UA79024C2 - Morpholine derivatives as dopamine agonists for treating sexual dysfunction - Google Patents

Abstract

The present invention provides for compounds of formula (I), (la) and (Ib) Wherein: A is selected from C-X and N, B is selected from C-Y and N, R1 is selected from H and (C1-C6)alkyl, R2 selected from H and (C1-C6)alkyl, X is selected from H, HO, C(O)NH2, NH2 Y is selected from H, HO, NH2, Br, Cl and F Z is selected from H, HO, F, CONH2 and CN; And pharmaceutically acceptable salts, solvates and prodrugs thereof; With the provisos that: for a compound of formula (I), (la) or (lb), when A is C-X, B is C-Y, at least one of X, Y and Z must be OH; for a compound of formula (I), when A is C-X and B is C-Y, Y is H, Z is H, R1 is H and R2 is H, then X cannot be OH; these compounds are useful as dopamine agonists for the treatment of i.a. sexual dysfunction. , (I) , (Ia) , (Ib)

Description

Description of the invention

The present invention relates to the class of dopamine agonists, more specifically, to the class of agonists that are selective for 2 rg2ios. These compounds can also be used to treat and/or prevent sexual dysfunction, such as female sexual dysfunction (FED), in particular, female sexual dysfunction in the form of sexual arousal disorder (SAD) and male sexual dysfunction, in particular, erectile dysfunction in men (MEOV). Sexual dysfunction, as used herein, in men refers to ejaculatory disorders such as premature ejaculation, anorgasmia (inability to reach orgasm), or sexual desire disorders such as hypoactive sexual desire disorder (HSD; lack of interest in sex). ). These compounds can also be used in the treatment of neuropsychiatric disorders and neurodegenerative disorders.

This invention provides compounds of formulas (I), (Ia) and (IB) and te

Cr

V. (Z

IN! . in the 2nd year of high school M know (6,

В и не о у « gl zo 2 (Iv) 0 s de

A selected from C-X and M, (ав)

V selected from SU and M, Fu

B" selected from H and (C.-Cv) alkyl, 3o B? selected from H and (C.-Cv) alkyl, in

X is selected from H, HO, С(О)МН», МН»

U selected from H, HO, MH", Vg, SI E 7 selected from H, HO, ER, SOMN" and CM; " and their pharmaceutically acceptable salts, solvates and prodrugs; From 70, provided that c is for compound (I), (Ia) or (IB), when A is C-X, B is C-Y, B! is H or (C4-C8)alkyl :z" and KE? is H or (C-C)alkyl, at least one of X, Y and 7 must be OH; for the compound of formula (I), when A is C-X and B is C-Y, U is H, Y is H, B!

IS H and B? is H, then X cannot be OH. -I Pharmaceutically acceptable salts of compounds of formula (I) include their acid addition salts and basic salts.

Pharmaceutically acceptable salts of compounds of formula (I) can be readily obtained by mixing together solutions of a compound of formula (I) and, if necessary, the desired acid or base. The salt can be precipitated out of solution and collected by filtration or can be extracted by evaporation of the solvent.

Suitable acid addition salts are formed from acids that form non-toxic salts, and examples are: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrophosphate, acetate, maleate,

T» fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, paratoluenesulfonate and pamoate.

Suitable basic salts are formed from bases that form non-toxic salts, and examples are sodium, 5B potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts.

An overview of the corresponding salts can be found in the publication (Vegde ei ai, 9. Rpagt. Zsi., 66, 1-19, 19771. (F) Pharmaceutically acceptable solvates of compounds of formula (I) include their hydrates. of formula (I) according to the invention, their polymorphs are also included.

The compound of formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more 60 stereoisomeric forms.

Isolation of diastereoisomers can be achieved by conventional techniques, for example fractional crystallization, chromatography or HPLC of a stereoisomeric mixture of a compound of formula (I) or its corresponding salt or derivative. The individual enantiomer of a compound of formula (I) can be obtained from the corresponding optically pure intermediate either by separation, such as by HPLC, of the corresponding racemate using a suitable chiral support, or by fractional crystallization of the diastereoisomeric salts formed by the reaction of the corresponding racemate with the corresponding optically active acid or base , depending on feasibility.

Preferred compounds according to the invention are compounds of formula (Ia) and (IB).

Compounds of formula (Ia) are particularly preferred.

Preferably, if A represents C-X, and B represents C-Y.

It is preferable if A represents M, and B represents C-Y.

It is preferable when A represents C-X, and B represents C-Y.

It is preferable that VC is selected from H and (C.-C.) alkyl.

It is preferable when EV! is H, methyl and ethyl.

Even more preferably, when B" represents H or methyl.

Most preferably, when EK! is N.

Preferably, EC is selected from H and (C.4-Ca) alkyl.

Preferably when 2? selected from H, methyl and ethyl.

Most preferably, KE is selected from H and methyl.

In a particularly preferred embodiment of VC? is N.

In another preferred embodiment, 2 is methyl.

Preferably, if X is selected from H, OH and MH".

Most preferably, X is selected from H and OH.

In a particularly preferred embodiment, X is H.

In another particularly preferred embodiment, X is OH.

Preferably, if U is selected from H, MN", SI and R.

Most preferably, if U is selected from H and MH".

In a particularly preferred embodiment, U is H.

In another particularly preferred embodiment, U is MH. Ha

Preferably, if 7 is selected from H, HO and B.

Most preferably, 7 is selected from H or HO. i9)

In a particularly preferred embodiment, 7 is H.

In another particularly preferred embodiment, 7 is HO.

Particularly preferred are the compounds (and their salts) according to the invention illustrated in this description; more "fF with the predominant ones are

K-(-)-3-(4-propylmorpholin-2-yl) phenol (Example 7A) c

C-(-)-3-(4-propylmorpholin-2-yl) phenol (Example 7B) av! K-(-)-3-(4-propylmorpholin-2-yl)phenol hydrochloride (Example 8)

Kk-5-(4-propylmorpholin-2-yl)benzene-1,3-diol (Example 15A) o 5-5-(4-propylmorpholin-2-yl)benzene-1,3-diol (Example 158) -

K-()-2-fluoro-5-(4-propylmorpholine-2-yl)phenol (Example 2ZA)

C-(-)-2-fluoro-5-(4-propylmorpholin-2-yl)phenol (Example 238) 2-bromo-4-(4-propylmorpholin-2-yl)phenol (Example 30) « 2-hydroxy-5 -(4-propylmorpholin-2-yl)benzamide (Example 35) 2-nitro-4-(4-propylmorpholin-2-yl)phenol (Example 36) - with 2-amino-4-(4-propylmorpholin-2- yl)phenol (Example 37) c 5-(4-propylmorpholin-2-yl)pyridin-2-ylamine (Examples 44A and 448) "» 2-chloro-5-(4-propylmorpholin-2-yl)uphenol (Example 54) 3-(55)-5-methyl-4-propylmorpholin-2-ylrenol (Example 60) 5-K25,55)-5-methyl-4-propylmorpholin-2-yl|Ipyridin-2-amine (Example 66 ) -I 5-K2K,55)-5-methyl-4-propylmorpholin-2-yl|Ipyridin-2-amine (Example 67)

The most preferred ones are K-(-)-3-(4-propylmorpholin-2-yl)uphenol (Example 7A) av! C-(-)-3-(4-propylmorpholin-2-yl)phenol (Example 7B) K-(-)-3-(4-propylmorpholin-2-yl)phenol hydrochloride (Example 8) di Kk-5- (4-propylmorpholin-2-yl)benzene-1,3-diol (Example 15A)

Chl» 5-5-(4-propylmorpholin-2-yl)benzene-1,3-diol (Example 158)

K-()-2-fluoro-5-(4-propylmorpholine-2-yl)phenol (Example 2ZA)

C-(-)-2-fluoro-5-(4-propylmorpholin-2-yl)phenol (Example 238) 5-(4-propylmorpholin-2-yl)pyridin-2-ylamine (Example 44A and 448) 2-chloro- 5-(4-propylmorpholin-2-yl)uphenol (Example 54)

Ф, 5-К25,55)-5-methyl-4-propylmorpholin-2-yl|Ipyridin-2-amine (Example 66) co 5-К2К,55)-5-methyl-4-propylmorpholin-2-yl| Ipyridine-2-amine (Example 67)

The compounds according to the invention can be obtained in a known manner in various ways. The paths described below illustrate methods of synthesis of the compound of formula (I); one of ordinary skill in the art will appreciate that compounds of formula (Ia) and (I) can be isolated using appropriate separation techniques.

Compounds of the general formula I, where A represents C-X, B represents C-Y, K 17 represents H or (C.-C)alkyl, B2 represents H, and where X, Y and 7 have the meaning that are determined in this description, can be obtained according to the reaction scheme 1. b5

She n i r (no) ha 70 |ch n 18 t

V. (PI ; I. in se

M o

Sho

FIsh « 2 m from. these (av)

Ge) ich-

Sh: and p a «

С - - and и з" |: -I (se) (ав) mu iz" (Ф) ko 60 65

IS! l-e

M ke or 2 ih t . uh

Mac le Main is not

In () p

Scheme 1 (o)

Compounds of the formula (II) can be obtained as a result of the reaction of the aldehyde of the formula I! with i) a source of cyanide or nitromethane followed by i) reduction with borane, lithium aluminum hydride or hydrogenation. Some compounds of formula II and NP are also commercially available. Compounds of formula (II) can be obtained as a result of the reaction of compounds of formula (III) with iii) with chlorides in the presence of a suitable base, such as triethylamine or 4-methylmorpholine. Typical conditions for the interaction of Ge include 1.0 equivalents of amine (I), 1.2-2.0 equivalents of a base (mainly triethylamine), 1.1-1.3 equivalents of hydrogen chloride in dichloromethane at 2596.

Compounds of formula (M) can be obtained by reducing compounds of formula (IM) with a reducing agent (o) with an agent such as borane or lithium aluminum hydride. Typical conditions include 1.0 equivalents of amide (IM), 1.2-3.0 M equivalents of borane in THF (tetrahydrofuran) under reflux. Compounds of formula (M) can also be obtained by reductive amination of compounds of formula (II) with the appropriate aldehyde in the presence of sodium cyanoborohydride.

Compounds of formula (MI) can be obtained by reacting compounds of formula M with M) chloroacetyl chloride or 20 2-substituted chloroacetyl chlorides (such as 2-chloropropionyl chloride or 2-chlorobutyryl chloride) in the presence of a base such as triethylamine, sodium carbonate, and potassium hydroxide . Typical conditions include 1.0 equivalents of IM amine, 1.0-1.3 equivalents of hydrogen chloride, 1.2-2.0 equivalents of triethylamine in dichloromethane at 2590, and the crude reaction mixture is then dissolved in IRA (isopropyl alcohol) with 1 2-3.0 equivalents of aqueous potassium hydroxide.

Compounds of formula (I) can be obtained as a result of the interaction of compounds of formula (MI) with mi) reducing -I agents, such as borane or lithium aluminum hydride. Typical conditions include 1.0 equivalents of MI amide, 1.2-3.0 equivalents of borane in THF under reflux. d) It will be clear to a person skilled in the art that due to the fact that one of X, M or 7 is a hydroxy group, it will be necessary to protect the hydroxy group(s) with an appropriate protecting group in the course of transformations according to scheme 1, then remove the protective group The methods of deprotection of the phenolic group depend on the protecting group. Examples of protection/unprotection methods | see in "Rgoiesiime dgoirv ip Ogdapis zupipeviv". TM

Their" Sgeepe apa ROM Mush). For example, when the hydroxy group is protected in the form of a simple methyl ether, the deprotection conditions include refluxing in 4895 aqueous HBr for 1-24 hours. or mixing with tribromoborane in trichloromethane for 1-24 hours. Alternatively, when the hydroxy group is protected in the form of a simple benzyl ether, the deprotection conditions include hydrogenation with a palladium catalyst under a hydrogen atmosphere. (F, Compounds of the general formula (I), where A or B represents M, BK' represents H or (C 41-Cv)alkyl, B represents H and X, Y and 7 have the values defined in this description, provided that one of X, Y or 7 represents

MH" can be obtained in accordance with reaction scheme 2. The scheme is illustrated for compounds where B is C-X and where U is MH 25; one of ordinary skill in the art will appreciate that alternative compounds can be used equally. b5

Y 7 in still Sun 2 M 70 | with and ex, nt

B and I Sm

In in! with o shk Ge)

M. H. Che In

Output - " pcs s ha "c) and -

I-Sh

AND

« m x te Neck o s m that "z y " - i ih) - ih se) o ih va 7 y

I" M i y. your:

And us? -

F) yuyu U (v

Scheme 2 60 Compounds of formula (MII) can be obtained using the method described in (P 2001048864).

Compounds of the formula (MI) can be obtained as a result of the reaction of epoxide (MI) with propylamine. Typical reaction conditions involve mixing the epoxide with an excess of amine either neat or in dimethylsulfoxide.

Compounds of formula (IX) can be obtained by reacting compounds of formula (MI) with M) chloroacetyl chloride or 2-substituted chloroacetyl chlorides (such as 2-chloropropionyl chloride or 2-chlorobutylyl chloride) in the presence of a base such as triethylamine, sodium carbonate and potassium hydroxide. Typical reaction conditions include 1.0 equivalents of amine (MI), 1.2-2.0 equivalents of triethylamine in dichloromethane at 259С, then the crude reaction mixture is dissolved in IRA with 1.2-3.0 equivalents of aqueous potassium hydroxide.

Compounds of formula (X) can be obtained by reacting compounds of formula (IX) with reducing agents such as lithium aluminum hydride. Typical reaction conditions include 1.0 equivalents of amide (X), 1.2 equivalents of lithium aluminum hydride in THF under reflux.

Compounds of formula (I) can be obtained by deprotection. Typical conditions include 1.0 equivalents of compound X and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

Compounds of the general formula I, where A represents C-X, B represents C-Y, K 1 1 represents H and B? represents H or (C.-C.)alkyl, and where X, M and 7 have the values defined in this description, can be obtained in accordance with the reaction scheme Z. d: o i -

I nok C) and - o - schu sch o |! you are) oh hi h sch vi y on Ge)

And, in the in the ap) and x - - - » ON n well

GI RIMI and "NS se) about | hi z 50 2» g dey y va

J

F) n i name) g (hu) 60 chemical b5

2 And more

Oh

M de o 7 F

Scheme Z

Compounds of the formula (XII) can be obtained as a result of the reaction of an amino acid ester (XI) with x) chlorides in the presence of a suitable base, such as triethylamine and 4-methylmorpholine. Typical conditions for 72 reactions include 1 equivalent of an amino acid ester (XI), 1 equivalent of hydrogen chloride and 3 equivalents of a base in dichloromethane at 252C. Some compounds of formula (XI) are commercially available.

Compounds of the formula (Xi) can be obtained as a result of the interaction of the compounds of the formula (Xi) with the borane-THF complex with subsequent destruction of the borane-nitrogen complex with acid and protection of the formed amine with tert-butyloxycarbonyl. Typical reaction conditions involve 1 equivalent of amide (XIII) with 3 equivalents of VNa-THF under reflux, cooling, careful addition of 6M aqueous NOS, and heating under reflux for another bh. Further evaporation of the solvent, re-dissolution in methanol:water (8:11) and addition of 5 equivalents of a base such as potassium hydroxide and 1.5 equivalents of di-tert-butyl dicarbonate and stirring of the mixture for 72h.

Compounds of the formula (XII) can be obtained as a result of the interaction of compounds of the formula (XIII) with xii) in an organic solution with

NOI, Typical interaction conditions include 1 equivalent of carbamate (XII) and 1-10 equivalents of a 4M solution of HCs (3 dioxane at 2596.

Compounds of the formula (XM) can be obtained by reacting the compounds of the formula (XM) with 2-bromoacetophenone in the presence of a base such as triethylamine or 4-methylmorpholine. The 2-bromoacetophenones can be obtained from commercial sources or, alternatively, can be obtained from the starting acetophenone by standard reservation methods well known to those skilled in the art. Typical conditions include 1 equivalent of si-aminoalcohol (CAM) with 1-3 equivalents of triethylamine and 1 equivalent of 2-bromoacetophenone at 6596.

Compounds of formula (I) can be obtained as a result of the interaction of compounds of formula (XM) with chem) triethylsilane and o trimethylsilyl triflate. Typical conditions involve the addition of 5-10 equivalents of triethylsilane to 1 (He) equivalent of morpholinol (XM) in dichloromethane at -782C, followed by the addition of 2 equivalents of trimethylsilyl triflate. uh-

One skilled in the art will appreciate that since one of X, M, or 7 is a hydroxy group, it will be necessary to protect the hydroxy group(s) with an appropriate protecting group during the transformations of Scheme 3, then remove the protecting group. Methods of deprotection of the phenolic group depend on the protecting group. Examples of protection/unprotection methods | see in "Rgoiesiime dgoirv ip Ogdapis zupipeviv". TM from

Sgeepe apa ROM Mush). For example, when the hydroxy group is protected in the form of a simple methyl ether, deprotection conditions include refluxing in 4895 aqueous HBr for 1-24 hours, or stirring with borane tribromide in trichloromethane for 1-24 hours. Alternatively, when the hydroxy group is protected in the form of a simple benzyl ether, the deprotection conditions include hydrogenation with a palladium catalyst under a hydrogen atmosphere. Compounds of the general formula (I), where the stereocenter alpha to the morpholine nitrogen is absolutely defined, can be obtained starting from homochiral compounds of the formula (XI), which may be commercially available or be se) prepared by methods readily available to a person skilled in the art from chemical literature. The resulting compounds of formula (I) will contain a mixture of diastereoisomers that can be isolated on an HPLC column. Typical conditions involve elution through a SpigaYse column! 0.)-H with a mobile phase of 10095 MeOnH. име) Compounds of the general formula (I), where one of A or B is M, B! represents H, B represents H or

Their" (C.-C.)alkyl, and X, Y, and 7 have the values described above, provided that one of X, Y, and 7 is MH 5, can be obtained in accordance with reaction scheme 4. The scheme is illustrated for compounds, where B is C-U, and where U is MH 25; one of ordinary skill in the art will appreciate that alternative compounds can be used equally.

F) name) 60 b5 nos che

VI ng H in (XM) and (KHIM) in that would be a cube, S h. ; m" and w- 2 (SS) | OILS) ka sch

And oh I ". x dl s n Kk o yk g and also E bos) v. " I - s z" wa sh 45 ii She om, and he av | Won I (XX) from the 50th" | their

F) t bo 65 z

And She about him

In ii no (xx

And fuck 15. you and

V. I with us () (o)

her

Scheme 4

Compounds of the formula (KHMIII) can be obtained as a result of the interaction of compounds of the formula (KHMI) with xu) amino alcohols ch«E of the formula (KHIM) in the presence of a base such as triethylamine or 4-methylmorpholine. Typical conditions involve 1 equivalent of an amino alcohol (AM) with 1-3 equivalents of triethylamine and 1 equivalent of a compound of the formula (CMI) with cm using toluene as a solvent at room temperature or above. Compounds of the formula (HMI) are commercially (a) available.

Compounds of the formula (XIX) can be obtained as a result of the interaction of the compounds of the formula (KHMIII) with chmi) organometallic Ф reagent formed from the bromide of the formula (KHMIII). Suitable organometallic reagents include reagents

Grignard (organomagnesium compound) or organolithium compounds that can be obtained from . bromide by metal halide exchange. Typical conditions involve the addition of isopropylmagnesium chloride to bromide (HMIII) in an anhydrous ethereal solvent such as tetrahydrofuran at room temperature (for a metal halide exchange reaction), followed by the addition of morpholinone (HMIII). Bromide (CHM) can be obtained using the method described in (MU09932475)I. - c Morpholinol (XIX) can be reduced to diol (XX) by reacting it with a hydride reducing agent such as sodium borohydride in an alcoholic solvent such as methanol. "» Compounds of formula (XXI) can be obtained from diol (XX) by deprotection. Typical conditions involve 1.0 equivalents of compound (XX) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux. -i Compounds of formula (I) can be obtained by chemical) cyclization of compounds of formula (XXI) under acid treatment. c Typical conditions include concentrated sulfuric acid and dichloromethane as a solvent at room temperature or above. ((c) All of the above interactions and methods of obtaining new initial substances used in t 50 previous methods, reagents and conditions of interaction are conventional and appropriate for their function or preparation, as well as the methods of isolation of the desired products are well known to specialists in this field, with reference to literary sources,

I" as well as examples and methods of obtaining presented in this description.

The compounds according to the invention are used as selective agonists of OZ for the treatment of pathological conditions.

There are a number of compounds with both agonist activity, 02 and 03; however, the use of such compounds is associated with a large number of side effects, including nausea, vomiting, syncope, hypotension, and bradycardia, some of which are of serious concern. o Previously, it was believed that the effectiveness of compounds of the prior art was related to their ability to exert an agonistic effect on 02; however, B2-agonism is believed to be the cause of the side effects listed above.

This invention is related to the class of selective OZ-agonists. Unexpectedly, they were found to be effective 60 while reducing the side effects associated with non-selective compounds of the prior art.

Compounds according to the invention can be used in the treatment of sexual dysfunction, sexual dysfunction in women, including hypoactive sexual desire disorder, sexual arousal disorder, orgasm disorder and sexual pain disorder; erectile dysfunction in men, hypertension, neurodegeneration, 65 psychiatric disorders, depression (eg, depression in cancer patients, depression in patients with

Parkinson's disease, post-myocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, depression in children, major depression, depression in the form of single episodes, recurrent depression, depression caused by child abuse, postpartum depression and irritability syndrome in the elderly). disorder in the form of generalized anxiety, phobias (for example, agoraphobia, social phobia and senile phobias), post-traumatic stress syndrome, personality disorder in the form of avoidance, premature ejaculation, eating disorders (for example, anorexia nervosa and bulimia nervosa), obesity, chemical addiction substance (eg, addiction to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), "histamine" headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (eg, dementia , amnestic/o disorders and age-related decline in cognitive function (ACSO)), min Parkinson's disease (eg, dementia in Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesia), endocrine disorders (eg, hyperprolactinemia), vasospasm (especially cerebral vasculature), cerebellar ataxia, gastrointestinal disorders (including motility changes and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, Tourette's syndrome, 7/5 trichotillomania, kleptomania, impotence in men, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (relative associated with vascular disorders), emotional lability, pathological crying, sleep disorder (cataplexy) and shock.

