HK1069815B - Omega-aminoalkylamides of r-2-aryl-propionic acids as inhibitors of the chemotaxis of polymorphonucleate and mononucleate cells - Google Patents

Description

Omega-aminoalkylamides of R-2-aryl-propionic acids as inhibitors of polymorphonuclear and monocyte chemotaxis

Technical Field

The present invention relates to omega-aminoalkylamides of (R) -2-arylpropionic acids which are useful as inhibitors of polymorphonuclear and mononuclear cell chemotaxis. In particular, the present invention relates to inhibitors of polymorphonuclear leukocyte and monocyte C5 a-induced chemotaxis for the treatment of diseases including psoriasis, rheumatoid arthritis and the like, and injury caused by ischemia and reperfusion.

Background

Animal studies have shown that some aminoalkyl esters and amide prodrugs of racemic ibuprofen and naproxen, specifically some N- (3-diethylaminopropyl) amides, have much better analgesic and anti-inflammatory activity than the parent compound, although they have been found to be poor inhibitors of prostaglandin synthesis "in vitro". It has been found that all of these prodrugs, except glycinamide, are much less irritating to the gastric mucosa than their precursor free acids. See citations herein (Shanbhag VR et al, J.Pharm.Sci., 81, 149, 1992 and references 8-19).

In current therapeutic applications, piogliprofen [ (±)2- (3-benzoylphenyl) -N- (4-methyl-2-pyridyl) propionamide ] and guazatemetine (also known as the guaiacol ester of tolmetin glycinamide, Eufans) are additional examples of non-steroidal anti-inflammatory prodrugs.

The series of N- [2- (1-piperidinyl) propyl ] amides of certain non-steroidal anti-inflammatory drugs are reported to have moderate anti-inflammatory activity, mild side effects and good gastrointestinal tolerability, for example racemic ibuprofen, indomethacin, p-chlorobenzoic acid, acetylsalicylic acid, diacetyl gentisic acid and adamantane-1-carboxylic acid (Nawladonski f. and Reewuski, pol.j.chem., 52, 1805, 1978). Other amides of racemic 2-arylpropionic acids are disclosed by s.biniecki et al [ PL114050(31.01.1981) ], h.akguen et al [ Arzneim-forsch, 46, 891, 1986], and g.l.levitt et al [ russ.j.org.chem., 34, 346, 1998 ].

It has been reported that the "in vivo" anti-inflammatory and analgesic efficacy of some N-3- [ (1-piperidinyl) propyl ] amides of racemic ketoprofen and flurbiprofen, as well as of certain mannich bases obtained by reacting their amides with formaldehyde and secondary amines such as morpholine, piperidine, dicyclohexylamine, dimethylamine, diethylamine, benzhydrylamine and dibutylamine, are comparable, sometimes even higher, than the anti-inflammatory and analgesic efficacy of the precursor free acid (n.kawatekar et al, indianj.pharm.sci., 60, 346, 1998).

The recent international patent application WO00/40088 reported that only amide derivatives converted to 2-arylacetic acids and/or 2-arylpropionic acids were sufficient to convert selective COX-1 inhibitors to COX-2 selective inhibitors, explaining the cause of the decrease in gastric damage (gastrosensitivity) of the amides, which has long been thought to decrease only in the case of non-steroidal anti-inflammatory prodrugs.

Inhibition of cyclooxygenase enzyme biotransformation with a portion of the R CoA-thioester was thought to be applicable only to the S enantiomer of 2-arylpropionic acids in the past. It was therefore found that the correlation between the "in vitro" inhibition of certain R, S2-arylpropionic acids by the enzyme and the "in vivo" analgesic effect is not great (Brune K et al, Experientaia, 47, 257, 1991), which led to the hypothesis that: other alternative mechanisms may be operated, such as inhibition of transcription of kB-nuclear transcription factor (NF-kB) and/or inhibition of interleukin 8(IL-8) -induced neutrophil chemotaxis.

In fact, WO00/40088 discloses that flurbiprofen, ketoprofen, naproxen, tioprofen (thiaprofen) and fenoprofen (phenoprofen) are inhibitors of NF-kB transcription factor activation, and are alleged to be useful in the treatment of NF-kB-dependent diseases (asthma, tumors, shock, Crohn's disease, ulcerative colitis and arteriosclerosis, etc.).

IL-8 is an important inflammatory mediator and has been found to be a potent chemotactic/cellular activator of polymorphonuclear neutrophils and basophils (PMNs) and T lymphocytes. Cell sources of IL-8 include monocytes, polymorphonuclear leukocytes, endothelial cells, pericytes, and keratinocytes when stimulated by factors such as lipopolysaccharide, IL-1, and TNF- α. On the other hand, complement fragment C5a has been found to induce IL-8 synthesis and monocyte release of high levels of IL-8 in addition to being a direct inflammatory mediator. Under similar conditions, C5 a-activated monocytes recovered from peripheral blood mononuclear cells exhibited up to 1000-fold greater amounts of IL-8 than released from comparable numbers of polymorphonuclear leukocytes. Thus, IL-8 released from C5a activated monocytes plays an important role in expanding and prolonging cell infiltration and activation of sites of infection, inflammation or tissue injury (Ember J.A et al, am. J. Pathol., 144, 393, 1994).

The response of the complement system to immune and infectious events is activated by direct membrane action and by the release of a series of peptide fragments generated by enzymatic cleavage of complement fragments C3, C4 and C5, commonly known as anaphylatoxins, to mediate an amplified inflammatory response. These peptides include C3a, C4a consisting of 77 amino acids; the C5 convertase cleaves complement fragment C5 to yield the 74 amino acid glycoprotein C5 a.

The interaction of anaphylatoxins with various cellular components facilitates the process of spreading inflammation; their common properties are vasoactive amine and lysosomal enzyme releasing cells, smooth muscle contraction and increased vascular permeability. In addition, C5a causes chemotaxis and aggregation of neutrophils, stimulates the release of leukotrienes and active oxidative species, induces transcription of IL-1 and antibody production in macrophages.

The C5a peptide fragment of complement was identified as a "complete" pro-inflammatory mediator. In contrast, other inflammatory mediators such as selected cytokines (e.g., IL-8, MCP-1 and RNATES) are highly selective for self-priming cells, whereas histamine and bradykinin are only weak chemotactic agents.

There is some compelling evidence that several pathological conditions are implicated "in vivo" in C5a, including ischemia/reperfusion, autoimmune dermatitis, membrane proliferative idiopathic glomerulonephritis, airway hyperresponsiveness (airway hyperresponsiveness), chronic inflammation, Acute Respiratory Distress Syndrome (ARDS) and Chronic Obstructive Pulmonary Disease (COPD), Alzheimer's disease, juvenile rheumatoid arthritis (n.p. gerard, ann.rev.immunol., 12, 755, 1994).

Considering the potential for C5a/C5a-desArg neuritis caused by local complement production and amyloid activation, coupled with astrocyte and microglial chemotaxis and direct C5 a-induced activation, it has been proposed to treat neurological diseases such as alzheimer's disease with complement inhibitors (McGeer & McGeer p.l., Drugs, 55, 738, 1998).

Therefore, control of local synthesis of complement fragments is considered to have good therapeutic prospects for treatment of shock and prevention of rejection (multiple organ failure and hyperacute transplant rejection) (Issekutz A.C. et al, int.J. immunopharmacol, 12, 1, 1990; Inagi R et al, Immunol.Lett., 27, 49, 1991). Recently, prevention of both preexisting and transplanted kidney injury has been reported to involve inhibition of complement fragments, considering that chronic interstitial and acute glomerular kidney injury involve complement (Sheerin N.S. & Sacks s.h., curr. opinion nephrol. hyper, 7, 395, 1998).

Genetic engineering and molecular biology research has led to the cloning of Complement Receptors (CRs) and the production of complement receptor agonists and antagonists.

The recombinant soluble receptor complement receptor 1 (sCR 1), which blocks the enzymes that activate C3 and C5, was identified as likely to be an inhibitor of ischemia/reperfusion injury C activation (Weisman H.F. et al, Science, 239, 146, 1990; Pemberton M. et al, J.Immunol., 150, 5104, 1993).

The cyclic peptide F- [ OPdChWR ] was reported to antagonize the binding of C5a to its CD38 receptor on polymorphonuclear leukocytes and to inhibit C5 a-dependent chemotaxis and cytokine production by macrophages as well as rat neutropenia induced by stimulation with C5a and LPS (Short a. et al, br.j. pharmacol., 126, 551, 1999; Haynes d.r. et al, biochem. pharmacol., 60, 729, 2000).

The C5aR antagonist CGS27913 and its dimer CGS32359 were reported to inhibit binding of rabbit C5a to neutrophil membrane, extracellular Ca, "in vitro²⁺Immobilization of (a), release of lytic enzymes, neutrophil chemotaxis and skin edema (Pellas t.c. et al, j.immunol., 160, 5616, 1998).

Finally, selection of phage libraries using "phage display" technology allows the isolation of specific C5aR antagonists that reduce immune complex-mediated diseases and inflammatory responses to ischemia and reperfusion injury (Heller t. et al, j.immunol., 163, 985, 1999).

Despite their therapeutic promise, only two of the C5a antagonists discussed above have demonstrated "in vivo" activity; moreover, their therapeutic use is limited by the nature of their peptides (Pellas t.c. et al, Wennogle p., curr. pharm. des., 10, 737, 1999).

In some pathological conditions, such as psoriasis, severe inflammation and intractable treatment sites, a characteristic accumulation of neutrophils may be observed. Chemotactic attraction and activation of neutrophils is achieved by the synergistic effect of chemokines released by stimulated keratinocytes, IL-8 and Gro-a, and fragments C5a/C5a-desArg produced by activation of another complement pathway (T.Terui et al, exp.Dermatol., 9,1, 2000). Therefore, there is an increasing demand for a single agent that combines inhibition of C5 a-induced chemotaxis with inhibition of IL-8-induced chemotaxis.

Non-peptide antagonists of complement fragments, such as substituted-4, 6-diamino-quinolines, have been prepared. In particular, [ N, N "-bis-2- (4-amino-2-methyl-6-quinolinyl) has been found]Urea and [ 6-N-2-chlorocinnamyl group]-4, 6-diamino-2-methylquinoline is a selective C5R antagonist, their IC₅₀Between 3.3 and 1.2 μ g/ml (Lanza t.j. et al, j.med.chem., 35, 252, 1992).

Recently, several serine-protease inhibitors [ nemostat mesylate (FUT175) and certain analogs ] have been reported to be inhibitors of complement activation and production of C3a/C5a (Ueda N. et al, InflumationRes.49, 42, 2000).

U.S. patent 6,069,172 reports the use of R (-) ketoprofen ammonium salts to inhibit IL-8 induced neutrophil chemotaxis.

WO00/24710 discloses the use of N-arylsulfonamides of R (-)2 arylpropionic acids as inhibitors of IL-8 dependent polymorphonuclear leukocyte chemotaxis.

Two recent patents (WO01/58852 and WO01/79189) disclose certain R-2-aryl-propionamides and R-2- (aminophenyl) propionamides, which are useful in preventing IL-8-induced leukocyte activation.

We have recently observed that formally only the reduction of the heteroaromatic ring of certain R2-aryl-N- (pyridyl) propionamides may result in a substantial decrease (1 or 2 log) in the ability to inhibit IL-8-induced neutrophil chemotaxis of polymorphonuclear leukocytes. Unexpectedly, R2-aryl-N- (piperidinyl) propionamide was found to be a potent inhibitor of chemotaxis induced by the complement fragment C5a in human polymorphonuclear leukocytes and monocytes.

These unexpected findings are derived from a new family of omega-aminoalkylamides of R-2-aryl-propionic acids that are capable of inhibiting C5a and other chemokine-induced chemotactic activities associated with activation of 7-membered domain receptors (7-TDs) homologous to the C5a receptor (e.g., C3a receptor and CXCR2 receptor; Neote K et al, Cell, 72, 415, 1993; Tornetta m.a., j.immun.158, 5277, 1997).

Disclosure of Invention

The object of the present invention is to provide a new class of omega-aminoalkylamides of R-2-aryl-propionic acids and pharmaceutical compositions containing them. The position "ω" of the alkyl chain refers to the carbon atom furthest from the N atom of the amide group to which the alkyl group is attached. These amides are useful for inhibiting C5a and other chemokine-induced chemotactic activities whose biological activity is associated with activation of the 7-membered domain receptor (7-TD) homologous to the C5a receptor. In particular, these amides are used to inhibit polymorphonuclear leukocytes, monocytes and lymphocytes, the chemotactic activation induced by the T complement fragment C5a and to treat pathologies associated with said activation.

Detailed Description

In the following, definitions of the various chemical groups which constitute the compounds of the present invention are given and are intended to be used uniformly throughout the specification and claims unless a broader definition is given otherwise.

The term "alkyl" refers to monovalent alkyl groups preferably having 1 to 6 carbon atoms. Examples of these terms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

"aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl groups include phenyl, biphenyl, naphthyl, phenanthryl, and the like.

"alkenyl" means an alkenyl group, preferably having 2 to 5 carbon atoms, having one or more sites of ethylenic unsaturation. Preferred alkenyl groups include vinyl (-CH = CH)₂) N-2-propenyl (allyl, -CH)₂CH=CH₂) And the like.

"alkylene", "alkenylene" and "alkynylene" refer to groups that are disubstituted at both ends. Preferred groups include methylene, ethylene, propylene, and the like.

