-CH3).M+1:344.1。
(2) Synthesis of intermediate 2 (L-thiazolealkanoic acid-L-proline methyl ester hydrochloride)：
4.74g of intermediate 1(13.7mmol) was dissolved in 30ml of ethyl acetate, 10ml of 4N HCl/ethyl acetate solution was added under ice bath, and after completion of the reaction, the reaction solution was dried by spinning to obtain 3.73g of a white solid with a yield of 96.1%.1H-NMR(400MHz,DMSO-d6),δppm:4.77(m,1H,-CH),4.43(m,1H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2).M+1:281.1。
(3) Preparation of intermediate 3 (N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine-L-thiazolanoic acid-L-proline methyl ester) Synthesis of：
Dissolving 2.2g of intermediate 2(7.8mmol) in 40ml of dichloromethane, adding 0.78g (7.8mmol) of triethylamine under ice bath condition, adding 2.15g (7.8mmol) of N-tert-butoxycarbonyl-O-tert-butyl-L-threonine, 1.05g (7.8mmol) of 1-hydroxybenzotriazole and 1.5g (7.8mmol) of 1-ethyl-3- (3-dimethylpropylamine) carbodiimide after dissolving the raw materials, stirring overnight, spin-drying the reaction solution after the reaction is completed, dissolving the concentrate with ethyl acetate and water, separating liquid,the ethyl acetate layer was washed with a citric acid aqueous solution, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate and concentrated. Petroleum ether: purification on a 1:1 column with ethyl acetate afforded 2.09g of a white solid in 53.6% yield.1H-NMR(400MHz,DMSO-d6),δppm:7.91(m,1H,-NH),4.94(m,1H,-CH),4.52-4.23(m,3H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2),1.37(m,9H,-CH3),1.12-1.01(m,13H,-CH3).M+1:484.3。
(4) Synthesis of intermediate 4 (N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine-L-thiazolanoic acid-L-proline)：
2.09g of intermediate 3 was dissolved in 20ml of methanol, 20ml of 2N sodium hydroxide solution was added at room temperature, after stirring for 3 hours, most of the solvent was evaporated off by rotation, 20ml of water was added to the remaining reaction solution, the pH was adjusted to 2-3 with a saturated citric acid solution in ice bath, 25ml of ethyl acetate was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to 2.03g of a white solid, with a yield of 100%.1H-NMR(400MHz,DMSO-d6),δppm:7.91(m,1H,-NH),4.94(m,1H,-CH),4.52-4.23(m,3H,-CH),3.71(m,2H,-CH2),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2),1.37(m,9H,-CH3),1.12-1.01(m,13H,-CH3).M+1:470.3。
(5) Intermediate 5 (N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine-L-thiazolanoic acid-L-proline-L-threonine Acid methyl ester) synthesis：
L-threonine methyl ester hydrochloride 0.35g (2mmol) was dissolved in 30ml dichloromethane0.21g (2mmol) of triethylamine was added under ice-bath conditions, and after 5 minutes, 1.0g (2mmol) of intermediate 4, 0.28g (2mmol) of 1-hydroxybenzotriazole, and 0.39g (2mmol) of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide were added, and the reaction was allowed to spontaneously warm to room temperature. And after the reaction is completed, spin-drying the reaction solution, dissolving the concentrate with ethyl acetate and water, separating the solution, washing an ethyl acetate layer with a citric acid aqueous solution, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, drying the ethyl acetate layer with anhydrous sodium sulfate, and concentrating to obtain a white solid. Dichloromethane methanol 40:1 column purification gave 890mg of white solid, 74.3% yield.1H-NMR(400MHz,DMSO-d6),δppm:7.94(m,1H,-NH)，6.4(m,1H,-NH)，5.05(m,1H,-CH)，4.91(m,1H,-CH),4.56-4.54(m,2H,-CH2),4.32(m,1H,-CH2),4.24(m,1H,-CH2)，4.12(m,1H,-CH2),3.72(m,2H,-CH2),3.60(s,3H,-CH3),3.50(m,1H,-CH2),2.91(m,1H,-CH2),2.17-1.86(m,5H,-CH2),1.37(s,9H,-CH3),1.21(m,1H,-CH3),1.11-1.01(m,13H,-CH3).M+1:603.3。
(6) Intermediate 6 (N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine-L-thiazolanoic acid-L-proline-L-threonine Acid amides) synthesis：