The compounds according to the invention are particularly suitable for the treatment of sexual dysfunction in women, erectile dysfunction in men, neurodegeneration, depression and psychiatric disorders.

Compounds according to the invention can be used for sexual dysfunction in men, especially for erectile dysfunction in men. Male sexual dysfunction (MES), otherwise known as erectile dysfunction in men, is defined as "the inability to achieve an erection of the penis and/or maintain it for satisfactory sexual function" (MIN Sopzepziz Rapei! op Itroiepse, 1993).

According to estimates, the prevalence of erectile dysfunction (ED) of all degrees (minimal, moderate, and complete impotence) is 5,295 in men aged 40-70 years, with higher frequencies in people over 70 years old. 1999, in). Ogoiodu, 161, p.5-11). This condition has a significant negative impact on the quality of life of i) the individual and his partner, often leading to increased anxiety and tension, leading to depression and low self-esteem. Although 2 decades ago MEO was considered primarily a psychological disorder (|Vepei ei ai 1994 Sotr. TNeg., 20: 669-673), at this time it is known that in most individuals there is an organic cause that lies at the root of this phenomenon. As a result, great progress was made in identifying the mechanism of normal penile erection and the pathophysiological mechanisms of MEO. with

Erection of the penis is a hemodynamic phenomenon that depends on the balance of contraction and relaxation of the smooth muscles of the cavernous bodies and the vascular network of the penis (| eteg eyi a! 1993, 3.

Ogoiodu, 149, 1255-1256). The smooth muscle of the corpora cavernosa is also referred to in this description as the smooth muscle of the body or in the plural of the corpora cavernosa. Relaxation of the smooth muscles of the cavernous bodies leads to increased blood flow in the trabecular spaces of the cavernous body, causing their expansion to the surrounding membrane, and squeezing the draining veins. This causes a large increase in blood pressure, which leads to an erection (Mauiog, 1998, U. Ogoiodu, 81, 424-431).

The changes that occur during the erection process are complex and require a high degree of coordinated "regulation involving the peripheral and central nervous systems and the endocrine system (Mauog, 1998, U. z s Ogoiodu, 81, 424-431. Contraction of the smooth muscles of the cavernous bodies is modulated by sympathetic noradrenergic innervation through the activation of postsynaptic o.-adrenoceptors. MEO can be "related to an increase in the endogenous tone of the smooth muscles of the corpus cavernosum. However, the process of relaxation of the smooth muscles of the corpus cavernosum is partially mediated by non-adrenergic, non-cholinergic (MAMO) neurotransmission .There are a number of other penile MAMS neurotransmitters other than MO, such as calcitonin gene-related peptide (GLP) and vasoactive intestinal peptide (VIP).The primary relaxant responsible for mediating this relaxation , is nitric oxide (NO), which is synthesized from I-arginine by nitric oxide synthase (MO5) 3 OgoiIodu, 42, 698-704). It is believed that reducing the tone of the smooth muscles of the corpora cavernosa can contribute to MO in the induction of relaxation of the corpora cavernosa.

During sexual arousal in men, MO is released from neurons and endothelium and binds to soluble de guanylate cyclase (505) and activates it in smooth muscle cells and endothelium, leading to elevated levels

Ta» of intracellular cyclic guanosine-3,5'-monophosphate (cCOMP). This rise in cOMR leads to relaxation of the corpus cavernosum due to a decrease in intracellular calcium (Ca 2 "), through unknown mechanisms believed to include activation of protein kinase (c (probably due to activation of Ca? and Ca?-activated pumps K"-channels). o Within the central nervous system, multiple potential sites for the modulation of sexual behavior have been identified. It is believed that the key neurotransmitters are serotonin, norepinephrine, oxytocin, nitric oxide, and dopamine. By imitating the actions of one of these neurotransmitters, sexual behavior can be regulated function

Dopamine OZ receptors are expressed almost exclusively in the limbic zone of the brain, in areas involved in motivation, emotional and cognitive processes.

Regardless of any theory, it appears that "due to its role in the regulation of motor activity, the unity of the nigrostriatal dopaminergic pathway is also essential for the expression of mating behavior. In some way, more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus and possibly at 65 the erectile sacral parasympathetic nucleus within the spinal cord At this time it appears that the significant area is the OZ, not 02 as previously thought.

In essence, OZ is the initiator of sexual behavior.

Accordingly, this invention provides for the use of a compound of formula (I) in the manufacture of a medicinal product for the treatment or prevention of erectile dysfunction.

Patients with mild to moderate MEO should benefit from the compounds of this invention, and patients with severe MEO may also respond to treatment. However, early studies indicate that the frequency of patient response to treatment is mild, moderate, and severe

MEO can increase under the influence of a combination of a selective agonist of JOHZ/POE5 inhibitor. Mild, moderate, and severe MEO are terms known to those of ordinary skill in the art, but guidance can be found in Ref. 7/0. Oi Ogoiodu, my. 151, 54-61 (suppl 1994)).

Early studies suggest that a selective BH agonist and a POE5 inhibitor (or other combinations presented below in this description) may benefit the following groups of patients with MEO. To this group of patients, described in detail in Siipisai Apagoiodu moiY.23, po.4 r.773-782 and chapter C of book I.

Eagaieu apa K. beiyia "EgesShe Ouvgiipsiop-Sygtepi Ipmesiidayop apa Mapadetepi", publishing house Mozbu-Uoige|, 7/5 Patients with psychogenic, organic, vascular, endocrine, neurogenic, arteriogenic, drug-induced (iatrogenic) sexual dysfunction and sexual dysfunction are included , associated with cavernous factors, in particular, venogenic causes.

Accordingly, the present invention provides for the use of a compound of formula (I), (Ia) or (IB) in the manufacture of a medicinal product in combination with a POE5 inhibitor for the treatment of erectile dysfunction.

Suitable POE5 inhibitors are described herein.

The compounds according to the invention can be used in the treatment or prevention of sexual dysfunction in women (E5O), in particular, EZAU.

According to the invention, ESO can be defined as a complication or inability of a woman to achieve sexual satisfaction. E5O is a collective term for several different sexual disorders Eirisht, 5.K. sch (1998)-YUOeipyiop apa siazziisayop oi Tetaye zehtsua| isogahege pb at 9. Itroiepse Kev., 10, 5104-5106;

Veptap, .K., Veptap, HER. 55 Soidvieiip, I. (1999)-Retae zehtsa! auviipsiop: Ipsidepse, raiyorpuzioiodu, i) emaItsaiopz apa igeaiytepi oriiope. Ogoiodu, 54, 385-391). A woman may have a lack of desire, difficulties in achieving arousal or orgasm, pain during intercourse, or a combination of these problems. Several types of diseases, types of drug treatment, injuries or psychological problems can cause E5O. Treatment methods for the development of the disorder are aimed at the treatment of certain subtypes of E5O, mainly disorders of desire and excitement. with

EBO categories are best determined by comparing them with the phases of the normal sexual reaction of women: desire, arousal and orgasm (eibisht, 5.K. (1998)-YuOeityop apa siazziysayop oi Teta|e zehtsai! dizogdege. pf 9. Itroiepse Kev., 10, 5104-5106). Desire or desire is an urge to me) c5 sexual expression. Its manifestations often include sexual thoughts either in the presence of an interested partner in the company or under the influence of other erotic stimuli. Arousal is a vascular response to sexual stimulation, and an important component is genital hyperemia, and it includes increased vaginal lubrication, vaginal lengthening, and increased genital sensation/sensitivity. Orgasm is the release of sexual tension that culminated during arousal. "

Therefore, E5O occurs when a woman has an inadequate or unsatisfactory response in any of these phases, with usually desire, arousal, or orgasm. E2EEO categories include sexual desire disorder,

And sexual arousal disorders, orgasm disorders and sexual pain disorders. Although the compounds according to the invention are improve genital response to sexual stimulation (as in female sexual arousal disorder), while they may also relieve associated pain, dysfunction, and discomfort associated with intercourse and thus treat other sexual disorders in women -I A hypoactive sexual desire disorder occurs when a woman has little or no desire to be sexual, and she has few or no sexual thoughts or fantasies. This type of E5O ik can be caused by low testosterone levels due to either natural menopause or surgical menopause. Other causes include illness, types of drug therapy, fatigue, depression, and anxiety. Sexual dysfunction in women in the form of sexual arousal disorder (SAD) is characterized by an inadequate response of the genitals to sexual stimulation. Genital organs do not undergo hyperemia, which characterizes normal sexual arousal. The walls of the vagina are poorly lubricated, and therefore sexual intercourse is painful. Orgasms can be suppressed. Arousal disorder can be caused by a reduced level of estrogen during menopause or after childbirth and during lactation, as well as diseases with a vascular component, such as diabetes and atherosclerosis. Other causes arise as a result of treatment with diuretics, (F), antihistamines, antidepressants, for example, selective serotonin reuptake inhibitors (SSRIs) or hypotensive agents.

Sexual pain disorders (including dyspareunia and vaginismus) are characterized by pain due to the penetration of the penis into the vagina, and it can be caused by types of drug therapy that reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease, or urinary tract pathology.

As discussed earlier, it is believed that OZ is the initiator of sexual behavior. The clitoris is considered a homologue of the penis (I emip, K.). (1991), Ehr. SNp. Epdosthipoi., 98, 61-69); the same mechanism that provides an 65 erectile response in men causes an increase in blood flow in the genital organs in women with a related effect on E5O. In addition, there are changes in proceptivity and receptivity.

Thus, according to a preferred aspect of the invention, it is proposed to use a compound of formula (I), (Ia) or (Iv) in the manufacture of a medicinal product for the treatment or prevention of sexual dysfunction in women, more specifically, a disorder in the form of hypoactive sexual desire, a disorder of sexual arousal, Orgasm disorder and sexual pain disorder.

Preferably, the compounds of formula (I) can be used in the treatment or prevention of sexual arousal disorder, orgasm disorder and disorder in the form of hypoactive sexual desire, and most preferably, in the treatment or prevention of sexual arousal disorder.

In a preferred embodiment, compounds of formula (I), (Ia) or (IB) can be used in the treatment of 7/0. Women with a disorder of sexual arousal and a concomitant disorder in the form of hypoactive sexual desire.

In the manual (Te Oiadpoviis apa iaiziisai Mapian! (OM) IM oi (she Ategisap Rvzuspiaiis Avzosiaiop" sexual dysfunction in women in the form of sexual arousal disorder (SAD) is defined as ".. a persistent or recurrent inability to acquire or maintain an adequate response to sexual arousal in the form of lubricants-swelling before the completion of sexual activity. The disorder must cause 7/5 marked dysfunction or complications in interpersonal communication...".

The arousal reaction consists of filling the vessels of the pelvic cavity, lubrication of the vagina, and an increase in the volume and swelling of the external genitalia. This disorder causes marked dysfunction or complications in interpersonal communication.

EBZA is a very common sexual disorder that affects women before, during and after menopause (with and without hormone replacement therapy (HRT)). It is associated with comorbid disorders such as depression, cardiovascular disease, diabetes mellitus, and genitourinary (00) disorders.

The primary consequences of EZAO are the absence of hyperemia/swelling, the absence of lubrication, and the absence of a pleasant sensation on the part of the genitals. Secondary consequences of EZAUO are reduced sexual desire, pain during sexual intercourse and difficulties in achieving orgasm. with

Recently, it has been hypothesized that there is a vascular basis in at least a proportion of symptomatic patients

EZAO (Soyazievip ei ai., Iii. 9. Itroi. Kev., 10, 584-590, 1998), and experimental data confirm (8) this point of view G(Ragk ei ai., Ipii. 9. Itroi. Kez, 9, 27-37, 1997).

KK... Hemip reports that due to the fact that "... male and female genital organs develop embryologically from a common tissue embryo, there are discussions about the fact that the structures of male and female genital organs are homologous each other. Thus, the clitoris is the homologue of the penis, and the labia are the homologues of the scrotal sac..." (emip, K.U. (1991), Ehr. Siip. Epadosthipoi, 98, 61-69). with

Prospective drugs for the treatment of EZAO, which are being studied for effectiveness, are primarily erectile dysfunction drugs that stimulate blood supply to the male genital organs. Me

The compounds according to the invention have the advantage of providing a means for restoring the normal response to sexual arousal, namely, increased blood flow in the genitals, which leads to hyperemia of the clitoris and labia. This leads to increased lubrication of the vagina due to transudation of plasma, increasing distensibility of the vagina and increased sensitivity of the genitals. Therefore, the present invention provides a means for restoring or enhancing the normal response of sexual arousal. "

Thus, according to a preferred aspect of the invention, it is proposed to use a compound of formula (I), with (Ia) or (IB) in the manufacture of a medicinal product for the treatment or prevention of sexual arousal disorder in women. ;" The female genital organs in this description correspond to the following definition: "The genital organs consist of an internal and an external group. The internal organs are located inside the pelvis and consist of the ovaries, fallopian tubes, uterus and vagina. The external organs are located superficially relative to the genitourinary diaphragm and under the -I pelvic arch . They include the pubic eminence, labia majora and labia minora, clitoris, vestibule, vestibular bulb and vestibular glands" |Sgau'v Apayotu, SO. Sietepie, 13 7 Ategisap ish Ediiyopi. aw! The compounds according to the invention are used in the following subpopulations of patients with EBO: young, elderly women, women before menopause, during menopause, after menopause, women receiving hormone replacement therapy and without it.

Chl» Compounds according to the invention are used in patients with E5O, which occurs as a result of vascular etiologies, for example, cardiovascular or atherosclerotic diseases, hypercholesterolemia, smoking, diabetes, hypertension, radiation and injuries of the perineum, traumatic damage to the subiliac-hypoabdominal genital vascular system. i) Neurogenic etiologies, such as spinal cord injuries or diseases of the central nervous system,

F, including multiple sclerosis, diabetes, parkinsonism, cerebrovascular events, peripheral neuropathies, trauma or radical operations on the pelvic organs. Her) Hormonal/(endocrine etiologies, such as dysfunction of the hypothalamic-pituitary-gonadal axis, or ovarian dysfunction, pancreatic dysfunction, surgical or medical castration, androgen deficiency, high levels of prolactin in the circulating blood, for example, hyperprolactinemia, natural menopause, premature ovarian failure, hyper- and hypothyroidism. them) Psychogenic etiologies such as depression, obsessive-compulsive disorder, anxiety disorder, postpartum depression/anxiety after the birth of a baby", emotional problems and problems related to 65 Interpersonal relationships, anxiety related to sexual function, family disorders, dysfunctional relationships, sexual phobias, religious suppression, or traumatic past experiences.

M) Sexual dysfunction caused by drugs, as a result of treatment with selective serotonin reuptake inhibitors (SSRIs) and other means for the treatment of depression (tricyclic drugs and major tranquilizers), means for the treatment of hypertension, sympatholytic drugs, chronic therapy with oral contraceptives.

The compounds of the invention can also be used in the treatment of depression.

Dopamine VZ receptors are expressed almost exclusively in the limbic zone of the brain, areas involved in motivation, emotional and cognitive processes. Chronic treatment with several classes of antidepressants is known to increase OZ expression in the limbic area, and the antidepressant effects of desipramine can be blocked by 7/0 bulpride (a 02/03 antagonist) when injected into the nucleus accumbens (an OZ-rich area) but not the caudate nucleus - cobweb (a zone rich in dopamine O2 receptors). In addition, antidepressant effects were observed in preclinical models of depression and in patients treated with pramipexole, an agonist that prefers JOH receptors. Available information indicates that OZ-receptors mediate antidepressant activity, and that selective agonists of YZ-receptors represent a new class of /5 antidepressant drugs. Since antidepressants are known to be effective in other psychiatric disorders, SSRI agonists could be used to treat psychiatric disorders.

This invention refers to the use of a selective US agonist in the manufacture of a medicinal product for the treatment of depression and psychiatric diseases.

Preferably, if the indicated OZ-agonist shows functional activity on the ХОЗ-receptor, which is expressed as ЕС5О lower than 1000OnNM, more preferably - lower than T00NM, even more preferably - lower than 5ОНМ, most preferably - lower than 1OnNM.

Preferably, if said OZ agonist has selectivity for OZ, compared to 02, where said agonist is a dopamine SZ agonist at least about 15-fold, preferably at least about 27-fold, more preferably at least about 30-fold, most preferably at least approximately 100 times more functionally selective in relation to the dopamine OZ-receptor, compared to the dopamine p2-receptor. and)

Relevant conditions include depression (eg depression in cancer patients, depression in illness

Parkinson's disease, post-myocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, depression in children, major depression, single-episode depression, recurrent depression, child abuse-induced depression, postpartum depression, and irritability syndrome in the elderly people), generalized anxiety disorder, phobias (eg, agoraphobia, social phobia, and senile phobias), post-traumatic stress disorder, avoidant personality disorder, eating disorder (eg, anorexia nervosa and bulimia nervosa), obesity, addiction from chemicals (eg, alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepine addiction), me) Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (eg, dementia, amnestic disorders and age-related decline in cognitive function (ADC)), Parkinson's disease (for example, dementia in Parkinson's disease, parkinsonism, in induced by antipsychotics, and tardive dyskinesias), endocrine disorders (eg, hyperprolactinemia), vasospasm (especially cerebral vessels), cerebellar ataxia, negative symptoms of schizophrenia, stress urinary incontinence, Tourette's syndrome, trichotillomania, "Kleptomania, attention deficit hyperactivity disorder (ASNO), chronic paroxysmal hemicrania, emotional lability, pathological crying, sleep disorders (catalepsy) and shock. . In a preferred embodiment, the present invention is intended for the use of compounds of formula (I), (Ia) and i? (IB) in the manufacture of a medicinal product for the treatment of depression or psychiatric disorders.

Corresponding depressive states and psychiatric disorders are described above.

Compounds according to the invention can also be used in the treatment of neurodegenerative processes; -And the sources of neurodegenerative processes include poisoning with neurotoxins; vision loss caused by neurodegeneration of the visual pathway, for example, a stroke in the visual pathway, for example, in the retina, optic nerve and/or occipital lobe; epileptic attacks; and as a result of disruption of the supply of glucose and/or oxygen to the brain.

Accordingly, this invention envisages the use of a selective UZ agonist in the manufacture of a medicinal product for the treatment of neurodegeneration. і» Predominantly specified OZ-agonist shows functional activity on the OZ-receptor, which manifests itself in the form of

ES5BO is lower than 1000 nm, preferably lower than 100 nm, even more preferably lower than 5 nm, most preferably lower than 1 nm.

Preferably, said OZ agonist has selectivity for OZ, compared to 02, where said agonist is a dopamine S3 agonist of at least about 15-fold, preferably at least about 27-fold,

F) more preferably at least approximately 30 times, most preferably at least approximately 100 times more functionally more selective in relation to the dopamine JOHZ-receptor, in comparison with the dopamine p2-receptor. In a preferred embodiment, the SSRI agonist is a compound of formula (I), (Ia) or (IB).

In addition to their role in the treatment of sexual dysfunction, depression, neurodegeneration and psychiatric disorders, the compounds of the invention are likely to have a number of additional indications.

Accordingly, the present invention provides the use of compounds of formula (I), (Ia) or (IV) in the manufacture of a medicinal product for the treatment of hypertension, premature ejaculation, obesity, "histamine" headache, migraine, 65 pain, endocrine disorders (for example, hyperprolactinemia) , vascular spasm (in particular, cerebral vessels), cerebellar ataxia, disorders of the gastrointestinal tract (including changes in motility and secretion),

premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, trichotillomania, kleptomania and chronic paroxysmal hemicrania, headache (associated with vascular disorders).

Analysis of the binding of YuZ/O02-agonists

Sopagae her! (Eshig. In Rpaptasyodu 272 (1995) K1-KZ)| described an analysis method for determining the ability of a compound to bind to OZ and/or ХО2-dopamine receptors and, thus, the selectivity of binding of such compounds. Thus, this analysis is referred to herein as a binding analysis.

Functional analysis of YZ3/02 agonists

The relevant analysis for the functional determination of the activity of the compound on OZ and/or О02-dopamine/o receptors is described in detail below.

Compounds are evaluated as agonists or antagonists at dopamine 02 and 03 receptors by studying the levels of CAMP (CAMP) in ZNASI and CHO cell lines expressing, respectively, human 02 and OZ receptors.

Experimental methods

Inhibition of the activity of adenylate cyclase stimulated by 7/5 forskolin with the help of dopamine receptors

Materials

Media for cell cultures:

Environment pPOZSNO

OMEM, high glucose content (Zidta 05671) 2MM I -glutamine (Bidta 57513) 1095 dialyzed EV5 (Zidta GO392)

NazsCHnO (Chinese hamster ovary) cells expressing the human dopamine JOH receptor were generated in situ. These cells lack the dihydrofolate reductase gene.

Fresh media were prepared weekly as described below and filtered through a 0.22 µm filter prior to use. Media are stored at 42C and heated to 372C before addition to the cells.

Cell dissociation solution (SO): (Zidta S-5914) o

Bml is used to collect cells from a flask with a volume of 225 cm2 (372C, Bhv. for cells of pra ONASI and 10 min. for cells PYUOZSNO).

Phosphate-buffered saline solution (РВ5): (Sirso. 14040-091) "I

Triptan blue: (Zidta T8154)

Forskolin (SaiIriospet 344213)

Dissolve to a concentration of 20MM in distilled water. (This mother liquor is stored at 422). 4x (F) analytical mother solutions of 40 μM are prepared by 500-fold dilution in PB5 buffer. 25 μM of a 40 μM mother solution are added to the final analytical volume of 100 μL, obtaining a final analytical concentration of TOμM. -

Test compounds

Dissolve in 10095 DMSO (Dimethylsulfoxide) to obtain a mother liquor concentration of 10 mM.

Pramipexole Standard «

Dissolve in 10095 DMSO to obtain a mother liquor concentration of 10 mM.

