阅读说明：本技术 用于治疗帕金森病的儿茶酚胺氨基甲酸酯前药 (Catecholamine carbamate prodrugs for the treatment of parkinson's disease ) 是由 M·约尔根森 E·阿希 K·斯杰丁 K.G.詹森 J·T·劳蒂奥 于 2020-05-19 设计创作，主要内容包括：本发明提供了用于治疗神经退行性疾病和障碍的作为儿茶酚胺的前药的具有式(Id)的化合物。本发明还提供了包含本发明化合物的药物组合物,以及使用本发明化合物治疗神经退行性或神经精神性疾病和障碍,特别是帕金森病的方法。(The present invention provides compounds having formula (Id) as prodrugs of catecholamines for use in the treatment of neurodegenerative diseases and disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compounds of the invention to treat neurodegenerative or neuropsychiatric diseases and disorders, particularly Parkinson's disease.)

1. A compound according to formula (Ie)

Wherein Y is selected from H and a carbamoyl group of formula (CONR1R2), wherein formula (CONR1R2) is as follows

And wherein X is selected from H and a carbamoyl group of formula (CONR3R4), wherein formula (CONR3R4) is as follows

(CONR3R4), and

wherein Y and X are not both H, and

wherein R1, R2, R3, and R4 are each individually selected from the group consisting of: H. c_1-6Alkyl, amino acids, amino acid residues and peptides;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide.

3. The compound of any one of claims 1 and 2, wherein at least one of R1, R2, R3, and R4 is an amino acid or amino acid residue selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

4. The compound of any one of claims 1-3, wherein at least one of R1, R2, R3, and R4 is a peptide comprising two or more amino acid residues selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline and glycine residues.

5. The compound of any one of claims 1-4, having formula (Id)

Wherein R1, R2, R3, and R4 are each individually selected from the group consisting of: H. c_1-6Alkyl, amino acids, amino acid residues and peptides;

or a pharmaceutically acceptable salt thereof.

6. The compound or pharmaceutically acceptable salt according to claim 1, wherein,

r1 ═ R3 and R2 ═ R4.

7. The compound or pharmaceutically acceptable salt according to any one of claims 1, 5 and 6, wherein,

r1 and R3 are the same C_1-6An alkyl group; and is

R2 and R4 are the same C_1-6Alkyl radical。

8. The compound of claim 1, wherein the compound is selected from the group consisting of:

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (methylcarbamate);

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diyl bis (ethylcarbamate);

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (dimethylcarbamate);

((((4aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] -quinolin-6-yl) oxy) carbonyl) glycine;

((((4aR,10aR) -6-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] -quinolin-7-yl) oxy) carbonyl) glycine; and

(S) -2-amino-3- (3- ((((((4 aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) amino) phenyl) propanoic acid

Or a pharmaceutically acceptable salt of any of these compounds.

9. The compound of claim 1, wherein the compound is selected from the group consisting of:

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (methylcarbamate);

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diyl bis (ethylcarbamate); and

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (dimethylcarbamate); or

A pharmaceutically acceptable salt of any of these compounds.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use as a medicament.

12. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

13. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use in a treatment according to claim 12, wherein the neurodegenerative disease or disorder is parkinson's disease.

14. A method for treating a disease or disorder comprising: neurodegenerative diseases or disorders, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the neurodegenerative disease or disorder is parkinson's disease.

16. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

17. The use of claim 16, wherein the neurodegenerative disease or disorder is parkinson's disease.

Technical Field

The present invention provides compounds which are carbamate derivatives and prodrugs of dopamine agonists (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] quinoline-6, 7-diol, and their use in parkinson's disease and/or other conditions for which treatment with dopamine agonists is therapeutically beneficial, such as, but not limited to, restless leg syndrome, huntington's disease, and alzheimer's disease; and also neuropsychiatric diseases and disorders such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder and drug addiction. The invention also provides a pharmaceutical composition containing the compound.

Background

Parkinson's Disease (PD) is a common neurodegenerative disorder that becomes more common with age and affects an estimated seven to ten million people worldwide. Parkinson's disease is a multifaceted disease characterized by both motor symptoms and non-motor symptoms. Motor symptoms include resting tremor (tremor), bradykinesia/akinesia (slowness and difficulty in movement), muscle rigidity, postural instability and gait disturbance; while non-motor symptoms include neuropsychiatric disorders (e.g., depression, psychotic symptoms, anxiety, apathy, mild cognitive impairment and dementia) as well as autonomic dysfunction and sleep disorders (Poewe et al, Nature Review (2017) Vol. 3, items 17013: 1-21).

A key hallmark of the pathophysiology of parkinson's disease is the loss of the pigment dopaminergic neurons in the substantia nigra pars compacta, which provide dopaminergic innervation to the striatum and other brain regions. Such progressive neurodegeneration leads to a reduction in dopamine striatal levels, which ultimately leads to a series of changes in the basal nuclear circuit, ultimately leading to the development of the four major motor features of parkinson's disease. The primary target of dopamine in the striatum consists of medium spiny gabaergic neurons (MSNs) that selectively express either the D1 or D2 receptors awaiting localization projections. Gamma-aminobutyric acid (GABA) projecting to the lateral globus pallidus (also known as striatum-globus pallidus 'indirect pathway') expresses the D2 receptor (MSN-2) MSN; whereas gaba, which projects to the substantia nigra pars compacta and lateral globus pallidus (also known as the striatum-substantia nigra 'direct pathway'), expresses the D1 receptor (MSN-1) by MSN. Depletion of dopamine due to neuronal loss leads to unbalanced activity of both pathways, leading to a significant decrease in thalamic and cortical export activity, and ultimately dyskinesias (Gerfen et al, Science [ Science ] (1990)250: 1429-32; Delong, (1990) Trends in Neuroscience [ Neuroscience trend ]13: 281-5; Alexander et Crutcher, (1990) Trends in Neuroscience [ Neuroscience trend ]13: 266-71; and for reviews, Poewe et al, Nature Review [ Nature Review ] (2017) Vol.3, items 17013: 1-21).

The most effective therapeutic strategies available for patients with parkinson's disease and aimed at controlling motor symptoms are mainly indirect and direct dopamine agonists. Classical and gold standard treatment regimens include chronic oral ingestion of L-3, 4-dihydroxyphenylalanine (L-DOPA), which decarboxylates in the brain to form dopamine. Other methods consist in administering dopamine receptor agonists (such as apomorphine, which acts on both the D1 and D2 receptor subtypes, or pramipexole, ropinirole, etc., which is directed primarily against the D2 receptor subtype). The best motor relief obtained with L-DOPA and apomorphine is due to their activation of both the D1 and D2 receptor subtypes and global rebalancing of the indirect-direct pathway (i.e., while D2 agonists only reverse the indirect pathway barrier).

L-DOPA and apomorphine have the structures depicted below and are currently the most potent PD drugs in clinical applications.

L-DOPA is a prodrug of dopamine and remains the most effective drug in the treatment of motor parkinson's disease. However, after several years of treatment (i.e. the honey month period), complications arise due to the intrinsic progression of the disease (sustained loss of dopaminergic neurons) and the poor Pharmacokinetic (PK) profile of L-DOPA. Those complications include: 1) dyskinesias, which are abnormal involuntary movements that occur during the optimal "duration effect" of a drug; and 2) fluctuations during which the positive effect of L-DOPA disappears and symptoms reappear or worsen (Sprenger and Poewe, CNS Drugs [ CNS Drugs ] (2013),27: 259-272).

Direct dopamine receptor agonists activate dopamine autoreceptors as well as postsynaptic dopamine receptors located on medium spiny neurons MSN-1 and MSN-2. Apomorphine belongs to a class of dopamine agonists that have a1, 2-dihydroxybenzene (catechol) moiety. Catecholamines generally have low or no oral bioavailability when combined with phenethylamine motifs, as is the case with apomorphine. Apomorphine is used clinically in PD therapy, albeit in non-oral delivery (typically intermittent subcutaneous administration via a pump or continuous daily parenteral infusion). For apomorphine, animal studies have shown that transdermal delivery or implants may provide possible forms of administration. However, when studying apomorphine delivery from implants in monkeys (Bibbiani et al, Chase Experimental Neurology (2005),192:73-78), it was found that in most cases animals had to be treated with the immunosuppressant dexamethasone in order to prevent local irritation and other complications after implant surgery. Alternative delivery strategies for apomorphine therapy in PD have been extensively developed, such as inhalation and sublingual formulations (see, e.g., Grosset et al, Acta Neurol Scand. [ Scandinavian neurology bulletin ] (2013),128: 166-. However, these efforts have not yet been used in clinical applications for the treatment of PD.

An alternative to non-oral formulations of catecholamines involves the use of prodrugs that mask free catechol hydroxyl groups to enable oral administration. However, a known problem associated with the development of prodrugs for clinical use is the difficulty associated with predicting conversion to the parent compound in humans.

Different ester prodrugs of catecholamines have been reported in the literature, such as enteric coated N-propyl-Noraporphine (NPA) and the mono-pivaloyl ester of apomorphine (see e.g. WO 02/100377) for duodenal delivery and the D1-like agonist adrulide (diacetyl prodrug of A-86929) (Giardina and Williams; CNS Drug Reviews [ CNS Drug review ] (2001), Vol.7 (3): 305-316). In humans, upon oral administration, acloritide undergoes extensive hepatic first pass metabolism and, as a result, has low oral bioavailability (about 4%). Intravenous (IV) aldrin has an anti-Parkinson efficacy comparable to L-DOPA in PD patients (Giardina and Williams; CNS Drug Reviews [ CNS Drug review ] (2001), Vol.7 (3): 305-.

In addition to ester prodrugs of catecholamines, alternative prodrug approaches involve masking the two catechol hydroxyl groups to the corresponding methylenedioxy derivatives, or to diacetal derivatives. For example, it has been described in Campbell et al, Neuropharmacology (1982); 21(10) 953-961 and US 4543256, WO2009/026934 and WO 2009/026935 describe the principle of this prodrug.

For catecholamine prodrugs, yet another proposed approach is the formation of enone derivatives, as proposed in, for example, WO 2001/078713 and Liu et al, Bioorganic med. For further examples of catecholamine prodrugs, see, e.g., Sozio et al, exp. 7(5):385-406.

The compound (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] quinoline-6, 7-diol described as compound (I) below is disclosed in WO 2009/026934. The trans isomer was previously disclosed in Liu et al, J.Med.chem. [ journal of medicinal chemistry ] (2006),49: 1494-. The racemate was first disclosed in Cannon et al, J.Heterocyclic Chem. [ J.Heterocycli Chem. (1980); 1633 and 1636.

Compound (I) is a dopamine agonist with mixed D1 and D2 activity. Three prodrug derivatives of compound (I) are known in the art.

Liu et al, J.Med.chem. [ J.Pharmacol. (2006),49:1494- & ltI & gt 1498 & Liu et al, Bioorganic Med.chem. [ bio-organic chemistry & medicinal chemistry ] (2008),16:3438- & ltJ.3444 & gt disclose the enone derivatives of formula (Ia) described below, showing that the enone derivatives are converted to the active compound (I) in rats.

WO2009/026934 and WO 2009/026935 disclose two types of prodrug derivatives of compound (I) including (6aR,10aR) -7-propyl-6, 6a,7,8,9,10,10a, 11-octahydro- [1,3] dioxolo [4',5':5,6] benzo [1,2-g ] quinoline, Methylenedioxy (MDO) derivatives having the following formula (Ib):

it has been demonstrated in WO 2010/097092 that compound (Ib) is converted to compound (I) in rat and human hepatocytes. Furthermore, the in vivo pharmacology of compounds (Ia) and (Ib) and the active "parent compound" (I) has been tested in different animal models for parkinson's disease (WO 2010/097092). Compound (I) and both compounds (Ia) and (Ib) were found to be effective, indicating that compounds (Ia) and (Ib) are converted to compound (I) in vivo. All three compounds have been reported to have a longer duration of action than observed for L-dopa and apomorphine.

Other prodrugs of compound (I) disclosed in WO2009/026934 and WO 2009/026935 are conventional ester prodrugs having formula (Ic):

despite the long-standing interest in the art, there is clearly an unmet need for the development of highly potent, well-tolerated and orally active drugs for the treatment of PD. Prodrug derivatives of mixed D1/D2 agonists that can provide continuous dopaminergic stimulation, giving stable PK profiles, can meet such unmet needs.

Carbamate derivatives have been previously proposed and explored for a variety of compounds containing catechol moieties because of the prodrug principle. Carbamate derivatives of apomorphine and N-N-propylnorapomorphine have been proposed as prodrug derivatives several decades ago (Edward et al (1976) J.Pharm Sci. [ J.Pharmacology ]65(11): 1682-. Apomorphine bis (dimethylcarbamate) has been synthesized and tested in mice, although the pharmacological effects are very limited compared to apomorphine itself, suggesting that its conversion to apomorphine is very slow. EP 0352815 demonstrates the oral bioavailability of carbamate derivatives of gamma-L-glutamyl-L-dopa for the treatment of parkinson's disease.