"substituted or unsubstituted": unless limited by the definition of an individual substituent, the groups listed above, such as "alkyl", "alkenyl", "aryl", and the like, may be optionally substituted with 1 to 5 substituents selected from "C₁-C₆Alkyl group "," C₁-C₆Alkylaryl group and C₁-C₆Alkyl heteroaryl group and C₂-C₆Alkenyl ", primary, secondary or tertiary amine groups or quaternary ammonium moieties," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," aryl "," heteroaryl ", carboxyl, cyano, halogen, hydroxyl, mercapto, nitro, sulfenyl, sulfonyl, alkoxy, thioalkoxy, trihalomethyl, and the like. Within the framework of the present invention, said "substitution" may also include the case where adjacent substituents have closed a ring, in particular when functional substituents in the vicinity are involved, thereby forming, for example, lactams, lactones, cyclic anhydrides or cycloalkanes, but also acetals, thioacetals, acetals and the like by ring closure, for example in order to obtain protecting groups.

"pharmaceutically acceptable salts" refers to salts or complexes of the compounds represented by formula I which retain the desired biological activity. Such salts include, but are not limited to, acidic addition salts formed from inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, and the like), and salts formed from organic acids such as acetic, oxalic, tartaric, succinic, malic, fumaric, maleic, ascorbic, benzoic, tannic, pamoic, alginic, polyglutamic, naphthalenesulfonic, naphthalenedisulfonic, and polygalacturonic acids.

These salts also include the acidic addition salts formed from inorganic bases such as sodium hydroxide, and organic bases such as trimethylamine, L-lysine, L-arginine, and the like.

The present invention provides (R) -2-arylpropionamide compounds represented by the general formula (I),

in the formula (I), the compound is shown in the specification,

ar represents a substituted or unsubstituted aryl group;

r represents H, represented by CO₂R₃C optionally substituted by radicals₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, wherein R₃Represents H, or a linear or branched C₁-C₆Alkyl or straight or branched C₂-C₆An alkenyl group;

x represents:

from CO₂R₃Or CONHR₄Straight-chain or branched C optionally substituted by radicals₁-C₆Alkylene radical, C₄C₆Alkenylene radical, C₄C₆Alkynylene, wherein R₄Represents H, straight or branched C₂-C₆Alkyl OR OR₃Group, R₃As defined above;

by CO as defined above₂R₃Or CONHR₄The radical being optionally substituted (CH)₂)_m-B-(CH₂)_nWherein B is an oxygen or sulfur atom, m is 0 or an integer of 2 to 3, and n is an integer of 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3, n is an integer from 2 to 3;

or the nitrogen atom of the omega-amino group to which X is bonded and R₁The radicals together forming a non-aromatic nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring, wherein the nitrogen atom carries the substituent Rc, which represents H, C₁-C₄Alkyl radical, C₁-C₄Hydroxyalkyl radical, C₁-C₄Acyl, substituted or unsubstituted phenyl, benzhydryl;

R₁and R₂Independently H, straight or branched C optionally interrupted by O or S atoms₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₃-C₆Alkenyl radical, C₃-C₆Alkynyl, aryl-C₁-C₃-alkyl, hydroxy-C₂-C₃-an alkyl group;

or R₁And R₂Together with the nitrogen atom to which they are attached form a nitrogen containing a 3-to 7-membered heterocyclic ring represented by the general formula (II),

in the formula (I), the compound is shown in the specification,

y represents a single bond, CH₂O, S, or an N-Rc group as defined above, p represents an integer from 0 to 3;

or, R₁As defined above, R₂Represents a group represented by the general formula (III):

in the formula (I), the compound is shown in the specification,

R_ais H, R_bIs H, hydroxy, C₁-C₄Alkyl or NR_dR_eGroup, wherein R_dAnd R_eEach independently is H, C₁-C₄Alkyl or phenyl;

or R_aAnd R_bTogether with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring, monocyclic ring or fused ring with benzene, pyridine or pyrimidine;

with the proviso that Ar is when the 4-diphenyl residue, X is an ethylene or propylene residue, R₁And R₂Is not ethyl;

with the proviso that when Ar is a 4- (2-fluoro) diphenyl residue, X is CO₂H-group substituted butylene, R_aAnd R_bIs not hydrogen;

with the further proviso that when Ar is phenyl, X is butylene, R₁And R₂And is not N- (2-methoxyphenyl) piperazine.

In addition, the present invention provides (R) -2-aryl-propionamide compounds represented by the general formula (I) useful as inhibitors of chemotaxis induced by polymorphonuclear leukocytes and monocytes C5a,

in the formula (I), the compound is shown in the specification,

ar represents a substituted or unsubstituted aryl group;

r represents H, represented by CO₂R₃C optionally substituted by radicals₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl radicalWherein R is₃Represents H, or a linear or branched C₁-C₆Alkyl or straight or branched C₂-C₆An alkenyl group;

x represents:

from CO₂R₃Or CONHR₄Straight-chain or branched C optionally substituted by radicals₁-C₆Alkylene radical, C₄-C₆Alkenylene radical, C₄-C₆Alkynylene, wherein R₄Represents H, straight or branched C₂-C₆Alkyl OR OR₃Group, R₃As defined above;

by CO as defined above₂R₃Or CONHR₄The radical being optionally substituted (CH)₂)_m-B-(CH₂)_nWherein B is an oxygen or sulfur atom, m is 0 or an integer of 2 to 3, and n is an integer of 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3, n is an integer from 2 to 3;

or the nitrogen atom of the omega-amino group to which X is bonded and R₁The radicals together forming a non-aromatic nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring, wherein the nitrogen atom carries the substituent Rc, which represents H, C₁-C₄Alkyl radical, C₁-C₄Hydroxyalkyl radical, C₁-C₄Acyl, substituted or unsubstituted phenyl, benzhydryl;

R₁and R₂Independently H, a linear or branched C optionally interrupted by an O or S atom₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₃-C₆Alkenyl radical, C₃-C₆Alkynyl, aryl-C₁-C₃-alkyl, hydroxy-C₂-C₃-an alkyl group;

or R₁And R₂Together with the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen heterocycle represented by the general formula (II),

in the formula (I), the compound is shown in the specification,

y represents a single bond, CH₂O, S, or an N-Rc group as defined above, p represents an integer from 0 to 3;

or, R₁As defined above, R₂Represents a group represented by the general formula (III):

in the formula (I), the compound is shown in the specification,

R_ais H, R_bIs H, hydroxy, C₁-C₄Alkyl or NR_dR_eGroup, wherein R_dAnd R_eEach independently is H, C₁-C₄Alkyl or phenyl; or R_aAnd R_bTogether with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring, a monocyclic ring, or a fused ring with benzene, pyridine, or pyrimidine.

Pharmaceutically acceptable salts of the compounds of formula (I) are also within the scope of the invention.

Examples of the aryl group preferably include:

a)Ar_amono-or poly-substituted aryl, or the most common heterocyclic ring found on 2-aryl-propionic acids currently used in therapy: alminoprofen (alminoprofen), benoxaprofen (benoxaprofen), carprofen (carprofen), fenbufen (fenbufen), fenoprofen (fenoprofen), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), indoprofen (indoprofen), ketoprofen (ketoprofen), loxoprofen (loxoprofen), naproxen (naproxen), pirprofen (pirprofen) and its dehydro and dihydro derivatives, pranoprofen (pranoprofen), suprofen (suprofen), tiaprofenic acid (tiaprofenic acid), zaltoprofen (zaltoprofen);

b) aryl-hydroxymethyl-aryl derived from the phenylketocarbonyl reduction of 2-aryl-propionic acid and represented by general formula (iva): ketoprofen, suprofen, tiaprofenic acid, in the form of individual (S ', R) and/or (R', R) diastereoisomers and diastereoisomeric mixtures,

in the formula (I), the compound is shown in the specification,

when Ar is₂When is phenyl, Ar₁Selected from the group consisting of phenyl, thiophen-2-yl when Ar₁When is phenyl, Ar₂Selected from the group consisting of phenyl, 4-thienyl, pyridyl,

an aryl group represented by the general formula (IVb):

φ-Ar_b (IVb)

in the formula (I), the compound is shown in the specification,

Ar_bis phenyl, mercapto and C mono-and polysubstituted by hydroxyl₁-C₃Alkoxy (alcoxy), C₁-C₃Alkylthio, chloro, fluoro, trifluoromethyl, nitro, amino, optionally substituted C₁-C₇An amido group; phi is H; from C₁-C₃Alkoxycarbonyl, substituted or unsubstituted phenyl, 2, 3-or 4-pyridyl, quinolin-2-yl substituted straight or branched C₁-C₅Alkyl radical, C₂-C₅Alkenyl or C₂-C₅An alkynyl residue; c₃-C₆A cycloalkyl group; 2-furyl; 3-tetrahydrofuranyl; 2-thiophenyl; 2-tetrahydrothiophenyl group or a residue represented by the general formula (IVc)

A-(CH₂)q- (IVc)

In the formula (I), the compound is shown in the specification,

a is C₁-C₅Dialkylamino group, C₁-C₈- (alkanoyl, cycloalkanoyl, arylalkanoyl) -C₁-C₅Alkylamino, such as dimethylamino, diethylamino, methyl-N-ethyl-amino, acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino; a nitrogen containing 5-7 membered monocyclic ring, optionally carrying one or two double bonds and optionally carrying another heteroatom separated from the nitrogen atom by at least 2 carbon atoms, to form, for example, a 1-pyrrolidinyl (pyrrolidino), 2, 5-dihydro-pyrrol-1-yl, 1-pyrrolyl, 1-piperidino (piperidino), 1-piperazinyl-4-unsubstituted or 4-substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, dibenzoyl or phenyl), 4-morpholino, 4-3, 5-dimethyl-morpholino, 4-thiomorpholino group; or a residue represented by the general formula (IVd),

in the formula (I), the compound is shown in the specification,

rg is H, C₁-C₃Alkyl or C₁-C₃An alkanoic acid residue;

q is 0 or the integer 1, and,

2- (phenylamino) -phenyl represented by general formula (ive e):

in the formula (I), the compound is shown in the specification,

P₁and P₂Denotes that two phenyl groups may be independently substituted by one or more C₁-C₄Alkyl radical, C₁-C₃Alkoxy, chloro, fluoro and/or trifluoromethyl.

Preferred compounds of the invention are those in which

R is a hydrogen atom(s) in the formula,

x is

C₁The position being defined by CO as above₂R₃A linear alkylene group optionally substituted with a group;

C₁bit by CONHR₄A linear alkylene group optionally substituted with R₄Is OH;

2-butynylene, cis-2-butynylene, trans-2-butynylene;

3-oxa-pentadienylenepentylene, 3-thio-pentadienylenepentylene, 3-oxa-hexylene, 3-thio-hexylene;

(CH₂)_m-CO-NH-(CH₂)_nwherein m and n are each independently an integer of 2 to 3;

(CHR’)-CONH-(CH₂)_nwherein n is an integer from 2 to 3, R' is methyl in the absolute configuration R or S;

or X together with the nitrogen atom of the omega-amino group forms a nitrogen containing cycloaliphatic ring, which is preferably 1-methyl-piperidin-4-yl or 1, 5-tropan-3-yl.

Preferred compounds are also those in which NR is₁R₂Represents NH₂A group, dimethylamino group, diethylamino group, diisopropylamino group, 1-piperidinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, or R₁And R₂Together form the residue of guanidine, aminoguanidine, hydroxyguanidine, 2-amino-3, 4, 5, 6-tetrahydropyrimidinyl, 2-amino-3, 5-dihydro-imidazolyl.

Particularly preferred aryl groups include:

4-isobutylphenyl, 4-cyclohexylmethylphenyl, 4- (2-methyl) allyl-phenyl, 3-phenoxyphenyl, 3-benzoyl-phenyl, 3-acetyl-phenyl, 3-C₆H₅-CH (OH) -phenyl, 3-CH₃-CH (OH) -phenyl, 5-C₆H₅-CH (OH) -thienyl, 4-thienylThe radicals-CH (OH) -phenyl, 3- (pyridin-3-yl) -CH (OH) -phenyl, 5-benzoyl-thiophen-2-yl, 4-thiophenoyl-phenyl, 3-nicotinoyl-phenyl, 2-fluoro-4-phenyl, 6-midoxy (methoxy) -2-naphthyl, 5-benzoyl-2-acetoxy-phenyl and the individual diastereomers (R), (S) and diastereoisomers (R, S mixtures) of 5-benzoyl-2-hydroxy-phenyl.

Particularly preferred aryl groups represented by the general formula (IVb) are those selected from the group consisting of isopropyl-1-en-1-yl, isopropyl, pent-2-en-3-yl; pent-3-yl; 1-phenylethen-1-yl; alpha-methylbenzyl groups, phenyl substituted at the 3-position of the group.

Particularly preferred aryl groups represented by formula (IVc) are 4- (pyrrolidin-1-yl) -methyl-phenyl, 3-chloro-4- (2, 5-dihydro-1-H-pyrrol-1-yl) -methyl-phenyl, 3-chloro-4- (thiomorpholin-4-yl) phenyl; 3-chloro-4- (piperidin-1-yl) -phenyl, 4- (N-ethyl-N-quinolin-2-yl-methylamino) -methyl) phenyl, 3-chloro-4- (morpholin-4-yl) -phenyl.

Particularly preferred aryl groups represented by formula (ive) are 2- (2, 6-dichloro-phenyl-amino) -phenyl; 2- (2, 6-dichloro-phenyl-amino) -5-chloro-phenyl; 2- (2, 6-dichloro-3-methyl-phenyl-amino) -phenyl; 2- (3-trifluoromethyl-phenyl-amino) -phenyl.