890mg of the intermediate 5 is dissolved in 3ml of methanol, 10ml of 10N ammonia gas/methanol solution is added under ice bath, the reaction is carried out for 12 hours, and the reaction solution is dried by spinning to obtain 860mg of white solid.1H-NMR(400MHz,DMSO-d6),δppm:7.94(m,1H,-NH)，7.18(s,2H,CO-NH2),6.4(m,1H,-NH)，5.04(m,1H,-OH)，4.91(t,1H,-CH，J＝6.54Hz),4.58-4.54(m,3H,-CH),4.32-4.25(m,2H,-CH),3.72(m,2H,-CH2),3.50(m,2H,-CH2),2.91(m,2H,-CH2),2.15-1.86(m,4H,-CH2),1.37(s,9H,-CH3),1.21(m,3H,-CH3),1.11-1.01(m,12H,-CH3).M+1:588.3
(7) Synthesis of Compound A-1：
Will be inAnd dissolving the intermediate 6 in 10ml of ethyl acetate, adding a 4N HCl/ethyl acetate solution under ice bath, reacting for 6 hours, and spin-drying the reaction solution to obtain a white solid which is 630mg of a final product.1H-NMR(400MHz,DMSO-d6),δppm:7.61(d,1H,CO-NH,J＝8.16Hz),7.05(s,2H,CO-NH2)5.20(d,1H,OH,J＝9.84Hz),4.93(t,1H,OH,J＝7.84Hz),4.59-4.24(m,4H,CH),4.4(m,2H,CH2),3.8(m,2H,-CH2),3.6(m,2H,2-CH),3.0(m,2H,-CH2),1.9-2.0(m,4H,-CH2),1.2(m,3H,-CH3),1.0(m,3H,-CH3)，M+1：432.2。
Examples A-2 to A-20: preparation of Compounds A-2 to A-20
The method is the same as A-1, and only the corresponding P2/P3 fragment needs to be replaced.
A-2: replacing the raw material N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine in the synthesis step of the intermediate 3 with N-tert-butyloxycarbonyl-O-tert-butyl-L-serine, and performing the same synthesis as the step A-1 except the operation;
a-3: replacing the raw material L-threonine methyl ester hydrochloride in the intermediate 5 synthesis step with L-serine methyl ester hydrochloride, and performing the same synthesis as the A-1 in the rest of operations;
a-4: replacing the raw material N-tert-butoxycarbonyl-O-tert-butyl-L-threonine in the intermediate 3 synthesis step with N-tert-butoxycarbonyl-O-tert-butyl-L-serine, replacing the raw material L-threonine methyl ester hydrochloride in the intermediate 5 synthesis step with L-serine methyl ester hydrochloride, and performing the same synthesis as A-1 except for the above operation;
a-5: replacing the raw material L-proline methyl ester hydrochloride in the intermediate 1 synthesis step with L-thiazolic acid methyl ester hydrochloride, replacing N-tert-butyloxycarbonyl-L-thiazolic acid with N-tert-butyloxycarbonyl-L-proline, and performing the rest operations in the same way as the A-1 synthesis;
a-6: replacing the raw material N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine in the synthesis step of the intermediate 3 with N-tert-butyloxycarbonyl-O-tert-butyl-L-serine, and performing the same synthesis as the step A-5 except the operation;
a-7: replacing the raw material L-threonine methyl ester hydrochloride in the intermediate 5 synthesis step with L-serine methyl ester hydrochloride, and performing the same synthesis as A-5 in the rest of operations;
a-8: replacing the raw material N-tert-butoxycarbonyl-O-tert-butyl-L-threonine in the intermediate 3 synthesis step with N-tert-butoxycarbonyl-O-tert-butyl-L-serine, replacing the raw material L-threonine methyl ester hydrochloride in the intermediate 5 synthesis step with L-serine methyl ester hydrochloride, and performing the same synthesis as A-5 except for the rest of the operation;
a-9: replacing the raw material L-proline methyl ester hydrochloride in the intermediate 1 synthesis step with L-thiazolealkanoate methyl ester hydrochloride, and performing the rest operations to synthesize the intermediate 1;
a-10: replacing the raw material N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine in the synthesis step of the intermediate 3 with N-tert-butyloxycarbonyl-O-tert-butyl-L-serine, and performing the same synthesis as the step A-9 except the operation;