Prodrugs targeting various Amino acids or peptide transporters are known in the art (see, e.g., Vale et al, 2018, Amino acids in the development of prodrugs, Amino acids in molecular development, 23(9),2318.) furthermore, Ninomiya et al (2011) disclose Amino acid conjugates of tricin and mention improved bioavailability following oral administration. Furthermore, Kim et al report that quercetin-amino acid derivatives exhibit favorable cell permeability In vitro through interaction with peptide transporter PEPT1 (In vitro solubility, stability and permeability of novel quercetin-amino acids ] (Kim, m.k.; Park, k. -s.; Yeo, w. -s.; Choo, h.; Chong, Y.), In vitro solubility, stability and permeability of novel quercetin-amino acid conjugates [ novel quercetin-amino acid conjugates In vitro solubility, stability and permeability of novel quercetin-amino acid conjugates ] (bioorg. chem. [ organic chemistry and chemistry ]2009,17, 1164. 63 06014429) and that these prodrugs contain peptides or prodrugs of ept 52. However, none of these documents discloses catecholamine prodrugs comprising amino acid or peptide moieties.

Disclosure of Invention

The present invention relates to novel compounds useful in the treatment of parkinson's disease. More specifically, the present invention relates to novel carbamate prodrug derivatives of the compound (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] quinoline-6, 7-diol (compound (I)). Representative compounds (1) - (3) of the present invention have proven to be particularly useful for oral delivery of compound (I).

Thus, in a first aspect, there is provided a compound according to formula (Ie)

Wherein Y is selected from H and carbamoyl having the formula CONR1R2

(CONR1R2), and

wherein X is selected from H and carbamoyl having the formula CONR3NR4

(CONR3R4)

Wherein Y and X are not both H, and

wherein R1, R2, R3, and R4 are each individually selected from the group consisting of: H. c_1-6Alkyl, amino acids, amino acid residues and peptides;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound according to formula (Id), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Further aspects of the invention relate to compounds according to formula (Id) for use as a medicament.

Further aspects of the invention relate to a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

A further aspect of the invention relates to a method for treating the following diseases or disorders: neurodegenerative diseases or disorders, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound having formula (Id) or a pharmaceutically acceptable salt thereof.

A further aspect of the invention relates to the use of a compound according to formula (Id) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome or alzheimer's disease; or for the treatment of a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

Definition of

Compounds of the invention

Reference to a compound encompassed by the invention includes the free material (e.g., free base or zwitterion) of the compound of the invention, pharmaceutically acceptable salts, such as acid addition salts or base addition salts, of the compound of the invention, as well as polymorphic and amorphous forms of the compound of the invention and pharmaceutically acceptable salts thereof. In addition, the compounds of the present invention and pharmaceutically acceptable salts thereof can potentially exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The present invention encompasses both solvated and unsolvated forms.

Pharmaceutically acceptable salts

In the context of the present invention, pharmaceutically acceptable salts are intended to indicate non-toxic, i.e. physiologically acceptable salts.

The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts, which are salts of an inorganic and/or organic acid formed at the nitrogen atom in the parent molecule. The acid may be selected from, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, gentisic acid, saccharine, and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid, 2-hydroxyethanesulfonic acid, and benzenesulfonic acid.

Further examples of useful acids to form pharmaceutically acceptable salts can be found, for example, in Stahl and Wermuth (editions) "Handbook of Pharmaceutical salts. Characteristics, selection and use ] ", Wiley-VCH (Willey-VCH Press), 2008.

Prodrugs

In the context of the present invention, the term "prodrug" or "prodrug derivative" indicates that, after administration to a living subject, such as a mammal, preferably a human; compounds that convert in vivo to pharmacologically active moieties. The transformation preferably takes place in a mammal, such as in a mouse, rat, dog, mini-pig, rabbit, monkey and/or human. In the context of the present invention, a "prodrug of the compound (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] quinoline-6, 7-diol", or a "prodrug of the compound of formula (I)", or a "prodrug of the compound (I)" is understood to be a compound which, after administration, is converted in vivo into the compound (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] quinoline-6, 7-diol. The administration may be by conventional routes of administration of pharmaceutical compositions known in the art, preferably by oral administration.

In the context of the present invention, the terms "parent compound" and "parent molecule" indicate the pharmacologically active moiety obtained after conversion of the corresponding prodrug. For example, a "parent compound" of one of the compounds (Ia), (Ib), (Ic) or of any of the compounds of the invention is understood to be a compound having formula (I).

Substituent group

In the context of the present invention, the given range may be indicated interchangeably with "-" (dash) or "to", for example the term "C₁-C₆Alkyl is "equivalent to" C₁To C₆Alkyl groups ".

The term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon having from 1 to 6 carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl.

Amino acids

The amino acid may be based on any of the twenty common amino acids found in naturally synthesized proteins, so long as the residue provides for oral bioavailability of compound (I) of the present invention. Common amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

In some embodiments of the invention, alpha-amino acids having both an amino group and a carboxylic acid group attached to the first alpha-carbon atom are preferred. The amino group attached to the alpha-carbon is sometimes referred to as an alpha-amino group. Similarly, the carboxylic acid group attached to the α -carbon is sometimes referred to as an α -carboxyl group. The alpha-amino acids, in addition to the cyclic amino acid proline, have the general formula H2NC^αHXCOOH, where X is an organic substituent called a "side chain", and the remainder is called a backbone, where the backbone has an (α -) carboxyl group and an (α -) amino group.

The term "amino acid residue" means an amino acid that lacks a portion of its structure. Thus, for example, when reference is made herein to an amino acid residue termed glycine, it is understood that the amino acid residue is glycine that lacks a portion of its structure. Examples include alpha-amino acids without an OH moiety for the alpha-carboxyl group or an H moiety lacking the alpha-amino group. Also included in the definition of amino acid residue are amino acids that lack part of their side chains, such as serine that lacks the H moiety of the side chain-OH group.

Amino acid residues may also be based on modified or unusual amino acids. Examples of modified or unusual amino acids include, but are not limited to, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, 2-aminobutyric acid, pipecolic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2, 4-diaminobutyric acid, desmosine, 2' -diaminopimelic acid, 2, 3-diaminopropionic acid, n-ethylglycine, N-ethylasparagine, hydroxylysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, N-methylglycine, N-methylisoleucine, N-methylvaline, norvaline, norleucine, ornithine and homoserine.

Similarly, a peptide, such as a dipeptide or tripeptide, may comprise any of the twenty common amino acids and any of the modified or unusual amino acids, as long as the peptide supports oral bioavailability of the compound (I) -carbamate derivative.

Both (D) and (L) stereoisomers of amino acid residues may be incorporated into the compounds of the invention. When no configuration is specified, the amino acid or residue may have configuration (D), (L) or (DL). For the purposes of this application, unless specifically indicated to the contrary, the named amino acids should be construed to include either the (D) or (L) stereoisomer. In a specific embodiment of the invention, the amino acid residue is an L-amino acid and the peptide is prepared from the L-amino acid.

Derivatives of amino acid residues are amino acid residues in which a part of their structure is substituted with an atom or a molecular group. Examples of such derivatives include, but are not limited to, ester derivatives having an-OR group substituted for an alpha-carboxy-OH group, wherein R is alkyl OR alkenyl. In particular embodiments, R is a C1-C20 alkyl or alkenyl group. Dipeptide or tripeptide derivatives are peptides containing at least one amino acid residue derivative.

Pharmacokinetic definitions and abbreviations

As used herein, a "PK profile" is an abbreviation for "pharmacokinetic profile". The pharmacokinetic profiles and pharmacokinetic parameters described herein are based on plasma concentration-time data obtained for compounds having formula (I) using a non-compartmental model following oral administration of a compound of the invention. Abbreviated PK parameters are: c_max(maximum concentration); t is t_max(to C)_maxTime of (d); t is t_1/2(half-life); AUC₀₂₄(area under the curve from time of administration and up to 24 hours post-administration) and "24 hour exposure" are the plasma concentrations of the compound of formula (I) as measured 24 hours post-administration.

A therapeutically effective amount

In the context of the present invention, the term "therapeutically effective amount" of a compound of the present invention means an amount sufficient to alleviate, block, partially block, eliminate or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention involving the administration of said compound. An amount sufficient to achieve this is defined as a "therapeutically effective amount". An effective amount for each purpose will depend, for example, on the severity of the disease or injury and the weight and general state of the subject. It will be appreciated that determining the appropriate dose can be achieved using routine experimentation by constructing a matrix of values and testing different points in the matrix, all within the ordinary skill of a trained physician.

In the context of the present invention, a "therapeutically effective amount" of a compound of the invention indicates an amount of said compound of the invention which, when administered (preferably by oral route) to a mammal (preferably a human), is capable of providing an amount of compound (I) sufficient to alleviate, block, partially block, remove or delay the clinical manifestations of a given disease and its complications.

Treatment (Treatment and healing)

In the context of the present invention, "treatment" is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partially arresting, removing the clinical manifestations of a disease or delaying its progression. The patient to be treated is preferably a mammal, in particular a human being.

For the treatment of disorders

The compounds of the invention are intended for use in the treatment of neurodegenerative diseases and disorders, such as parkinson's disease and/or other conditions for which treatment with dopamine agonists is therapeutically beneficial.

Therapeutic indications include various central nervous system disorders characterized by movement and/or non-movement disorders, and for which a part of the underlying pathophysiology is a disorder of the striatum-mediated circuit. Such dysfunctions may be found in neurodegenerative diseases such as, but not limited to, Parkinson's Disease (PD), restless leg syndrome, huntington's disease and alzheimer's disease, as well as neuropsychiatric diseases such as, but not limited to, schizophrenia, attention deficit hyperactivity disorder and drug addiction.

In addition to neurodegenerative diseases and disorders, other conditions in which an increase in dopaminergic turnover may be beneficial are improved in different aspects of mental function, including cognition. It also has positive effects in depressed patients, and it can also be used as an appetite suppressant for the treatment of obesity, and for the treatment of drug addiction. It can improve Mild Brain Dysfunction (MBD), narcolepsy, attention deficit hyperactivity disorder and, potentially, negative, positive and cognitive symptoms of schizophrenia.

Restless Leg Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) are alternative indications that are clinically treated with dopamine agonists. In addition, impotence, erectile dysfunction, SSRI-induced sexual dysfunction, ovarian hyperstimulation syndrome (OHSS) and certain pituitary tumors (prolactinomas) may also be ameliorated by treatment with dopamine agonists. Dopamine is involved in the regulation of the cardiovascular and renal systems, and therefore renal failure and hypertension can be considered as alternative indications for the compounds of the invention.

The present invention encompasses the use of the compounds of the present invention for the treatment of the diseases and disorders listed above.

Combination of

In one embodiment of the invention, the compound having formula (Ie) is used as the sole active compound as a stand-alone treatment. In another embodiment of the invention, the compound having formula (Ie) may be used in combination with other agents useful in the treatment of neurodegenerative diseases or disorders, such as parkinson's disease. The terms "combined use", "combination with … …", and "combination of … …" and the like as used herein in the context of the methods of the invention (including the combined administration of a therapeutically effective amount of a compound of formula (Ie) and another compound which may be used to treat a neurodegenerative disease or disorder) are intended to mean the administration of a compound of formula (Ie) either simultaneously or sequentially (in any order) with the other compound.

The two compounds may be administered simultaneously or with a time interval between the administration of the two compounds. The two compounds may be administered as part of the same pharmaceutical formulation or composition, or in separate pharmaceutical formulations or compositions. The two compounds may be administered on the same day or on different days. They can be administered by the same route, such as, for example, by oral administration, subcutaneous injection, by transdermal administration, by depot (depot) type, by intramuscular injection or intravenous injection; or by different routes, wherein one compound is administered, e.g. orally or placed through a depot, and e.g. another compound is injected. The two compounds may be administered by the same dosing regimen or interval, such as once or twice daily, weekly, or monthly; or by different dosing regimens, e.g., wherein one compound is administered once daily and the other compound is administered daily or twice weekly or monthly.

In some cases, when starting treatment with a compound having formula (Ie), the patient to be treated may have been treated with one or more other compounds useful for treating a neurodegenerative disease or disorder. In other cases, a patient may have been treated with a compound having formula (Ie) or (Id) when treatment is initiated with one or more other compounds useful for treating a degenerative disease or disorder. In other cases, treatment with a compound having formula (Ie) and treatment with one or more other compounds useful for treating a neurodegenerative disease or disorder begin simultaneously.

Compounds for combination therapy

In the context of the present invention, the compound to be used in combination with the compound having formula (Ie) may be selected from, for example, L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as itraphylline, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, and antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole.