Particularly preferred compounds of the invention are:

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (4-dimethylaminobutyl) -propionamide hydrochloride;

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-N-morpholinylpropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (2-dimethylaminoethyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl-propionyl ] -N- (2- (4-methyl-piperazin-1-yl) ethyl ] propionamide;

(R) -N- (exo-8-methyl-8-aza-bicyclo [3, 2, 1] oct-3-yl) -2- (4-isobutylphenyl) -propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-N-thiomorpholinopropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [4- (N' -methyl) piperidinyl ] propionamide hydrochloride;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- (1-carboxy-2-dimethylaminoethyl) -propionamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- [ (1-carboxy-4-piperidin-1-yl) butyl ] propionamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- (1-carboxy-4-aminobutyl) -propionamide;

(R) -2- (4-isobutyl) phenyl-N- [2- (dimethylaminoethyl) aminocarbonylmethyl ] propionamide hydrochloride;

2- (2, 6-dichlorophenylamino) -phenyl-N- (3-dimethylaminopropyl) propanamide;

(R), (R ', S') -3- [3- (α -methyl) benzyl ] phenyl-N- (3-dimethylaminopropyl) -propionamide;

(R) -2- [ (3-isopropyl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R) -2- [3- (pent-3-yl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-guanidinopropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [ (3-hydroxy-guanidino) propyl ] propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [ (3-amino-guanidino) propyl ] propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [3- (2-amino-2-imidazoline) propyl ] propanamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [ N-methyl-N- (2-hydroxyethyl) aminoethoxy ] propionamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- (1-carboxy-5-aminopentyl) -propionamide.

The compounds of formula (I) are prepared by known methods, for example by reacting an appropriately activated form of R-2-arylpropionic acid of formula (V) with an amine of formula (VI) under non-racemic conditions, preferably in excess of 1 mole of base:

in the formula:

AT is a residue that activates the carboxyl group. The activated form of 2-arylpropionic acid represented by formula (V, AT is OH) is chloride (AT is chloride), acylimidazole (AT is 1-imidazole), and phenol ester such as p-nitrophenol (AT is p-NO)₂-C₆H₄O-) or an activated form obtained by reaction with 1-Hydroxybenzotriazole (HOBT) or a carbodiimide, such as dicyclohexylcarbodiimide.

Ar、R、X、R₁And R₂As defined above, the option to be protected is available when needed.

The reaction of the activated form of the 2-arylpropionic acid of the formula (V) with a protected amine of the formula (VI) is generally carried out at room temperature using customary protic or aprotic solvents and/or mixtures thereof, preferably anhydrous solvents, for example esters, such as methyl acetate, ethyl formate, nitriles, such as acetonitrile, linear or cyclic ethers, such as diethyl ether, sulfolane, dioxane, tetrahydrofuran, amides, such as dimethylformamide, formamide, halogenated solvents, such as dichloromethane, aromatic hydrocarbons, such as toluene, chlorobenzene or heteroaromatic hydrocarbons, such as pyridine and picoline. The reaction can also be carried out under basic conditions; preferred inorganic bases are alkali metal and alkaline earth metal carbonates and bicarbonates, such as finely divided potassium carbonate, potassium bicarbonate and magnesium carbonate and/or calcium carbonate.

The resulting protected amide may be converted to an amide represented by formula (I) by cleaving the protecting group and any ester groups that may be present. A particularly preferred ester is allyl ester which can be removed under highly selective conditions, for example, by adding a palladium (0) catalyst to convert the allyl group to a morpholine molecule which can act as a hydrogen converting agent and a nucleophile acceptor, according to the methods disclosed in j.

Reacting primary and secondary amines of formula (I) with isothioureides of formula (IIIa) or the corresponding isothioureas(isothiouronium) salts are reacted to form amides of the general formula (I) wherein R is₂Is a group of the general formula (III),

wherein Alk is C₁-C₃-alkyl, R_aAnd R_bAs defined above.

Bernd Clement (arch. pharm. (Wheineim)319, 968(1986)) describes a process for the preparation of hydroxy-isothioureas represented by the general formula (iiia); other compounds of the general formula (IIIa) are known compounds or can be prepared by customary alkylation methods in basic media of the corresponding linear and/or cyclic thioureas and thiosemicarbazides. The isolated compound of the formula (IIIa) is isothioureaSalts can be reacted with amines of the general formula ie according to the method disclosed by bodansky m et al (j.am. chem. soc., 86, 4452, 1964). Furthermore, isothioureas of the general formula IIIaAdding excessive solvent such as ethyl acetate into the saline solution or suspension, adding equal amount of alkaline solution (sodium hydroxide N, potassium carbonate N) under strong stirring to neutralize isothioureaSalifying to form the corresponding isothiourea.

An amide represented by the general formula (Ia),

in the formula Ar₁、Ar₂、X、R、R₁And R₂As defined above, the phenyl carbonyl reduction reaction can be carried out to produce diastereomer pairs R ', S' alcohol, and the individual diastereoisomers represented by general formula (Ib) can be obtained by selective separation of the diastereomer pairs produced by fractional crystallization and/or preparative chromatography.

The absolute configuration S' of the most polar diastereomer is shown by conventional means.

The compounds of formula (i) may be converted into pharmaceutically acceptable salts by salification of the structural base or acid group with a pharmaceutically acceptable acid or base, respectively. Salts with pharmaceutically acceptable bases are salts with alkali metals or alkaline earth metals, preferably lithium, sodium and magnesium, or with organic bases, such as trimethylamine, D-glucamine, lysine, arginine.

The compounds of formula (I) are usually isolated in the form of addition salts with pharmaceutically acceptable organic and inorganic acids. Examples of such acids are: hydrochloric, sulfuric, nitric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic and succinic, malonic and methanesulfonic, D and L-tartaric acids.

The R enantiomer of a 2-arylpropionic acid represented by the general formula (va):

wherein Ar is as defined above, are weak inhibitors of cyclooxygenase and are often known compounds.

An acid represented by the general formula (vb):

in the formula, phi and Ar_bAs defined above, and as described below, by alkylation of a tin salt of a polysubstituted 2-phenyl-propionic acid, said tin salt bearing a perfluorobutanesulfonate group in the ortho or meta or para position.

International patent application WO01/58852 discloses compounds represented by the general formula (vb). Specifically, the preferred amide precursors of formula (I) are 2- [ (3 ' -isopropyl) phenyl ] -propionic acid, 2- [3 ' - (alpha-methyl) phenylmethylphenyl ] -propionic acid and 2- [3 ' - (3-isoamyl) phenyl ] -propionic acid.

The various 2-arylpropionic acids are prepared by complete and stereospecific synthesis or by conversion of the racemate into one of the individual enantiomers after conversion into 2-aryl-2-propyl-enone, as described by Larsen r.d. et al (j.am. chem.soc., 111, 7650, 1989) and myersa.g. (ibidem, 119, 6496, 1997). Stereospecific synthesis of 2-arylpropionic acids is usually directed to the S enantiomer, but the R enantiomer is easily obtained by modification thereof by simple selection of chiral auxiliary.

For example, b.m. trost and j.h.rigby (j.org.chem., 14, 2926, 1978) describe the use of arylalkyl ketones as reactants in the synthesis of alpha-aryl alkanoic acids, j.t. piney and R.A.

Rowe (tetra h.lett., 21, 965, 1980) describes the arylation of meldrum's acid; castaldi et al (j. org. chem.52, 3019, 1987) describe the use of tartaric acid as a chiral auxiliary; r.d. larsen et al (j.am. chem.soc., 111, 7650, 1989) and US patent US4,940,813 and the citations thereof report the use of alpha-hydroxy esters as chiral auxiliaries.

Italian patent No. 1,283,649 discloses a process for the preparation of 2- (2-OH-phenyl) -propionic acid and its esters. The above disclosed test and efficient method for the preparation of the R enantiomer of (R, S) -2- (5-benzoyl-2-acetoxy) -propionic acid and the acid represented by general formula (vb) involves conversion of the chloride of the prop-1-enonic acid, i.e. reaction with a triamine, such as dimethylethylamine, followed by reaction of the enone with R (-) pantolactone to produce an ester of the R enantiomer of the acid with R-dihydro-3-hydroxy-4, 4-dimethyl-2 (3H) -furan 2-one. The ester is then saponified with lithium hydride to form the corresponding free acid.

General procedure for the preparation of R (-) -2-arylpropionic acids of formula (vb) comprises reacting one or more substituted hydroxyaryl ketones of formula (Vc) with perfluorobutanesulfonyl fluoride to form perfluorobutanesulfonic acid esters of formula (vd) wherein n is an integer from 1 to 9.

After esterification and methylation of the carbon atom in the alpha position, the compounds of the general formula (vd) are reacted

Willgeodt rearrangement to give arylpropionic acid derivatives of the general formula (ve), wherein n is an integer from 1 to 9, R₃Is represented by C₁-C₄Alkyl or C₂-C₄An alkenyl group.

A compound of the formula (ve) and a compound of the formula Bu₃SnR₅A suitable tributylstannane reaction of formula (I), wherein R₅Is unsubstituted or aryl-substituted straight-chain or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl or straight-chain or branched C₂-C₆Alkynyl to give the corresponding (R, S) -2-arylpropionate salt of the formula (vf).

Under the condition of catalytic hydrogenation, the alkenyl or alkynyl can be subjected to hydrogenation reaction to obtain the corresponding saturated alkyl. As mentioned above, the compounds of general formula (vf) can be deracemized by converting the corresponding acid chloride into an enone, which can be converted into the pure R enantiomer by reaction with R (-) -pantolactone and hydrolysis.

The amines of the formula (VI) are known products, most of which are commercially available or can be prepared by known methods. R.dalhome et al (j.med.chem., 9, 843, 1966) and t.singh et al (ibidem, 12, 368, 1969) describe the synthesis of 4-dialkylamino-2-butynyl-amines and, on the basis thereof, of cis-and trans-4-dialkylamino-2-butenamines, respectively.

To be provided with-hydroxy alpha-amino acids, carboxyl groups and amino groups which have been protected in a simple manner, are prepared by known methods as starting materials for alpha-amino acids having the general formula NR bound to a terminal carbon atom₁’R₂' of (a). Alcohol groups are reacted with triphenylphosphine and CBr₄The reaction is converted to the bromide (RG Weiss et al, J.org.chem.36, 403, 1971 and M.Kang., ibidem, 64, 5528, 1966), which is reacted with the halide, thereby obtaining the desired compound in at least an excess of 2MAmine (i.e., dimethylamine, piperidine). Commercially available substrates for this use are serine and homoserine: with C₁And an amino-protected, commercially available dicarboxylic alpha-amino acid, free carboxyl group, which can be selectively reduced to an alcohol by reduction with excess diborane in THF at room temperature, can be used as starting materials to prepare higher analogs.

The present invention provides compounds represented by general formula (I), which are R enantiomers of 2-arylpropionamides for use as medicaments.

The ability of the compounds of general formula (I) of the invention to inhibit polymorphonuclear leukocytes (hereinafter PMNs) and the monocyte complement fragments C5a and C5 a-desArg-induced chemotaxis was assessed "in vitro". To this end, liver blood was drawn from healthy adult volunteers, polymorphonuclear leukocytes were separated from the blood, monocytes were removed by glucose sedimentation (according to the method disclosed by w.j.ming et al, j.immunol., 138, 1469, 1987), and red blood cells were removed by treatment with hypotonic solution. Cell viability was calculated as trypan blue exclusion and the percentage of PMNs in the cell pellet was estimated after Diff Quinck staining.

Chemotaxis experiments used fragments hr-C5a and hrC5a-desarg (Sigma) as stimulating agents and gave virtually the same results.

Lyophilized C5a was dissolved in HBSS containing 0.2% BSA in a volume of 10^-5Mother liquor of M, diluted to 10 with HBSS^-9M was used for chemotaxis analysis.

In chemotaxis experiments polymorphonuclear leukocytes were incubated with the compounds of the general formula (I) according to the invention at 37 ℃ for 15 minutes in an atmosphere containing 5% carbon dioxide.

Evaluation of 1.5X10 per ml⁶C5a chemotactic activity of human circulating polymorphonuclear leukocytes in HBSS suspensions of polymorphonuclear leukocytes.

In the course of the chemotaxis determination (according to w.falkett et al, j.immunol.methods, 33, 239, 1980), filters without PVP were used, with a porosity of 5 micro-centimeters and with a fine chamber suitable for the test to be carried out.

The compounds of the general formula (I) according to the invention were evaluated at a concentration of 10^-6And 10^-10M, for this purpose, they are added to the bottom and top wells of the chamber in the same concentration. The wells of the bottom fraction contain a C5a solution or simple vehicle and the wells of the top fraction contain a polymorphonuclear leukocyte suspension.

For chemotaxis analysis, various compounds of general formula (I) of the present invention were evaluated for inhibition of C5 a-induced chemotactic activity by incubating the microchamber at 37 ℃ for 60 minutes in an atmosphere containing 5% carbon dioxide.

The ability of the compounds of general formula (i) of the invention to inhibit C5 a-induced chemotaxis of human monocytes was assessed according to the method described above (Van Damme j. et al, eur.j. immunol., 19, 2367, 1989). For chemotaxis analysis, the inhibition of C5 a-induced chemotactic activity of human monocytes by various compounds of the general formula (I) of the present invention was evaluated by incubating the microchamber for chemotaxis at 37 ℃ for 120 minutes in an atmosphere containing 5% carbon dioxide, and the concentration was evaluated at 10^-6And 10^-10M is greater than or equal to the total weight of the composition.

The ability of the compounds of the invention to inhibit IL-8-induced chemotaxis of human polymorphonuclear leukocytes can also be assessed. For this purpose, recombinant human interleukin-8 (rhIL-8, Pepro Tech) was used: the lyophilized protein was dissolved in HBSS (i.e., Hank's balanced salt solution) to prepare a solution with a concentration of 100. mu.g/ml, which was then diluted to 10 ng/ml in a chemotaxis assay. R (-) -2- [ (4' -isobutyl) phenyl group as described in WO00/24710 is selected]-propionylmethanesulfonamide (ED)₅₀＝10^-9M) as reference standard.

Table I lists the results of inhibition of chemotaxis induced by C5a and IL-8.

These results show that different structures of the amide groups can lead to different selectivities of the compounds of the invention.

