Pyridyl nonaromatic nitrogen-containing heterocyclo-1-carboxylate derivative

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

 

The scope of the invention

The present invention relates to pyridinium non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative or its pharmaceutically acceptable salts, useful as pharmaceuticals, in particular as a drug for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain with activity, inhibition of fatty acid amide-hydrolases (hereinafter indicated as FAAH). The present invention also relates to a method of screening to identify inhibitors of FAAH activity that serves as a drug for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain; and to pharmaceutical compositions for the treatment of frequent urination and urinary incontinence, for the treatment of increased activity of the bladder and/or for treatment of pain, which contains the substance obtained in accordance with the method of screening according to the present invention, or contains a substance that inhibits the activity of fatty acid amide-hydrolases.

Background of the invention

It is known that girocollo the Naya amide hydrolase (FAAH) hydrolyzes endocannabinoid, inactivating it (see non-patent reference documents 1-4). Endocannabinoid is a generic term for a biological substance, which acts on the cannabinoid receptor for the manifestation of its physiological activity. Typical endocannabinoids are anandamide, palmitoylethanolamide, oleamide, 2-arachidonoylglycerol; and it is known that they are hydrolyzed under the action of FAAH with the loss of their activity. It is known that Δ9-tetrahydrocannabinol, which is the active ingredientCannabis(marijuana), activates the cannabinoid receptor (see non-patent reference document 5).

In mammals to date, there are two known types of cannabinoid receptors - CB1 and CB2. CB1 is expressed in the Central and peripheral nervous system and when activated, shows the effect on the psyche and analgesic action. CB2 is expressed in the immune system and when activated, exerts anti-inflammatory and analgesic (and anti-inflammatory action.

On the other hand, in the model of cystitis in the rat cannabinoid receptor increases the capacity of the bladder and the threshold urination (non-patent reference document 6 and non-patent reference document 7); and side effects such as hallucinations, delirium, tachycardia, orthostatic hypotension observed with the introduction of the ago the East cannabinoid receptor animals not observed with the introduction of inhibitor of FAAH (non-patent reference document 8). Given the above, expect that the FAAH inhibitor will be a drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for the treatment of pain.

As compounds having activity of inhibiting FAAH, known compounds that can serve as analgesic assets, against fear, ANTIEPILEPTICS tools, antidepressant, antiemetic, cardiovascular drugs or anti-glaucoma [C1-4 alkyl or polycyclic aromatic ether derivatives containing aromatic ring or phenyl-substituted aliphatic hydrocarbon karbinovykh acids (patent reference document 1) and phenylcyclohexylamine (patent reference document 2)]. Dioxane-2-allylcarbamate derivatives, which are compounds that have the activity of inhibiting FAAH, described as medicines for urinary incontinence that is one option a large number of disorders listed in the reference document (patent reference document 3). However, patent reference document 3 does not disclose the results of the experts the cops, confirming curative effect in the treatment of frequent urination and incontinence of urine and/or treatment of increased activity of the bladder, it does not have any assumptions such effect. 4-Aminopiperidin-1-carboxylate, representing the type peredelnyh nonaromatic nitrogen-containing heterocycle-1-carboxylates described as an inhibitor of acetylcholinesterase (non-patent reference document 9); however, in this reference document says nothing about the fact that the connection is a drug for the treatment of frequent urination and incontinence of urine and/or drug treatment for elevated activity of the bladder.

Patent reference document 1: WO2003/065989.

Patent reference document 2: WO2004/033422.

Patent reference document 3: JP-A 2003-192659.

Non-patent reference document 1: Prostaglandins Leukotrienes and Essential Fatty acids, (England), 2002, Vol. 66, pp. 143-160.

Non-patent reference document 2: British Journal of Pharmacology (England), 2004, Vol. 141, pp. 253-262.

Non-patent reference document 3: Nature (England), 1996, Vol. 384, pp. 83-87.

Non-patent reference document 4: Biochemical Pharmacology, (USA), 2001, Vol. 62, pp. 517-526.

Non-patent reference document 5: Current Medicinal Chemistry (USA), 1999, Vol. 6, pp. 635-664.

Non-patent reference document 6: The Journal of Neuroscience, 2002, Vol. 22, pp. 7147-7153.

Non-patent reference document 7: Pain, 1998, Vol. 76, pp. 189-199.

Non-patent Ref is CNY document 8: Nature Medicine, (England), 2003, Vol. 9, pp. 76-81.

Non-patent reference document 9: Journal of Pharmaceutical Science, 1992, Vol. 81, pp. 380-385.

Disclosure of invention

The problems solved by the present invention

The aim of the present invention is the provision of medicines for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain, which have no or significantly less related cannabinoids side effects and addiction. Other objectives are to provide a way of screening to identify compounds having activity of inhibiting FAAH, or drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain; and in the provision of pharmaceutical compositions for the treatment of frequent urination and urinary incontinence, for the treatment of increased activity of the bladder and/or for treatment of pain, which contains the substance obtained in accordance with the method of screening according to the present invention, or a substance capable of inhibiting the activity of fatty acid amide-hydrolases.

Means for solving problems

The authors of this izobretatelni investigated the problem of getting a connection, having the activity of inhibiting FAAH, and as a result has found new peredelnye nitrogen-containing heterocycle-1-carboxylate derivatives.

In addition, the authors present invention it was discovered that when the compounds having activity of inhibiting FAAH, administered to rats suffering from frequent urination, induced by ciclofosfamida, then the effective capacity of the urinary bladder of rats increases and, in addition, it was found that the compounds having activity of inhibiting FAAH, has excellent therapeutic effect in the model of pain in rats, the result is provided a method of screening drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain by selection of the FAAH inhibitor, thus was established the present invention.

Specifically, the present invention relates to:

[1] Pyridinium nonaromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (I)and its pharmaceutically acceptable salt:

where:

HET1is a 5-7-membered nonaromatic nitrogen-containing heterokonta,

R1, R2and R3are the same and the and are different from each other, and each represents a

(1) H,

(2) OH,

(3) optionally esterified carboxyl,

(4) cyano,

(5) lower alkyl-CO-,

(6) oxo (=O)

(7) the formula [R101-(O)m1]m2-[ALK1, optionally substituted by OH]-(O)n1-,

(m1 and n1 are the same or different from each other, where each has a value of 0 or 1,

m2 has a value of from 1 to 5,

ALK1represents the lowest alkylene, lower albaniles or lower akinyan,

R101represents a

(i) H,

(ii) Ar1a, optionally substituted by at least one Deputy, selected from the group including:

(a) H2N-,

(b) halogen,

(c) cyano,

(d) optionally esterified carboxyl,

(e) the group of R1011aR1012aN-CO-,

(f) HET2,

(g) Ar1a, optionally substituted with halogen, cyano, OH, lower alkyl or lower alkyl,

Ar1arepresents aryl,

(h) lower alkyl,

(j) OH,

(k) lower alkyl-O-, optionally substituted by a group Ar1aor halogen-Ar1a,

(l) HET2-CO-, optionally substituted with halogen, Ar1aor HETAr1a,

HET2represents a nitrogen-containing heterokonta,

HETAr1arepresents a nitrogen containing heteroaryl,

(s) HET2-CONR1011a-,

(t) H2NCONH-, and

(u) optionally esterified carboxyl-ALK2a/sup> ,

ALK2arepresents a lower alkyl or lower alkenyl,

(iii) ALK2a, optionally substituted by a group R1011aR1012aN or Ar1a,

R1011aand R1012aare the same or different from each other, and each represents a

(a) H,

(b) cALK,

cALK is cycloalkyl,

(c) ALK2a, optionally substituted with halogen, cALK, OH, lower alkyl or Ar1aor

(d) Ar1a-SO2-, optionally substituted with halogen,

(iv) HET2, optionally substituted by at least one Deputy, selected from the group including

(a) ALK2a, optionally substituted by a group Ar1aor halogen-Ar1a,

(b) Ar1a,

(c) HETAr1a, optionally substituted lower alkyl,

(d) Ar1a-CO - or halogen-Ar1a-CO-,

(v) cALK, optionally substituted ALK2a,

or

(vi) optionally esterified carboxyl,

(when m2 has a value from 2 to 5, then the group [R101-(O)m1] may be the same or different from each other),

(8) the group of R102-ALK1-N(R103)-CO-,

(R102represents a

(i) H,

(ii) cALK,

(iii) HETAr1aor

(iv) Ar1a, optionally substituted by at least one Deputy, selected from the group including

(a) HO,

(b) ALK2a-O-,

(c) cALK-ALK1-O,

(d) cALK-Ar1a-ALK1-O - and

(e) Ar1a-ALK1-O-,

R103represents a

(i) H,

(ii) cALK,

(iii) ALK2a, optionally substituted by at least one Deputy, selected from the group including

(a) HET2,

(b) Ar1aand

(c) halogen-Ar1a,

(iv) HETAr1aor

(v) Ar1a-[CO]m1, optionally substituted by at least one Deputy, selected from the group including

(a) cALK,

(b) H2N

(c) the group of R1011aR1012aN-CO - or

(d) ALK2a),

(9) the group of RAR105AN-[CO]m1-ALK1-,

(R104aand R105aare the same or different from each other, and each represents a group R103),

(10) the group of R106-ALK3-L1-,

(R106represents a

(i) a group R101-(O)ml-,

(ii) the group R104aR105aN-,

(iii) a group ALK2a-CONH - or

(iv) a group Ar1a-CONH-,

ALK3represents the lowest alkylene, lower albaniles or cycloalkyl,

L1- represents-C(=O)- or-SO2-),

(11) ALK2a-CONH-, optionally substituted group AG1A,

(12) AG1Asubstituted by halogen,

(13) group [R107-(O)m1]m2-Ar2-(O)n1-,

(AG2represents Allen,

R107represents a

(i) H,

(ii) halogen,

(iii) ALK2anot necessarily alseny, at least one Deputy, selected from the group including

(a) BUT,

(b) cALK,

(c) NO2,

(d) Ar1a, optionally substituted with halogen, lower alkyl, lower alkyl-O-group, R1011aR1012aN-[CO]p-, cyano or optionally esterified by carboxyla,

(e) optionally esterified carboxyl,

(f) HET2-[CO]p-, optionally substituted by a group R1011aR1012aN-[CO]p-, and

(g) the group of R1011aR1012aN-[CO]p-,

p is 0 or 1,

(iv) the group R1011aR1012aN-[CO]p -, or

(v) the group of R1011aR1012aN-[CO]p-Ar1a,

in this case, when m2 has a value from 2 to 5, then the group [R107-(O)m1] may be the same or different from each other, and, in addition, the group [R107-(O)m1]m2 can represent methylenedioxy with the formation of the rings),

(14) group [R107-(O)m1]m2-Ar2-N(R103) -CO-,

(when m2 has a value from 2 to 5, then the group [R107-(O)m1] may be the same or different from each other),

(15) group [R1011aR1012aN-[CO]m1]m2-Ar2-(O)n1-,

(when m2 has a value from 2 to 5, then the group [R1011aR1012aN-[CO]m1] may be the same or different from each other),

(16) group [R108]m2-Ar2-L2-,

[R108represents a

(i) H,

(ii) halogen,

(iii) HO,

(iv) cALK-O-,

(v) R 109-ALK1-(0) ml-,

(R109represents a

(a) H,

(b) cALK,

(c) AG1A, optionally substituted by at least one Deputy, selected from the group including

(1') halogen,

(2') cyano,

(3') NO2,

(4') ALK2a, optionally substituted with halogen,

(5') BUT,

(6') ALK2a-O-, optionally substituted with halogen,

(7') optionally esterified carboxyl or

(8') group R104aR105aN

(d) HETArlaor

(e) the group of R104aR105aN-[CO]m1-),

(vi) the group R1013R1014N-,

R1013and R1014are the same or different from each other, and each represents a

(i) H,

(ii) ALK2a,

(iii) cALK-ALK1or

(iv) Ar1a-ALK1-, optionally substituted by at least one Deputy, selected from the group including

(1') halogen,

(2') cyano,

(3') ALK2A, optionally substituted with halogen,

(4') ALK2a-O-, optionally substituted with halogen,

(vii) HET2-(O)m1-, optionally substituted lower alkyl,

L2represents-CO - or-S(O)q-,

q is 0, 1 or 2,

in this case, when m2 has a value from 2 to 5, then the group [R108] may be the same or different from each other],

(17) group [R101]m2-Ar2-CONH-,

(when m2 has znachenie 2 to 5, then the group [R101] may be the same or different from each other),

(18) group [R111]m2-HETAr2-(O)m1-,

(R111represents a

(i) H,

(ii) halogen,

(iii) oxo (=O) or

(iv) the group R103a-(O)n1-,

R103arepresents a

(i) H,

(ii) cALK,

(iii) ALK2a, optionally substituted by at least one Deputy, selected from the group including

(a) HET2,

(b) Ar1a,

(c) cALK and

(d) a halogen-Ar1a,

(iv) HETAr1aor

(v) Ar1a, optionally substituted by at least one Deputy, selected from the group comprising (a) cALK, (b) H2N and (c) the group of R1011aR1012aN-CO-,

HETAr2represents a nitrogen-containing heteroaryl,

in this case, when m2 has a value from 2 to 5, then the group [R111] may be the same or different from each other),

(19) the formula [R112]m2-HETAr2-N(R103)-CO-,

(R112represents a

(i) H,

(ii) cALK,

(iii) ALK2aor

(iv) Ar1a, optionally substituted by at least one Deputy, selected from the group including

(a) halogen,

(b) HO,

(c) ALK2a-O - and

(d) Ar1a-ALK1-O-,

in this case, when m2 has a value from 2 to 5, then the group [R112] may be the same or different from each other,

(20) the formula [R108]m2-HETAr2-L2 -,

(when m2 has a value from 2 to 5, then the group [R108] may be the same or different from each other),

provided that when any of the groups R1, R2and R3is a group [R111]m2-HETAr2-(O)m1 -, and when m1 is 0, then the rest of the group R1, R2and R3represent H;

R4, R5, R6and R7are the same or different from each other, and each represents a

(1) H,

(2) halogen,

(3) optionally esterified carboxyl,

(4) HO,

(5) the group of R113-ALK4-(O)m3-,

(ALK4represents the lowest alkylene, lower albaniles or lower akinyan,

m3 is 0 or 1,

R113represents a

(i) H,

(ii) HO,

(iii) lower alkyl-O-, optionally substituted optionally esterified by carboxyla,

(iv) optionally esterified carboxyl,

(v) lower alkyl-CO-O - or

(vi) the group R104bR105bN-[CO]m3- (R104band R105bare the same or different from each other, and each represents a group R103),

(6) R114R115N (R114and R115are the same or different from each other, and each represents a

(i) H or

(ii) ALK2b, optionally substituted by a group R104bR105bN

ALK 2brepresents a lower alkyl or lower alkenyl),

(7) the group of R116-(ALK4)n2-N(R117)-CO-,

(n2 is 0 or 1,

R116represents a

(i) H,

(ii) HO,

(iii) lower alkyl-O-,

(iv) optionally esterified carboxyl, (v) the group of R104bR105bN-[CO]m3-,

(vi) Arlb, optionally substituted (a) or (b) ALK2b-O-,

Arlbrepresents aryl,

(vii) NO3, optionally substituted by a group R104bR105bN-[CO]m3 - or optionally esterified by carboxyla,

NO3represents a nitrogen-containing heterokonta,

(viii) Arlb, optionally substituted by a group R104bR105bN-[CO]m3-, or

(ix) SO3H)

R117represents (i) H or (ii) ALK2b, optionally substituted Arlb),

(8) Arlb, optionally substituted by at least one Deputy, selected from the group comprising optionally esterified carboxyl and the group R1011bR1012bN-[(CO)]m3-,

R1011band R1012bare the same or different from each other, and each represents a

(i) H,

(ii) cALK,

(iii) ALK2b, optionally substituted with halogen, cALK, HE, lower alkyl or Arlbor

(iv) Arlb-SO2-, optionally substituted with halogen,

(9) NO3not necessarily Zam is placed optionally esterified by carboxyla,

(10) NO3-CO-, optionally substituted by at least one Deputy, selected from the group comprising ALK2band the group R104bR105bN-[CO]m3-, or

(11) cyano,

provided that 4-aminopyridine-3-yl piperidine-1-carboxylate is excluded - this condition applies to listed below].

[2] Compound [1]represented by the General formula (II):

where:

R1-R7have the values defined in [1],

T represents CH2, NH, NHCH2or O,

and also includes the case where the hydrogen in T replaced by R1-R3- the same applies to the description below].

[3] Compound [2], where R1-R3are the same or different from each other, and each represents a group [R101-(O)m1]m2-[ALK1, optionally substituted by OH]-(O)n1-, R102-ALK1-N(R103)-CO-group, R106-ALK3-L1-group [R107-(O)m1]m2-Ar2-(O)n1 -, [R107-(O)m1]m2-Ar2-N(R103)-CO - or a group [R108]m2-Ar2-L2-.

[4] Pyridinium non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (III) and its pharmaceutically acceptable salt:

where:

ring A represents a benzene ring, cyclopentane ring, cyclohexane ring, cyclohepta the TV ring or a 5-7 membered nitrogen-containing heterokonta;

L represents a simple bond, a lower alkylene, lower albaniles, -N(R15)-C(=O)-, -C(=O)-N(R15)-, -(lower albaniles)-C(=O)-, -O - or-C(=O)-,

R15represents H or lower alkyl,

X represents CH or N,

R8-R10are the same or different from each other, and each represents a

group selected from the following group G,

aryl, optionally substituted by the same or different from each groups selected from the following group G,

the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G,

R16-(lower alkylene)-O-,

R16-(lower alkylene)-N(R15)- or

R17R18N-C(=O)-,

R16represents a

aryl, optionally substituted by the same or different from each groups selected from the following group G,

the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G, or

3-8-membered cycloalkyl,

R17and R18are the same or different from each other and each represents H, lower alkyl or 3-8-membered cycloalkyl,

(in addition, R17and R18can obrazovym the diamonds together with the N atom, related, 3-8-membered nitrogen-containing heterokonta),

group G includes H, halogen, -CN, -CF3, lower alkyl or-O-lower alkyl,

R11represents H, lower alkyl or oxo (=O)

R12-R14are the same or different from each other and each represents H, lower alkyl, -C(=O)-O-(lower alkyl), -CO2H or-CONH2].

[5] the Compound [4], where ring A is a benzene ring, cyclohexane ring, piperidine ring or pieperazinove ring.

[6] the Compound [5], where R9, R10, R11, R12and R13represent H.

[7] Pyridinium non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (IV) and its pharmaceutically acceptable salt:

where:

ring A1represents a benzene ring, piperidine ring or pieperazinove ring;

L1represents the lowest alkylene, lower albaniles, -N(R15)-C(=O)- or-O-;

R15represents H or lower alkyl,

R19represents a

group selected from the following group G,

the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G,

R16-(lower alkyl is)-O - or R 17R18N-C(=O)-,

R16represents a

aryl, optionally substituted by the same or different from each groups selected from the following group G,

the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G, or

3-8-membered cycloalkyl,

R17and R18are the same or different from each other and each represents H or lower alkyl,

(in addition, R17and R18may form, together with the N atom associated with them, a 5 - or 6-membered nitrogen-containing heterokonta),

group G includes H, halogen, -CN, -CF3, lower alkyl or-O-lower alkyl,

R20represents H, -C(=O)-O-(lower alkyl), -CO2H or-CONH2].

[8] Pyridinium non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (V) and its pharmaceutically acceptable salt:

where:

L2represents the lowest alkylene, lower albaniles or -(lower albaniles)-C(=O)-,

R21represents H, halogen, -CN, -CF3, lower alkyl or-O-lower alkyl,

R22represents H, -C(=O)-O-(lower alkyl), -CO2H or-CONH2].

[9] the Compound of [1]selected from the following groups:

pyridine-3-yl-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate,

5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}nicotinic acid,

5-({[4-(2-phenylethyl)piperidine-1-yl]carbonyl}oxy)-nicotinic acid,

5-[({4-[4-(2-cyclohexylmethoxy)phenoxy]piperidine-1-yl}carbonyl)oxy]nicotinic acid,

5-[({4-[(E)-2-phenylphenyl]piperidine-1-yl}carbonyl)-oxy]nicotinic acid,

5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidine-4-yl]propyl}piperidine-1-yl)carbonyl]oxy}nicotinic acid,

5-(aminocarbonyl)pyridine-3-yl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}piperidine-1-carboxylate,

5-(aminocarbonyl)pyridine-3-yl 4-(2-{3-[(dimethylamino)carbonyl]phenyl}ethyl)piperidine-1-carboxylate,

5-(aminocarbonyl)pyridine-3-yl 4-{2-[3-(piperidine-1-ylcarbonyl)phenyl]ethyl}piperidine-1-carboxylate,

5-(aminocarbonyl)pyridine-3-yl 4-{2-[3-(pyrrolidin-1-ylcarbonyl)phenyl]ethyl}piperidine-1-carboxylate,

pyridine-3-yl 4-[(2E)-3-phenylprop-2-enoyl]piperazine-1-carboxylate,

pyridine-3-yl 4-(anilinoacrolein)piperidine-1-carboxylate,

5-(aminocarbonyl)pyridine-3-yl 4-(2-phenylethyl)piperidine-1-carboxylate,

pyridine-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate,

5-(methoxycarbonyl)pyridine-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate,

5-(aminocarbonyl)pyridine-3-yl 4-[2-(3-forfinal)ethyl]piperidine-1-carboxylate,

5-(aminocarbonyl)pyridine-3-yl 4-[2-(3-cyanophenyl)ethyl]piperidine-1-carboxylate.

[10] a Pharmaceutical composition, in the connection with [1] as its active ingredient.

[11] the Pharmaceutical composition of [10], which is an inhibitor of FAAH.

[12] the Pharmaceutical composition of [10], which is a drug for the treatment of frequent urination, urinary incontinence and/or increased activity of the bladder.

[13] the Pharmaceutical composition of [10], which is a drug for the treatment of pain.

[14] the Use of compounds [1] to obtain an inhibitor of FAAH or drugs for the treatment of frequent urination, urinary incontinence and/or increased activity of the bladder.

[15] the Use of compounds [1] to obtain an inhibitor of FAAH or drugs for the treatment of pain.

[16] the Method of treatment of frequent urination, urinary incontinence and/or increased activity of the bladder, including the introduction to the patient a therapeutically effective amount of compound [1].

[17] the Method of treating pain comprising the administration to a patient a therapeutically effective amount of compound [1].

[18] the Method of screening to identify drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain, including (1) the stage of contacting the test substance with a polypeptide, which which contains (a) amino acid sequence, represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, (b) amino acid sequence derived from the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 by deletion, substitution and/or insertion in this sequence from 1 to 10 amino acids, (c) amino acid sequence having a homology of at least 70% with the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) the amino acid sequence of the complete amino acid sequence encoded by polynucleotides represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5 or SEQ ID NO:7, or polynucleotides capable gibridizatsiya with its complementary sequence in harsh environments, or part thereof, not containing, at least, containing the transmembrane region amino-terminal segment of this sequence, and which can hydrolyze the substrate, (2) the analysis stage of the polypeptide to a change in its activity, and (3) the stage of selecting a substance capable of inhibiting the activity of the polypeptide,

(where "substrate"that is in contact with FAAH or functional FAAH may be any endocannabinoid capable gibridizatsiya under the action of FAAH or functional FAAH; and, specifically, it contains anandamide, palmitoylethanolamide, 2-arachidonoylglycerol, oleamide; and a substrate, mehanny the 3H or14C, and you can also use a mixture of labeled substrate and unlabeled substrate, the same applies below).

[19] the Method of screening to identify drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain, including (1) the stage of contacting the test substance with a polypeptide, which contains (a) the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, (b) amino acid sequence derived from the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 by deletion, substitution and/or insertion in this sequence from 1 to 10 amino acids, (c) amino acid sequence having a homology of at least 70% with the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) the amino acid sequence of the complete amino acid sequence encoded by polynucleotides represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5 or SEQ ID NO:7, or polynucleotides capable gibridizatsiya with its complementary sequence in harsh conditions or part thereof, not containing at least the transmembrane region amino-terminal teaching the TKA this sequence, and that can hydrolyze the substrate, in the presence of the substrate polypeptide, (2) the stage of measuring the amount of hydrolyzed product, converted from a substrate, and (3) the stage of selecting a substance capable of inhibiting the hydrolysis of the substrate.

[20] the Method of screening to identify drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain, including (1) the stage of contacting the test substance with a cell or tissue expressing the polypeptide, which contains (a) the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, (b) amino acid sequence derived from the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 by deletion, substitution and/or insertion in this sequence from 1 to 10 amino acids, (c) amino acid sequence having a homology of at least 70% with the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) the amino acid sequence of the complete amino acid sequence encoded by polynucleotides represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5 or SEQ ID NO:7, or polynucleotides capable gibridizatsiya with her comp is ementary sequence harsh, or part of it, does not contain, at least, containing the transmembrane region amino-terminal segment of this sequence, and which can hydrolyze the substrate, or a lysate or a homogenate of cells or tissue in the presence of the substrate polypeptide, (2) the stage of measuring the amount of hydrolyzed product, converted from a substrate, and (3) the stage of selecting a substance capable of inhibiting the hydrolysis of the substrate.

[21] the Method of screening to identify drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain, including (1) the stage of contacting the test substance with a fatty acid amide-hydrolases, (2) the analysis stage of the enzyme to change its activity and (3) the stage of selecting a substance capable of inhibiting the activity of an enzyme.

The results of the invention

Pharmacological test Examples 438 - 442 confirmed the effectiveness of the compounds of the present invention. For example, a typical connection is shown in Table 64, have an excellent effect of inhibiting FAAH; typical connection is shown in Example 441, are useful as drugs for the treatment of frequent urination and urinary incontinence, as well as medications the frame means to ensure increased activity of the bladder; and a typical connection is shown in Example 442, are useful as drugs for the treatment of pain. In addition, the compounds of the present invention are highly stable in aqueous solutions and have excellent qualities as a medicinal product.

The invention described in patent reference document 2, is useful as analgesic assets, against fear, ANTIEPILEPTICS tools, antidepressant, antiemetic, cardiovascular drugs or medicines for glaucoma; however, the authors of the present invention discovered that the present invention is useful for medicinal products for the treatment of frequent urination and incontinence of urine and/or drug treatment for elevated activity of the bladder, non-patent reference document 2. In addition, the compounds of the present invention have an excellent effect of inhibiting FAAH and therefore are useful for medicines for the treatment of (1) neuropsychiatric disorders (e.g., fear, depression, epilepsy), (2) mental disorders, neurodegenerative disorders (e.g., head injury, cerebral ischemia, dementia), (3) immunological and inflammatory diseases, (4) vomiting, (5) eating disorders, (6) sin is Roma irritated colon, ulcerative colitis, (7) hypertension, (8) glaucoma or (9) of sleep disorders. In addition, the compounds have no or significantly less related cannabinoids side effects and addiction.

In addition, in accordance with the method of screening according to the present invention, the drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for the treatment of pain, which have no or significantly less related cannabinoids side effects and addiction, can be selected on the basis of the activity of FAAH inhibition. The substance obtained in accordance with the method of screening compounds having activity of inhibiting FAAH, can form a pharmaceutical composition, useful for the treatment of frequent urination and urinary incontinence, for the treatment of increased activity of the bladder and/or for the treatment of pain.

The best way of carrying out the invention

Below is a detailed description of the present invention.

Compounds of the present invention are described in detail below.

Definition

Unless specifically stated otherwise, the term "lower" in the definition of structural formulas in the present description means a linear or branched angle is the same circuit, containing from 1 to 6 carbon atoms.

"Lower alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl; preferably methyl, ethyl, propyl, butyl, tert-butyl.

"Lower alkenyl" means an aliphatic hydrocarbon group containing at least one double bond, including, for example, vinyl, propenyl, allyl, Isopropenyl, 1,3-butadienyl, hexenyl.

"Cycloalkyl" means mono - tricyclic aliphatic saturated hydrocarbon ring group containing 3 to 14 carbon atoms, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloheptene, bicycloalkyl, tricyclodecane, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

"Aryl" means a mono - to tricyclic aromatic hydrocarbon ring group containing from 6 to 14 carbon atoms, where phenyl may be condensed with cycloalkyl. For example, this group includes phenyl, indenyl, naphthyl, antril, tenantry, indanyl, tetrahydronaphtyl, preferably phenyl, naphthyl.

"Heterocyclic" means 4-16-membered, monocyclic, bicyclic or tricyclic, saturated or nanosys the TES ring, containing from 1 to 4 heteroatoms selected from N, S and O. the Heterocyclic group may be Poperechnaya or have spirotrichous. Unsaturated ring includes an aromatic ring (heteroaryl) and non-aromatic ring. Monocyclic group includes azetidinol, oxetanyl, pyrrolidinyl, 1,3-DIOXOLANYL, pyrazolidine, piperazinil, piperidyl, piperazinil, morpholinyl, thiomorpholine, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, triazolyl, thiadiazolyl, pyridazinyl, oxadiazolyl, tetrazolyl; bicyclic group includes indolyl, isoindolyl, 3,4-methylenedioxyphenyl, 3,4-atlanticcity, benzofuranyl, benzothiazol, benzothiadiazoles, benzothiazolyl, benzimidazolyl, indolyl, isoindolyl, hinely, ethanolic, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, decahydroquinoline, honokalani; tricyclic group includes carbazolyl, acridines, phenothiazinyl. Poperechnaya heterocyclic group includes hinokitiol, 2,5-diazabicyclo[2.2,1]heptyl, 8-azabicyclo[3.2.1]octyl, 7-azabicyclo[2.2.1]heptyl. Having spirotrichous heterocyclic group include 1,4-dioxa-8 azaspiro[4,5]decenyl.

"Nitrogen containing heteroaryl" means 4-10-membered, mono - or bicyclic aromatic nitrogen containing heteroaryl containing from 1 to 4 atoms AZ is that in the above heterocyclic group. This group includes, for example, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, benzopyranyl, hinely, ethanolic, honokalani, preferably imidazolyl, thiazolyl, pyridyl, benzimidazolyl, hinely.

"Nitrogen-containing saturated heterocyclic group" means a 3 to 10-membered mono - or bicyclic nitrogen-containing geterotsyklicescoe group containing from 1 to 3 nitrogen atoms in the above heterocyclic group. This group includes, for example, aziridinyl, azetidin, pyrrolidinyl, piperidyl, piperazinil, morpholinyl, hexahydroazepin, 1,4-diazepine, 1,4-oxazepine, hinokitiol, 2,5-diazabicyclo[2.2.1]heptyl, azabicyclo (for example, azabicyclo[3.2,1]octyl), diazabicyclo, azabicycloalkanes, azabicycloalkanes, 1,4-dioxa-8 azaspiro[4,5]decenyl, preferably pyrrolidinyl, piperidyl, piperazinil, morpholinyl, hexahydroazepin, 1,4-diazepine, 1,4-oxazepine, hinokitiol, 2,5-diazabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl.

"Nitrogen-containing heterokonta" means the above-mentioned nitrogen-containing heteroaryl group, the above-mentioned nitrogen-containing saturated heterocyclic group or a condensed group of nitrogen-containing heteroaryl and nitrogen geterotsiklicheskie. P is edocfile, it is pyrrolidinyl, piperidyl, piperazinil, morpholinyl, hexahydroazepin, azabicyclo[3.2.1]octyl, 1,4-dioxa-8 azaspiro[4.5]decenyl, imidazolyl, pyridyl, hinely.

"Non-aromatic nitrogen-containing heterokonta" means a nitrogen-containing saturated heterocyclic group and an unsaturated nitrogen-containing heterocyclic group, with the exception of nitrogen-containing heteroaryl of the above nitrogen-containing heterocyclic group. Preferably such a group represents a 5-7 membered non-aromatic nitrogen-containing heterocyclic group.

"Lower alkylene", "lower albaniles", "cycloalkyl", "Allen" and "nitrogen-containing heteroaryl" represents a divalent group derived from the above lower alkyl, lower alkenyl, cycloalkyl, aryl and nitrogen heteroaryl by the removal of any hydrogen atom.

"The esterified carboxyl" means lower alkyl-O-CO-, aryl-lower alkyl-O-CO - or H2N-CO-aryl-lower alkyl-O-CO-.

"Halogen" means a halogen, specifically comprising fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine.

"Optionally substituted" means unsubstituted or substituted by identical or different from each other 1-5 substituents".

Depending on the type of substituents in this connection, the compound (I) this is the overarching invention may contain optical isomers (optically active isomers, diastereoisomers) or geometric isomers. Accordingly, the compound (I) of the present invention includes a mixture or a dedicated connection such optical isomers or geometrical isomers.

The compound (I) of the present invention can form pharmaceutically acceptable salts such as acid additive salts or salts with bases. For example, the salts include acid additive salts formed with inorganic acid, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid; or organic acid, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonate acid, econsultancy acid, glutamic acid; and salts with an inorganic base, such as salts of sodium, potassium, magnesium, calcium, aluminum; or an organic base such as methylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine, ornithine. In addition, compound (I) or its pharmaceutically acceptable salt according to the present invention can image is the close co hydrates, the solvate with ethanol or the like, and crystalline polymorphs.

In addition, compound (I) of the present invention includes all compounds capable of metabolites in terms of the body it is converted into compound (I) or its pharmaceutically acceptable salt according to the present invention, which are prodrugs. Group forming a prodrug of compound (I) of the present invention, include compounds described in Prog. Med., 5:2157-2161 (1985), and compounds described in “PHARMACEUTICAL RESEARCH and DEVELOPMENT”, VOLUME 7 Drug Design, pp. 163-198 by Hirokawa Publishing, 1990. Specifically, this group that can be converted into a primary amine or secondary amine or HO-, HO-CO -, or the like in the present invention through hydrolysis or solvolysis or under physiological conditions. Prodrugs HO represents, for example, optionally substituted lower alkyl-CO-O-, optionally substituted aryl-CO-O-, optionally substituted heteroaryl-CO-O-, RO-CO-optionally substituted lower alkylene-CO-O- (R is H or lower alkyl, the same applies to the following), RO-CO-optionally substituted lower albaniles-CO-O-, RO-CO-lower alkylene-O-lower alkylene-CO-O-, RO-CO-CO-O-, ROS(=O)2-optionally substituted lower albaniles-CO-O-, phthalidyl-O-, 5-methyl-1,3-dioxolan-2-he-4-yl-metiloksi.