In addition to small molecules, compounds for combination may also be included in the treatment of neurodegenerative diseases or disorders, emerging biologics approaches such as, for example, antibodies targeting α -synuclein, tau protein or a- β protein.

Route of administration

Pharmaceutical compositions comprising a compound having formula (Ie) as the sole active compound or in combination with another active compound may be specifically formulated for administration by any suitable route, such as the oral, rectal, nasal, buccal, sublingual, pulmonary, transdermal and parenteral (e.g., subcutaneous, intramuscular and intravenous) routes. In the context of the present invention, the oral route is the preferred route of administration.

It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.

Pharmaceutical formulations and excipients

Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutical excipient including, but not limited to, carriers, fillers, diluents, antiadherents, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, carriers, and adjuvants.

The present invention also provides a pharmaceutical composition comprising a compound having formula (Ie) (one of the compounds as disclosed in the experimental section herein). The invention also provides a process for the manufacture of a pharmaceutical composition comprising a compound having formula (Ie). The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable excipients according to conventional techniques such as those disclosed in: remington, The Science and Practice of Pharmacy 22 nd edition (2012), editors Allen, Loyd v., Jr.

Preferably, the pharmaceutical composition comprising a compound of the invention is a pharmaceutical composition for oral administration. Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups, as well as powders and granules to be dissolved or suspended in a suitable liquid.

Solid oral dosage forms may be presented as discrete units (e.g., tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients. Where appropriate, solid dosage forms may be prepared with coatings, such as enteric coatings, or they may be formulated to provide modified release, such as delayed or extended release, of the active ingredient, according to methods well known in the art. Where appropriate, the solid dosage form may be one which disintegrates in saliva, such as, for example, an orodispersible tablet.

Examples of excipients suitable for use in solid oral formulations include, but are not limited to: microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talc, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid formulations may contain excipients known in the art for delayed or extended release formulations, such as glyceryl monostearate or hypromellose. If solid materials are used for oral administration, the formulations may be prepared, for example, by mixing the active ingredient with solid excipients and subsequently compressing the mixture in a conventional tableting machine; or the formulation may be placed in a hard capsule, for example, in the form of a powder, pill or mini-tablet. The amount of solid excipient will vary widely, but will typically range from about 25mg to about 1g per dosage unit.

Liquid oral dosage forms may be presented as, for example, elixirs, syrups, oral drops or liquid filled capsules. Liquid oral dosage forms may also be presented as powders, for solution or suspension in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral formulations include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamers, sorbitol, polysorbates, mono-and diglycerides, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

Additional excipients (e.g., coloring agents, flavoring agents, preservatives, and the like) may be used in the solid and liquid oral formulations.

Pharmaceutical compositions for parenteral administration include: sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion and sterile powders to be reconstituted in a sterile solution or dispersion for injection or infusion prior to use. Examples of excipients suitable for parenteral formulation include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. The aqueous formulation should be suitably buffered if necessary and made isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, skin patches, implants and formulations for buccal or sublingual administration.

The essential requirement is that the excipients used in any pharmaceutical formulation are compatible with the intended route of administration and with the active ingredient.

Dosage form

In one embodiment, the compounds of the present invention are administered in an amount of from about 0.0001mg/kg body weight to about 5mg/kg body weight per day. In particular, the daily dose may be in the range of 0.001mg/kg body weight to about 2mg/kg body weight per day. The precise dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject to be treated, the condition to be treated, the nature and severity of any concomitant diseases to be treated, the desired therapeutic effect and other factors known to those skilled in the art.

Typical oral dosages for adults will be in the following ranges: 0.01-100 mg/day of a compound of the invention, e.g. 0.05-50 mg/day, e.g. 0.1-10 mg/day or 0.1-5 mg/day. Conveniently, the compounds of the invention are administered in a unit dosage form comprising the compound in the following amounts: about 0.01 to 50mg, such as 0.05mg, 0.1mg, 0.2mg, 0.5mg, 1mg, 5mg, 10mg, 15mg, 20mg or up to 50mg of a compound of the invention.

Drawings

FIG. 1: schematic representation of the conversion of compounds (1) to (3) of the present invention to compound (I). Solid arrows: demonstrated transformation was obtained in vitro and in vivo. Striped arrow: demonstrated transformation was obtained in vivo.

Detailed Description

The inventors of the present invention have identified novel compounds which are carbamate derivatives and prodrugs of (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] quinoline-6, 7-diol [ compound (I) ] which are dual D1/D2 agonists (see e.g. WO 2009/026934).

The compounds of the present invention are carbamate derivatives of compound (I).

The inventors of the present invention found that oral administration of representative compounds (1) - (3) of the present invention in Wistar rats provided systemic exposure of compound (I) in plasma, indicating the usefulness of the compound as an orally active prodrug of compound (I).

For the compounds tested in vivo, the dose was corrected by molecular weight to a dose equal to 300. mu.g/kg of compound (Ib) (corresponding to 287. mu.g/kg of compound (I)). It was found that oral administration of compounds (Ia) and (Ib) to Wistar rats resulted in early and high peak concentrations of compound (I). In humans, such high peak concentrations may be associated with dopaminergic side effects, such as, for example, nausea, vomiting, and mild headaches. In contrast, for the compounds of the present invention, a slower absorption rate was observed, with continued exposure of compound (I), avoiding the fast peak plasma concentrations. Thus, in Wistar rats, plasma exposure of compound (I) was maintained for 24 hours, although the AUC obtained for compound (I) was lower compared to the AUC obtained after administration of compounds (Ia) and (Ib). However, because the peak concentration of compound (I) that is expected to drive side effects is lower, higher doses of the compounds of the invention can be administered, potentially achieving higher overall plasma concentrations of compound (I) than can be achieved from administration of compounds (Ia) and (Ib). When investigating the PK properties of compound (Ic), the inventors of the present invention found that the plasma concentrations of compound (I) were extremely low, rendering compound (Ic) unsuitable for oral administration as a prodrug of compound (I), and confirmed that the oral bioavailability of the compound of the present invention was highly unpredictable. PK parameters for PK studies in Wistar rats are listed in table 4.

The biotransformation of compounds (1) to (3) of the invention to compounds of formula (I) was also assessed by incubation in human plasma as described in example 1. For the parent compound (I) itself, a short half-life was observed in the plasma assay, which may explain that for one of the compounds of the invention, the formation of compound (I) cannot be determined, as it may be metabolized at the same time as it is formed. For all compounds (1) to (3) of the present invention, the conversion into compound (I) was demonstrated in vitro or both in vivo and in vitro, see table 1 below and fig. 1.

Table 1: in vitro and in vivo transformation of Compounds (1) to (3) of the invention

In summary, the compounds of the invention (e.g. from compound(s) (ii))1) Represented by (3) can be used as orally active prodrugs of compound (I) and has been observed in rats, providing a PK profile that avoids the peak C observed for known prodrugs (Ia) and (Ib)_maxAnd provides a significantly higher AUC for compound (I) compared to compound (Ic).

Finally, an important problem associated with compound (Ib) is that it is an agonist of the 5-HT2B receptor. Since 5-HT2B receptor agonists have been implicated in the pathogenesis of Valvular Heart Disease (VHD) after long-term exposure, such compounds are not suitable for the treatment of chronic diseases (Rothman et al, Circulation [ loop ] (2000),102: 2836-2841; and also Cavero and Guillon, J.Pharmacol.Toxicol.methods [ J.Pharmacol.methods ] (2014),69: 150-161). Thus, a further advantage of compounds (1) - (3) of the present invention is that these compounds are not 5-HT2B agonists, see example 2 and table 3.

Peptide transporters (PEPT1 and PEPT2) and LAT1 and LAT2 have been used as targets for prodrugs, where amino acids or peptides have been linked to the active compound through the use of ester or carbamate linkages. The L-amino acid transporters 1(LAT1) and 2(LAT2) are responsible for the transport of large neutral amino acids from the extracellular fluid into the cell. The natural substrate of LAT1 is a large neutral amino acid such as L-leucine, L-tryptophan, and L-phenylalanine. Furthermore, PEPT1 is known to play a key role in the absorption of various drugs and prodrugs from the intestinal tract. PEPT1 is located in the apical intestinal cell membrane of the upper small intestine, with PEPT1 acting as a symporter, using the electrochemical proton gradient as its driving force. Human PEPT1(hPEPT1) contains 708 amino acids, oriented in 12 transmembrane domains. Since PEPT1 is an important amino acid/dipeptide/tripeptide transporter in human intestinal cells, the transport of hundreds of different possible dipeptides, thousands of possible tripeptides, and multiple drugs and prodrugs means that the transporter has a broad substrate specificity.

In one embodiment of the invention, the carbamate derivative compound of compound (I) is capable of being transported by one or more peptide transporters, such as PEPT1, PEPT2, LAT1 and LAT 2. In a more specific embodiment of the invention, the carbamate derivative compound of compound (I) as defined herein is capable of being transported by PEPT 1.

PEPT1 has been shown to have high affinity for L-amino acids or peptides comprising L-amino acids. Thus, in one embodiment of the invention, the amino acid or amino acid residue is an L amino acid or L-amino acid residue. Similarly, in one embodiment of the invention, the peptide comprises or consists of L-amino acids.

The amino acid or amino acid residue according to the invention may be any of the twenty common amino acids found in naturally synthesized proteins. Thus, in one embodiment, the amino acid or amino acid residue is selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

In one embodiment of the invention, the peptide comprises amino acid residues of two or more amino acids selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

In some studies, PEPT1 has been found to have a preference from specific amino acids or peptides comprising specific amino acids such as phenylalanine, valine, leucine, isoleucine, glycine and alanine. Thus, in one embodiment of the invention, the amino acid is selected from the group consisting of: phenylalanine, valine, leucine, isoleucine, glycine and alanine, wherein the L-form of the amino acids in this group is preferred. In even more particular embodiments of the invention, the amino acid is selected from the group consisting of: phenylalanine and glycine.

Similarly, in one embodiment, the peptide comprises or consists of: one or more amino acids selected from the group consisting of: phenylalanine, valine, leucine, isoleucine, glycine and alanine, with the L-form of the amino acids in this group being preferred. In even more particular embodiments of the invention, the peptide comprises one or more amino acids selected from the group consisting of: phenylalanine and glycine.

PEPT1 can transport single amino acid derivatives of the active compound as well as dipeptide derivatives and tripeptide derivatives. Thus, in one embodiment of the invention, the carbamate derivative of compound (I) comprises one amino acid residue.

In another embodiment of the invention, the compounds of the invention comprise di-or tripeptides.

In one embodiment of the invention, the compound of the invention comprises a dipeptide comprising or consisting of: one or more amino acids selected from the group consisting of: phenylalanine, valine, leucine, isoleucine, glycine and alanine, with the L-form of the amino acids in this group being preferred. In a particular embodiment of the invention, the compounds of the invention comprise a dipeptide comprising or consisting of: one or more amino acids or amino acid residues selected from the group consisting of phenylalanine and glycine. In even more particular embodiments, the compounds of the present invention include dipeptides comprising a phenylalanine residue. In even more particular embodiments, the compounds of the present invention include dipeptides comprising a glycine residue. In a particular embodiment of the invention, the dipeptide consists of phenylalanine and glycine residues.

In another specific embodiment, the compounds of the invention comprise a dipeptide comprising or consisting of: at least two of the amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

In a particular embodiment of the invention, the dipeptide consists of two alanine residues, or two phenylalanine residues, or two leucine residues, or two isoleucine residues, or two valine residues.

In one embodiment of the invention, the compounds of the invention comprise a tripeptide comprising or consisting of: one or more amino acids selected from the group consisting of: phenylalanine, valine, leucine, isoleucine, glycine and alanine, with the L-form of the amino acids in this group being preferred. In a particular embodiment of the invention, the compounds of the invention comprise tripeptides comprising or consisting of: one or more amino acids or amino acid residues selected from the group consisting of phenylalanine and glycine.

In another specific embodiment, the compounds of the present invention comprise a tripeptide comprising or consisting of: at least two of the amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

In another specific embodiment, the compounds of the present invention comprise a tripeptide comprising or consisting of: at least three of the amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

In a particular embodiment of the invention, the tripeptide consists of three alanine residues, or three phenylalanine residues, or three leucine residues, or three isoleucine residues, or three valine residues.

Thus, in a more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, glycine and alanine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, glycine and isoleucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, glycine and leucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, glycine and valine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, alanine and isoleucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, alanine and leucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, alanine and valine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, isoleucine and leucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of phenylalanine, isoleucine and valine.

In another more specific embodiment, the tripeptide comprises or consists of the amino acid residues of phenylalanine, leucine and valine.

In another more specific embodiment, the tripeptide comprises or consists of the amino acid residues of phenylalanine, leucine and valine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, alanine and isoleucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, alanine and leucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, alanine and valine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, isoleucine and leucine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, isoleucine and valine.