The selected number of compounds are dual inhibitors, inhibiting both C5 a-induced chemotaxis and IL-8-induced chemotaxis, the others being selective inhibitors of C5 a-induced chemotaxis.

For example N- (1-methyl-pyridin-4-yl) -amides, beta-tropylamides, N- (H) of the formula (I)₂N-alkyl) -amides at 10^-6And 10^-8The concentration ranges between M are selective inhibitors of polymorphonuclear leukocyte and monocyte C5 a-induced chemotaxis. All of these compounds have poor activity as inhibitors of IL-8-induced chemotaxis at the same concentration range.

A selected number of compounds of the invention are at 10^-6And 10^-8The concentration range between M is sufficient to inhibit both the polymorphonuclear leukocyte and lymphocyte T-interleukin 8-induced chemotaxis and also the polymorphonuclear leukocyte and monocyte C5 a-induced chemotaxis. More specifically, compounds represented by the general formula (I) wherein R is₁And R₂Is a group other than hydrogen, and has an activity of inhibiting C5 a-induced chemotaxis and IL-8-induced chemotaxis. Compounds having both activities are those in which the N of the terminal base is 2 to 4 carbon atoms, preferably 3 carbon atoms, from the amide N. It can be said that the compounds of the invention have a dual inhibitory effect in this structural framework, being inhibitors of C5 a-induced chemotaxis and of IL-8-induced chemotaxis.

The compounds of the invention were evaluated in whole blood in vitro using the procedure described by Patrignani et al (J.Pharmacol. Exper. Ther., 271, 1705, 1994) and were found to be completely ineffective as inhibitors of COX enzymes.

In most cases, the compounds of formula (I) are present at 10^-5To 10^-7In the concentration range between M, the PGE production induced by lipopolysaccharide (LPS11 microgram/ml) on mouse macrophages is not interfered₂. The majority of the statistically significant limits are seen to suppress PGE₂The phenomenon occurs that the inhibition value is more than 15-20% lower than the base number.

Given the experimental results discussed above and the effects of complement activation on several pathologies through its fragment C5a, for example psoriasis (r.j. nicholoff et al, am.j. pathol., 138, 129, 1991), pemphigus, pemphigoid, rheumatoid arthritis (m.selz et al, j.clin.invest., 87, 463, 1981), chronic intestinal inflammation such as ulcerative colitis (y.r.mahida et al, clin.sci., 82, 273, 1992), acute respiratory distress syndrome, cystic fibrosis, idiopathic fibrosis (e.j.miller and p.c.carr et al, j.clin.invest., 88, 1882, 1991), Chronic Obstructive Pulmonary Disease (COPD), glomerulonephritis (t.wada et al, j.exp.180, 1135, treatment and local reperfusion injury) and the present invention is particularly developed by these compounds for the prevention and prevention of ischemia, 1994.

Accordingly, the present invention provides compounds represented by the general formula (i) for use in the treatment of psoriatic psioriasis, pemphigus (pemphigus) and pemphigoid (pemphigoid), rheumatoid arthritis (rheumatoid arthritis), chronic intestinal inflammation (intensive respiratory inflammation modalities) including ulcerative colitis (ulcerative colitis), acute respiratory distress syndrome (acute respiratory syndrome), systemic idiopathic pulmonary fibrosis (systemic inflammatory pulmonary fibrosis), cystic fibrosis (cystic fibrosis), chronic obstructive pulmonary disease (chronic pulmonary fibrosis), glomerulonephritis (glomerular nephritis), and for the prevention and treatment of injury caused by ischemia and reperfusion.

The invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and prophylaxis of said pathologies.

The compounds of the present invention, together with adjuvants, carriers, diluents or excipients conventionally employed, may be formulated into pharmaceutical compositions and unit dosages thereof in the form of solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs or filled capsules thereof, all of which may be administered orally or parenterally (including subcutaneously) in the form of sterile injectable solutions. These pharmaceutical compositions and unit dosage forms thereof may comprise the ingredients in conventional proportions, with or without the addition of the active compound or active ingredient, and the unit dosage forms may also contain any effective amount of the appropriate active ingredient commensurate with the dosage amount taken per day.

When the amides of the invention are used as medicaments, they are generally administered in the form of pharmaceutical compositions. These compositions may be prepared in a manner known per se in the pharmaceutical art and comprise at least one active compound. Typically, the compounds of the present invention are administered in a pharmaceutically effective amount. The actual amount of the compound to be administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the route of delivery chosen, the compounds are preferably formulated as injectable solutions or oral compositions. The oral composition can be made into bulk solution or suspension or bulk powder. However, it is most common to formulate compositions in unit dosage form to facilitate accurate dosage calculation. The term "unit dosage form" refers to a unit dosage of matter suitable for human beings and other mammals, each unit containing a pre-calculated predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include a pre-filled and pre-measured syringe or syringe of a liquid composition or a pill, tablet, capsule, or solid composition, and the like. In these compositions, the amide compound is often a minor component (about 0.1 to 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that assist in forming the desired dosage form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous medium containing buffers, suspending and distributing agents, coloring and flavoring agents and the like. Liquid forms, including the injectable compositions mentioned below, are generally stored in a dark environment to avoid any catalytic effects, such as hydroperoxide or peroxide formation, upon exposure to light. The solid form may comprise, for example, any of the following or a compound of the same nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, for example, alginates, xanthan gum or corn starch; lubricants, such as magnesium stearate; slip agents, such as colloidal silica; sweetening agents, such as sucrose or saccharin; or a flavoring agent, such as a mint, salicylate, or orange flavoring agent.

Injectable compositions are generally based on the injection of sterile saline or phosphate buffered saline or other injection vehicles known in the art. As described above, the amide derivative represented by the general formula (I) in these compositions is a minor component, and the weight thereof is usually between 0.05 and 10%, and the remainder is an injection carrier or the like. The average daily dose depends on many factors, such as the severity of the disease and the condition of the patient (age, sex, body weight). The daily dosage of the compounds of formula (I) is usually not fixed and may be divided into multiple administrations from 1 mg or a few mg up to as high as 1500 mg. Higher doses can be administered due to the low toxicity of the compounds of the invention when taken over a long period of time.

The above ingredients of the oral or injectable compositions are merely representative. Other materials or processing techniques, etc. may be referred to herein by reference (Mack Press, Remingto's pharmaceutical series Handbook, eighth part, 18 th edition, 1990), Pa.

The compounds of the present invention can also be administered in sustained release form or by a sustained release drug delivery system. Exemplary sustained release materials are also described in Remingto's Pharmaceutical Seiences handbook, referenced above.

The present invention is illustrated in detail by the following examples, which should not be construed as limiting the scope of the present invention.

In describing the compounds of formula (I) of the present invention, the absolute configuration of any other chiral substituent optionally contained in the structure of the compound is indicated by the starting symbols (e.g., R ', S', S ", etc.) in accordance with common practice.

Abbreviations for the examples are: AcOH represents acetic acid, AcOEt represents ethyl acetate, BOC represents N-tert-butoxycarbonyl, DCC represents dicyclohexylcarbodiimide, DCU represents dicyclohexylurea, DMF represents dimethylformamide, EtOH represents ethanol, Et2O represents diethyl ether, HOBZ represents 1-hydroxy-benzothiazole, hr represents hours, hrs represents several hours, MeOH represents methanol, r.t. represents room temperature, THF represents tetrahydrofuran, and Z represents N-benzyloxycarbonyl.

Examples

The intermediate compounds used in the following examples were prepared as follows.

1-amino, 4-dimethylamino-butane

A suspension of potassium carbonate (4.3 g; 31 mmol) and acetone (5 ml) at 25 ℃ is added dimethylamine hydrochloride (1.2 g; 12.5 mmol) and after 1 hour 4-bromobutyl phthalimide (3.5 g; 12.4 mmol); the suspension was then refluxed overnight. After cooling at room temperature, the mixture was filtered, evaporated to dryness and the residual oil was purified by flash chromatography on silica gel (chloroform/methanol 8: 2 as eluent) to give N- (4-dimethylamino-butyl) -phthalimide (2.2 g; 8.94 mmol) as a white solid.

The compound was dissolved in ethanol, the solution treated with 35% aqueous hydrazine solution (0.45 ml), heated at reflux temperature until all reagents disappeared (about 2 hours), filtered and evaporated to dryness. Finally, 0.85 g (7.32 mmol; 82% yield) of 1-amino, 4-dimethylamino-butane was crystallized from dichloromethane/methanol (98: 2) as a white solid.

¹H-NMR(CDCl₃)：δ7.75(m，2H)；7.65(m，2H)；2.72(m，2H)；2.35(t，2H，J=7Hz)；2.23(s，6H)；1.75(m，2H)；1.56(bs，2H，NH₂)；1.48(m，2H)。

1-amino, 4-methylamino-butane

Methylamine was used instead of dimethylamine in the above procedure to produce a large amount of 1-amino, 4-methylamino-butane.

1- (3-aminopropyl) -thiomorpholine

A solution of 3-BOC-aminopropylbromide (3.07 g; 12.9 mmol) and thiomorpholine (2.6 ml; 25.8 mmol) in dichloromethane (25 ml) was heated at reflux temperature for 24 h. The mixture was cooled at room temperature, filtered, washed with water (2 × 50 ml), dried over sodium sulfate and evaporated to dryness in vacuo. Purification by flash chromatography on silica gel (chloroform/methanol 9: 1 as eluent) gave 1- (3-BOC-aminopropyl) -thiomorpholine (3.1 g; 11.96 mmol) as clear oil.

1.4 g (5.4 mmol) of the compound was dissolved in 3N aqueous hydrochloric acid (6 ml) and the protecting group was cleaved at room temperature; after 18 h, 2N aqueous sodium hydroxide solution was added until pH equal to 8, the solution was basified and extracted with dichloromethane (2 × 10 ml). The combined extracts were dried over sodium sulfate and evaporated to dryness to give clear oil- (3-aminopropyl) -thiomorpholine (0.63 g; 3.96 mmol).

¹H-NMR(CDCl₃)：δ7.75(m，2H)；7.65(m，2H)；2.72(m，2H)；2.35(t，2H，J=7Hz)；2.23(s，6H)；1.75(m，2H)；1.56(bs，2H，NH₂)；1.48(m，2H)。

1- (3-aminopropyl), 4-methyl-piperazine (isolated as the hydrochloride salt)

In the same step 4-methyl-piperazine replaces thiomorpholine to give 1- (3-aminopropyl), 4-methyl-piperazine¹H-NMR(D₂O)：δ3.75(m，7H)；3.45(m，3H)；3.15(m，2H)；3.05(m，4H)；2.20(m，2H)。

1- (3-aminopropyl) -piperidine

In the same step 4-methyl-piperidine is substituted for thiomorpholine to give 1- (3-aminopropyl) -piperidine¹H-NMR(CDCl₃)：δ2.85(t，2H，J=8Hz)；2.45(m，6H)；1.90(bs，2H，NH₂)；1.8-1.62(m，6H)；1.55(m，2H)。

1-BOC-propane-1, 3-diamine：

To a solution of 3-BOC-amino-propyl bromide (5 g; 21.5 mmol) in toluene (10 ml) was added, with stirring, an aqueous solution of sodium nitride (1.4 g; 21.5 mmol) (5 ml) and 2-3 drops of Aliquat 336; the mixture was heated at reflux temperature for 4 hours. After cooling at room temperature, the organic phase was separated, dried over sodium sulfate and evaporated in vacuo to yield the clear oil 3-BOC-amino-propyl azide (3.75 g; 18.3 mmol) (85% yield).

To a solution of the above azide in THF (30 ml)/water (0.3 ml; 18.3 mmol) was added dropwise, with stirring, a solution of triphenylphosphine (4.8 g; 18.3 mmol) in THF (15 ml); stirring was continued at room temperature for 24 hours. After the solvent was removed in vacuo to dryness, the residue was dissolved in a small amount of ethanol and stirred at room temperature for 6 hours to isolate triphenylphosphine oxide as a white precipitate. Finally, the ethanol was removed to dryness under reduced pressure to give 3.22 g (18 mmol) of 1-BOC-propane-1, 3-diamine as a pale yellow oil.

¹H-NMR(CDCl₃)：δ4.90(bs，1H，CONH)；3.25(m，2H)，2.85(t，2H，J=7Hz)；1.75(t，2H，J=7Hz)；1.60(bs，2H，NH₂)；1.55(s，9H)。

3- (BOC-methylamino) -propylamine

3- (BOC-methylamino) -propylamine was prepared in the above procedure using 3- (BOC-methylamino) -propyl bromide.

(S) -2-amino-3-dimethylamino-propionic acid methyl ester

To a solution of (S) methyl 2-BOC-amino-3-bromo-propionate (0.45 g; 1.42 mmol) (Weiss r.g. et al, j.org.chem, 36, 403, 1971; Kang m.et al, ibidem, 61, 5528, 1996) in anhydrous THF (10 ml) was added dropwise a 2N solution of dimethylamine in THF (2.5 ml) with stirring at 25 ℃. The mixture was stirred at room temperature overnight and evaporated to dryness in vacuo. The residue was partitioned between diethyl ether (30 ml) and 0.5N aqueous sodium hydroxide (2 × 5 ml); the ether extracts were combined, washed with brine, dried over sodium sulfate and evaporated to dryness to give 0.34 g (1.22 mmol) of (S) -2-amino-3-dimethylamino-propionic acid methyl ester as a pale yellow oil.