Analysis of cyclase activation on a flash tablet (MEM 5МРОО4В) supplied by Regkiip-EIteg I Ge Zsiepsev, ps h» Г251|- cyclic adenosine monophosphate (cAMP) (MEH 130) " Supplied by Regkiip-EIteg I Ge Zsiepsev, ps

Special equipment

Microplate titration shaker/incubator U/eziragi - Raskaga Torsotspi MHT (ESABA compatible program) with Tesap Sepeziz

Я arzuviete Miyi-agor OMU o Protocol for testing the activity of compounds on cells of NYUZSNO with 50 Dilution of compounds

Pramepixol is included as a reference standard. A 10-point, semi-logarithmic curve is constructed for every 4

T" tablets. The results for the compounds are normalized to the minimum (ONM pramipexole) and to the maximum (t100nM pramipexole) reactions generated by the cells. All test compounds can also be tested using a 10-point (semi-log) curve. 59 The tested compounds are dissolved in 10095 DMSO to obtain a stock concentration of 10 mM. These

HF) solutions are then diluted in 10095 DMSO to 1mM using a 10-fold dilution (necessary final analytical concentration of 1000x, for example, 1mM, gives an upper concentration of 1μM). where Pramepixol is dissolved in 10096 DMSO to obtain a concentration of T0mMM. Pramepixol is further diluted to 0.1 mM in 10095 DMSO using a 100-fold dilution. 60 Further dilution and addition is carried out in 0.495 DMSO/РВ5З using the protocol according to the recommendations of Tesap Sepevziz for performing serial dilutions of 3.159 times (semi-logarithmic unit).

Dilution according to Tesap Sepev's recommendations 10 μl of the tested compounds are added to column 1 of the microplate. 240 μl of 0.496 DMSO/РВ5 is added to them to obtain a 25-fold dilution (0.04 mM). 20 μl of the 0.04 mM dilution is transferred to the wells of column 2, where 180 μl of 0.495 DMSO/PB5 is added, giving a further 10-fold dilution, to achieve a 4-fold upper analytical concentration (0.004 mM).

Perform serial dilutions (3.159 times) to achieve a series of semi-logarithmic dilutions: 4mM, 1.27m, 40onM, 127nM, 4OonM, 1ZnNM, ZNM, 1.27nM, 0.4nM, 0.tM. 25 μl (in two replicates) of serial dilutions are transferred to columns 2-11 of the flash tablet (see Appendix).

Since the final analytical volume is 10Oml, the final analytical concentrations will be 100Om, 317nM, 10OnM, 32nM, tTonM, 3.2nM, tM, 0.33nM, 0.1nM, 0.o3nM.

Minimal control (low control): 25 μl of 0.496 DMSO/RVZ (carrier) is added to the next well (column 1 well BE-H and column 2 well A-Y)). Clitinikforskolin is added later.

Maximum control (high control): 10 mM pramipexole is diluted in PB5 using a 250-fold 7/0 dilution (1 µm2490 µl PB5) to generate 40 µM pramipexole. 40µM pramipexole is further diluted by 100-fold dilution in 0.495 DMSO/RVZ5 (100µl99O0µl carrier) to generate 400nM (4-fold analytical concentration of standard pramipexole). 25μl of 400nM pramipexole is added to the next well of the flash plate to obtain a final concentration of pramipexole of 100nM; column 1 well A-O and column 12 well B-H. Clitinikforskolin is added later.

Analysis of cyclase activation in the RLES-tablet HMEM 5МРОО4В)

As described in the Materials section, forskolin was dissolved in distilled water to achieve a stock concentration of 20 mM. It is then diluted to 40 μM (4 times the analytical concentration) using

RVB5. 25 μl of 40 μM mother solution is added to all wells using Miyi-dhor, obtaining a final concentration of 1 μM. The tablets are then sealed and incubated at 372C in a Uuweviragie incubator, while

Cells are collected.

Cells that are confluent at 7095-8095 are harvested from the flasks. It is important that all the components that are added to the cells are heated to 372C. Add 5 ml of CO to flask 1225 and incubate at 372C for 5 min. before neutralization of BML РВ5. The cells are then centrifuged at 1,609 (1,000 rpm) for 5 minutes. The resulting supernatant is poured out and the cells are resuspended in the stimulation buffer (heated to 372C) to reach a concentration of 5 x 10" cells/ml. 5µl of the cell suspension will then be distributed into all the wells of the flash plate. o

Tablets are immediately incubated at 372C in a shaking incubator for 15 minutes. The reaction is stopped with 100 μl of detector mixture in all wells (100 μl of 725 cCAMP: 11 ml of detection buffer per tablet).

The tablets are resealed and incubated in the dark for to ensure that equilibrium can be reached between anti-cAMP antibody (covering the wells), I722I-labeled cAMP and cellular cAMP. t

The counting of pulses in the tablets is carried out on the Raskaga Torsotspi MHT device using the appropriate SI protocol compatible with ESAVA (protocol 75).

Restoration of viability of frozen cells in ampoules

Remove the ampoules from the liquid nitrogen and allow them to equilibrate for 2 min., since entrapped He) gas or liquid can cause rapid expansion and explosion of the ampoules. they can also be stored at -202C for 2 minutes. before thawing. hey

Ampoules are quickly and completely thawed at 372C in a water bath.

The cell suspension is transferred to a 75 cm flask containing 1 Oml of growth medium and incubated for 24 hours. at 372, 5906 SO". After cell attachment (3 days), the medium is removed and replaced with fresh medium (to remove DMSO). After 24 hours when approaching confluence, the cells are transferred to a flask with a volume of 225 cm37. If not, the cells are kept until they are confluent at 7095-8095. Cell collection and separation "» Cells are separated on Friday to provide cells for Monday and Tuesday assays. Cells needed for other days of the week are separated on Monday.

It is essential not to allow the pZZZZSNO cells to reach more than 8090 fusion or to make -I separation 21:20, as this has harmful effects on their proliferative response, and will subsequently affect the ability of the cells to function in the assay.

Ф Cells are grown in flasks with a volume of 225 cm2 (duitrozv). Each component added to the cells must (a) be heated to 372C before use. 7 50 Collection of cells

The growth medium is removed from the flasks, the cells are washed with warm RV5 (birso. 14040-091) and removed. 100 ml of buffer for cell dissociation is added to the cells and placed in the incubator for about 5 minutes.

The flasks are punctured to remove any cells remaining from the tissue culture plastic. bml PB5 is added to the cells and used to wash the base and the flask. Cells are centrifuged during Bhv. at 1609 (1000o6./min.) for sedimentation of cells. o The supernatant is removed and ml of stimulation buffer is used to resuspend the cells. Trypan blue exclusion analysis is performed to determine the number of viable cells. o Cells are diluted with stimulating buffer to obtain a concentration of 5x10 cells/ml.

To move to the cells, the centrifugation stage is omitted, and the cell suspension is introduced into new flasks with a volume of 60 T225 containing 10 ml of medium.

Ratios when dividing cells "OZSNO are divided in a ratio of 1:5 to 1:10. The culture cannot be continued after the 30th passage, because the characteristics of the cell line are lost with more passages.

Cryopreservation of cell lines because it is essential to create a bank of one's own cells for revival with the purpose of further use.

Cells are harvested as described in the previous section. After trypan blue exclusion analysis, the cells are diluted in a medium containing 1095 DMSO to reach a concentration of 2-4x10 cells/ml.

Cells are divided into ml aliquots and immediately step-frozen in "Mg Egoviu" medium (containing fresh IRA (isopropyl alcohol)) at -802C before transferring to a storage vessel in the gaseous phase of liquid nitrogen. (Cells can be stored in "Mg Egoviu" medium for a period of up to 2 days).

It is recommended to test cell viability by thawing one ampoule after freezing. Viability values below 7095 may cause recovery problems due to low cell counts and the presence of cell fragments.

Data analysis

The data is analyzed using ESAVA. before normalization (relative to pramipexole) is determined for all compounds using the following formula: before normalization (X-BO)U(Max-BO)x100, where x is the average total number of pulses for a given concentration of the tested compound,

VO - average total number of pulses of minimal control (ONM of pramipexol) and

Mach - average total number of impulses obtained from the maximum control (100NM pramipexole)

Curves can be constructed by plotting 95 normalization (y) as a function of agonist concentration y

NM (x). The data were fitted using non-linear regression with a steepness of the slope of the curve kept within the limits of 1. They are used to determine EC5O and 96Emax for the compound being tested.

Plavsalshignehemaekh zlelesesi 1 b-tachksna SS 50: and GG Ton zm: 17717177 rn yah VIT Te sch

SI" s MAN NI PO SH YAM OH SSZ o zi Ennenyann i m i yu i 1 re z

Bk Ek Ssoy SCHO NI NO PO NI VANN NO POS sch che hop Fo

MAX - maximum b

MIM - minimum 3o Column 1: Wells A-O - MAX: high controls (cellulforskolin-t1OOnNM pramipexole) -

Pits BE-N - MIM: low controls (cellulitisforskolintenosium)

Column 12: Pits A-O - MIM: low controls (cellulitis)

Pits B-H - MAX: high controls (cellinforskolin-1OOnM pramipexole) «

Columns 2-11: 10-point serial dilution (in duplicate) of test compounds. Decreasing concentrations from column 2 to column 11 (from Т000ОНМ to 0.0ЗнНМ). Pramipexole replaces Siv in the first tablet. C c Inhibition through dopamine O2 receptors of forskolin-stimulated adenylate cyclase activity "c Materials " Media for cell culture:

Environment NO2 SNASI/O"

Natv B-12 (Zidta MbO13) - 2MM I-glutamine (Bidta 57513)

Ge) 1095 ЕВ5 (СиБсо 10106-169) 7OOmkg/ml geneticin (бирсо 10131-019) about ЕНнас/пр»| are rat pituitary cells that express the human dopamine receptor 02 op. co 50 Fresh medium is prepared weekly as indicated below and filtered through a 0.22 µM filter before use. The medium is stored at 42 and heated to 372C for addition to the cells.

T» Solution for cell dissociation (CO5): (Zidta C-5914)

BML is used to collect cells from a flask with a volume of 225 cm3.

Phosphate-buffered saline solution (РВ5): (Sirso. 14040-091) 59 Tryptan blue: (Zidta T8154)

GF) Forskolin (CaIriospet 344273) 7 Dissolve to a concentration of 20 mM in distilled water. (This mother liquor is stored at 42). 4x analytical stock solutions of 20 μM are prepared by 1000-fold dilution in PB5 buffer. 25 µM in a 20 µM stock solution is added to the final analytical volume of 100 µL, obtaining a final analytical concentration of 5 µM.

Test compounds

Dissolve to a concentration of 10MM in 1009565 DMSO.

Standard pramipexol v5 Dissolve in 10095 DMSO to obtain a concentration of the mother solution of 10 mM.

Analysis of cyclase activation on a flash tablet (MEM 5МРОО4В)

It is supplied by the company RegkKkip-EIteg I Te Zsiepsev, ps

G 251) cyclic adenosine monophosphate (cAMP) (MEH 130)

It is supplied by the company RegkKkip-EIteg I Te Zsiepsev, ps

Special equipment

U/eziragi titration microplate shaker/incubator

Raskaga Torsotspi MHT (program compatible with ESABA)

Tesap Sepeziz

I arzuviete Miyi-agor WMD 70 Protocol of operations

Dilution of compounds

Pramepixol is included as a reference standard. A 10-point, semi-logarithmic curve is built for every 4 tablets. The reactions of the compounds are normalized to the minimum (0 NM pramipexole) and to the maximum (10000nM pramipexole) reactions generated by the cells. All tested compounds can also be tested using a 75 10-point (semi-log) curve.

The tested compounds are dissolved in 10095 DMSO to obtain a concentration of the mother solution of 10MM (required final analytical concentration of 1000x, for example, 10MM gives an upper concentration of 1000ОНМ).

Pramepixol is dissolved in 10096 DMSO to obtain a concentration of T0mMM. Pramepixol is further diluted to 1 mM in 10095 DMSO using a 10-fold dilution.

Further dilutions and additions are carried out in 0.496 DMSO/РВ5 using the protocol according to the recommendations of Tesap Sepevziz to perform serial dilutions of 3.159 times (semi-logarithmic unit).

Dilution according to Tesap Sepev's recommendations 10 μl of the tested compounds are added to column 1 of the microplate. 240 μl of 0.496 DMSO/РВ5 is added to them to obtain a 25-fold dilution (0.04 mM). 20 μl of the 0.04 mM dilution is transferred to the wells of column 2, where 180 μl of 0.496 DMSO/PB5 is added, giving a further 10-fold dilution, to achieve a 4-fold upper analytical concentration (0.04 mM). i9)

Perform serial dilution (3.159 times) to achieve semi-logarithmic dilution series: 40µM, 12.7mµM, 4µM, 1.27µM, 40OnM, 1ZOonM, 4OonM, 13nM, 4nM, 1.3nM. 25 μl (in two replicates) of serial dilutions are transferred to columns 2-11 of the flash tablet (see Appendix). "AND

Since the final analytical volume is 1O00Oml, the final analytical concentrations will be 1000Om, 317OnM, 100OnM, 32onM, 3OnM, 32nM, 1Onim, 3NM, 1nM, 0.3nM. with

Minimal control (low control): 25 μl of 0.495 DMSO/RVZ (carrier) is added to the following wells (column 1 of wells B-H and column 2 of wells A-O). Cells and forskolin are added later.

Maximum control (high control): 10 mM pramipexole is diluted in PB5 using a 250-fold dilution (1µl2490μl PB5) to generate 40μM pramipexole. 40 μM pramipexole is further diluted using a 10-fold dilution in 0.495 DMSO/RVZ (100 μl 3900 μl carrier) to generate 4000 NM (4-fold analytical concentration of standard pramipexole). 25 μl of 400O0nM pramipexole is added to the following wells of the flash tablet to obtain the final concentration of pramipexole T100OnM; column 1 of pits A-O and column "

T2 pits B-N. Clitininforskolin is added later.

Analysis of the activation of cyclase in the rlesh tablet (MEM 5МРОО4В) - s As described in the "Materials" section, forskolin is dissolved in distilled water to achieve a concentration of 20MM mother solution. It is further diluted to 20μM (4-fold analytical concentration) using "» RVB5. 25μl of 40μM mother solution is added to all wells using Miyi-dgor, obtaining a final concentration of 0.5μM. Then the plates are sealed and incubated at 372C in the incubator of Muezirai, while

Cells are collected. -And Cells that are fused at 7095-8095 are collected from the flasks. It is important that all the components that are added to the cells are heated to 372C. Bml of POPs added to a flask with a volume of 225 cm? and incubated at 372C for 5 minutes. before neutralization of Bbml РВ5. The cells are then centrifuged at 1609 (1000 rpm) for 10 minutes. The resulting supernatant is poured out, and the cells are resuspended in the stimulating buffer (heated to 372C) for 20 minutes to reach a concentration of 1x10 cells/ml. 5 µl of the cell suspension will then be distributed into all the wells of the flash plate.

Tablets are immediately incubated at 372C in a shaking incubator for 15 minutes. The reaction is stopped by adding 100 μl t" of the detector mixture to all wells (100 μl 725| TsAMP: 11 ml of detector buffer per tablet).

The tablets are resealed and incubated in the dark for to ensure the possibility of reaching equilibrium between the anti-cAMP antibody (covering the wells), the label | 22II cAMP and cellular cAMP.

Counting of pulses in the tablets is carried out on the Raskaga Torsoshpi MHT device using the appropriate (Ф) protocol compatible with ESABA (protocol 75). ko Restoration of viability of frozen cells in ampoules

Remove the ampoules from liquid nitrogen and allow them to equilibrate for 2 minutes, as trapped in the pelvis or liquid can cause rapid expansion and explosion of the ampoules. they can also be stored at -202C for 2 minutes. before thawing.

Ampoules are quickly and completely thawed at 372C in a water bath.

Transfer the cell suspension to a 75 cm2 flask containing 10 ml of growth medium and incubate for 24 hours. at 372, 596 SO". After cell attachment (3 days), the medium is removed and replaced with fresh medium (to remove DMSO). After 24 hours when approaching confluence, the cells are transferred to a flask with a volume of 225 cm7. If not, the cells are kept until they are fused at 6095.

Collection and separation of cells

Cells are split on Friday to provide cells for Monday and Tuesday assays. Cells needed for other days of the week are allocated on Monday.

It is essential not to allow the cells to achieve more than bO95 confluence, as this has detrimental effects on their proliferative response and will subsequently affect the ability of the cells to function in the assay.

Are the cells grown in 225 cm flasks? ()itrov). Each component added to the cells must be heated to 372C before use.

Collection of cells 70 The growth medium is removed from the flasks, the cells are washed with warm РВ5 (birso. 14040-091) and removed.

BbBml of cell dissociation buffer is added to the cells and placed in the incubator for about 5 minutes.

The flasks are punctured to remove any residual cells from the tissue culture plastic. bml PB5 is added to the cells and used to wash the base and flask. Cells are centrifuged for 5 minutes. at 1609 (1000 rpm) for cell sedimentation.

The supernatant is removed and ml of stimulation buffer is used to resuspend the cells. Trypan blue exclusion analysis is performed to determine the number of viable cells.

The cells are diluted with a stimulating buffer to obtain a concentration of 1x10 cells/ml.

To move to the cells, the centrifugation stage is omitted, and the cell suspension is introduced into new flasks with a volume of 1225, containing 5HOml of the medium.

Ratios when separating cells of eNnasturi are divided in a ratio from 1:3 to 1:5.

Cryopreservation of cell lines

It is essential to create a bank of your own cells to be revived for later use.

Cells are harvested as described in the previous section. After trypan blue exclusion analysis, He cells are diluted in a medium containing 1095 DMSO to reach a concentration of 2-4x10 cells/ml. heh)

Cells are divided into ml aliquots and immediately gradually frozen in Mg Egoviu medium (containing fresh IRA) at -809C before being transferred to a storage vessel in the gaseous phase of liquid nitrogen. (Cells can be stored in "Mg Egoviu" medium for a period of up to 2 days).

It is recommended to test cell viability by thawing one ampoule after freezing. Viability values below 7095 may cause recovery problems due to the low number of cells and the presence of cell fragments.

Analysis of data about

The data is analyzed using ESAVA. b before normalization (relative to pramipexole) is determined for all compounds using the following formula: 905 normalization-(x-BO)/(Max-BO)x100, - where x x are the average total number of pulses for a given concentration of the tested compound,

VO - average total number of pulses of minimal control (ONM of pramipexol) and "

Mach - the average total number of pulses obtained from the maximum control (100NM pramipexole) C 70 Curves can be constructed by plotting 95 normalization (y) depending on the agonist concentration in NM (x). The data were fitted using non-linear regression with the steepness of the slope of the curve kept within the limits of "» 1. They determine EC5O and 96Emax for the compound under test. 111 še 777111 um y: yu o re 711 Hrnze i trzh ha. 1 17171 1717171 vve miny scha NI SHO I M MY SHA NOde We M 35 wines and 111 "leads t o Xia

MAX - maximum, where MIN - minimum

Column 1: Wells A-O - MAX: high controls (cellulforskolin-1OOnM pramipexole) 60 Wells BE-N - MIM: low controls (cellulforskolin tenosium)

Column 12: Pits A-O - MIM: low controls (cellulitis)

Wells B-H - MAX: high controls (cellinforskolin-1OOnM pramipexole)

Columns 2-11: 10-point serial dilution (in duplicate) of test compounds. Decreasing concentrations from column 2 to column 11 (from 1000 ОНМ to 0.0З3nНМ). Pramipexole replaces C1 in the first tablet. 65 When using the analysis described above, all compounds according to the invention show functional activity on the OZ receptor, which is expressed as ESB5O lower than TO00OHM, and 10-fold selectivity in relation to OZ, compared to 02.

The compound of example 8 has a functional activity on the OZ receptor, which is manifested in the form of ES5O of 7.6 nM and selectivity in relation to OZ, which is 1315.8 times higher than 02. The selectivity is calculated as the value of ESB5O

Or2, divided by the value of ЕС5О 03. When the value of ЕС5О 02 was 210,000, the number 10,000 was used in the calculation.

It should be understood that all references in this description to treatment include radical, palliative and prophylactic treatment.