"Frequent urination"as that term is used in the present description, snakedoctor, when the frequency of urination is increased compared with normal limits. "Incontinence" means involuntary urination, which is a social and hygienic problem.

"Increased activity of the bladder", as the term is used in the present description, means a syndrome diagnosed as a subjective symptom, such as frequent urination or the urge to urinate (Neurourology and Urodynamics, USA, 2002, Vol. 21, pp. 167-178). Pathogenic cause includes, for example, neuropathy (e.g., caused by a neurogenic bladder, cerebral infarction), obstruction of the lower urinary tract (e.g., benign prostatic hypertrophy) and aging; and as a pathogenic mechanism common to these States, hyperactivity capsaicin-sensitive afferent neurons.

Increased activity of the bladder can be treated by facilitating condition of frequent urination, urinary incontinence and urge to urinate. This is evident, for example, from the fact that the introduction of antihistaminergic tools, oxybutynin hydrochloride (Japan Standard Product Classification Number 87259; by Aventis Pharma) to a patient suffering from increased activity of the bladder, at a dose of 2 to 3 mg/introduction and three times a day can relieve the condition of frequent urination, ned is Jania urine and urine urgency, and this introduction is therefore effective for the treatment of increased activity of the bladder.

The effect of treatment of frequent urination and incontinence of urine and/or treatment effect of increased activity of the bladder can be confirmed by methods known to experts in this field, or ways, which is a modification of such methods. For example, in the art often use the pathogenic model, induced by the introduction of 50 to 200 mg cyclophosphamide (CPA) rats, Guinea pigs, dogs or the like (Ozawa et al., The Journal of Urology, Vol. 162, pp. 2211-2216, 1999; Boucher et al., The Journal of Urology, Vol. 164, pp. 203-208, 2000). This pathogenic model, which is accompanied by haemorrhagic cystitis, and because capsaicin-sensitive afferent neuron is involved in the pathogenic mechanism of frequent urination can be considered that this model may be appropriate pathological model for different types of increased activity of the bladder, including neuropathic bladder (Carlo Alberto Maggi et al., Journal of the Autonomic Nervous System, Vol. 38, pp. 201-208, 1992). The condition of frequent urination can be confirmed by the decrease of the effective bladder capacity. Pathological model animal an effective dose of the pharmaceutical composition is administered orally, intraperitoneally or intravenously, once or several times; and when the effective capacity is the terrain of the bladder of the animal increases, then can be confirmed by the effect of a pharmaceutical composition for the treatment of frequent urination and incontinence of urine and/or for the treatment of increased activity of the bladder.

"Pain," as the term is used in the present description, is a generic term for neuropathic pain, nociceptive pain and inflammatory pain, of which "neuropathic pain" means pain, caused by dysfunction of the peripheral or Central nervous system, and includes diabetic neuropathic pain, pain and cancer pain, trigeminal neuralgia, phantom pain, post herpetic pain and thalamic pain. The main clinical symptom of neuropathic pain includes pain as if squeezing pain type of burning, hyperalgesia and allodynia.

Non-steroidal anti-inflammatory medicines and narcotic analgesics, such as morphine, are the usual analgesics, known as weakly effective in neuropathic pain. In medical institutions for pain relief use of anti-epileptic agent, such as gabapentin, and means against arrhythmia, such as meksiletin, but their analgesic activity is not sufficient.

The effect of treatment of neuropathic pain can be confirmed by methods known to experts in the field, or with the persons, which is a modification of such methods. For example, using rats L5/L6 with legirovannym spinal nerve that is carried out in accordance with a partially modified method of Kim and Chung (Pain, Vol. 50, pp. 355-363, 1992), evaluate relieving effect of the compounds, expressed in a significant reduction in the threshold of response to tactile stimulation (allodynia), and based on this can be confirmed by the effect of the test compounds for the treatment of neuropathic pain.

The compound of the present invention includes compounds effective for the treatment of frequent urination and urinary incontinence, as well as increased activity of the bladder; compounds effective for treating pain, in particular neuropathic pain; and compounds effective in both of the above cases.

Ways to get

The compound and its pharmaceutically acceptable salt according to the present invention can be obtained by using various known methods of obtaining, using features based on the basic link structure or type of substituents in this connection.

Depending on the type of functional group in the compound can often be effective from the point of view of the production technology, the substitution of a functional group suitable protective group can be easily converted into the functional group) at the stage e is about the source of the substance or intermediate compounds. The functional group includes, for example, amino group, hydroxyl group and carboxyl group; and protective groups are, for example, the groups described in “Protective groups in Organic Synthesis (2nd Ed)” by Greene & Wuts. Such groups can appropriately be selected and used depending on the reaction conditions.

In this way the protective group is removed, if necessary, after their introduction and implementation of the reaction to give the desired compound.

Typical methods of producing compounds of the present invention and their intermediates described below.

(Abbreviations used below in the description indicate the following:

DMF: N,N-dimethylformamide,

DMSO: dimethyl sulfoxide,

THF: tetrahydrofuran,

TFU: triperoxonane acid,

Tol: toluene

EtOAc: ethyl acetate;

DCE: 1,2-dichloroethane,

TEA: triethylamine)

Typical methods of obtaining the compounds of the present invention are described below, but the present invention is not limited to them.

When in a certain position of the compounds of the present invention there is such Deputy, and not as stated in the formula of the reaction in the production method of connection, the connection is covered by the present invention can be easily obtained through the modification of the Deputy.

The method of obtaining 1 (Formation of the carb is ATA):

where X represents a group to delete, is advantageous for the reaction, the same applies to the following.

This reaction is an esterification ketone derivative of General formula (VI) and suitable for this reaction the number hydroxypyridine derivative of General formula (VII)in a solvent inert to the reaction, with stirring, while cooling or at room temperature, or when heated. Delete group X includes, for example, halogen atom, lower alkoxygroup, fenoxaprop, imidazolidinyl group. The inert solvent includes, for example, DMF, dimethylacetamide, THF, dioxane, dimethoxyethane, diethoxyethane, benzene, Tol, xylene and mixtures of such solvents. For promotion of the reaction, preferably to the reaction mixture is added a base (such as sodium, sodium hydride, sodium methoxide, ethoxide sodium).

The method of obtaining 2 (Formation of carbamate):

This reaction is carried out by mixing nitrogen-containing heterocyclic compounds of General formula (VIII) and suitable for this reaction, the amount of the pyridine derivative of General formula (IX) in a solvent inert to the reaction, while cooling or at room temperature, or when heated. For promotion of the reaction predpochtitel what about to the reaction mixture is added a base (for example, sodium, sodium hydride, sodium methoxide, ethoxide sodium, TEA, pyridine).

The method of obtaining 3 (Hydrolysis):

The compound (I-3) according to the present invention contains a carboxyl group, can be obtained through hydrolysis of the corresponding compounds containing esterified carboxyl group, for example, in accordance with the removal of the protective groups described in “Protective groups in Organic Synthesis (2nd Ed)” by Greene & Wuts.

where ROCO means esterified carboxyl group, the same applies to the following.

The method of obtaining 4 (Amidation):

The compound (I-3) or a compound, where R1is a carboxylic acid, can interact with an amine, and a compound where R1is an amine, can interact with carboxylic acid, thus, can be obtained from various amide compounds. When the nitrogen-containing heterocyclic compound is a piperidine, then it can be subjected to interaction with carboxylic acid or sulfonic acid or its reactive derivative to produce different types of amide compounds. The reaction can be performed in the presence of a condensing agent (for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimetilan npropyl)carbodiimide (WSC), 1,1'-carbonylbis-1H-imidazole (CDI)and optionally additionally in the presence of additives (for example, N-hydroxysuccinimide (HONSu) of 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP)). Reactive derivative of carboxylic acid or sulfonic acid include acid halides, acid anhydrides, active esters. The reaction can also be carried out, for example, in accordance with the methods described in “Jikken Called koza (Courses in Experimental Chemistry, 4th Ed), Vol. 22, edited by the Chemical Society of Japan, Maruzen, 1992.

The method of obtaining 5 (Reaction mix):

where X represents halogen or-O-SO2CF3and Y represents-B(OH)2, dealkiller, dialkoxy or triamcinolone. X can be a-B(OH)2, dealkiller, dialkoxy or triamcinolone, and Y represents a halogen or-O-SO2CF3.

Two aromatic rings or, in particular, the combination of the compound (I-6) and compound (I-7) is subjected to interaction preferably in the presence of a catalyst based on a transition metal and a suitable additive, thereby obtaining bailee compound (I-8). Typical methods of obtaining described in “Jikken Called koza (Courses in Experimental Chemistry, 4th Ed), Vol. 25, Organic Synthesis VII, pp. 353-366, pp. 396-427, 1991 (Maruzen). The preferred catalyst based on transition metal for use in the present invention includes various palladium complexes, such as tetrakis(triphenylphosphine)palladium, and various complexes of Nickel, such as dibromobis(triphenylphosphine)Nickel. Also preferred for use in the present invention the additive include triphenylphosphine, sodium carbonate, zinc; and they accordingly selected depending on the way in which they are used. Typically, the reaction is carried out in a solvent at room temperature or when heated. In addition to these reactions, it is also preferable to use reaction formation bareley patterns, for example the reaction of halogenated aryl compounds with aryl Grignard reagent in the presence of a suitable catalyst based on a transition metal.

The means of obtaining the source connections

Starting compound used for obtaining the compounds of the present invention may be a known compound or can be obtained by optional processing of known compounds in accordance with the above methods of obtaining, or in accordance with methods well known to specialists in this area (J. March, ADVANCED ORGANIC CHEMISTRY (John WILEY & SONS (1992)) (e.g., acylation, alkylation, formation of urea, oxidation, recovery (preferably COMPREHENSIVE ORGANIC SYNTHESIS 8 REDUCTION (Pergamon Press) (1991)), halogenation).

The method of obtaining (i)

The reaction Mitsunobu:

The original compound (X) can be obtained through the reaction of Mitsunobu alcohols of General formula (XI) and (XII). This reaction is carried out by mixing the compounds (XI) and (XII) in the presence of an equivalent or excess amount of triphenylphosphine and diethylazodicarboxylate in an inert solvent, as a way to discover 1 in condition from cooling to heating.

where:

U represents an amino-protective group,

ALK3represents ALK1, optionally substituted by HO, and the same applies to the following.

The method of obtaining (ii):

The substitution reaction:

This reaction is an alkylation. Primary amine, secondary amine, alcohol, thiol, primary amide or secondary amide is subjected to interaction with suitable for this reaction the number of compounds containing the group that you want, in a solvent inert to the reaction, the equivalent ratio of these two components, or in such relation that when any of them is in excessive amount, with stirring, under conditions of from cooling to heating. There are cases when the reaction is advantageously carried out in the presence of a base (for example, inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate; organic bases, such ka the TEA, diisopropylethylamine; metal alkoxide such as tert-piperonyl potassium tert-piperonyl sodium; sodium hydride, lithium hydride) and additives (iodide, Tetra-n-butylamine, potassium iodide, sodium iodide) for smooth promotion of the reaction. The solvent inert to the reaction, and includes, for example, dichloromethane, DCE, chloroform, benzene, Tol, xylene, simple ether, THF, dioxane, EtOAc, ethanol, methanol, 2-propanol, acetonitrile, DMF, N,N-dimethylacetamide, N-organic, dimethylimidazolidine, DMSO, acetone, methyl ethyl ketone, water, and a homogeneous or heterogeneous mixture of such solvents. The solvent can be appropriately selected depending on various used reaction conditions.

where:

Q represents O, S or NH,

Z represents a group to delete (for example, Cl, Br, I or OMs).

The method of obtaining (iii):

This method of obtaining includes the interaction of the aldehyde or ketone of General formula (XVI) with a Wittig reagent (Wittig) or reagent Horner-Emmons General formula (XVII) with obtaining, thus, compound (XVIII).

This reaction is carried out in the presence of an equivalent or excess amount of a base (e.g. organic bases such as TEA, diisopropylethylamine; inorganic bases such as potassium carbonate, sodium carbonate, carbonate CE is s) by mixing the compound (XVI) and compound (XVII) in the above inert solvent, in the equivalent ratio of these two components, or in such relation that when any of them is found in excessive quantities in condition from cooling to heating. There are times when it is advantageous to add in the supplements (e.g., iodide, Tetra-n-butylamine, potassium iodide) for smooth promotion of the reaction.

Z1is a group used in the Wittig reagent or Horner reagent of Ammonia (for example, phosphonium salt or fluids phosphoric acid),

n is 0 or 1.

[1] the screening Method of the present invention:

Fatty acid amide hydrolase (hereinafter may be specified as FAAH) includes enzymes with activity in the hydrolysis of anandamide, palmitoylethanolamide, oleamide and/or 2-arachidonoylglycerol, and because they are identified as substances of one molecular species can be distinguished from any species, e.g., mammalian, such as human (GenBank Accession Number N_001441), mouse (GenBank Accession Number N__010173), rat (GenBank Accession Number N__024132), pig (GenBank Accession Number AB027132), rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey. In addition, it is not limited to the natural polypeptide, and may include artificially derived mutants.

Regarding (a) the polypeptide that contains the amino acid posledovatelnostei amino acid sequence, represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or a part of such amino acid sequences that do not contain at least containing the transmembrane region amino-terminal segment of this sequence, and which can hydrolyze anandamide, palmitoylethanolamide, oleamide and/or 2-arachidonoylglycerol;

(b) a polypeptide that contains the amino acid sequence of the full amino acid sequence selected from the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 by deletion, substitution and/or insertion of 1 to 10, preferably from 1 to 7, more preferably from 1 to 5, it contains amino acids, or part of such amino acid sequences that do not contain at least containing the transmembrane region amino-terminal segment of this sequence, and which can to hydrolyze anandamide, palmitoylethanolamide, oleamide and/or 2-arachidonoyl glycerin;

(c) a polypeptide that contains an amino acid sequence having a homology of at least 70%, preferably at least 80%, more preferably at least 90%, most preferably at least 95% with the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, and which can hydrolyze anandamide, n is letoletolia, oleamide and/or 2-arachidonoyl glycerin;

(d) a polypeptide that contains the amino acid sequence of the complete amino acid sequence encoded by polynucleotides represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5 or SEQ ID NO:7, or polynucleotides capable gibridizatsiya with its complementary sequence in harsh environments or her part, does not contain, at least, containing the transmembrane region amino-terminal segment of this sequence, and which can hydrolyze anandamide, palmitoylethanolamide, oleamide and/or 2-arachidonoylglycerol;

the above (a)to(d) has the generic name "functional FAAH".

The above "containing the transmembrane region amino-terminal site"as described in the present description, refers to amino-terminal site, which includes the extracellular region at the amino end and the transmembrane region located in the cell membrane, with the formation of sandwiches design between the extracellular region and the intracellular region. The existence and location of the transmembrane region can be predicted on the basis of amino acid sequences using the program of determination of membrane protein structure, TMpred, PSORT, SOSUI. Specifically, "containing the transmembrane region amino-terminal site" represents the t a, for example, the area from the 1st to the 30th in SEQ ID NO:2 and the area from the 1st to the 29th in SEQ ID NO:6. It is known that a polypeptide represented by the amino acids from the 30th to 579 in SEQ ID NO:6, with the exception of the area from the 1st to the 29th in SEQ ID NO:6, also has the same enzymatic activity as the polypeptide, which has not excluded this plot (Matthew et al., Biochemistry, Vol. 37, pp. 15177-15178, 1998).

"Homology", as indicated in the present description, means the identity values obtained by using the parameters prepared in sufficient number through a search using the program Clustal V (Higgins &Sharp, Gene, Vol. 73, pp. 237-244, 1998; Thompson et al., Nucleic Acid Res., Vol. 22, pp. 4673-7680, 1994). These parameters are the following:

Pairwise built parameters

K tuple 1

Gap Penalty 3

Window 5

Diagonals Saved 5.

The above "stringent conditions" for hybridization, as described in the present description, means conditions that do not cause any nonspecific binding. Specifically, for example, hybridization is carried out in a solution comprising 50% formamide, 5×SSC (0,75 M NaCl, of 0.075 M sodium citrate, pH 7), 5× Denhardt solution (With 0.1% Ficoll 400, 0.1% polyvinylpyrrolidone, 0.1% of BSA), DNA modified salmon sperm (50 g/ml), 0.1% of SDS and 10% dextran sulfate, at temperatures from 37 to 42°C, for from about 12 to 18 hours, and then optionally after pre-wash rinse wash a solution (0.2×SSC, 0,1% SDS) in the temperature conditions of from 50 to 60°C.

Above the hydrolysis of anandamide, palmitoylethanolamide, oleamide and/or 2-arachidonoylglycerol", as indicated in the present description, specifically means in accordance with the method described in Examples 1-4, anandamide (N-arachidonoylethanolamine) is decomposed into arachidonic acid and ethanolamine; palmitoylethanolamide (N-Palmitoyl ethanolamine) - palmitic acid and ethanolamine; oleamide (CIS-9,10-octadecenoamide) - oleic acid and ammonia, and 2-arachidonoylglycerol - to arachidonic acid and glycerol by hydrolysis in a buffer having a pH of from 7 to 9, at temperatures from 4°C to 37°C, during the time from 30 minutes to 90 minutes.

The method of screening according to the present invention includes a method of screening to identify drugs for the treatment of frequent urination and urinary incontinence, medications for the treatment of increased activity of the bladder and/or the medicinal product for the treatment of pain, including (1) the stage of contacting the test substance with FAAH or functional FAAH, (2) the analysis stage of this substance on the activity of FAAH or functional FAAH and (3) the stage of selecting a substance that inhibits the activity of FAAH or functional FAAH.

(1) the stage of contacting the test substance with FAAH or functional FAAH:

For contacting the test substance with FAAH or unctionally FAAH test substance can be added to any of the following:

a) a cell or tissue expressing FAAH or functional FAAH,

b) transformant transformed by the expression vector containing polynucleotide that encodes FAAH or functional FAAH,

(c) lysate or homogenate (a) or (b),

d) a purified product FAAH or functional FAAH, purified from c) and incubated for a specified period of time; or

e) tissue homogenate or blood test animal, which injected the substance.

a) a Cell or tissue expressing FAAH or functional FAAH:

Specifically, the cell expressing FAAH or functional FAAH includes neurons, glial cells, epithelial cells, endothelial cells, lymphocytes, macrophages, platelets, mast cells, monocytes, dendritic cells, hepatocytes, kidney cells, enterocytes, pancreatic cells, cells, urine, placentalia cells, cells of the bladder, the cells of the prostate gland, keratinizing cells and muscle cells. Provided that they expresses FAAH or functional FAAH, these cells can be isolated from any species; and, for example, in this invention using cells isolated from mammals such as human, mouse, rat, pig, rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey.

For cells used established cell lines; the you can also use cells, exfoliated or extracted from animal tissue. Established cell lines used in the present invention include cells 5673 cell line cancer of the bladder epithelium human cells PC-3 cell line prostate cancer human cells RBL-2H3 basophilic cell line leukemia rat cell cell line N18TG2 neuroblastoma rat C6 cells cell line of rat glioma cells, J774 cell line of rat macrophages, cells PC-12 isolated from the brain substance of adrenal cell line of rat pheochromocytoma cells U937 cell line human monocytes, cells MFC-7 cell line breast cancer human cells EFM-19 cell line breast cancer human cells CaCo-2 cancer cell lines human colon (these cell lines available from the American Type Culture Collection (ATCC)), cells HaCaT cell lines epidermal keratinocytes and CHP100 cells cell line human neuroblastoma. Preferred are cells 5673 cell line cancer of the bladder epithelium of human cells and RBL-2H3 basophilic cell line leukemia rat.

Tissue expressing FAAH or functional FAAH specifically includes the brain, bladder, prostate, kidney, liver, testes, muscle, blood vessels, pancreas, digestive tract, lung, uterus, is lecanto, leather, lymphocyte, platelet, macrophage, monocyte, fat cell and prostate gland. Preferably use the brain, liver and monocytic. Provided that they expresses FAAH or functional FAAH, these tissues can be isolated from any species. For example, you can use tissue isolated from mammals such as human, mouse, rat, pig, rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey.

To determine expresses or not the cell or tissue FAAH or functional FAAH, cell or tissue extract can be used and analyzed using analysis Western blotting using antibodies capable of detecting interest of the polypeptide, or by PCR (polymerase chain reaction) using primers capable of specific detection of polynucleotide that encodes an polypeptide. In addition, the lysate or homogenate of cells or tissue is subjected to interaction with the substrate, such as anandamide, palmitoylethanolamide, oleamide and/or 2-arachidonoylglycerol, in a buffer having a pH from 7 to 9 at a temperature of 4°C to 37°C, during the time from 30 minutes to 90 minutes, after which the system determines hydrolysed or not a substrate for the intended definition.

b) the Transformant transformed with the vector of expr the hurt, containing polynucleotide that encodes FAAH or functional FAAH:

Polynucleotide that encodes FAAH or functional FAAH may be isolated from a cDNA library by screening using PCR or hybridization using primers and probe designed and synthesized on the basis of information about the known amino acid sequences and sequences of bases.

The fragment, which contains the selected polynucleotide, is inserted into a suitable expression vector, and can be transliterate into host cells of eukaryotes or prokaryotes; and in a host cell polypeptide encoded transfitsirovannykh polynucleotides, can thus be expressed. The expression vector may be any known vector selected depending on the host cell for which you can also use vector plasmid, appropriately selected depending on the host cell and contains inserted at a suitable promoter and is associated with the expression of the phenotype of the sequence. You can also use the expression vector with a specific sequence, inserted into it so that the polypeptide encoded by the inserted polynucleotide, could be expressed as a fusion with glutathione-S-transferase (GST) or tag, such as Flag or His. In the case, to the Yes one cell simultaneously transformed some other types of polynucleotides, then used one expression vector can be constructed in such a way that it included different types of polynucleotides, or such polynucleotide may be present separately in different expression vectors. Alternatively, you can get the cell with chromosomal DNA with this type of structure, and it can be used.

The expression vector with the desired polynucleotide inserted in it can be introduced into host cells in accordance with the method of DEAE-dextran (Luthman et al., Nucleic Acids Res., Vol. 11, pp. 1295-1308, 1983), by the method of coprecipitation of calcium phosphate-DNA (Graham et al., Virology, Vol. 52, pp. 456-457, 1973), a method using a commercially available reagent for transfection, Lipofectamine 2000 (Invitrogen) or FeGENE 6 (Roche Molecular Biochemicals) or electroporation (Neumann et al., EMBO J. Vol. 1, pp. 841-845, 1982) for the desired transformation. In case, when a host cell is usedE. colicompetent cellE. coliget in the presence of simultaneously CaCl2, MgCl2or RbCl, in accordance with the method of Hanahan (Hanahan et al., Mol. Biol. Vol. 166, pp. 557-580, 1983), and the expression vector with the inserted desired polynucleotide give it to transform cells.

(c) Lysate or homogenate (a) or (b):

The cell homogenate can be obtained by washing the cells several times with buffer, followed by homogenization using homogenized the RA Potter-Elvehjem or the like, obtaining, thus, a homogeneous solution. Tissue homogenate can be achieved by adding buffer, cooled with ice, to the tissue in 5-10 times the volume per mass of tissue, followed by homogenization using a homogenizer Potter-Elvehjem in ice with obtaining, thus, a homogeneous solution, and then subjecting it to further ultrasonic homogenization in a few seconds. The buffer may be a Tris buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA) or Hepes buffer (1 mm EDTA, 100 mm NaCl, 12.5 mm Hepes, pH 8.0). For example, in this case, the applicable test methods of Example 438 and Example 439. The lysate of E. coli transformed with the expression vector, which contains polynucleotide encoding FAAH or functional FAAH, can be obtained by collecting the cells of E. coli by centrifugation, and then dissolving them in a buffer for lysis (for example, 20 mm Tris-HCl (pH 8.0), 500 mm NaCl, 10% glycerol, 0.2 mm EDTA, 0.5 mm DTT, 10 mm imidazole, 1% n-octyl-R-B-glucopyranoside).

d) the Purified product FAAH or functional FAAH cleaned out with):

The purified product FAAH or functional FAAH can be obtained from (a) a cell or tissue expressing FAAH or functional FAAH, or b) lysate or homogenate transformant transformed by the expression vector, which contains polynucleotide encoding FAAH or functional FAAH, in accordance with the normal is the procedure of cleaning, such as affinity chromatography, electrochromatography, gel filtration chromatography, ion exchange chromatography or chromatography separation.

Specifically, cleaning is as follows: a Cell or tissue expressing FAAH or functional FAAH, homogenized in a solvent containing sucrose and then centrifuged and the ultra high performance centrifugation to obtain the fraction microsomes, then it is dissolved in a solvent containing Triton-X, and again centrifuged to remove the precipitate and the resulting protein lysate is treated in the liquid Express chromatography of proteins (FPLC) (Pharmacia) (Ueda et al., J. Biol. Chem., Vol. 270, pp. 23813-23827, 1995).

Alternative,E. colitransformed so that it is expressed fused with His tag FAAH or functional FAAH, is dissolved in a buffer for lysis, then treated with ultrasound and centrifuged (for example, at 10,000 × g for 20 minutes) and the resulting supernatant is mixed with the resin, pre-equilibrated with buffer for lysis and having a high affinity with His label, at a low temperature, for at least 12 hours. Then the resin is washed and flushed with His label FAAH or functional FAAH release from the resin with getting her pure product.

For contacting the test substance with asanas above cell or tissue or cell or tissue lysate or homogenate, received the above method, or purified product of FAAH or functional FAAH is possible to apply the method of incubation for a given period of time by adding to them or without the addition of test substances. Specifically, the test substance is dissolved in the solution, is selected appropriately depending on the solubility therein of the substance, such as distilled water or dimethylsulfoxide (DMSO)and added to the above cell, or tissue, or cellular or tissue lysate or homogenate or purified product of FAAH or functional FAAH with obtaining concentrations from 0.003 nm to 10 μm. Cell or tissue sample is incubated in CO2incubator at 37°C for 30 to 60 minutes; and other substances at a temperature of from 4°C to 37°C for 30 to 90 minutes, so achieving the desired contact with the test substance.

e) Tissue homogenate or blood test animal, which injected the substance:

When the test substance is administered test animal, then the test substance may come into contact with FAAH or functional FAAH, existing in the tissue or blood test animal. Experienced animal includes, for example, mammals, such as mouse, rat, dog. The substance can enter the experience is the PTO animal as follows: the test substance suspended or dissolved in the carrier, which is usually used in accordance with the properties of the test substances, such as physiological aqueous solution, a solution of DMF (dimethylformamide) or a 10% solution of methylcellulose, and you can enter the test animal orally, subcutaneously, intraperitoneally or intravenously. After the introduction of the tissue extract and the tissue homogenized in accordance with the method described above in (c), thereby obtaining tissue homogenate. Specifically, for example, from 1 to 3 mg/kg of the test substance orally administered 9-week-old rats and extracted from them after 30 minutes of this brain, liver or monocytes homogenized with obtaining tissue homogenate. Alternatively, from 0.3 to 3 mg/kg of the test substance is injected 13-18-month dogs and extracted from them after 30 minutes of this brain, liver or monocytes homogenized with obtaining tissue homogenate. More specifically, for example, tissue homogenate can be obtained in accordance with the method described in Example 440. Blood can be taken from the heart or the descending aorta of the test animal, which injected the substance.

(2) the stage of analysis of changes in the activity of FAAH or functional FAAH:

To analyze changes in the activity of FAAH or functional FAAH you can use the method of determining changes in fermentation.antipathy FAAH or functional FAAH, based on the presence or absence of contact with the test substance. The enzymatic activity of FAAH or functional FAAH can be determined by contacting FAAH or functional FAAH with the substrate for a predetermined period of time and measuring the amount of decomposed product of the substrate. Alternatively, it also can be determined by measuring the amount of endocannabinoids, which is an endogenous substrate for FAAH contained in the tissue or blood test animal.

For the analysis of dependent test substance changes the enzymatic activity of FAAH or functional FAAH substrate is subjected to contact with FAAH or functional FAAH within a specified period of time in the presence or in the absence of the test substance and get the ratio of the number of decomposed product of the substrate in the presence of the test substance to the amount of the decomposed product of the substrate in the absence of the test substance for the intended analysis.

Alternatively, FAAH or functional FAAH, which was previously subjected to contacting with the test substance, and FAAH or functional FAAH, which is not contacted with the test substance separately subjected to contact with the substrate for a predetermined period of time and get the ratio of the number of Razlog is segosa product substrate by the action of FAAH or functional FAAH, which was preliminarily subjected to contacting with the test substance to the amount of the decomposed product of the substrate as a result of FAAH or functional FAAH, which is not contacted with the test substance, whereby it is possible to determine the dependent test substances modification of the enzymatic activity.

In addition, dependent on the test substance, the change in enzymatic activity can also be determined by measuring the amount of endocannabinoid in tissue or blood test animal before and after administration of the test substance test animal, followed by obtaining the ratio of endocannabinoid after administration of the test substance to the amount of endocannabinoid before the introduction of the test substance; or by measuring the amount of endocannabinoid in tissue or blood test animal, which was introduced or which did not enter the test substance, followed by obtaining a ratio of the number of endocannabinoid in tissue or blood test animal, which injected a substance to the number of endocannabinoid in tissue or blood test animal, which did not enter the test substance, whereby it is possible to determine the dependent test substance modifying enzymatic Akti the property.

FAAH and functional FAAH can be subjected to contacting with the substrate under the conditions specified below, in accordance with the state of FAAH or functional FAAH.

To contact FAAH or functional FAAH expressed in a cell or tissue (a) or (b) in (1) above, with the substrate you can use the method of adding the substrate to the cultured cells or tissue in a buffer having a pH from 7 to 9, and their interaction in CO2incubator at 37°C or room temperature, preferably for 30 to 60 minutes. The reaction can be stopped by transfer of the cells or tissues are on ice for rapid cooling, after which the FAAH inhibitor can be subjected to contact with them in sufficient concentrations; or by adding a 1:1 (by volume) solution of chloroform and methanol. Cells or tissue are lysed or homogenized in accordance with the method described in (1) (c) above, thereby obtaining them lysate or homogenate.

To contact FAAH or functional FAAH in the lysate or homogenate of cells or tissues in c) or (e) from (1) above with the substrate you can use the method of adding the substrate to the lysate or homogenate, which was diluted with a buffer having a pH from 7 to 9, so that the protein concentration is preferably ranged from 10 to 100 μg/ml, and their interaction in temperatures from 4°C to 37°C. Premariacco can appropriately be determined depending on conditions, such as the number of added enzyme, the amount of added substrate and the reaction temperature. For example, when interact at room temperature, the reaction time may be from 30 to 90 minutes.

For contacting the purified FAAH or functional FAAH in (1) (d) above, the substrate can be used a method of adding the substrate to the lysate or homogenate, which was diluted with a buffer having a pH from 7 to 9, and their interaction in temperatures from 4°C to 37°C. the reaction Time can be appropriately determined depending on conditions such as the amount of added enzyme, the amount of added substrate and the reaction temperature. For example, when interact at room temperature, the reaction time may be from 30 to 90 minutes.

To measure the amount of decomposed product of the substrate unreacted substrate and decomposed product of the enzyme reaction solution is separated from each other, and it is possible to measure the quantity of decomposed product. To separate the unreacted substrate from the decomposed product can be used, the solubility of decomposed product of ethanolamine. For example, 1:1 (by volume) solution of chloroform and methanol added to the reaction solution of the enzyme in the amount of 2 times more than the number of reactio the aqueous solution, with further stirring, and then by centrifugation, resulting in containing the decomposed product of the upper layer, the water/ethanol layer can be separated from unreacted substrate contained in the lower layer (chloroform layer. Alternatively, the system can be mixed with the liquid agent representing a scintillation liquid, which does not absorb water, while fat-soluble unreacted radioactive substrate may be immersed in such liquid and decomposed product can thus be separated from the unreacted substrate. In another alternative method, the unreacted substrate can be separated from the decomposed product using thin-layer chromatography or high performance liquid chromatography.

When using3H or14C-labeled substrate or a mixture of labeled substrate and unlabeled substrate, the quantity of decomposed product or the amount of unreacted substrate can be measured using a liquid scintillation counter or can be obtained in the form of x-ray latent image on the photographic plate and measured using a reading device for photographic plates.

When using unlabeled substrate, the absorption in the system at 205 nm can tracking is tested by high performance liquid chromatography and thus, it is possible to measure the quantity of decomposed product or the amount of unreacted substrate (Lang et al., Anal. Biochem., Vol. 238, pp. 40-45, 1996).

When a measured quantity of unreacted substrate, then the amount of unreacted substrate can be deducted from the amount of substrate added to the reaction and, thus, it is possible to obtain the quantity of decomposed product. Alternatively, the quantity of decomposed product of the substrate, measured in a buffer not containing FAAH or functional FAAH, as a control, you can subtract the number of decomposed product of the substrate with FAAH or functional FAAH, thus, it is possible to obtain the pure quantity of decomposed product of the substrate with FAAH or functional FAAH.

The number of endocannabinoid in tissue homogenate can be measured, for example, by homogenizing the tissue sample with a 2:1:1 (by volume) solution of chloroform, methanol, and 50 mm Tris (pH 8.0), and then measuring the amount of endocannabinoid contained in the organic layer (chloroform layer) using liquid chromatography/mass spectrometry using isotope (Cravatt et al., Proc., Natl. Acad. Sci. USA, Vol. 98, pp. 9371-9376, 2001).

The number of endocannabinoid in the blood can be measured, for example, as follows: the plasma separated from the blood sample, and plasma protein can be removed by using centrifugual the deposits together with the same amount of added acetone (-20°C). The acetone is evaporated using a stream of nitrogen, supplied to the system, add 1:2 (by volume) solution of methanol and chloroform and measure the amount of endocannabinoid contained in the organic layer (chloroform layer) using liquid chromatography/mass spectrometry using isotope (Giuffraida et al., Eur. J. Pharmacol., Vol. 408, pp. 161-168, 2000).