¹H-NMR(CDCl₃)：δ7.45(m，5H)；5.73(bs，1H，CONH)；5.15(s，2H)，4.32(m，1H)；3.82(s，3H)；2.75(m，2H)；2.22(s，6H)。

A solution of the methyl ester (0.34 g; 1.22 mmol) in acetonitrile (12 mL) was treated with trimethylsilyliodide (0.21 mL; 1.46 mmol) while stirring at room temperature; after 3h, the mixture was quenched with methanol (0.24 ml; 5.9 mmol) and evaporated in vacuo. The residue was dissolved in diethyl ether (2 × 10 ml), extracted with 30% aqueous acetic acid (2 × 5 ml), collected basified to pH equal to 8, and extracted with dichloromethane (2 × 10 ml). The dichloromethane extracts were combined, dried over sodium sulfate and evaporated to dryness to yield 0.16 g (1.1 mmol) of (S) 2-amino-3-dimethylamino-propionic acid methyl ester.

¹H-NMR(CDCl₃)：δ4.32(m，1H)；3.82(s，3H)；3.24(bs，2H，NH ₂ )；2.75(m，2H)，2.22(s，6H)。

(S) -2-amino-5- (piperidin-1-yl) -pentanoic acid methyl ester

The reaction temperature was maintained between 20-25 ℃ with stirring and external cooling, 0.03 molar equivalent of B2H6 (diborane) was dissolved in THF to make a 1N solution, which was added to a 0.01M solution of (S) 2-BOC-amino-1, 5-glutaric acid 1-hemi-methyl ester in THF (15 ml); after 2 hours, the excess diborane was destroyed by careful addition of water. After concentration in vacuo to a small volume, the solution was diluted with ethyl acetate (25 ml). The organic phase was washed to neutrality with 5% aqueous sodium bicarbonate, brine and water, dried over sodium sulfate and evaporated to dryness.

With triphenylphosphine and CBr₄The crude residue (S) methyl 2-BOC-amino-5-hydroxy-valerate was treated to give a crude sample (S) methyl 2-BOC-amino-5-bromo-valerate.

The latter compound was reacted with piperidine in THF to give (S) 2-BOC-amino-5- (piperidin-1-yl) -pentanoic acid methyl ester, which was treated with a solution of trifluoroacetic acid in dichloromethane to give (S) -2-amino-5- (piperidin-1-yl) -pentanoic acid methyl ester cis-trifluoroacetate.

¹H-NMR(CDCl₃)：δ4.32(m，1H)；3.82(s，3H)；3.54(m，1H)；2.85(t，2H，J=7Hz)；2.45(m，6H)，δ1.85(bs，2H，NH2)；δ1.75-1.6(m，6H)，δ1.5(m，2H)。

5-BOC-Ornithine-methyl ester hydrochloride

To a suspension of finely ground potassium carbonate (0.38 g; 2.7 mmol) in anhydrous DMF (20 ml) was added solid 2-Z, 5-BOC-ornithine (1g 2.7 mmol; commercial reagent) with stirring while maintaining the reaction temperature about 0-5 ℃ by external cooling and after 15 minutes iodomethane (0.34 ml, 5.4 mmol) was added. The mixture was stirred at 0-5 ℃ and room temperature, respectively, for 1 more hour, then diluted with ethyl acetate (40ml) and filtered. The clear solution was washed with water (40ml) and brine (3 × 30ml), dried over sodium sulfate, and evaporated to dryness. Purification by flash chromatography on silica gel (eluent 8: 2 chloroform/methanol) gave 2-Z, 5-BOC-ornithine methyl ester (0.8 g; 2.1 mmol).

The Z protecting group is cleaved hydrolytically (according to the method of Meienhofer J. et al, tetrahedron. Lett., 3259, 1974) to yield 5-BOC-ornithine methyl ester hydrochloride as a white solid (0.73 g; 2.0 mmol).

¹H-NMR(CDCl₃)：δ9.25(bs，3H，NH ₃ ⁺)；5.40(bs，1H CONH)；4.40(m，1H)；3.8(s，3H)；3.0(m，2H)；1.8(m，4H)；1.4(s，9H)。

Exo-8-methyl-8-aza-bicyclo [3, 2, 1]Octane-3-amine (beta-1H, 5H-tropane amine)

The samples were prepared from tropinone according to Burks j.e. et al (org.proc.res.dev., 1, 198, 1997).

4- (N, N-dimethylamino) aniline

4-nitroaniline (1.83 g; 13.24 mmol) was added dropwise to frozen (temperature +4 ℃ C.) formic acid (3 ml; 66.2 mmol). Formaldehyde (37% aqueous solution (wt.); 2.72 mL; 29.13 mmol) was added and the resulting mixture was refluxed for 24 hours. After cooling at room temperature, 6N hydrochloric acid (2.2 ml) was added, and the resulting precipitate was filtered off. The filtrate was diluted with 1N sodium hydroxide (5 ml) and extracted with dichloromethane (3 × 20 ml); the organic phase was collected, dried over sodium sulfate and evaporated in vacuo to yield a solid residue which was purified by filtration over a 1: the 1 diisopropyl ether/acetone mixture was treated and filtered to give 4-nitro-N, N-dimethylaniline (1.65 g; 9.93 mmol) as a yellow powder.

Iron powder (2.145 g; 38.3 mmol) and 37% hydrochloric acid (28. mu.l) were suspended in 96% ethanol (35 ml) and the mixture was refluxed for 30 minutes; at the end of reflux 4-nitro-N, N-dimethylaniline (0.64 g; 3.84 mmol) was added and the mixture was stirred under reflux for 2 hours. The heated mixture was filtered through a plug of celite and after cooling at room temperature the filtrate was evaporated in vacuo. The oily residue was diluted with dichloromethane (25 ml), washed with 1N sodium hydroxide (3 × 25 ml), dried over sodium sulfate and evaporated in vacuo to give 4- (N, N-dimethylamino) aniline as a pale yellow oil (0.44 g; 3.26 mmol).

¹H-NMR(CDCl₃)：δ7.10(d，2H，J=8Hz)；6.60(d，2H，J=8Hz)；3.55(bs，2H，NH₂)；2.25(s，6H)。

The same procedure was used to prepare 4- (N, N-dimethylaminomethyl) aniline, a weak butter.

¹H-NMR(CDCl₃)：δ7.12(d，2H，J=8Hz)；6.64(d，2H，J=8Hz)；3.50(bs，2H，NH₂)；3.28(s，2H)；2.25(s，6H)。

N, N-dimethylbutyn-2-yl diamine

Propargyl bromide (1.3 ml, 17.4 mmol) was dissolved in DMF (30 ml) and potassium phthalimide (3.4 g; 18.4 mmol) was added. The mixture was refluxed for 5 hours. After cooling at room temperature, the mixture was diluted with diethyl ether, washed with water (3 × 50 ml), dried over sodium sulfate and evaporated in vacuo to yield N-propynylphthalimide (phtalimide) (3.15 g; 17 mmol) as a white solid.

N-Propynylphthalimide (0.64 g; 3.4 mmol) was dissolved in 1, 4-dioxane (20 ml), and then dimethylamine (8.5 ml; 17 mmol), cuprous chloride (0.35 g) and paraformaldehyde (1g) were added. The solution was refluxed for 3 hours. After cooling at room temperature, the resulting precipitate was filtered off and the filtrate was evaporated in vacuo to yield a green oily residue which, after dissolving in dichloromethane, was washed with a saturated solution of calcium bicarbonate (2 × 30ml) and water (2 × 30 ml). The organic phase was dried over sodium sulfate and evaporated in vacuo. The crude product was purified by treatment with diethyl ether to give N-phthalimido-N ', N' -dimethylbutyn-2-yl-1, 4-diamine (0.5 g; 2.05 mmol) as a pale yellow solid.

A suspension of N-phthalimido-N ', N' -dimethylbutyn-2-yl-1, 4-diamine (0.5 g; 2.05 mmol) and ethanol (10 ml) was treated with hydrazine hydrate (98. mu.l; 2 mmol) and the mixture was refluxed overnight. After cooling at room temperature, the precipitate formed is filtered off and the filtrate is evaporated in vacuo; the crude residue was treated with acetone at room temperature to remove the resulting precipitate and the pure product N, N-dimethylbutyn-2-yl-1, 4-diamine (0.2 g; 1.78 mmol) was obtained as a red oil.

¹H-NMR(CDCl₃)：δ3.52(m，2H)；3.27(m，2H)；2.35(s，6H)；1.90-1.65(bs，2H，NH₂)。

2- (Aminoxy) -N-methyl-N- (2-hydroxyethyl)]Ethylamine (ethylamine)

a) (Z-Aminooxy) -acetic acid

Benzyl chloroformate (1.41 ml, 10 mmol) and 4N aqueous sodium hydroxide (2.23 ml) were added dropwise alternately to a solution of 2.18 g (10 mmol) of carboxymethoxyamine hemihydrochloride [ (commercial reagent), also known as (aminoxy) acetate ] in 2N aqueous sodium hydroxide (5 ml) while maintaining the reaction temperature at about 0-5 ℃ by external cooling. Stirring was continued for 15 minutes then any organic impurities were removed with diethyl ether (2 × 15 ml); finely divided ice was added and acidified to pH equal to 2 with 37% hydrochloric acid, the resulting solid was filtered, washed with cold water and dried under vacuum at 40 ℃ to give 2.62 g (8.2 mmol) of (Z-aminoxy) -acetic acid.

b)2- (Z-Aminooxy) -N-methyl-N- (2-hydroxyethyl) acetamide

To a solution of (Z-aminoxy) -acetic acid (2.62 g, 8.2 mmol) in methanol (10 ml) was added thionyl chloride (0.78 ml, 9 mmol) with stirring. The mixture was left overnight at room temperature and after evaporation of the solvent under high vacuum according to conventional methods, a crude sample of (Z-aminoxy) -acetyl chloride was obtained. To a solution of 2-methylaminoethanol (1.44 ml, 18 mmol) in dichloroethane (5 ml) was added dropwise a solution of the compound in dichloroethane (10 ml) at room temperature with stirring, without any further purification; after 18 hours, the reaction mixture was diluted with 1N aqueous hydrochloric acid (15 ml). Separating the organic phase; washed with water (2 × 15 ml), dried over sodium sulfate and evaporated to give 2- (Z-aminoxy) -N-methyl-N- (2-hydroxyethyl) acetamide (2.64 g, 7 mmol) as a clear oil.

c)2- (Z-Aminooxy) -N-methyl-N- (2-hydroxyethyl) ethylamine

Selective reduction of 2- (Z-aminoxy) -N-methyl-N- (2-hydroxyethyl) acetamide with diborane according to Brown's method (J.A m. chem. soc.86, 3566, 1964 and j. org. chem., 38, 912, 1973) produced 2.1 g (5.8 mmol) of an oil, i.e. 2- (Z-aminoxy) -N-methyl-N- (2-hydroxyethyl) ethylamine.

d)2- (Aminooxy) -N-methyl-N- (2-hydroxyethyl) ethylamine

Following Makowski's procedure (Liebigs Ann. chem., 1457, 1985), the benzyloxycarbonyl group was hydrocracked in the presence of ammonium formate to yield the clear oil 2- (aminooxy) -N-methyl-N- (2-hydroxyethyl) ethylamine (1.06 g, 4.64 mmol).

¹H-NMR(CDCl₃)：δ5.28(bs，2H，ONH ₂ )；4.67(t，2H，J=7Hz)；3.40(m，2H)；2.75(t，2H，J=7Hz)；2.42(t，2H，J=7Hz)；2.21(s，3H)；1.8(bs，1H，OH)。

2-aryl-propionyl chloride represented by the formula V(general procedure)

A solution of 72.8 mmol of 2-arylpropionic acid represented by formula V [ e.g., (R) -2- (4-isobutylphenyl) propionic acid, (R) (-) ibuprofen, 72.8 mmol ] in thionyl chloride (37.5 mL) was refluxed for 3 hours. The mixture was cooled at room temperature and the excess reagent was evaporated in vacuo to dryness; a small amount of anhydrous dioxane was then added in two consecutive portions and evaporated to dryness under high vacuum to completely remove any residual thionyl chloride. The resulting oily residue was used in the following reaction.

IR (film)/cm: 1800(ClC = O).

(S)2- (4-isobutylphenyl) -N- (3-dimethylaminopropyl) -propionamide hydrochloride

(S) (+) ibuprofen (Fluka reagent) was converted into propionyl chloride using the method described previously, and treated with 3-dimethylaminopropylamine in the procedure of example 1 to obtain sample (S)2- (4-isobutylphenyl)]-N- (3-dimethylaminopropyl) -propionamide hydrochloride having a melting point of 97-98 ℃, [ alpha ]]_D= 27(c = 1; methanol).

¹H-NMR(D₂O)：δ7.45-7.21(m，4H)；3.75(q，1H，J₁=7Hz，J₂=7Hz)；3.45-3.15(m，2H)；2.95(t，2H，J=8Hz)；2.85(s，6H)；2.52(d，2H，J=7Hz)；1.98(m，1H)；1.47(d，3H，J=7Hz)；0.90(d，6H，J=7Hz)。

Example 1

(R)2- (4-isobutylphenyl) -N- (3-dimethylaminopropyl) propanamide hydrochloride

To a solution of 3-dimethylaminopropylamine (19 ml; 152 mmol) at a reaction temperature below 40 ℃ by means of external heating, a solution of (R)2- (4-isobutylphenyl) -propionyl chloride (16.35 g; 72.8 mmol) in dichloromethane (10 ml) is slowly added with stirring. After standing overnight at room temperature, the reaction mixture was diluted with water (100 ml), the organic phase was separated, washed with water (50 ml) and dried over sodium sulfate. After removal of the solvent under reduced pressure, 20 g (68.8 mmol) of crude (R)2- (4-isobutylphenyl) -N- (3-dimethylaminopropyl) propionamide are obtained as a pale yellow oil.