Suitable auxiliary active substances for use in combinations according to the invention include 70 1) natural or synthetic prostaglandins or their esters. Suitable prostaglandins for use in the present invention include such compounds as alprostadil, prostaglandin E 3, prostaglandin Eod, 13,14-dihydroprostaglandin E;, prostaglandin Ez, eprostinol, natural, synthetic and semi-synthetic prostaglandins and their derivatives, including those described in (MMO-00033825 and/or in US patent Mo 6037346, issued March 14, 2000), all of which are incorporated into this description by reference, ROE 0, ROEZ, ROA;, ROVU,

ROHio, 19-hydroxy-RSA;, 19-hydroxy-ROV., ROB», ROV»o, 19-hydroxy-ROA», 19-hydroxy-ROV», ROEz»9, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipoprost , hemeprost, metenoprost, sulprost, tiaprost and moxisylate; 2) antagonist compounds of A-adrenergic receptors, also known as o-adrenoceptors or o-receptors or o-blockers. Suitable compounds for use in the present invention include: blockers of α-adrenergic receptors, as described in the application |PCT U/099/30697, published on June 14, 1998|, the provisions of which relating to α-adrenergic receptors are included in this description is by reference and includes selective β-adrenoceptor or β-adrenoceptor blockers and non-selective adrenoceptor blockers, examples of suitable α/--adrenoceptor blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramine, naftopidil, tamsulosin , dapiprazole, phenoxybenzamine, idazoxan, sefaraxan, yohimbine, rauwolfia alkaloids, Kesogaii 15/2739, 5ЗМАР 1069, 5МАР 5089, К517053, 5I 89.0591, Ge) doxazosin, terazosin, abanochil and proazosin; oo-adrenoceptor blockers from (US patent Mobo 37346 (|March 14, 2000 || dibenamine, tolazoline, trimazosin and dibenamine; o-adrenergic receptors as described in (US MoMo patents: 4188390, 4026894, 3511836, 4315007, 3527761, 399766 2503059, 4703063, 3381009, 4252721 and 2599000), each of which is incorporated herein by reference; agadrenoceptor C blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a karyotonic agent such as pirksamine;

C) MO donor compounds (MoO agonists). Suitable MO donor compounds for use in the present invention include organic nitrate, such as mono-, di-, and trinitrates, or organic nitrate esters, He» including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate , isosorbide dinitrate, pentaerythritol 3o tetranitrate, erythritol tetranitrate, sodium nitroprusside (5MR), 3-morpholinosydnonimine in molsidimine, 3-nitroso-M-acetylpenicillamine (5MAP), 5-nitroso-M-glutathione (5MO-51 0), M- oxy-I-arginine, amyl nitrate, linsidomine, linsidomine hydrochloride, (5IM-1) Z-nitroso-M-cysteine, diazenium diolates, (MOMoOates), 1,5-pentane dinitrate, I-arginine, ginseng, ginseng fruit, molsidomine, Ke-2047, derivatives of nitrosylated maxisillite, such as MMI-678-11 and MMI-937, as described in (published application RO-T UMO 0012075); With 4) means that open or modulate potassium channels. Suitable agents that open or modulate potassium channels for use in this invention include nicorandil, cromokalim, leucromakalim,

With" lemakalim, pinacidil, kliazoxide, minoxidil, charybdotoxin, glyburide, 4-aminopyridine, Vasi"; 5) vasodilators. Suitable vasodilators for use in this invention include nimodepine, pinacidil, cyclandelate, isoxsuprine, chlorpromazine, haloperidol, Kes 15/2739, trazodone; and 6) thromboxane A2 agonists; (Te) 7) means acting on the central nervous system; 8) wormwood alkaloids; related wormwood alkaloids are described in (US Patent Mob037346, issued March 14, 2000) and include acetergamine, brassergoline, bromerguride, cyanergoline, delorgotril, disulergine, ka 20 ergonovine maleate, ergotamine tartrate, etisulergine, lergotril, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride;

T" 9) compounds that modulate the action of natriuretic factors, in particular, atrial natriuretic factor (also known as atrial natriuretic peptide), natriuretic factors of type B and type C, such as neutral endopeptidase inhibitors; 29 10) compounds that inhibit angiotensin-converting enzyme, such as enapril, and combined inhibitors

HF) angiotensin-converting enzyme and neutral endopeptidase, such as omapatrilat; 11) angiotensin receptor antagonists, such as losartan; o 12) substrates for MO-synthase, such as I-arginine; 13) blockers of calcium channels, such as amlodipine; 60 14) endothelin receptor antagonists and endothelin-converting enzyme inhibitors; 15) cholesterol-lowering drugs, such as statins (for example, atorvastatin/iriog - trade name) and fibrates; 16) antiplatelet and antithrombotic agents, for example, IRA, ChRA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin-activating factor inhibitors; because 17) insulin-sensitizing agents, such as resulin, and hypoglycemic agents, such as glipizide;

18) G-OASA or carbidopa; 19) acetylcholinesterase inhibitors, such as donezipil; 20) steroidal or non-steroidal anti-inflammatory drugs; 21) estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-ylethoxy)phenyl|)- 5,6,7 8-tetrahydronaphthalen-2-ol and their pharmaceutically acceptable salts, the preparation of which is described in detail in (MO 96/216561; 22) POE (phosphodiesterase) inhibitor, more specifically, POE inhibitor 2, 3, 4, 5, 7 or 8, preferably, an inhibitor of 7/0 ROE? or ROEB, and most preferably, an inhibitor of ROE5 (see below in this description), and said inhibitors preferably have IC5BO against the corresponding enzyme of less than 100nM (provided that the ROE2 inhibitor or ROEZ and the 4 inhibitors are administered only topically or by injection into penis); 23) vasoactive intestinal protein (MIR), MIR mimetic, MIR analogue, more specifically, mediated by one or more subtypes of MIR receptors MRASI, MRAS or RASAR (pituitary β-adenylate cyclase-activating peptide), one or more agonists of MIR receptors or MIR analogues ( for example, Ko-125-1553) or a fragment of MIR, one or more 5x-adrenoceptor antagonists with a combination of MIR (for example, Ipumisogr, Amiriavdia); 24) agonist or modulator of melanocortin receptors or enhancer of melanocortin, such as melanotan II,

RT-14, RT-141 or compounds declared in (|MUO-09964002, UUO-00074679, MUUO-09955679, UUO-00105401, uOo-00058361, M/O-00114879, M/O-00113112, MUO-099543581; 25) an agonist, antagonist or modulator of serotonin receptors, more specifically, agonists, antagonists or modulators of receptors ZHT1A (including UMI. 670), 5HT2A, 5HT2C, 5NTZ and/or 5HTb, including receptors described in MUO-09902159, UUMO-00002550 and/ or M/O-00028993); 26) a means that replaces testosterone (including dihydroandrostenedione), testosterone (Tozigeie), dihydrotestosterone or a testosterone implant; p 27) estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (i.e., in the form of a combination), or a means of hormone replacement therapy estrogen and methyltestosterone (for example, NKT, or in particular, Premarin, Cenestin, Estrofeminal, Equin, Estreis, Estrophem ) 28) modulator of transporters for norepinephrine, dopamine and/or serotonin, such as bupropion, (zUuU-320659; "I 29) agonist and/or modulator of purinergic receptors; 30) antagonist of neurokinin (MC) receptors, including antagonists described in (M/O-09964008); c 31) agonist, antagonist or modulator of opioid receptors, preferably, agonists for the OKI-1 receptor; o 32) agonist or modulator for oxytocin/vasopressin receptors, preferably, a selective agonist or modulator of oxytocin; o 33) modulators of cannabinoid receptors; and 34) a 5ER inhibitor (ZERI), for example, a ZERI having an IC50 equal to less than T00nM, more preferably, at a level of less than 50nM.

Preferably, EP inhibitors according to this invention have a selectivity for EP more than 30 times, preferably, more than 50 times, compared to the neutral peptidase MER EC 3.4.24.11 and "angiotensin-converting enzyme (ACE). Preferably, ZERI also has a selectivity 100 times higher than that for endothelin-converting enzyme (ECE). y In this description, by cross-referencing the compounds contained in patents and patent applications, which "" can be used according to the invention, the applicants mean the therapeutically active compounds defined in the claims of the invention (in particular, in clause 1), and in specific examples (all of which are incorporated herein by reference).

If a combination of active agents is administered, they can be administered simultaneously, separately, or sequentially. -I Auxiliary means-inhibitors of ROE5

The suitability of any specific COMP inhibitor of ROE5 can be easily determined by evaluating its activity and selectivity using methods described in the literature followed by an assessment of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with standard pharmaceutical practice.

IC5BO values for cOMR of POE5 inhibitors can be determined using the POE5 assay (see below in the description).

Preferably, cOMR inhibitors of ROEB5 used in pharmaceutical combinations according to this invention are selective for the enzyme ROEB5. Preferably (when administered orally), they are more selective than for ROEZ, more preferably than for ROEZ and for ROE4. Preferably (when administered orally), the POE5 COMP inhibitors of the invention have a selectivity ratio greater than 100, more preferably greater than

Z00, in comparison with ROEZ, more preferably, with ROEZ and ROE4. iF) The selectivity ratio can be easily determined by one skilled in the art. The IC5O values for the enzyme COEZ and ROE4 can be determined using the established methodology described in the literature | see 5.A.

Vaigaga ei ai, doigpai oi Ogoiodu, 1998, my. 159, pages 2164-2171) and as detailed below in this description. Suitable CMP inhibitors of ROEB5 for use in accordance with the present invention include pyrazolo|4,3-4|pyrimidin-7-ones disclosed in (EP-A-04637561; pyrazolo|4,3-4|pyrimidin-7-ones , disclosed in (ER-A-05260041; pyrazolo|4,3-4|pyrimidin-7-ones, disclosed in the published international patent application (MO 93/061041; isomeric pyrazolo|3,4-4|pyrimidin-4-ones , disclosed in the published international patent application (MO 93/071491; 65 quinazolin-4-ones, disclosed in the published international patent application (MO 93/12095); pyridoyiZ,2-4|Ipyrimidin-4-ones, disclosed in the published international patent applications (M/O 94/056611;

purine-6b-ones disclosed in the published international patent application (MO 94/00453); pyrazolo|4,3-4|pyrimidin-7-ones, disclosed in the published international patent application (MO 98/491661; pyrazolo|4,3-4|pyrimidin-7-ones, disclosed in the published international patent application (MO 99/ 543331; pyrazolo|4,3-4|pyrimidin-4-ones, disclosed in (EP-A-09957511; pyrazolo|4,3-4|pyrimidin-7-ones, disclosed in the published international patent application (MO 00/247451 ; pyrazolo|4,3-4|pyrimidin-4-ones disclosed in (EP-A-09957501; compounds disclosed in published international patent application (M/O 95/199781; compounds disclosed in published international patent application (MUO 99/24433), and compounds disclosed in 7/0 published international patent application (MO 93/07 1241; pyrazolo|4,3-4|pyrimidin-7-ones disclosed in published international patent application (MO 01/271121; pyrazolo|4,3-4|pyrimidin-7-ones disclosed in published international patent application (MO 01/271131; compounds disclosed in (EP-A-1092718) and compounds disclosed in (EP-A-1092719) .

Other suitable POE5 inhibitors for use in accordance with this invention include 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|-1-methyl-3-n-propyl-1,6-dihydro- 7H-pyrazolo|4,3-4|pyrimidin-7-one (sildenafil), also known as 1-((3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H- pyrazoloi|4,3-4|pyrimidin-5-yl)-4-ethoxyphenyl|sulfonyl|-4-methylpiperazine (see EP-A-0463756); 5-(2-ethoxy-5-morpholineacetylphenyl)-1- methyl-Z-n-propyl-1,6-dihydro-7H-pyrazolo|4,3-4|Ipyrimidin-7-one (see

ER-A-0526004);

3-ethyl-5-15-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl|-2-(pyridin-2-yl)umethyl-2,6b-dihydro-7H-pyrazolo|4,3 -4|Ipyrimidin-7-one (see MUO98/49166);

3-ethyl-5-(5-(4-ethylpiperazin-1-ylsulfonyl)-2-(2-methoxyethoxy)pyridin-3-yl|-2-(pyridin-2-yl)methyl-2,6-dihydro -7H-pyrazolo|4,3-4|Ipyrimidin-7-one | see МУ099/543331; сч (-3-3-ethyl-5-15-(4-ethylpiperazin-1-ylsulfonyl)-2-(2 -methoxy-1(K)-methylethoxy)pyridin-3-yl|-2-methyl-2,6-dihydro-7H-pyrazolo|4,3-4|pyrimidin-7-one, also known as (8)

3-ethyl-5-15-(4-ethylpiperazin-1-ylsulfonyl|-2-((1K)-2-methoxy-1-methylethyl|oxy)pyridin-3-yl)-2-methyl-2,6- didro-7H-pyrazoloi|4,3-4|Ipyrimidin-7-one | see UU099/543331; 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)|-2,6-dihydro-7H-pyrazole 9|I4,3-4|Ipyrimidin-7-one, also known as 1-I6-ethoxy-5-|3-ethyl-b,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H- pyrazoloi4,3-a) with pyrimidine-5-yl|-3-pyridylsulfonyl)-4-ethylpiperazine see UUO 01/27113, example 81; o 5-(2-isobutoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(1-methylpiperazin-4-yl)-2,6-dihydro o-7Н -pyrazolo|4,3-4|Ipyrimidin-7-one see UUO 01/27113, example 15); me) 5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-phenyl-2,6b-dihydro-7H-pyrazolo|4,3- 4a|pyrimidin-7-one | see MO 01/27113, example 66); 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3-4|pyr midin-7-one | see UMO 01/27112, example 1241; 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazoloi|4,3-4|pyrimidine - « 7-on | see MO 01/27112, example 1321; with c (bK,12ak)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazine(2",1":6,1|IpyridoiZ,4 -indo l-1,4-dione (IS-351), i.e., the compounds of examples 78 and 95 of the published international application (M/095/199781, as well as the compound of examples 1, 3, 7 and 8; 2 -(2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl)phenyl|-5-methyl-7-propyl-ZH-imidazoi5,1-41,2,Agriazine-4-45. OH ( vardenafil), also known as -I 1-((3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo|5,1-P-asymmetric.-triazin-2-yl)-4 -ethoxyphenyl|sulfonyl/|-4-ethylpiperazine, i.e., the compound of examples 20, 19, 337 and 336 of the published international application |(МУ099/244331; and the compound of example 11 of the published international application (МУ093/07124 (ЕИЗАЙ!))І; and compounds Ж and 14 from the publication on Ikoelia 0. R., U. Med. Spet., 2000, 43, 1257).

Other suitable POE5 inhibitors include 4-bromo-5-(pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)|-3(2H)pyridazinone; i» monosodium salt of 1-N4-K1,3-benzodioxol-5-ylmethyl)amino)-b-chloro-2-quinozolinyl-4-piperidinecarboxylic acid; (t3)-cis-5,ba,7,9,9,9a-hexahydro-2-(4--trifluoromethyl)phenylmethyl-5-methylcyclopenti(4,b|imidazo|2,1-c)|purine-4 (two ZN)on; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,ba,7,8,9,Za-octahydrocyclopenti4,5imidazo|2,1-8|Hipurin-4-one;

F) 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-b-carboxylate; ka 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-b-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone; in the monosodium salt of 1-methyl-5-(5-morpholineacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-4)trimidin-7-one; 1-14-K1,3-benzodioxol-5-ylmethyl)amino)-b-chloro-2-quinazolinyl-4-piperidinecarboxylic acid; pharmaceutical projects Mo4516 (Siaho M/eyYsote); pharmaceutical projects Mo5051 (Vaueg); pharmaceutical projects Мо5064 |(Kuozha NakKko; see МО 96/26940); pharmaceutical projects Mo5069 (Zspegipd Riotsdn); CE-196960 65 (Siaho Uueisote); E-8010 and E-4010 (Eivai); Vau-38-3045 8. 38-9456 (Vaueg) and 5sp-51866.

Compounds of formula (I) may be administered alone, but generally should be administered in admixture with an appropriate pharmaceutical excipient, diluent, or carrier selected based on the intended route of administration and standard pharmaceutical practice.

Accordingly, the present invention provides a composition comprising compounds of formula (I), (Ia) or (IB) and a pharmaceutically acceptable diluent or carrier.

For example, compounds of formula (I), (Ia) or (IB) can be administered orally, buccally or sublingually in the form of tablets, capsules, pellets, elixirs, solutions or suspensions, which may contain flavoring or coloring substances, with immediate, delayed, modified , sustained, pulsatile or controlled release. 70 Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium dibasic phosphate and glycine, disintegrants such as starch (predominantly corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPD), sucrose, gelatin, and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type can also be used as fillers in gelatin capsules.

Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of formula (1), (Ia) or (IB) can be combined with various sweetening or flavoring agents, coloring matter or dyes, emulsifying and/or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin, and their combinations.

Compounds of formula (I), (a) or (IB) can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, submucosally, intracerebroventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they can be

Administer by infusion methods. For such parenteral administration, they are best used in the form of a sterile aqueous solution, which may contain other substances, for example, enough salts or glucose i) to make the solution isotonic with blood. If necessary, aqueous solutions should be appropriately given buffer properties (mainly at pH from 3 to 9). Preparation of appropriate parenteral compositions under sterile conditions is easily carried out by standard pharmaceutical techniques well known to those skilled in the art.

The compounds of formula (I), (Ia) or (IB) can also be administered intranasally or by inhalation, usually in the form of a dry powder (or separately, in the form of a mixture, for example, in a dry mixture with lactose, or in the form of a mixed component particle , for example, mixed with phospholipids) from a dry powder inhaler or in the form of an aerosol that is sprayed from a container with contents under excessive pressure, a pump, a spray, a Mez5 nebulizer (predominantly a nebulizer in which electrohydrodynamics is used to create a mist from small droplets), cha or a sprinkler with or without the use of a suitable propellant such as dichlorofluoromethane.

A pressurized container, pump, spray, nebulizer, or sprinkler contains a solution or suspension of an active compound, including, for example, ethanol (optionally aqueous ethanol) or a suitable alternative to disperse, solubilize, or prolong the release of the active compound. substances, a propellant gas(es) as a solvent and optionally a surfactant such as sorbitan trioleate or oligolactic acid.

Before use in a composition in the form of a dry powder or suspension, the medicinal product is micronized; to a size suitable for delivery by inhalation (typically less than bµm). This can be achieved by any suitable milling method, such as spiral vortex milling, fluidized bed milling in a vortex mill, surface liquid processing to form nanoparticles, and high pressure homogenization or spray drying.

A suitable composition in the form of a solution for use in a sprayer using ik electrohydrodynamics to create a fog from small droplets can contain from 1mkg to 1Omg of the compound according to the invention per launch, and the launch volume can vary from 1mL to 1O0O0mL. Usually, the composition can include compounds of formula (I), (Ia) or (IB), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Capsules, blisters and cartridges (made, for example, from gelatin or HPMS) for use in an inhaler or insufflator can be filled with the contents in the form of a powder mixture of the compound according to the invention, or a suitable powder base, such as lactose or starch, and a functional modifier such as as

I-leucine, mannitol or magnesium stearate. (F) Compositions for inhalation/intranasal administration can be formulated for immediate and/or modified release.

Alternatively, the compounds of formula (I), (Ia) or (IB) may be administered as a suppository or pessary, or they may be applied topically as a gel, hydrogel, lotion, solution, cream, ointment or powder for powder. Compounds of formula (I), (Ia) or (Iv) can also be administered dermally or transdermally, for example, using a skin patch. they can also be administered pulmonary or rectal.

They can also be administered by eye. For ophthalmic use, the compounds can be included in the composition in the form of micronized suspensions in isotonic, sterile saline solution with a pH of 65 or, preferably, as solutions in an isotonic, sterile saline solution with a pH of 65, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they can be formulated as an ointment such as petroleum jelly.

For local application to the skin, the compounds of formula (I), (Ia) or (IB) can be put into a composition in the form of a suitable ointment containing the active compound, suspended or dissolved, for example, in a mixture with one or more of the following substances: mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene-polyoxypropylene compounds, emulsifying wax and water. Alternatively, they can be formulated as a lotion or cream, suspended or dissolved, for example, mixed with one or more of the following substances: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol , 2-octyldodecanol, benzyl alcohol and water. 70 Compounds of formula (I), (Ia) or (IB) can also be used in combination with cyclodextrin. It is known that cyclodextrins form inclusion and non-inclusion compounds with drug molecules. The formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and/or stability of the drug molecule. Drug-cyclodextrin complexes are mainly useful for most dosage forms and routes of administration. As an alternative to the direct formation of 7/5 Complexes with a medicinal substance, cyclodextrin can be used as an auxiliary admixture, for example, in the form of a carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrins are most widely used, and relevant examples are described in (MUO-A-91/11172, MMO-A-94/02518 and MMO-A-98/55148).

The present invention is further illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:

Fo optical rotation at 587nm

Agraseksh filtering agent ush Shiroky

Vos tert-butoxycarbonyl si

SOSIZ3 / chloroform-y1

СО300 methanol-а4 о 5 chemical shift d doublet dd doublet of doublets - рсмМ dichloromethane Ge

DMF M,M-dimethylformamide

DMSO | dimethyl sulfoxide at hours b

Her hydrogen chloride km mass spectrum of low resolution -

M multiplet t/x peak mass spectrum min. minutes "

T.pl. tОe melting -o masn sodium hydroxide s NUM nuclear magnetic resonance:z» kv quartet s singlet t triplet -I te trifluoromethanesulfonyl

TEA trifluoroacetic acid is) tgF tetrahydrofuran o TLC thin-layer chromatography is) 50 Melting points were determined using the device Regkip EIteg 0537 at a heating rate of 202С/min.

T» X-ray diffraction data were recorded at room temperature using a diffractometer VKOKEK AH5 5MAKT-AREH SSO AKEA-OETESTOK (radiation MO K 9). Intensity indicators were integrated over several series of impacts. Each exposure covered 0.32 in o, with an exposure time of bosec., dv | the complete data set was larger than the sphere.

Example 1 (F, 2-amino-1-(3-methoxyphenyl)ethanol g p rod 60

3-Methoxybenzaldehyde (27.2g, 0.2mol) in THF (150ml) was added to a stirred solution of ZM NOSI (aq.) (150ml, 0.Zmol) and sodium sulfate (37.8g, 0.Zmol) at room temperature. After 10 minutes potassium cyanide (19.53 g, O.Zmol) is added in portions, and the reaction mixture is then stirred for 30 minutes. Diethyl ether 65 (800ml) and water (300ml) are added and the layers formed are separated. The aqueous solution was re-extracted with diethyl ether (5O0Oml), the organic layers were combined, dried over aqueous magnesium sulfate, filtered, then concentrated in a vacuum to obtain the cyanohydrin intermediate in the form of a colorless oil (35.57g, 0.22mol, 210095). Borane-tetrahydrofuran complex (1M in THF) (400ml, 0.4mol) is then carefully added to cyanohydrin in THF (100ml). After the cessation of violent gas evolution, stirring is continued under reflux for 1.5 hours. in a nitrogen atmosphere. The reaction mixture was cooled, then the reaction was quenched with methanol (400 mL) before concentration in vacuo to give a colorless oil. Add b6M

NOI (aq.) (200 ml) and the reaction mixture are stirred at reflux for 2 hours. before concentration in vacuo to give a white solid. It is preabsorbed on 7/0 silicon dioxide, then purified by column chromatography, eluting with a mixture of dichloromethane:methanol:ammonia (90:10:1), to obtain the title compound in the form of a colorless oil (31.3g, 0.19mol, 9490).

TN NMR (SOSIZ, 400 MHz) 5: 1.60 (us.s, 2H), 2.80 (dd, 1H), 3.02 (dd, 1H), 3.46 (s, 1H), 3.81 (c, 3H), 4.60 (dd, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 6.93 (c, 1H), 7.22 (t, 1H) . I VM5: t/: 168 (M-H"7). Analysis found C, 56.66; H, 8.28; M, 6.9195. SeNizMO""1, ZZZN"O calculated C, 56.33; N, 8.27; M, 7.3090.