(3) the stage of selecting a substance that inhibits the activity of FAAH or functional FAAH:

A substance that inhibits the activity of FAAH or functional FAAH, you can choose the following way: the test substance is subjected to contact with FAAH or functional FAAH, the result is compared with the case where they are not contacted with the test substance, and you can choose a substance that reduces the quantity of decomposed product of the substrate.

Specifically, the test substance is subjected to contact with FAAH or functional FAAH and the result compared with the case where they are not contacted with the test substance. If this substance, in the presence of a quantity of decomposed product of the enzyme is reduced preferably to 1/2 or less, you can skanirovat the drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for Leche is of pain.

Alternatively, the test substance in various concentrations is subjected to contact with FAAH or functional FAAH; and based on the amount of decomposed product of the substrate not exposed to the test substance taken as 100%, get relative quantity (%) of decomposed product of the substrate exposed to the test substance used in various concentrations; or on the basis of the number of decomposed product of the substrate not exposed to the test substance taken as 100%, and based on the amount of decomposed product of the substrate in the case where the known FAAH inhibitor having a sufficient concentration, contact with FAAH or functional FAAH within sufficient period of time taken for 0%, get relative quantity (%) of decomposed product of the substrate exposed to the test substance used in different concentrations. Using inhibition curve on the graph, where the relative amount (%) of decomposed product of the substrate is represented on the vertical axis, and the concentration of the test substance on the horizontal axis, calculate the concentration of the test substance, which gives a relative value, 50%, decomposed product of the substrate (value IR50); and a substance whose value is the IR 50is preferably not more than 1 μm, more preferably not more than 100 nm, sceneroot the drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for the treatment of pain. For example, see the tests in Example 438 - 440.

In another alternative embodiment, the test substance is administered the test animal and the number of endocannabinoid in the tissue or blood of the animal is compared before and after administration of the test substance; a substance that increases the amount is preferably up to 1.5 times may be selected as a substance that inhibits the activity of FAAH or functional FAAH, and it is this substance can be skanirovat the drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for the treatment of pain.

[2] Test substance:

Not a particular test substance for use in the screening method of the present invention includes, for example, commercially available products (including peptides), various known compounds registered in the Chemical File (including peptides), the group of the compounds obtained according to the accordance with the methods of combinatorial chemistry (Terrett et al., J. Steele. Tetrahedron, Vol. 51, pp. 8135-8173, 1995), cultural supernatant isolated from microorganisms derived from plants or marine organisms natural ingredients, extracts of animal tissues, as well as compounds (including peptides), obtained by chemical or biological modification of compounds (including peptides)selected in accordance with the method of screening according to the present invention.

[3] the Pharmaceutical composition for the treatment of frequent urination and urinary incontinence, for the treatment of increased activity of the bladder and/or for the treatment of pain:

As the active ingredient of the pharmaceutical compositions of the present invention use a substance that inhibits the activity of FAAH or functional FAAH, where inhibitory substance may be selected, for example, in accordance with the method of screening according to the present invention.

The pharmaceutical composition of the present invention is not limited to a pharmaceutical composition, which contains as its active ingredient the substance obtained in accordance with the method of screening according to the present invention, but may include any and every pharmaceutical composition for the treatment of frequent urination and urinary incontinence, for the treatment of increased activity of the bladder and/or for treatment of pain, which contains, to the operation of its active ingredient a substance for inhibiting the activity of FAAH or functional FAAH; and preferably it is a pharmaceutical composition for the treatment of frequent urination and urinary incontinence, for the treatment of increased activity of the bladder and/or for the treatment of pain.

The effect of treatment of frequent urination and urinary incontinence, the treatment effect increased activity of the bladder and/or treatment effect of pain can be confirmed, as described above.

Composition containing as its active ingredient a substance that inhibits the activity of FAAH or functional FAAH, such as DNA, protein (including an antibody or fragment of antibody), peptide or any other connection that can be obtained in the form of a pharmaceutical composition using a pharmaceutically acceptable carrier, excipient and/or any other additives that are commonly used to obtain pharmaceutical compositions, depending on the type of active ingredient.

The introduction of the composition can be accomplished, for example, by oral administration in the form of tablets, pills, capsules, granules, fine granules, powders or oral fluids; or parenteral administration by injection, such as intravenous, intramuscular or intra-articular injections, suppositories, percutaneous preparations, or preparations for the introduction of the mucous membrane. In particular, for peptides that parivar who are in the stomach, parenteral administration such as intravenous injection is preferred.

Solid compositions for oral administration can include a mixture of at least one or more active ingredients and at least one inert diluent such as lactose, mannitol, glucose, microcrystalline cellulose, hydroxypropylcellulose, starch, polyvinylpyrrolidone or aluminometasilicate magnesium. Besides inert diluents, the solid compositions may contain other additives, as is customary, for example, lubricants, disintegrating agents, stabilizers, solubilizing substances or substances that promote solubilization. Pills and tablets, optionally, can have a sugar coating or may have gastro - or intersolubility floor.

Liquid composition for oral administration includes, for example, emulsions, solutions, suspensions, syrups and elixirs, and may contain conventional inert diluents, such as distilled water or ethanol. Besides inert diluents, the liquid composition may also contain, for example, wetting agents, suspendresume substances, sweeteners, flavorings or preservatives.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions or emulsions. Aqueous solutions is whether suspensions can contain, for example, distilled water for injection or saline as a diluent. Thinners insoluble in water solutions or suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oil (e.g. olive oil), alcohols (e.g. ethanol) or Polysorbate 80. Such compositions may also contain wetting agents, emulsifiers, dispersing agents, stabilizers, solubilizing substances or substances that promote solubilization, or antiseptics. Such compositions can be sterilized, for example, by filtration through a bacterial filter or by adding to them germicide or by irradiation. If desirable, can be obtained a solid composition that does not contain pathogenic microorganisms, before their application was dissolved in does not contain pathogenic microorganisms in water or any other not containing pathogenic microorganisms environment for injection.

The dose of the composition respectively determined depending on the activity level of active ingredient or, more specifically, the substance obtained in accordance with the method of screening according to the present invention, and from the symptom, age, sex of the entity to which it is administered.

For example, when administered orally, the dose generally may be from about 0.1 to 100 mg/day, preferably about is 0.1 to 50 mg/day, for an adult (body weight 60 kg). When parenteral dose injections can range from 0.01 to 50 mg/day, preferably from 0.01 to 10 mg/day.

EXAMPLES

The present invention is described in more detail with reference to the following Examples. Compounds of the present invention should not be limited to the compounds described in the Examples presented here. The means of obtaining the source compounds are presented in the Reference Examples. Some compounds of the present invention can also be a source connections to others; and for convenience, the methods for their preparation may be presented in the present application as Reference Examples. Chemical structural formulas and physical-chemical properties of the compounds obtained in Reference Examples are shown in Tables 1-15. The chemical structural formulas of the compounds obtained in the Examples presented in Tables 16-34; and their physico-chemical properties are presented in Tables 35-63. Structures of other compounds of the present invention are presented in Tables 65-73. These compounds can be easily obtained in accordance with the above methods of obtaining or methods, described in the following Reference Examples and Examples, or in accordance with methods which are obvious to experts in the field, or in accordance the with modifications of such methods.

When using commercially available kits, you can refer to the written instructions that came with it.

Used in the present description, the abbreviations have the following meanings:

Rex: Reference Example

Ex: Example

Str: structural formula

DAT: physicochemical properties

1H-NMR δ(ppm)solvent: spectrum of nuclear magnetic resonance

In physico-chemical data of the compounds of Examples:

DMSO: DMSO-d6

MS m/z: mass spectrometry

Com: connection

NC: cyano

Ph: phenyl

Me: methyl

diMe: dimethyl

Et: ethyl

Pr: propyl

iPr: isopropyl

Bu: butyl

tBu: tert-butyl

iBu: isobutyl

Pen: pencil

Hex: hexyl

Hep: heptyl

Oct: octal

cPr: cyclopropyl

cPen: cyclopentyl

cHex: cyclohexyl

cHep: cycloheptyl

cOct: cyclooctyl

Ac: acetyl

Cl: chlorine

diCl: dichloro

CN: cyano

F: fluorine

diF: debtor

FPh forfinal

NCPh: cyanophenyl

diFPh: differenl

O2N: nitro

MeO: methoxy

diMeO: dimethoxy

Br: bromine

diBr: dibromo

BrPh: Bromphenol

F3C: trifluoromethyl

AcO: acetoxy

MeOCO or COOMe: methoxycarbonyl

tBuOCO or COOtBu: tert-butoxycarbonyl

HO: hydroxy

HOPh: hydroxyphenyl

H2N: amino

PhCONH: benzoylamine

EtCONH: ethylcarbodiimide

Me2N: dimethylamino

Et2N: diethylamino

BIP2: 2-iphenyl

BIP3: 3-biphenyl -

BIP4: 4-biphenyl -

BIP5: 5-biphenyl -

BIP6: 6-biphenyl -

Thiop2: thiophene-2-yl

Thiop3: thiophene-3-yl

Thiop4: thiophene-4-yl

Thiop5: thiophene-5-yl

PYRR1: pyrrolidin-1-yl

PYRR2: pyrrolidin-2-yl

PYRR3: pyrrolidin-3-yl

PYRR4: pyrrolidin-4-yl

PYRR5: pyrrolidin-5-yl

Py2: pyridine-2-yl

Py3: pyridine-3-yl

Py4: pyridine-4-yl

Py5: pyridine-5-yl

IM1: imidazol-1-yl

IM2: imidazol-2-yl

IM3: imidazol-3-yl

IM4: imidazol-4-yl

BenzIM1: benzimidazole-1-yl

BenzIM2: benzimidazole-2-yl

BenzIM3: benzimidazole-3-yl

BenzIM4: benzimidazole-4-yl

BenzIM5: benzimidazole-5-yl

BenzIM6: benzimidazole-6-yl

Pyrazi1: pyrazin-1-yl

Pyrazi2: pyrazin-2-yl

Pyrazi3: pyrazin-3-yl

Pyrazi4: pyrazin-4-yl

Pyrazi5: pyrazin-5-yl

Pyrazi6: pyrazin-6-yl

PIPE1: piperidine-1-yl

PIPE2: piperidine-2-yl

PIPE3: piperidine-3-yl

PIPE4: piperidine-4-yl

PIPE5: piperidine-5-yl

PIPE6: piperidine-6-yl

PIPERA: piperazine

PIPERA1: piperazine-1-yl

PIPERA2: piperazine-2-yl

PIPERA3: piperazine-3-yl

PIPERA4: piperazine-4-yl

PIPERA5: piperazine-5-yl

Pyrazo1: pyrazole-1-yl

Pyrazo2: pyrazole-2-yl

yrz3: pyrazole-3-yl

Pyrazo4: pyrazole-4-yl

Pyrazo5: pyrazole-5-yl

Mo: morpholine

Mo: morpholine-2-yl

Mo: morpholine-3-yl

Mo: morpholine-4-yl

Mo: morpholine-5-yl

Azep: hexahydroazepin

Azep1: hexahydroazepin-1-yl

Azep2: hexahydroazepin-2-yl

Azep3: hexahydroazepin-3-yl

Aze4: hexahydroazepin-4-yl

Thiaz2: thiazol-2-yl

Thiaz3: thiazol-3-yl

Thiaz4: thiazol-4-yl

Thiaz5: thiazol-5-yl

QUI1: quinoline-1-yl

QUI2: quinoline-2-yl

QUI3: quinoline-3-yl

QUI4: quinoline-4-yl

QUI5: quinoline-5-yl

QUI6: quinoline-6-yl

QUI7: quinoline-7-yl

QUI8: quinoline-8-yl

ISOQUI2: isoquinoline-2-yl

ISOQUI3: isoquinoline-3-yl

ISOQUI4: isoquinoline-4-yl

ISOQUI5: isoquinoline-5-yl

ISOQUI6: isoquinoline-6-yl

ISOQUI7: isoquinoline-7-yl

ISOQUI8: isoquinoline-8-yl

NAPH1: naphthalene-1-yl

NAPH2: naphthalene-2-yl

NAPH3: naphthalene-3-yl

NAPH4: naphthalene-4-yl

NAPH5: naphthalene-5-yl

TEA: triethylamine

Sal: additional salt

HCl: hydrochloride

oxal: oxalate

fum: fumarate

p-tol: g-toluensulfonate

Reference Example 1:

Solution in THF (10 ml)containing phenol (471 mg) and diethylazodicarboxylate (2.83 g, 40% Tol solution)was added dropwise to a solution in THF (15 ml)containing tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1,57 g) and triphenylphosphine (1.70 g), at 0°C, followed by stirring at room temperature for 24 hours. To the reaction solution were added water (40 ml) followed by extraction using EtOAc. The organic layer was washed with an aqueous solution of 1 M sodium hydroxide and saturated saline in that order, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified colon is the offered by chromatography on silica gel (eluent: hexane:EtOAc=4:1 (vol./about.)) obtaining a colorless oil (1,14 g). The compound obtained was dissolved in EtOAc, the solution was added 4 M hydrogen chloride/EtOAc (9.6 ml), followed by stirring at room temperature for 5 hours to obtain hydrochloride of 4-(phenoxymethyl)piperidine (680 mg) as colorless powder.

In the same manner as in Reference Example 1 was obtained compounds of Reference Examples 2 to 27.

Reference Example 28:

Water (10 ml), sodium carbonate (4,76 g) and tetranitropentaerithrite (866 mg) were added in that order to the solution in dimethoxyethane (50 ml)containing 3-bromobenzene (3.0 g) and (3-hydroxyphenyl)boric acid (2,27 g), followed by stirring at 60°C for 24 hours. The reaction solution was cooled, diluted with EtOAc and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: EtOAc) to give pale yellow powder (2,74 g). Using the compounds obtained and the same method as in Reference Example 1 was obtained compound of Reference example 28.

Reference Example 29:

Solution in THF (80 ml)containing 4-(benzyloxy)phenol (8.0 g) and diethylazodicarboxylate (26 ml, 40% Tol solution)was added dropwise to a solution in THF (80 ml)containing tert-butyl 4-hydroxypiperidine-1-carboxylate (12 g) and Trifan fastin (16 g), at a temperature of 00C, followed by stirring at room temperature for 24 hours. To the reaction solution were added water (40 ml) followed by extraction using EtOAc. The organic layer was washed with an aqueous solution of 1 M sodium hydroxide and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=8:1 (vol./about.)) obtaining a colorless oil (12.4 g).

10% Palladium on carbon (catalytic amount) were added to ethanol (100 ml) solution containing the resulting compound (5,18 g), followed by stirring in an atmosphere of hydrogen gas at room temperature under normal pressure for 16 hours. The catalyst was removed by filtration and the resulting filtrate was concentrated under reduced pressure to obtain a pale brown solid (4.0 g).

1-(methyl bromide)-3-torbenson (2.5 ml) and potassium carbonate (2.8 g) was added to the solution in acetonitrile (100 ml)containing the compound obtained (4.0 g), followed by heating at a temperature of 80°C for 22 hours. Solids were removed by filtration, the obtained filtrate was concentrated under reduced pressure and the residue was purified column chromatography naselesele (eluent: hexane:EtOAc=8:1 (vol./about.)) to obtain a colorless solid matter (5,15 g).

The compound obtained (5,15 g) was dissolved in EtOAc (20 ml), was added a solution of 4M hydrogen chloride/EtOAc (20 ml) followed by stirring at room temperature for 5 hours. The solvent is then evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous solution of 1 M sodium hydroxide and the resulting solid was dried to obtain 4-{4-[(3-terbisil)oxy]phenoxy}piperidine (3,70 g).

In the same manner as in Reference Example 29 was obtained compounds of Reference Examples 30-36.

Reference Example 37:

Diethylazodicarboxylate (11 ml, 40% Tol solution) was added dropwise to a solution in THF (30 ml)containing tert-butyl 4-hydroxypiperidine-1-carboxylate (4.6 g), triphenylphosphine (6,1 g) and 6-chloro-2-pyridinol (2.0 g) at 0°C, followed by stirring at room temperature for 24 hours. To the reaction solution was added water, followed by extraction using EtOAc. The organic layer was washed with an aqueous solution of 1M sodium hydroxide and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=10:1 (vol./about.)) to obtain tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (3.8 g).

(3-Forfinal)methanol (220 mg) and tert-piperonyl potassium (200 mg) was added to rastvorov DMF (5 ml), containing tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (500 mg), followed by heating at 100°C for 30 minutes. Then to the mixture was added (3-forfinal)methanol (220 mg) and tert-piperonyl potassium (200 mg) followed by heating at 110°C for 30 minutes. To the reaction solution were added water and then was extracted using EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=10:1 (vol./about.)) obtaining a white solid (420 mg).

The obtained compound (400 mg) was dissolved in EtOAc (5 ml), was added a solution of 4M hydrogen chloride/EtOAc (3 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 2-[(3-terbisil)oxy]-6-(4-piperidinyloxy)pyridine (310 mg).

In the same manner as in Reference Example 37, received the compound of Reference example 38.

Reference Example 39:

Water (4 ml), sodium carbonate (610 mg) and tetranitropentaerithrite (110 mg) were added in that order to a solution of Tol (10 ml)containing tert-butyl 4-[(6-chloro-2-pyrid the Nile)oxy]-1-piperidinecarboxylate (500 mg) and [3-(aminocarbonyl)phenyl]boric acid (320 mg), followed by heating overnight at 100°C. the Reaction solution was cooled and diluted with EtOAc. The organic layer was washed with an aqueous solution of anhydrous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:2 (vol./about.)) obtaining a pale yellow powder (590 mg).

The obtained compound (590 mg) was dissolved in EtOAc (5 ml) and the solution was added 4M hydrogen chloride/EtOAc (5 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 3-[6-(4-piperidinyloxy)-2-pyridinyl]benzamide (440 mg).

Reference Example 40:

TEA (4.6 ml) and methanesulfonamide (2.0 ml) was added dropwise to a solution in methylene chloride (80 ml)containing tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5.0 g), at 0°C, followed by stirring at room temperature for 3 hours. To the reaction solution was added an aqueous solution of sodium bicarbonate and methanol, followed by stirring at room temperature for 30 minutes. The mixture was extracted with chloroform and the organic layer was washed with saturated saline and dried the over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=10:1 (vol./about.)) to obtain a colorless solid matter (6,1 g).

Sodium hydride (541 mg, 60% in oil) was added to a solution in DMF (80 ml)containing the compound obtained (2.0 g) and phenylpropanol (1.3 g), at 0°C followed by heating at 100°C for 20 hours. The reaction solution was cooled, added with water, followed by extraction using EtOAc. The mixture was washed with an aqueous solution of 1 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=20:1 (vol./about.)) obtaining a yellow oil (1,96 g).

The compound obtained (1,96 g) was dissolved in EtOAc (5 ml) and the solution was added 4M hydrogen chloride/EtOAc (10 ml) followed by stirring at room temperature for 2 hours. The formed solid substance was collected by filtration and dried to obtain hydrochloride of 4-[2-(3-phenylpropoxy)ethyl]piperidine (1.55 g).

Reference Example 41:

TEA (2.30 ml) and methanesulfonamide (1,22 ml) was added dropwise to a solution in THF (40 m is), containing tert-butyl 4-hydroxypiperidine-1-carboxylate (3,02 g), at 0°C, followed by stirring at room temperature for 1 hour. To the reaction solution was added EtOAc (50 ml) and water (50 ml). The organic layer is washed with aqueous 5% citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated saline solution in that order and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to obtain a pale orange oil. The resulting oil was dissolved in DMA (25 ml) and cesium carbonate (5,38 g) and to the mixture was added 4-sulfonylurea (1,89 g) followed by heating at 50°C for 2 hours. The reaction solution was cooled, added with water, followed by extraction using EtOAc. The organic layer was washed with an aqueous solution of 1 M hydrochloric acid and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=4:1 (vol./about.)) to obtain tert-butyl 4-[(4-hydroxyphenyl)sulfonyl]piperidine-1-carboxylate (3,40 g) as colorless powder.

1-(methyl bromide)-3-torbenson (0,436 ml) and potassium carbonate (670 mg) was added to the solution in acetonitrile (15 ml)containing tert-Buti is 4-[(4-hydroxyphenyl)sulfonyl]piperidine-1-carboxylate (1,00 g), followed by heating at a temperature of 80°C for 2 hours. The reaction solution was cooled, added to it a saturated saline solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=8:1 (vol./about.)) to obtain tert-butyl 4-({4-[(3-terbisil)oxy]phenyl}sulfonyl)piperidine-1-carboxylate (1.50 g) as colorless powder.

Tert-butyl 4-({4-[(3-terbisil)oxy]phenyl}-sulfonyl)piperidine-1-carboxylate (501 mg) was dissolved in EtOAc (5 ml) and the solution was added 4M hydrogen chloride/EtOAc (3 ml) followed by stirring at room temperature for 3 hours. The solvent is then evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous solution of 1M sodium hydroxide followed by extraction with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to obtain 4-({4-[(3-terbisil)oxy]phenyl}sulfonyl)piperidine (328 mg).

In the same manner as in Reference Example 41, received the compound of Reference Example 42.

Reference Example 43:

mCPBA (1.64 g) was added to a solution in chloroform (20 ml), containing what he tert-butyl 4-({4-[(3-terbisil)oxy]phenyl}sulfonyl)piperidine-1-carboxylate (1.50 g), obtained in the method of Reference example 41, at a temperature of 0°C, followed by stirring at room temperature for 17 hours. The solid was removed by filtration and to the filtrate was added 10% aqueous solution of sodium sulfate, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=2:1 (vol./about.)) to obtain a colorless powder (1,58 g). The obtained powder (1.56 g) was dissolved in EtOAc (10 ml), was added a solution of 4M hydrogen chloride/EtOAc (8 ml), followed by stirring at room temperature for 2 hours. Then the solid was collected by filtration and washed with EtOAc to obtain hydrochloride of 4-({4-[(3-terbisil)oxy]phenyl}sulfonyl)piperidine (1.13 g) as colorless powder.

In the same manner as in Reference Example 43 was obtained compounds of Reference Examples 44-46.

Reference Example 47:

Solution in THF (5 ml) of tert-butyl 4-[(4-hydroxyphenyl)sulfonyl]piperidine-1-carboxylate (495 mg)obtained in the method of Reference Example 41, and diethylazodicarboxylate (1.04 g, 40% Tol solution) was added dropwise to a solution in THF (5 ml)containing cyclohexylmethanol and triphenylphosphine (69 mg), at 0°C, followed by stirring at room temperature for 24 hours. To the reaction solution were added water (40 ml) followed by extraction using EtOAc. The organic layer was washed with an aqueous solution of 1M sodium hydroxide and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=9:1 (vol./about.)) to obtain tert-butyl 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (744 mg) as a pale yellow oil.

The obtained tert-butyl 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (635 mg) was dissolved in EtOAc (7 ml) and the solution was added 4M hydrogen chloride/EtOAc (3.6 ml), followed by stirring at room temperature for 6 hours. The solid is collected by filtration and washed with EtOAc to obtain hydrochloride of 4-{[4-(cyclohexylmethoxy)phenyl]-sulfonyl}piperidine (485 mg) as colorless powder.

In the same manner as in Reference Example 47, received the compound of Reference Example 48.

Reference Example 49:

Sodium hydride (355 mg, 60% in oil) and benzyl bromide (1.0 ml) was added to a solution in THF (40 ml)containing tert-butyl 4-hydroxypiperidine-1-carboxylate (1.5 g), with subsequent heating is at a temperature of 60°C for 13 hours. The reaction solution was cooled, added with water, followed by extraction using EtOAc. The mixture was washed with an aqueous solution of 1 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=10:1 (vol./about.)) obtaining a colorless oil (1,91 g).

The compound obtained (1.8 g) was dissolved in EtOAc (5 ml) and the solution was added 4M hydrogen chloride/EtOAc (15 ml), followed by stirring at room temperature for 3 hours. The reaction solution was diluted simple isopropyl ether and the resulting solid was collected by filtration and dried to obtain hydrochloride of 4-(benzyloxy)piperidine (1,32 g).

In the same manner as in Reference Example 49 was obtained compounds of Reference Examples 50-53.

Reference Example 54:

Diethylazodicarboxylate (2,6 ml, 40% Tol solution) was added dropwise to a solution in THF (10 ml)containing (3-forfinal)methanol (730 mg), triphenylphosphine (1.5 g) and 6-chloro-3-pyridinol (500 mg)at 0°C, followed by stirring at room temperature for 24 hours. The reaction solution was diluted with the aid of EtOAc. The organic layer was washed the feast upon the major aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=8:1 (vol./about.)) obtaining a white solid (810 mg).

Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) and tert-piperonyl potassium (570 mg) was added to a solution in DMF (10 ml)containing the obtained white solid (800 mg), followed by heating at a temperature of 130°C for 1 hour. Then to the mixture was added tert-piperonyl potassium (400 mg), and then continued heating at a temperature of 130°C for 1 hour. The reaction solution was cooled to room temperature, diluted with the aid of EtOAc, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=7:1 (vol./about.)) obtaining a white solid (350 mg).

The obtained compound (345 mg) was dissolved in EtOAc (3 ml) and the solution was added 4M hydrogen chloride/EtOAc (2 ml) followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 6-[(3-terbisil)oxy]-2-(4-piperidinyloxy)pyridine (260 mg).

Reference Example 55:

[1-(Tert-butoxycarbonyl who yl)piperidine-4-yl]acetic acid (0,60 g) was dissolved in dimethylformamide (12 ml) and to the mixture was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0,89 g), 1-hydroxybenzotriazole (0.50 g) and benzylamine (0.40 g), followed by stirring at room temperature for 15 hours. To the reaction solution was added water and was stirred for 1 hour. Then to the mixture was added a solution of sodium bicarbonate, followed by extraction using EtOAc. The organic layer was washed with a solution of 0.5 M hydrochloric acid and saturated saline in that order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:2 (vol./about.)) to obtain a colorless powder (0,69 g).

The compound obtained (0,69 g) was dissolved in EtOAc (10 ml) and the solution was added 4M hydrogen chloride/EtOAc (2.2 ml), followed by stirring at room temperature for 20 hours. The reaction solution was concentrated until dry solids to obtain hydrochloride of N-benzyl-2-piperidine-4-ylacetamide (0,62 g).

Reference Example 56:

Phosphoric acid (7 ml) and dephosphorylated (14 g) was heated at 150°C for 30 minutes, to the mixture was added N-methylbenzol-1,2-diamine (1.3 g) and hydrochloride 4-piperidine-4-inputanalog acid (1.5 g) followed by heating at a temperature of 120°C for 3 hours. The reaction solution was poured into water, neutralized water is astorm sodium hydroxide and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol:aqueous ammonia=10:1:0,1 (about./about./about.)) obtaining 1-methyl-2-(3-piperidine-4-ylpropyl)-1H-benzimidazole (1,61 g).

Reference Example 57 and Reference Example 58:

tert-Piperonyl potassium (1,72 g) was added to a solution in THF (30 ml)containing [4-(methoxycarbonyl)benzyl](triphenyl)phospholipase (7.51 g), at 0°C, followed by stirring for 1 hour. To the reaction solution was added dropwise a solution in THF (20 ml)containing tert-butyl 4-formylpiperidine-1-carboxylate (Beilstein Registry No. 7704210, 2,96 g), at 0°C, followed by stirring for 14 hours. To the reaction solution was added water, followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=9:1 (vol./about.)) obtaining a yellow oil (3.77 g).

The obtained compound (3.75 g) was dissolved in methanol (20 ml) and THF (10 ml) was added an aqueous solution of 1 M sodium hydroxide (16,3 ml) followed by stirring at 50°C for 4 hours. The reaction solution which was gladly and the solvent evaporated under reduced pressure. The mixture was acidified by adding a solution of 1 M hydrochloric acid and the precipitated solid substance was collected by filtration and washed with water to obtain a pale brown powder (2,82 g).

Ammonium chloride (of 2.26 g), the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (3,24 g), 1-hydroxybenzotriazole (1,14 g) and TEA (5,88 ml) was added to the solution containing the compound obtained (2,80 g)in DMF (30 ml) followed by stirring at room temperature for 32 hours. To the reaction solution were added water and the precipitated solid substance was collected by filtration and washed with water to obtain a pale brown powder (2,61 g).

The obtained compound (2.58 g) was dissolved in EtOAc (15 ml) and the solution was added 4M hydrogen chloride/EtOAc (15 ml), followed by stirring at room temperature for 8 hours. The formed solid substance was collected by filtration, washed with EtOAc and dried to obtain hydrochloride of 4-[(E)-2-piperidine-4-elwenil]benzamide (1.92 g) (Reference Example 57).

10% Palladium on carbon (catalytic amount) was added to the solution containing the hydrochloride of 4-[(E)-2-piperidine-4-elwenil]benzamide (800 mg)in methanol (15 ml)/water (5 ml), followed by stirring in an atmosphere of hydrogen gas at room temperature under normal pressure for 4 hours. The catalyst was removed by filtering and the resulting filtrate was concentrated under reduced pressure. The obtained solid was recrystallized from ethanol/acetonitrile to obtain hydrochloride of 4-(2-piperidine-4-retil)benzamide (451 mg) (Reference Example 58).

Reference Example 59:

Triacetoxyborohydride sodium (2.2 g) was added to a solution in dichloromethane (30 ml)containing tert-butyl 4-(4-aminophenoxy)-1-piperidinecarboxylate (2.0 g, Beilstein Registry No. 9262581), cyclohexanecarboxaldehyde (770 mg) and acetic acid (1.25 ml), at 0°C, followed by stirring at room temperature for 2 hours. To the reaction solution was added nasishenna aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting solid is recrystallized from EtOAc/hexane to obtain pale brown crystals (2.0 g).

Triacetoxyborohydride sodium (1.1 g) was added to a solution in dichloromethane (20 ml)containing the resulting crystalline substance (970 mg), aqueous 37% formaldehyde solution (0,94 ml) and acetic acid (0.75 g), at 0°C, followed by stirring at room temperature for 2 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate followed the second extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting oil was dissolved in EtOAc (15 ml). Solution was added 4M hydrogen chloride/EtOAc (5 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of N-(cyclohexylmethyl)-N-methyl-4-(4-piperidinyloxy)aniline (820 mg).

Reference Example 60:

In the atmosphere of argon flow Tris(dibenzylideneacetone)dipalladium (95 mg) was added to a solution of Tol (10 ml)containing benzyl 3-itfinally simple ether (1.1 g), tert-butyl 1-piperidinecarboxylate (640 mg), tert-piperonyl sodium (500 mg) and 2-biphenylyl(DICYCLOHEXYL)phosphine (70 mg), followed by heating at a temperature of 80°C for 1 hour. The reaction solution was cooled, diluted with the aid of EtOAc and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=5:1 (vol./about.)) to obtain brown solid (950 mg).

The obtained solid (940 mg) was dissolved in EtOAc (5 ml) and the solution was added 4M chlorite is th hydrogen/EtOAc (5 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain the dihydrochloride of 1-[3-(benzyloxy)phenyl]piperazine (840 mg).

Reference Example 61:

Diethylazodicarboxylate (4.8 ml, 40% Tol solution) was added dropwise to a solution in THF (60 ml)containing 4-(benzyloxy)-2-chlorophenol (1.7 g, Beilstein Registry No. 6582932), triphenylphosphine (2.8 g) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.1 g) at 0°C, followed by stirring at room temperature for 24 hours. The reaction solution was diluted with the aid of EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:tOAc=5:1 (vol./about.)) obtaining a white solid (2.3 g).

The compound obtained (1.0 g) was dissolved in EtOAc (10 ml) and the solution was added 4M hydrogen chloride/EtOAc (10 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 4-[4-(benzyloxy)-2-chlorophenoxy]piperidine (690 mg).

Reference Example 62:

Thionyl chloride (10 ml) was added dropwise to a solution of 4-hydroxybenzyl is onata sodium (1,00 g) in DMF (5 ml) followed by heating at 65°C for 3 hours. The reaction solution was cooled and added Tol (10 ml). The solvent is evaporated under reduced pressure, added with water, followed by extraction with chloroform. The organic layer is washed with aqueous saturated saline solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a colorless solid (587 mg).

At a temperature of 0°C. the solution obtained at the previous stage of the compounds (57 9 mg) in acetonitrile (10 ml) was added to the solution in acetonitrile (10 ml)containing 1-tert-butoxycarbonylmethyl (672 mg) and pyridine (0,58 ml), followed by stirring at room temperature for 2 hours. The solvent is evaporated under reduced pressure, was added Tol (10 ml) and subjected to azeotropic presence. Then added water, followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a colorless solid matter (0,41 g).

Potassium carbonate (248 mg) was added to the solution in acetonitrile (20 ml)containing the compound obtained (0,41 g) and 1-(methyl bromide)-3-torbenson (340 mg), followed by heating at a temperature of 80°C for 3 hours. The solid was removed by filtration, the obtained filtrate was concentrated under p the lower the pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=5:1 (vol./about.)) obtaining a colorless solid (469 mg).

The obtained compound (460 mg) was dissolved in a mixed solution of EtOAc (5 ml) and THF (5 ml) and the solution was added 4 M hydrogen chloride/EtOAc (20 ml) followed by stirring at 70°C for 3 hours. The solvent is then evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous solution of 1M sodium hydroxide and the resulting solid was dried to obtain 4-{4-[(3-terbisil)oxy]benzazolyl}piperazine (304 mg).

Reference Example 63

Diethylazodicarboxylate (3,3 ml, 40% Tol solution) was added dropwise to a solution in THF (30 ml)containing 4-(benzyloxy)-3-chlorophenol (1.2 g, Beilstein Registry No. 5527577), triphenylphosphine (1.9 g) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1.5 g), at 0°C, followed by stirring at room temperature for 24 hours. The reaction solution was diluted using EtOAc and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=5:1 (vol./about.)) obtaining a white solid (1.7 g).

The compound obtained (1.6 g) was dissolved in EtOAc (20 ml) and the solution was added 4M hydrogen chloride/EtOAc (15 ml), followed by stirring overnight at room Tempe is the atur. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 4-[4-(benzyloxy)-3-chlorophenoxy]piperidine (1.3 g).