A solution of a portion of the amide (58 mmol) in isopropanol (200 ml) was treated by slowly adding 37% aqueous hydrochloric acid (6 ml) at room temperature with stirring; after 2 hours, the reaction mixture was evaporated to dryness under reduced pressure. A small amount of anhydrous isopropanol was added and the residual water was azeotroped under vacuum. Finally, a white powder crystallized from ethyl acetate (300 ml) was filtered, washed with anhydrous ethyl acetate and dried under vacuum at 40 ℃ for 24 hours to yield 18 g (55 mmol) of (R)2- (4-isobutylphenyl) -N- (3-dimethylaminopropyl) propionamide hydrochloride.

The melting point is 95-98 ℃,

[α]_D= 26(c = 1.6; methanol).

¹H-NMR(D₂O)：δ7.5-7.2(m，4H)；3.75(q，1H，J₁=7Hz，J₂=7Hz)；3.45-3.15(m，2H)；3.05(t，2H，J=8Hz)；2.80(d，6H，J=4.5Hz)；2.55(d，2H，J=7Hz)；1.95(m，1H)；1.45(d，3H，J=7Hz)；0.93(d，6H，J=7Hz)。

Example 2

The following compound was produced by substituting 2-dimethylaminoethylamine and 4-dimethylaminobutylamine for 3-dimethylaminopropylamine in the procedure of example 1:

(R) -2- (4-isobutylphenyl) -N- (2-dimethylaminoethyl) propionamide hydrochloride

The melting point is 90-93 ℃; [ alpha ] to]_D= 16(c = 1; methanol).

¹H-NMR(CDCl₃)：δ12.25(bs，1H，NH⁺)；7.82(bs，1H，CONH)；7.45(d，2H，J=8Hz)；7.05(d，2H，J=8Hz)；3.85(m，2H)；3.70(m，1H)；3.10(m，2H)；2，80(s，3H)；2.75(s，3H)；2.55(d，2H，J=7Hz)；1.97(m，1H)；1.65(d，3H，J=7Hz)；0.98(d，6H，J=7Hz)。

(R)2- (4-isobutylphenyl) -N- (4-dimethylaminobutyl) propionamide hydrochloride

The melting point is 95-97 ℃; [ alpha ] to]_D= 16(c = 0.52; methanol).

¹H-NMR(CDCl₃)：δ7.25(d，2H，J=8Hz)；7.10(d，2H，J=8Hz)；6.18(bs，1H，CONH)；3.60(q，1H，J₁=7Hz，J₂=7Hz)；3.25-3.15(m，2H)；2.95(m，2H)；2.75(s，6H)；2.45(d，2H，J=7Hz)；1.85(m，1H)；1.65(m，4H)；1.48(d，3H，J=7Hz)；0.93(d，6H，J=7Hz)。

Example 3

(R)2- (4-isobutylphenyl) -N-2- (N-morpholinylethyl) propionamide hydrochloride

Crude (R)2- (4-isobutylphenyl) -N- [2- (1-morpholinyl) ethyl ] propionamide is formed using 1-aminoethyl-morpholine in the procedure of example 1.

To a solution of the amide (0, 416 g, 1.3 mmol) in absolute ethanol (5 ml) was added dropwise a solution of 4.2N acetyl chloride in absolute ethanol (3 ml) with stirring. The mixture was stirred at room temperature for an additional 2 hours, then the solvent was removed at low pressure. The residue was dissolved in ether, and 0.39 g (1.1 mmol) of a white solid was isolated, filtered, and washed with the same solvent to give (R)2- (4-isobutylphenyl) -N- [2- (1-morpholinyl) ethyl ] propionamide hydrochloride.

Melting point is 123-; [ alpha ] to]_D= 36.3(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ12.55(bs，1H，NH⁺)；7.80(bs，1H，CONH)；7.45(d，2H，J=8Hz)；7.05(d，2H，J=8Hz)；4.25(m，2H)；3.95(m，1H)；3.70(m，4H)；3.41(m，1H)；3.05(m，3H)；2.75(m，2H)；2.45(d，2H，J=7Hz)；1.97(m，1H)；1.65(d，3H，J=7Hz)；0.95(d，6H，J=7Hz)。

Example 4

1- (3-aminoethyl) morpholine was replaced in the procedure of example 3 with the following amines: 1- (3-aminopropyl)Morpholine1- (3-aminopropyl) -4-thiomorpholine, 1- (2-aminoethyl) -piperazine-4-methyl, 1- (3-aminopropyl) piperidine and exo-8-methyl-8-aza-bicyclo [3, 2, 1]Octane-3-amine to produce the following compounds:

(R)2- (4-isobutylphenyl) -N-3- (N-morpholinylpropyl) propanamide hydrochloride

The melting point is 90-93 ℃,

[α]_D= 22.6(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ12.55(bs，1H，NH⁺)；7.80(bs，1H，CONH)；7.45(d，2H，J=8Hz)；7.05(d，2H，J=8Hz)；4.25(m，2H)；3.95(m，1H)；3.70(m，4H)；3.41(m，1H)；3.05(m，3H)；2.75(m，2H)；2.45(d，2H，J=7Hz)；2.15(m，2H)；1.97(m，1H)；1.65(d，3H，J=7Hz)；0.95(d，6H，J=7Hz)。

(R)2 (4-isobutylphenyl) -N-3- (N-thiomorpholinylpropyl) propanamide hydrochloride

The melting point is 70-73 ℃; [ alpha ] to]_D= 23(c = 0.5; methanol).

¹H-NMR(D₂O)：δ8.15(bs，1H，CONH)；7.40(m，4H)；3.82(q，1H，J=7Hz)；3.65(m，2H)；3.41(m，1H)；3.25(m，1H)；3.15-2.80(m，8H)；2.45(d，2H，J=7Hz)；1.95(m，3H)；1.55(d，3H，J=7Hz)；0.95(d，6H，J=7Hz)。

(R)2- (4-isobutylphenyl) -N- [2- (4-methyl-piperazin-1-yl) ethyl]Propionamide hydrochloride

A melting point of 240 ℃ or higher; [ alpha ] to]_D= 33.7(c = 0.5; methanol).

¹H-NMR(DMSO-d₆)：δ7.15(m，4H)；4.45(M，1H)；4.13(m，2H)；3.02(m，3H)；2.75(m，4H)；2.38(d，2H，J=7Hz)；1.85(m，1H)；1.30(d，3H，J=7Hz)；0.81(d，6H，J=7Hz)。

(R)2- (4-isobutylphenyl) -N- [3- (4-methyl-piperazin-1-yl) propyl]Propionamide dihydrochloride

Melting point is 216 ℃ and 220 ℃; [ alpha ] to]_D= 20.5(c = 0.5; methanol).

¹H-NMR(D₂O)：δ7.25(m，4H)；3.75(m，1H)；3.55(m，8H)；3.25(m，2H)；3.15(m，1H)；3.00(s，3H)；2.48(d，2H，J=7Hz)；1.95(m，3H)；1.45(d，3H，J=7Hz)；0.90(d，6H，J=7Hz)。

(R)2- (4-isobutylphenyl) -N- [3- (1-piperidinyl) propyl]Propionamide hydrochloride

The melting point is 76-80 ℃,

[α]_D= 29(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ11.4(bs，1H，NH ⁺)；7.45(d，2H，J=8Hz)；7.35(bs，1H，CONH)；7.05(d，2H，J=8Hz)；3.85(q，1H，J=7Hz)；3.45(m，4H)；2.75(m，2H)；2.52(m，4H)；2.25(m，2H)；2.05(m，2H)；1.97(m，3H)；1.60(d，3H，J=7Hz)；0.97(d，6H，J=7Hz)。

(R)2- (4-isobutylphenyl) -N- (exo-8-methyl-8-aza-bicyclo [3.2.1]Oct-3-yl) propan Amide hydrochloride

The melting point is 72-75 ℃; [ alpha ] to]_D= 3.3(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ7.15(d，2H，J=8Hz)；7.05(d，2H，J=8Hz)；6.15(bs，1H，CONH)；4，34(m，1H)；3.75(m，2H)；3.47(q，1H，J=7Hz)；2.72(s，3H)；2.60-2.38(m，4H)；2.30-1.98(m，6H)；1.92(m，2H)；1.45(d，3H，J=7Hz)；0.9(d，6H，J=7Hz)。

Example 5

(R)2- (4-isobutylphenyl) -N- (3-aminopropyl) propanamide hydrochloride

To a suspension of (R) (-) ibuprofen (3 g; 17.5 mmol), DCC (3.8 g; 18 mmol) and HOBZ (2.8 g; 18 mmol) in dichloromethane (50 ml) was added dropwise, with stirring, a solution of 3-BOC-aminopropylamine (3.22 g; 18 mmol) in dichloromethane (10 ml) at 25 ℃. Continuously stirring for 18 hours at room temperature; after filtering off the DCU, the reaction mixture was evaporated to dryness in vacuo. The residual oil was dissolved in acetonitrile several times and the collected extracts were filtered and evaporated to dryness to give a crude sample of (R)2- (4-isobutylphenyl) -N-3- (BOC-aminopropyl) propionamide, which was dissolved in hot methanol (50 ml), cooled at +4 ℃ for 18 hours and crystallized to precipitate 3.4 g (9.25 mmol, 53% yield) of pure (R)2- (4-isobutylphenyl) -N-3- (BOC-aminopropyl) propionamide.

The suspension of the compound with 10 ml of 3N aqueous hydrochloric acid is stirred at room temperature for 48 hours to give (R)2- (4-isobutylphenyl) -N-3- (aminopropyl) propionamide hydrochloride (1.9 g; 6.3 mmol);

melting point is 160-;

[α]_D= 31(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ8.2(bs，1H，NH ₃ ⁺)；7.18(d，2H，J=8Hz)；7.05(d，2H，J=8Hz)；6.83(bs，1H，CONH)；3.65(q，1H，J=7Hz)；3.30(m，2H)；3.00(m，2H)；2.40(d，2H，J=7Hz)；1.95-1.74(m，3H)；1.45(d，3H，J=7Hz)；0.92(d，6H，J=7Hz)。

Example 6

(R)2- (4-isobutylphenyl) -N- (1-methyl-piperidin-4-yl) propanamide hydrochloride

Ammonium formate (15.4 g; 240 mmol) and 10% Pd/C (3.14 g; 29 mmol) are added to a solution of 1-methyl-4-piperidone (3.26 ml; 26.5 mmol) in aqueous methanol (80 ml, methanol/water 9: 1); the mixture was stirred at room temperature for 24 hours; the catalyst was filtered off with celite, and the solvent was evaporated to dryness at low pressure to give a pale yellow residue, 1-methyl-4-aminopiperidine. 37% hydrochloric acid (4.6 ml) was added dropwise to the amine solution in ethanol (5O ml) with stirring, cooled at +4 ℃ for 18 hours, and after 18 hours the white precipitate 1-methyl-4-aminopiperidine hydrochloride was isolated by filtration. Finally, the aqueous hydrochloride solution was treated with an excess of 0.1N sodium hydroxide (about 10 ml) and extracted with dichloromethane (3 × 10 ml). After the usual work-up procedure, the solvent was evaporated to dryness to give pure 1-methyl-4-aminopiperidine (1.4 g; 12.4 mmol).

¹H-NMR(CDCl₃)：δ2.85(m，2H)；2.58(m，1H)；2.25(s，3H)；2.01(m，2H)；1.85(m，2H)；1.63(bs，2H，NH ₂ )；1.47(m，2H)。

A solution of (R)2- (4-isobutylphenyl) -propionyl chloride (1.12 g; 5 mmol) in dichloromethane (20 ml) was slowly added dropwise at room temperature to a solution of 1-methyl-4-aminopiperidine (1.1 g; 10 mmol) in dichloromethane (10 ml). After 3h, the reaction mixture was diluted with dichloromethane (10 ml), washed with 1N hydrochloric acid (25 ml) and brine, dried over sodium sulfate and the solvent was removed completely to give (R)2- (4-isobutylphenyl) -N- (1-methyl-piperidin-4-yl) propionamide hydrochloride (1.2 g; 3.5 mmol) as a glassy solid.

[α]_D= 11(c = 0.5; methanol).

¹H-NMR(D₂O)：δ7.28(m，5H)；3.95(m，1H)；3，75(q，1H，J=7Hz)；3.54(m，2H)；3.15(m，2H)；2.90(s，3H)；2.53(d，2H，J=7Hz)；2.28-2.05(m，2H)；1.95-1.65(m，4H)；1.45(d，3H，J=7Hz)；0.95(d，6H，J=7Hz)。

Example 7

(R), (S)2- (4-isobutylphenyl) -N- (1-carboxy-2-dimethylamino-ethyl) propanamide sodium salt

To a suspension of (R) (-) ibuprofen (0.23 g; 1.1 mmol), DCC (0.23 g; 1.1 mmol) and HOBZ (0.17 g; 1.1 mmol) in dichloromethane (5 ml) was added dropwise, while stirring at room temperature, a solution of (S) methyl 3-dimethylamino-2-amino-propionate (0.16 g; 1.1 mmol) in dichloromethane (2 ml). Continuously stirring for 18 hours at room temperature; after filtering off the DCU, the reaction mixture was evaporated to dryness in vacuo. Dissolving the residue with acetonitrile for multiple times; the collected extracts were filtered again and evaporated to dryness in vacuo. After purification by flash chromatography on silica gel (eluent dichloromethane/methanol 95: 5), 0.3 g (0.88 mmol) of clear oil (S), (R) 3-dimethylamino-2- [2- (4-isobutylphenyl) propionyl ] amino-propionic acid methyl ester (yield 80%) was obtained.