Example 2

IM-(2-hydroxy-2-(3-methoxyphenyl)ethyl|propionamide

What

Triethylamine (52 ml, 0.37 mol) is added to the amine of example 1 (31.3 g, 0.19 mol) in dichloromethane (400 ml) and the reaction mixture is stirred in an atmosphere of gaseous nitrogen at 09C for 1 hour. Add propionyl chloride (16.3 ml, 0.19 mol) and after stirring for 30 minutes. the temperature of the reaction mixture is increased by He to room temperature for another 5 hours. The reaction mixture was quenched with 1M HCl (aq.) (10Oml) and then extracted with dichloromethane (2x5Oml). The organic fractions were combined, dried over aqueous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless oil, which crystallized on standing to form white crystals (28g, O0.1Zmol, 67905).

IN NMR (SOSIz, 400 MHz) 5: 1.18 (t, ЗН), 2.22 (sq., 2Н), 2.51 (ush.s, 1Н), 3.31 (m, 1Н), 3.71 (dd, 1H), F 3.80 (s, ЗН), 4.81 (m, 1H), 5.95 (ush.s, 1H), 6.80 (d, 71H), 6.90 (d , 1H), 6.91 (s, 1H), 7.22 (t, 1H). EM5: s t/2 224, T.pl.: 77-7890. Analysis found C, 63.86; N, 7.82; M, 6.2895. С12Н47МО5.0.138250 was calculated С, 64.04; N, 7.70; M, 62295. Fr

Example Z F 1-(3-methoxyphenyl)-2-propylaminoethanol

Nn i - ru «

The borane-tetrahydrofuran complex (1M in THF) (37 bml, 0.4 mol) is added to the amide of example 2 (28 g, 0.13 mol) in -) with dry THF (100 ml), then the reaction mixture is stirred in an atmosphere of nitrogen gas, boiled with return and refrigerator for 2.5 hours. The reaction mixture was cooled, then quenched with methanol (40 mL) before "" concentration in vacuo to give a cloudy white oil. Add 6M NA (water) (200 ml) and stir the reaction mixture under reflux for 2 hours. The reaction mixture is cooled, then dichloromethane (200 ml) is added and the layers are separated. Basic properties are added to the aqueous layer by adding potassium carbonate, then re-extracted with dichloromethane (2x20Oml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to obtain the compound indicated in the title in the form of a colorless oil, which crystallizes on standing with the formation of colorless av | crystals (15.3 g, O0.07 mol, 59905). t 50 "YAN nMR (SOSIS, 400MHz) 5: 0.93 (t, ЗН), 1.62 (sq, 2H), 2.71 (sq, 2H), 2.81 (t, 2H), 3, 00 (d, 1H), 3.80 (s, ЗН), 4.30 (ush.s, 1H), 4.89 (d, 1H), 6.81 (d, 1H), 6.91 (d . , 9.02; M, 6.4595. C12H19MO". 0.2H20 calculated C, 67.70; H, 9.19; M, 6.58965.

Example 4 2-M-(2-hydroxy-2-(3-methoxyphenyl)ethyl|-M-propylacetamido MK re M in 60

Sodium hydroxide (15.1g, 0.38mol) in water (1830ml) was added to the amine of Example C (15.8g, 0.08mol) in dichloromethane (500ml) and the solution was vigorously stirred at room temperature. Then chloroacetyl chloride (7.22 ml, 0.09 mol) is added, and the reaction mixture is stirred for another 30 minutes. The layers are separated and the aqueous layer is re-extracted with dichloromethane (200 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a colorless oil (17.8 g, 0.025 g, 83905).

TN nMR (SOSIZ, 400 MHz) 5: 0.96 (t, ЗН), 1.62 (sq, 2H), 3.21 (sq, 2H), 3.57-3.71 (m, 2H), 3 ... 6.91-6.99 (m, 2H), 7.22 (m, 1H). IKM5: t/: 286, Analysis found S, 57.38; H, 6.95; M, 4.6795. С44Н2ОМозСИ.0.33Н»О calculated C, 57.64; H, 7.14; M, 4.80905.

Example 5 on that kru

Potassium hydroxide (4.2g, 0.07mol), isopropyl alcohol (50O0ml) and amide of example 4 (17.8g, 0.Obmol) 75 are mixed together in the form of a cloudy solution with water (15ml) for 2 hours. The reaction mixture is concentrated in vacuo and the yellow residue is dissolved in ethyl acetate (200 ml). It is separated with water (200 ml), then with a saturated salt solution (200 ml). The organic fraction was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil (15.8g, 0.Obmol, 100965).

TN NMR (SOSIZ, 400MHz) 5: 0.96 (t, ЗН), 1.62 (m, 2Н), 3.36 (m, 2Н), 3.51 (q, 2Н), 3.81 (s ) (c, 1H), 7.29 (t, 1H). IKM5: t/2 272,

Analysis found C, 66.80; N, 7.78; M, 5.5290. С144Н19МО3.0.1Н20 was calculated С, 66.96; N, 7.71; M, 5.5896.

Example 6 2-(3-methoxyphenyl)-4-propyl morpholine

The borane-tetrahydrofuran complex (1M in THF) (200ml, 0.19mol) (200ml, 0.19mol) is added dropwise to the zo Mmorpholine-Z-one of example 5 (15.8g, O0.Omol) in dry THF (100ml ) in a nitrogen atmosphere during ЗОхв. The reaction mixture is refluxed for 1 h, then cooled and the reaction is quenched by adding methanol (3 mL). The reaction mixture is then concentrated in vacuo and the colorless residue is carefully suspended in (3 4M NOI (aq.) (400ml) before refluxing for 2.5h. The reaction mixture is cooled and dichloromethane (200ml) is added. The layers are separated and the aqueous layer is added the main properties of Me. by adding potassium carbonate before repeated extraction with dichloromethane (3 x 100 Oml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless oil (12.51 g, 0.05mol, 8490). "YAN NMR (SOSIS, 400MHz) 5: 0.95 (t, ЗН), 1.59 (q, 2Н), 2.05 (t, 1Н), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 « (d, 1), 2.98 (d, 71H), 3.80 (c, ЗН), 3.85 (t, 1H), 4 .05 (d, 1H), 4.60 (d, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 7.21 (t, 1), 7.23 (s, 1). IKM5: t/2 236, Analysis found C, 68.94; H, 8.80; M, 5.7995. С44Н24МО". 0.5Н2О0 - calculated C, 68.82; H, 9.08 ; M, 5.73905. "» Example 7A " K-(-)-3-(4-propylmorpholin-2-yl)uphenol

Example 7B 5-(()-3-(4-propylmorpholin-2-yl)uphenol -i still i no M o u z 50

Their hydrobromic acid (2500ml) and anisole of example b (8.62g, 0.0Zmol) are heated at reflux together for an hour. After cooling, the reaction mixture is diluted with water (100 ml), then neutralized by adding MH OH (20 ml). The yellow cloudy solution is then extracted with dichloromethane (2x10Oml). The organic extracts are combined, then dried over anhydrous magnesium sulfate, 59 filtered and concentrated in vacuo to obtain a racemic mixture of the compound in the form of a yellow oil (7.78 g,

GF) Oh, OZmol, 9695). Enantiomers are separated by chiral chromatography (SpigaIrak column AO 250"20mm), eluting with 7 mixture of hexane:isopropyl alcohol:diethylamine (70:30:0.05), with obtaining enantiomer 1 (ee 29595) and enantiomer 2 (ee »9995). Each the enantiomer is purified by column chromatography on silicon dioxide, eluting with a mixture of dichloromethane:methanol (95:5), obtaining enantiomer 1 (7a) (3.02g, 0.014mol, 3996) and enantiomer 2 (75) (3.15g, 0.014 mol, 4095) in the form of a colorless oil.

Enantiomer 1 (7a):

TN nMR (SOSIS, 400MHz) 5: 0.96 (t, ЗН), 1.60 (q, 2Н), 2.13 (t, 1Н), 2.31 (t, 1Н), 2.41 (t , 2H), 2.85 (d, 1), 3.02 (d, 1H), 3.90 (t, 1H), 4.02 (dd, 71H), 4.60 (d, 1H), 6 .78 (d, 1H), 6.80 (s, 1H), 6.91 (d, 1H), bB 720 (t, 18). KM: t/2 222 (М-Н7.

Enantiomer 2:

TN nMR (SOSIZ, 400 MHz) 5: 0.96 (t, HN), 1.60 (q, 2H). 2.13 (t, 1H), 2.31 (t, 1H), 2.41 (t, 2H), 2.85 (d, 1), 3.02 (d, 1H), 3.90 (t , 1H), 4.02 (dd, 71H), 4.60 (d, 1H), 6.78 (d, 1H), 6.80 (c, 1H), 6.91 (d, 1H), 7 ,20 (t, 1). IEM: t/: 222 (М-Н7).

Example 8

K-(-)-3-(4-propylmorpholin-2-yl)phenol hydrochloride

Enantiomer 1 (7a) of example 7 (3.00g, 0.014mol) is dissolved in diethyl ether (18Oml) and hydrogen chloride (2.0M solution in diethyl ether) (1Oml) is added. The reaction mixture was stirred at room temperature for 30 h, then the solvent was decanted and dried in vacuo to give the title compound 75 as a white solid (3.115 g, 0.012 mol, 9096).

TN NMR (С0О500, 400 MHz) 5: 1.06 (t, ЗН), 1.81 (m, 2Н), 3.02 (t, 1Н), 3.16 (t, 2Н), 3.20 (t , 1H), 3.60 (t, 2), 4.01 (t, 1), 4.26 (d, 1H), 4.71 (d, 71H), 6.78 (d, 71H), 6 .82 (s, 1H), 6.83 (d, 1H), 7.21 (t, 1H).

IEM: t/2 222 (M-NU). Analysis found C, 59.74; N, 7.98; M, 5.25905. С413Н419МО».0.18820 calculated С, 59.82; N, 7.86; M, 5.37905. (4p0--9.662 (methanol 10.bmg/1Oml). 720 A sample of the compound indicated in the title is recrystallized by vapor diffusion using a methanol:diethyl ether mixture and an X-ray crystal structure is obtained. The absolute stereochemistry of the compound indicated in the title is determined from diffraction data by the RIG ASK method ", and it is shown to have a "B" configuration.

Reference 1: N.O. RiaskK, Asia Stguzi. 1983, 439, 8766-8811

Example 9 g of 2-amino-1-(3,5-dimethoxyphenyl)ethanol

It is obtained according to the similar method of example 1, starting from 3,5-dimethoxybenzaldehyde (5.00 g, b 0 O, OZmol). After refluxing in EM NOI (aq), the reaction mixture is cooled and extracted with diethyl ether (2x8Oml). The organic layers are discarded and the basic properties are added to the aqueous layer by adding potassium carbonate. The aqueous residue is then extracted with ethyl acetate (3x7Oml). The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (3.47g, 0.018mol, 59905). "

TN NMR (С0О500, 400 MHz) 5: 2.77-2.86 (m, 2H), 3.78 (s, 6H), 4.60 (m, 1H), 6.38 (s, 1H), 6 ,52 (c, 2H). Z7Z 70 I EM: t/z 198 (M-NU). with Example 10; t IM-(2-(3,5-dimethoxyphenyl)-2-hydroxyethyl|propionamido -I o se) o r g) 50 Obtained, according to the similar method of example 2, starting from the amine of example 9 (3.41 g, O0 .017 mol).

The crude reaction mixture is purified by column chromatography on silicon dioxide, eluting with a mixture of dichloromethane:methanol (95:5), to obtain the title compound in the form of a bright yellow oil (3.08 Hg,

O, 12mol, 7096).

TN nMR (SOSIS, 400MHz) 5: 1.18 (m, 3H), 2.24 (m, 2H), 3.34 (m, 1H), 3.68 (m, 1H), 3.81 (s , 6H), 4.80 25 (dd, 1H), 5.95 (ush.s, 1H), 6.39 (s, 1H), 6.51 (s, 2H). I KM: t/2 252 (M-NU.

HF) Example 11 7 1-(3,5-dimethoxyphenyl)-2-propylaminoethanol is obtained, according to the similar method of example C, starting from the amide of example 10 (C3,Obg, 0.012 mol), with obtaining the indicated in of the title compound as an orange oil (2.72g, 0.011mol, 9495).

TN nMR (C0O300, 400 MHz) 5: 0.95 (t, 3H), 1.56 (m, 2H), 2.61 (m, 2H), 2.77 (d, 2H), 3.78 (s , 6H), 4.70 (t, 1H), 6.38 (s, 1H), 6.51 (s, 2H). And EM: t/2 240 (М-Н7).

Example 12 2-chloro-M-(2-(3,5-dimethoxyphenyl)-2-hydroxyethyl|-M-propylacetamide

About three shk

Obtained, according to the similar method of example 4, starting from the amine of example 11 (2.70OHg,

0.011 mol), to obtain the title compound in the form of a yellow oil (3.56 g, 0.011 mol, 10090).

TN nMR (SOSIZ, 400MHz) 5: 0.92 (t, ЗН), 1.61 (m, 2), 3.20 (m, 2H), 3.51-3.64 (m, 2H), 3 .80 (d, 6H), 4.13 (s, 2H), 4.95 (m, 1H), 6.40 (m, 1H), 6.55 (s, 23). I KM: t/2 316 (М-Н 7).

Example 13 6-(3,5-dimethoxyphenyl)-4-propylmorpholin-3-one (8)

Obtained, according to the similar method of example 5, starting from the amide of example 12 (3.43 g, "I 0.011 mol), with obtaining the compound indicated in the title in the form of a yellow oil (2.44 g, 0.009 mol, 7890). sch "YAN NMR (SOSIz, 400 MHz) 5: 0.94 (t, ЗН), 1.61 (m, 2Н), 3.30 (m, 2Н), 3.49 (m, 2Н), 3.80 (c, 6H), 4.30 (d, 1H), 4.42 (d, 1H), 4.73 (dd, 1H), 6.42 (c, 1H), 6.53 (c, 2H) . I EM: t/2 280 (M-N U. o

Example 14 Ge») 2-(3,5-dimethoxyphenyl)-4-propylmorpholine t o "shi s cy i"? Received, according to the similar method of example b, starting from the amide of example 13 (23.42 g,

O.009 mol). After refluxing in 6M HCl (aq.), the cooled reaction mixture was extracted with diethyl ether (2x8Oml). The organic layers are discarded and the basic -I properties are added to the aqueous layer by adding potassium carbonate. The aqueous residue is then extracted with ethyl acetate (3 minOml) and the organic extracts are combined, dried over magnesium sulfate, filtered, then concentrated in vacuo to give the title compound as a pale orange oil (2.14g, 0.008mol, 9396) . o TN nMR (СОО500, 400MHz) 5: 0.95 (t, ЗН), 1.58 (m, 2Н), 2.01 (m, 1Н), 2.22 (dt, 1Н), 2.38 ( t, 2H), 2.83 ka 20 (d, 1H), 2.93 (d, 1H), 3.78 (m, 7H), 4.01 (dd, 1H), 4.45 (dd, 1H ), 6.39 (c, 1H), 6.49 (c, 2H). I EM: t/:2 266 (М-Н 7).

Example 15A

T» Kk-5-(4-Protylmorpholin-2-yl)benzene-1,3-diol

Example 158 5-5-(4-propylmorpholin-2-yl)benzene-1,3-diol also

O yu If name) 60 on

Obtained according to the similar method of example 7, starting from the 3,5-dimethoxyphenyl compound of example 14 (1.00g, 0.004mol), obtaining the racemic compound specified in the title in the form of a brown oil (145mg, 0.6b1mmol, 1695). Enantiomers are separated by chiral chromatography (Spigairak AO column 250" 20mm), eluting with a mixture of hexane:isopropyl alcohol (80:20), obtaining enantiomer 1 (15a) (5.2mg) (ee 298.9490) and enantiomer 2 (155) (5.1mg) (ee 296.4690), both as brown oil.

Enantiomer 1 (15a):

TN nMR (С0О50О0, 400 MHz) δ: 0.96 (t, ЗН), 1.58 (m, 2Н), 2.01 (t, 1), 2.20 (dt, 1Н), 2.37 (t , 2H), 2.81-2.92 (m, 2H), 3.89 (dt, 1H), 3.99 (dd, 1H), 4.38 (dd, 1H), 6.18 (t, 1H), 6.26 (s, 2H). I VM: t/2 238 (М-Н7).

Enantiomer 2 (1565):

TN nMR (С050О0, 400 MHz) 5: 0.95 (t, ЗН), 1.58 (m, 2Н), 2.01 (t, 1), 2.20 (dt, 1Н), 2.38 (t , 2H), 2.80-2.92 (sq, 2H), 3.78 (dt, 1H), 3.98 (dd, 1H), 4.38 (dd, 1H), 6.18 (s, 1H), 6.25 (s, 2H). I KM5: t/:2 238 (М-Н 7).

Example 16 is 4-fluoro-3-methoxybenzaldehyde

IS

(4-fluoro-3-methoxyphenyl)methanol (5.00g, 0.003mol) and manganese dioxide (33.4g, 0.38mol) are stirred in dichloromethane (100ml) under a nitrogen atmosphere under careful reflux for 16 hours .

The cooled reaction mixture was then filtered through Arbacel and concentrated in vacuo to give the title compound as a white solid (4.18g, 0.027mol, 85905).

T"H NMR (SOCIz, 400 MHz) 5: 3.96 (s, ЗН), 7.23 (d, 1H), 7.43 (m, 1H), 7.50 (d, 1H) 9.91 ( s, 1N). T.pl.: 61-632S.

Analysis found C, 62.18; N, 4.5495. SYAONURO" calculated by C, 62.34; H, 4.5890.

Example 17 2-amino-1-(4-fluoro-3-methoxyphenyl)ethanol and mn

It is obtained, according to the similar method of example 1, starting from 4-fluoro-3-methoxybenzaldehyde (4.17 g, 0.02 mol). After boiling with reflux in 6M NS! (aq.) the reaction mixture is cooled and extracted with diethyl ether (2xboOml). The organic layers are discarded and the basic chemical properties are added to the aqueous layer by adding potassium carbonate. The aqueous residue is then extracted with ethyl acetate (3 minOml). The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered, then concentrated in vacuo to give the title compound as an orange oil (2.36g, 0.01Zmol, 47965). b

TN NMR (C0300, 400 MHz) 5: 2.80-2.91 (m, 2H), 3.86 (s, ЗН), 4.64 (m, 1H), 6.89 (m, IN), 7 ,03 (t, 1H),

Aphids (dd, IN). IVM8: t/z 186 (M-N). uh-

Example 18

IM-(2-(4-fluoro-3-methoxyphenyl)-2-hydroxyethyl|propionamide " - c I ;" " Obtained, according to the similar method of example 2, starting from the amine of example 17 (1.32 g, 0.007 mol). The crude reaction mixture is purified by column chromatography on silicon dioxide, eluting with a mixture of ethyl acetate:pentane (2:11), to obtain the title compound as a yellow oil, which

It crystallizes on standing (0.59g, O0.002mol, 3590). (Se) "YAN NMR (SOSIZ, 400MHz) 85: 1.18 (t, ZN), 2.24 (sq., 2H), 2.58 (ush.s, 1H), 3.34 (m, 1H) , 3.63 (m, 1H), 3.88 o (s, ЗН), 4.82 (dd, 1H), 5.98 (ush.s, 1H), 6.82 (m, 1H), 7 ,01 (m, 2H). And EM: t/2 242 (M-NU).

Example 19) 1-(4-fluoro-3-methoxyphenyl)-2-propylaminoethanol is obtained according to the similar method of example C, starting from the amide of example 18 (585 mg, 2.42 mmol). After refluxing in 6M NaCl (aq), the reaction mixture is cooled and extracted with diethyl ether (2x5Oml). Organic layers are discarded and basic properties are added to the aqueous layer by adding potassium carbonate. The aqueous residue is then extracted with ethyl acetate (3 x 50 ml). The organic 60 extracts were combined and dried over anhydrous magnesium sulfate, filtered, then concentrated in vacuo to give the title compound as a pale yellow oil (448 mg, 1.97 mol, 81905).

TN nMR (CO3O0, 400 MHz) 5: 0.96 (t, 3H), 1.58 (m, 2H), 2.63 (m, 2H), 2.79 (d, 2H), 3.96 (s , ZH), 4.77 (t, 1H), 6.90 (m, 1H), 7.03 (t, 1H), 7.11 (d, 1H). I EM: t/2 228 (М-Н7). 65 Example 20 2-chloro-M-(2-(4-fluoro-3-methoxyphenyl)-2-hydroxyethyl|-M-propylacetamide which

According to the similar method of example 4, starting from the amine of example 19 (0.84t. 4, 00mol), 70 is obtained to obtain the compound indicated in the title in the form of a yellow oil (0.97g, C, 000mmol, 8790). | KM: t/7 304 (M-NU), then used in an unrefined form.

Example 21 6-(4-fluoro-3-methoxyphenyl)-4-propylmorpholin-3-one in | that ru

IS

Obtained, according to the similar method of example 5, starting from the amide of example 20 (0.96 g,

C.0Omol), to obtain the title compound as a yellow oil (0.64g, 2.40mmol, 7590).

TN NMR (SOCI3, 400 MHz) 5: 0.94 (t, ЗН), 1.62 (m, 2Н), 3.33 (m, 2Н), 3.48 (m, 2Н), 3.91 (s , ZH), 4.34 (d, 1H), 4.43 (d, 1H), 4.76 (dd, 1H), 6.85 (m, 1H), 7.01-7.08 (m, 2H). And KM5: t/2 268.