In another more specific embodiment, the tripeptide comprises or consists of amino acid residues of glycine, leucine and valine.

In another more specific embodiment, the tripeptide comprises or consists of the amino acid residues isoleucine, leucine and valine.

As described above, peptide transporters such as hPEPT1 are capable of transporting dipeptides. In particular embodiments, the compounds of the invention comprise a dipeptide comprising or consisting of: at least two of the amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

In another specific embodiment, the compound of the invention comprises a dipeptide consisting of two of the amino acid residues selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

In a particular embodiment of the invention, the dipeptide consists of two alanine residues, or two phenylalanine residues, or two leucine residues, or two isoleucine residues, or two valine residues.

In particular embodiments, the compounds of the present invention include dipeptides comprising a phenylalanine residue.

In another specific embodiment, the compounds of the present invention include dipeptides comprising a glycine residue.

Thus, in a more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of phenylalanine and alanine.

In another more specific embodiment of the invention, the peptide consists of the amino acid residues of phenylalanine and glycine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of phenylalanine and isoleucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of phenylalanine and leucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of phenylalanine and valine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of alanine and glycine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of alanine and isoleucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of alanine and leucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of alanine and valine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of glycine and isoleucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of glycine and leucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues glycine and valine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of isoleucine and leucine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of isoleucine and valine.

In another more specific embodiment of the invention, the peptide comprises or consists of the amino acid residues of leucine and valine.

In a particular embodiment of the invention, one or more of R1, R2, R3 and R4 is an amino acid, amino acid derivative or peptide linked through the ca atom of the amino acid, amino acid residue or peptide.

In particular embodiments of the invention, one or more of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide linked through the C α atom of a glycine residue.

In a preferred embodiment of the invention, one or more of R1, R2, R3 and R4 is an amino acid, amino acid derivative or peptide linked through the carboxyl group of the amino acid, amino acid residue or peptide.

In a preferred embodiment of the invention, one or more of R1, R2, R3 and R4 is an amino acid or amino acid derivative linked through the backbone carboxyl group of the amino acid or amino acid residue.

In another embodiment of the invention, one or more of R1, R2, R3 and R4 is phenylalanine or a derivative thereof attached through the benzyl group of an amino acid or amino acid residue side chain.

In another embodiment of the invention, one or more of R1, R2, R3 and R4 is phenylalanine or a residue thereof attached through the benzyl group of an amino acid or amino acid residue side chain.

In a preferred embodiment of the invention, one or more of R1, R2, R3 and R4 is a peptide linked through a carboxyl group at the C-terminus of the peptide backbone.

In a preferred embodiment of the invention, one or more of R1, R2, R3 and R4 is a dipeptide linked through a carboxyl group at the C-terminus of the peptide backbone.

In a preferred embodiment of the invention, one or more of R1, R2, R3 and R4 are tripeptides linked through a carboxyl group at the C-terminus of the peptide backbone.

The compounds of the invention are useful in the treatment of neurodegenerative diseases and disorders, such as parkinson's disease and/or other conditions for which treatment with dopamine agonists is therapeutically beneficial. Compounds suitable for oral administration have the potential to provide a new therapeutic paradigm for parkinson's disease.

In one embodiment of the invention, these compounds are useful as stand-alone treatments for neurodegenerative diseases or disorders. In another embodiment of the invention, these compounds are used in combination with other agents for treating PD, such as a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

Examples of the invention

In the following, some specific embodiments of the present invention are disclosed. The first embodiment is denoted as E1, the second embodiment as E2, and so on

E1. A compound according to formula (Id)

Wherein

R1, R2, R3 and R4 are each independently selected from H and C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

E2. A compound or pharmaceutically acceptable salt according to embodiment E1, wherein R1 ═ R3 and R2 ═ R4.

E3. The compound or pharmaceutically acceptable salt of any one of embodiments E1-E2, wherein

R1 and R3 are both H and R2 and R4 are the same C_1-6An alkyl group; or

R1 and R3 are the same C_1-6Alkyl and R2 and R4 are both H.

E4. The compound or pharmaceutically acceptable salt of any one of embodiments E1-E2, wherein

R1 and R3 are the same C_1-6An alkyl group; and is

R2 and R4 are the same C_1-6An alkyl group.

E5. The compound or pharmaceutically acceptable salt of any one of embodiments E1-E2, wherein

R1 and R3 are both H and R2 and R4 are both methyl or both ethyl; or

R1 and R3 are both methyl or both ethyl and R2 and R4 are both H.

E6. The compound or pharmaceutically acceptable salt of any one of embodiments E1-E2, wherein

R1 and R3 are both ethyl or both methyl; and is

R2 and R4 are both ethyl or both methyl.

E7. The compound according to embodiment E1, wherein the compound is selected from the group consisting of:

compound (1): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diylbis (methylcarbamate)

Compound (2): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diyl bis (ethylcarbamate); and

compound (3): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (dimethylcarbamate);

or a pharmaceutically acceptable salt of any of these compounds.

E8. A compound which is the compound (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g]Prodrug of quinoline-6, 7-diol (compound (I)), wherein the prodrug provides a PK profile, wherein the (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] when measured at a concentration corresponding to 287. mu.g/kg]Dosing of quinoline-6, 7-diol when the prodrug is administered orally to Wistar rats, (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g [, j]C of quinoline-6, 7-diol_maxBetween 25 and 200pg/mL, such as between 50 and 150pg/mL, such as between 50 and 100 pg/mL;

or a pharmaceutically acceptable salt of said compound.

E9. The compound according to embodiment E8 or a pharmaceutically acceptable salt thereof, which is the compound (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g]Prodrug of quinoline-6, 7-diol (compound (I)), wherein the prodrug provides a PK profile, wherein the (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ] when measured at a concentration corresponding to 287. mu.g/kg]Dosing of quinoline-6, 7-diol when the prodrug is administered orally to Wistar rats, (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g [, j]AUC of quinoline-6, 7-diol_0-24Greater than 1000pg x h/mL.

E10. A compound according to any one of embodiments E8-E9, or a pharmaceutically acceptable salt thereof, wherein the PK profile has been obtained by a PK experiment as described in example 3 herein.

E11. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use in therapy.

E12. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use as a medicament.

E13. The compound or pharmaceutically acceptable salt for use as a medicament according to embodiment E12, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

E14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

E15. The pharmaceutical composition of embodiment E14, wherein the pharmaceutical composition is for oral administration.

E16. The pharmaceutical composition of any one of embodiments E14-E15, wherein the pharmaceutical composition is an oral pharmaceutical composition.

E17. The pharmaceutical composition of any one of embodiments E14-E16, wherein the pharmaceutical composition is a solid oral dosage form.

E18. The pharmaceutical composition of any one of embodiments E14-E17, wherein the pharmaceutical composition is a tablet or capsule for oral administration.

E19. The pharmaceutical composition of any one of embodiments E14-E18, wherein the pharmaceutical composition further comprises another agent useful for treating a neurodegenerative disease or disorder, such as parkinson's disease.

E20. The pharmaceutical composition of any one of embodiments E14-E19, wherein the pharmaceutical composition further comprises a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or antibodies targeting alpha-synuclein, tau protein, or A-beta protein.

E21. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

E22. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use in a treatment according to embodiment E21, wherein the neurodegenerative disease or disorder is parkinson's disease.

E23. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments E21-E22, wherein the compound is to be used in combination with another agent useful in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

E24. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments E21-E23, wherein the compound is to be used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, folligurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or to be used in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

E25. A compound according to any one of embodiments E1-E10 or a pharmaceutically acceptable salt thereof for use in a treatment according to any one of embodiments E21-E24, wherein the treatment is by oral administration of the compound.

E26. A compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments E21-E25, wherein the compound is comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

E27. A method for treating a disease or disorder comprising: neurodegenerative diseases or disorders, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof.

E28. The method of embodiment E27, wherein the neurodegenerative disease or disorder is parkinson's disease.

E29. The method according to any one of embodiments E27-E28, wherein the compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, is used in combination with another agent useful in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

E30. The method according to any one of embodiments E27-E29, wherein the compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

E31. The method of any one of embodiments E27-E30, wherein the administering is by oral route.

E32. The method according to any one of embodiments E27-E31, wherein the compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, is comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

E33. Use of a compound according to any one of embodiments E1-E10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

E34. The use of embodiment E33, wherein the neurodegenerative disease or disorder is parkinson's disease.

E35. The use of any one of embodiments E33-E34, wherein the medicament is used in combination with another medicament useful in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

E36. The use of any one of embodiments E33-E35, wherein the medicament is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

E37. The use of any one of embodiments E33-E36, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

Further embodiments of the invention

Embodiments and aspects of the invention are further described in the following sections. The first embodiment is denoted EE1, the second embodiment is denoted EE2, and so on.

EE1. A Compound according to formula (Ie)

Wherein Y is selected from H and carbamoyl having the formula (CONR1R2)

(CONR1R2)，

And wherein X is selected from H and carbamoyl of formula (CONR3R4)

(CONR3R4), and

wherein Y and X are not both H, and

wherein R1, R2, R3, and R4 are each individually selected from the group consisting of: H. c_1-6Alkyl, amino acids, amino acid residues and peptides;

or a pharmaceutically acceptable salt thereof.

A compound or pharmaceutically acceptable salt according to embodiment EE1, wherein

Y is a carbamoyl group having the formula (CONR1R2), and

x is H.

EE3. the compound or pharmaceutically acceptable salt according to example EE1, wherein

Y is H, and

x is a carbamoyl group having the formula (CONR3R 4).

EE4. the compound or pharmaceutically acceptable salt according to example EE1, wherein

Y is a carbamoyl group having the formula (CONR1R2), and

x is a carbamoyl group having the formula (CONR3R 4).

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE4, wherein at least one of R1, R2, R3 and R4 is an amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE5, wherein at least one of R1, R2, R3 and R4 is an amino acid, amino acid residue or peptide, and wherein said amino acid, amino acid residue or peptide has an L-conformation.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3 and R4 is an amino acid, amino acid residue or peptide, and wherein N is attached to an amino acid backbone atom of said amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to the C α atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3 and R4 is an amino acid, amino acid residue or peptide, and wherein N is attached to the backbone carbonyl of said amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3 and R4 is an amino acid, amino acid residue or peptide, and wherein N is attached to a side chain atom of said amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3 and R4 is an amino acid, amino acid residue or peptide, and wherein N is attached to the C β atom of said amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to the C γ side chain atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to the C δ side chain atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt of any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to the C epsilon side chain atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt of any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to the C zeta side chain atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to a side chain oxygen atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to the side chain nitrogen atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE6, wherein at least one of R1, R2, R3, and R4 is an amino acid, amino acid residue, or peptide, and wherein N is attached to a side chain sulfur atom of the amino acid, amino acid residue, or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE18, wherein

R1 and R3 are both H, and

at least one of R2 and R4 is an amino acid, amino acid residue or peptide; or

Wherein R2 and R4 are both H, and

at least one of R1 and R3 is an amino acid, amino acid residue or peptide.

EE20.EE23. the compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE18, wherein

R1 and R3 are both H, and

only one of R2 and R4 is an amino acid, amino acid residue or peptide; or

Wherein R2 and R4 are both H, and

only one of R1 and R3 is an amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE18, wherein

R1 and R3 are both H, and

one of R2 and R4 is an amino acid, an amino acid residue or a peptide, and

one of R2 and R4 is H; or

Wherein R2 and R4 are both H, and

one of R1 and R3 is an amino acid, an amino acid residue or a peptide, and

one of R1 and R3 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE21, wherein R1, R2 and R3 are H, and

r4 is an amino acid, amino acid residue or peptide.

The compound or pharmaceutically acceptable salt of any one of embodiments EE1-21, wherein

R1, R2 and R4 are H, and

r3 is an amino acid, amino acid residue or peptide.

The compound or pharmaceutically acceptable salt of any one of embodiments EE1-EE21, wherein

R1, R3 and R4 are H, and

r2 is an amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE21, wherein

R2, R3 and R4 are H, and

r1 is an amino acid, amino acid residue or peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE21, wherein R1 is an amino acid residue.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE26, wherein R2 is an amino acid residue.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE27, wherein R3 is an amino acid residue.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE28, wherein R4 is an amino acid residue.

The compound or pharmaceutically acceptable salt of any one of embodiments EE1-EE21, wherein

R1 and R3 are both H, and wherein at least one of R2 and R4 is an amino acid residue; or therein

R2 and R4 are both H, and wherein at least one of R1 and R3 is an amino acid residue.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE2, EE7-EE21, wherein

R1 and R3 are both H, and wherein one of R2 and R4 is an amino acid residue, and wherein one of R2 and R4 is H; or therein

R2 and R4 are both H, and wherein one of R1 and R3 is an amino acid residue, and wherein one of R1 and R3 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE31, wherein the amino acid is selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE32, wherein the amino acid residue is selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE33, wherein the amino acid residue is selected from the group consisting of: phenylalanine, valine, leucine, isoleucine, glycine and alanine.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE34, wherein the amino acid residue is selected from the group consisting of: phenylalanine and glycine.