a-11: replacing the raw material L-threonine methyl ester hydrochloride in the intermediate 5 synthesis step with L-serine methyl ester hydrochloride, and performing the same synthesis as A-9 in the rest of operations;
a-12: replacing the raw material N-tert-butyloxycarbonyl-L-thiazolanoic acid in the synthesis step of the intermediate 1 with N-tert-butyloxycarbonyl-2, 2-dimethyl-L-thiazolanoic acid, and performing the rest operations in the same way as the synthesis of A-1;
a-13: replacing the raw material L-thiazolidine acid methyl ester hydrochloride in the intermediate 1 synthesis step with 2, 2-dimethyl-L-thiazolidine acid methyl ester hydrochloride, and performing the same synthesis as A-5 except for the operation;
a-14: replacing the raw material N-tert-butyloxycarbonyl-O-tert-butyl-L-threonine in the synthesis step of the intermediate 3 with N-tert-butyloxycarbonyl-O-tert-butyl-L-serine, and performing the same synthesis as A-13 except for the operation;
a-15: replacing the raw material L-threonine methyl ester hydrochloride in the intermediate 5 synthesis step with L-serine methyl ester hydrochloride, and performing the same synthesis as A-13 in the rest of operations;
a-16: replacing the raw material L-thiazolidine acid methyl ester hydrochloride in the intermediate 1 synthesis step with 2-methyl-L-thiazolidine acid methyl ester hydrochloride, and performing the same synthesis as the A-5 in the rest operations;
a-17: replacing the raw material L-thiazolidine acid methyl ester hydrochloride in the intermediate 1 synthesis step with 2-ethyl-L-thiazolidine acid methyl ester hydrochloride, and performing the same synthesis as A-5 except for the operation;
a-18: replacing the raw material L-thiazolidine acid methyl ester hydrochloride in the intermediate 1 synthesis step with 2-isopropyl-L-thiazolidine acid methyl ester hydrochloride, and performing the same synthesis as A-5 except for the operation;
a-19: replacing the raw material L-thiazolidine acid methyl ester hydrochloride in the intermediate 1 synthesis step with 2-benzyl-L-thiazolidine acid methyl ester hydrochloride, and performing the same synthesis as the A-5 in other operations;
a-20: the starting material L-thiazolidine acid methyl ester hydrochloride in the intermediate 1 synthesis step was replaced with 2-phenyl-L-thiazolealkanoic acid methyl ester hydrochloride, and the rest of the procedure was the same as in the a-5 synthesis.
Examples A-21 to A-24: preparation of Compounds A-21 to A-24
The synthesis of compounds A-21 to A-24 is essentially identical to compound A-1, with only corresponding adjustments in the following steps:
a-21: deprotection of intermediate 5 with 4N HCl/ethyl acetate solution affords compound A-21.
A-22: and aminolysis is carried out on the intermediate 5 by methylamine/methanol solution, and deprotection is carried out by 4N HCl/ethyl acetate solution, thus obtaining the compound A-22.
A-23: the L-threonine methyl ester hydrochloride was replaced with L-threonine ethyl ester hydrochloride and then deprotected in the intermediate 5 step with 4N HCl/ethyl acetate solution by the same synthetic route as for Compound A-1 to give Compound A-23.
A-24: the L-threonine methyl ester hydrochloride was replaced with L-threonine isopropyl ester hydrochloride and then deprotected in the intermediate 5 step using the same synthetic route as for Compound A-1, with 4N HCl/ethyl acetate solution to give Compound A-24.
The synthetic routes for compounds B-1 to B-9 are as follows:
wherein the content of the first and second substances,
r is respectively and sequentially selected from the following 9 groups:
the synthetic route of intermediate b5 is similar to that of intermediate 5, except that the starting material N-tert-butoxycarbonyl-thiazolanoic acid is replaced by N-tert-butoxycarbonylproline.