Reference Example 64:

3-Forbindelsesfaneblad (3.2 g) was added to a solution in pyridine (30 ml)containing tert-butyl 4-(4-aminophenoxy)-1-piperidinecarboxylate (4.0 g, Beilstein Registry No. 9262581), at 0°C, followed by stirring overnight at room temperature. The solvent is evaporated under reduced pressure and diluted with chloroform. The organic layer is washed with aqueous 10% citric acid solution, water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=60:1 (vol./about.)) to obtain white solids (5.3g).

Potassium carbonate (280 mg) and methyliodide (of 0.28 ml) was added to the solution in acetonitrile (10 ml)containing the compound obtained (700 mg), followed by stirring at 50°C for 3 hours. The reaction solution was diluted with the aid of EtOAc, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified colon is the offered by chromatography on silica gel (eluent: hexane:EtOAc=3:1 (vol./about.)) obtaining a colorless oil (700 mg).

The obtained oil (700 mg) was dissolved in EtOAc (10 ml) and the solution was added 4M hydrogen chloride/EtOAc (5 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 3-fluoro-N-methyl-N-[4-(4-piperidinyloxy)phenyl]benzosulfimide (480 mg).

Reference Example 65:

Hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (630 mg) and 1-hydroxybenzotriazole (440 mg) was added to a solution in DMF (10 ml)containing 1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2-piperidinylcarbonyl acid (1.0 g), followed by stirring at room temperature for 1 hour. Then was added concentrated aqueous ammonia solution (2 ml) followed by stirring at room temperature for 3 hours. To the reaction solution were added water and the precipitated solid substance was collected by filtration, washed with water and dried under reduced pressure to obtain a colorless solid (870 mg).

The obtained solid (860 mg) was dissolved in EtOAc (10 ml) and the solution was added 4M hydrogen chloride/EtOAc (5 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to receive the drug hydrochloride benzyl 2- (aminocarbonyl)-1-piperidinecarboxylate (700 mg).

Reference Example 66:

Pyridine (1,62 ml) and 4-nitrophenylarsonic (2,22 g) was added to the solution in acetonitrile (20 ml)containing methyl 4-(hydroxymethyl)benzoate at a temperature of 0°C, followed by stirring at room temperature for 2 hours. To the reaction solution was added 5% aqueous citric acid solution and then was extracted using EtOAc. The organic layer was washed saturated aqueous bicarbonate and saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:t=4:1 (vol./about.)) to obtain a pale brown powder (2,39 g).

Tert-butyl piperazine-1-carboxylate (1.47 g) was added to the solution in acetonitrile (30 ml)containing the resulting compound (2.37 g), followed by stirring at room temperature for 8 hours. The reaction solution was diluted with the aid of EtOAc and washed with an aqueous solution of 0.5 M sodium hydroxide. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=2:1 (vol./about.)) to obtain a colorless solid matter (of 3.32 g).

To rastvorov THF (30 ml), containing the compound obtained (3,30 g)was added methanol (0,34 ml) and an aqueous solution of 1 M sodium hydroxide (charged 8.52 ml) followed by stirring at room temperature for 26 hours. The solvent is evaporated under reduced pressure, to the residue was added an aqueous solution of 1 M hydrochloric acid followed by extraction with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The obtained residue was recrystallized from hexane/EtOAc to obtain a colorless powder (2.37 g).

Ammonium chloride (321 mg), the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (767 mg), 1-hydroxybenzotriazole (270 mg) and TEA (or 0.83 ml) was added to a solution in DMF (10 ml)containing the compound obtained (729 mg), followed by stirring at room temperature for 3 hours. To the reaction solution were added water and the precipitated solid substance was collected by filtration and washed with water to obtain a pale brown powder (722 mg).

The obtained compound (700 mg) was dissolved in EtOAc (6 ml), was added a solution of 4M hydrogen chloride/EtOAc (4.8 ml), followed by stirring at room temperature for 3 hours. The formed solid substance was collected by filtration, washed with EtOAc and dried to obtain the hydrochloride is 4-(aminocarbonyl)benzyl piperazine-1-carboxylate (541 mg).

Reference Example 67:

Solution in THF (5 ml)containing methyl 4-hydroxybenzoate (460 mg) and diethylazodicarboxylate (0,71 ml)was added dropwise to a solution in THF (5 ml)containing cyclohexylmethanol (510 mg) and triphenylphosphine (1.18 g), at 0°C, followed by stirring at room temperature for 2 to 4 hours. To the reaction solution was added an aqueous solution of 1 M sodium hydroxide (40 ml) followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:t=4:1 (vol./about.)) obtaining a colorless solid (930 mg).

An aqueous solution of 1 M sodium hydroxide (4.4 ml) was added to a solution in methanol (5 ml)/THF (3 ml)containing the resulting compound (920 mg), followed by stirring at 50°C for 6 hours. The mixture was cooled to room temperature and was added EtOAc (40 ml) and water (30 ml), followed by stirring. The organic layer was extracted with aqueous solution of 1M sodium hydroxide. The aqueous layers were combined and brought to pH 1 using concentrated hydrochloric acid. Then the aqueous layer was extracted with chloroform and then dried over anhydrous sodium sulfate. Rest ritel evaporated under reduced pressure and the residue was recrystallized from hexane/EtOAc to obtain 4-(cyclohexylmethoxy)benzoic acid (600 mg).

Hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (359 mg) and 1-hydroxybenzotriazole (254 mg) was added to a solution in DMF (10 ml)containing the compound obtained (370 mg) was added tert-butyl 1-piperidinecarboxylate (350 mg), followed by stirring at room temperature for 12 hours. To the reaction solution were added water and the precipitated solid substance was collected by filtration, washed with water and dried under reduced pressure to obtain a colorless solid (610 mg).

The compound obtained (600 mg) was dissolved in EtOAc (6 ml) and the solution was added 4M hydrogen chloride/EtOAc (4 ml), followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 1-[4-(cyclohexylmethoxy)benzoyl]piperazine (580 mg).

In the same manner as in Reference Example 67, received the compounds of Reference Examples 68-72.

Reference Example 73:

At -70°C a solution of 1.59 M normal-utility/THF (14.6 ml) was added to a solution of 2 M dimethylamine/THF (11,6 ml) followed by stirring for 10 minutes. The mixture was heated to 0°C was added 3-chloro-5-hydroxypyridine (1,00 g), followed by stirring overnight at room temperature. Added ethanol (15 ml) and the solvent evaporated under ponie nom pressure. To the residue was added water, followed by extraction with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=10:1 (vol./about.)) with 3-dimethylamino-5-hydroxypyridine (176 mg).

Reference Example 74:

Tris-dibenzylideneacetone (21 mg), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (124 mg) and tert-piperonyl sodium (160 mg) was added, in order, to the solution of Tol (10 ml)containing 3-benzyloxy-5-bromopyridine (400 mg) and morpholine (158 mg), followed by heating at 85°C for 4 hours. The solvent is evaporated under reduced pressure and the residue was purified column chromatographie on silica gel (eluent: chloroform:methanol=20:1 (vol./about.)) obtaining a colorless oil (372 mg).

10% Palladium on carbon (catalytic amount) was added to an ethanol solution (20 ml)containing the compound obtained (370 mg), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature and under normal pressure for 1.5 hours. The catalyst was removed by filtration and the resulting filtrate was concentrated under reduced pressure to obtain 5-hydroxy-3-morpholinopropan (248 mg).

In the same way, it is in Reference Example 74, received connection Reference Examples 75 and 76.

Reference Example 77:

The sodium methoxide (393 mg) was added to a methanol solution (20 ml)containing 5-(benzosulfimide)-2-(methyl bromide)pyridine (Beilstein Registry No. 7430370, 800 mg), followed by stirring at room temperature for 4 hours. To the reaction solution was added water, followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: EtOAc) to give 6-(methoxymethyl)pyridine-3-ol (200 mg).

Reference Example 78:

TEA (of 0.21 ml) and di-tert-butyl dicarbonate (463 mg) were added in that order to a solution in THF (10 ml) of 3-benzyloxy-5-aminopyridine (250 mg) followed by heating at 60°C for 3 hours. The solvent is evaporated under reduced pressure, added with water, followed by extraction using EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:1 (vol./about.)) to obtain a colorless solid matter what (153 mg).

10% Palladium on carbon (catalytic amount) was added to an ethanol solution (20 ml)containing the compound obtained (240 mg), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure for 1.5 hours. The catalyst was removed by filtration and the resulting filtrate was concentrated under reduced pressure to obtain tert-butyl (5-hydroxypyridine-3-yl)carbamate (167 mg).

Reference Example 79:

At a temperature of 0°C. suspension of sodium hydride (60% oil blend, 13 9 mg) in THF (10 ml) was added to a solution in THF (10 ml) methyldiethanolamine (732 mg), followed by stirring for 15 minutes. Then added 5-(benzyloxy)nicotinamidase (495 mg), followed by stirring at room temperature for 4 hours. To the reaction solution was added water, followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a colorless solid (680 mg).

10% Palladium on carbon (catalytic amount) was added to an ethanol solution (20 ml)containing the resulting compound (330 mg), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure in the tip is of 2 hours. The catalyst was removed by filtration and the resulting filtrate was concentrated under reduced pressure to obtain methyl 3-(5-hydroxypyridine-3-yl)propanoate (150 mg).

Reference Example 80:

At a temperature of -78°C. solution in THF (30 ml) of methyl 5-(benzyloxy)nicotinate (to 3.52 g) was added to a solution in THF (100 ml) suspension of sociallyengaged (1,49 g), followed by stirring for 15 minutes and then stirring at room temperature for 2 hours. The reaction solution was cooled to 0°C and then added water (1,49 ml), 15% aqueous sodium hydroxide solution (1,49 ml) and water (4,47 ml), in the specified order. The solid was removed by filtration and the resulting filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol=10:1 (vol./about.)) to obtain a colorless solid matter (1,41 g).

Tert-butyl bromoacetate (609 mg), tetrabutylammonium bisulfate (35 mg) and 50% aqueous sodium hydroxide solution (2 ml) was added, in order, to a benzene solution (20 ml)containing the compound obtained (450 mg), followed by stirring overnight at room temperature. The mixture was neutralized with an aqueous solution of 1 M hydrochloric acid followed by extraction using EtOAc. The organic layer was washed with saturated saline solution and sushiland anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:t=6: 4 (about./about.)) obtaining a colorless oil (576 mg).

10% palladium on carbon (catalytic amount) was added to an ethanol solution (20 ml)containing the resulting compound (570 mg), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure for 1 hour. The catalyst was removed by filtration and the resulting filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol=15:1 (vol./about.)) to obtain tert-butyl [(5-hydroxypyridine-3-yl)methoxy]acetate (400 mg).

Reference Example 81:

Pentamethylbenzyl (826 mg) was added to the solution in TFU (10 ml)containing methyl (2E)-3-[5-(benzyloxy)pyridine-yl] acrylate (300 mg), followed by stirring overnight at 60°Systemical evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=10:1 (vol./about.)) to obtain tert-butyl (5-hydroxypyridine-3-yl)acetate (180 mg).

Reference Example 82:

Diisopropylethylamine (2,05 ml) and methoxymethane (0,89 ml) were added in that order to a solution in THF (60 ml) of methyl 3-hydroxynicotinate (1.50 g) and then per massively over night at room temperature. The solvent is evaporated under reduced pressure, adding water and then was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a colorless oil (2,01 g).

At a temperature of -78°C. solution in THF (20 ml) of the obtained compound (1.98 g) was added to a solution in THF (50 ml) suspension of sociallyengaged (838 mg), followed by stirring for 30 minutes and then stirring at room temperature for 2 hours. The reaction solution was cooled to 0°C and was added water (0,84 ml), 15% aqueous sodium hydroxide solution (0,84 ml) and water (2,52 ml), in the specified order. The solid was removed by filtration and the resulting filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: EtOAc) to give a colorless oil (838 mg).

To a solution of pyridine (10 ml)containing the compound obtained (828 mg), was added acetic anhydride (1.39 ml), followed by stirring at room temperature for 1.5 hours. The solvent is evaporated under reduced pressure, was added Tol (10 ml) and subjected to azeotropic distillation to obtain a colorless oil (1.01 g).

A solution of 4 M hydrogen chloride/dioxane (to 3.58 ml) was added to a solution of poluchennogo the compound (1.01 g) in dioxane (10 ml) followed by stirring at room temperature for 1 hour. The solvent is evaporated under reduced pressure obtaining hydrochloride (5-hydroxypyridine-3-yl)acetate (973 mg).

Reference Example 95:

Triphenylphosphine (2.8 g) was added to a solution of Tol (50 ml) of 3-cyanobenzaldehyde (2.0 g), followed by stirring at a temperature of 80°C for 5 hours. The mixture was cooled to room temperature and the precipitated solid substance was collected by filtration and washed Tol. The mixture was dried under reduced pressure to obtain (3-cyanobenzyl)(triphenyl)factorybased (3.4 g).

Under ice cooling sodium hydride (60% in oil, 141 mg) was added to a solution in DMF (20 ml) of (3-cyanobenzyl)(triphenyl)factorybased (1.6 g) and tert-butyl 4-formyl-1-piperidinecarboxylate (0.75 g), followed by stirring overnight at room temperature. The reaction liquid was diluted with the aid of EtOAc, washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=6:1 (vol./about.)) getting oil. 10% Palladium on carbon (100 mg) was added to a solution of the obtained oil in EtOAc (30 ml), followed by stirring in an atmosphere of hydrogen flow for 2 hours. The catalyst was removed through celite and the solvent was concentrated to obtain oil. The resulting oil was dissolved in EtOAc (10 ml) and to the mixture was added p is the target 4 M hydrogen chloride/EtOAc (5 ml), then was stirred at room temperature for 6 hours and then concentrated. The obtained solid substance was washed with a simple ether and dried under reduced pressure to obtain hydrochloride of 3-[2-(4-piperidinyl)ethyl]benzonitrile (506 mg).

In the same manner as in Reference Example 95, received the compounds of Reference Examples 96-101.

Reference Example 102:

Triphenylphosphine (85,8 g) was added to a solution of Tol (400 ml) of methyl 3-bromoethylamine (50.0 g), followed by stirring at a temperature of 80°C for 10 hours. After cooling the mixture to room temperature, precipitated crystals were collected by filtration and washed Tol. The mixture was dried under reduced pressure to obtain methoxycarbonylbenzyl)(triphenyl)factorybased (107,6 g).

Under ice cooling tert-piperonyl potassium (22,5 g) was added to a solution in DMF (250 ml) (3-methoxycarbonylbenzyl)(triphenyl)factorybased (84,6 g), followed by stirring at room temperature for 30 minutes. Then to the mixture under ice cooling was added a solution of tert-butyl 4-formyl-1-piperidinecarboxylate (30,6 g) in DMF (50 ml) and then stirred over night at room temperature. To the reaction liquid was added acetic acid (11.5 ml), followed by stirring at room temperature for 1 hour. The mixture is then diluted with the aid of EtOAc, washed with the water and with saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=7:1 (vol./vol.)). The residue was dissolved in EtOAc, to the mixture was added activated carbon, followed by stirring at room temperature for 2 hours. The activated carbon was removed through celite and the solvent evaporated under reduced pressure to obtain a colorless oil.

10% Palladium on carbon (4,58 g) was added to a solution of the obtained oil in EtOAc (400 ml), followed by stirring in an atmosphere of hydrogen flow for 2 hours. The catalyst was removed through celite and the solvent was concentrated to obtain tert-butyl 4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45,4 g).

In the same manner as in Reference Example 102, received the compound of Reference Example 103.

Reference Example 104:

An aqueous solution of 1 M sodium hydroxide (196 ml) was added to a solution of tert-butyl 4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45,4 g) in THF (200 ml)/methanol (50 ml) followed by stirring at 60°C for 2 hours. The organic solvent evaporated under reduced pressure and under ice cooling, to the residue was added a 0.5 M solution of hydrochloric acid (400 ml). The reaction liquid was diluted with the aid of EtOAc, washed with water and neymann the m saline solution and dried over anhydrous sodium sulfate. The solvent is evaporated to obtain 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (43,5 g).

In the same manner as in Reference Example 104, received the compound of Reference Example 105.

Reference Example 106:

3-{2-[1-(Tert-butoxycarbonyl)-4-piperidinyl]ethyl}-benzoic acid (17.8 g) was dissolved in DMF (200 ml) and to the mixture was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (15,4 g) and 1-hydroxybenzotriazole (10,8 mg), followed by stirring at room temperature for 2 hours. To the reaction solution was added ammoniacal (to 8.57 g) and TEA (22,3 ml), followed by stirring overnight at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, the precipitated crystals were collected by filtration and dried to obtain tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (10.8 g). In the same manner as in Reference Example 106, obtained compounds of Reference Examples 107-118.

Reference Example 119:

Tert-butyl 4-[2-(4-{[(2-hydroxyethyl)amino]carbonyl}-phenyl)ethyl]piperidine-1-carboxylate (280 mg), tetrabromide carbon (247 mg) and 2,6-lutidine (103 μl) was dissolved in dichloromethane (5.6 ml) and cooled with ice was added triphenylphosphine (195 mg), followed by stirring at room temperature for 3 hours. The solvent issue is rival and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=3:7 (vol./about.)) to obtain tert-butyl 4-{2-[4-(1-aziridinyl)phenyl]ethyl}-1-piperidinecarboxylate (136 mg) as a colourless oil.

Reference Example 120:

Tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (13.8 g) was dissolved in EtOAc (200 ml) and the solution was added 4 M hydrogen chloride/EtOAc (130 ml), followed by stirring at room temperature for 4 hours and then concentrated. To the obtained residue was added acetonitrile, followed by heating and precipitated crystals were collected by filtration, washed with EtOAc and dried under reduced pressure to obtain hydrochloride of 3-[2-(4-piperidinyl)ethyl]benzamide (11.2 g). In the same manner as in Reference Example 120 was obtained compounds of Reference Examples 121-139.

Reference Example 140:

In the atmosphere of argon flow sodium carbonate (0,43 g) and tetrakis(triphenylphosphine)palladium (80 mg) was added to a solution of Tol (6 ml)/water (2 ml) of tert-butyl 4-[2-(3-bromophenyl)ethyl]-1-piperidinecarboxylate (0.50 g) and phenylboronic acid (0.20 g), followed by heating under stirring at 100°C for 7 hours. The mixture was cooled to room temperature, diluted with the aid of EtOAc and washed with saturated aqueous solution of sodium bicarbonate. The mixture was dried over anhydrous magnesium sulfate, then the solvent is evaporated and the obtained residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=10:1 (vol./about.)) to obtain tert-butyl 4-[2-(3-biphenyl)ethyl]-1-piperidinecarboxylate (0,41 g).

A solution of 4 M hydrogen chloride/EtOAc (1.5 ml) was added to a solution of tert-butyl 4-[2-(3-biphenyl)ethyl]-1-piperidinecarboxylate (0,41 g) in EtOAc (4 ml), followed by stirring overnight at room temperature. Precipitated crystals were collected by filtration, washed with EtOAc/hexane and dried under reduced pressure to obtain hydrochloride of 4-[2-(3-biphenyl)ethyl]piperidine (0.31 g).

In the same manner as in Reference Example 140 was obtained compounds of Reference Examples 141 and 142.

Reference Example 143:

Under ice cooling di-tert-BUTYLCARBAMATE (2.6 g) was added to a solution of 4,4'-(1,3-propane-diyl)piperidine (5.0 g) in dichloromethane (50 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (eluent: chloroform:methanol:aqueous concentrated ammonia solution=4:1:0,1 (about./about.)) to obtain tert-butyl 4-[3-(4-piperidinyl)propyl]-1-piperidinecarboxylate (2.2 g).

In an argon atmosphere tert-piperonyl sodium (0.52 g), Tris(dibenzylideneacetone)dipalladium (100 mg) and 2-(dicyclohexylphosphino)biphenyl (76 mg) was added to a solution of Tol (22 ml) of 2-chloro-6-methylpyridine (0.56 g) and tert-butyl 4-[3-(4-piperidinyl)propyl]-1-PIP is reincorporate (1/1 g) followed by heating under stirring at 100°C for 1 hour. The mixture was cooled to room temperature, diluted with the aid of EtOAc and washed with aqueous saturated solution of sodium bicarbonate. The mixture was dried over anhydrous magnesium sulfate, the solvent evaporated and the obtained residue was purified column chromatography on silica gel (eluent:hexane:EtOAc=10:1 (vol./about.)) to obtain tert-butyl 4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidyl]propyl}-1-piperidinecarboxylate (1.3 g).

A solution of 4 M hydrogen chloride/EtOAc (10 ml) was added to a solution of tert-butyl 4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidinyl]propyl}-1-piperidinecarboxylate (1.3 g) in EtOAc (25 ml) followed by stirring overnight at room temperature. The reaction liquid was concentrated, then added 2-propanol/diethyl simple ether, followed by stirring. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the dihydrochloride of 2-methyl-6-{4-[3-(4-piperidinyl)propyl]-1-piperidyl}pyridine (1.1 g).

In the same manner as in Reference Example 143 was obtained compounds of Reference Examples 144 and 145.

Reference Example 146:

Methanesulfonanilide (2.7 ml) was added dropwise to a solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (8.00 g) and TEA (4.8 ml) in methylene chloride (200 ml) at 0°C, followed by stirring overnight at room temperature. The reaction is idcast washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, then was dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: EtOAc:hexane=1:3 (vol/about.)) to obtain tert-butyl 4-{3-[(methylsulphonyl)oxy]propyl}piperidine-1-carboxylate (10.1 g).

A suspension of tert-butyl 4-{3-[(methylsulphonyl)oxy]propyl}piperidine-1-carboxylate (1,00 g)of the dihydrochloride of 1-piperazine-1-yl-isoquinoline (980 mg), cesium carbonate (1,02 g) and sodium iodide (467 mg) in DMI (20 ml) was stirred at a temperature of 140°C for 1 hour. To the reaction liquid was added EtOAc, washed with water and saturated aqueous sodium hydrogen carbonate, in that order, then dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:1 (vol./about.)) to obtain tert-butyl 4-[3-(4-isoquinoline-1-reparation-1-yl)propyl]piperidine-1-carboxylate (1.07 g) as a pale yellow oil.

A solution of 4 M hydrogen chloride/EtOAc solution (5.0 ml) was added dropwise to a solution of tert-butyl 4-[3-(4-isoquinoline-1-reparation-1-yl)propyl]piperidine-1-carboxylate (1.44 g) in EtOAc (15 ml), followed by stirring overnight. The solvent is evaporated, the solid is washed with EtOAc and collected by filtration to obtain the dihydrochloride of 1-[4-(3-piperidine-4-ylpropyl)piperazine-1-yl]isoquinoline (1,32 g) as a white solid in the society.

In the same manner as in Reference Example 146, received the compound of Reference Example 154.

Reference Example 147:

4-Nitrophenylphosphate (7.0 g) was added to a solution of methyl 5-hydroxynicotinate (5.3g) and diisopropylethylamine (6,1 ml) in dichloromethane (100 ml) followed by stirring at room temperature for 1 hour. The reaction liquid was washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting solid is washed with EtOAc/hexane and dried under reduced pressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (8,4 g).

In the same manner as in Reference Example 147, received the compound of Reference Example 148.

Reference Example 151:

Solution in DMF (15 ml) of 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]benzoic acid (1.25 g), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (863 mg) and 1-hydroxybenzotriazole (608 mg) was stirred at room temperature for 1 hour and then added to the solution of the hydrobromide of 2-brometalia (2.30 g) in TEA (1.6 ml) followed by stirring overnight. To the reaction liquid was added a saturated aqueous solution of sodium bicarbonate, followed by extraction using EtOAc, then washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated from the floor is the group of the crude product tert-butyl 4-[2-(3-{[(2-bromacil)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate.

A solution of 4 M hydrogen chloride/EtOAc (5 ml) was added to a solution of the crude tert-butyl 4-[2-(3-{[(2-bromacil)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate in EtOAc (15 ml) at room temperature, followed by stirring overnight. The solvent is evaporated under reduced pressure to obtain hydrochloride of N-(2-bromacil)-3-(2-piperidine-4-retil)benzamide (1.27 g) as a white solid.

TEA (from 0.90 ml) was added dropwise to a suspension of N-(2-bromacil)-3-(2-piperidine-4-retil)benzamide hydrochloride (1.20 g) and methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (1,02 g) in acetonitrile (30 ml), followed by stirring overnight at room temperature. The solvent of the reaction mixture is evaporated under reduced pressure, and then to the mixture was added saturated aqueous sodium hydrogen carbonate solution, was extracted using EtOAc and dried over anhydrous magnesium sulfate. The mixture was filtered, the solvent evaporated and the residue was purified twice a column chromatographie on silica gel (native silicon dioxide with eluent: hexane:EtOAc=1:2 (vol./vol.), then the neutral silicon dioxide with eluent: chloroform:methanol=19:1 (vol./about.)) to obtain methyl 5-[{(4-[2-(3-{[(2-bromacil)amino]carbonyl}phenyl)ethyl]piperidine-1-yl}carbonyl)oxy]

the nicotinate (762 mg) as a white powder.

A suspension of methyl 5-[{(4-[2-(3-{[(2-bromacil)amino]carbonyl}phenylethyl]piperidine-1-yl}carbonyl)oxy]

the nicotinate (750 mg), potassium carbonate (300 mg) and potassium iodide (361 mg) in DMF (10 ml) was stirred at a temperature of 80°C for 1 hour. The reaction liquid was left to cool, then to the mixture was added EtOAc, washed with saturated aqueous sodium bicarbonate and saturated saline in that order, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol=20:1 (vol./about.)) to obtain methyl 5-{[(4-{2-[3-(aziridine-1-ylcarbonyl)phenyl]ethyl}piperidine-1-yl)carbonyl]oxy}nicotinate (630 mg) as a colourless oil.

Reference Example 152:

Under ice cooling diphenylphosphinite (540 mg) was added to a solution of 3-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl]benzoic acid (600 mg) and TEA (0.3 ml) in Tol (10 ml) followed by stirring at room temperature for 2 hours. To the reaction solution was added EtOAc, washed with saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a colorless oil (630 mg). A solution of the obtained oil (400 lhs) in Tol (10 ml) was stirred at 110°C for 1 hour. The mixture was cooled to room temperature and added Wodny% ammonia solution (0.2 ml) followed by stirring at room temperature for 15 hours. To the reaction solution was added EtOAc, then washed with 1 N. aqueous solution of hydrochloric acid and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: chloroform:methanol=95:5 (vol./about.)) to obtain tert-butyl 4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227 mg).

A solution of 4 M hydrogen chloride/EtOAc (4 ml) was added to a solution of tert-butyl 4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227 mg) in EtOAc (9 ml), followed by stirring at room temperature for 3 hours. The solvent is evaporated under reduced pressure to obtain hydrochloride of 1-{3-[2-(4-piperidyl)ethyl]phenyl}urea (185 mg).

Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (228 mg) was added to the solution in acetonitrile (5 ml) of the hydrochloride of 1-{3-[2-(4-piperidinyl)ethyl]phenyl}urea (185 mg) and TEA (0.2 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with the aid of EtOAc, washed with saturated aqueous sodium bicarbonate and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was column purified chromium is cografya on silica gel (eluent: chloroform:methanol=10:1 (vol./about.)) to obtain methyl 5-({[4-(2-{3-[(aminocarbonyl)amino]phenyl}-ethyl)-1-piperidyl]carbonyl}oxy)nicotinate (183 mg).

In the same manner as in Reference Example 152, received the compound of Reference Example 153.

Reference Example 155:

Tert-butyl 4-ethynylpyridine-1-carboxylate (12.5 g) and iadanza (12.8 g) was dissolved in a solvent mixture of THF:TEA=1:1 (vol./about.) (125 ml), then at room temperature, to the mixture was added copper iodide (455 mg) and palladium complex-tetranitroaniline (1,38 g), in that order, followed by stirring overnight at room temperature. The solvent is evaporated, to the mixture was added EtOAc and washed with an aqueous solution of 1 M hydrochloric acid, water and saturated saline in that order. The mixture was dried over magnesium sulfate and the solvent evaporated to obtain a light brown oil. The mixture was purified column chromatography on silica gel (eluent: hexane:EtOAc=19:1 (vol./about.)) to obtain tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (15.5 g) as a light brown oil.

A solution of 4 M hydrogen chloride/EtOAc (70 ml) was added to tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (7.0 g), followed by stirring at room temperature for 30 minutes. The solvent is evaporated to obtain hydrochloride of 4-(phenylethynyl)piperidine (5,4 g) as a white powder.

Example 1:

3 Hydroxypyridine (400 mg), TEA (1,17 ml) and DMAP (catalytic amount) were added in this order is a solution in THF (10 ml), containing piperidine-1-carbonylchloride (745 mg)and then heated at 60°C for 5 hours. The reaction solution was cooled, then added water (3 ml) and was extracted using EtOAc. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:1 (vol./about.)) obtaining a colorless oil. The resulting oil was dissolved in ethanol and to the mixture was added an ethanolic solution of oxalic acid (378 mg) to obtain a colorless powder. The mixture was recrystallized from hexane/ethanol to obtain (pyridin-3-yl) piperidine-1-carboxyglutamate (761 mg).

Example 2:

Solution in methylene chloride (20 ml)containing 3-hydroxypyridine (568 mg) and pyridine (724 μl)was added dropwise to a solution in methylene chloride (25 ml)containing triphosgene (590 mg), followed by stirring at room temperature for 1 hour. The solvent is evaporated under reduced pressure, the residue was dissolved in pyridine (30 ml), then to the mixture was added the compound (1.2 g)obtained in Reference Example 22, followed by heating at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure, then was added chloroform and aqueous sodium hydrogen carbonate solution and the organic the cue layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:2 (vol./about.)) obtaining a colorless powder. The mixture was recrystallized from hexane/EtOAc to obtain (pyridin-3-yl) 4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (861 mg).

In the same way as in Example 2, were obtained compounds of Examples 3-118, 389-391, 416 and 417, and Reference Examples 83-93.

Example 119:

Solution in methylene chloride (20 ml)containing 3-hydroxypyridine (1,43 g) and pyridine (1,46 ml)was added dropwise to a solution in methylene chloride (30 ml)containing triphosgene (1.48 g, followed by stirring at room temperature for 1 hour. To the reaction solution was added dropwise a solution of methylene chloride (5 ml)containing tert-butyl 1-piperidinecarboxylate (2.0 g) and pyridine (0,97 ml), and then to the mixture was added pyridine (20 ml) followed by heating at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with the aid of EtOAc and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on basic silica gel (eluent: hexane:EtOAc=4:1 (vol./about.)) obtaining a colorless solid fuel is Dogo substances (3.0 g).

The compound obtained (3.0 g) was dissolved in EtOAc (20 ml)/2-propanol (10 ml), and then to the mixture was added a solution of 4 M hydrogen chloride/EtOAc (10 ml), followed by stirring overnight at room temperature. The reaction solution was concentrated under reduced pressure and the obtained solid is washed with EtOAc and dried under reduced pressure to obtain dihydrochloride 3-pyridyl 1-piperidinecarboxylate (2.66 g).

Hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (150 mg), 1-hydroxybenzotriazole (110 mg) and diisopropylethylamine (0,23 ml) was added to a solution in DMF (5 ml)containing the resulting compound (190 mg) and 4-(cyclooctylmethyl)benzoic acid (176 mg), obtained from cyclooctylmethyl in accordance with Reference Example 70, followed by stirring overnight at room temperature. The reaction solution was diluted with the aid of EtOAc, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was recrystallized from EtOAc/hexane to obtain 3-pyridyl 4-[4-(cyclooctylmethyl)benzoyl]-1-piperidinecarboxylate (240 mg).

In the same manner as in Example 119, obtained compounds of Examples 120-136.

Example 137:

tert-Piperonyl potassium (810 mg) was added to a solution in DMF (10 ml)is holding a 6-chloronicotinamide (1.0 g) and 3-chlorbenzoyl alcohol (1.0 g), followed by stirring overnight at room temperature. To the reaction solution were added water and the precipitated solid substance was collected by filtration, washed with water and hexane in this order, and dried under reduced pressure to obtain a brown solid (1.3 g).

To an ethanol solution (10 ml)containing the compound obtained (1.3 g)was added an aqueous solution of 5 M sodium hydroxide (10 ml) followed by stirring at 100°C for 4 hours. After cooling the mixture to room temperature, was added 1 n solution of hydrochloric acid (56 ml) and the precipitated solid substance was collected by filtration, washed with water and dried under reduced pressure to obtain a colorless solid matter (0,82 g).

To a solution in DMF (5 ml)containing the resulting compound (176 mg) and the dihydrochloride of 3-pyridyl 1-piperidinecarboxylate (166 mg), was added the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (150 mg), 1-hydroxybenzotriazole (110 mg) and diisopropylethylamine (0,23 ml), followed by stirring overnight at room temperature. The reaction solution was diluted with the aid of EtOAc, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue on the imali column chromatography on basic silica gel (eluent: hexane:EtOAc=1:2 (vol./about.)) obtaining a colorless oil (140 mg).

To a solution of 2-propanol containing the resulting compound (140 mg)was added oxalic acid (35 mg), followed by stirring for 30 minutes. The precipitated solid was collected by filtration, washed with 2-propanol/hexane and dried under reduced pressure to obtain 3-pyridyl 4-({6-[(3-Chlorobenzyl)oxy]-3-pyridyl}carbonyl)-1-piperidinecarboxylate of 0.5 oxalate (120 mg).

In the same way as in Example 137, received the compound of Example 138.

Example 139:

Potassium carbonate (1.04 g) and ethylbromoacetate (0,610 ml) was added to the solution in acetonitrile (15 ml)containing 4-hydroxybenzamide (686 mg), followed by heating at a temperature of 80°C for 2 hours. The reaction solution was cooled, added to water (45 ml) and the precipitated solid substance was collected by filtration, washed with water and dried to obtain ethyl [4-(aminocarbonyl)phenoxy]acetate (893 mg) as pale brown powder.

The obtained compound (870 mg) was dissolved in THF (10 ml) and to the mixture was added ethanol (0,274 ml) and an aqueous solution of 1 M sodium hydroxide (4,68 ml) followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, acidified with an aqueous solution of 1 M hydrochloric acid and the precipitated solid substance was collected by filtration and dried to obtain a pale brown p. the Rosca [4-(aminocarbonyl)phenoxy]acetic acid (714 mg).