The compound or pharmaceutically acceptable salt of any one of embodiments EE1-EE25, wherein

R1 and R3 are both H, and wherein at least one of R2 and R4 is a peptide; or wherein R2 and R4 are both H, and wherein at least one of R1 and R3 is a peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25, wherein

R1 and R3 are both H, and wherein one of R2 and R4 is a peptide, and wherein one of R2 and R4 is H; or therein

R2 and R4 are both H, and wherein one of R1 and R3 is a peptide, and wherein one of R1 and R3 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25, wherein

R2, R3 and R4 are H, and

r1 is a peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25, wherein

R1, R3 and R4 are H, and

r2 is a peptide.

EE40. the compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25, wherein

R1, R2 and R4 are H, and

r3 is a peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25, wherein

R1, R2 and R3 are H, and

r4 is a peptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE41, wherein the peptide is a dipeptide, tripeptide, or derivative of a dipeptide or tripeptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE42, wherein the peptide comprises two or more amino acid residues selected from the group consisting of: arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, tryptophan, methionine, alanine, isoleucine, leucine, phenylalanine, valine, proline and glycine residues.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE43, wherein the peptide comprises or consists of: two or more amino acids selected from the group consisting of phenylalanine, valine, leucine, isoleucine, glycine and alanine.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE44, wherein the peptide comprises or consists of: two or more L-amino acids.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE45, wherein the peptide is a dipeptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE2 and EE36-EE46, wherein the peptide is a tripeptide.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE47, wherein the peptide comprises one or more amino acid residues selected from the group consisting of: phenylalanine and glycine.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE25 and EE36-EE48, wherein the peptide is a dipeptide comprising one or more amino acid residues selected from the group consisting of: phenylalanine and glycine.

The compound or pharmaceutically acceptable salt of any one of embodiments EE1-EE35, wherein

One of R1, R2, R3 and R4 is a glycine residue.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE35 and EE50, wherein

One of R1, R2, R3 and R4 is a glycine residue, and three of R1, R2, R3 and R4 are H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE35 and EE50-EE51, wherein

One of R1, R2, R3 and R4 is CH2 COOH.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE35 and EE50-EE52, wherein one of R1, R2, R3 and R4 is CH2COOH and three of R1, R2, R3 and R4 are H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE35, EE50 and EE52, wherein

One of R1, R2, R3 and R4 is a phenylalanine residue.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1-EE35 and EE54, wherein

One of R1, R2, R3 and R4 is a phenylalanine residue, and three of R1, R2, R3 and R4 are H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE2 and EE4, wherein

R1 is H and R2 is C_1-6An alkyl group; or

R1 is C_1-6Alkyl and R2 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE2 and EE4, wherein R1 and R2 are the same C_1-6An alkyl group.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE2 and EE4, wherein

R1 is H and R2 is methyl or ethyl; or

R1 is methyl or ethyl and R2 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE2 and EE4, wherein R1 and R2 are independently selected from methyl and ethyl.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE2 and EE4, wherein R1 and R2 are both methyl.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE2 and EE4, wherein R1 and R2 are both ethyl.

The compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE3 and EE4, wherein

R3 is H and R4 is C_1-6An alkyl group; or

R3 is C_1-6Alkyl and R4 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE3 and EE4, wherein R3 and R4 are the same C_1-6An alkyl group.

The compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE3 and EE4, wherein

R3 is H and R4 is methyl or ethyl; or

R3 is methyl or ethyl and R4 is H.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE3 and EE4, wherein R3 and R4 are independently selected from methyl and ethyl.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE3 and EE4, wherein R3 and R4 are both methyl.

A compound or pharmaceutically acceptable salt according to any one of embodiments EE1, EE3 and EE4, wherein R3 and R4 are both ethyl.

A compound or pharmaceutically acceptable salt of the compounds according to examples EE1 and EE4, wherein the compound has the formula (Id)

Wherein R1, R2, R3, and R4 are each individually selected from the group consisting of: H. c_1-6Alkyl, amino acids, amino acid residues and peptides;

or a pharmaceutically acceptable salt thereof.

A compound or pharmaceutically acceptable salt according to embodiment EE68, wherein R1, R2, R3, and R4 are each individually selected from the group consisting of: H. straight chain C_1-6Alkyl, amino acids, amino acid residues and peptides.

EE70. the compound or pharmaceutically acceptable salt according to example EE68-EE69, wherein

R1 ═ R3 and R2 ═ R4.

A compound or pharmaceutically acceptable salt according to embodiment EE68-EE70, wherein

R1 and R3 are both H and R2 and R4 are the same C_1-6An alkyl group; or

R1 and R3 are the same C_1-6Alkyl and R2 and R4 are both H.

The compound or pharmaceutically acceptable salt according to embodiment EE68-EE71, wherein

R1 and R3 are the same C_1-6An alkyl group; and is

R2 and R4 are the same C_1-6An alkyl group.

A compound or pharmaceutically acceptable salt according to embodiment EE68-EE72, wherein

R1 and R3 are the same straight chain C_1-6An alkyl group; and is

R2 and R4 are the same straight chain C_1-6An alkyl group.

A compound or pharmaceutically acceptable salt according to embodiment EE68-EE71, wherein

R1 and R3 are both H and R2 and R4 are both methyl or both ethyl; or

R1 and R3 are both methyl or both ethyl and R2 and R4 are both H.

A compound or pharmaceutically acceptable salt according to embodiment EE68-EE73, wherein

R1 and R3 are both ethyl or both methyl; and R2 and R4 are both ethyl or both methyl.

A compound according to embodiment EE1, wherein the compound is selected from the group consisting of:

compound (1): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diylbis (methylcarbamate)

Compound (2): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diyl bis (ethylcarbamate); and

compound (3): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (dimethylcarbamate);

compound (4): ((((4aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) glycine;

compound (5): ((((4aR,10aR) -6-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-yl) oxy) carbonyl) glycine;

compound (6): (S) -2-amino-3- (3- ((((((4 aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) amino) phenyl) propanoic acid and pharmaceutically acceptable salts of any of these compounds.

A compound according to embodiment EE1, wherein the compound is selected from the group consisting of:

compound (1): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diylbis (methylcarbamate)

Compound (2): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diyl bis (ethylcarbamate); and

compound (3): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6, 7-diylbis (dimethylcarbamate);

and pharmaceutically acceptable salts of any of these compounds.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in therapy.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use as a medicament.

A compound or pharmaceutically acceptable salt according to EE79 for use as a medicament, wherein the medicament is an oral medicament, such as a tablet or capsule for oral administration.

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Ee82. the pharmaceutical composition according to embodiment EE81, wherein the pharmaceutical composition is for oral administration.

A pharmaceutical composition according to any one of embodiments EE81-EE82, wherein said pharmaceutical composition is an oral pharmaceutical composition.

The pharmaceutical composition according to any one of embodiments EE81-EE83, wherein said pharmaceutical composition is a solid oral dosage form.

The pharmaceutical composition according to any one of embodiments EE81-EE84, wherein said pharmaceutical composition is a tablet or capsule for oral administration.

The pharmaceutical composition according to any one of embodiments EE81-EE85, wherein said pharmaceutical composition further comprises another agent useful for the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

The pharmaceutical composition according to any one of embodiments EE81-EE86, wherein said pharmaceutical composition further comprises a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or antibodies targeting alpha-synuclein, tau protein, or A-beta protein.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in a treatment according to embodiment EE88, wherein the neurodegenerative disease or disorder is parkinson's disease.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments EE88-EE89, wherein the compound is to be used in combination with another agent useful in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments EE88-EE90, wherein the compound is to be used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or to be used in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments EE88-EE90, wherein the treatment is by oral administration of the compound.

A compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for use in a treatment according to any one of embodiments EE88-EE92, wherein the compound is comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

A method for treating the following diseases or disorders: neurodegenerative diseases or disorders, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or a neuropsychiatric disease or disorder, such as schizophrenia, attention deficit hyperactivity disorder or drug addiction; the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof.

The method of embodiment EE94, wherein the neurodegenerative disease or disorder is parkinson's disease.

The method according to any one of embodiments EE94-EE95, wherein the compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, is used in combination with another agent useful in the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

The method according to any one of embodiments EE94-EE96, wherein the compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

The method according to any one of embodiments EE94-EE97, wherein said administration is by oral route.

The method of any one of embodiments EE94-EE98, wherein the compound of any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, is comprised in an oral pharmaceutical composition, such as a tablet or capsule for oral administration.

Use of a compound according to any one of embodiments EE1-EE77, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder, such as parkinson's disease, huntington's disease, restless leg syndrome, or alzheimer's disease; or for the treatment of neuropsychiatric diseases or disorders such as schizophrenia, attention deficit hyperactivity disorder or drug addiction.

Ee101. the use according to embodiment EE100, wherein said neurodegenerative disease or disorder is parkinson's disease.

The use of any one of embodiments EE100-EE101, wherein said agent is used in combination with another agent useful for the treatment of a neurodegenerative disease or disorder, such as parkinson's disease.

The use according to any one of embodiments EE100-EE102, wherein said agent is used in combination with a compound selected from the group consisting of: L-DOPA, droxidopa, folioglurax, MAO-B inhibitors, such as selegiline or rasagiline, COMT inhibitors, such as entacapone or tolcapone, adenosine 2a antagonists, such as eltanopine, anti-glutamines, such as amantadine or memantine, acetylcholinesterase inhibitors, such as rivastigmine, donepezil or galantamine, antipsychotics, such as quetiapine, clozapine, risperidone, pimavanserin, olanzapine, haloperidol, aripiprazole or ipiprazole; or in combination with antibodies targeting alpha-synuclein, tau protein or A-beta protein.

The use of any one of embodiments EE100-EE103, wherein said medicament is an oral medicament, such as a tablet or capsule for oral administration.

All documents, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each document were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

Unless stated otherwise or clearly contradicted by context, use herein of terms relating to one or more elements such as "comprising," "having," "containing," or "containing" in the description of any one or more aspects of the invention is intended to provide support for a similar one or more aspects of the invention "consisting of," "consisting essentially of," or "consisting essentially of" that one or more particular elements (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element unless stated otherwise or clearly contradicted by context).

The use of any and all examples, or exemplary language (including "for instance", "for example", e.g ") and" as such ", in this specification is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

It should be understood that various aspects, embodiments, implementations, and features of the invention mentioned herein may be claimed separately or in any combination.

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

Compounds of the invention

Table 2: exemplary Compounds of the invention

Experimental part

Preparation of the Compounds of the invention

The compounds of formula (Id) may be prepared by the methods described below, as well as synthetic methods known in the art of organic chemistry or modifications familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by conventional Methods known in the art, such as those described in standard reference books such as "Compendium of Organic Synthetic Methods [ outline of Organic Synthetic Methods ], volume I-XII (published by Wiley-Interscience). Preferred methods include, but are not limited to, those described below.

These schemes are representative of methods that can be used to synthesize the compounds of the invention. They are not intended to limit the scope of the invention in any way.

List of abbreviations for Compounds

BF₃-OEt₂: boron trifluoride diethyl etherate

BnBr: benzyl bromide

BnCl: benzyl chloride

DCM: methylene dichloride

DMF: dimethyl formamide

ee: enantiomeric excess

EtOAc: ethyl acetate

MeCN: acetonitrile

MeOH: methanol

MeI: methyl iodide

MOM-Cl: chloromethyl methyl ether

Pd/C: palladium on carbon

pyridine-HF: pyridine hydrofluoride salts

TBAF: tetrabutylammonium fluoride

TFA: trifluoroacetic acid

TMS-I: trimethyliodisilane

LC-MS method

Analytical LC-MS data were obtained using the methods identified below, unless otherwise detailed in the experimental protocol below.

The method 550 comprises the following steps:

running the LC-MS on a Waters liquidy UPLC-MS, consisting of: waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector, and TQ-MS equipped with APPI source operating in positive ion mode.

LC-conditions: the column is Acquity UPLC BEH C181.7 μm; 2.1X 50mm, operated at 60 ℃ with a binary gradient of 1.2ml/min consisting of water + 0.05% trifluoroacetic acid (A) and acetonitrile/water (95:5) + 0.05% trifluoroacetic acid.

Gradient:

total run time: 1.15 minutes

Method 10-90AB (Shimadzu LC-20AD & MS 2010):

LC-conditions: the column was Luna-C18(2)2.0 x 30mm, (3 micron particles) operated at 40 ℃ with a gradient of 0.8mL/min (0.01-1.51min) and 1.2mL/min (1.52-2.00min) of water + 0.037% TFA (A) and MeCN + 0.018% TFA (B).