Example B-1: EXAMPLES preparation of Compound B-1
(1) 2.3g of intermediate b5(3.9mmol) are dissolved in 20mL of methanol, 20mL of 2N sodium hydroxide solution are added with stirring and stirred for 4 hours, after the reaction is completed, most of the solvent is evaporated off by rotary evaporation, 30mL of water are added to the residual solution, the pH value is adjusted to 2-3 with a saturated citric acid solution, ethyl acetate is added for extraction for 3 times, 20mL of ethyl acetate is used for each time, the organic phases are combined, dried over anhydrous sodium sulfate and dried by rotary drying, and 2.2g of white solid intermediate b is obtained.
1H-NMR(400MHz,DMSO-d6),δppm:12.58(br,1H,CO-OH),7.6(m,1H,CO-NH),6.4(m,1H,CO-NH),5.05(s,1H,-OH),4.63(m,1H,-CH),4.56-4.54(m,2H,-CH),4.32(m,1H,-CH),4.24(m,1H,-CH),4.12(m,1H,-CH),3.42(m,4H,-CH2),2.91(m,4H,-CH2),2.17-1.86(m,4H,-CH2),1.37(s,9H,-CH3),1.21(m,3H,-CH3),1.11-1.01(m,12H,-CH3).M+1:571.3。
(2) 2.2g of intermediate b6(4mmol) was dissolved in 60ml of dichloromethane, 1.25g (8mmol) of natural menthol, 0.54g (4.4mmol) of 4-dimethylaminopyridine and 1.1g (5.2mmol) of dicyclohexylcarbodiimide were added under ice-bath, stirred overnight, filtered after completion of the reaction, the filtrate was washed with citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, spin-dried, purified by glass chromatography, dichloromethane: methanol 50:1 gave 1.5g of white solid in 53.5% yield. The white solid was dissolved in 20ml of ethyl acetate, and 6ml of HCl/ethyl acetate solution was added under ice-bath to react for 4 hours, followed by spin-drying of the reaction solution, to obtain 1.2g of Compound B-1.
1H-NMR(400MHz,DMSO-d6),δppm:8.11(s,2H,-NH2),7.47(s,1H,CO-NH),5.17-5.14(m,2H,-OH),4.61-4.30(m,5H,-CH),4.11-3.65(m,6H,CH),2.34-1.35(m,18H,-CH2),1.22-0.83(m,16H,CH2,-CH3).M+1:553.4。
Examples B-2 to B-5: preparation of Compounds B-2 to B-5
The procedure is as in example B-1, except that the natural menthol in step (2) is replaced with (+) -2-borneol, L-oxiracetam, hydroxyethyltheophylline and hydroxypropyltheophylline, respectively, to prepare compounds B-2 to B-5.
Example B-6: preparation of Compound B-6
570mg of intermediate b6(1mmol) was dissolved in 60ml of dichloromethane, 165mg (1mmol) of amantadine, 135mg (1mmol) of 1-hydroxybenzotriazole, 200mg (1mmol) of 1-ethyl- (3-dimethylpropylamine) carbodiimide were added under ice-bath, stirred overnight, filtered after completion of the reaction, the filtrate was washed with citric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution in order, dried over anhydrous sodium sulfate, spin-dried, dichloromethane: purification on a 50:1 column afforded 260mg of a white solid in 36.2% yield. The product was dissolved in 20ml ethyl acetate, 6ml HCl/ethyl acetate solution was added under ice-bath, and after 4 hours reaction, the reaction solution was spin-dried to obtain 200mg of compound B-6.
1H-NMR(400MHz,DMSO-d6),δppm:8.38(s,1H,CO-NH),8.11(s,2H,-NH2),7.47(s,1H,CO-NH)5.14(s,1H,-OH),4.61(s,1H,-OH),4.33-3.60(m,10H,-CH，-CH2),2.33-1.81(m,8H,-CH2),1.80-1.71(m,6H,-CH2),1.59-1.55(m,4H,-CH2),1.32-1.22(m,7H,-CH2),1.10-0.80(m,8H,-CH2,-CH3).M+1:576.4。
Examples B-7 to B-9: preparation of Compounds B-7, B-8, B-9
The procedure is as in example B-6, except that amantadine is replaced with memantine, dopamine and 2- (7-methoxynaphthyl-1-) ethylamine, respectively, to give compounds B-7, B-8 and B-9, respectively.