TEA (0,251 ml), the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (259 mg), 1-hydroxybenzotriazole (122 mg) obtained above and [4-(aminocarbonyl)phenoxy]acetic acid (184 mg) was added to a solution in DMF (5 ml)containing the dihydrochloride of 3-pyridyl 1-piperidinecarboxylate (252 mg)obtained in the method of Example 121, followed by stirring at room temperature for 5 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=95:5 (vol./about.)) and the obtained solid was recrystallized from EtOAc/acetonitrile to obtain pyridine-3-yl 4-{[4-(aminocarbonyl)phenoxy]acetyl}piperidine-1-carboxylate (274 mg).

In the same manner as in Example 139 was obtained compounds of Examples 140 and 141.

Example 142:

TEA (0,23 ml) and benzosulphochloride (0.075 ml) was added to a solution in dichloromethane (5 ml)containing the dihydrochloride of 3-pyridyl 1-piperidinecarboxylate (150 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with chloroform, the organic layer was washed with a saturated aqueous solution of bicarbonate on the rija and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue was purified column chromatography on silica gel (eluent: chloroform) and the obtained solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-(phenylsulfonyl)-1-piperidinecarboxylate (130 mg).

In the same manner as in Example 142, received the compound of Example 143.

Example 144:

To a solution of pyridine (3 ml)containing the dihydrochloride of 3-pyridyl 1-piperidinecarboxylate (150 mg) was added benzylchloride (91 mg), followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with the aid of EtOAc and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue was diluted with 2-propanol (3 ml) and was added to hydrate toluensulfonate acid (100 mg), followed by stirring. Precipitated crystals were collected by filtration and recrystallized from 2-propanol to obtain tosilata benzyl 3-pyridyl 1,4-piperidinecarboxylate (98 mg).

In the same way as in Example 144 was obtained compounds of Examples 145 and 146.

Example 147:

10% Palladium on carbon (catalytic amount) was added to a solution in THF (20 ml)/2-propanol (20 ml)containing 3-iridal 4-[(4-benzyloxy)benzoyl]-1-piperidinecarboxylate (1.3 g), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure for 12 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure and the resulting solid is recrystallized from EtOAc/hexane to obtain 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperidinecarboxylate (950 mg).

Solution In THF (5 ml)containing 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperidinecarboxylate (300 mg) and diethylazodicarboxylate (of 0.62 ml, 40% Tol solution)was added dropwise to a solution in THF (5 ml)containing 3-chlorbenzoyl alcohol (200 mg) and triphenylphosphine (360 mg)at 0°C, followed by stirring at room temperature for 3 days. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=95:5 (vol./about.)) and the obtained solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzoyl)oxy]benzyl}-1-piperidinecarboxylate (260 mg).

In the same way as in Example 147 was obtained compounds of Examples 148-166.

Example 167:

Potassium carbonate (270 mg) was added to the solution in acetonitrile (10 ml), soderjasim-pyridyl 4-(4-hydroxybenzoyl)-1-piperidinecarboxylate (530 mg) and methyl 3-(methyl bromide)benzoate (450 mg), followed by stirring at a temperature of 80°C for 1 hour. To the reaction solution was added water, followed by extraction using EtOAc. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:4 (vol./about.)) obtaining a colorless solid (470 mg).

The obtained solid (100 mg) was recrystallized from EtOAc to obtain 3-pyridyl 4-(4-{[3-(methoxycarbonyl)benzyl]oxy}benzoyl)-1-piperidinecarboxylate (88 mg).

Example 168:

4-Ethyl 1-pyridin-3-yl piperidine-1,4 -, in primary forms (0,732 g) was dissolved in THF (15 ml) and ethanol (8.0 ml) and cooled with ice to the mixture was added dropwise an aqueous solution of 1 M sodium hydroxide (3.9 ml). The mixture was stirred at room temperature for 2 hours and neutralized with 1 M hydrochloric acid (0.5 ml). The reaction liquid was concentrated under reduced pressure, to the residue was added methanol and the precipitated salt was removed by filtration with suction. The filtrate was concentrated to obtain 1-[(pyridine-3-yloxy)carbonyl]piperidine-4-carboxylic acid (0,727 g) as a colourless solid.

The compound obtained (0,60 g) was dissolved in dimethylformamide (10 ml) and to the mixture was added the hydrochloride of 1-[3-(dimethylene is about)propyl]-3-ethylcarbodiimide (0,93 g), 1-hydroxybenzotriazole (0.51 g) and cyclohexanemethylamine (0,43 g), followed by stirring at room temperature for 15 hours. To the reaction solution was added water, and then was stirred for 1 hour. Then to the mixture was added a solution of sodium bicarbonate, followed by extraction using EtOAc. The organic layer was washed with a solution of 0.5 M hydrochloric acid and saturated saline in that order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:4 (vol./about.)) to obtain a colorless powder (0,69 g). The mixture was recrystallized from ethanol and hexane to obtain (pyridin-3-yl) 4-{[(cyclohexylmethyl)amino]carbonyl}piperidine-1-carboxylate (261 mg).

In the same manner as in Example 168, obtained compounds of Examples 169-192, 383-388, and Reference Example 94.

Example 193:

3-Pyridinedicarboxylate (330 mg) was added to a solution in pyridine (10 ml)containing 1-benzyl-2-methyl-1,2-piperidinecarboxylate (660 mg, Beilstein Registry No. 4236331), followed by stirring at a temperature of 80°C for 7 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform and the organic layer was washed with a saturated aqueous solution of hydrocarb the Nata sodium and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on basic silica gel (eluent: hexane:EtOAc=l:1 (vol./about.)) obtaining a colorless oil (700 mg).

To a solution in THF (5 ml)containing the compound obtained (430 mg)was added an aqueous solution of 1 M sodium hydroxide (1.2 ml), followed by stirring at 50°C for 3 hours. To the mixture was added an aqueous solution of 1 M sodium hydroxide (0.8 ml) and continued heating at 50°C for 1 hour, then cooled to room temperature and was added 1 n hydrochloric acid (2 ml). The reaction solution was extracted using EtOAc, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the precipitated solid is washed with EtOAc/hexane and dried under reduced pressure to obtain 1-[(benzyloxy)carbonyl]-4-[(3-pyridyloxy)carbonyl]-2-piperidinecarboxylic acid (140 mg).

In the same manner as in Example 193, obtained compounds of Examples 194 and 195.

Example 196:

Pyridine-3-yl 4-({[2-(methylamino)phenyl]amino}carbonyl)piperidine-1-carboxylate (0,41 g) was dissolved in acetic acid (10 ml) followed by heating at the boiling point under reflux for 2 hours. The solvent is evaporated the residue was recrystallized from methanol and diethyl ether to obtain (pyridin-3-yl) 4-(1-methyl-1H-benzimidazole-2-yl)piperidine-1-carboxylate (307 mg).

Example 197:

Pyridine-3-yl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (0,249 g) was dissolved in THF (5.0 ml) and cooled with ice to the mixture was added a solution of 4 M hydrogen chloride/EtOAc (2.10 ml) followed by stirring at room temperature for 24 hours. The reaction solution was concentrated to dryness to obtain dihydrochloride pyridine-3-yl 4-aminopiperidin-1-carboxylate (0,280 g).

The compound obtained (0.28 g) was dissolved in dimethylformamide (10 ml) and to the mixture was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.28 g), 1-hydroxybenzotriazole (0.16 g), TEA (0.54 ml) and 6-phenylhexanoic acid (0.18 g), followed by stirring at room temperature for 15 hours. To the reaction solution were added water and continued the stirring for 1 hour. Then to the mixture was added a solution of sodium bicarbonate, followed by extraction using EtOAc. The organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: EtOAc) to give a colorless powder. The mixture was recrystallized from methanol and diethyl ether to obtain (pyridin-3-yl) 4-[(6-phenylhexanoic)amino]piperidine-1-carboxylate (108 mg).

Example 198:

10% PAL is ADI on carbon (catalytic amount) was added to a solution in THF (75 ml)/2-propanol (75 ml), containing 3-pyridyl 4-[3-(benzyloxy)phenoxy]-1-piperidinecarboxylate (4.0 g), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure and the obtained solid is washed with EtOAc/hexane and dried under reduced pressure to obtain 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).

Example 199:

10% Palladium on carbon (catalytic amount) was added to a solution in THF (75 ml)/2-propanol (75 ml)containing 3-pyridyl 4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure and the obtained solid is washed with EtOAc/hexane and dried under reduced pressure to obtain 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).

Example 199:

10% Palladium on carbon (catalytic amount) was added to a solution in THF (75 ml)/2-propanol (75 ml)containing 3-pyridyl 4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal Yes is the Department within 24 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure and the obtained solid is washed with EtOAc/hexane and dried under reduced pressure to obtain 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (2.4 g).

Example 200:

Diethylazodicarboxylate (0.35 ml, 40% Tol solution) was added dropwise to a solution in THF (5 ml)containing 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), cyclohexylmethanol (87 mg) and triphenylphosphine (200 mg)at 0°C, followed by stirring at room temperature for 24 hours. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:1 (vol./vol.)). The resulting oil was dissolved in EtOAc (5 ml), was added a solution of 4 M hydrogen chloride/EtOAc (1 ml) followed by stirring at room temperature. The solvent is evaporated under reduced pressure and the precipitated solid is washed with EtOAc/2-propanol and dried under reduced pressure to obtain 3-pyridyl hydrochloride 4-[3-(cyclohexylmethoxy)phenoxy]-1-piperidinecarboxylate (94 mg).

In the same manner as in Example 200 was obtained compounds of Examples 201 d is 205.

Example 206:

Diethylazodicarboxylate (0.35 ml, 40% Tol solution) was added dropwise to a solution in THF (5 ml)containing 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), 3-chlorbenzoyl alcohol (110 mg) and triphenylphosphine (200 mg)at 0°C, followed by stirring at room temperature for 24 hours. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:t=1:3 (vol/vol.)). The resulting oil was dissolved in EtOAc (5 ml) and the solution was added 4 M hydrogen chloride/EtOAc (1 ml) followed by stirring at room temperature. The solvent is evaporated under reduced pressure and the precipitated solid is recrystallized from EtOAc/2-propanol to obtain hydrochloride of 3-pyridyl 4-{4-[(3-Chlorobenzyl)oxy]phenoxy}-1-piperidinecarboxylate (45 mg).

In the same manner as in Example 206, the received connection Examples 207-212.

Example 213:

10% Palladium on carbon (catalytic amount) was added to an ethanol solution (100 ml)containing methyl 5-[({4-[4-(benzyloxy)phenoxy]piperidine-1-yl}carbonyl)oxy]nicotinate, and in the atmosphere of hydrogen gas and the mixture was stirred during the night at room temperature under normal pressure. The catalyst was removed by filtration, the obtained filtrate was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=15:1 (vol./about.)) obtaining a colorless oil (1.08 g).

To a solution in THF (20 ml)containing the compound obtained (450 mg) and 3-cyclohexyl-1-propanol (315 mg)was added 2,2 M diethylazodicarboxylate (1,01 ml) and triphenylphosphine (581 mg) followed by heating at 50°C for 22 hours. To the reaction solution were added water and then was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=2:1 (vol./about.)) to obtain methyl 5-[({4-[4[(3-cyclohexylpropionic)phenoxy]piperidine-1-yl}carbonyl)oxy]nicotinate (242 mg).

In the same way as in Example 213, obtained compounds of Examples 214-216.

Example 217:

10% Palladium on carbon (catalytic amount) was added to a solution in THF (10 ml)containing 5-[({4-[4-(benzyloxy)phenoxy]piperidine-1-yl}carbonyl)oxy]nicotinic acid (200 mg), and in the atmosphere of hydrogen gas and the mixture was stirred at room temperature under normal pressure for 3 hours. The catalyst was removed filters is observed and the obtained filtrate was concentrated under reduced pressure to obtain 5-[({4-[4-(hydroxy)phenoxy]piperidine-1-yl}carbonyl)oxy]nicotinic acid (55 mg).

Example 218:

The compound (4.0 g) of Example 29, in the same way as in Example 2, was dissolved in THF (30 ml) and methanol (15 ml) and to the mixture was added dropwise under ice cooling an aqueous solution of 1 M sodium hydroxide (12 ml). The mixture was stirred at room temperature for 30 minutes and then under ice cooling, the mixture was neutralized with aqueous 1 M hydrochloric acid (12 ml). Colourless precipitated solid substance was collected by filtration to obtain 5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}-nicotinic acid (3,52 g).

In the same way as in Example 218, obtained compounds of Examples 219-224 and Examples 226-243.

Example 225:

Solution in methylene chloride (30 ml)containing methyl 5-hydroxynicotinate (2.20 g) and pyridine (4 ml)was added dropwise to a solution in methylene chloride (50 ml)containing triphosgene (1.56 g), followed by stirring at room temperature for 1 hour. The solvent is evaporated under reduced pressure, the residue was dissolved in pyridine (50 ml) and to the mixture was added the hydrochloride of 4-(2-phenylethyl)piperidine (2.70 g) and then heated overnight at a temperature of 80°C. the Reaction solution was concentrated under reduced pressure, then added EtOAc and an aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent in perivale under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:1 (vol./about.)) obtaining a colorless powder. The mixture was recrystallized from hexane/EtOAc to obtain methyl 5-({[4-(2-phenylethyl)piperidine-1-yl]carbonyl}oxy)nicotinate (3,95 g).

Methyl 5-({[4-(2-phenylethyl)piperidine-1-yl]carbonyl}-oxy)nicotinate (3,95 g) was dissolved in THF (32 ml) and methanol (16 ml) and cooled with ice to the mixture was added dropwise an aqueous solution of 1 M sodium hydroxide (16 ml). The mixture was stirred at room temperature for 30 minutes and under ice cooling, the mixture was neutralized with aqueous 1 M hydrochloric acid (16 ml). Colourless precipitated solid substance was collected by filtration and recrystallized from methanol/water to obtain 5-({[4-(2-phenylethyl)piperidine-1-yl]carbonyl}oxy)nicotinic acid (3,70 g).

Example 244:

The compound of Example 219, 5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}nicotinic acid (0.50 g)was dissolved in DMF (8.0 ml) and to the mixture was added the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0,38 g), 1-hydroxybenzotriazole (0,22 g) and tert-butyl ester of glycine (0.21 g), followed by stirring at room temperature for 15 hours. To the reaction solution was added water, followed by stirring for 1 hours. Then to the mixture was added a solution of sodium bicarbonate, followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over betwedn the m magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:1 (vol./about.)) obtaining a colorless oil (0,444 g).

The compound obtained (0,444 g) was dissolved in methylene chloride (5.0 ml) and cooled with ice was added TFU (1,15 ml). The mixture was stirred at the same temperature for 24 hours and then the reaction liquid was concentrated to obtain a yellow solid. The mixture was recrystallized from ethanol and diethyl ether to obtain {[(5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}pyridine-3-yl)carbonyl]amino}acetic acid (348 mg).

In accordance with the method of amidation as described in Example 244, obtained compounds of Examples 245-257.

Example 258:

Water (4 ml), sodium carbonate (337 mg) and tetranitroaniline palladium (115 mg) were added, in that order, to the solution in dimethoxyethane (12 ml)containing the compound (400 mg) of Example 54 and [3-(aminocarbonyl)phenyl]Bronevoy acid (176 mg), followed by heating at a temperature of 80°C for 5 hours. The reaction solution was cooled and diluted with the aid of EtOAc. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:5 (the b./about.)) to obtain 5-[3-(aminocarbonyl)phenyl]pyridine-3-yl-4-benzylpiperidine-1-carboxylate (205 mg).

In the same way as in Example 258 was obtained compounds of Examples 259, 265, 266 and 399.

Example 260:

A solution of 4 M hydrogen chloride/dioxane (1.8 ml) was added to a solution in THF (10 ml)containing 5-[(tert-butoxycarbonyl)amino]pyridine-3-yl 4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (174 mg), followed by stirring at 60°C for 4 hours. The solvent is evaporated under reduced pressure to obtain hydrochloride of 5-aminopiperidin-3-yl 4-{4-[(3-terbisil)oxy]phenoxy}pyridine-1-carboxylate (74 mg).

Example 261:

To a solution in THF (10 ml)containing 5-[4-(etoxycarbonyl)piperidine-1-yl]pyridine-3-yl oxalate 4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (240 mg) was added an aqueous solution of 1 M sodium hydroxide (3,24 ml) followed by stirring at 60°C for 5 hours. To the reaction solution was added a solution of 1 M hydrochloric acid (3,24 ml) and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol=10:1 (vol./vol.)). The resulting oil was dissolved in ethanol/water, then to the mixture was added oxalic acid (24 mg) for crystallization to obtain the oxalate of 1-(5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}pyridine-3-yl)piperidine-4-carboxylic acid (93 mg).

Example 262:

To a solution of methyl is chloride (10 ml), containing 5-[(2-tert-butoxy-2-oksidoksi)methyl]pyridine-3-yl 4-{4-[(3-(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (333 mg)was added TFU (1.0 ml), followed by stirring overnight at room temperature. The solvent is evaporated under reduced pressure to obtain [(5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}pyridine-3-yl}methoxy]

acetic acid (232 mg).

Example 263:

To a solution in THF (20 ml)containing 5-[(acetoxy)methyl]pyridine-3-yl oxalate 4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (1.10 g) was added an aqueous solution of 1 M sodium hydroxide (7.65 ml) followed by stirring at 65°C for 3 hours. The reaction liquid was neutralized with aqueous 1 M hydrochloric acid followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=12:1 (vol./about.)) obtaining 5-(hydroxymethyl)piperidine-3-yl 4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (770 mg).

Example 264:

To a solution in THF (5 ml)containing 5-[(1E)-3-methoxy-3-oxoprop-1-EN-1-yl]pyridine-3-yl 4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-carboxylate (158 mg)was added an aqueous solution of 1 M sodium hydroxide (1,11 ml) followed by stirring n and 60°C for 3 hours. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=10:1 (vol./about.)) to obtain (2E)-3-(5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}pyridine-3-yl)acrylic acid (88 mg).

Example 267:

(a) Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (723 mg) was added to a solution of hydrochloride of 3-[2-(4-piperidyl)ethyl]benzonitrile(475 mg) and TEA (of 0.58 ml) in acetonitrile 10 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted using EtOAc, then washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, the obtained residue was subjected to column chromatography on basic silica gel (eluent: hexane:EtOAc=1:1 (vol./about.)) and removing by-product - NITROPHENOL. Then the mixture was purified column chromatography on silica gel (eluent: hexane:EtOAc=3:2 (vol./about.)) to obtain methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (284 mg).

(b) To a solution of methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (272 mg) in THF (5 ml)/water (4 ml) was added an aqueous solution of 1 M sodium hydroxide (0,69 ml), followed by stirring overnight at room temperature. To the reaction liquid was added a solution of 1 M chlorite is todarodes acid (0,69 ml) and precipitated crystals were collected by filtration. The crystals were washed with a hot solution of methanol/water and dried to obtain 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (240 mg).

In the same way as in stage (a) of Example 267, obtained compounds of Reference Examples 149-150 and Examples 268-272, 392, 396, 400, 402, 413, 419, 421 and 422.

In accordance with the same method, which contains the phase (b) after stage (a), as in Example 267, obtained compounds of Examples 273-317, 393-395, 401, 403, 405, 406, 414 418.

Example 318:

Hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (62 mg), 1-hydroxybenzotriazole (43 mg), ammonium chloride (43 mg) and TEA (0,038 ml) was added to a solution of 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (102 mg) in DMF (3.0 ml), followed by stirring overnight at room temperature. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution and the precipitated crystals were collected by filtration and dried. The resulting crystalline substance was recrystallized from EtOAc/hexane to obtain 5-(aminocarbonyl)-3-pyridyl 4-[2-(3-cyanophenyl)ethyl]-1-piperidinecarboxylate (81 mg).

In the same way received connection Examples 319-382, 397, 398, 404, 408-412, 415, 420 and 423.

Example 407:

Under ice cooling tert-piperonyl potassium (2,73 g) was added to a solution of hydrochloride triphenyl (pyridine-4-ylmethyl)phosphonylated and 4.75 g) and tert-BU is Il 4-formylpiperidine-1-carboxylate (1,91 g) in DMF (50 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with the aid of EtOAc, washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue was purified column chromatography on silica gel (eluent: hexane:EtOAc=1:2 (vol./about.)) obtaining a white solid (2.05 in).

The obtained solid (2,04 g) was dissolved in EtOAc (30 ml) and to the mixture was added 10% palladium on carbon (200 mg), followed by stirring in the presence of hydrogen at room temperature for 3 hours. The catalyst was removed by filtration, the solvent was concentrated and the residue was purified column chromatography on silica gel (eluent: hexane:ethyl acetate=1:1 (vol./about.)) to obtain tert-butyl 4-[(E)-2-pyridine-4-elwenil]piperidine-1-carboxylate (1.70 g) as a white solid.

A solution of 4M hydrogen chloride/EtOAc (from 0.88 ml) and platinum oxide (100 mg) was added to ethanol (25 ml) solution of tert-butyl 4-[(E)-2-pyridine-4-elwenil]piperidine-1-carboxylate (1,02 g), followed by stirring in the presence of hydrogen (3.5 ATM) for 24 hours. The mixture was purged with argon, diluted with methanol, filtered through celite and concentrated under reduced pressure. The precipitated solid is washed with EtOAc/hexane and dried under reduced pressure to obtain hydrochloride tert-butyl 4-(2-piperidine-4-retil)Pieper is DIN-1-carboxylate (850 mg) as a white solid.

2-(Dicyclohexylphosphino)biphenyl (71 mg) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-palladium (93 mg) was added to the suspension in toluene (10 ml) hydrochloride tert-butyl 4-(2-piperidine-4-retil)piperidine-1-carboxylate (1.13 g), 2-chloro-6-methylpyridine (431 mg) and tert-butoxide sodium (487 mg), followed by stirring at a temperature of 120°C for 1 hour. The reaction liquid was left to cool, then to the mixture was added saturated aqueous solution of sodium carbonate followed by extraction using EtOAc. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is then evaporated and the residue was purified column chromatography on silica gel (eluent: hexane:t=10:1 (vol./about.)) to obtain tert-butyl 4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-carboxylate (660 mg) as a red oil.

To a solution of tert-butyl 4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-carboxylate (650 mg) in EtOAc (10 ml) was added a solution of 4M hydrogen chloride/EtOAc (2 ml) followed by stirring at room temperature for 2 days. The reaction liquid was concentrated to obtain the dihydrochloride of 2-methyl-6-[4-(2-piperidine-4-retil)piperidine-1-yl]pyridine (644 mg) as a yellow amorphous substance.

Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added to a solution in acetone is threal (10 ml) of the dihydrochloride of 2-methyl-6-[4-(2-piperidine-4-retil)piperidine-1-yl]pyridine (520 mg) and TEA (0,50 ml) followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with the aid of EtOAc, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated and the obtained residue was purified column chromatography on silica gel (eluent: chloroform:methanol=98:2 (about./about.)) to obtain methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-yl}carbonyl]oxy}

the nicotinate (424 mg).

To a solution of methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-yl)carbonyl]oxy}

the nicotinate (208 mg) in THF (5 ml) was added an aqueous solution of 1 M sodium hydroxide (0.45 ml), followed by stirring overnight at room temperature. The reaction liquid was concentrated to obtain 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-yl)carbonyl]oxy}

the sodium nicotinate (158 mg).

Hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (103 mg), 1-hydroxybenzotriazole (90 mg) and ammonium chloride (119 mg) was added to a solution in DMF (10 ml) of 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-yl)carbonyl]oxy}

the sodium nicotinate (210 mg), followed by stirring overnight at room temperature.

The reaction liquid was diluted with the aid of EtOAc, washed with saturated aqueous sodium bicarbonate and saturated saline in that order, and the land is over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was recrystallized from EtOAc/hexane to obtain 5-(aminocarbonyl)pyridine-3-yl 4-{2-[1-(6-methylpyridin-2-yl)piperidine-4-yl]ethyl}piperidine-1-carboxylate (150 mg).

Example 438:

Screening to identify compounds having activity of inhibiting FAAH using homogenate of rats brain:

(1) Preparation of brain homogenate of rat brain:

The head of the male 10-week rat lines SD (Japan SLC) were cut off and the brain were removed and weighed. Added ice buffer (50 mm Tris-HCl (pH 7,4), of 0.32 M sucrose) in five times the volume per weight of the animal and the mixture is homogenized using a homogenizer in ice to obtain a homogeneous suspension. The mixture was centrifuged (1500×g, 4°C, 15 minutes) and the supernatant centrifuged (15000×g, 4°C, 20 minutes) to obtain the precipitate. Then, using an ultrasonic generator (UR-20P, Tommy Seiko), and the mixture was treated with ultrasound (power dial 4) within 5 seconds. The protein concentration in the resulting homogenate was measured according to the method of coloring-linking (protein assay CBB solution (Nacalai Tesque). Using buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA, 0.1 mg/ml BSA, 100 mm NaCl), the suspension of rats brain was diluted so that the concentration of protein was 60 μg/ml, obtaining, thus, the enzyme solution is.

(2) Screening to identify compounds having activity of inhibiting FAAH:

Got a substrate solution, containing 2 µci/ml radiochango of anandamide (Anandamide [ethanolamine 1-3H] (American Radiolabelled Chemical)), 8 μm anandamide (Funakoshi), 50 mm Tris-HCl (pH 8.0), 1 mm EDTA, 0.1 mg/ml BSA and 100 mm NaCl. Received solutions ispytyvaesh substances were dissolved in DMSO to obtain a concentration from 1 nm to 100 μm. 50 μl of the substrate solution and 1 μm solution of test substance was added to 50 μl of an enzyme solution and left for 1 hour. As control was used DMSO instead of the solution of the test substance. To the solution was added 200 μl of 1:1 (by volume) solution of chloroform/methanol, and then stirred with a twist. The mixture was centrifuged (15,000 rpm, 2 minutes), resulting in a decomposed product of ethanolamine (ethanolamine 1-3H) was separated in the upper layer (water/methanol layer), and unreacted radiolucency anandamide (Anandamide [ethanolamine 1-3H]) was in the lower layer (chloroform layer). 30 µl of the upper layer was transferred into a 96-well resistant to organic solvents white microplate (PicoPlate-96; Perkin Elmer)was added to 150 μl of Microscint-20 (Perkin Elmer) and the mixture was measured using a scintillation counter for microplates (TopCountTM; Beckman). Compared with the control substance which gives a lower value was chosen as the substance, and generouse activity of FAAH.

(3) Measurement values IR50for a substance that inhibits the activity of FAAH:

The test compound was dissolved in DMSO to produce different concentrations from 1 nm to 100 μm, to obtain solutions of the test substances. In accordance with the foregoing, the compound was analyzed for its effect on the activity of FAAH. As control was used DMSO. The measured value for the case where the buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA, 0.1 mg/ml BSA, 100 mm NaCl) were subjected to interaction instead of an enzyme solution, subtracted from each measured value. On the basis of the measured value of the control, 100%received value IR50for test substances. For example, the value IR50for the compounds of Examples 2, 151, 225, 228, 273, 324, 325 and 359 amounted to 0.14 nm, 27 nm and 0.37 nm, 0,19 nm to 0.65 nm, of 0.54 nm, 2.5 nm and 1.3 nm, respectively.

The above results confirm that, when the substance is in contact with the tissue homogenate, which expresses FAAH or functional FAAH, and when you can measure dependent test substance changes in the activity of FAAH, then it can be skanirovat on the substance, inhibiting FAAH activity, or, in other words, a drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/illegalstate tool for the treatment of pain.

Example 439:

Screening to identify compounds having activity of inhibiting FAAH using cancer cells the human urinary bladder:

(1) Screening to identify compounds having activity of inhibiting FAAH:

Cells 5678 cancer cells human urinary bladder (HTB-9; ATCC) were sown in a 48-hole culture plate in a quantity of 1 × 105cells/well using RPMI1640 medium (Invitrogen)containing 10% fetal bovine serum (HyClone). After incubation at 37°C for at least 12 hours cells were washed with 400 μl/well buffer (balanced salt solution Hank, 20 mm Hepes-NaOH (pH 7,4)). The test substance dissolved in DMSO, was added to the substrate solution (the above buffer containing 3 µci/ml radiochango of anandamide (Anandamide [ethanolamine 1-3H]) and 10 μm anandamide) thus, to obtain the concentration from 0.003 nm to 30 nm. As control was added only DMSO. To the above cells were added 100 μl/well of substrate solution and incubated in CO2incubator at 37°C for 30 minutes. Then the culture plate with cells were transferred to ice and the substrate solution was removed by suction; and 75 (ál/well cytolytic solution (the above buffer containing 0.5% Triton X-100, and added 10 μm of the compounds of latausha activity of inhibiting FAAH, 3'-carbamoylbiphenyl-3-yl of cyclohexylcarbamate (URB597; Cayman chemical; Kathuria et al., Nature Med., Vol. 9, pp. 76-81, 2003)), followed by stirring. The obtained cell lysate from each well separately transferred into 1.5-ml test tube for sample, to which was added 150 μl of a solution of 1:1 (by volume) chloroform/methanol, and then stirred with a twist. The mixture was centrifuged (15,000 rpm, 2 minutes), resulting in a decomposed product, ethanolamine (ethanolamine 1-3H) was separated in the upper layer (water/methanol layer), and unreacted radiolucency anandamide was in the lower layer (chloroform layer). 25 µl of the upper layer was transferred into a 96-well resistant to organic solvents white microplate (PicoPlate-96; Perkin Elmer)was added to 150 μl of Microscint-20 (Perkin Elmer) and the mixture was measured using a scintillation counter for microplates (TopCountTM; Beckman). Compared with the control substance which gives a lower value was chosen as a substance that inhibits the activity of FAAH.

(2) Measurement values IR50for a substance that inhibits the activity of FAAH:

The test compound dissolved in DMSO to obtain a concentration of 10 mm, was dissolved in a solution of the substrate so as to obtain different concentrations from 0.003 nm to 30 μm. In accordance with the foregoing, the compound was analyzed for its effect on the activity of FAAH. As neg is a high control used DMSO. As a positive control for the substrate solution was added URB597 obtaining a concentration of 10 μm. On the basis of the measured values of the positive control, 0%, and the measured values of the negative control, 100%received value IR50for test substances. The test results are presented in Table 64.

The above results confirm the excellent inhibitory activity of typical compounds of the present invention in respect of FAAH. In addition, the data show that when the substance is in contact with a cell which expresses FAAH or functional FAAH, and when you can measure dependent test substance changes in the activity of FAAH, then it can be skanirovat on the substance, inhibiting FAAH activity, or, in other words, a drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for the treatment of pain.

Example 440:

Screening to identify compounds having activity of inhibiting FAAH, using the homogenate of the tissue of the rats, which were administered the test substance:

(1) Introduction the rat and preparation of tissue homogenate:

The test substance suspended in 0.5% solution of methylcellulose (MC), peroral who have introduced two 9-week old male Wistar rats (Japan SLC) at a dose of from 1 to 3 mg/kg As a control, the other two rats were administered 0.5% MC solution. 30 minutes later each rat took the blood under ether anesthesia through the aorta. In this case the head of each rat was cut and removed the brain.

3 ml of the collected blood was diluted in the same amount of water and saline solution was carefully placed in 3 ml hematit-separating agent (Nycoplep; AXIS-SHIELD) in a centrifuge tube. The mixture was centrifuged (400 x g, 20 minutes) to collect the layer of monocytes. The obtained monocytes were washed twice with saline, frozen and kept at -20°C until their use for measurement.

To assembled the brain of rats was added a buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA) in a five-fold amount based on the weight of the animal and the mixture is homogenized using a homogenizer in ice to obtain a homogeneous suspension. Then, using an ultrasonic generator (UR-20P, power dial 4) Tommy Seiko), and the mixture was treated with ultrasound for 5 seconds. To these frozen monocytes were added to 100 ál of ice buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA) and, using an ultrasonic generator (UR-20P, power dial 4) Tommy Seiko), and the mixture was treated with ultrasound for 5 seconds. The concentration of protein in each homogenate brain and monocytes was measured in accordance with the method of colouring-linking (protein assay CBB solution (Nacalai Teque). Using buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA, 0.1 mg/ml BSA, 100 mm NaCl), homogenates of brain and monocytes were diluted so that the concentration of protein was 80 μg/ml and 400 μg/ml, obtaining, thus, enzyme solutions.

(2) Measurement of activity of FAAH:

50 μl of enzyme solution was subjected to interaction with 50 µl of substrate solution (2 µci/ml radiochango of anandamide (Anandamide [ethanolamine 1-3H] (American Radiolabeled Chemical))was added to 8 μm anandamide (Funakoshi), 50 mm Tris-HCl (pH 8.0), 1 mm EDTA) at room temperature for 1 hour. To the mixture was added 200 μl of a solution of 1:1 (by volume) of chloroform and methanol and then stirred with a twist. The mixture was centrifuged (12000 x g, 2 minutes), resulting in a decomposed product of ethanolamine (ethanolamine 1-3H) was separated in the upper layer (water/methanol layer), and unreacted radiolucency anandamide (Anandamide [ethanolamine 1-3H]) was in the lower layer (chloroform layer). 25 µl of the upper layer was transferred into a 96-well resistant to organic solvents white microplate (PicoPlate-96; Perkin Elmer)was added to 150 μl Microscinti-20 (Perkin Elmer) and the mixture was measured using a scintillation counter for microplates (TopCountTM; Beckman).

On the basis of FAAH activity in the control containing no test substance homogenate brain or rat monocytes, 100%, and on the basis of the asset is the spine of FAAH in not containing tissue homogenate buffer (50 mm Tris-HCl (pH 8.0), 1 mm EDTA, 0.1 mg/ml BSA, 100 mm NaCl), 0%, was obtained relative value (%) FAAH activity in tissue homogenate of rats, which were administered the test substance. The substance, which reduced the relative value of FAAH activity, was selected as a substance that inhibits the activity of FAAH.

The above results confirm that, when the test substance is administered test giocomo and when you can measure dependent test substances change FAAH activity in the homogenate of the tissue of the animal, then it can be skanirovat on the substance, inhibiting FAAH activity, or, in other words, a drug for the treatment of frequent urination and urinary incontinence, drug treatment for elevated activity of the bladder and/or the medicinal product for the treatment of pain.