Gradient:

total run time: 2.00min

LC-MS method B:

the LC-MS was run on an Agilent 1260HPLC consisting of column components, binary pump, Hip sample, and single Q-MS equipped with ESI source operating in positive ion mode.

LC-conditions: column: inertsustatin AQ-C18 HP 3.0 μm; 3.0X 50mm, operated at 35 ℃ with a binary gradient of 1.2ml/min consisting of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 0.05% trifluoroacetic acid (B).

Gradient:

0.00min 0％B

3.00min 95％B

4.00min 95％B

total run time: 4.0 minutes

General schemes for preparing Compounds (1) to (3) of the present invention

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diol hydrochloride [ compound (I) ] (which may be prepared, for example, as disclosed in WO 2009/026934) was used as a substrate to synthesize compounds (1) - (3) of the present invention according to the following scheme.

Prodrugs with two identical carbamate groups can be prepared by reaction of the compounds with a base such as triethylamine or K₂CO₃By treating compound (I) with a carbamoyl chloride, e.g. N, N-dimethylcarbamoyl chloride, in the presence of e.g. a compound of formula (I) such as (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]Quinoline-6, 7-diylbis (dimethylcarbamate). Compound (I) can be reacted with an isocyanate such as ethyl isocyanate and a suitable base such as triethylamine or K₂CO₃Reactions, e.g. with (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]Quinoline-6, 7-diylbis (ethylcarbamate).

Prodrugs in which only one of the catechol hydroxyl groups is alkylated may be prepared from compounds like (4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol (compound a2) or (4aR,10aR) -7-methoxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol (compound a6) by treatment with carbamoyl chloride or an isocyanate in the presence or absence of a suitable base like triethylamine, diethyl-isopropylamine or potassium carbonate. In these reactions, compounds A2 and A6 can be used in their free form or as acid addition salts, such as hydrogen iodide (A2-HI), hydrogen bromide or hydrogen chloride. The synthesis of two precursors is described herein. The opposite regioisomer can be prepared in an analogous manner from (4aR,10aR) -6-methoxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-ol or (4aR,10aR) -6-benzyloxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-ol.

With BnCl and a base such as triethylamine or K₂CO₃Treatment of compound (I) will give (4aR,10aR) -6- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo[g]Quinolin-7-ol and (4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]A mixture of quinolin-6-ols; these regioisomers can be separated. Using MeI instead of BnCl will provide the corresponding methyl ether mixture, which can be isolated.

Provided herein are alternative pathways to (4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol and (4aR,10aR) -7-methoxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol.

(4aR,10aR) -6-methoxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-ol may be prepared from (4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol by methylation followed by debenzylation or by using a MOM-based protecting group strategy for the synthesis of (4aR,10aR) -7-methoxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol.

To (4aR,10aR) -6- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]An alternative route to quinolin-7-ols may be based on the use of suitable Lewis acids like BF₃-OEt₂Treatment of (4aR,10aR) -1-propyl-7- ((triisopropylsilyl) oxy) -1,2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] with benzyl 2,2, 2-trichloroacetimido-benzoate in the Presence of (2 a, 2 a-trichloroacetimido-benzyl ester]Quinoline-6-ol, followed by cleavage of the silyl protecting group with KOH, TBAF or pyridine-HF.

Intermediates of the invention

A1: (4aR,10aR) -6, 7-bis (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]Quinoline derivatives Quinoline (III)

A single-necked 1-L round-bottom flask with a magnetic stir bar was charged with the hydrochloride salt of compound (I) (10.75g) and K₂CO₃(17.5 g). The flask was evacuated and backfilled with nitrogen, followed by dry DMF (107 mL). Subsequently, benzyl chloride (8.55mL) was added and the mixture was stirred at room temperature for 18 hours, then warmed to 100 ℃ for 5 hours, and then cooled to room temperature and stirred for another 19 hours. Subsequently, additional K is added₂CO₃(7.48g) and benzyl chloride (6.29mL), and the mixture was stirred at 100 ℃ for 5 hours. The mixture was then cooled to room temperature and water (500mL) and heptane (250mL) were added. The aqueous phase was extracted with heptane (3 × 100mL) and the combined organic phases were washed with brine (100mL), dried over sodium sulfate, filtered and concentrated to give the title compound (14.6 g).

A2-HI: (4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]Quinoline derivatives Lin-6-ol hydrogen iodide

A1L single neck round bottom flask was charged with a magnetic stir bar and (4aR,10aR) -6, 7-bis (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline (11.9 g). A rubber stopper was placed in the flask, and the flask was evacuated and back-filled with nitrogen. MeCN (180mL) was added and the mixture was stirred until all starting material was dissolved. TMS-I (10.0mL) was added and the mixture was stirred at room temperature for 2 hours. Then, MeOH (5.5mL) was added and the mixture was stirred for 1 hour. Subsequently, 1:15(v/v) isopropyl acetate/heptane (160mL) was added and the mixture was cooled (ice bath) and stirred for 60 minutes. The precipitate was filtered off and washed with 1:15(v/v) isopropyl acetate/heptane (1X 50 mL). The solid was dried to give the title compound (7.6 g).

LCMS (method 550), retention time 0.55 min, [ M + H]⁺＝352.5。

¹H NMR(600MHz,CDCl₃)δ10.42(bs,1H),7.43-7.33(m,4H),7.26(d,J＝1.0Hz,1H),6.78(d,J＝8.3Hz,1H),6.58(d,J＝8.3Hz,1H),5.72(s,1H),5.08(s,2H),3.71(dd,J＝11.70,15.0Hz,1H),3.58(d,J＝11.70,1H),3.25-3.11(m,4H),2.94-2.86(m,1H),2.77-2.57(m,2H),2.26(dd,J＝11.70Hz,17.0Hz 1H),2.19(d,J＝13.80,1H),2.01-1.92(m,2H),1.80-1.69(m,1H),1.56-1.53(m,1H),1.39(qd,J＝3.60Hz,13.30Hz,1H),1.06(t,J＝7.2Hz,3H)。

A3: (4aR,10aR) -7- (benzyloxy) -6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10a- Octahydrobenzo [ g)]Quinolines

To a mixture of (4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-ol (20g) in DMF (400mL) at 0 deg.C was slowly added NaH (4.17g, 60% dispersion). The mixture was stirred at 0 ℃ for 30 minutes. Then MOMCl (3.5mL) was added dropwise at 0 ℃. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (400mL) and stirred for 20 minutes. The aqueous phase was extracted with EtOAc (300 mL. times.3). The combined organic layers were washed with brine (500mL), dried over sodium sulfate, filtered and concentrated to give the title compound (20 g).

LCMS (methods 10-90AB), retention time 0.90 min, [ M + H [ ]]⁺＝396.3。

A4: (4aR,10aR) -6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]] Quinoline-7-ols

In N₂To the next was (4aR,10aR) -7- (benzyloxy) -6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]]Quinoline (20g) in MeOH (140mL) was added 10% Pd/C (30 g). Degassing the suspension and applying H₂And (5) purging. Mixing the mixture in H₂(50psi) at 25 ℃ for 12 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to give the title compound (15.4 g).

LCMS (methods 10-90AB), retention time 0.65 min, [ M + H [ ]]⁺＝306.1。

A5: (4aR,10aR) -7-methoxy-6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octa-1 Hydrobenzo [ g ]]Quinolines

To (4aR,10aR) -6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] at 20 ℃ in 0.5 hours]Quinolin-7-ol (15g) in MeOH (150mL) was added dropwise trimethylsilyl) diazomethane (TMSCH)₂N₂(ii) a 2M in hexane, 246 mL). The mixture was concentrated to give the title compound (15 g).

A6: (4aR,10aR) -7-methoxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g)]Quinoline-6- Alcohol(s)

(4aR,10aR) -7-methoxy-6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] at 20 deg.C]Quinoline (15g) and 4M HCl in MeOH (150mL) were charged to the reactor (100 mL). The reaction mixture was stirred at 20 ℃ for 1 hour, after which it was concentrated. The residue was dissolved in water (100mL) and the aqueous layer was washed with NaHCO₃Basifying to pH 7-8. The aqueous layer was extracted with EtOAc (100X 1mL, 50mL X1). The organic layers were combined and washed with brine (100mL), dried over sodium sulfate, filtered and concentrated to provide the title compound (7 g).

¹H NMR(400MHz,CDCl₃)δ6.70(d,J＝8.4Hz,1H),6.62(d,J＝8.0Hz,1H),5.71(br s,1H),3.86(s,3H),3.07-3.18(m,2H),3.01(dd,J＝5.2,17.6Hz,1H),2.72-2.89(m,2H),2.58-2.68(m,1H),2.29-2.44(m,2H),2.24(dd,J＝12.0,17.6Hz,1H),1.97(d,J＝13.2Hz,1H),1.70-1.92(m,3H),1.54-1.63(m,2H),1.10-1.23(m,1H),0.93(t,J＝7.2Hz,3H)。

Preparation of exemplary Compounds of the invention from Compound (I)

Compound (1): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g]Quinoline-6, 7- Diylbis (methyl carbamate)

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diol hydrochloride (500mg), ascorbic acid (30mg) and 4- (dimethylamino) pyridine (11mg) were weighed into a vial. DMF (5mL) was added. The vial was evacuated and backfilled with nitrogen. Triethylamine (0.7mL) and N, N-dimethylcarbamoyl chloride (0.39mL) were added and the mixture was stirred at room temperature for 2 hours. Additional triethylamine (0.7mL) and N, N-dimethylcarbamoyl chloride (0.6mL) were then added and the mixture was stirred at room temperature for 1 hour. The mixture was purified by chromatography (EtOAc/heptane/triethylamine 20:19:1) to give the crude product. The material was dissolved in THF (20mL) and cooled to 0 ℃. To the well-stirred mixture was added dropwise 0.1M HCl in THF until slightly acidic. A dense white precipitate gradually formed. The mixture was stirred on ice. The solid was collected and dried to give the title compound as an HCl salt (233 mg).

¹H NMR(600MHz,DMSO-d6)δ10.54(s,1H),7.05(s,2H),3.54-3.40(m,2H),3.32-3.26(m,1H),3.26-3.18(m,1H),3.12-2.98(m,6H),2.95(s,3H),2.90(s,3H),2.89(s,3H),2.84(dd,J＝17.3,4.9Hz,1H),2.25(dd,J＝17.3,11.8Hz,1H),2.09-2.00(m,1H),2.00-1.88(m,2H),1.88-1.80(m,1H),1.79-1.61(m,2H),1.40-1.28(m,1H),0.96(t,J＝7.4Hz,3H)。

LCMS (method 550_ ESI): retention time 0.42 min; UV-purity 100%; ELS-purity 100%; m/z 404.5[ M + H ] +.

Compound (2): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g]Quinoline-6, 7- Diylbis (ethylcarbamate)

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diol hydrochloride (500mg) and ascorbic acid (28mg) were weighed into a vial, followed by addition of DMF (4.0 mL). The vial was evacuated and backfilled with nitrogen. Triethylamine (1mL) and ethyl isocyanate (0.35mL) were added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (EtOAc/heptane/triethylamine 10:9:1) to give the crude product. The material was dissolved in EtOAc (20mL) and cooled to 0 ℃. To the well stirred mixture was added dropwise 0.2M HCl in EtOAc until pH 3-4. The white precipitate formed was collected and dried to give the title compound as an HCl salt (239 mg).

¹H NMR(600MHz,DMSO-d6)δ10.52(brs,1H),7.78(t,J＝5.6Hz,1H),7.70(t,J＝5.6Hz,1H),7.02(d,J＝8.4Hz,1H),6.98(d,J＝8.4Hz,1H),3.48(d,J＝12.1Hz,1H),3.42(dd,J＝16.0,5.3Hz,1H),3.35-3.25(m,1H),3.26-3.18(m,1H),3.18-2.95(m,7H),2.78(dd,J＝17.2,4.9Hz,1H),2.22(dd,J＝17.2,11.9Hz,1H),2.10-1.89(m,3H),1.87-1.80(m,1H),1.80-1.64(m,2H),1.34(qd,J＝13.1,4.0Hz,1H),1.14-1.02(m,6H),0.96(t,J＝7.3Hz,3H)。

LCMS (method 550): retention time 0.41 minutes; UV-purity 100%; ELS-purity 98%; 404.6[ M + H ] M/z]⁺。

Compound (3): (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g]Quinoline-6, 7- Diylbis (dimethylcarbamate)

(4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline-6, 7-diol hydrochloride (500mg) and ascorbic acid (28mg) were weighed into a vial, followed by addition of DMF (4.0 mL). The vial was evacuated and backfilled with nitrogen. Triethylamine (1.0mL) and methyl isocyanate (0.21mL) were added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (EtOAc/heptane/triethylamine 14:5:1) to give the crude product. This material was dissolved in a hot mixture of THF (10mL) and EtOAc (15 mL). Heptane (10mL) was added and the mixture was concentrated to a volume of about 15 mL. The solution was cooled to 0 ℃ to precipitate a solid, which was collected and dried to give the title compound (310 mg).