Example 22 Ha 2-(4-fluoro-3-methoxyphenyl)-4-propylmorpholine o

More about We "

EE p

Obtained, according to the similar method of example b, starting from morpholin-3-one of example 21 (63Zmg, 2.37mmol). After refluxing in 6M NaCl (aq), the reaction mixture is cooled and extracted with diethyl ether (2x20ml). The organic layers are discarded and the basic Fd) properties are added to the aqueous layer by adding potassium carbonate. The aqueous residue is then extracted with ethyl acetate (3 x 20 Oml). The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil (552mg, 2.18mmol, 9295). "YAN nMR (СОО500, 400MHz) 5: 0.95 (t, ЗН), 1.58 (m, 2Н), 2.02 (t, 1Н), 2.22 (dt, 1Н), 2.38 ( t, 2H), 2.85 (d, 1H), 2.93 (d, 1H), 3.80 (m, 1H), 3.84 (s, ЗН), 4.01 (dd, 1H), 4.50 (dd, 1H), 6.88 (m, 1H), 7.02 (t, tn), « 40. 7.09 (d, 1H). KM: t/2 254 (M-H U ).

C-(-)-2-fluoro-5-(4-propylmorpholin-2-yl)uphenol also

V. but We are poor! !

Obtained according to the same method as in example 7, starting from the anisole of example 22 (200 mg, 0.789 mmol). The crude reaction mixture is purified by column chromatography on silicon dioxide, eluting

T" with a dichloromethane:methanol (90:10) mixture to obtain the title compound in the form of a dark yellow viscous oil (149 mg, O0.62 mmol, 79965). Enantiomers are separated by chiral chromatography (SpigaIrak column

Ar 250"20 mm), eluting with a mixture of hexane:isopropyl alcohol (90:10), with obtaining enantiomer 1 (23Za) in the form of a cloudy oil (15 mg) (ee »99.5965) and enantiomer 2 (235) in the form of a crystalline solid (1bmg) (ee 29996). (F) Enantiomer 1 (23a): co TN nMR (СОО3О0, 400MHz) 85: 0.95 (t, ЗН), 1.58 (m, 2Н), 2.01 (t . dd, 1H), 4.43 (d, 1H), 6.78 (m, 1H), 6.89-7.01 (m, 2H). IKM5: t/2 240 6o 0 (M-NU). sar-0.91 (ethanol 1.10mg/ml).

Enantiomer 2 (2365): "NMR (СОО500, 400MHz) δ: 0.96 (t, ЗН), 1.58 (m, 2Н), 2.01 (t, 1Н), 2.22 (dt, 1Н ), 2.38 (t, 2H), 2.78 (dd, 2H), 3.78 (dt, 1H), 4.00 (dd, 1H), 4.43 (dd, 1H), 6.78 (m, 11H, 6.91 (d, 1H), 6.98 (t, 1H). IKM5: t/2 240 (M-H7). ar--0.40 (ethanol 1.00Omg/ml). b5

Example 24

2-amino-1-(4-benzyloxyphenyl)ethanol on

Mn,

WITH

Potassium cyanide (20.15 g, 0.3 mol) and ammonium chloride (16.4 g, 0.0 mol) are dissolved in water (bOml), to which 4-benzyloxybenzaldehyde (32.9 g, 0.155 mol) is added, followed by the addition of diethyl ether (100 ml).

The reaction mixture is vigorously stirred for 48 hours. at room temperature before extraction with ethyl acetate (2x200ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the cyanohydric intermediate as a yellow solid (34.2g, 0.14mol, 9095). Then the cyanohydrin is dissolved in dry THF (300ml) and the borane-methylsulfide complex (26.bml, 0.28mol) is added. The reaction mixture is refluxed for 2 hours. before quenching with methanol (50 ml). Add water (5O0ml) followed by conc. CARRIER (4 Oml) and the reaction mixture are stirred for 2 hours. until the exothermic reaction weakens. Then the reaction mixture is concentrated in a vacuum the residue is diluted with water (10O0ml). Then the basic properties are added to the aqueous solution by adding MH OH (3 ml) and extracted with ethyl acetate (3 x 15 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (24.8g, 0.1Omol, 7395). "YAN iNMR (SOSIZ, 400 MHz) 5: 1.62 (us.s, ZN), 2.81 (dd, 1H), 2.99 (d, 1H), 4.61 (sq, 1H), 5, 07 (s, 2H), 6.95 (d, 2H), 7.22-7.45 (m, 7H). And EM: t/z 244 (M-H). s

Example 25 o

M-(2-(4-benzyloxyphenyl)-2-hydroxyethyl)propionamid ah Ky" and "

Su ie b sch "c)

The amine of example 24 (24.8 g, 0.100 mol) is dissolved in dichloromethane (7/0 Oml) and triethylamine (20.8 bml, o

Oh, 15 mol). The reaction mixture was stirred and cooled to 0°C before the dropwise addition of propionyl chloride (7.12 mL, 0.082 mol). Then the reaction mixture is allowed to warm up to room temperature for - 16 hours. before extinguishing ZM NSIII (aqueous) (20ml) and water (10Oml). Then the reaction mixture is extracted with dichloromethane (3x20Oml) and the combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain the compound in the form of a transparent viscous resin (27.5g, O0.092mol, 9095). NMR (SOSIS, 400 MHz) 5: 1.10 (t, ZN), 2.19 (sq, 2H), 3.32-3.43 (m, 4H), 4.81 (s, 2H) . z» 1 benzyloxyphenium) tropylaminoethanol

Y. -I

F Fa (in)

To the amide of example 25 (27.5 g, 0.092 mol) in dry THF (10 ml) add the borane-methyl sulfide complex (17.5 ml, where 0O.18 mol). The reaction mixture is cooled and then the reaction is quenched with methanol (3 mL). Add water (5 Oml) and conc.

T» NOI (35 ml) and the reaction mixture are stirred until the formation of bubbles stops, then concentrated in a vacuum. Water (250 ml) is added to the residue and then basic properties are added by adding MH OH (30 ml).

The aqueous layer is extracted with ethyl acetate (3x200ml and the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (26.1g, 0.09mol, 9990). i) TN NMR (СО300, 400MHz) 5: 0.95 (t, ЗН), 1.58 (kv, 2Н), 2.6; (m, 2H), 2.81 (m, 2H), 4.72 (dd, 1H), 5.05 de (s, 2H), 6.95 (d, 2H), 7.24 (m, ЗН ), 7.35 (t, 2H), 7.41 (d, 2H). IEM: t/z2 286 (М-Н7).

Example 27 60 6-(4-benzyloxyphenyl)-4-propylmorpholin-3-one b5 and m

FI

Sodium hydroxide (22.5g, 0.5bmol) in water (1000ml) was added to the amine of example 26 (26.0g, 0.09mol) in dichloromethane (4000ml) and the solution was vigorously stirred at room temperature. Then chloroacetyl chloride (8.bml, 0.11 mol) is added and the reaction mixture is stirred for another 20 minutes. The layers are separated and the aqueous layer is re-extracted with dichloromethane (200 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a colorless oil. Potassium hydroxide (15.0 g, 0.27 mol), isopropyl alcohol (400 ml) and the remainder of the colorless oil are mixed together as a cloudy solution with water (30 ml) for 2 hours. The reaction mixture is concentrated in vacuo and the yellow residue is dissolved in ethyl acetate (200 ml). It is separated with water (200 ml), then with a saturated salt solution (200 ml).

The organic fraction was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (19.9g, 0.00bmol, 67905). "YAN NMR (SOSIz, 400MHz) 5: 0.95 (t, ЗН), 1.62 (m, 2Н), 3.34 (m, 2Н), 3.51 (m, 2Н), 4.32 ( d, 1H), 441 (d, 1H), 4.72 (dd, 1H), 5.04 (s, 2H), 6.98 (d, 2H), 7.31-7.43 (m, 7H ).And EM: t/2 326 (М-Н 7).

Example 28 2-(4-benzyloxyphenyl)-4-propylmorpholine still

We, i) about « sch

Obtained, according to the similar method of example 26, using morpholin-3-one of example 27 (19.9g, 0.061mol), to obtain the compound indicated in the title in the form of a colorless oil (17g, 0.055mol, about 9096). (22) "YAN NMR (SOSIZ, 400 MHz) 5: 0.95 (t, ЗН), 1.55 (kv, 2Н), 2.06 (t, 1Н), 2.21 (dt, 1Н), 2 .35 (dd, 2H), 2.80 m 79 (d, 1H), 2.91 (d, 1H), 3.82 (dt, IN), 4.02 (dd, 1H), 4.52 ( dd, 1H), 5.05 (s, 2H), 6.98 (t, 2H), 7.24-7.42 (m, 7H). M: t/2 312 (M-H7).

Example 29 4-(4-propylmorpholin-2-yl)uphenol « with shk Z i- Wash with no

The simple benzyl ether of example 28 (3.0g, 9.b4mmol) is dissolved in methanol (150ml) and 1090 -I palladium on activated carbon (80Omg) is added. The reaction mixture was stirred for several minutes before ammonium formate (6.17 g, 96.4 mmol) was added portionwise. The reaction mixture is carefully heated to 802C until gas evolution stops. After cooling, the reaction mixture was filtered through Arbacel, (ab) washed with methanol (50ml) and concentrated in vacuo to give the title compound as a white crystalline solid (1.51g, 6.83mmol, 71965). "YAN NMR (SOSIZ, 400 MHz) 5: 0.91 (t, ЗН), 1.58 (kv, 2Н), 2.10 (Т, 1Н), 2.22 (Т, 1), 2.40 ( dd, 2H), 2.81 t" (d, 1H), 2.93 (d, 1H), 3.85 (t, 1H), 4.02 (dd, 1H), 4.57 (d, 1H ), 6.79 (d, 2H), 7.21 (d, 2H). And EM: t/z2 222 (M-H7).

Example 30 2-bromo-4-(4-propylmorpholin-2-yl)uphenol a

F) well, on

M-bromosuccinimide (161mg, 0.9mmol) was added to the phenol of example 29 (200ml, 0.9mmol) in dichloromethane (bml). The reaction mixture is stirred at room temperature for 55 hours. before concentration under vacuum. The crude product was purified by column chromatography on silicon dioxide, eluting with a mixture of dichloromethane:methanol (95:5), to give the title compound as a white foam (117.5 mg, 65 O.ZOmole, 44905). "YAN iNMR (SOSIZ, 400 MHz) 5: 0.96 (t, ЗН), 1.59 (q, 2Н), 2.03 (t, 1Н), 2.23 (t, 1Н), 2.40 ( t, 2H), 2.81

(d, 1), 2.98 (d, 71Н), 3.82 (t, 1Н), 4.01 (d, 71Н), 4.56 (d, 1Н), 6.96 (d, 71Н) , 7.20 (d, 1H), 7.49 (c, 1H).

IM: t/2 302 (M-N"U, Hg isotope).

Example 31 2-(4-benzyloxy-3-bromophenyl)-4-propylmorpholine in 70 va

Potassium carbonate (75mg, 0.54mmol) and benzyl bromide (0.07ml, 0.54mmol) were added to the phenol of example 30 (117.5mg, O0.39mol) in dry DMF (10ml) under a nitrogen atmosphere. The reaction mixture is heated to 1509 for 75 48 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (BOml) and water (5Oml). The aqueous layer is then re-extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as a brown oil. The oil was purified by column chromatography on silicon dioxide, eluting with a mixture of dichloromethane:methanol (98:2), to obtain the title compound as a colorless oil (153 mg, 0.39 mmol, 100965).

TN nMR (SOSIZ, 400 MHz) 5: 0.93 (t, ЗН), 1.56 (q, 2Н), 2.05 (t, 1Н), 2.25 (t, 1Н), 2.37 (t , 2H), 2.82 (d, 1), 2.92 (d, 1H), 8.85 (t, 71H), 4.02 (d, 1H), 4.52 (d, 1H), 5 ,15 (s, 2H), 6.87 (d, 71H), 7.20 (d, 1H), 7.30 (d, 1H), 7.37 (t, 2H), 7.45 (d, 2H), 7.58 (s, 1H). I EM: t/2 392 (M-NU).

Example 32 p

2-Benzyloxy-5-(4-propylmorpholin-2-yl)benzoic acid methyl ether

Triethylamine (2.1 ml, 0.78 mmol) and F) methanol (2 ml) were added to the bromide of example 31 (153 mg, 0.39 mmol) in dry DMF (4 ml) and the reaction mixture was stirred for 10 minutes. Complex M

I1,1-bis(diphenylphosphine)ferrocene|dichloropalladium (II) and dichloromethane (1:1) (1 mg, 0.02 mmol) were added before carbon monoxide (gas) (3 filled cylinders) was bubbled through the reaction mixture. Then the reaction mixture is heated to 1002 for 1 hour. in a carbon monoxide atmosphere. After cooling, the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (25 mL) and water (200 mL). The organic layer was separated, washed with saturated salt solution (20 ml) and dried over anhydrous magnesium sulfate, filtered in c and concentrated in vacuo to obtain a black solid. Purification by column chromatography on silicon dioxide eluting with a mixture of dichloromethane:methanol:ammonia (90:10:1) gave the title compound "c" as a colorless oil (105 mg, 0.28 mmol, 73905). "YAN iNMR (SOSIZ, 400 MHz) 5: 0.94 (t, ЗН), 1.60 (m, 2Н), 2.18 (s, 4Н), 2.43 (m, 2Н), 3.00 ( m, 2H), 3.90 (s, ЗН), 4.04 (d, 1H), 5.18 (s, 2H), 5.97 (d, 1H), 7.26-7.47 (m . 0 out of 50 but I eat it

To the complex methyl ether of example 32 (105 mg, 0.28 mmol) in methanol (bml) add 1090 sodium hydroxide (aq.) (15 ml) and boil the milky-white suspension under reflux for 2 hours. Reactionary

Ф) the mixture, which has become colorless, is cooled, then neutralized by adding 2M NSII (aqueous) (several drops). The reaction mixture was then concentrated in vacuo to give the title compound as an off-white solid (99mg, 0.28mmol, 10095). IEM: t/2 355 (M-H"). The specified substance is used unpurified in example 34.

Example 34 2-benzyloxy-5-(4-propylmorpholin-2-yl)benzamide b5

AND

"uh

Where

Thionyl chloride (ml) is added to the crude benzoic acid of example 33 (9Omg, 0.28 mmol) and the reaction mixture 7/0 is heated to 502C for 2 hours. The reaction mixture is cooled and excess thionyl chloride is removed in vacuo. Then the residue is dissolved in dichloromethane (10ml) and ammonia (gas) is bubbled through the reaction mixture for 10h. The resulting suspension is stirred at room temperature for an hour. before concentration under vacuum. The crude material is purified by silica column chromatography, eluting with a mixture of dichloromethane:methanol:ammonia (95:5:0.5), to give the title compound as a 7/5 off-white solid (88mg, 0.25mmol, 9096 ).

TN nMR (SOSIZ, 400MHz) 5: 0.94 (t, ЗН), 1.59 (m, 2Н), 2.15-2.42 (m, 4Н), 2.87 (m, 1Н), 3 .03 (m, 1H), 3.96 (m, 71H), 4.02 (d, 1H), 4.67 (m, 1H), 5.19 (s, 2H), 5.72 (m, 1), 7.04 (d, 1H). 7.41 (m, 5H), 7.50 (d, 1H), 7.70 (m, 1H), 8.21 (s, 1H). I KM: t/2 355 (М-Н7).

Example 35 20 2-hydroxy-5-(4-propylmorpholin-2-yl)benzamide in nm

Obtained, according to the similar method of example 29, using the complex benzyl ether of example 34 (8Omg, 0.22mmol), with obtaining the compound indicated in the title in the form of a not quite white solid material (5bmg, 0.21mmol, 9696). "zo"YAN NMR (СОО500, 400MHz) 5: 0.95 (t, ЗН), 1.55 (m, 2Н), 2.13 (t, 1Н), 2.29 (t, 1Н), 2, 42 (m, 2H), 2.88 (d, 1), 2.97 (d, 71H), 3.81 (t, 1H), 4.00 (d, 1H), 4.49 (d, 1H ), 6.87 (d, 71H), 7.42 (d, 1H), 7.78 (s, 1H).

And EM: t/2 265 (M-N). (av)

Example 36 2-nitro-4-(4-propylmorpholin-2-yl)phenol F 35 x i-

Om M

M « no no 70 Phenol of example 29 (100 mg, 0.45 mmol) is dissolved in a mixture of nitric acid: water (1:3) (2 ml) and stirred at room temperature for 1 hour. Then the reaction mixture is diluted with water (5 ml) and the main :c» properties of MNAOH (1 ml) are added before extraction with ethyl acetate (3 x 1!0 ml). The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (95mg, 0.35mmol, 7990). -I "YAN NMR (SOSIZ, 400 MHz) 5: 0.97 (t, ZN), 1.33 (t, 2H), 1.43-1.79 (ush.m, 4H), 2.02 (d , ZH), 4.06 (m, 2H), 7.17 (d, 1H), 7.60 (d, 1H), 8.16 (s, 1H), 10.55 (ush. I EM: t/2 267 (M-NU. i-o Example 37 av | 2-amino-4-(4-propylmorpholin-2-yl)phenol with 50 more

T» nm p no 22 To the nitro compound of example 36 (95 mg, 0.35 mmol) in ethanol (1 Oml) add 1095 palladium on activated

Gee! coal (5Omg) and ammonium formate (100mg, X5). The reaction mixture is carefully heated to 102C, kept at this temperature for an hour. and then allowed to cool to room temperature. Then the reaction mixture is filtered through Arbacel and washed with ethanol (20 ml), then with dichloromethane (20 ml). The organic washings were combined and concentrated in vacuo to give the title compound as a yellow solid (b5mg, 0.28mmol, 7890).

TN nMR (SOSIS, 400 MHz) 5: 0.91 (t, ЗН), 1.55 (m, 2Н), 2.12 (t, 71Н), 2.25 (dt, 1Н), 2.40 (t , 2H), 2.81-2.92 (dd, 2H), 3.82 (t, 1H), 4.00 (d, 1H), 4.42 (d, 1H), 6.60 (m, 2H), 6.71 (s, 1H). I KM: t/2 237 (М-Н 7).

Example 38 in 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine

VG

, vi

My

In addition, 5-bromopyridin-2-ylamine (13.8 g, 0.08 mol), acetonylacetone (14.1 mL, 0.12 mol), and paratoluenesulfonic acid (100 mg) were dissolved in toluene (18 mL) and refluxed in conditions of Dean-Stark 70 for 14 hours. After cooling, the brown solution is poured into water (200ml) and extracted with toluene (2x20Oml). The organic extracts are combined and washed with saturated salt solution (5 Oml), then dried over anhydrous magnesium sulfate. Filter and concentrate in a vacuum to obtain a crude product.

The product was purified by column chromatography on silicon dioxide, eluting with a mixture of ethyl acetate:pentane (1:3), to obtain the title compound as a brown oil (18.4 g, 0.07 mol, 9296).

TN NMR (SOSI, 400 MHz) 5: 2.18 (s, 6H), 5.90 (s, 2H), 7.11 (d, 1H), 7.92 (d, 1H), 8, 62 (s, 1H). IEM: t/:2 253 (M-NU, Wu isotope).

Example 39 2-chloro-1-(6-(-2,5-dimethylpyrrol-1-yl)pyridin-3-ilyethanone

What is itinnt se o

Butyllithium (2.5M in hexanes) (3.5ml, 8.8mmol) was added dropwise over 20min to a solution of bromopyridine of example 38 (2g, 8.0mmol) at -782C in dry THF (30ml). The reaction mixture was stirred for 30 h, then 2-chloro-M-methoxy-M-methylacetamide (1.2 g, 8.8 mmol) in dry THF (20 ml) was added dropwise, maintaining the temperature at -78C. Stirring is continued during ZOkhv. at this temperature before the addition of 1M Nei (aq.) (5Oml), and the reaction mixture is heated to room temperature. The organic layer was separated and the aqueous layer was washed with ethyl acetate (50 ml). The organic layers are combined, then washed with ZM Mahon (aq.) and saturated salt solution (10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain the title compound as a brown oil (1.34 g, 5.4 mmol, 6796). F "YAN NMR (SOSIZ, 400 MHz) 5: 2.20 (s, 6H), 4.68 (s, 2H), 5.92 (s, 2H), 7.32 (d, 1H), 8.38 (d, 1H), 9,16 (c, 18), I8M8: ti/" 249 (M-H7). -

Example 40 2-(2,5-dimethylpyrrol-1-yl)-5-oxyranylpyridine o "5 shi s - :" dk lush, 15 To the ketone of example 39 (1.34 g, 5.4 mmol) dissolved in dry THF (20 ml), cooled to 02C, sodium borohydride (308 mg, 8.1 mmol) is added in portions -I. The reaction mixture is stirred for 2 hours, then ZM (Se) Mahon (aq.) (1 Oml) is added and stirring is continued for another 1 hour. The reaction mixture was extracted with ethyl acetate (2x2Oml) and the combined organic extracts were washed with saturated salt solution (ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silicon dioxide, eluting with a mixture of ethyl acetate: pentane (1:5), to obtain the

Their" title compound as a colorless oil (900mg, 4.2mmol, 78965).

TN nMR (SOSIS, 400 MHz) 5: 2.13 (s, 6H), 2.91 (dd, 1H), 3.25 (t, 1H), 3.98 (t, 1H), 5.90 (s , 2H), 7.20 (d, 1H), 7.62 (dd, 1H), 8.58 (s, 1H). And EM5: t/2 215 (М-Н7). 5B Example 41 o 1-(6--2,5-dimethylpyrrol-1-yl)pyridin-3-yl|-2-propylaminoethanol o M i, "m She: 60 i di --i

Propylamine (4 ml, 4.8 mmol) was added to the epoxide of Example 40 (900 mg, 4.2 mmol) in DMSO (5 ml) and the reaction mixture was heated to 402C for 4 days. The reaction mixture was then cooled and 3M NOI (aq.) (1Oml) and water (1Oml) were added before washing with diethyl ether (2 x 1Oml). The organic layer is removed, the basic properties of MNAOH (bml) are added to the aqueous layer and extracted with ethyl acetate (3x1Oml). The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an oil (1.15g, 4.2mmol, 100905).