A solution of the ester (0.3 g; 0.88 mmol) in dioxane (2 ml) was treated with a stoichiometric amount of sodium hydroxide (0.88 ml) under stirring, held at room temperature for 18 hours and diluted with cold water (20 ml). The frozen solution was lyophilized to give 0.307 g (0.88 mmol) of a white solid(R)，(S) 2- (4-Isobutylphenyl) -N- (1-carboxy-2-dimethylamino-ethyl) propionamide sodium salt。

The melting point is above 240 ℃;

[α]_D= 25(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ7.35(m，4H)；6.25(bs，1H，CONH)；4.72(m，1H)；3.60(m，1H)；2.51(d，2H，J=7Hz)；2.30(d，2H，J=7Hz)；2.22(m，6H)；1.55(d，3H，J=7Hz)；0.95(d，6H，J=7Hz)。

Example 8

(S) 3-dimethylamino-2-amino-propionic acid methyl ester was replaced with (S) -5- (piperidin-1-yl) -2-amino-pentanoic acid methyl ester in the procedure of example 7 to give(R), (S)2- (4-isobutylphenyl) -N- (1-carboxy -2-piperidin-1-yl-butyl) propanamideA sodium salt; and(R), (S)2- (4-isobutylphenyl) -N- (1-ethane Oxycarbonyl-2-piperidin-1-yl-butyl) propionamide。

Example 9

HOBZ (0.607 g; 4.49 mmol) is added to a solution of (R) (-) ibuprofen (1.01 g; 4.9 mmol) in DMF (4 ml) with stirring at 0 ℃ and stirred for 30 minutes. A mixture of N- (3-dimethylaminopropyl) glycinamide hydrochloride (0.64 g; 4.47 mmol) in DMF (8 ml) and triethylamine (0.6 ml; 4.45 mmol) was then added, followed by a small amount of N, N-dicyclohexylcarbodiimide (1 g; 4.85 mmol). The mixture was stirred at 0 ℃ for 2 hours and then at room temperature for 18 hours. After filtration of the DCU, most of the DMF was removed again at low pressure. The residue was dissolved with water and extracted with diethyl ether (3 × 25 ml); the combined organic extracts were dried over sodium sulfate and evaporated at low pressure to give a clear oil (1 g; 3.43 mmol). A solution of this compound in dioxane (3.5 ml) was then treated with 1N sodium hydroxide solution (3.5 ml), stirred at room temperature for 24 h, diluted with water (10 ml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3X10 ml). The organic extracts were combined, dried over sodium sulfate and evaporated at low pressure to give R-2- [ (4' -isobutyl) phenyl ] -N- [2- (dimethylaminoethyl) aminocarbonylmethyl ] -propionamide hydrochloride as a pale yellow oil (0.68 g; 2.04 mmol).

[α]_D= 25(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ7.24(m，2H)；7.10(m，2H)；6.10(bs，1H，CONH)；3.55(m，1H)；3.30(m，2H)；2.45(d，2H，J=7Hz)；2.35(m，2H)；2.18(s，6H)；1.85(m，1H)；1.52(d，3H，J=7Hz)；0.90(d，6H，J=7Hz)。

Example 10

(R) -2- [2- (2, 6-dichlorophenylamino) -phenyl]-N-3- (dimethylaminopropyl) propanamide

A suspension of (R)2- [2- (2, 6-dichlorophenylamino) ] phenyl ] propionic acid (0.15 g; 0.48 mmol), DCC (0.173 g; 0.84 mmol) and HOBZ (0.075 g; 0.56 mmol) in dichloromethane (6 ml) was stirred at room temperature for 4 hours; a solution of 3- (dimethylamino) propylamine (0.06 ml; 0.48 mmol) in dichloromethane (5 ml) was added dropwise. Stirring was continued at room temperature for 18 hours, after which the separated DCU was filtered and the solvent was removed at low pressure. The residue was dissolved twice with acetonitrile, the extracts were mixed, filtered to remove DCU completely and evaporated at low pressure. Purification by flash chromatography (eluent dichloromethane/methanol 95: 5) gave clear oil (R)2- [2- (2, 6-dichlorophenylamino) -phenyl ] -N-3- (dimethylaminopropyl) propanamide (0.141 g; 0.36 mmol; 75% yield).

[α]_D= 30(c = 1; methanol).

¹H-NMR(D₂O)：δ7.38(m，4H)；7.15(m，1H)；7.05(m，1H)；6.60(m，1H+CONH)；4.25(dd，2H，J₁=7Hz，J₂=3Hz)；3.30(m，2H)；2.35(m，2H)；2.10(s，6H)；1.65(m，2H)；1.65(d，3H，J=7Hz)。

Example 11

The following amide was formed in the procedure of example 10 using (R), (R ', S') -2- [3- (. alpha. -hydroxybenzyl) phenyl ] propanoic acid, 2- [3 '- (. alpha. -hydroxyethyl) phenyl ] propanoic acid and (R), (R', S ') 2- [ 3' - (. alpha. -hydroxy,. alpha. -methylbenzyl) phenyl ] propanoic acid as starting materials in place of (R)2- [2- (2, 6-dichlorophenylamino) ] phenyl ] propanoic acid:

(R), (R ', S') 2- [3- (. alpha. -hydroxybenzyl) phenyl]-N-3- (dimethylaminopropyl) propanamideThis was a colorless oil.

[α]_D= 24(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.41-7.3(m，3H)；7.31-7.14(m，6H)；5.75(s，1H)；4.02(bs，1H，OH)3.31(m，2H)；2.38(t，2H，J=8Hz)；2.15(s，6H)；1.75(m，2H)；3.68(q，1H，J=7Hz)；1.4(d，3H，J=7Hz)。

(R), (R ', S ') 2- [3 ' - (alpha-hydroxy, alpha-methylbenzyl) phenyl]-N-3- (dimethylaminopropyl) amino acid ester Mesityl) propionamideThis was a colorless oil.

[α]_D= 28(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.41-7.3(m，3H)；7.31-7.14(m，6H)；4.02(bs，1H，OH)3.31(m，2H)；2.38(t，2H，J=8Hz)；2.15(s，6H)；1.75(m，2H)；3.68(q，1H，J=7Hz)；1.4(d，3H，J=7Hz)。

(R), (R ', S') 2- [3- (. alpha. -hydroxyethyl) phenyl]- (3-dimethylaminopropyl) propanamide

¹H-NMR(DMSO-d₆)：δ8.12(bs，1H，CONH)；7.31(s，1H)；7.25-7.10(m，3H)；5.1(bs，1H，OH)；4.7(m，1H)；3.62(m，1H)；3.10(m，2H)；2.91(m，2H)；3.65(s，6H)；1.73(m，2H)；1.30(m，6H)。

Example 12

Using (R), (R ', S') 2- [3- (. alpha. -methylbenzyl) phenyl) in the procedure of example 1]Propionyl chloride instead of (R)2- (4-isobutylphenyl) -propionyl chloride to obtain a light yellow oil(R)，(R’，S’) 2- [ 3' - (alpha-methylbenzyl) phenyl]-N-3- (dimethylaminopropyl) propanamide (1.2 g; 3.52 mmol) Er)。

[α]_D= 30(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.38-7.13(m，9H)；6.60(bs，1H，CONH)4.20(m，1H)；3.78(m，1H)；3.27(m，2H)；2.30(m，2H)；2.12(s，6H)；1.72(d，3H，J=7Hz)；1.65(m，2H)；1.55(d，3H，J=7Hz)。

Further, using (R)2- (3-isopropylphenyl) propionyl chloride, (R)2- (3-isobutylphenyl), (R)2- [3- (styryl-1-yl) phenyl ] propionyl chloride, (R)2- [ 3' - (pent-3-yl) phenyl ] propionyl chloride in the procedure of example 1, the following compounds were produced:

(R)2- (3-isopropylphenyl) -N-3- (dimethylaminopropyl) propanamide

¹H-NMR(CDCl₃)：δ7.21-7.13(m，4H)；6.95(bs，1H，CONH)3.53(m，1H)；3.30(m，2H)；2.90(m，1H)；2.37(m，2H)；2.15(s，6H)；1.65(d，3H，J=7Hz)；1.23(d，3H，J=7Hz)。

(R)2- (3-isobutylphenyl) -N-3- (dimethylaminopropyl) propanamide

[α]_D= 30(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.21-7.13(m，4H)；6.85(bs，1H，CONH)3.53(m，1H)；3.25(m，2H)；2.48(d，2H，J=7Hz)；2.30(t，2H，J=7Hz)；209(s，6H)；1.9(m，1H)；1.55(m，2H)；1.45(d，3H，J=7Hz)；0.95(d，3H，J=7Hz)。

(R)2- [3- (Styren-1-yl) phenyl]-N-3- (dimethylaminopropyl) propanamide

[α]_D= 31(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.8-7.13(m，9H)；6.95(bs，1H，CONH)5.0(s，2H)；3.53(m，1H)；3.30(m，2H)；2.37(m，2H)；2.15(s，6H)。

(R)2- [ 3' - (pent-3-yl) phenyl]-N-3- (dimethylaminopropyl) propanamide

[α]_D= 28(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.25(m，3H)；7.12(m，1H)；7.08(bs，1H，CONH)3.65(m，1H)；3.5-3.13(m，2H)；2.75(m，2H)；2.55(s，6H)；2.35(m，1H)；1.95(m，2H)；

1.70(m，2H)；1.58(m，2H)；1.50(d，3H，J=7Hz)；0.76(t，6H，J=7Hz)。

(R) -2- [ (3-benzoyl) phenyl]-N- (3-diethylaminopropyl) propanamide

[α]_D= 11.5(c = 3; methanol).

¹H-NMR(CDCl₃)：δ7.8(m，3H)；7.70-7.55(m，3H)；7.50-7.28(m，3H)；7.25(bs，1H，CONH)；3.75(m，1H)；3.50-3.20(m，2H)；3.3.15-2.80(m，6H)；2.05(m，2H)；1.65(d，3H，J=7Hz)；1.70-1.53(m，3H)；1.50-1.45(m，3H)。

(R) -2- [ (3-benzoyl) phenyl]-N- (3-dimethylaminopropyl) propanamide

[α]_D= 20(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.88-7.78(m，3H)；7.75-7.58(m，3H)；7.55-7.46(m，3H)；7.25(bs，1H，CONH)；3.62(m，1H)；3.28(m，2H)；2.35(m，2H)；2.12(s，6H)；1.68-1.53(m，5H)。

Example 13

(R)2- (4-isobutylphenyl) -N-3 (guanidinopropyl) propanamide hydrochloride

(R)2- [ (4-isobutylphenyl) -N-3- (aminopropyl) propionamide hydrochloride of example 5 was converted to the free amine according to Bodanszky M. et al (J.Am.chem.Soc., 86, 4452, 1964) and used as isothioureaTreatment with chlorine yielded (R)2- (4-isobutylphenyl) -N-3 (guanidinopropyl) propionamide hydrochloride.

Melting point is 142 ℃ and 146 ℃; [ alpha ] to]_D= 24(c = 1; methanol).

¹H-NMR(D₂O)：δ7.2(d，2H，J=8Hz)；7.1(d，2H，J=8Hz)；6.8(bs，1H，CONH)；3.6(q，1H，J=7Hz)；3.55(m，2H)；2.95(m，2H)；2.4(d，2H，J=7Hz)；2.0-1.8(m，3H)；1.5(d，3H，J=7Hz)；0.9(d，6H，J=7Hz)。

In addition, using N-hydroxy-ureido methyl thioate hydrochloride and N-amino-ureido methyl thioate in the same step, the following are formed:

(R)2- (4-isobutylphenyl) -N- [3- (hydroxyguanidino) propyl]Propionamide hydrochloride，

(R)2- (4-isobutylphenyl) -N- [3- (aminoguanidino) propyl]Propionamide hydrochloride。

Example 14

(R)2- (4-isobutylphenyl) -N- [3- (imidazolin-2-yl) aminopropyl]Propionamide

(R)2- [ (4-isobutylphenyl) -N-3- (aminopropyl) propionamide hydrochloride (see example 5) was converted to the free amine and treated with 2-methylthio-2-imidazoline iodohydrate (commercial reagent) to give (R)2- (4' -isobutylphenyl) -N- [3- (imidazolin-2-yl) aminopropyl ] propionamide according to the method of Bodanszky cited above (J.A m. chem. Soc., 86, 4452, 1964).

Melting point is 155-; [ alpha ] to]_D= 15(c = 1; methanol).

¹H-NMR(D₂O)：δ7.2(d，2H，J=8Hz)；7.1(d，2H，J=8Hz)；6.8(bs，1H，CONH)；3.6(q，1H，J=7Hz)；3.55(m，2H)；3.40(s，4H)；2.90(m，2H)；2.35(d，2H，J=7Hz)；2.0-1.8(m，3H)；1.55(d，3H，J=7Hz)；1.0(d，6H，J=7Hz)。

Using 2-methylthio-tetrahydropyrimidine in the above step to form(R)2- (4-isobutylbenzene Yl) -N- [3- (tetrahydropyrimidin-2-yl) aminopropyl]Propionamide。

¹H-NMR(D₂O)：δ7.2(d，2H，J=8Hz)；7.1(d，2H，J=8Hz)；6.8(bs，1H，CONH)；3.6(q，1H，J=7Hz)；3.55(m，2H)；3.40(s，4H)；2.90(m，2H)；2.35(d，2H，J=7Hz)；2.0-1.8(m，5H)；1.55(d，3H，J=7Hz)；1.0(d，6H，J=7Hz)。

Example 15

(R), (S') 2- (4-isobutylphenyl) -N- [ (1-carboxy-4-amino) butyl]Propionamide

A solution of (R)2- (4-isobutylphenyl) propionyl chloride (0.54 g; 2.42 mmol) in dichloromethane (10 ml) was slowly added dropwise at 25 ℃ to a suspension of 5-BOC-ornithine methyl ester hydrochloride (0.69 g; 2.42 mmol) and triethylamine (0.68 ml; 4.84 mmol) in dichloromethane. The mixture was stirred at room temperature overnight and diluted with water (10 ml). The organic phase was separated, washed with a saturated solution of sodium bicarbonate (10 ml), dried over sodium sulfate and evaporated to give the crude product which was purified by flash chromatography (chloroform/methanol 9: 1 as eluent) to give the clear oil (R), (S) methyl 2- (4-isobutylphenyl) propanoyl- (5-BOC) ornithine (0.6 g; 1.4 mmol). The compound was treated with 3N hydrochloric acid (8 ml) at room temperature for 18 hours, and then the solvent was evaporated to give (R), (S') 2- (4-isobutylphenyl) -N- [ (1-methoxycarbonyl-4-amino) butyl ] propionamide hydrochloride (0.41 g, 1.25 mmol).