¹H NMR(600MHz,DMSO-d6)δ7.63(q,J＝4.6Hz,1H),7.57(q,J＝4.6Hz,1H),6.97(d,J＝8.3Hz,1H),6.89(d,J＝8.3Hz,1H),3.20(dd,J＝16.3,4.9Hz,1H),2.91(d,J＝11.2Hz,1H),2.77-2.58(m,8H),2.52-2.43(m,1H),2.31(ddd,J＝13.1,9.5,4.8Hz,1H),2.18-2.03(m,3H),1.85-1.77(m,1H),1.65-1.58(m,1H),1.59-1.36(m,4H),1.04(qd,J＝12.8,4.1Hz,1H),0.86(t,J＝7.3Hz,3H)。

LCMS (method 550): retention time 0.32 min; UV-purity 100%; ELS-purity 100%; m/z is 376.53[ M + H ] +.

Compound (4): ((((4aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [g]-quinolin-6-yl) oxy) carbonyl) glycine

Compound (4) can be prepared, for example, from the intermediate (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H, 4aH,5H,10 aH-benzo [ g ] quinolin-6-ol hydrogen iodide (compound a2-HI) using a two-step process as described below:

preparation of benzyl ((4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) glycinate (Compound A7)

To a stirred solution of benzyl 2-aminoacetate hydrochloride (1.01g, 5.0mmol) and triphosgene (0.59g, 2.0mmol) in DCM (50mL) at 0 deg.C was added Et₃N (1.69g, 16.7 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour. To the above mixture was added (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ]]Quinolin-6-ol hydrogen iodide (2.00g, 4.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water/ice (50 mL). The aqueous layer was extracted with DCM (3 × 50 mL). Combining the organic extractsConcentrating the extract. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient 0% to 75% over 30 min; detector, UV 220nm, gave the title compound (2.1g) sufficiently pure for the next step.

Preparation of (((((4aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) glycine (Compound (4)) from Compound (A7)

To ((((4aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ]) in a 250mL round bottom flask under a nitrogen atmosphere]Quinolin-6-yl) oxy) carbonyl) benzyl glycinate (2.10g, 3.9mmol) in MeOH (100mL) was added Pd (OH)₂C (10%, 0.4 g). The mixture was hydrogenated using a hydrogen balloon at room temperature under a hydrogen atmosphere for 2 hours, filtered through a celite pad, and concentrated under reduced pressure. The residue was purified by trituration with EtOH (100mL) to give the title compound (693 mg).

LC/MS: retention time: 1.35 min, UV-purification: 95.5 percent; (ES, M/z) < M + H + 363. The instrument comprises the following steps: shimadzu LCMS-2020 equipped with Shim-Pack XR-ODS C18, L50 mm and D3.0 mm column operating at 40 ℃. Mobile phase A: 0.05% TFA in water; mobile phase B: 0.05% TFA in acetonitrile. The flow rate was 1.2 mL/min.

Gradient:

0-3.2 minutes A: B95: 5;

3.2min-3.7min：A:B 1:1；

3.7min-4.75min：A:B 0:1；

4.75min-5.0min：A:B 95:5。

1H NMR(400MHz,DMSO)δ6.84-6.82(d,1H),6.73-6.71(d,1H),3.73-3.69(m,3H),3.52-3.49(d,1H),3.30-3.27(m,2H),2.85-2.79(m,2H),2.72-2.66(m,2H),2.32-2.22(m,1H),1.94-1.57(m,6H),1.32-1.27(m,1H),0.98-0.91(t,3H)。

compound (5): ((((4aR,10aR) -6-hydroxy-1-propyl-1, 2,3,4,4a,5, 1)0,10 a-octahydrobenzo [g]-quinolin-7-yl) oxy) carbonyl) glycine

Compound (5) can be prepared, for example, from the intermediate (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H, 4aH,5H,10 aH-benzo [ g ] quinolin-6-ol hydrogen iodide, compound (a2-HI) using a four-step process as described below:

preparation of (4aR,10aR) -7- (benzyloxy) -6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinoline (Compound (A3))

To (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ] at 0 deg.C]Quinoline-6-ol Hydrogen iodide ((5.00g, 10.4mmol) in DMF (100mL) was added portionwise NaH (60% oily Dispersion; 1.04g, 26.0mmol) in a stirred solution, the resulting mixture was stirred at 0 ℃ under nitrogen for 0.5 h, MOM-Cl (0.83g, 12.4mmol) was added dropwise to the above mixture at 0 ℃ after which the mixture was stirred at 0 ℃ for 2h, after which the reaction was quenched with water (300mL), the resulting mixture was extracted with EtOAc (3X 200mL), and the combined organic extracts were concentrated, the residue was purified by reverse flash chromatography in the following conditions column, C18 silica gel, mobile phase, in water (10mM NH) and₄HCO₃) MeCN of (1), gradient 0% to 80% over 40 min; detector, UV 220nm, gave the title compound (2.4g) sufficiently pure for the next step.

Preparation of (4aR,10aR) -6- (methoxymethyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-ol (Compound (A4))

To (4aR,10aR) -7- (benzyloxy) -6- (methoxymethyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ] under a nitrogen atmosphere]Quinoline (2.40g, 6.1mmol) in MeOH (50mL) with addition of Pd (OH)₂/C(0.5g，10％)。The mixture was hydrogenated overnight at room temperature under hydrogen atmosphere using a hydrogen balloon. The crude mixture was filtered through a pad of celite and concentrated under reduced pressure to give the title compound (1.9g) sufficiently pure for the next step.

Preparation of t-butyl ((((4aR,10aR) -1-ethyl-6- (methoxymethyloxy) -1,2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-yl) oxy) carbonyl) glycinate (compound (A8))

To a stirred solution of tert-butyl 2-aminoacetate (0.52g, 3.9mmol) and triphosgene (0.47g, 1.6mmol) in DCM (30mL) at 0 deg.C was added Et₃N (1.33g, 13.1 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, after which (4aR,10aR) -6- (methoxymethyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ] was added]Quinolin-7-ol (1.00g, 3.3 mmol). The resulting mixture was stirred at room temperature overnight, after which the reaction was quenched with water/ice (50 mL). The aqueous layer was extracted with DCM (3 × 50mL) and the combined organic extracts were concentrated. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient 0% to 75% over 30 min; detector, UV 220nm, gave the title compound (0.8g) sufficiently pure for the next step.

Preparation of (((((4aR,10aR) -6-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-yl) oxy) carbonyl) glycine (Compound (5)) from Compound (A8)

To a stirred solution of tert-butyl ((((4aR,10aR) -1-ethyl-6- (methoxymethyloxy) -1,2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-7-yl) oxy) carbonyl) glycinate (0.8g, 1.7mmol) in DCM (10mL) was added TFA (3.0 mL). The resulting mixture was stirred at room temperature for 4 hours, after which it was concentrated. The residue was purified by preparative HPLC under the following conditions (column: Xbridge Shield RP18 OBD column, 19X 250mm, 10 um; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 12% B to 14% B254 nm over 10 min to give the title compound (225 mg).

LC/MS: retention time: 1.48min, UV-purity: 97.3 percent; (es, M/z) [ M + H ]]⁺363. The instrument comprises the following steps: shimadzu LCMS-2020 equipped with Shim-Pack XR-ODS C18, L50 mm and D3.0 mm column operating at 40 ℃. Mobile phase A: 0.05% TFA in water; mobile phase B: 0.05% TFA in acetonitrile. The flow rate was 1.2 mL/min. Gradient:

0-3.2min A:B 95:5；

3.2min-3.7min：A:B 1:1；

3.7min-4.75min：A:B 0:1；

4.75min-5.0min：A:B 95:5。

¹H NMR(400MHz,DMSO)δ6.84-6.82(d,1H),6.73-6.71(d,1H),3.79(s,2H),3.64-3.52(d,1H),3.29-3.28(m,1H),3.14-2.92(m,4H),2.80-2.72(m,2H),2.22-2.18(m,1H),1.94-1.57(m,6H),1.40-1.31(m,1H),0.98-0.94(t,3H)。

compound (6): (S) -2-amino-3- (3- (((((4aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5, 10,10 a-octahydrobenzo [ g)]Quinolin-6-yl) oxy) carbonyl) amino) phenyl) propanoic acid

Compound (6) can be prepared from intermediate (2S) -2- [ (tert-butoxycarbonyl) amino ] -3- (3-nitrophenyl) propionic acid compound (A9) (commercially available, for example, from Nan Jing Crystal Peptide Biotechnology, Inc. (Nan Jing Peptide Biotechnology Co. Ltd.) using, for example, a five-step process as described below

Preparation of benzyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-nitrophenyl) propionate from compound (A9) (Compound (A10))

To (2S) -2- [ (tert-butoxycarbonyl) amino group]To a stirred solution of (3) - (3-nitrophenyl) propionic acid (5.00g, 16.1mmol) and BnBr (3.31g, 19.3mmol) in acetone (100mL) was added K₂CO₃(4.45g, 32.2 mmol). The resulting mixture was stirred at 50 ℃ overnight. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent pentane/EtOAc 10:1) to give the title compound (4.0g) sufficiently pure for the next step.

Preparation of benzyl (S) -3- (3-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propionate from compound (A10) (Compound (A11))

To (2S) -2- [ (tert-butoxycarbonyl) amino group]-benzyl 3- (3-nitrophenyl) propionate (4.0g, 9.9mmol) and NH₄Cl (2.14g, 40mmol) in EtOH (100mL) and H₂To a stirred solution in O (25mL) was added Fe (1.67g, 30 mmol). The resulting mixture was stirred at 80 ℃ for 3 hours. The resulting mixture was diluted with water (200mL) and approximately 100mL of solvent was removed under vacuum. The resulting mixture was extracted with EtOAc (2 × 100mL) and the combined organic extracts were concentrated. The residue was purified by silica gel column chromatography (eluent: pentane/EtOAc 5:1) to give the title compound (3.1g) sufficiently pure for the next step.

Preparation of benzyl (S) -3- (3- (((((((4 aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] -quinolin-6-yl) oxy) carbonyl) amino) phenyl) -2- ((tert-butoxycarbonyl) amino) propionate from Compound (A11) (Compound (A12))

To (2S) -3- (3-aminophenyl) -2- [ (tert-butoxycarbonyl) amino group at 0 deg.C]To a stirred solution of benzyl propionate (928mg, 2.5mmol) and triphosgene (297mg,1.0mmol) in DCM (30mL) was added Et₃N (845mg, 8.4 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, after which (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ] was added]Quinolin-6-ol hydrogen iodide (1.00g, 2.1 mmol). The resulting mixture was allowed to stand at room temperatureStir overnight. The reaction was quenched with water/ice (50 mL). The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic extracts were concentrated. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient 0% to 65% over 40 min; detector, UV 220nm, gave the title compound (730mg) sufficiently pure for the next step.

Preparation of benzyl (S) -2-amino-3- (3- ((((((4 aR,10aR) -7- (benzyloxy) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) amino) phenyl) propanoate trifluoroacetate from Compound (A12) (Compound (A13))

To a stirred solution of benzyl 3- [3- [ ([ [ (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ] quinolin-6-yl ] oxy ] carbonyl) amino ] phenyl ] -2- [ (tert-butoxycarbonyl) amino ] propanoate (730mg, 1.0mmol) in DCM (15mL) was added TFA (3.0 mL). The resulting mixture was stirred at room temperature for 6 hours, after which it was concentrated to give the title compound (810mg) sufficiently pure for the next step.

Preparation of (S) -2-amino-3- (3- ((((((4 aR,10aR) -7-hydroxy-1-propyl-1, 2,3,4,4a,5,10,10 a-octahydrobenzo [ g ] quinolin-6-yl) oxy) carbonyl) amino) phenyl) propanoic acid (Compound (6))

To 3- [3- [ ([ [ (4aR,10aR) -7- (benzyloxy) -1-propyl-2H, 3H,4H,4aH,5H,10H,10 aH-benzo [ g ] in a 250mL round-bottom flask under nitrogen atmosphere]Quinolin-6-yl]Oxy radical]Carbonyl) amino]Phenyl radical]-2-Aminopropionic acid benzyl ester trifluoroacetate (810mg, 1.3mmol) in MeOH (100mL) with addition of Pd (OH)₂C (0.2g, 10%). The mixture was hydrogenated using a hydrogen balloon at room temperature for 2 hours, filtered through a pad of celite and concentrated. The residue was purified by preparative HPLC under the following conditions (column: X)Bridge Shield RP18 OBD column, 19 x 250mm, 10 um; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 10% B to 12% B in 10 minutes; 254nm, the title compound (380mg) was obtained.