TN nMR (SOSIZ, 400 MHz) 5: 0.93 (t, ЗН), 1.62 (m, 2Н), 2.11 (s, 6Н), 2.69-2.82 (m, ЗН), 3 .06 (dd, 1H), 3.60 (ush.s, 2H), 4.92 (dd, 1H), 5.84 (s, 2H), 7.20 (d, 1H), 7.88 ( d, 1H), 8.61 (c, 1H). And EM5: t/z2 274 (M-H7).

Example 42 6-I(I6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl|-4-propylmorpholin-3-one bte 7 with M

Obtained according to the similar method of example 27, using the amine of example 41 (1.15 g, 4.2 mmol). Purification by column chromatography on silica eluting with dichloromethane:methanol (98:2) gave the title compound as a brown film (191 mg, 0.1 mmol, 1496).

TN nMR (SOSIS, 400 MHz) 5: 0.97 (t, ЗН), 1.65 (m, 2Н), 2.13 (s, 6Н), 3.38 (m, 1Н), 3.42-3 .56 (m, 2H), 6.61 (t, 1H), 4.35 (d, 1H), 4.45 (d, 1H), 4.91 (dd, 1H), 6.91 (s, 2H), 7.22 (d, 1H), 7.89 (d, 1H), 8.61 (s, 1H). 1 KM: t/2 314 (М-Н7).

Example 43 s nin s o

Bunch of her tn - sch p | "in)

To a solution of morpholin-3-one of example 42 (191 mg, 0.61 mmol) in dry THF (5 ml) is added aluminum hydride (IM F solution in diethyl ether) (1.25 ml, 0.1 bimmol) and the reaction mixture is heated at boiling with the reverse

Refrigerate for 2.5 hours. The reaction mixture is cooled to room temperature, then 1M -

Mmaon (1.25 ml), with a white precipitate. The reaction mixture is filtered and concentrated in vacuo. The white solid is removed. The concentrated filtrate was purified by column chromatography on silicon dioxide, eluting with a mixture of dichloromethane:methanol (95:5), to obtain the title compound in the form of a white film (108 mg, 0.3 mmol, 59905). with s 70 TN NMR (SOSIZ, 400MHz) 5: 0.92 (t, ЗН), 1.61 (sq, 2Н), 2.10 (s, 6Н), 2.15 (m, 1Н), 2, 29 (dt, 1H), 2.40 (t, 2), 2.82 (d, 1), 3.02 (d, 1H), 3.90 (t, 1H), 4.08 (d, 1H ), 4.71 (d, 1H), 5.89 (c, 2H), 7.20 (d, 1H), ;" 7.81 (d, 1H), 8.60 (c, 1H). I VM: t/2 300 (MN).

Examples 44A and 448 5-(4-propylmorpholin-2-yl)pyridin-2-ylamine - more ee, ru o | r with 50 p

To 2,5-dimethylpyrrole of example 43 (45 mg, 0.15 mmol) in ethanol (3 ml) add hydroxylamine hydrochloride (52 mg, 0.75 mmol) and the reaction mixture is heated to 802 for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue is purified by column chromatography on silicon dioxide, eluting with a mixture of dichloromethane:methanol:ammonia (90:10:11), to obtain racemic compound 29 in the form of a colorless film (31 mg, 0.14 mmol, 9495).

HF) TN nMR (SOSI, 400 MHz) 85: 0.92 (t, ЗН), 1.60 (m, 2Н), 2.11 (t, 71Н), 2.25 (dt, 1Н), 2.41 (t, 2H), d) 2.82-2.91 (dd, 2H), 3.89 (dt, 1H), 4.01 (dd, 1H), 4.57 (ush.d, ZN), 6.49 (d, 1H), 7.42 (d, 1H), 8.02 (c, 1H).

I EM: t/:2 222 (М-Н7). in A sample of the racemic product (58Omg) is separated into its constituent enantiomers by chiral HPLC.

Conditions used: Spigrask AYU column (250 x 21.2 mm), eluent methanol:ethanol (1:1), volume flow rate 15 ml/min.

The more eluted enantiomer of example 44A is obtained (retention time 8, Зхв.) at 299965, ee.

H NMR data (SOCI, 400 MHz) were identical to those of the racemate. | KM5: t/2 222. Analysis found C, 63.54; H, 65 8.60; M, 18.3895. С12Н419М30. С3НО calculated С, 63.58; H, 8.71; M 18.5396.

Iodine 29-21 (c-0.12, MeOH); (odalzv2-8.9 (c-0.12, MEON).

The more slowly eluted enantiomer of example 44B is obtained (retention time 9 4 min.) with an ee of 98.9965.

H NMR data (SOCI, 400 MHz) were identical to those of the racemate. | KM5: t/2 222. Analysis found C, 63.53; H, 8.57; M, 18.36905. С12Н19М50.3НоО calculated С, 63 .58; H, 8.71; M 18.5390.

Iodine 2.4 (c-0.12, MeOH); (odlzv 972 (s-0.12, MeOH)

Example 45 2-ethyl-6-(3-methoxyphenyl)-4-propylmorpholin-3-one 70 Kha ru

Sodium hydroxide (0.48g, 12.00mmol) in water (2ml) was added to the product of example C (0.50g, 2.4mMmol) in dichloromethane (bml) and the mixture was stirred at room temperature. Then 2-chlorobutyl chloride (0.28ml, 2.87mmol) was added dropwise and the reaction mixture was stirred for 2h. The reaction mixture is diluted with dichloromethane (1 Oml) and the aqueous layer is separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as a clear oil (containing a mixture of cyclized and uncyclized product) (0.57 g). IM: t/2 314 (M-H" of non-cyclized product), 296 (M-H' less water), 278 (M-H" of cyclized product). Potassium hydroxide (0.13g, 2.20mmol) was dissolved in water (ml) and added to a solution of the crude product (0.57g, 1.83mmol) in isopropyl alcohol (bml). The reaction mixture is stirred at room temperature overnight and the organic solvent is then evaporated in vacuo. The residue is dissolved in ethyl acetate (1 Oml) and the aqueous layer is separated. The organic layer (Ge) is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to obtain a crude product in the form of an oil. The residue was purified by silica column chromatography, eluting with ethyl acetate:pentane (1:5 to 1:1) to give the title compound as a clear oil (326 mg, 1.17 mmol, 4995) as a mixture of diastereomers. " "YAN NMR (SOSIZ, 400 MHz) 5: 0.90 (t, ЗН), 1.00 (t, ЗН), 1.60 (m, 2Н), 2.00 (ush.m, 2Н), 3 ,10-3.60 (m, 4H), s 3.80 (s, ZH), 4.20 (d, 0.5 H), 425 (d, 0.5 H), 4.75 (d, 0.5 N), 4.90 (d, 0.5 N), 6.80 (d, 1H), 6.90 (m, 2H), 7.25 (m, 1H). EM5 (ARSI): t/2 278 (MN), 276 (MN. o

Examples 46A and 4685 Ge) 2-ethyl-6-(3-methoxyphenyl)-4-propylmorpholine m g « z З - с . is" The borane-tetrahydrofuran complex (1M in THF) (Zml, Zmmol) is added dropwise to the product of example 45 (0.33g, 1.18mmol) in dry THF (4ml) under a nitrogen atmosphere. The reaction mixture is heated at 8523 for 1 h, then cooled and the reaction is quenched by adding methanol (1 mL). Then the reaction mixture is concentrated in a vacuum - and the residue is suspended in EM NOSE (1 Oml) and heated to 602 for 1.5 hours. The reaction mixture is cooled and co-extracted with diethyl ether (2x1Oml). Basic properties (pH 9-10) are added to the aqueous layer by adding solid potassium carbonate before repeated extraction with dichloromethane (2x15ml). The dichloromethane extracts are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as a clear oil. Purification by column chromatography on silica eluting with a mixture of ethyl acetate:pentane (1:10) gives the 2 compounds indicated in the title as single diastereoisomers. Example 46A: clear oil (0.10g, 0.3v8mmol, 32960):

TN NMR (SOSIZ, 400MHz) 5: 1.00 (m, 6H), 1.60 (us.m, ЗН), 1.85 (m, 1Н), 2.25 (us.t, 2Н), 2 .35 (s, 1H), 2.45 (m, 1), 2.60 (m, 1H), 2.65 (m, 71H), 3.70 (s, 1H), 3.80 (s, ЗН), 4.80 (s, 1Н), 6.80 (d, 71Н), 7.00 (m, 2Н), 7.25 (m, 1Н). And KM5 (ARSI): t/: 264

GF) Example 468: clear oil (0.10g, О.Св8mmol, 3295):

GI "YAN NMR (SOSIz, 400MHz) 5: 0.90 (t, ZN), 1.00 (t, ZN), 1.60 (us.m, 4H), 1.80 (us.s, 1H) , 2.00 (ush.s, 1H), 2.35 (ush.s, 2H), 2.85 (ush.d, 71H), 2.95 (ush.d, 1H), 3.60 (s . IKM5 (ARSI): t/2 264 (MN).

Example 47A 3-(6b-ethyl-4-propylmorpholine-2-iluphenol b5)

Hydrobromic acid (4895 aq., 5ml) and the product of example 46A (0.10g, 0.3vmmol) are heated at 802С 70 for 16bh. After cooling, the reaction mixture is concentrated in vacuo. The residue is distributed between aqueous ammonia (0.880, 15 ml) and dichloromethane (15 ml), the layers are separated and the aqueous layer is re-extracted with dichloromethane (2x15 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica, eluting with dichloromethane, then with a mixture of dichloromethane:methanol (from 99:11 to 95:5), to obtain the title compound indicated in 75 in the form of a clear oil (b5mg, 0.2bmmol, 6990) as of a single diastereoisomer.

TN NMR (SOSIZ, 400 MHz) 5: 0.95 (m, 6H), 1.60 (m, ЗН), 1.85 (m, 1H), 2.25 (m, 2H), 2.45 (m , 2H), 2.55 (sq, 1H), 2.75 (d, 1H), 3.75 (s, 1H), 4.80 (m, 1H), 6.70 (d, 1H), 6 .90 (s, 1H), 7.00 (1H, d), 7.25 (t, 1H).

And EM5 (ARSI): t/2 250 (MH"). Analysis found C, 70.9495; H, 9.1695; M, 5.5395. C15NozMO". 0.3H2O calculated C, 70.7290; H, 9.34905; M, 5.5090.

Example 478 3-(6b-ethyl-4-propylmorpholine-2-iluphenol with o

M

7 | ze chit -th "

Obtained, according to the similar method of example 47A, using the product of example 468 ml (0.10 g, 0.38 mmol). Purification by column chromatography on silicon dioxide is not required. The title compound was obtained as a yellow oil (57mg, 0.23mmol, 6090) as a single diastereoisomer. (ав) "YAN NMR (SOSIZ, 400 MHz) 5: 0.90 (t, ЗН), 1.00 (Т, ЗН), 1.60 (m, 4Н), 1.85 (t, 1Н), 2 .00 (t, 1H), 2.35 (m, o 2H), 2.90 (d, 1), 3.00 (d, 1H), 3.65 (m, 1H), 4.60 (m , 1H), 6.75 (d, 71H), 6.80 (s, 1H), 6.90 (1H, d), 7.20 (t, 18). IKM5 (EBI): t/2 250 ( MNyayu, 248 (M-NU. Analysis found S, 71.6390; H, 9.1995; M, 5.5596. -

C.5nNoZMO,.01Noo calculated C, 71.7390; H, 9.3195; M, 5.5895.

Example 48 2-methyl-6-(33-methoxyphenyl)-4-propylmorpholin-3-one It is obtained according to the similar method of example 45, using the product of example C (0.44 g, with 2.1 mmol) and 2-chloropropionyl chloride (0.25 ml, 2.50 mmol). Purification by silica column chromatography of the title compound is not required. The title compound in the form of a clear oil (c) (0.42g, 1.6O0mmol, 7695) is obtained as a mixture of diastereomers.

He 20 "YAN yNMR (SOSIZ, 400MHz) 5: 0.95 (t, ZN), 1.60 (m, 5H), 3.30 (ush.m, 2H), 3.50 (ush.m, 2H ), 3.80 (s, ЗН), 4.40 (sq, 0.5 N), 4.55 (sq, 0.5 N), 4.80 (dd, 0.5 N), 4.95 (dd, 0.5 H), 6.85 (d, 1H), 6.95 (s, 2H), 7.25 (m,

T" 1H). GEM5 (ARSI): t/2 264 (MN), 262 (MN).

Examples 49A and 49831 rya 2-methyl-6-(3-methoxyphenyl)-4-propylmorpholine (F) X with 60

Obtained according to the similar method of example 46, using the product of example 48 (0.42g, 1.bmol). Purification by column chromatography on silica eluting with a mixture of ethyl acetate:pentane (1:6) gives the 2 compounds indicated in the title as single diastereomers. for Example 49A: clear oil (0.10g, 0.4Omol, 25965):

TN nMR (SOSIZ, 400MHz) 5: 0.95 (t, ЗН), 1.30 (d, ЗН), 1.60 (m, 2Н), 2.20-2.35 (m, ЗН), 2 .50 (d, 1H), 2.60 (m, 1), 2.65 (d, 1H), 3.80 (s, ЗН), 4.00 (s, 1H), 4.85 (s, 1H), 6.80 (d, 1H), 7.05 (m, 2H), 7.25 (m, 1H). GEM5 (ARSI): t/2 250 (MN).

Example 49B: transparent oil (0.10g, 0.4Omol, 2596): "YAN NMR (SOSIz, 400MHz) 5: 0.90 (t, ZN), 1.25 (m, ZN), 1.60 (m , 2H), 1.80 (m, 1H), 2.00 (ush.m, 1H), 2.35 (s, 2H), 2.80 (d, 71H), 2.90 (d, 71H) , 3.80 (s, ЗН), 3.85 (s, 1H), 4.60 (s, 1H), 6.80 (d, 71H), 7.00 (m, 2H), 7.25 ( m, 1H). ' EM5 (ARSI): t/: 250 (MN).

Example 50A is yours

Obtained according to the similar method of example 47A, using the product of example 49A (0.10 g, 0.4 mmol). Purification by column chromatography on silica eluting with dichloromethane, then dichloromethane:methanol (199:1) gave the title compound as a clear oil (7Omg,

O, ZOmmol, 7495) in the form of a single diastereoisomer.

TN NMR (SOCIz, 400MHz) 5: 0.95 (t, ЗН), 1.35 (d, ЗН), 1.55 (m, 2Н), 2.25 (m, 2Н), 2.35 (m , 1H), 2.50 (m, 1H), 2.55 (m, 1H), 2.75 (d, 1H), 4.05 (s, 1H), 4.85 (m, 71H), 6 .70 (d, 71H), 6.90 (s, 1H), 7.00 (1H, d), 7.20 (t, 13). GKM5 (ARSI): t/2 236 (Mnya). Analysis found C, 70.6290; H, 8.8990; M, 5.9595.. C44H»4MO».0.18250 s calculated C, 70.91905; H, 9.01905; M, 5.91965.

Example 508 i) 3-(6-methyl-4-propylmorpholin-2-yl)phenol as chI i; You cm "c)

Obtained according to the similar method of example 47A, using the product of example 498 (0.10g, 0.4mmol). Purification by silica column chromatography is not required. The title compound is obtained in the form of a yellow oil (100mg, O0.42mmol, 10390 - contains 395 starting substances) in the form of a single diastereomer. "YAN NMR (SOSIz, 400 MHz) 5: 0.90 (t, ZN), 1.25 (d, ZN), 1.60 (m, 2H), 1.85 (m, 1H), 2.00 ( m, 1H), 2.35 (m, « 2H), 2.85 (d, 1), 3.00 (d, 1H), 3.85 (s, 1H), 4.60 (d, 1H) , 6.75 (d, 1H), 6.80 (s, 1H), 6.90 (1H, d), 7.20 C to (m, 1H). (MH). Analysis found C, 69.38905; H, 8.8690; M, 5.7395.. C44H24MO". 0.45H50 s calculated C, 69.33905; H, 9.0690; M, 5.7890 Example 51 1-(4-chloro-3-methoxyphenyl)-2-propylaminoethanol

Sodium triacetoxyborohydride (1.25 g, 5.89 mmol) is carefully added to a solution of 2-amino-1-(4-chloro-3-methoxyphenyl)ethanol M. Mei.Spet., 30(10), 1997, (1987) ( bOOmg, 2.98 mmol) (i

T" of propionaldehyde (0.22 ml, 2.9 mmol) in dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for an hour. Sodium bicarbonate solution (saturated, aqueous, 10 ml) is added dropwise and then the reaction mixture is further diluted with water (20 ml) and dichloromethane (20 ml). The aqueous layer is separated and re-extracted with dichloromethane (2 x 20 ml). The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography on (F; silicon dioxide, eluting with a mixture of dichloromethane:methanol:0.880 ammonia (from 95:5:0.5 to 92:8.0.8), obtaining

GI of the title compound as a solid (32Omg, 1.31mmol, 44905). "YAN iNMR (SOSIZ, 400 MHz) 5: 0.90 (t, ЗН), 1.50 (kv, 2Н), 2.50-2.70 (m, 5Н), 2.90 (dd, 1Н), 3.80 (c, ZN), 60 4.65 (dd, 1H), 6.85 (d, 1H), 7.00 (1H, d), 7.30 (ush.d, 1H). I EM (ARSI): t/2 244 (MNU), 226 (MN" without H2O).

Example 52 6-(4-chloro-3-methoxyphenyl)-4-propylmorpholin-3-one

Chloroacetyl chloride (0.1ml, 1.33mmol) is added to a solution of the product of example 51 (0.31g, 1.27mmol) and triethylamine (0.19ml, 1.3bmmol) in dichloromethane (LOml) and stirred at room temperature for 7/0 bH . The reaction mixture is diluted with dichloromethane (20ml) and washed with hydrochloric acid (aqueous 1M, 10ml), water (1Oml) and sodium bicarbonate solution (saturated, aqueous, 1Oml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the uncyclized product as an oil (0.40 g). | EM5 (ARSI): t/2 320 (MH "of the non-cyclized product), 302 (MH" without water), 284 (MH" of the cyclized product). Potassium hydroxide (0.75 g, 1.33 mmol) is added to a solution of the non-cyclized product 75 ( . the aqueous layer was re-extracted with dichloromethane (2 x 20 ml). The combined organic layers were washed with water (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an oil (0.34 g, 1.19 mmol, 9496). "YAN yNMR (SOSIZ, 400 MHz) 5: 0.95 (t, ZN), 1.60-1.70 (m, 2H), 3.30-3.40 (m, 2H), 3, 40-3.55 (m, 2H), 3.95 (s, ZN), 4.35 (ush.d, 1H), 4.42 (ush.d, 1H), 4.78 (dd, 1H) , 6.85 (dd, 1H), 7.00 (c, 1H), 7.38 (dd, 1H). 1 KM5 (ARSI): t/2 284 (МН.

Example 53 6-(4-chloro-3-methoxyphenyl)-4-propylmorpholine

The borane-tetrahydrofuran complex (1 M in THF) (33.5 ml, C, 5 mmol) was added dropwise to a solution of the product of example 52 (0.33 g, 1.1 mmol) in dry THF (3 ml) under a nitrogen atmosphere. The reaction mixture is refluxed in a refrigerator for 2.5 hours, then cooled and the reaction is quenched by adding methanol (ml). The reaction mixture is concentrated in a vacuum, the residue is suspended in 4M NS! (aqueous, ml) and boil with the reverse

Refrigerate for 2 hours. The reaction mixture was cooled and extracted with dichloromethane (2 x 1 Oml). Organic layers are discarded. Basic properties (pH 9-10) are added to the aqueous layer by adding solid potassium carbonate before repeated extraction with dichloromethane (2 x 15 ml). The dichloromethane extracts were washed with water (1 Oml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain the title compound as an oil (0.31 g, 1.15 mmol, 9996). 7 th TN NMR (SOCIz, 400MHz) 5: 0.95 (t, ЗН), 1.45-1.60 (m, 2H), 2.00 (t, 1H), 2.20 (t, 1H) , 2.35 (t, 2H), s 2.80 (d, 1H), 2.90 (d, 71H), 3.80 (t, 1H), 3.90 (s, ЗН), 4.03 (dd, 1H), 4.55 (d, 1H), 6.85 (dd, 1H), 7.00 (s, with 1H), 7.30 (dd, 1H). I EM (ARSI): t/2 270 (MN).

Example 54 2-chloro-5-(4-propylmorphin-2-yl)uphenol - C

Fo We ("in) from the 50s

HT" Obtained according to the similar method of example 7rB (although refluxing is continued for 2.5 hours, not 1 hour), using the product of example 53 (0.28g, 1.02mmol). Purification by silica column chromatography is not required. The title compound is obtained as a pale brown resin (0.21g, O0.82mmol, 81905). 25 TN iNMR (SOSIZ, 400 MHz) 5: 0.93 (t, ЗН), 1.55 (q, 2Н), 2.0 (t, 1Н), 2.20 (dt, 1Н), 2.30- 2.40 (m, 2H), (F) 2.80 (ush.d, 71H), 2.90 (ush.d, 1H), 3.80 (dt, 71H), 4.0 (dd, 71H ), 4.30 (d, 1H), 6.87 (dt, 1H), 7.02 (fd, 1H), ko 7.25 (c, 18). IEM5 (ARSI): t/2 256 (MN). Analysis found C, 60.7190; H, 7.1095; M, 5.4595.. С43Н18МО»СИ calculated С, 61.05905; H, 7.0990; M, 5.4890. in Example 55

Methyl-(25)-2-(propionylamino)propanoate "ХА 65 o

The hydrochloride salt of the methyl ether of I-alanine (14g, 0.1mol) is dissolved in dichloromethane (150ml) and treated with triethylamine (30.45g, 0.3mmol). The solution is stirred and propionyl chloride is added dropwise.

After stirring overnight, the mixture is quenched by adding 1M hydrochloric acid (200 Oml) and the organic layer is separated. The aqueous layer was re-extracted with dichloromethane (3 x 20 Oml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to a clear oil (16.0 g, quantity).

TN NMR (DMSO-a6, 400 MHz) 5: 0.95 (t, ЗН), 1.25 (d, ЗН), 2.1 (q, 2Н), 3.6 (s, ЗН), 4.2 (queen, 1H), 8.2 (ush.d, 1H). KM5 (E5I) t/: 160 (MN).