To a solution of the hydrochloride in dioxane was added 4N sodium hydroxide solution (0.625 ml; 2.5 mmol) at room temperature, the mixture was stirred overnight and evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate (15 ml); the organic phase was washed with a saturated solution of sodium chloride (2 × 15 ml) and dried over sodium sulfate. Evaporation of ethyl acetate gave (R), (S') 2- (4-isobutylphenyl) -N- [ (1-carboxy-4-amino) butyl ] propionamide as a white solid,

the melting point is above 240 ℃;

[α]_D= 29(c = 0.5; methanol).

¹H-NMR(DMSO-d₆)：δ7.3(d，2H)；δ7.1(d，2H)；6.25(bs，1H，CONH)；4.20(m，1H)；3.70(m，1H)；3.50(m，2H)；2.5(d，2H)；1.9(m，1H)；1.8(m，4H)；1.6(d，3H)；0.95(d，6H，J=7Hz)。

Preparation by replacing ornithine derivative with the corresponding (L) lysine derivative(R), (S ') 2- (4' -isobutyl group Phenyl) -N- (1-carboxy-5-aminopentyl) propanamide hydrochloride。

[α]_D= 28.3(c = 1; methanol).

¹H-NMR(DMSO-d₆)：δ12.62(bs，1H，COOH)；8.25(d，1H，CONH，J=8Hz)；7.75(bs，3H，NH ₃ ⁺)；7.25(d，2H，J=8Hz)；7.06(d，2H，J=8Hz)；4.15(m，1H)；3.70(m，1H)；2.63(m，2H)；2.38(d，2H，J=7Hz)；1.92-2.78(m，1H)；1.70-1.38(m，4H)；1.35(d，3H，J=7Hz)；1.20(m，2H)；0.92(d，6H，J=7Hz)。

Example 16

(R)2- (4-isobutylphenyl) -N- [ (N '-methyl, N' 2-hydroxyethyl) -aminoethoxy]Propionamide

A solution of (R)2- (4-isobutylphenyl) propionyl chloride (0.42 g; 1.875 mmol of the flight) in dichloromethane (10 ml) was slowly added dropwise at 25 ℃ to a solution of 0.85 g (3.75 mmol of the flight) 2- (aminooxy) -N-methyl-N- (2-hydroxyethyl) ethylamine in dichloromethane (10 ml). The mixture was stirred at room temperature for 3 hours and then diluted with water (10 ml). The phases were shaken and the organic phase was separated, washed with water (5 ml), dried over sodium sulphate and evaporated to give 0.59 g (1.43 mmol of the tall oil) of an oil, namely (R)2- (4-isobutylphenyl) -N-2- [ (N '-methyl, N' 2-hydroxyethyl) -aminoethoxy ] propionamide.

[α]_D= 35(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.25(m，4H)；6.15(bs，1H，CONH)；4.67(t，2H，J=7Hz；3.40(m，2H)；2.75(t，2H，J=7Hz)；2.55(d，2H，J=7Hz)；2.35(bs，1H，OH)；2.42(t，2H，J=7Hz)；2.21(s，3H)；1.95(m，1H)；1.53(d，3H，J=7Hz)；1.00(d，6H，J=7Hz)。

Example 17

R-2- [ (4-isobutyl) phenyl]-N- [4- (dimethylamino) -2-butynyl]Propionamide

R (-) -ibuprofen (0.34 g; 1.65 mmol) is dissolved in anhydrous dichloromethane; DCC (0.37 g; 1.8 mmol) and HOBZ (0.24 g; 1.78 mmol) were added and the solution was stirred at room temperature for 3 hours. To this solution was added a solution of N, N-dimethylbutyn-2-yl-1, 4-diamine (0.2 g; 1.78 mmol) in anhydrous dichloromethane (2 ml), and the resulting mixture was stirred overnight. After 18 h, the DCU was filtered off, the filtrate was diluted with dichloromethane, washed with a saturated solution of sodium bicarbonate (2x10 ml), water (2x10 ml) and brine, dried over sodium sulfate and evaporated in vacuo to give a crude residue as a red oil. Purification by flash chromatography gave a yellow oil, R (-) -2- [ (4' -isobutyl) phenyl ] -N- [4- (dimethylamino) -2-butynyl ] propionamide (0.347; 1.155 mmol).

[α]_D= 4.4(c = 0.5; methanol).

¹H-NMR(CDCl₃)：δ7.15-7.10(m，2H)；7.09-7.05(m，2H)；5.45(bs，1H，CONH)；4.05(m，2H)；3.55(m，1H)；3.15(s，2H)；2.47(d，2H，J=7Hz)；2.22(s，6H)；1.85(m，1H)；1.48(d，3H，J=7Hz)；0.91(d，6H，J=7Hz)。

Example 18

R-Z-2- [ (4-isobutyl) phenyl]-N- [4- (dimethylamino) -2-butenyl]Propionamide

R (-) -2- [ (4' -isobutyl) phenyl ] -N- [4- (dimethylamino) -2-butynyl ] propionamide from example 17 (0.08 g; 0.27 mmol) is dissolved in absolute ethanol (5 ml) and 5% palladium calcium carbonate (Lindlar catalyst; 0.08 g) is added. The mixture was combined with hydrogen at room temperature and atmospheric pressure, reacted for 2 hours, and then filtered through a pad of celite. The filter cake was washed thoroughly with ethanol and the filtrate evaporated in vacuo to yield a pale yellow oil, pure R-Z-2- [ (4-isobutyl) phenyl ] -N- [4- (dimethylamino) -2-butenyl ] propionamide (0.07 g; 0.23 mmol).

[α]_D= 26.5(c = 1.1; methanol).

¹H-NMR(CDCl₃)：δ7.20-7.12(d，2H，J=8Hz)；7.10-7.05(d，2H，J=8Hz)；5.95(bs，1H，CONH)；5.67-5.55(m，2H)；3.93-3.85(m，2H)；5.02(m，1H)；3.05(d，2H J=8Hz)；2.47(d，2H，J=7Hz)；2.25(s，6H)；1.93(m，1H)；1.55(d，3H，J=7Hz)；0.95(d，6H，J=7Hz)。

Example 19

R-2- [ (4-isobutyl) phenyl]-N- [4- (dimethylaminomethyl) phenyl]Propionamide

R (-) ibuprofen (0.31 g; 1.5 mmol) was dissolved in thionyl chloride (5 ml) and the solution was refluxed for 90 minutes. Cooling at room temperature, monitored by Infrared (IR) until the starting carboxylic acid is completely eliminated; after removal of the solvent by addition of 1, 4-dioxane, the oily residue was diluted with anhydrous DMF (5 mL) and a solution of 4- (N, N-dimethylaminomethyl) aniline (0.27 g; 1.8 mmol) in anhydrous DMF (3 mL) was added dropwise at room temperature with stirring. The solution was stirred overnight; the solvent was evaporated in vacuo and the residue was purified by flash chromatography to give R-2- [ (4-isobutyl) phenyl ] -N- [4- (dimethylaminomethyl) phenyl ] propionamide (0.406 g; 1.2 mmol) as a pale yellow oil.

[α]_D= 98(c = 1; methanol).

¹H-NMR(CDCl₃)：δ7.40-7.18(m，9H)；3.75(m，1H)；3.47(s，2H)；2.50(d，2H，J=7Hz)；2.17(s，6H)；1.95(m，1H)；1.56(d，3H，J=7Hz)；0.94(d，6H，J=7Hz)

Prepared by the same methodR-2- [ (4-isobutyl) phenyl]-N- [4- (dimethylamino) phenyl]C3 Amides of carboxylic acids。

[α]_D= 131(c = 0.25; methanol).

¹H-NMR(CDCl₃)：δ7.28-7.25(m，4H)；7.22-7.15(m，2H)；6.83-6.79(bs，1H，CONH)；6.73-6.65(m，2H)；3.72(m，1H)；2.80(s，6H)；2.48(d，2H，J=7Hz)；1.85(m，1H)；1.52(d，3H，J=7Hz)；0.97(d，6H，J=7Hz)。

TABLE I

Claims (8)

1. Use of at least one (R) -2-aryl-propionamide compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament having an inhibitory activity on C5 a-induced chemotaxis of polymorphonuclear leukocytes and monocytes,

in the formula (I), the compound is shown in the specification,

ar is selected from 4-isobutylphenyl, 2- (2, 6-dichloro-phenyl)-amino) -phenyl, 3-C₆H₅-CH (OH) phenyl group,

or phenyl substituted in position 3 by isopropyl, pent-3-yl, 1-phenylethen-1-yl, alpha-methylbenzyl;

r represents H;

x represents:

from CO₂R₃Optionally substituted straight chain C₁-C₆Alkylene radical, C₄-C₆Alkenylene radical, C₄-C₆Alkynylene, wherein R is₃Is H;

(CH₂)_m-B-(CH₂)_nwherein B is a CONH group, m is an integer of 1 to 3, and n is an integer of 2 to 3;

or, X together with the nitrogen atom of the omega-amino group forms a nitrogen-containing cycloaliphatic ring selected from the group consisting of 1-methyl-piperidin-4-yl or 1, 5-tropan-3-yl;

R₁and R₂Independently selected from H, straight chain C₁-C₆Alkyl, hydroxy-C₂-C₃-an alkyl group;

or, R₁As defined above, R₂Represents a group represented by the general formula (III):

in the formula (I), the compound is shown in the specification,

R_ais H, R_bIs H; or R_aAnd R_bTogether with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring;

or R₁And R₂Together with the nitrogen atom to which they are attached form a nitrogen-containing 3-to 7-membered heterocyclic ring represented by the general formula (II),

in the formula (I), the compound is shown in the specification,

y represents a single bond, CH₂O, S, or N-Rc group, wherein R_cIs CH₃And p represents an integer of 0 to 3.

2. The use of claim 1, wherein: the said drugs also have inhibitory activity against polymorphonuclear interleukin 8-induced chemotaxis.

3. Use according to claim 1 or 2, characterized in that: the medicine is used for treating psoriasis, pemphigus, pemphigoid, rheumatoid arthritis, chronic intestinal inflammation, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, and glomerulonephritis.

4. Use according to claim 1 or 2, wherein the chronic intestinal inflammation is ulcerative colitis.

5. Use according to claim 1, characterized in that: the medicine is used for preventing and treating injury caused by ischemia and reperfusion.

6. Use of a compound selected from the group consisting of: (R) -2- [ (4-isobutyl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R) -2- (4-isobutylphenyl) -N-3- (1-piperidinylpropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (4-dimethylaminobutyl) -propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-N-morpholinylpropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (2-dimethylaminoethyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [2- (4-methyl-piperazin-1-yl) ethyl ] propionamide;

(R) -N- (exo-8-methyl-8-aza-bicyclo [3, 2, 1] oct-3-yl) -2- (4-isobutylphenyl) -propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-N-thiomorpholinopropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [4- (N' -methyl) piperidinyl ] propionamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- (1-carboxy-2-dimethylaminoethyl) -propionamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- [ (1-carboxy-4-piperidin-1-yl) butyl ] propionamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- (1-carboxy-4-aminobutyl) -propionamide;

(R) -2- (4-isobutyl) phenyl-N- [2- (dimethylaminoethyl) aminocarbonylmethyl ] propionamide;

2- [2- (2, 6-dichlorophenylamino) -phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R), (R ', S ') 2- [3 ' - (α -methylbenzyl) phenyl ] -N-3- (dimethylaminopropyl) -propionamide;

(R) -2- [ (3-isopropyl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R) -2- [3- (pent-3-yl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-guanidinopropyl) propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [ (3-hydroxy-guanidino) propyl ] propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [ (3-amino-guanidino) propyl ] propionamide;

(R) -2- [ (4-isobutyl) phenyl ] -N- [3- (2-amino-2-imidazoline) propyl ] propanamide;

(R), (S') -2- [ (4-isobutyl) phenyl ] -N- (1-carboxy-5-aminopentyl) -propionamide;

(R) -2- [ (3-benzoyl) phenyl ] -N- (3-diethylaminopropyl) propionamide;

(R) -2- [ (3-benzoyl) phenyl ] -N- (3-dimethylaminopropyl) propionamide;

(R)2- [3- (styren-1-yl) phenyl ] -N- (3-dimethylaminopropyl) propanamide;

(R)2- (4-isobutylphenyl) -N-2- (N-morpholinylethyl) propionamide;

(R), (R ', S') 2- [3- (α -hydroxybenzyl) phenyl ] -N-3- (dimethylaminopropyl) propanamide;

(R)2- (4-isobutylphenyl) -N- [3- (tetrahydropyrimidin-2-yl) aminopropyl ] propionamide;

r-2- [ (4-isobutyl) phenyl ] -N- [4- (dimethylamino) -2-butynyl ] propionamide;

R-Z-2- [ (4-isobutyl) phenyl ] -N- [4- (dimethylamino) -2-butenyl ] propionamide;

r-2- [ (4-isobutyl) phenyl ] -N- [4- (dimethylaminomethyl) phenyl ] propionamide; or a pharmaceutically acceptable salt thereof.

7. The use of claim 6, wherein: the compound is:

(R) -2- [ (4-isobutyl) phenyl ] -N- (3-dimethylaminopropyl) propanamide hydrochloride.

8. The use of claim 6, wherein: the compound is: (R)2- (4-isobutylphenyl) -N-3- (1-piperidinylpropyl) propanamide hydrochloride.