In addition, the structures of the prepared compounds were verified by mass spectrometry, as shown in table 2 below; the prepared compound has correct structure.
Table 2: compound structure confirmation (Mass Spectrometry)
Numbering
MS：(M+1)
Numbering
MS：(M+1)
A-1
432.2
A-2
418.2
A-3
418.2
A-4
404.2
A-5
432.2
A-6
418.2
A-7
418.2
A-8
404.2
A-9
450.1
A-10
436.1
A-11
436.1
A-12
460.2
A-13
460.2
A-14
446.2
A-15
446.2
A-16
446.2
A-17
460.2
A-18
474.2
A-19
522.2
A-20
508.2
A-21
447.1
A-22
446.2
A-23
461.2
A-24
475.2
B-1
553.4
B-2
551.3
B-3
555.3
B-4
621.3
B-5
635.3
B-6
576.4
B-7
548.3
B-8
549.3
B-9
598.3
GLYX-13
414.2
Experimental example 1: in vitro receptor binding assays
1. Purpose of experiment
GLYX-13 (Rapasinetel) was used as a control to study the affinity of the tested compounds for NMDA receptors by receptor ligand binding experiments.
2. Experimental methods the experimental methods
(1) Preparation of crude synaptosome of prefrontal cortex and hippocampus
After death of SD rats from decapitation, the prefrontal cortex and hippocampus were rapidly separated on ice, and 10-fold volume of 50mM Tris-HCl buffer (50mM Tris-HCl, 5mM MgCl) was added after weighing2·6H2O, 1mM EDTA, 0.5% (W/V) BSA, 1mM PMSF, 0.32M sucrose, pH 7.4), 1500 rpm/min for 5 homogenates, 30s each time. Centrifuging the homogenate at 1000 Xg for 10min, and collectingCentrifuging the supernatant at 40000 Xg for 10min, collecting precipitate, resuspending with 10 times volume of Tris-HCl buffer solution, incubating at 37 deg.C for 10min, centrifuging at 40000 Xg for 10min, resuspending the obtained precipitate with the above buffer solution, and packaging at-80 deg.C.
(2) A crude synaptosome of the test drug to rat3H]Detection of MK-801 binding inhibition function
The amount of rat crude synaptosome protein, 50. mu.g, was added to all tubes in sequence. MK-801(dizocilpine) was added to the non-specific binding tube in a volume of 50. mu.l at a final concentration of 100. mu.M, and the reaction was carried out for 15 min. 20 μ L of control drug with corresponding concentration was added to the test tube and reacted for 15 min. All the test tubes are sequentially added with a labeled ligand [ 2 ]3H]MK-801 in a volume of 30. mu.l, at a final concentration of 10 nM. With 50mM Tris-HCl buffer (50mM Tris-HCl, 5mM MgCl)2·6H2O、1mM EDTA、0.5％(W/V)BSA、0.1％NaN3pH 7.4) to make up for a total reaction tube volume of 200. mu.l. The reaction was carried out at 37 ℃ for 10 min. A type 49 glass fiber filter was prepared and spotted at the same time. The filter membrane was placed in a multiheaded cell collector, the reaction system was suction filtered under negative pressure and washed with ice-cold 50mM Tris-HCl buffer, 10ml each time, for a total of 5 times. After the filter membrane is dried by pumping, 1ml of scintillation liquid is added into the filter membrane and is placed on a shaking table to be shaken for 1.5h, and the next day, the filter membrane is placed in a liquid scintillation counter to measure the radioactivity intensity.