Example 441:

The effect of compounds on cyclophosphamide (CPA)-induced frequent urination in rats:

Compounds were tested for their effect on reducing the irritation of the bladder, using pathological model. It is known that systemic injection of cyclophosphamide (CPA) converts the compound into its metabolite, acrolein, and when it is present in the urine, it damages the mucosa of the bladder. In rats introduction CPA causes pain in the bladder or frequent urination, accompanied by hemorrhagic C the connection, and therefore, using these rats, it is possible to evaluate the activity of the medicinal product in relation to these symptoms. In this experiment used a 9-week-old female Wistar rats (Charles River). Rats were injected intraperitoneally CPA (100 mg/kg) and after 2 days the rats were tested. Rats were administered orally (P.O.) test connection and after 15 minutes oral was administered involuntarily distilled water (30 ml/kg). Rats were placed in a metabolic cage and constantly measured the amount of urine within 1 hour. The total number of urine divided by the total number of urination and, thus, the expected effective capacity of the bladder. As a result, the group has introduced a solvent, 0.5% solution of methylcellulose (MC), the effective bladder capacity decreased, and the rats showed frequent urination. When administered orally effective dose of the compounds of Examples 2, 218, 261 amounted to 3 mg/kg; and the effective dose of the compounds of Examples 225, 228, 273, 313, 324, 325 and 359 was 1 mg/kg of These compounds increased the reduced effective capacity of the bladder and facilitated the condition of frequent urination.

Example 442:

The effect of the compounds against allodynia in rats with legirovannym spinal nerve L5/L6 (model of neuropathic pain):

5-6-week-old male SD rats were subjected to surgery for legirovanie left L5 and L spinal nerves using silk threads. To assess the analgesic effect of the test substances used in the test needle von Frey. In short, the hind leg of the animal pricked with a needle, resulting in minimal power needle, causing OTDELENIE feet, took over the threshold of response (log gram) to mechanical stimulation. In the preliminary test, it was confirmed that the threshold response of the operated legs of the animal were significantly within 7-14 days after surgery (when allodynia), and the effect of the test compound against allodynia assessed on any day between 7 and 14 after surgery. On the day before the test measured the threshold of the response before introduction of the test compounds. The test animals were divided into groups so that the average difference and the deviation threshold value before the introduction of the test compounds in the groups were small. In the evaluation test of the test compounds was measured threshold response after administration of the test compounds. The test compound orally was administered 60 minutes prior to measurement threshold response. On the basis of the threshold response of the operated and unoperated paws in the group, which was injected solvent, 0% and 100%, respectively, expected activity of the test compound for its effect against allodynia. As a result, when orally administered at dose is 10 mg/kg compound of Example 126 this compound showed activity against allodynia 74%.

Table 1
No. of reference exampleThe structural formulaMS m/z
(M+H)+
1192:FAB
2284:FAB
3284:FAB
4222:ESI
5236:ESI
6250:ESI
7221:FAB
8235:FAB
9249:AB
10221:FAB
11235:FAB

Table 2
No. of reference exampleThe structural formulaMS m/z
(M+H)+
12235:FAB
13249:FAB
14221:FAB
15263:FAB
16340:ESI
17213:FAB
18 213:FAB
19291:FAB
20277:FAB
21245:FAB
22192:FAB

263:FAB
Table 3
No. of reference exampleThe structural formulaMS m/z
(M+H)+
23206:FAB
24296:ESI
25220:FAB
26263:FAB
27
28297:FAB
29302:FAB
30314:FAB
31290:FAB
32264:ESI
33268:ESI

td align="justify"> 220:FAB
Table 3
No. of reference exampleThe structural formulaMS m/z
(M+H)+
23206:FAB
24296:ESI
25
26263:FAB
27263:FAB
28297:FAB
29302:FAB
30314:FAB
31290:FAB
32264:ESI
33268:ESI

Table 4
No. of reference exampleThe structural formulaMS m/z
(M+H)+
34/td> 302:FAB
35309:FAB
36304:FAB
37303:FAB
38305:FAB
39298:FAB
40248:ESI
41318:FAB
42318:FAB
43350:FAB
44332:FAB

No. of reference exampleThe structural formulaMS m/z
(M+H)+
45357:FAB
46366:FAB
47338:FAB
48352:FAB
49192:ESI
50235:FAB
51220:ESI
52206:ESI
53232:ESI
54 303:FAB

Table 6
No. of reference exampleThe structural formulaMS m/z
(M+H)+
55233:ESI
56232:ESI
57258:FAB
58233:FAB
59303:FAB
60269:FAB
61318:FAB
62351:ESI
63 318:FAB
64365:FAB
65264:FAB

Table 7
No. of reference exampleThe structural formulaMS m/z
(M+H)+
66264:FAB
67303:FAB
68315:FAB
69317:FAB
70317:FAB
71297:FAB
72 320:FAB
73139:ESI
74181:ESI

Table 8
No. of reference exampleThe structural formulaMS m/z
(M+H)+
75196:ESI
76251:ESI
77140:ESI
78209:ESI
79182:ESI
80240:ESI
81 180:ESI
82186:ESI
83369:ESI
84370:FAB
85383:ESI

Table 9
No. of reference exampleThe structural formulaMS m/z
(M+H)+
86412:FAB
87483:FAB
88384:FAB
89538:ESI
90 567:ESI
91483:ESI
92493:ESI
93522:ESI
94251:ESI

Table 10
No. of reference exampleThe structural formulaMS m/z
(M+H)+or
(M-N)-or (M)+
FAB or
ESI or
EI
95215 (M+H)+
FAB
96268, 270 (M+H)+
FAB
97208 (M+H)+
FAB
98 220 (M+H)+
FAB
99224 (M+H)+
FAB
100215 (M+H)+
FAB
101215 (M+H)+
FAB
102348 (M+H)+
FAB
103348 (M+H)+
ESI
104332 (M-H)-
ESI
105332 (M-H)-
ESI
106333 (M+H)+
ESI

Table 11
No. of reference exampleArticle is alturna formula MS m/z
(M+H)+or
(M-N)-or (M)+
FAB or
ESI or
EI
107375 (M+H)+
ESI
108389 (M+H)+
ESI
109377 (M-H)-
API
110375 (M-H)-
API
111361 (M+H)+
ESI
112387 (M+H)+
FAB
113401 (M+H)+
FAB
114377 (M+H)+
ESI
115389 (M+H)+
ESI
116387 (M+H)+
ESI
117478 (M+H)+
ESI
118479 (M+H)+
FAB

Table 12
No. of reference exampleThe structural formulaMS m/z
(M+H)+or
(M-N)-or (M)+
FAB or
ESI or
EI
119359 (M+H)+
ESI
120233 (M+H)+
FAB
121247 (M+H)+
FAB
122275 (M+H)+
ESI
123 289 (M+H)+
ESI
124315 (M+H)+
FAB
125279 (M+H)+
ESI
126277 (M+H)+
ESI
127261 (M+H)+
FAB
128287 (M+H)+
ESI
129301 (M+H)+
ESI
130303 (M+H)+
ESI

Table 13
No. of reference exampleThe structural formulaMS m/z
(M+H)+or
(M-N)-or (M)+
FAB or
ESI or
EI
131378 (M+H)+
ESI
132379 (M+H)+
ESI
133233 (M+H)+
ESI
134260 (M)+
ESI
135288 (M+H)+
ESI
136259 (M+H)+
ESI
137286 (M+H)+
ESI
138378 (M+H)+
ESI
139379 (M+H)+
ESI
140266 (M+H)+
FAB
141291 (M+H)+
FAB
142267 (M+H)+
FAB
143302 (M+H)+
FAB

Table 14
No. of reference exampleThe structural formulaMS m/z
(M+H)+or
(M-N)-or (M)+
FAB or
ESI or
EI
144338 (M+H)+
ESI
145338 (M+H)+
FAB
146339 (M+H)+
ESI
147341 (M+Na)+
ESI
148 261 (M+H)+
ESI
149466 (M+H)+
FAB
150480 (M+H)+
ESI
151438 (M+H)+
ESI
152427 (M+H)+
ESI
153481 (M+H)+
FAB

Table 15
No. of reference exampleThe structural formulaMS m/z
(M+H)+or
(M-N)-or (M)+
FAB or
ESI or
EI
154338 (M+H)+
ESI
155186 (M+H)+
ESI

Table 16# exampleTR1R2R4Sol001CHHHHoxalate002CH4-(3-FPhCH2O)PhOHHfree003CH4-(3-FPhCH2O)PhCOHHfree004N4-(3-FPhCH2O)PhCOHHoxalate005N4-cHexCH2OPhCOHHfree 006N4-cHex(CH2)2OPhCOHHfree007N4-cHepCH2OPhCOHHfree008N4-PhCH2OPhCOHHfree009CH4-cHexCH2OPhOHHfree010CHPhCH2HHoxalate011CH3-PhCH2OPhOHHfree012CH4-PhCH2OPhOH Hfree013CH4-(3-FPhCH2O)PhOH6'-MeHCl014CHPhCOHHfree015CH4-FPhHHfree016CHPhCONHHHfree017NPh(CH2)2HHfree018CHHHHCl019CH HHfree020CHHHHCl021CHPhOHHHCl023NPhHHfree024CH4-H2NCOPhOHHfree

4-H2NCOCH2PhO
Table 17
# exampleTR1R2R4Sol
025CHHHfree
026CH4-H2NCO(CH2)2PhOHHfree
027CH3-H2NCOPhOHHoxalate
028CH3-H2NCOCH2PhOHHoxalate
029CH4-(3-FPhCH2O)PhOH5'-COOMefree
030CH4-(3-FPhCH2O)PhOH5'-NMe2HCl
031CH4-cHexCH2N(Me)PhOHH033NPh(CH2)5HH2HCl
034N4-PhCH2OPhHHfree
035CHPh(CH2)2HHHCl
036CHPhCH2OHHHCl
037CPh4-HOHHCl
039CPh4-AcHfree
040CHPhHHHCl/td>
041CH4-H2NCOPhOCH2HHfree
042CH4-(3-FPhCH2O)PhOH5'-Clfree
043CH4-H2NCOPhO(CH2)2HHfree
044CH4-(3-FPhCH2O)PhOH5'-Brfree
045CH4-(3-FPhCH2O)PhOH5'-Mo4HCl
046CH4-H2NCOPhCH2OHHfree
047CHPhCH 2NHCOHHfree
048N3-PhCH2OPhHH2HCl
049NPh(CH2)4HHfree
050NtBuOCOHHfree
051CH2-Cl-4-PhCH2OPhOHHHCl
052CHPhCH2H6'-MeHCl
053CHPhCH2O(CH2)2HHHCl
054PhCH2H5'-Brfree
055CHPhCH2H6'-CH2OMefree
056CH4-(3-FPhCH2O)PhOH5'-N(Me)(CH2)2NMe22HCl
057CH2-H2NCOPhOHHoxalate
058N4-(3-FPhCH2O)PhSO2HHfree
059CHPh2(HO)CHHHCl
060CH3-HOPhHH061CH4-(3-FPhCH2O)PhOH5'-(CH2)2COOMefree
062NPh(CH2)2OCOHHfree
063CH4-H2NCOPh(CH2)2HHfree
064CHPhCH2NHCOCH2HHHCl

td align="center"> Ph(CH2)2
Table 18
# exampleTR1R2R4Sol
066CH 1-MeBenzIM2(CH2)3HHfree
067CPh4-NCHHCl
068CH2-oxoBenzIM 1HHfree
069CH4-H2NCOPhO(CH2)3HHfree
070CH3-Cl-4-PhCH2OPhOHHoxalate
071CH4-[3-FPhSO2N(Me)]PhOHHHCl
072NPhCH2OCO3-H2NCOHHCl
073CH4-(3-FPhCH2O)PhOH5'-(4-EtOCOPIPE1)-oxalate
074CPhCH24-HOHHCl
075N4-BuNHCOCH2OPhCOHHp-tol.
076CH4-(3-FPhCH2O)PhSHHp-tol.
077CH3-EtOCOCH2OPhHHoxalate
078CH3-PhCH2OPhHHoxalate
079CH4-PhCH2OCOPhO(CH2)2H Hfree
080CH4-(3-FPhCH2O)PhSO2HHfree
081CHPhCH2OCH2HHoxalate
082CH4-PhCH2OPhOH5'-COOMefree
083CH3-(3-H2NCOPh)PhOHHHCl
084NPh(CH2)23-oxoHfree
085NPh(CH2)2H5'-Clfree
086NH5'-COOMefree
087CH6-ClPy3OHHfree
088CH4-PhCH2OPhSO2HHfree
089CH4-(3-NCPhCH2O)PhSO2HHfree
090CH4-cHexCH2OPhSO2HHfree
091CH4-cHex(CH2)2OPhSO2HHfree
092CH6-ClPy2OHH HCl
093CH6-(3-FPhCH2O)Py2OHHoxalate
094CH6-(3-H2NCOPh)Py2OHHfree
095CH4-(3-ClPhCH2O)PhSO2HHfree
096N4-H2NCOPhCH2OCOHHfree
097CH4-(3-FPhCH2O)PhOH5'-Mefree
098CH4-Me2NCOPhO(CH2)3HHp-tol.
099CH 4-MeNHCOPhO(CH2)3HHfree
100CH4-(3-FPhCH2O)PhOH5'-CH2OAcoxalate
101CH3-(3-FPhCH2O)PhSHHp-tol.

119
Table 19
# exampleTR1R2R4Sol
102CH6-[cHex(CH2)2O]Py2OHHoxalate
103CH5-(3-FPhCH2O)Py2OHHoxa is at
105CH3-(3-FPhCH2O)PhSO2HHfree
106CH4-NCPhO(CH2)3H5'-COOMefree
107CHH3-PhOCH2Hp-tol.
108CH4-NCPhO(CH2)3HHfree
109CHHOHHfree
110CHPhOCH2HHfree
111CHPhO(CH2)2 HHp-tol.
112CHPh(CH2)3O(CH2)2HHoxalate
113CH3-Ph(CH2)3OPhHHoxalate
114CHPhO(CH2)3HHfree
115CH2-H2NCOPhO(CH2)3HHfree
116CH3-H2NCOPhO(CH2)3HHp-tol.
118CH4-(3-FPhCH2O)PhOH5'-FHCl
N4-cOctCH2OPhCOHHfree
120N4-[3-FPhCH2N(Me)]PhCOHHfree
121N4-cHexCH2N(Me)PhCOHHfree
122N3-cHexCH2OPhCOHHHCl
123N3-cHexCH2N(Me)PhCOHHHBr
124NPh(CH2)2COHHp-tol.
125NPhCOHH free
127NPhOCH2COHHp-tol.
128NPhCH2COHHp-tol.
129NPhNHCH2COHHfree
130NPh(CH2)3COHHp-tol.
132NPhCONHCH2COHHoxalate
133NPhN(Me)CH2COHHOxalate
134N4-HepOPhCOH Hp-tol.
135N4-(3-NCPhCH2O)PhCO2-MeHHCl
136N4-(3-NCPhCH2O)PhCO3-MeHfree
137N6-(3-ClPhCH2O)Py3COHHoxalate
138N3-(3-ClPhCH2O)PhCOHHHCl
139N4-H2NCOPhOCH2COHHfree
140N2-H2NCOPhOCH2COHHfree
141NHHfree
142NPhSO2HHfree

Table 20
# exampleTR1R2R4Sol
143NPhCH2SO2HHfree
144NPhCH2O-COHHp-tol.
145NPy3O-COHHfree
46 NPhCH2NHCOHHfree
147N4-(3-ClPhCH2O)PhCOHHfree
148N4-(3-MePhCH2O)PhCOHHoxalate
149N4-(3-F3CPhCH2O)PhCOHHfree
150N4-(3-MeOPhCH2O)PhCOHHoxalate
151N4-(3-NCPhCH2O)PhCOHHfree
152N4-(3,5-diFPhCH2O)PhCOH Hfree
153N4-(3-F3COPhCH2O)PhCOHHfree
154N4-(3-O2NPhCH2O)PhCOHHfree
155N4-(4-FPhCH2O)PhCOHHfree
156N4-(2-FPhCH2O)PhCOHHfree
157N4-Py2CH2OPhCOHHfree
158N4-(1-MeAzep3O)PhCOHHfree
159N 4-(3-BrPhCH2O)PhCOHHfree
160N4-[3-ClPh(CH2)2O]PhCOHHfree
161N4-(4-NCPhCH2O)PhCOHHfree
162N4-(3-IPhCH2O)PhCOHHfree
163N4-(3-Me2NPhCH2O)PhCOHHfree
164N2-Cl-4-(3-NCPhCH2O)PhCOHHfree
165N3-Cl-4-(3-NCPhCH2O)PhCOHH free
166N4-(3-NCPhCH2O)-3-MeO-PhCOHHHCl
167N4-(3-MeOCOPhCH2O)PhCOHHfree
168CHcHexCH2NHCOHHfree
169CHMeOCO(CH2)3HHoxalate
170CHH2NCO(CH2)3HHoxalate
171CHPhCH2N(Me)COHHfree
172CHPy3CH2 HHfree
173CHPhNHCOHHfree
174CHPh(CH2)2NHCOHHfree
175CHPh(CH2)4NHCOHHfree
176CH4-OctPhNHCOHHfree
177CH4-H2NCOPhNHCO(CH2)3HHfree
178CH3-H2NCOPhNHCO(CH2)3HHfree
179CH3-H2NCOCH2OPhHHHCl

190
Table 21
# exampleTR1R2R4Sol
180CH3-(4-H2NCOPIPE1COCH2O)PhHHHCl
181CH2-H2NCOPhNHCO(CH2)3HHFUM.
182CH4-BuPhNHCOHHfree
183CH4-BuOPhNHCOH Hfree
184CH4-HexOPh(CH2)2NHCOHHfree
185CH4-Ph(CH2)4OPh(CH2)2NHCOHHfree
186CH4-cPen(CH2)3OPh(CH2)2NHCOHHfree
187CH4-HexPhNHCOHHfree
188CH4-[4-MeOCOPh(CH2)2]PhNHCOHHfree
189CH4-HO(CH2)2PhNHCOHHfree
CH4-PhCH2OPhNHCOHHfree
191CH2-H2NCO(CH2)2PhNHCOHHfree
192CH4-Phenyl-1,3-Thiaz2NHCOHHfree
193NPhCH2OCO3-COOHHfree
194CH4-HOOCPhO(CH2)2HHfree
195CH3-HOOCCH2OPhHHfree
196CH1-MeBenzIM2H Hfree
197CHPh(CH2)5CONHHHfree
198CH3-HOPhOHHfree
199CH4-HOPhOHHfree
200CH3-cHexCH2OPhOHHHCl
201CH3-cHex(CH2)2OPhOHHHCl
202CH3-(3-FPhCH2O)PhOHHHCl
203CH3-(2-FPhCH2O)PhO HHHCl
204CH3-(4-FPhCH2O)PhOHHHCl
205CH3-(3-NCPhCH2O)PhOHHoxalate
206CH4-(3-ClPhCH2O)PhOHHHCl
207CH4-cHex(CH2)2OPhOHHHCl
208CH4-(2-FPhCH2O)PhOHHHCl
209CH4-(4-FPhCH2O)PhOHHHCl
210CH4-(-NCPhCH 2O)PhOHHoxalate
211CH4-(3-MeOCOPhCH2O)PhOHHfree
212CH4-(3-H2NCOPhCH2O)PhOHHfree
213CH4-cHex(CH2)3OPhOH5'-COOMefree

Table 22
# exampleTR1R2R4Sol
214CH4-PIPE1(CH2)2OPhOH5'-COOMeHC
215CH4-(3-NCPhCH2O)PhOH5'-COOMeoxalate
216CH4-cHexCH2OPhOH5'-COOMefree
217CH4-HOPhOH5'-COOHfree
218CH4-(3-FPhCH2O)PhOH5'-COOHfree
219CHPhCH2H5'-COOHfree
220CHPhH5'-COOHfree
221CH4-PhCH2OPhOH 5'-COOHfree
223CHPhCOH5'-COOHfree
224CHPhCH2OH5'-COOHfree
225CHPh(CH2)2H5'-COOHfree
226CH4-PIPERI1(CH2)2OPhOH5'-COOHfree
227CH4-NCPhO(CH2)3H5'-COOHfree
228CH4-cHex(CH2)2OPhOH5'-COOHfree
CH4-cHex(CH2)3OPhOH5'-COOHfree
230CH4-(3-NCPhCH2O)PhOH5'-COOHfree
231NPh(CH2)2H5'-COOH2HCl
232CHPhCH2OCH2H5'-COOHfree
233CH4-(3-MeOPhCH2O)PhOH5'-COOHfree
234CH3-(3-FPhCH2O)PhOH5'-COOHfree
235CH3-(3-NCPhCH2O)PhO H5'-COOHfree
236CH4-(3-MeOCOPhCH2O)PhOH5'-COOHfree
237CH4-cHexCH2OPhOH5'-COOHfree
238CHPh(CH2)3H5'-COOHfree
239CHPhO(CH2)3H5'-COOHfree
240CHPhO(CH2)2H5'-COOHfree
241CH4-H2NCOPh(CH2)2H5'-COOHfree
242CH3-cHex(CH2)2OPhOH5'-COOHfree
243NPh(CH2)3H5'-COONafree
244CH4-(3-FPhCH2O)PhOH5'-CONHCH2COOHfree
245CH4-(3-FPhCH2O)PhOH5'-CONH2free
246CH4-PhCH2OPhOH5'-CONH2free
247CHPhCH2H5'-CONHCH2CONH2HCl
248CH/td> PhCH2H5'-(4-H2NCOPIPERI1CO)-HCl

Table 23
# exampleTR1R2R4Sol
249CH4-(3-FPhCH2O)PhOH5'-CONHCH2CONH2HCl
250CH4-(3-FPhCH2O)PhOH5'-Mo4(CH2)2NHCO-oxalate
251CH4-(3-FPhCH2O)PhOH5'-CONH(CH2)2OMeoxalate
252CH4-(3-FPhCH2O)PhO H5'-(4-H2NCOPIPE1CO)-free
253CH4-(3-FPhCH2O)PhOH5'-CONH(CH2)2CONH2HCl
254CH4-(3-FPhCH2O)PhOH5'-PIPE1(CH2)2NHCO-2HCl
255CH4-(3-FPhCH2O)PhOH5'-CONH(CH2)2OHHCl
256CH4-(3-FPhCH2O)PhOH5'-(4-HOPh(CH2)2NHCO)-free
257CH4-(3-FPhCH2O)PhOH5'-(4-MePIPERA1CO)-oxalate
258CHPhCH2H 5'-(3-H2NCOPh)-free
259CHPhCH2H5'-Py3free
260CH4-(3-FPhCH2O)PhOH5'-NH2HCl
261CH4-(3-FPhCH2O)PhOH5'-(4-HOOCPIPE1)-oxalate
262CH4-(3-FPhCH2O)PhOH5'-CH2OCH2COOHfree
263CH4-(3-FPhCH2O)PhOH5'-CH2OHfree

Table 24
# exampleThe structural formulaSol
022free
0322HCl
038free
065free
104FUM.
117free
126p-tol.
131p-tol.
222free
264free

Table 25
# exampleTR1R4Sol
265CHPh(CH2)25'-(4-MeOCOPh)-free
266CHPh(CH2)25'-(3-H2NCOPh)-free
267CH3-NCPh(CH2)25'-COOHfree
268CHHfree
269CHHfree
270CHPh(CH2)25'-B free
271CHcHex(CH2)2Hfree
272CHcHex(CH2)25'-COOMefree
273CH5'-COOHfree
274CH3-ClPh(CH2)25'-COOHfree
275CH4-NCPh(CH2)25'-COOHfree
276CH3-MeOPh(CH2)25'-COOHfree
277CH3-FPh(CH2)25'-COOHfree
278CH2-NCPh(CH2)25'-COOHfree
279CH3-H2NCOPh(CH2)25'-COOHfree
280CH3-Me2NCOPh(CH2)25'-COOHfree
281CHBIP4(CH2)25'-COOHNa
282CH4-FPh(CH2)25'-COOHfree
283CH2-ClPh(CH2)25'-COOHfree
284CH4-ClPh(CH2)25'-COOHfree
285CH 4-BrPh(CH2)25'-COOHfree

Table 26
# exampleTR1R4Sol
286CH4-MeOPh(CH2)25'-COOHfree
287CHPh(CH2)45'-COOHfree
288CH2-FPh(CH2)25'-COOHfree
289CHcHex(CH2)25'-COOHfree
290CH4-Py2Ph(CH2)25'-COOH free
291CHPh(CH2)2free
292CH3-BrPh(CH2)25'-COOHfree
293CHBIP3(CH2)25'-COOHfree
294CH3'-NCBIP3(CH2)25'-COOHfree
295CHPy4Ph(CH2)25'-COOHfree
296CHPy3Ph(CH2)25'-COOHfree
297CHPy2(CH2)25'-COOHfree
298CH3-Py2Ph(CH2)25'-COOHNa
299CH4'-FBIP4(CH2)25'-COOHfree
300CH4'-MeOBIP4(CH2)25'-COOHfree
301CH4'-NCBIP4(CH2)25'-COOHfree
302CH3'-FBIP4(CH2)25'-COOHfree
303CH3'-MeOBIP4(CH2)25'-COOHfree
304CH2'-FBIP4(CH2)25'-COOHfree
305CH 3-cHexNHCOPh(CH2)25'-COOHNa
306CH3-PIPE1COPh(CH2)25'-COOHNa
307CH3-Mo4COPh(CH2)25'-COOHNa
308CH4-PIPE1COPh(CH2)25'-COOHNa
309CH4-Mo4COPh(CH2)25'-COOHNa
310CH3-PYRR1COPh(CH2)25'-COOHNa
311CH3-(4-Py2PIPERA1CO)Ph(CH2)25'-COOHfree

td align="center"> CH
Table 27
# exampleTR1R4Sol
312CH4-Et2NCOPh(CH2)25'-COOHfree
313CH1-(6-MePy2)PIPE4(CH2)35'-COOHNa
314CH1-ISOQUI1PIPE4(CH2)35'-COOHNa
315CH1-QUI2PIPE4(CH2)35'-COOHNa
316CH4-ISOQUI1PIPERA1(CH2)35'-COOHNa
317CH1-NAPH1PIPE4(CH2)35'-COOHNa
318CH 3-NCPh(CH2)25'-CONH2free
319CHPh(CH2)25'-CONH(CH2)2OHoxalate
320CHPh(CH2)25'-CONH2free
321CH3-MeOPh(CH2)25'-CONH2free
322CH3-FPh(CH2)25'-CONH2free
323CH2-NCPh(CH2)25'-CONH2free
324CH3-H2NCOPh(CH2)25'-CONH2free
325CH 3-Me2NCOPh(CH2)25'-CONH2free
326CHcHex(CH2)25'-CONH2free
327CH3-ClPh(CH2)25'-CONH(CH2)2OHoxalate
328CH3-MeOPh(CH2)25'-CONH(CH2)2OHoxalate
329CH3-FPh(CH2)25'-CONH(CH2)2OHoxalate
330CH3-NCPh(CH2)25'-CONH(CH2)2OHoxalate
331CH2-NCPh(CH2)25'-CONH(CH2)2OHoxalate
332Ph(CH2)25'-CONH(CH2)2SO3HHCl
333CHPh(CH2)25'-CONH(CH2)2CONH2free
334CH2-FPh(CH2)25'-CONH2free
335CHPh(CH2)2free
336CHPy4(CH2)25'-CONH2free

td align="center"> CHtr>
Table 28
# exampleTR1R4Sol
337 CHPy3(CH2)25'-CONH2free
338CH4'-FBIP4(CH2)25'-CONH2free
339CH4'-MeOBIP4(CH2)25'-CONH2free
340CHBIP3(CH2)25'-CONH2free
341CH3'-NCBIP3(CH2)25'-CONH2free
342CHPh(CH2)25'-CONH(CH2)3OHoxalate
343CHPh(CH2)25'-CONH(CH2)3NMe2oxalate
3444'-NCBIP4(CH2)25'-CONH2free
345CH3'-FBIP4(CH2)25'-CONH2free
346CH2'-FBIP4(CH2)25'-CONH2free
347CHPh(CH2)25'-CONH(CH2)2Py4oxalate
348CHPh(CH2)25'-CONH(CH2)2Py3oxalate
349CH3-Py2Ph(CH2)25'-CONH2free
350CH2-Me2NCOPh(CH2)25'-CONH2free
31 CH3-cHexNHCOPh(CH2)25'-CONH2free
352CH3-MeNHCOPh(CH2)25'-CONH2free
353CH4-H2NCOPh(CH2)25'-CONH2free
354CH4-Me2NCOPh(CH2)25'-CONH2free
355CH3-PIPE1COPh(CH2)25'-CONH2free
356CH3-Mo4COPh(CH2)25'-CONH2free
357CH4-PIPE1COPh(CH2)25'-CONH2free
358CH4-Mo4COPh(CH2)25'-CONH2free
359CH3-PYRR1COPh(CH2)25'-CONH2free
360CH3-Et2NCOPh(CH2)25'-CONH2free
361CH5'-CONH2free

Table 29
# exampleTR1R4Sol
362CH4-Et2NCOPh(CH2)25'-CONH2free the
363CH4-PYRR1COPh(CH2)25'-CONH2free
364CH5'-CONH2free
365CH3-(4-Py2PIPERA1CO) Ph(CH2)25'-CONH2free
366CH3-(4-PhPIPERA1CO) Ph(CH2)25'-CONH2free
367CH4-(4-Py2PIPERA1CO) Ph(CH2)25'-CONH2free
368CH4-(4-PhPIPERA1CO) Ph(CH2)25'-CONH2free
369CH3-FCH2CH2NHCOPh(CH2)2 5'-CONH2HCl
370CH3-HO(CH2)2NHCOPh(CH2)25'-CONH2free
371CH3-tBuNHCOPh(CH2)25'-CONH2free
372CH3-iPrNHCOPh(CH2)25'-CONH2free
373CH4-(2,2-DIFPYRR1CO)Ph(CH2)25'-CONH2free
374CH3-H2NCONHPh(CH2)25'-CONH2free
375CH3-PYRR1CONHPh(CH2)25'-CONH2free
376CH3-(2,2-DIFPYRR1COPh(CH 2)25'-CONH2free
377CH3-(4-NAPH1PIPERA1CO)Ph(CH2)25'-CONH2free
378CH1-(6-MePy2)PIPE4(CH2)35'-CONH2free
379CH1-ISOQUI1PIPE4(CH2)35'-CONH2free
380CH1-QUI2PIPE4(CH2)35'-CONH2free
381CH4-ISOQUI1PIPERA1(CH2)35'-CONH2free
382CH1-NAPH1PIPE4(CH2)35'-CONH2free

Table 30
# exampleR1R4Sol
3833-HepOPhNHCOHfree
3844-HepOPhNHCOHfree
385Py2NHCO(CH2)3H2HCl
3864-OctPhNHCO(CH2)3Hoxalate
387Ph(CH2)4NHCO(CH2)3Hoxalate
3884-HexPhNHCOCONH2free
3894-(3-FPhCH2O)PhOOAcoxalate
3904-(3-FPhCH2O)hO OHfree
3914-(3-FPhCH2O)PhOCNfree
3924-cHex(CH2)4OPhOHfree
393CO2Hfree
394CO2Hfree
3954-cPen(CH2)2OPhOCO2Hfree
3964-(3-FPhCH2O)PhOCH2Hfree

Table 31
# exampleR1R4 Sol
397CONH2free
398CONH2free
399Ph(CH2)2free
4004-(3-FPhCH2O)PhCH2HHCl
4014-(3-FPhCH2O)PhCH2CO2Hfree
402Ph(CH2)2OHfree
403CO2Hfree
404CONH2free
4054-NAPH1PIPERA1(CH2)3CO2HNa
4061-(6-MePy2)PIPE4(CH2)2CO2HNa
4071-(6-MePy2)PIPE4(CH2)2CONH2free
4084-NAPH1PIPERA1(CH2)3CONH2free

Table 32
# exampleR1R4Sol
409Ph(CH2)3CONH2free
410PhCONH2free
411Ph(CH2)5 CONH(CH2)2OH2HCl
412Ph(CH2)5CONH2free
4134-(3-FPhCH2O)PhCH2H2HCl
414BIP4(CH2)2CO2HNa
415BIP4(CH2)2CONH2free

Table 33
# exampleThe structural formulaSol
416p-tol.
417free
418free
419 p-tol.
420oxalate
421free
422HCl
423free

Table 34
# exampleTR1Sol
424CHPh(CH2)2free
425NPh(CH2)2free
426CHPh(CH2)3free the NYY
427CH4-H2NCOPh(CH2)2free
428CH3-cHex(CH2)2OPhOfree
429NPh(CH2)3free
430CH4-cHex(CH2)2OPhOfree
431CH4-(3-MeOPhCH2O)PhOfree
432CH4-(3-MeOCOPhO)PhOfree
433CH3-PYRR1COPh(CH2)2free
434CH3-PIPE1COPh(CH2)2free
435CH free
436CH3-H2NCONHPh(CH2)2free
437CH3-PIPE1CONHPh(CH2)2free