LC/MS: retention time: 1.71 min; UV-purity: 96.1 of the total weight of the mixture; (ES, M/z) < M + H]⁺468. The instrument comprises the following steps: shimadzu LCMS-2020 equipped with Shim-Pack XR-ODS C18, L50 mm and D3.0 mm column operating at 40 ℃. Mobile phase A: 0.05% TFA in water; mobile phase B: 0.05% TFA in acetonitrile. The flow rate was 1.2 mL/min. Gradient: 0-3.2min A: B95: 5; 3.2min-3.7 min: a is B1: 1; 3.7min-4.75 min: a is B0: 1; 4.75min-5.0 min: a: B95: 5.

¹H NMR(400MHz,DMSO)δ7.73-7.41(d,2H),7.30-7.26(t,1H),6.95-6.93(d,1H),6.90-6.88(d,1H),6.80-6.78(d,1H),4.14-4.11(t,1H),3.54-3.51(d,1H),3.28-3.0(m,5H),2.87-2.78(m,3H),2.32-2.28(m,1H),1.91-1.66(m,6H),1.40-1.30(m,1H),0.98-0.95(t,3H)。

In vitro and in vivo characterization of the Compounds of the invention

Example 1: transformation of the Compounds of the invention in human plasma

Frozen human plasma was thawed and then centrifuged at 3200x g for 5 minutes to remove debris. The pH of the supernatant was then measured and adjusted to 7.4 ± 0.1 by adding 1% phosphoric acid or 1N sodium hydroxide. mu.L of dosing solution (50. mu.M for test compound and 100. mu.M for positive control (propantheline bromide)) was mixed with 98. mu.L of blank plasma to obtain the final concentrations of 1. mu.M test compound and 2. mu.M positive control. The mixture was incubated in a water bath at 37 ℃ and samples were taken from the incubations at predetermined time points of 0, 0.5, 1,2, 4 and 6 hours (in duplicate). At each respective time point, 10 μ L of inhibitor and 20 μ L ascorbic acid and 2 μ L formic acid (20%) were added, and then 400 μ L "stop solution" (200 ng/mL tolbutamide plus 200ng/mL labetalol in 50% ACN/MeOH) was added to precipitate the protein. The material was mixed well and thereafter centrifuged at 4,000rpm for 20 minutes. Aliquots of supernatant (50. mu.L) were then transferred from each well to a sample plate and mixed with 100. mu.L of ultrapure water. The plate was shaken at 800rpm for about 10 minutes before being subjected to LC-MS/MS analysis.

Instrument set for analyzing plasma incubation samples

Mass spectrometer (LC-MS/MS) Shimadzu LC 20-AD Shimadzu UHPLC API 4000. Analytical column ACQUITYBEH Phenyl 1.7 μm 2.1X 50 mm. Mobile phase A: 0.1% formic acid in water. Mobile phase B: 0.1% formic acid in acetonitrile. The gradient was run from 95%/5% to 5%/95% over 2.0 minutes. The flow rate was 0.7 mL/min. MRM monitoring (multiple reaction monitoring) of test items and added analytical standards (labetalol or tolbutamide).

Example 2: 5-HT2B agonist Activity and binding assays

5-HT2B agonist Activity assay

Evaluation of agonist activity of compounds (I), (Ia) and (Ib) at the human 5-HT2B receptor was performed by the european/western seph company (Eurofins/Cerep) (france) using HTRF detection method to measure the effect of compounds on inositol-phosphate (IP1) production. Briefly, human 5-HT2B receptor was expressed in transfected CHO cells. Cells were suspended in a suspension containing 10mM Hepes/NaOH (pH 7.4), 4.2mM KCl, 146mM NaCl, 1mM CaCl₂0.5mM MgCl2, 5.5mM glucose and 50mM LiCl, then dispensed in microplates at a density of 4100 cells/well and incubated at 37 ℃ for 30min in the presence of buffer (basal control), test compound or reference agonist. For control measurements of stimulation, the assay wells alone contained 1 μ M5-HT. After incubation, cells were lysed and a fluorescence acceptor (fluorobenzene D2-labeled IP1) and a fluorescence donor (anti-IP 1 antibody labeled with europium cryptate) were added. After 60 minutes at room temperature, fluorescence transfer was measured using a microplate reader (Rubystar, BMG) at λ (Ex)337nm and λ (Em)620 and 665 nm. The IP1 concentration was determined by dividing the signal measured at 665nm by the signal measured at 620nm (ratio). Results are expressed as a percentage of controls responding to 1 μ M5-HT. The standard reference agonist was 5-HT, in each experiment, in severalIt was tested at concentration to generate a concentration-response curve from which its EC was calculated as described above for the dopamine functional assay₅₀The value is obtained.

5-HT2B binding assay

Evaluation of the affinity of a compound for the human 5-HT2B receptor was determined in a radioligand binding assay at Europe/Western Hipport (France). At room temperature, in the presence of 50mM Tris-HCl (pH 7.4), 5mM MgCl₂Membrane homogenates prepared from CHO cells expressing the human 5HT2B receptor and 0.2nM [125I ] in a buffer of 10. mu.M pargyline and 0.1% ascorbic acid in the absence or presence of test compound](±) DOI (1- (4-iodo-2, 5-dimethoxyphenyl) propan-2-amine) were incubated for 60 minutes. Nonspecific binding was determined in the presence of 1. mu.M (. + -.) DOI. After incubation, the samples were rapidly filtered through glass fiber filters (GF/B, Packard) pre-impregnated with 0.3% Polyethylenimine (PEI) under vacuum using 96 sample cell collectors (Unifilter, Packard) and rinsed several times with ice-cold 50mM Tris-HCl. The filters were dried and radioactivity was counted in a scintillation counter (Topcount, Packard) using scintillation cocktail (Microscint0, Packard). Results were expressed as percent inhibition of specific binding of control radioligands. The standard reference compound was (±) DOI, which was tested at several concentrations in each experiment to obtain a competition curve from which its IC was calculated₅₀。

TABLE 3 in vitro Activity of Compounds (1) to (3) according to the invention obtained according to example 2

Indicates binding affinity (% inhibition of control, specific binding at the indicated concentration)

Example 3: PK experiments in rats

For all experiments, approximately 0.68mL of blood sample was withdrawn from the tail vein or sublingual vein and placed in K which had been precooled and prepared with a stable solution consisting of 80. mu.L ascorbic acid and 40. mu.L 100mM D-glucaric 1,4 lactone in water₃EDTA tubes. The tubes were gently inverted 6-8 times to ensure thorough mixing and then placed in wet ice. The collection tube was placed in wet ice for up to 30 minutes until centrifugation. Centrifugation was started immediately upon removal from the wet ice. Immediately after centrifugation, the samples were returned to wet ice. Three subsamples of 130 μ Ι _ plasma were transferred to each of three appropriately labeled cryo tubes containing 6.5 μ Ι _ pre-cooled formic acid (20%) (the tubes were pre-blended and frozen for storage prior to use). The tube cap was immediately replaced and the plasma solution was mixed well by gently inverting 6-8 times. The samples were stored frozen at nominal-70 ℃ within 60 minutes after sampling. Centrifugation was carried out at 3000G at 4 ℃ for 10 minutes. After collection, the plasma was placed on water-ice. Finally stored at about-70 ℃.

Plasma samples were analyzed by solid phase extraction or direct protein precipitation followed by UPLC-MS/MS. MS detection using electrospray in positive ion mode, where specific mass-nuclear transitions of compound (I) are monitored, the reaction is corrected using an internal standard. The concentration-time data was analyzed using standard software using appropriate non-compartmentalization techniques to obtain estimates of derived PK parameters.

Instrumentation for the analysis of compound (I) from the administration of compound (Ia):

mass spectrometer (LC-MS/MS) was obtained from Acquity-Sciex API 5000, Watcht corporation. BEH UPLC Phenyl 100X 2.1mm column from column Watts corporation, 1.7 μm particle size. Mobile phase A: 20mM ammonium formate (aq) + 0.5% formic acid. Mobile phase B: and (3) acetonitrile. Over 6.1 minutes, the gradient ran from 95%/5% to 2/98. The flow rate was 0.5 mL/min. MRM monitoring of test items and added analytical standards (multiple reaction monitoring).

Dosing and blood sampling:from the German Sutzfeld Chals river laboratory (Charl)es River Laboratories, Sulzfeld, Germany) provides Han Wistar rats. A12 hour artificial, self-controlled, light-dark cycle was maintained. Rats received a standard laboratory diet from Brogaarden corporation (Altromin 1324 pellet). Rats have received this diet without restriction. During the study period (4-week toxicity study), rats received oral dosing of (Ia) once daily by gavage. From rats given 300 μ g/kg (ia), on day 29 after dosing: blood samples from 3 male satellites were collected at the following time points of 0.5, 1,2, 4, 6, 8, 12 and 24 hours.

Instrumentation for the analysis of compound (I) from the administration of compound (Ib):

mass spectrometer (LC-MS/MS) was obtained from Acquity-Sciex API 5000, Watcht corporation. BEH UPLC Phenyl 100X 2.1mm column from column Watts corporation, 1.7 μm particle size. Mobile phase A: 20mM ammonium formate (aq) + 0.5% formic acid. Mobile phase B: and (3) acetonitrile. Over 6.1 minutes, the gradient ran from 95%/5% to 2/98. The flow rate was 0.5 mL/min. MRM monitoring of test items and added analytical standards.

Dosing and blood sampling:han Wistar rats were provided by Charles River Laboratories, UK. A12 hour artificial, self-controlled, light-dark cycle was maintained. Rats received a standard laboratory diet (Teklad 2014C diet). Rats have received this diet without restriction. During the study period (26 week toxicity study), rats received (Ib) orally once daily by gavage. From rats given 300 μ g/kg (ib), on day 182 post-dose: blood samples from 3 male satellites were collected at the following time points of 0.5, 1,2, 4, 8 and 24 hours.

Instrument set for analysis of compound (I) from administration of compound (Ic), compound (1), compound (2), and compound (3)

Mass spectrometer (LC-MS/MS) was acquired by Vortex, Acquity-Vortex, Xevo TQ-S. Analytical column Acquity BEH C18100 x 2.1.1 mm, 1.7 μm. Mobile phase A: 20mM NH₄Formate + 0.2% formic acid. Mobile phase B: acetonitrile + 0.2% formic acid. The gradient was run from 95%/5% to 5%/95% over 11.0 minutes. The flow rate was 0.3 mL/min. MeasuringMRM monitoring of test items and added analytical standards.

Dosing and blood sampling:han Wistar rats are provided by Envigo, UK. A12 hour artificial, self-controlled, light-dark cycle was maintained. Rats received a standard laboratory diet Teklad 2014C. Rats have received this diet without restriction. Male Han Wistar rats were dosed with a single oral gavage administration of the test compound, orally by gavage. Rats were dosed with 494. mu.g/kg of compound (ic), 0.505mg/kg of compound (1), 0.505mg/kg of compound (2) and 0.430mg/kg of compound (3). On day 1 post-dose: 1. blood samples from 3 males were collected at the following time points of 2,4, 6, 8 and 24 hours.

TABLE 4 according to example 3 after mixing 0.300mg/kg of (Ia), 0.300mg/kg of (Ib), 494. mu.g/kg of (ic), 0.505. mu.g/kg of (ic) The mg/kg of Compound (1), 0.505mg/kg of Compound (2) and 0.430mg/kg of Compound (3) were orally administered to Wistar rats Then (4aR,10aR) -1-propyl-1, 2,3,4,4a,5,10,10 a-octahydro-benzo [ g ]]Quinoline-6, 7-diol (Compound (I)) PK parameters of (a).

Example 4: competitive binding studies

The following assay as described in WO 06014429 was used to determine the binding affinity of the amino acid or peptide carbamate derivatives of the invention to hPEPT 1:

the Ki values of amino acid or peptide-carbamate derivative compounds (1) - (6) can be determined in a hPEPT1 overexpressing cell line (DC5) using 3H glycine-sarcosine (Gly-Sar). DC5 cells were seeded (12,000 cells/well) in 96-well tissue culture plates (Falcon corporation) and allowed to grow for 4 days. Cells were washed once with 200 μ l of aspiration buffer and aspirated. The plate was cooled to 4 ℃ and 25. mu.L of the draw buffer containing 50. mu.M Gly-Sar (0.5. mu. Ci/ml) was added. The draw buffer also contains a range of concentrations of the test compound. The pipetting was started by placing the plate in a shaker water bath (37 ℃) and stopped at 10 minutes by rapid washing with multiple changes of 4 ℃ PBS (Sigma). Radioactive peptides were extracted from the cell layer using 200. mu.l methanol: water (1:1) and counted in 4mL Cytosint ESTM scintillation cocktail (ICN). Nonlinear regression analysis of the data was used to determine IC50 using the solving function in Microsoft Excel.