(3) Detection of NMDA receptor agonistic activity in rat crude synaptosome protein by test drug
The amount of rat crude synaptosome protein 100. mu.g was added to all tubes in sequence. To the non-specific binding tube, 50. mu.l of 5, 7-dichloro-canine-quinolinic acid was added to a final concentration of 10. mu.M. All tubes were pre-charged with 50. mu.M glutamic acid and pre-reacted for 15 min. 20 μ L of control drug with corresponding concentration was added to the test tube and reacted for 15 min. 1mM glycine was added to the maximum reaction tube. All the test tubes are sequentially added with a labeled ligand [ 2 ]3H]MK-801 in a volume of 30. mu.l, at a final concentration of 10nM, and reacted for 15 min. With 50mM Tris-HCl buffer (50mM Tris-HCl, 5mM MgCl)2·6H2O、1mM EDTA、0.5％(W/V)BSA、0.1％NaN3pH 7.4) make up for a total reaction tube volume of 500. mu.l. The reaction was carried out at 37 ℃ for 15 min. A type 49 glass fiber filter membrane was prepared,and simultaneously spotting. The filter membrane was placed in a multiheaded cell collector, the reaction system was suction filtered under negative pressure and washed with ice-cold 50mM Tris-HCl buffer, 10ml each time, for a total of 5 times. After the filter membrane is dried by pumping, 1ml of scintillation liquid is added into the filter membrane and is placed on a shaking table to be shaken for 1.5h, and the next day, the filter membrane is placed in a liquid scintillation counter to measure the radioactivity intensity.
(4) Statistical processing of data
The data were analyzed using graphpad5.0 software and the percentage of competitive inhibition was calculated by non-linear fitting. Wherein:
percent inhibition ═ 100% (total bound cpm number-loading tube cpm number)/(total bound cpm number-non-specific tube cpm number) ];
non-linear fitting of the log concentration of test compounds as percent inhibition to obtain a competitive inhibition curve and calculating IC50The value is obtained.
Maximum agonistic potency ═ 100% (test compound cpm number-5, 7 dichloro canine uroquinolinic acid cpm number)/(1 mM glycine cpm number-5, 7 dichloro canine uroquinolinic acid cpm number) ].
Table 3: affinity and maximal agonistic potency of the compounds of the examples to the NMDA receptor
The experimental results show that the compounds of the examples have NMDA receptor agonistic activity, the maximum agonistic potency is between 13% and 90%, and the compounds belong to partial NMDA receptor agonists.
Experimental example 2: animal pharmacodynamic experiment
Pharmacodynamic evaluation is carried out by adopting a rat forced swimming experiment. The experimental animals are SD rats, male animals, 150-180 g of body weight and SPF grade, are adaptively raised for one week after purchase, are subjected to forced swimming experiments, and are fasted for 12 hours before the experiments. Dissolving the compounds of the examples in normal saline, and establishing a blank control group (normal saline), a positive control group (GLYX-13 tail vein injection group and fluoxetine intragastric administration group), a compound administration group of the examples and a GLYX-13 intragastric administration group; each group had 8-10 rats.
One day before the experiment, rats are placed in a glass jar with the height of 40cm, the inner diameter of 18cm and the water depth of 23cm for pre-swimming for 15min, and the water temperature is 28 ℃. After the pre-swimming, the rat is taken out, the electric heater is baked after the dry cloth is wiped, and the rat is put back into the rearing cage. The drug is respectively administered 1h before the main experiment, and a swimming experiment is carried out for 5min after the drug is administered 1h, and the cumulative immobile time within 5min is recorded. The criterion for immobility was that the animal stopped struggling in the water, was floating, with only slight limb movement to keep the head floating on the water. The results are shown in Table 4, and the experimental data are statistically analyzed by using GraphPad Prism 5.0 software, and are expressed by the reduced ratio of the floating time compared with the blank control group, N/A represents that the floating time of the group of experiments is not significantly different from that of the blank control group, and "-" represents that the group of experiments is not performed.
Table 4: results of forced swimming test in rats of the example Compounds
The experimental result shows that the control compound GLYX-13 is effectively administered in the tail vein, and the drug effect is still maintained after 3 days; GLYX-13 administration by gavage was ineffective; the control drug fluoxetine is effective on the same day of intragastric administration, but the drug effect cannot be maintained until the next day; the compounds of the various examples are effective in gavage and the efficacy of the drug can be maintained until after the next day to 3 days.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.