Table 35
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
001207(M+H)+FAB
0021,59-of 1.74 (2H, usher.), 1,90-2,05 (2H, usher.), 3,33 is-3.45 (1H, usher.), 3,45-3,55 (1H, usher.), the 3.65-with 3.79 (1H, usher.), 3,84-of 3.94 (1H, usher.), 4,45-4,55 (1H, m), 5,07 (2H, s), 6,97 (4H, s), to 7.15 (1H, dt,J=the 2.4 and 8.1 Hz), 7.24 to 7,30 (2H, m), 7,40-7,47 (2H, m), of 7.64-7,66 (1H, m), to 8.41-to 8.45 (2H, m), DMSO: 423(M+H)+FAB
0031,40-1,70 (2H, m), of 1.85 (2H, d,J=a 12.7 Hz), 3,10 (1H, t,J=12,7 Hz) of 3.25 (1H, t,J=and 12.2 Hz), 3,65 of 3.75 (1H, m)4,06 (1H, d,J=and 12.2 Hz), 4,23 (1H, d,J=a 12.7 Hz), of 5.26 (2H, s), 7,14-7,22 (3H, m), 7,29-7,34 (2H, m), 7,42-to 7.50 (2H, m), of 7.64-to 7.67 (1H, m), 8,03 (2H, d,J=9,3 Hz), 8,44-to 8.45 (2H, m), DMSO: 435(M+H)+FAB
004436(M+H)+FAB
005 424(M+H)+FAB
006438(M+H)+FAB
007438(M+H)+FAB
008418(M+H)+FAB
009411(M+H)+FAB
0101,10-1,30 (2H, usher.), of 1.64 (2H, d,J=a 12.7 Hz), 1,71-to 1.82 (1H, m), of 2.56 (2H, d,J=7,4 Hz), and 2.83 (1H, t,J=11.8 Hz), 2,99 (1H, t,J=11.8 Hz), 4,00 (1H, d,J=11.8 Hz), 4,15 (1H, d,J=11.8 Hz), 7,16-of 7.23 (3H, m), 7,26-to 7.32 (2H, m), 7,44 (1H, DD,J=4,4, 8,3 Hz), to 7.59-to 7.64 (1H, m), 8,40 (1H, d,J=2.0 Hz), 8,43 (1H, d,J=4.4 Hz), DMSO: 297(M+H)+FAB
0111,59 is 1.75 (2H, usher.), 1,90 e 2.06 (2H, usher.), 3,33-of 3.43 (1H, usher.), 3,45-3,55 (1H, usher.), the 3.65-with 3.79 (1H, usher.), 3,83-of 3.94 (1H, usher.), 4,60-4,69 (1H, m), 5,09 (2H, s), 6,57 of 6.66 (3H, m), 7,19 (1H, t,J=8,3 Hz), 7,30-7,47 (6H, m), 7,62-7,66 (1H, m), to 8.41-to 8.45 (2H, m), DMSO: 405(M+H)+FAB
0121,59-of 1.74 (2H, usher.), 1,90-2,05 (2H, usher.), 3,33-of 3.43 (1H, usher.), 3,45-3,55 (1H, usher.), the 3.65-with 3.79 (1H, usher.), 3,84-of 3.94 (1H, usher.), 4,47-4,55 (1H, m), 5,04 (2H, s), to 6.95 (4H, s), 7,30-7,46 (6H, m), to 7.61-7,66 (1H, m), to 8.41-to 8.45 (2H, m), DMSO: 405(M+H)+FAB
0131,59 to 1.76 (2H, usher.), 1,90-2,05 (2H, usher.), 2,69 (3H, s), 3.33 and is-3.45 (1H, usher.), 3,45-of 3.60 (1H, usher.), the 3.65-with 3.79 (1H, usher.), 3,84-of 3.94 (1H, usher.), 4,48-of 4.57 (1H, m), 5,07 (2H, s), 6,97 (4H, s), 7,15 1H, dt,J=2,4, and 8.3 Hz), 7.24 to 7,30 (2H, m), 7,40-7,47 (2H, m), 7,81 (1H, d,J=8,7 Hz), 8,19 (1H, DD,J=2,5, and 8.3 Hz), a total of 8.74 (1H, d,J=2,4 Hz), DMSO: 437(M+H)+FAB
0141,50-1,70 (2H, usher.), 1,89 (2H, d,J=a 12.7 Hz), 3,11 (1H, t,J=11.7 Hz), with 3.27 (1H, t,J=11.7 Hz in), 3.75 (1H, TT,J=3,2, 11.3 Hz), 4,07 (1H, d,J=11.7 Hz), 4,23 (1H, d,J=11.7 Hz), was 7.45 (1H, DD,J=5,4, 8,3 Hz), EUR 7.57 (2H, t,J=7,8 Hz), 7,63-of 7.69 (2H, m), 8,03 (2H, DD,J=1,4, 8,3 Hz), 8,44 (2H, DD,J=1,4, a 4.9 Hz), DMSO: 311(M+H)+FAB

Table 36
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MS m/z
0151,55-1,75 (2H, usher.), to 1.83 (2H, d, J=and 12.2 Hz), of 2.81 (1H, TT, J=3,4, and 12.2 Hz), 4,15 (1H, d, J=and 12.2 Hz), or 4.31 (1H, d, J=and 12.2 Hz), 7,10-7,17 (2H, m), 7,31-7,37 (2H, m), 7,44-of 7.48 (1H, m), 7,63-to 7.67 (1H, m), 8,43-8,46 (2H, m), DMSO: 301(M+H)+FAB
016326(M+H)+FAB
0172,46-2,62 (6H, m), 2,72 is 2.80 (2H, m), 3,40-3,50 (2H, usher.), 3,57-the 3.65 (2H, usher.), 7,16-to 7.32 (5H, m), 7,45 (1H, DD, J=4,6, 8,3), 7,61-7,65 (1H, m), 8,42-to 8.45 (2H, m), DMSO: 312(M+H)+FAB
0181,60-1,75 (2H, usher.), 1,95-2,10 (2H, usher.), 3,33-to 3.41 (1H, usher.), 3,47 of 3.56 (1H, usher.), 3,69-of 3.78 (1H, usher.), 3,84-a 4.03 (1H, usher.), 5,96 (2H, s), 6,46 1H, DD,J=2,4, and 8.7 Hz), 6.73 x (1H, d,J=2,4 Hz), PC 6.82 (1H, d,J=8,7 Hz), 7,74 for 7.78 (1H, m), of 8.04 (1H, d,J=8,3 Hz), to 8.62 (1H, d,J=4,9 Hz), 8,72 (1H, s), DMSO: 343(M+H)+FAB
0191,20-1,40 (2H, usher.), 1,79-1,89 (2H, usher.), 1,94-2,04 (1H, m)to 2.94 (1H, t,J=11.8 Hz), of 3.07 (1H, t,J=11.8 Hz), 3,80 (2H, d,J=6.3 Hz), of 4.05 (1H, d,J=11.8 Hz), 4,22 (1H, d,J=11.8 Hz), 5,95 (2H, s), 6,37 (1H, DD,J=2,5, and 8.3 Hz), only 6.64 (1H, d,J=2,5 Hz), to 6.80 (1H, d,J=8,3 Hz), was 7.45 (1H, DD,J=4,9, 8,3 Hz)7,630 (1H, d,J=8,3 Hz), 8,40-to 8.45 (2H, m), DMSO: 357(M+H)+FAB
0201,16-1,32 (2H, usher.), 1,64-to 1.82 (3H, m), 2,92 (1H, t,J=11.7 Hz), 3,06 (1H, t,J=11.7 Hz), of 3.96 (2H, t,J=6,4 Hz)to 4.01 (1H, d,J=11.7 Hz), 4,17 (1H, d,J=11.7 Hz), 5,95 (2H, s), 6,37 (1H, DD,J=2,5, and 8.3 Hz), 6,63 (1H, d,J=2,5 Hz), to 6.80 (1H, d,J=8,3 Hz), 7,74 - 7,80 (1H, m), 8,02-8,07 (1H, m), 8,61 (1H, d,J=5.4 Hz), 8,71 (1H, users), DMSO: 371(M+H)+FAB
0211,63 and 1.80 (2H, usher.), 1,97 of 1.99 (2H, usher.), 3,35 is-3.45 (1H, usher.), 3,50-3,60 (1H, usher.), 3,71-with 3.79 (1H, usher.), 3,86-of 3.95 (1H, usher.), 4,63-4,70 (1H, m)6,94 (1H, t,J=7,3 Hz), 7,01 (2H, d,J=8,3 Hz), 7,30 (2H, t,J=7,3 Hz), 7,76 (1H, DD,J=4,8, 8,3 Hz), with 8.05 (1H, d,J=8,3 Hz), to 8.62 (1H, d,J=4,8 Hz), 8,73 (1H, s), DMSO: 299(M+H)+FAB
0222,85 are 2.98 (2H, m), 3,68 (1H, t,J=4,9 Hz), a-3.84 (1H, t,J=5.8 Hz), to 4.62 (1H, s), 4,82 (1H, s), 7,20-7,28 (4H, m), 7,46 (1H, DD,J=4,4, 8,3 Hz), 7,65-of 7.69 (1H, m), 8,44-of 8.47 (2H, m), DMSO: 255(M+H)+/sup> FAB
0233,20-3,24 (4H, usher.), 3,55-the 3.65 (2H, usher.), 3,72-of 3.80 (2H, usher.), 6,83 (1H, t, J=7,1), of 7.00 (2H, d, J=8,3), 7,25 (2H, t, J=7,3), 7,46 (1H, DD, J=4,4, 8,3), 7,63-7,69 (1H, m), 8,43-8,46 (2H, m), DMSO: 284(M+H)+FAB
0241,61 and 1.80 (2H, m), 1,97-2,12 (2H, m), 3,28-3,62 (2H, m), 3,68-3,99 (2H, m), 4,71-4,80 (1H, m), 7,05 (2H, d,J=8,8 Hz), 7,12-7,22 (1H, m), 7,45 (1H, DD,J=4,9 Hz and 8.3 Hz), to 7.61-to 7.68 (1H, m), 7,78-7,88 (3H, m), to 8.41-8,46 (2H, m), DMSO: 342(M+H)+FAB
025356(M+H)+FAB
026370(M+H)+FAB
027342(M+H)+FAB

Table 37
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
028356(M+H)+FAB
029481(M+H)+FAB
0301,60-of 1.78 (2H, m), 1.93 and e 2.06 (2H, m), 3.04 from (6H, s), 3,30-3,93 (4H, m), 4,49-4,56 (1H, m), 5,07 (2H, s), of 6.96 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,52 (2H, m), 8,05-8,08 (2H, m), DMSO: 466(M+H)+FAB
031 424(M+H)+FAB
0322,04-of 2.20 (1H, m), 2,40-2,60 (1H, m), 3,10-4,10 (8H, m), 4,32-of 4.44 (2H, m), 7,41-to 7.50 (3H, m), 7,66-of 7.82 (2H, m), 8,05-8,16 (1H, m), to 8.62 (1H, usher.), 8,80 (1H, d, J=a 12.7 Hz), 11,58 (1H, usher.), DMSO: 312(M+H)+FAB
0331,25-1,35 (2H, m), 1,55-of 1.66 (2H, m), 1.70 to to 1.83 (2H, m)2,60 (2H, t,J=7,3 Hz), 3.00 and-up 3.22 (4H, m), 3,40-3,70 (4H, m), 4,00 is 4.35 (2H, m), 7,15-7,33 (5H, m), a 7.62 (1H, usher.), the 7.85 (1H, usher.), 8,50-8,65 (2H, m), 10,90-11,40 (1H, usher.), DMSO: 354(M+H)+FAB
034to 3.09 (4H, usher.), 3,50-of 3.80 (4H, m), 5,04 (2H, s)6,94 (4H, d,J=1.7 Hz), 7,30-7,49 (6H, m), 7,63-to 7.68 (1H, m), 8,43-8,46 (2H, m), DMSO: 390(M+H)+FAB
0351,10-1,32 (2H, m), 1,46 is 1.60 (3H, m)1,80 (2H, d,J=11.7 Hz), 2,62 (2H, t,J=7,8 Hz), is 2.88 (1H, t,J=and 12.2 Hz), 3,03 (1H, t,J=and 12.2 Hz), 4,17 (1H, t,J=and 12.2 Hz), 7,16-of 7.23 (3H, m), 7,27-7,31 (2H, m), 7,89 (1H, DD,J=5,3, 8,8 Hz), 8,18 is 8.22 (1H, m), 8,69 (1H, DD,J=1,0, a 5.3 Hz), 8,82 (1H, d,J=2,5 Hz), DMSO: 311(M+H)+FAB
0361,52 by 1.68 (2H, usher.), 1,88 is 2.01 (2H, usher.), 3,22-to 3.33 (1H, usher.), 3,37-of 3.48 (1H, usher.), 3,65 of 3.75 (2H, m), 3,82-3,91 (1H, usher.), 4,56 (2H, s), 7,26-to 7.32 (1H, m), of 7.36 (4H, d,J=4.4 Hz), of 7.70 (1H, DD,J=4,9, 8,3 Hz), 7,95 (1H, DD,J=1,0, 8,3 Hz), 8,58 (1H, d,J=4,9 Hz), 8,66 (1H, s), DMSO: 313(M+H)+FAB
0371,69 (2H, d,J=a 12.7 Hz), 1,91-2,11 (2H, m)to 3.33 (1H, t,J=a 12.7 Hz), 3,47 (1H, t,J=12,GC), 3,93-4,07 (2H, m), 4,13 (1H, d,J=a 12.7 Hz), 7.23 percent (1H, t,J=7,4 Hz), 7,35 (2H, t,J=7,4 Hz), 7,52-of 7.55 (2H, m), 7,81 (1H, DD,J=5,4, 8,3 Hz), 8,10-to 8.14 (1H, m), 8,63 (1H, d,J=4,9 Hz), 8,77 (1H, d,J=2,4 Hz), DMSO: 299(M+H)+FAB
038of 2.58 (1H, usher.), of 2.64 (1H, usher.), to 3.67 (1H, usher.), a 3.83 (1H, usher.), of 4.13 (1H, s), 4,32 (1H, s), 6,21 (1H, s), 7,29 (1H, t,J=7,3 Hz), 7,37 (2H, t,J=7,3 Hz), 7,44 is 7.50 (3H, m), to 7.67 (1H, d,J=8,3 Hz), 8,44-of 8.47 (2H, m), DMSO: 281(M+H)+FAB
039of 1.95 (3H, s), 2.00 in of 2.16 (2H, usher.), 2,39-2,47 (2H, usher.), 3,20-3,30 (1H, usher.), 3,35 is-3.45 (1H, usher.), 3,63-to 3.73 (1H, usher.), 3,79-to 3.89 (1H, usher.), 7,29-7,34 (1H, m), 7,37-7,46 (5H, m), 7,60-to 7.64 (1H, m), 8,40-8,43 (2H, m), DMSO: 325(M+H)+FAB

Table 38
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
0401,61-of 1.81 (2H, m)and 1.83 (2H, d, J=and 12.2 Hz), 2.77-to 2,87 (1H, m), 3,05 (1H, t, J=and 12.2 Hz), 3,19 (1H, t, J=and 12.2 Hz), 4,16 (1H, d, J=12,2 Hz)to 4.33 (1H, d, J=and 12.2 Hz), 7,19-7,24 (1H, m), 7,27 and 7.36 (5H, m), to $ 7.91 (1H, DD, J=5,3, 8,3 Hz), was 7.36 (1H, d, J=8,3 Hz), to 8.70 (1H, d, J=4.9 Hz), cent to 8.85 (1H, s), DMSO: 283(M+H)+FAB
04135(M+H)+FAB
0421,60 to 1.76 (2H, m), 1,92-of 2.05 (2H, m), 3,30-to 3.92 (4H, m), 4,48-4,55 1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.23 percent-7,30 (2H, m), 7,39-of 7.48 (1H, m), 7,93-of 7.96 (1H, m), 8,44 (1H, d, J=2.0 Hz), charged 8.52 (1H, d, J=2.0 Hz), DMSO: 457(M+H)+FAB
043to 1.14 and 1.35 (2H, m), 1,68-of 1.84 (5H, m), 2,89 (1H, t, J=11.7 Hz), 3,05 (1H, t, J=11.7 Hz), 3.96 points-is 4.21 (4H, m), 6,98 (2H, d, J=8,8 Hz), 7,16 (1H, users), 7,44 (1H, DD, J=4,9, 8,3 Hz), 7,60-the 7.65 (1H, m), 7,76-7,87 (3H, m), 8,40-8,44 (2H, m), DMSO: 370(M+H)+FAB
0441,60-1,75 (2H, m), 1,92-of 2.05 (2H, m), 3,30-to 3.92 (4H, m), 4,46-4,55 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,29 (2H, m), 7,40-7,47 (1H, m), 8,06-8,086 (1H, m), of 8.47 (1H, d, J=2.0 Hz), 8,59 (1H, d, J=2.0 Hz), DMSO: 501(M+)FAB
0451,60-of 1.78 (2H, m), 1.93 and e 2.06 (2H, m), 3,31 is 3.57 (6H, m), 3,70-3,93 (6H, m), 4,49-4,56 (1H, m), 5,07 (2H, s), of 6.96 (4H, s), 7,12-7,17 (1H, m), 7.24 to 7,30 (2H, m), 7,41-7,47 (1H, m), 7,78 (1H, s), 8,19 is 8.22 (1H, m,), 8,30-of 8.33 (1H, m), DMSO: 508(M+H)+FAB
0461,51 is 1.70 (2H, m), 1,87-2,02 (2H, m), 3,20-of 3.31 (1H, m), 3,36-3,47 (1H, m), 3,62-and 3.72 (1H, m), 3,66-of 3.77 (1H, m), 3,80-3,93 (1H, m), br4.61 (2H, s), 7,33 (1H, user. C), 7,42 (2H, d, J=8,3 Hz), 7,44 (1H, DD, J=8,3, 4,4 Hz), 7,63 (1H, DDD, J=8,3, 2,4, 1.5 Hz), 7,86 (2H, d, J=8,3 Hz), 7,94 (1H, user. C)8,42 (1H, s), 8,43 (1H, DD, J=6,3, 1.5 Hz), DMSO: 356(M+H)+FAB
047340 (M+H)+FAB
048390(M+H)+FAB
0491,40-of 1.52 (2H, m), 1,55-1,65 (2H, m), 2,30 at 2.45 (4H, m)2,60 (2H, t, J=7,6 Hz), 3,38-of 3.64 (4H, m), 7,12-7,22 (3H, m), 7,25-7,31 (2H, m), 7,44 (1H, DD, J=4,8, 7.5 Hz), 7,60-the 7.65 (1H, m), 8,40-to 8.45 (2H, m), DMSO: 340(M+H)+FAB
050308(M+H)+FAB
0511,60-of 1.84 (2H, usher.), 1,92 e 2.06 (2H, usher.), 3,40-to 3.52 (1H, usher.), 3,55 of 3.75 (2H, usher.), 3,79-3,91 (1H, usher.), 4,59 with 4.65 (1H, m), to 5.08 (2H, s), 6,97 (1H, DD, J=2,9, and 9.3 Hz), to 7.15 (1H, d, J=2,9 Hz), 7,22 (1H, d, J=8,8 Hz), 7,31-7,47 (5H, m), 7,88 (1H, DD, J=5,4, 8,8 Hz), to 8.20 (1H, d, J=8,3 Hz), 8,68 (1H, d, J=5.4 Hz), 8,83 (1H, d, J=1.9 Hz), DMSO: 439(M+H)+FAB

Table 39
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
052311(M+H)+FAB
0531,07-of 1.27 (2H, m)of 1.53 (2H, square, J=6.4 Hz), 1,62 to 1.76 (3H, m), 2,90 (1H, t, J=13,2 Hz), 3.04 from (1H, t, J=13,2 Hz), 3,50 (2H, t, J=6.4 Hz), 3,99 (1H, d, J=13,2 Hz), 4,15 (1H, d, J=13,2 Hz), to 4.46 (2H, s), 7,26-7,39 (5H, m), 7,73 for 7.78 (1H, m), 8,03 (1H, d, J=8,3 Hz), to 8.62 (1H, d, J=4.4 Hz), to 8.70 (1H, s), DMSO: 341(M+H)+FAB
054374, 376(M+H)+FAB
0551,10-1,30 (2H, m), 1,64 (2H, d, J=13,2 Hz), 1,71 of-1.83 (1H, m), of 2.56 (2H, d, J=7,4 Hz), and 2.83 (1H, t, J=and 12.2 Hz), 2,98 (1H, t, J=12,2 Hz)to 3.36 (3H, s)to 3.99 (1H, d, J=and 12.2 Hz), 15 (1H, d, J=12,2 Hz)and 4.65 (2H, s), 7,17-7,22 (3H, m), 7,27-to 7.32 (2H, m), the 7.43 (1H, d, J=8,8 Hz), 7,60 (1H, DD, J=2.5 a, 8,8 Hz), with 8.33 (1H, d, J=2.5 Hz), DMSO: 341(M+H)+FAB
056523(M+H)+FAB
057342(M+H)+FAB
058471(M+H)+FAB
059389(M+H)+FAB
060299(M+H)+FAB
0611,58 is 1.75 (2H, m), 1,90-2,04 (2H, m), 2,69 (2H, t, J=7.8 Hz), 2,89 (2H, t, J=7.8 Hz), 3,30-3,91 (7H, m), 4,47-4,55 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.23 percent-7,30 (2H, m), 7,39-7,47 (1H, m), 7,51-of 7.55 (1H, m),8,24-of 8.27 (1H, m), 8,30-to 8.34 (1H, m), DMSO: 509(M+H)+FAB
062356(M+H)+FAB
063of 1.07 to 1.31 (2H, m), 1,42-of 1.55 (1H, m), 1,52-of 1.64 (2H, m), 1,72 is 1.86 (2H, m), 2,68 (2H, t, J=7.5 Hz), 2,78-only 2.91 (1H, m), 2,94-of 3.07 (1H, m), 3,93-4,07 (1H, m), 4.09 to to 4.23 (1H, m), 7,26 (1H, user. C), 7,29 (2H, d, J=8.6 Hz), 7,44 (1H, DD, J=8,6, 4,8 Hz), to 7.61 (1H, DDD, J=8,6, 2.7, and 1.5 Hz), 7,80 (2H, d, J=8.0 Hz), 7,89 (1H, user. C)to 8.41 (1H, d, J=2.7 Hz), 8,42 (1H, DD, J=4,8, 1.1 Hz), DMSO: 354(M+H)+FAB
064354(M+H)+FAB
0651,34-of 1.57 (2H, m), of 1.78-1.90 (2H, m), 2.40 a-2,48 (1H, m), 2,92-is 3.08 (1H, m), 3,07 is 3.23 (1H, m), 3,98-4,13 1H, m), 4,14-to 4.28 (1H, m), 6,44 (1H, DD, J=16,1, 5,9 Hz), 6,50 (1H, d, J=16.1 Hz), 7,30 (1H, user. C)was 7.45 (1H, DD, J=8,3, 4,4 Hz), of 7.48 (2H, d, J=8,3 Hz), 7,63 (1H, DDD, J=8,3, of 2.5, 1.5 Hz), 7,83 (2H, d, J=8,3 Hz), 7,92 (1H, user. C)8,43 (1H, d, J=1.9 Hz), 8,43 (1H, DD, J=4,4, 1.9 Hz), DMSO: 352(M+H)+FAB
0661,03 is 1.23 (2H, m), 1,35 was 1.43 (2H, m), 1,46-of 1.62 (1H, m), 1,72-to 1.87 (4H, m), 2,82 of 2.92 (3H, m), 3,03 (1H, t, J=11.8 Hz), 3,74 (3H, s)to 4.01 (1H, d, J=11.8 Hz), 4,17 (1H, d, J=11.8 Hz), 7,11-7,21 (2H, m), 7,42-7,49 (2H, m), 7,52-7,56 (1H, m), to 7.59-7,63 (1H, m), 8,40-8,44 (2H, m), DMSO: 379(M+H)+ESI

Table 40
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
067308(M+H)+FAB
068339(M+H)+FAB
0691,04-of 1.26 (2H, m), 1,35-1,45 (2H, m), 1,48-to 1.61 (1H, m), 1.70 to to 1.83 (4H, m), 2,80-to 2.94 (1H, m), 2,94-3,10 (1H, m), 3.96 points-4,06 (1H, m), a 4.03 (2H, t, J=6.4 Hz), 4,12-4,22 (1H, m), of 6.96 (2H, d, J=8,8 Hz), to 7.15 (1H, user. C), 7,44 (1H, DD, J=8,3, a 4.9 Hz), to 7.61 (1H, DDD, J=8,3, to 2.9, 1.5 Hz), 7,81 (1H, user. C), 7,83 (2H, d, J=8,8 Hz), to 8.41 (1H, d, J=2.4 Hz), 8,42 (1H, DD, J=4,9, 1,4 Hz), DMSO: 384(M+H)+FAB
0701,57 is 1.75 (2H, usher.), 1,90 e 2.06 (2H, usher.), 3,30-of 3.42 (1H, usher.), 3,45 of 3.56 (1H, usher.), the 3.65-of 3.78 (1H, usher.), ,80-3,95 (1H, user.), 4,55 - br4.61 (1H, m), 5,14 (2H, s), to 6.95 (1H, DD, J=2,9, and 9.3 Hz), 7,14-to 7.18 (2H, m), 7,31-of 7.48 (6H, m), 7,62-to 7.67 (1H, m), 8,42-to 8.45 (2H, m), DMSO: 439(M+H)+FAB
071486(M+H)+FAB
072385(M+H)+FAB
073578(M+H)+FAB
074313(M+H)+FAB
075441(M+H)+FAB
076439(M+H)+FAB
077to 1.21 (3H, t, J=7.4 Hz), 1,58-of 1.78 (2H, m)and 1.83 (2H, d, J=a 12.7 Hz), 2,77 (1H, TT, J=3,8, and 12.2 Hz), 2,98 (1H, t, J=and 12.2 Hz), 3,14 (1H, t, J=and 12.2 Hz), 4,10-is 4.21 (3H, m), or 4.31 (1H, d, J=and 12.2 Hz), was 4.76 (2H, s), 6,76 (1H, DD, J=2.0 a, 7,4 Hz), 6.87 in (1H, t, J=2.0 Hz), 6.90 to (1H, d, J=7.4 Hz), 7.23 percent (1H, t, J=7.8 Hz), 7,46 (1H, DD, J=4,9, 8,3 Hz), of 7.64-to 7.67 (1H, m), 8,42-of 8.47 (2H, usher.), DMSO: 385(M+H)+FAB
0781,58-of 1.78 (2H, m)and 1.83 (2H, d, J=and 12.2 Hz), 2,77 (1H, TT, J=3,4, and 12.2 Hz), 2,98 (1H, t, J=and 12.2 Hz), 3,14 (1H, t, J=and 12.2 Hz), 4,15 (1H, d, J=and 12.2 Hz), or 4.31 (1H, d, J=and 12.2 Hz), 5,10 (2H, s), 6,84-of 6.90 (2H, m), 6,95 (1H, t, J=2.0 Hz), 7.23 percent (1H, t, J=7.8 Hz), 7,31-of 7.48 (6H, m), of 7.64-to 7.67 (1H, m), 8,42-of 8.47 (2H, m), DMSO: 389(M+H)+FAB
079461(M+H)+FAB
0801,40-of 1.66 (2H, m), 1,88 is 2.00 (2H, m),2,82-of 2.97 (1H, m), 2,97-3,14 (1H, m), 3,47 is 3.57 (1H, m), 4,01-4,17 (1H, m), 4,18-to 4.33 (1H, m), of 5.26 (2H, s), 7,16-of 7.23 (1H, m), 7,30 (2H, d, J=9.0 Hz), 7,30 and 7.36 (2H, m), 7,41-7,46 (1H, m), 7,45-7,51 (1H, m), a 7.62 (1H, DDD, J=8,3, 2.7, and 1.5 Hz), 7,81 (2H, d, J=8,8 Hz), 8,40 (1H, d, J=2.4 Hz), 8,42 (1H, DD, J=4,7, 1.5 Hz), DMSO: 471(M+H)+FAB
081of 1.10 to 1.34 (2H, m) 1,70-1,80 (2H, m), 1,80-of 1.92 (1H, m), 2,80-2,95 (1H, m), 2.95 and-3,10 (1H, m), 2,70-of 3.95 (1H, user. C)to 3.34 (2H, d, J=6.4 Hz), 3.95 to 4,07 (1H, m), 4,11-to 4.23 (1H, m), 4,48 (2H, s), 7,25-7,38 (7H, m), 7,44 (1H, DD, J=8,3, 4.6 Hz), a 7.62 (1H, DDD, J=8,3, 2,6 1.2 Hz), DMSO: 327(M+H)+FAB
082462(M+)FAB
083418(M+H)+FAB

Table 41
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MS m/z
084326(M+H)+FAB
0852,49-2,62 (6H, m), 2,73-of 2.81 (2H, m), 3,40-3,66 (4H, m), 7,15-to 7.32 (5H, m), to 7.93 (1H, t, J=1.9 Hz), 8,44 (1H, d, J=2.4 Hz), charged 8.52 (1H, d, J=2.0 Hz), DMSO: 346(M+H)+FAB
0862,49-2,62 (6H, m), 2,73-of 2.81 (2H, m), of 3.46 (2H, usher.), 3,62 (2H, usher.), are 3.90 (3H, s), 7,15-to 7.32 (5H, m), 8,11 (1H, DD, J=2.0, the 2.7 GHz), to 8.70 (1H, d, J=2,8 Hz), to 8.94 (1H, d, J=1.7 Hz), DMSO: 370(M+H)+FAB
087 1,63 and 1.80 (2H, usher.), 1,97-2,11 (2H, usher.), 3,33-to 3.41 (1H, usher.), 3,43-to 3.58 (1H, usher.), 3,68-3,82 (1H, usher.), 3,83-of 3.96 (1H, usher.), 4,72 - 4,80 (1H, m), 7,43-of 7.48 (2H, m), to 7.59 (1H, DD, J=3.2, and an 8.8 Hz), 7,62-to 7.67 (1H, m), 8,19 (1H, d, J=2.2 Hz), 8,43-to 8.45 (2H, m), DMSO: 334(M+H)+FAB
0881,39-of 1.65 (2H, m), 1,88-to 1.98 (2H, m), 2,83-3,13 (2H, m), 3.46 in-3,55 (1H, m), a 4.03-to 4.33 (2H, m), 5,23 (2H, s), 7,29 (2H, d, J=8,8 Hz), 7,33-7,51 (6H, m), a 7.62 (1H, DDD, J=1,5, 2,9, 8,3 Hz), 7,80 (2H, d, J=8,8 Hz), to 8.40 (1H, d, J=2.4 Hz), 8,42 (1H, DD, J=1,5, a 4.9 Hz), DMSO: 453(M+H)+FAB
0891,40-of 1.65 (2H, m), 1,88 of 1.99 (2H, m), 2,83-3,14 (2H, m), 3,47 is 3.57 (1H, m), a 4.03-4,34 (2H, m), and 5.30 (2H, s), 7,31 (2H, d, J=8,8 Hz), 7,44 (1H, DD, J=4,9, 8,3 Hz), to 7.59-to 7.68 (2H, m), 7,79-7,87 (4H, m), of 7.96-7,98 (1H, m), 8,40 (1H, d, J=2.4 Hz), 8,42 (1H, DD, J=1,5, a 4.9 Hz), DMSO: 478(M+H)+FAB
090469(M+H)+FAB
091473(M+H)+FAB
092334(M+H)+FAB
093424(M+H)+FAB
094419(M+H)+FAB
095487(M+H)+FAB
096385(M+H)+FAB
097437(M+H)+FAB
0981,06-of 1.26 (2H, m), 1,37-of 1.44 (2H, m), 1,50-1,60 (1H, m), 1,73-to 1.82 (4H, m), 2,86 (1H, t, J=12,2 Hz)to 2.94 (6H, s), 3,05 (1H, t, J=and 12.2 Hz), 3,97-Android 4.04 (3H, m), 4,18 (1H, d, J=11.7 Hz), of 6.96 (2H, d, J=8,8 Hz), of 7.36 (2H, d, J=8,8 Hz), 7,73 (1H, DD, J=4,8, 8,3 Hz), of 7.96 shed 8.01 (1H, m), 8,59 (1H, DD, J=1.5 and 4.8 Hz), 8,67 (1H, d, J=2.4 Hz), DMSO: 412(M+H)+FAB
0991,02-1,22 (2H, m), 1,36-of 1.44 (2H, m), 1,49-to 1.61 (1H, m), 1,72-to 1.82 (4H, m)of 2.75 (3H, d, J=4.4 Hz), 2,87 (1H, t, J=and 12.2 Hz), to 3.02 (1H, t, J=and 12.2 Hz), 3,98-of 4.05 (3H, m), 4,17 (1H, d, J=and 12.2 Hz), 6,97 (2H, d, J=8,8 Hz), the 7.43 (1H, DD, J=4,4, 8,3 Hz), to 7.59-to 7.64 (1H, m), 7,78 (2H, d, J=8,3 Hz), by 8.22-of 8.27 (1H, m), scored 8.38-8,43 (2H, m), DMSO: 398(M+H)+FAB