Example 56

Tert-butyl-(15)-2-hydroxy-1-methylethyl(propyl)ucarbamate

Her Wife

The product of example 55 is dissolved in tetrahydrofuran (200 ml) and the borane-tetrahydrofuran complex (300ml, 0.2mol) is added to the stirred solution at room temperature. The mixture is then heated at reflux overnight. After cooling to room temperature, the reaction is quenched by careful addition of 1M hydrochloric acid (100ml) and then heated at reflux for 2h. The reaction mixture was allowed to cool to room temperature overnight and then evaporated to dryness (11.77g). The crude mixture gave m/: 118, consistent with the desired amino alcohol intermediate. The crude mixture is then dissolved in methanol (50ml) and water (4000ml) before potassium hydroxide (28.22g, O0.Bmol) is added. Di-tert-butyl dicarbonate (32.87 tg, se 015 mol) is added to the mixture and stirring is continued for 3 hours. The reaction mixture is distributed between OSM (dichloromethane) about (500ml) and water (10Oml), the organic layer is separated and the aqueous layer is re-extracted two more times with OSM. The combined organic fractions are dried with magnesium sulfate, filtered and evaporated to a crude product. Purification by flash chromatography at 505", eluting with dichloromethane:methanol:880 MH with (97:3:0.3) afforded the desired product as a clear oil in 4.5 g (2195) along with an additional 10 g of partially purified product. "

TN nMR (DMSO-ab6, 400MHz) 5: 0.8 (t, ЗН), 1.05 (us.s, ЗН), 1.4 (m, 11Н), 2.95 (us.s, 2Н) , 3.35 (ush.m, p

ZN), 4.6 (ush.s, 1H). EM5 (E8IU t/:2 240 (MMa") o

Example 57

Hydrochloride (25)-2-(propylamino)propan-1-ol (Ge)

X, i - va: s dn. gna

The pure product of example 56 (4.2g, 0.021mol) is dissolved in dioxane (10ml) and treated with 4M NOSI in dioxane (30ml). The mixture is stirred at room temperature for 16 hours. and then evaporated to obtain a white solid (2.74 g, 9295) no) with TN NMR (DMSO-a6, 400 MHz) 5: 0.9 (t, ЗН), 1.15 (d, ЗН), 1.6 (m, 2H), 2.8 (m, 2H), 3.15 (m, tn), 3.5:z" (ush.m, 1H), 3.6 (m, 1H), 5.4 (high school, 1H), 8.8 (high school, 2H). And EM5 (ARSI kyu) 118 (MN).

Example 58 15 (55)-2-(3-methoxyphenyl)-5-methyl-4-propylmorpholin-2-ol -i M (Ce) Zo C (av) M pk; from 50 s"

The product of example 57 (1.0g, b,bmmol) was dissolved in toluene (1Oml) and treated with triethylamine (1.38Hg, 4mmol) before the addition of 2-bromo-3-methoxyacetophenone (1.5g, b,bmmol). The mixture is heated to 65 2C and stirred for 3 days. After cooling to room temperature, the mixture is distributed among

F, saturated salt solution and ethyl acetate, the organic layer is separated, dried with magnesium sulfate, filtered and co-evaporated. The residue was purified by flash chromatography on 5µO, eluting with ethyl acetate to give the desired morpholinol compound as a mixture of stereoisomers as a pale yellow oil (1.0g, 5890). 60 TN NMR (DMSO-a6, 400MHz) 5: 0.8 (m, ЗН), 0.95 (d, ЗН), 1.35 (m, 2Н), 2.1 (m, 2Н), 2, 4 (sh.m, 1H), 2.6 (m, 7), 2.75 (m, 1H), 3.5 (d, 1H), 3.75 (m, 4H), 6.0 (s , 0.75Н), 6.1 (s, 025Н), 6.85 (d, 1Н), 7.05 (m, 2Н), 7.25 (t, 18). And M5 (EBIZHK) t/2 248 (М-Н2О), 266 (МН), 288 (ММа").

Example 59 (55)-2-(3-methoxyphenyl)-5-methyl-4-propylmorpholine b5 o

Ko» tk. evil

The product of example 58 (77Omg, 2.9mmol) is dissolved in dichloromethane (2Oml) and cooled to -789C in a nitrogen atmosphere. Triethylsilane (3.7 mL, 23 mmol) was added to the stirred mixture, followed by trimethylsilyl triflate (1.1 mL, 5.8 mmol). Stirring is continued overnight and the reaction mixture is allowed to reach room temperature. The reaction is quenched by adding a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3 times). The combined organic layers are dried with magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on ZO", eluting with a mixture of dichloromethane:methanol: 880 ammonia (97:3:0.3) gives the desired compound morpholine (b0Omg, 8395) "YAN nNMR (SOSIZ, 400 MHz) 5: 0.95 ( m, ZN), 1.1 (ush.d, ZN), 1.6 (ush.m, 2H), 2.2-3.1 (5H), 3.5 (ush.m, 1H), 4 .85 (m, 4H), 4.6 (B, 1), 6.8 (d, 1H), 6.95 (m, 2H), 7.25 (m, "NASNeSII"). And KM5 (ARSIK) t/2 250 (MN"). Analysis found C, 71.5395; H, 9.2190; M, 5.55905. C1BNazMO". 0.15Н250 calculated C, 71.4895; H, 9 ,3290; M, 5,5690.

Example 60 3-(55)-methyl-4-propylmorpholin-2-yl|phenol o c

BUT 1 o m" " g sch

The product of example 59 (400mg, 1.bmol) was dissolved in 4895 aqueous hydrobromic acid (ml) and the mixture was heated to 802 overnight. After cooling to room temperature, the mixture is quenched by adding saturated aqueous sodium bicarbonate and the mixture is extracted with dichloromethane (3 times). The combined organic layers (F) were dried with magnesium sulfate, filtered and evaporated to obtain products in the form of a white solid (28BMg, 7696). - "YAN NMR (SOSIZ, 400 MHz) 5: 0.9 (m, ЗН), 1.1-1.2 (2ха, ЗН), 1.5 (m, 2Н), 2.3 (m, 2Н) , 2.5 (sh.m, 1H), 2.8 (sh.m, 7H), 3.1 (d, 1), 3.5 (sh.m, 1H), 3.85 (sh.m , 1H), 4.6 (d, 71H), 6.8 (m, 2H), 6.95 (m, 1H), 7.2 (t, 1nH). HAM (ARSIK), 236 (MH") . Analysis found C, 70.6190; H, 9.00905; M, 5.8695. С44Н24МО». 0.1Н250 calculated С, « 40...70.9190; H, 9.01905; M, 5, 91905. - c A mixture of diastereoisomers is separated on a Spigaise HPLC column! 0О-Н (250721.2mm). The mobile phase is 10095 MeonN, the volumetric rate is 15 ml/min. Preparation of a sample of 200 Ωg, dissolved in 4 ml of Meon, injection of 250 μl. 2 main peaks are obtained at a retention time of 5.822 min (example boA, 57 mg, 28905) and 7.939 min (example 608, 12 mg, bo)

Example of BOA: "IN NMR (SOSI", 400 MHz) 5: 0.85 (t, ZN), 1.05 (d, ZN), 1.5 (m, 2H--H-O), 2.2 ( M, 2H), 2.4 (m, 1H), 2.8 (m, 1H), and 3.0 (dD, 71H), 34 (t, 71), 3.9 (dd, 1H), 4 .55 (d, 1H), 5.6 (ush.s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 6.95 (d,

He) 1H), 7.2 (t, 1H). NEM5 t/ 236.1643 (MN.

Example 608: o "YAN NMR (SOSIz, 400MHz) 5: 0.95 (t, ЗН), 1.15 (d, ЗН), 1.55 (m, 2Н), 2.4 (m, 2Н), 2.55 (t, 1H), 2.65 (dd, ko 50 1H), 2.95 (ush.m, 1H), 3.8 (d, 1H), 3.95 (d, 1H), 4 .55 (dd, 1H), 6.75 (d, 1H), 6.85 (c, 1H), 6.95 (d, 1H), 7.2

T" (t, 1H). NKEM5 t/ 236.1643 (MN.

Example 61

Hydrochloride (5)-2-propylaminopropan-1-ol and

IF) nm ey at 60 To (5)-(-)-2-amino-1-propanol (19.6bg, 0.2bmol) dissolved in dichloromethane (500ml) is added propionaldehyde (20.b9ml, 0.28ml) with with further addition of pre-dried, powdered molecular sieves 4A (40g) and the mixture is stirred at room temperature overnight. The mixture is filtered through a layer of celite, the specified layer is washed with dichloromethane and the solvent is evaporated to obtain a clear oil. Oil is dissolved in methanol (200 ml) and Mavn is added in portions over 15 minutes. The mixture is stirred at room temperature overnight, then quenched by the careful addition of 2M NOSI (aq.) (200ml), basic properties are added by the addition of 2M Mahon (200ml) and the methanol is removed by evaporation. Di-tert-butyldicarbonate (115g, O0.52mol) was added followed by 1,4-dioxane (200ml) and the mixture was stirred at room temperature overnight. 1,4-dioxane is removed by evaporation to give a clear oil. To this oil is added 4M NSI in 1,4-dioxane (200ml) and the mixture is stirred at room temperature overnight. The solvent was removed by evaporation to give a white solid (24Hg).

TN NMR (DMSO, 400 MHz) 5: 0.95 (t, ЗН), 1.2 (d, ЗН), 1.6 (m, 2Н), 2.8 (m, 2Н), 3.15 ( m, 1H), 3.5 (ush.m, 1H), 3.6 (m, 1), 5.4 (B, 1H), 8.6-8.9 (ush.d, 2H). I VM5 (ARSI»h), 118 (MN).

Example 62 (55)-4-propyl-o--methylmorpholin-2-one ke!

SH

7

The product of example 61 (4 g, 2 mmol) was dissolved in benzene with subsequent addition of M-ethyldisopropylamine (9.07 ml, 52 mmol) and methyl bromoacetate (2.4 ml, 2 mmol). The mixture is heated at reflux with azeotropic removal of water overnight. The solvent is removed by evaporation, the crude substance is dissolved in methanol, pre-absorbed at 5% and subjected to flash chromatography on

ZO", eluting with a mixture of 4095 E(Ac/pentane, with obtaining the morpholino indicated in the title in the form of a clear oil (1.78 g). "YAN NMR (SOCI3, 400 MHz) 5: 0.9 (t, ЗН), 1.1 (d, ZN), 1.5 (m, 2H), 2.25 (m, 1H), 2.6 (m, 1H), 2.8 (m, yin), E 3.2 (d, 1H ), 3.6 (d, 1H), 4.05 (dd, 1H), 4.3 (dd, 1H). TLC RI-0.18 (5095 E (OAc/pentane, UV visualization). o

Example 63. F - 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine (1.5 g, 5.9 mmol) was azeotropically distilled with toluene and dissolved in THF (20 ml). The mixture is cooled to -782C and tert-butyllithium (1.7M in pentane, 7ml, 11.9mmol) is added, maintaining the temperature below -702C. The product of example 62 is dissolved in THF (20 Oml) and added to the mixture immediately after the addition of tert-butyllithium. The mixtures are allowed to stir at -78 °C for 30 minutes, with the simultaneous addition of MNACI (1095 aq., 150 ml), and the mixture is extracted with EtOAc (200 ml), dried with 3 s over magnesium sulfate, filtered and evaporated. Step-gradient flash chromatography on ZIO 5 eluting with a mixture of 2590 EtOAc/pentane to 5095 EtOAc/pentane afforded the title compound as an approximately 3.5:1 mixture of diastereoisomers as a yellow oil (480 mg).

TN nMR (SOSIS, 400 MHz) (diastereoisomers) 5: 0.95 (m, ЗН), 1.1, 1.2 (2ха, ЗН), 1.5 (m, 2Н), 2.15 (с, - 1 395 6H), 2.4 (m, 7), 2.5 (d, 1), 2.6 (m, 1H), 2.75 (m, 1H), 3.85-3.95 (m ) 8.05 (dd, 1H), 8.8 (s, 1H). And EM5 (EByuU), 330 (MN), 352 (MMa"). And KM5 (E5-), 328 se) (М-Н). o Example 64 ю 50 (25)-2-I(2K5) -2-16-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl|-2-hydroxyethyl)propyl)amino|propan-1-ol (55)-2- (6-(-2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl|-4-propyl-5--methylmorpholin-2-ol (480 mg, 1.45 mmol) is dissolved in ethanol ( 5ml) and water (2ml) and treated with sodium borohydride (220mg, 5.dmol). The reaction mixture was left to stir overnight at room temperature before quenching the reaction by adding saturated aqueous MNACI and extracting with ethyl acetate (2x10000ml). The organic extracts were combined, dried

Ma5Oo, and evaporated to give 400mg of a loose white solid, which was used without further purification. 65 TN nMR (SOCI3, 400 MHz) diastereoisomers 5: 0.8-1.1 (m, 6H), 1.15, 1.35 (2ха, ЗН), 1.6-2.0 (m, 2Н) 2 /1 (s, 6H), 2.5-4.05 (m, 7H), 4.8-5.2 (m, 1H), 5.9 (s, 2H), 7.2 (m, 1H ), 7.8-8.1 (m, 1H), 8.55 (m, 1H). And KEM5 (Ek), 332 (MN).

Example 65 (25)-2-I(2К5)-2-(6-aminopyridin-3-yl)-2-hydroxyethylI(propyl)amino|propan-1-ol

(25)-2-I(2K5)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl(propyl)amino|propan-1-ol (480 mg, 1.2 mmol) is dissolved in 5ml), add hydroxylamine hydrochloride (419mg, mmol) and the mixture is heated to 802 overnight. The solvent is removed in vacuo and the precipitate is purified by flash chromatography at 5% eluting with dichloromethane/methanol/880 ammonia (95:5:0.5, increasing polarity to 93:7:1) to obtain the title compounds as a mixture of diastereoisomers (Z0Omg, 98965).

TN NMR (SOCI5, 400MHz) (2 diastereoisomers) 5: 0.82-0.97 (6Н, m), 2.40-2.77 (2Н, m), 3.27-3.51 (2Н, m ), 4.51 (1Н, m), 6.58 (1Н, m), 7.49 (1Н, m), 7.86 (1Н, m). I EM (ARSIKH), 254 (MN).

Examples 66 and 67 5-K25,55)-5-methyl-4-propylmorpholin-2-yl|pyridin-2-amine and 5-MSH2K,55)-5-methyl-4-propylmorpholin-2-yl|pyridin- 2-amine. sv sil p y H me M i sch

E g o "Diol" of example 65 (30 Omg, 1.2 mmol) is dissolved in dichloromethane (3 ml) and concentrated sulfuric acid (3 ml) is added. The mixture is stirred at room temperature for The reaction mixture is cooled to 02, the reaction is quenched by careful addition of EM sodium hydroxide solution and then extracted with dichloromethane "I (4x5Oml). The combined extracts were dried (Mo95O)) and evaporated to a brown resinous solid. high school

Purification by flash chromatography on ZiO 2 eluting with 1095 methanol in ethyl acetate gives 5 mg of the product enriched in the less polar diastereomer (approximately 8095, ee), 12 mg of the product enriched in the less polar | "c) diastereomer (approximately 8095, ee) and 150 mg of the product of a mixture of diastereoisomers approximately 1:1 (total yield Fo 167 mg, 5995). The final 1:11 mixture is subjected to HPLC purification using a SpPigagrak 00-H column

Zo (250x21.2mm), eluting with a mixture of methanol:ethanol (1:1). in.

A faster eluted diastereoisomer (retention time 8.1 min.) with ae 29995 (bOmg, 21905) is obtained.

TN nMR (SOSIS, 400 MHz) 0.88 (ZH, t), 1.01 (ZH, d), 1.26 (ZH, t), 1.37-1.58 (2H, m), 2.18 -2.28 (2Н, m), 2.36-2.47 (1Н, m), 2.69-2.77 (1Н, m), 2.90 (IN, m), 3.38 (IN , m), 3.72 (2H, d), 3.82 (IN, m), 4.40 (2H, « du ush.s), 4.45 (1H, dd), 6.48 (1H, d), 7.45 (1H, dd), 8.04 (1H, d). GKM5 (EC): t/2 236 (MN). with oya? 46.28 (c 0.13, MeOH). c The more slowly eluted diastereoisomer (retention time 10.5 min.) is obtained from de 299965 (62 mg, 22965). ;" "YAN NMR (SOSIZ, 400MHz) 0.93 (ZN, t), 1.11 (ZN, d), 1.49 (2Н, m), 2.38 (2Н, m), 2.50-2, 56 (2H, m), 2.89 (IN, m), 3.75 (IN, m), 3.89 (IN, m), 4.40 (2H, ush.s), 4.46 (1H . 58 (c 0.13, MeOH). se) o

Claims (15)

The formula of the invention from 50 1. Compounds of formulas (I), (Ia) and (IB) V. ex 60th b5 EE (c) g; ko sha V. ех и EE ; (c) g /5 ko IN B. where A is selected from C-X im, He B is selected from SU and M, o B" is selected from H and (C1-Cb)alkyl, B: is selected from H and (C1-Cb)alkyl, X is selected from H, HO, C(CO)MN", MH", U selected from H, HO, MH", B", SI E, - 7 selected from H, HO, E, SOMN" and CM; sch and their pharmaceutically acceptable salts, solvates and prodrugs; provided that for a compound of formula (I), (Ia) or (IB), when A is C-X, B is C-Y, B" is H or He") (C.-Sv)alkyl and B? is H or (C-C)alkyl, at least one of X, Y and 7 must be OH; m for the compound of formula (I), when A is C-X and B is C-Y, U is H, 7 is H, B! is H and K? is H, X cannot be OH. 2. Compounds of formulas (I), (Ia) and (IB) according to claim 1, where A is C-X or M, and B is C-Y. 3. Compounds of formulas (I), (Ia) and (IB) according to claims 1-2, where KE! is H, methyl and ethyl. " 4. Compounds of formulas (I), (Ia) and (IB) according to claims 1-3, where B? selected from H and methyl. - with 5. Compounds of formulas (I), (Ia) and (IB) according to claims 1-4, where X is selected from H, OH and MH". and 6. Compounds of formulas (I), (Ia) and (IB) according to claims 1-5, where ХУ is selected from H, МН», SI and R. "» 7. Compounds of formulas (I), (Ia) and (IB) according to claims 1-6, where 7 is selected from H, HO and BE. 8. The compound according to claim 1 is selected from K-(-)-3-(4-propylmorpholin-2-yl)phenol, -and C-()-3-(4-propylmorpholin-2-yl)phenol, with hydrochloride K -(-)-3-«4-propylmorpholin-2-yl)phenol, Kk-5-(4-propylmorpholin-2-yl)benzene-1,3-diol, (ав) 5-5-(4-propylmorpholine -2-yl)benzene-1,3-diol, t 50 K-()-2-fluoro-5-(4-propylmorpholine-2-iluphenol, C-(-)-2-fluoro-5-(4- propylmorpholin-2-yl)phenol, 5-(4-propylmorpholin-2-yl)pyridin-2-ylamine, 2-chloro-5-(4-propylmorpholin-2-yl)phenol, 5-25, 55) -5-methyl-4-propylmorpholin-2-yl|pyridin-2-amine, 5-M2K, 55)-5-methyl-4-propylmorpholin-2-yl|pyridin-2-amine. 9. Compounds of formulas (I), (Ia) and (IB) according to any of claims 1-8 for use as a medicinal product. at 10. The use of compounds of formula (I), (Ia) and (Iv) according to any of claims 1-8 for obtaining a medicinal product (i.e.) for the treatment of a condition selected from sexual dysfunction, sexual dysfunction in women, including a disorder in in the form of reduced activity of sexual desire, disorder of sexual arousal, violation of 60 orgasm and sexual pain disorder; erectile dysfunction in men, hypertension, neurodegeneration, psychiatric disorders, depression (eg, depression in cancer patients, depression in patients with Parkinson's disease, depression after myocardial infarction, subsyndromal symptomatic depression, depression in women with infertility, depression in children, major depression , single episodes of depression, recurrent depression, depression caused by child abuse, postpartum depression, and irritable bowel syndrome in the elderly), generalized anxiety disorder, phobias (eg, agoraphobia, social phobia, and simple phobias), post-traumatic stress disorder, personality disorders in the form of avoidance, premature ejaculation, eating disorders (for example, anorexia nervosa and bulimia nervosa), obesity, dependence on chemical compounds (for example, addiction to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), "histamine" headaches , migraine, pain, Alzheimer's disease RA, obsessive-compulsive disorder, panic disorder, memory disorders (eg, dementia, amnestic disorders and age-related memory loss (AMD)), Parkinson's disease (eg, Parkinson's disease dementia, antipsychotic-induced parkinsonism, and tardive dyskinesias), endocrine disorders (for example, hyperprolactinemia), vascular spasm (in particular, cerebral vessels), cerebellar ataxia, disorders of the gastrointestinal tract (including changes in motility and secretion), negative symptoms of schizophrenia, 7/0 premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, impotence in men, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associated with vascular disorders), emotional lability, pathological crying, sleep disorder (catalepsy ) and shock. 11. Application according to claim 10, where the condition is sexual dysfunction in women, erectile dysfunction 7/5 in men, neurodegeneration, depression and psychiatric disorders. 12. Application according to claim 10, where the condition is erectile dysfunction in men. 13. Application according to claim 10, where the condition is a disorder in the form of reduced activity of sexual desire, a disorder of sexual arousal, a violation of orgasm and a sexual pain disorder in women. 14. Application according to claim 13, where the condition is a disorder of sexual arousal in women and a concomitant disorder in the form of reduced activity of sexual desire. 15. A composition containing compounds of formula (I), (Ia) and (IB) according to any of claims 1-8 and a pharmaceutically acceptable diluent or carrier. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuits about Microcircuits", 2007, M 6, 10.05.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. i) « c «c) (o) and - - and? -i se) ((c) name) c" name) 60 b5 -BO0-