Table 42
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
1001,58-of 1.74 (2H, m), 1,90 e 2.06 (2H, m)of 2.50 (3H, s), 3,30-of 3.95 (4H, m), 4,48-4,58 (3H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), 7,54-EUR 7.57 (1H, m), 8,27-to 8.34 (1H, m,), 8.34 per-8,42 (1H, m), DMSO: 495(M+H)+FAB
1011,40-of 1.64 (2H, m), 1,90-2,03 (2H, m), 3,05-3,18 (1H, m), 3,20-to 3.34 (1H, m), 3,51-3,62 (1H, m), 3,88-4,01 (1H, m), as 4.02-to 4.14 (1H, m), 5,16 (2H, s), 6.90 to-6,95 (1H, m), 6,98-7,03 (1H, m), 7.03 is-7,06 (1H, m), 7,13-7,19 (1H, m), 7,25-to 7.32 (3H, m), 7,41-7,47 (1H, m), 7,72 (1H, DD, J=8,8, 5,4 Hz), to 7.99 (1H, DDD, J=8,3, 2,4, 1.0 Hz), 8,56-8,61 (1H, m), 8,67 (1H, d, J=2.4 Hz), DMSO: 439(M+H)+ FAB
102426(M+H)+FAB
1031,58-of 1.78 (2H, usher.), 1,97-2,11 (2H, usher.), 3,30-of 3.60 (2H, usher.), 3,70-with 3.79 (1H, usher.), 3,85-of 3.96 (1H, usher.), 5,11-5,16 (3H, m), 6,79 (1H, d, J=8,8 Hz), 7,12-7,20 (1H, m), 7,25-7,30 (2H, m), 7,40-to 7.50 (3H, m), to 7.61-to 7.67 (1H, m), to 7.93 (1H, d, J=3.5 Hz), 8,40-8,46 (2H, usher.), DMSO: 424(M+H)+FAB
1041,16-1,32 (2H, m) 1,70-to 1.82 (2H, m), 1,79 is 1.91 (1H, m), 2,82-2,99 (1H, m), 2.95 and-of 3.12 (1H, m)to 3.34 (2H, d, J=6.3 Hz), 3,98-4,07 (1H, m), 4,11 (2H, DD, J=5,8, and 1.4 Hz), 4,14-to 4.23 (1H, m), 6,36 (1H, DDD, J=16,1, 5,8, 5.8 Hz), is 6.61 (1H, d, J=16.1 Hz), 6,63 (1H, s), 7,21-7,29 (1H, m), 7,30-7,38 (2H, m), 7,40-7,49 (3H, m), to 7.61 (1H, DDD, J=8,3, 2,4, and 1.4 Hz), of 8.37-8,64 (2H, m), 13,12 (1H, user. C), DMSO: 353(M+H)+FAB
105471(M+H)+FAB
106424(M+H)+FAB
107313(M+H)+FAB
1081,04-1,24 (2H, usher.), 1,36 was 1.43 (2H, m), 1,48-to 1.61 (1H, m), 1,72-to 1.82 (4H, m), 2,87 (1H, t, J=11.7 Hz), 3,03 (1H, t, J=11.7 Hz), 4,01 (1H, d, J=11.7 Hz), 4,07 (2H, t, J=6.4 Hz), 4,17 (1H, d, J=11.7 Hz), 7,10 (2H, d, J=8,8 Hz), 7,44 (1H, DD, J=5,4, 8,3 Hz), to 7.59-7,63 (1H, m), 7,76 (2H, d, J=8,8 Hz), 8,40-8,44 (2H, m), DMSO: 366(M+H)+FAB
109223(M+H)+FAB
1101,23 was 1.43 (2H, m)to 1.86 (2H, the, J=a 12.7 Hz), 1,97-of 2.09 (1H, m), with 2.93 (1H, t, J=12,2 Hz)to 3.09 (1H, t, J=and 12.2 Hz), 3,88 (2H, d, J=a 12.7 Hz), 4,07 (1H, d, J=12,2 Hz)to 4.23 (1H, d, J=and 12.2 Hz), 6.90 to-of 6.96 (3H, m), 7,26-7,31 (2H, m), 7,44 (1H, DD, J=4,4, 8,3 Hz), to 7.61-the 7.65 (1H, m), to 8.41-8,44 (2H, m), DMSO: 313(M+H)+FAB
1111,16-of 1.36 (2H, m), 1,67-of 1.85 (5H, m), with 2.93 (1H, t, J=and 12.2 Hz), is 3.08 (1H, t, J=and 12.2 Hz), 4,00 (1H, d, J=and 12.2 Hz), a 4.03 (2H, t, J=6.3 Hz), 4,17 (1H, d, J=and 12.2 Hz), 6.90 to-of 6.96 (3H, m), 7,26-7,31 (2H, m), 7,78 (1H, DD, J=4,9, 8,3 Hz), 8,03-8,08 (1H, m), to 8.62 (1H, DD, J=1,0, a 4.9 Hz), 8,72 (1H, d, J=2.5 Hz), DMSO: 327(M+H)+FAB

Table 43
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
1121,05-1,25 (2H, m), 1,47-of 1.52 (2H, m), 1,58 by 1.68 (1H, m), 1.70 to of 1.84 (4H, m), 2,62 (2H, t, J=7.4 Hz), 2,87 (2H, t, J=and 12.2 Hz), 3,03 (1H, t, J=and 12.2 Hz), 4,00 (1H, d, J=and 12.2 Hz), 4,15 (1H, d, J=and 12.2 Hz), 7,15-7,22 (3H, m), 7,25-7,30 (2H, m), 7,45 (1H, DD, J=4,9, 8,3 Hz), to 7.59-to 7.64 (1H, m), scored 8.38-8,44 (2H, m), DMSO: 369(M+H)+FAB
113of 1.65 and 1.75 (2H, m)and 1.83 (2H, d, J=and 12.2 Hz), 1,98-of 2.05 (2H, m), 2,72 is 2.80 (3H, m), 2,98 (1H, t, J=and 12.2 Hz), 3,14 (1H, t, J=and 12.2 Hz), of 3.97 (2H, t, J=6.3 Hz), 4,15 (1H, d, J=11.7 Hz), or 4.31 (1H, d, J=11.7 Hz), 6.75 in-6,79 (1H, m), 6,83-6,87 (2H, m), 7,16-to 7.32 (6H, m), 7,46 (1H, DD, J=4,9, 8,8 Hz), of 7.64-7.68 per (1H, m), 8,42-of 8.47 (2H, usher.), DMSO: 417(M+H)+FAB
1141,10-of 1.26 (2H, m), 1,5-a 1.45 (2H, m), 1,48-of 1.62 (1H, m), 1.70 to to 1.82 (4H, m), 2,80-2,95 (1H, m), 2,96-3,11 (1H, m), of 3.96 (2H, t, J=6.4 Hz), 3,97-4,07 (1H, m), 4,10-4,24 (1H, m), 6,89-to 6.95 (3H, m), 7.24 to to 7.32 (2H, m), 7,44 (1H, DD, J=8,3, 3,9 Hz), to 7.61 (1H, DDD, J=8,3, to 2.9, 1.5 Hz), 8,40 (1H, d, J=2,9 Hz), 8,42 (1H, DD, J=4,4, 1.5 Hz), DMSO: 341(M+H)+FAB
1151,06-of 1.26 (2H, usher.), 1,37-to 1.45 (2H, m), 1,50-of 1.62 (1H, m), 1,72-of 1.88 (4H, m), is 2.88 (1H, t, J=13,2 Hz), 3,03 (1H, t, J=13,2 Hz)to 4.01 (1H, d, J=11.7 Hz), of 4.13 (2H, t, J=6.3 Hz), 4,18 (1H, d, J=11.7 Hz), 7,02 (1H, t, J=7.8 Hz), 7,14 (1H, d, J=7.8 Hz), 7,42-7,49 (2H, m), 7,53-to 7.64 (3H, m), 7,81 (1H, DD, J=1,9, and 7.8 Hz), 8,40-8,44 (2H, m), DMSO: 384(M+H)+FAB
1161,05-1,25 (2H, usher.), 1,36-to 1.45 (2H, m), 1,52-of 1.64 (1H, m), 1,73 of-1.83 (4H, m), is 2.88 (1H, t, J=12,7 Hz), 3,05 (1H, t, J=12,7 Hz), 3,99-of 4.05 (3H, m), 4,18 (1H, d, J=a 12.7 Hz), 7,05-to 7.09 (1H, m), 7,34 (2H, t, J=8,3 Hz), 7,41-7,46 (2H, m,), 7,73 (1H, DD, J=4,9, 8,3 Hz), 7,92-8,02 (2H, m), 8,57 at 8.60 (1H, m), 8,67 (1H, d, J=2.4 Hz), DMSO: 384(M+H)+FAB
1171,59-of 1.74 (2H, m), 1,96-2,03 (2H, m), 3.27 to of 3.56 (2H, m), 3,70-of 3.95 (5H, m), 4,48-4,58 (3H, m), to 5.08 (2H, s), 6,85 (1H, d, J=16.1 Hz), of 6.96 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), 7,72 (1H, d, J=16.1 Hz), 8,10 (1H, DD, J=1.5 Hz, 2.4 Hz), 8,46 (1H, d, J=2.4 Hz), the rate of 8.75 (1H, d, J=1.5 Hz), DMSO: 507(M+H)+FAB
1181,60 to 1.76 (2H, m), 1,92-of 2.05 (2H, m), 3,30-3,55 (2H, m), 3,66-3,93 (2H, m), 4,48-4,56 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.23 percent-7,30 (2H, m), 7,39-7,47 (1H, m), 7,75-of 7.82 (1H, m), 8,35-to 8.40 (1H, m), and 8.50 (1H, d, J=2.5 Hz), DMSO: 441(M+H)+FAB
119 452(M+H)+FAB
120449(M+H)+FAB
121437(M+H)+FAB
1220,96-of 1.27 (5H, m), 1.60-to to 1.86 (6H, m), 3,26-3,82 (8H, m), 3,82 (2H, d, J=6.3 Hz), 6,92? 7.04 baby mortality (3H, m), of 7.36 (1H, t, J=8,3 Hz), 7,62-of 7.69 (1H, m), of 7.90 (1H, usher.), 8,50-8,66 (2H, m), DMSO: 424(M+H)+FAB
123437(M+H)+FAB

Table 44
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
124to 2.29 (3H, s), 2,68 (2H, t, J=7,3 Hz), 2,84 (2H, t, J=7,3 Hz), 3,37-3,62 (8H, m), 7,12 (2H, d, J=7.9 Hz), 7,15-7,22 (1H, m), 7.24 to to 7.32 (4H, m), 7,49 (2H, d, J=7.8 Hz), 7,80 (1H, DD, J=4,9, 8,3 Hz), 8,05-8,10 (1H, m), 8,63 (1H, DD, J=1,0, a 4.9 Hz), 8,73 (1H, d, J=2.4 Hz), DMSO: 340(M+H)+FAB
125312(M+H)+FAB
126of 3.46-3,59 (2H, m), 3,61-of 3.77 (4H, m), 3,78-to 3.92 (2H, m), 7,30 (1H, d, J=15,5 Hz), of 7.36 was 7.45 (2H, m), of 7.48 (1H, d, J=8.0 Hz), 7,54 (1H, d, J=15,5 Hz), 7,71-7,76 (1H, m), 7,80 (1H, DD, J=8,6, 4,8 Hz), 8.07-a to 8.12 (1H, m)8,64 (1H, DD, J=5,3, 1.1 Hz), the rate of 8.75 (1H, d, J=2.2 Hz), DMSO: 338(M+H)ES
127342(M+H)+ ESI
128326(M+H)+FAB
129341(M+H)+ESI
130354(M+H)+FAB
131352(M+H)+FAB
132369(M+H)+FAB
133355(M+H)+FAB
134426(M+H)+FAB
135457(M+H)+FAB
136457(M+H)+FAB
137453(M+H)+FAB
1383,30-3,82 (8H, usher.), to 5.08 (2H, s), 7,02 (1H, d, J=7,8), 7,06-was 7.08 (1H, m), 7,11-7,14 (1H, m), 7,38-7,47 (4H, m), 7,53 (1H, s), 7,70-7,80 (1H, usher.), 7,95-8,08 (1H, usher.), 8,58 (2H, m), DMSO: 452(M+H)+FAB
139385(M+H)+ESI
140385(M+H)+ESI
141385(M+H)+ESI
142348(M+H)+FAB
143 362(M+H)+FAB
144to 2.29 (3H, s), 3,40-3,71 (8H, m), 5,12 (2H, s), 7,12 (2H, d, J=7.8 Hz), 7,30-7,41 (5H, m), 7,49 (2H, d, J=8,3 Hz), 7,80 (1H, DD, J=5,4, 8,3 Hz), 8,02-8,11 (1H, m), 8,63 (1H, d, J=5.4 Hz), 8,73 (1H, d, J=1,9 Hz), DMSO: 342(M+H)+FAB
145329(M+H)+FAB
146341(M+H)+FAB
1473,44-3,71 (8H, m), is 5.18 (2H, s), 7,10 (2H, d, J=8,8 Hz), 7,38-to 7.50 (6H, m), 7,54 (1H, s), to 7.61-to 7.67 (1H, m), 8,40-8,44 (2H, m), DMSO: 452(M+H)+FAB
148432(M+H)+FAB
1493,40-3,71 (8H, m), 5,28 (2H, s), 7,12 (2H, d, J=8,8 Hz), 7,40-of 7.48 (3H, m), 7,62-to 7.68 (2H, m), 7,72 (1H, d, J=7.8 Hz), 7,79 (1H, d, J=7,3 Hz), to 7.84 (1H, s), 8,42-8,46 (2H, m), DMSO: 486(M+H)+FAB

Table 45
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
150448(M+H)+FAB
1513,43-3,74 (8H, m), 5,23 (2H, s), 7,10 (2H, d, J=8,8 Hz), 7,40-of 7.48 (3H, m), 7,60-to 7.67 (2H, m), 7,79-a 7.85 (2H, m), 7,95 (1H, usher.), 8,42-8,46 (2H, m), DMSO: 443(M+H)+FAB
1523,43-3,74 (8H, m), 5,20 (2H, s), to 7.09 (2H, d, J=8,8 Hz), 7,14-7,26 (3H, m), 7,40-7,49 (3H, m), 7,60-to 7.68 (1H, m), 8,42-8,46 (2H, m), DMSO: 454(M+H)+FAB
153502(M+H)+FAB
1543,42-3,74 (8H, m), 5,33 (2H, s), 7,13 (2H, d, J=8,8 Hz), 7,42-7,49 (3H, m), 7,63-to 7.67 (1H, m), 7,72 (1H, t, J=7.8 Hz), 7,94 (1H, d, J=8.1 Hz), 8,19-8,23 (1H, m), a 8.34 (1H, usher.), 8,42-8,46 (2H, m), DMSO: 463(M+H)+ESI
1553,43-3,74 (8H, m), 5,14 (2H, s), 7,07 (2H, d, J=8,8 Hz), 7.23 percent (2H, t, J=8,8 Hz), 7,40-7,56 (5H, m), 7,60-to 7.67 (1H, m), 8,40-8,46 (2H, m), DMSO: 436(M+H)+FAB
156436(M+H)+FAB
157419(M+H)+FAB
158439(M+H)+ESI
1593,43-3,74 (8H, m)to 5.17 (2H, s), 7,10 (2H, d, J=8,8 Hz), 7,38 (1H, t, J=7.8 Hz), 7,40-to 7.50 (4H, m), 7,55 (1H, d, J=7.8 Hz), 7,63-of 7.70 (2H, m), 8,42-of 8.47 (2H, m), DMSO: 496 (M+H)+FAB
160of 3.07 (2H, t, J=7.0 Hz), 3,43-3,74 (8H, m), 4.26 deaths (2H, t, J=6.6 Hz), 7,01 (2H, d, J=8.6 Hz), 7.24 to of 7.48 (7H, m), 7,62-to 7.67 (1H, m), 8,42-8,46 (2H, m), DMSO: 466(M+H)+FAB
161443(M+H)+FAB
162544(M+H)+FAB
163461(M+H)+FAB
164477(M+H)+FAB
165477(M+H)+FAB
166473(M+H)+FAB
167476(M+H)+FAB
168346(M+H)+FAB
169307(M+H)+FAB
1701,00-1,20 (2H, m), 1.18 to 1,25 (2H, m), 1,35 of 1.50 (1H, m), 1,45 is 1.58 (2H, m), 1,68-of 1.78 (2H, m), and 2.14 (2H, t, J=7.4 Hz), 2.77-to only 2.91 (1H, m), 2,92-to 3.09 (1H, m), 3,90-4,07 (1H, m), 4,10-4,22 (1H, m), of 6.68 (1H, user. C), 7,22 (1H, user. C)was 7.45 (1H, DD, J=8,3, a 4.9 Hz), 7,56-7,66 (1H, m), 8,25-of 8.50 (2H, m), DMSO: 292(M+H)+FAB
171354(M+H)+FAB
172341(M+H)+FAB

Table 46
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
1731,54-to 1.79 (2H, m), 1,82 is 1.96 (2H, m), 2,62 (1H, dddd, J=11,2, 11,2, 3,4, 3,4 Hz), 2,88-of 3.07 (1H, m), 3.04 from is 3.23 (1H, m), 4,00-4,16 (1H, m), 16-4,32 (1H, m), 6,99-7,07 (1H, m), 7,25-7,34 (2H, m), 7,45 (1H, DD, J=8,3, a 4.9 Hz), 7,58-the 7.65 (2H, m), the 7.65 (1H, DDD, J=8,3, 2,4, and 1.4 Hz), to 8.41-8,46 (2H, m), 9,94 (1H, s), DMSO: 326(M+H)+FAB
1741,42-of 1.65 (2H, m), 1,65-to 1.79 (2H, m), 2,35 (1H, dddd, J=11,3, 11,3, 3,4, 3,4 Hz), of 2.72 (2H, t, J=7,3 Hz), 2,83-2,99 (1H, m), 3.00 and-and 3.16 (1H, m), or 3.28 (2H, t, J=7,3 Hz), 3,91-4,06 (1H, m), 4,08-to 4.23 (1H, m), 7,16-of 7.23 (3H, m), 7,25-7,33 (2H, m), 7,44 (1H, DD, J=8,3, a 4.9 Hz), a 7.62 (1H, DDD, J=8,3, of 2.5, 1.0 Hz), of 7.90 (1H, user. t, J=5.4 Hz), to 8.41 (1H, d, J=2.5 Hz), 8,43 (1H, DD, J=4,9, 1.5 Hz), DMSO: 354(M+H)+FAB
175of 1.40 (2H, TT, J=7,3, 7,3 Hz), and 1.56 (2H, TT, J=7,3, 7,3 Hz), 1,47-of 1.66 (2H, m), 1,68-to 1.79 (2H, m), 2,30-to 2.40 (1H, m), to 2.57 (2H, t, J=7.8 Hz), 2,86-to 2.94 (1H, m), 3.00 and-is 3.08 (1H, m), of 3.07 (2H, dt, J=6,9 and 6.9 Hz), 3,93-4,07 (1H, m), 4,10-4,24 (1H, m), 7,12-7,21 (3H, m), 7.23 percent-7,31 (2H, m), 7,44 (1H, DD, J=8,3, a 4.9 Hz), a 7.62 (1H, DDD, J=8,3, 3,0, 1.5 Hz), 7,81 (1H, user. t, J=5.4 Hz), to 8.41 (1H, d, J=2.4 Hz), 8,43 (1H, DD, J=4,4, 3.0 Hz), DMSO: 382(M+H)+FAB
176of 0.85 (3H, t, J=6.4 Hz), 1,17-of 1.32 (10H, m), 1,45 is 1.58 (2H, m), 1,54 to 1.76 (2H, m), 1,80-of 1.93 (2H, m), of 2.51 (2H, t, J=6.4 Hz), 2,55-of 2.64 (1H, m), 2,88 totaling 3.04 (1H, m), 2,99-3,20 (1H, m), 4,00-to 4.14 (1H, m), 4,15-4,30 (1H, m), 7,10 (2H, d, J=8,3 Hz), was 7.45 (1H, DD, J=8,3, 4,4 Hz)to 7.50 (2H, d, J=8,3 Hz), to 7.64 (1H, DDD, J=8,3, of 2.5, 1.5 Hz), 8,40-8,46 (2H, m), 9,85 (1H, s), DMSO: 438(M+H)+FAB
177411(M+H)+FAB
178411(M+H)+FAB
1791,58-of 1.78 (2H, m), 1.85 to (2, d, J=and 12.2 Hz), 2,75-and 2.83 (1H, m), 3,03 (1H, t, J=and 12.2 Hz), 3,18 (1H, t, J=and 12.2 Hz), 4,15 (1H, d, J=a 12.7 Hz), 4,32 (1H, d, J=a 12.7 Hz), 4,42 (2H, s), to 6.80 (1H, DD, J=2.0 a, 8,3 Hz), 6,88-6,92 (2H, m), 7,24 (1H, t, J=8,3 Hz), 7,38 (1H, usher.), 7,52 (1H, usher.), to 7.77 (1H, DD, J=5,3, 8,3 Hz), 8,02-of 8.09 (1H, m), to 8.62 (1H, d, J=5.3 Hz), a total of 8.74 (1H, d, J=2.0 Hz), DMSO: 356(M+H)+FAB
180467(M+H)+ESI
181411(M+H)+FAB
182382(M+H)+FAB
183398(M+H)+FAB
184454(M+H)+FAB
185502(M+H)+FAB
186480(M+H)+FAB
187410(M+H)+FAB
188488(M+H)+FAB
189370(M+H)+FAB
190432(M+H)+FAB

Table 47
Example No.Physico-chemical properties
1H-NMR δ (ppm), dissolve Italy: MS m/z
191397(M+H)+FAB
192409(M+H)+ESI
193386(M+H)+FAB
194371(M+H)+FAB
195357(M+H)+ESI
196337(M+H)+FAB
1971,20-1,32 (2H, m), of 1.28 to 1.48 (2H, m), 1,47-of 1.62 (4H, m), 1.70 to to 1.86 (2H, m)to 2.06 (2H, t, J=7,3 Hz), of 2.56 (2H, t, J=7,3 Hz), 2,98-3,10 (1H, m), 3,12-of 3.25 (1H, m), of 3.73-3,86 (1H, m), 3,83-of 3.97 (1H, m), 3,98-4,13 (1H, m), 7,12-7,21 (3H, m), 7,22-7,30 (2H, m), 7,45 (1H, DD, J=8,3, 4,4 Hz), a 7.62 (1H, DDD, J=8,3, of 2.5, 1.5 Hz), 7,78 (1H, userd, J=7,3 Hz), to 8.41 (1H, d, J=2.5 Hz), 8,43 (1H, DD, J=4,9, 1.5 Hz), DMSO: 396(M+H)+FAB
198315(M+H)+FAB
1991,57 is 1.75 (2H, usher.), 1,90-2,03 (2H, usher.), 3,28 is 3.40 (1H, usher.), 3,43 is 3.57 (1H, usher.), 3,64-with 3.79 (1H, usher.), 3,82-3,93 (1H, usher.), to 4.38 - to 4.46 (1H, m), 6,69 (2H, userd, J=8,8 Hz), 6,83 (2H, userd, J=8,8 Hz), 7,44 (1H, DD, J=4,9, 8,3 Hz), to 7.61-7,66 (1H, m), 8,43 (2H, d, J=3.0 Hz), 8,96 (1H, s), DMSO: 315(M+H)+FAB
2000,96-of 1.30 (5H, m), 1.60-to to 1.83 (8H, m), 1,94-of 2.09 (2H, m), 3.33 and-3,44 (1H, usher.), 3,48-of 3.60 (1H, usher.), 3,70-of 3.80 (1H, usher.), of 3.75 (2H, d, J=6.3 Hz), 3,85-of 3.95 (1H, usher.), with 4.64-4,0 (1H, m), 6,50-6,60 (3H, m), 7,17 (1H, t, J=13,7 Hz), 7,87 (1H, DD, J=5,4, 8,3 Hz), 8,18 (1H, d, J=8,8 Hz), 8,68 (1H, d, J=5.4 Hz), 8,82 (1H, d, J=1.9 Hz), DMSO: 411(M+H)+FAB
201425(M+H)+FAB
2021,60 to 1.76 (2H, usher.), 1,95-2,07 (2H, usher.), 3,33 is-3.45 (1H, usher.), 3,47-to 3.58 (1H, usher.), 3,70-of 3.80 (1H, usher.), 3,85-of 3.96 (1H, usher.), 4,63-4,70 (1H, m)to 5.13 (2H, s), 6,59-only 6.64 (3H, m), 7,13-of 7.23 (2H, m), 7,26-7,31 (2H, m), 7,41-of 7.48 (1H, m), 7,78 (1H, DD, J=5,4, 8,8 Hz), of 8.06 (1H, userd, J=7,3 Hz), to 8.62 (1H, d, J=4,8 Hz), 8,73 (1H, d, J=2,4 Hz), DMSO: 423(M+H)+FAB
2031,60-1,80 (2H, usher.), 1,90-2,07 (2H, usher.), 3,33 is-3.45 (1H, usher.), 3,47-of 3.60 (1H, usher.), 3,70-3,81 (1H, usher.), 3,85-of 3.96 (1H, usher.), 4,63-4,71 (1H, m), 5,12 (2H, s), 6,60-6,69 (3H, m), 7.18 in-7,28 (3H, m), 7,39-7,47 (1H, m), 7,56 (1H, dt, J=1,4, and 7.8 Hz), 7,83-7,89 (1H, m), 8,15-to 8.20 (1H, m), 8,68 (1H, userd, J=5.4 Hz), 8,81 (1H, usher.), DMSO: 423(M+H)+FAB
204423(M+H)+FAB
2051,60-of 1.84 (2H, usher.), 1,94 e 2.06 (2H, usher.), 3,30-of 3.42 (1H, usher.), 3,45 of 3.56 (1H, usher.), 3,70-of 3.80 (1H, usher.), 3,84-of 3.96 (1H, usher.), br4.61 - 4,69 (1H, m), 5,16 (2H, m), is 6.61 (1H, d, J=2.5 Hz), 6,63 (1H, d, J=2.5 Hz), 6,66 (1H, t, J=1.9 Hz), 7,20 (1H, t, J=7.8 Hz), 7,46 (1H, DD, J=4,9, 8,3 Hz), 7,60-to 7.67 (2H, m), 7,78-7,83 (2H, m), 7,92 (1H, user.), to 8.45 (2H, m), DMSO: 430(M+H)+FAB

Table 48
P the emer no Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
2061,59 to 1.76 (2H, usher.), 1,91-2,07 (2H, usher.), 3,33-of 3.42 (1H, usher.), 3,45 of 3.56 (1H, usher.), 3,69-of 3.80 (1H, usher.), 3,82-of 3.94 (1H, usher.), 4,45-4,55 (1H, m), is 5.06 (2H, s), of 6.96 (4H, s), of 7.36-7,46 (3H, m)to 7.50 (1H, usher.), of 7.75 (1H, DD, J=4,9, 8,3 Hz), 8,02 (1H, d, J=8,3 Hz), at 8.60 (1H, d, J=4.9 Hz), to 8.70 (1H, d, J=2.5 Hz), DMSO: 439(M+H)+FAB
2070,88-a 1.01 (2H, m), 1,09-of 1.30 (3H, m), 1,40-is 1.51 (1H, m), 1.55V to 1.76 (9H, m), 1.93 and-2,05 (2H, m), 3,30-of 3.42 (1H, usher.), of 3.46-of 3.60 (1H, usher.), 3,70-of 3.80 (1H, usher.), 3,85-of 3.95 (3H, m), 4,45-4,55 (1H, m), 6,84-6,94 (4H, m), 7,66 (1H, DD, J=4,9, 8,3 Hz), 7,98 (1H, d, J=8,3 Hz), 8,58 (1H, d, J=4,8 Hz), 8,66 (1H, d, J=1.9 Hz), DMSO: 425(M+H)+FAB
2081,60-1,80 (2H, usher.), 1,94-2,07 (2H, usher.), 3,31-3,44 (1H, usher.), of 3.46-of 3.60 (1H, usher.), 3,69-3,82 (1H, usher.), 3,84-of 3.96 (1H, usher.), 4,50-4,58 (1H, m), to 5.08 (2H, s), 6,97 (4H, s), 7,20-7,28 (2H, m), 7,39 was 7.45 (1H, m), 7,54 (1H, dt, J=1,5, and 7.3 Hz), 7,81 (1H, DD, J=5,4, 8,3 Hz), 8,10 (1H, userd, J=8,3 Hz)8,64 (1H, d, J=5.3 Hz), 8,77 (1H, s), DMSO: 423(M+H)+FAB
2091,60-1,80 (2H, usher.), 1,94-2,07 (2H, usher.), 3,31-3,44 (1H, usher.), of 3.46-of 3.60 (1H, usher.), 3,69-of 3.80 (1H, usher.), 3,82-of 3.96 (1H, usher.), 4,48 - 4,58 (1H, m), of 5.03 (2H, s), of 6.96 (4H, s), 7.18 in-7,26 (2H, m), 7,45-7,51 (2H, m), 7,78-7,89 (1H, m), 8.07-a 8,19 (1H, m), 8,67 (1H, userd, J=4,9 Hz), 8,80 (1H, usher.), DMSO: 423(M+H)+FAB
2101,60-1,75 (2H, usher.), 1,91-2,6 (2H, user.), 3,30-of 3.42 (1H, usher.), 3,45 of 3.56 (1H, usher.), 3,70-of 3.80 (1H, usher.), 3,84-of 3.96 (1H, usher.), 4,49-4,56 (1H, m), 5,11 (2H, m), of 6.96 (4H, s), 7,46 (1H, DD, J=4,8, 8.6 Hz), to 7.61 (1H, t, J=7.5 Hz), of 7.64-7.68 per (1H, m), 7,76-7,83 (2H, m), of 7.90 (1H, usher.), 8,43-of 8.47 (2H, m), DMSO: 430(M+H)+FAB
211463(M+H)+FAB
2121,58-of 1.74 (2H, usher.), 1,91-2,05 (2H, usher.), 3,30-of 3.42 (1H, usher.), 3,45-3,55 (1H, usher.), the 3.65-with 3.79 (1H, usher.), 3,83-of 3.94 (1H, usher.), 4,48 - 4,55 (1H, m), 5,09 (2H, s), of 6.96 (4H, s), of 7.36-to 7.50 (3H, m), to 7.59 (1H, d, J=7.9 Hz), 7,62-7,66 (1H, m), to 7.84 (1H, d, J=7.8 Hz), of 7.96 (1H, s), 8,00 (1H, usher.), to 8.41-to 8.45 (2H, m), DMSO: 448(M+H)+FAB
213497(M+H)+FAB
214484(M+H)+FAB
215488(M+H)+FAB
2160,96-1,08 (2H, m), of 1.10 to 1.31 (3H, m), 1.60-to to 1.83 (8H, m), 1.91 a-2,05 (2H, m), 3,25 is 3.57 (2H, m), 3,65-of 3.95 (7H, m), 4,46-of 4.54 (1H, m), for 6.81-6.87 in (2H, m), 6.89 in-6,95 (2H, m), 8,13 (1H, DD, J=2.0 Hz, 2.4 Hz), to 8.70 (1H, d, J=2.4 Hz), to 8.94 (1H, d, J=2.0 Hz), DMSO: 469(M+H)+FAB
217was 1.58 to 1.76 (2H, m), 1,90-2,04 (2H, m), 2,80-4,00 (4H, m), of 4.38-4,47 (1H, m), 6,70 (2H, d, J=8,8 Hz), 6,83 (2H, d, J=8,8 Hz), 8,05-8,10 (1H, m), 8,66 (1H, d, J=2.4 Hz), 8,90-to 8.94 (1H, m), DMSO: 359(M+H)+FAB

Table 49
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
2181,60-of 1.78 (2H, m), 1.93 and-2,05 (2H, m), 3,35-of 3.95 (4H, m), 4,48-4,56 (1H, m), 5,07 (2H, s), of 6.96 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), 8.07-a 8,10 (1H, m), 8,67 (1H, d, J=2.4 Hz), 8,91-to 8.94 (1H, m), 13,30-of 13.75 (1H, usher.), DMSO: 467(M+H)+FAB
219341(M+H)+FAB
220327(M+H)+ESI
221449(M+H)+FAB
222325(M+H)+ESI
223353(M-H)-FAB
224355(M-H)-FAB
2251,12-1,32 (2H, m), 1,45-to 1.60 (3H, m)to 1.79 (2H, d, J=11.7 Hz), 2,63 (2H, t, J=7.5 Hz), 2,87 (1H, t, J=and 12.2 Hz), to 3.02 (1H, t, J=12,2 Hz)to 4.01 (1H, d, J=a 12.7 Hz), 4,18 (1H, t, J=12,7 Hz), 7,15-7,31 (5H, m), 8,05 (1H, DD, J=2.0 a, 2,4 Hz), 8,65 (1H, d, J=2.4 Hz), of 8.92 (1H, t, J=2.0 Hz), 13,59 (1H, user. C), DMSO: 355(M+H)+FAB
226470(M+H)+FAB
227410(M+H)+FAB
2280.88 to 1.00 and (H, m), 1,08 of 1.28 (4H, m), 1,39-is 1.51 (1H, m), and 1.54-1.77 in (10H, m), 1.91 a-2,05 (2H, m), 3,20-of 3.96 (6H, m), 4,46-of 4.54 (1H, m), 6,83-to 6.88 (2H, m), 6.90 to-6,95 (2H, m), 8,08 (1H, DD, J=2.0 Hz, 2.4 Hz), 8,66 (1H, d, J=2,4 Hz), of 8.92 (1H, d, J=1.5 Hz), DMSO: 469(M+H)+FAB
229483(M+H)+FAB
230474(M+H)+FAB
231356(M+H)+FAB
232371(M+H)+FAB
2331,58-of 1.78 (2H, m), 1.91 a e 2.06 (2H, m), 3.25 to of 3.95 (7H, m), 4,49-4,56 (1H, m), 5,02 (2H, s), 6,86-7,03 (7H, m), 7,30 (1H, DD, J=7,8 Hz and 8.3 Hz), 8,07 (1H, s)8,64 (1H, s)of 8.92 (1H, s), DMSO: 479(M+H)+FAB
2341,60-1,80 (2H, usher.), 1,92 is 2.10 (2H, usher.), 3,30-of 3.60 (2H, usher.), 3,70-of 3.80 (1H, usher.), 3,85-of 3.96 (1H, usher.), 4,60-4,70 (1H, m), 5,12 (2H, s), 6,58 of 6.68 (3H, m), 7.24 to to 7.32 (4H, m), 7,42-7,50 (1H, m), of 8.09 (1H, t, J=2.4 Hz), 8,67 (1H, d, J=2.4 Hz), of 8.92 (1H, d, J=1.9 Hz), 13,50 (1H, usher.), DMSO: 467(M+H)+FAB
2351,60-1,80 (2H, usher.), 1,92 is 2.10 (2H, usher.), 3,30-of 3.60 (2H, usher.), 3,70-of 3.80 (1H, usher.), 3,85-of 3.96 (1H, usher.), ,4,60-4,72 (1H, m), 5,16 (2H, s), 6,60 of 6.68 (3H, m), 7,21 (1H, t, J=8,3 Hz), a 7.62 (1H, t, J=8,3 Hz), 7,78-to 7.84 (2H, m), 7,92 (1H, s), of 8.09 (1H, DD, J=1,4, 2,4 Hz), 8,67 (1H, d, J=3.0 Hz), 8,93 (1H, d, J=the 1.4 Hz), 13,50 (1H, usher.), DMSO: 474(M+H)+FAB

Table 50
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
2361,60-of 1.74 (2H, m), 1.91 a e 2.06 (2H, m), 3,30-of 3.95 (7H, m), 4,47-of 4.57 (1H, m), 5,14 (2H, s), of 6.96 (4H, s), 7,55 (1H, DD, J=7,4 Hz, 7.8 Hz), 7,72 (1H, d, J=7,4 Hz), 7,92 (1H, d, J=7.8 Hz), of 8.04 (1H, s), 8,08 (1H, DD, J=2.0 Hz, 2.4 Hz), 8,67 (1H, d, J=2.4 Hz), of 8.92 (1H, d, J=2.0 Hz), DMSO: 507(M+H)+FAB
237455(M+H)+FAB
238369(M+H)+ESI
239385(M+H)+ESI
240371(M+H)+ESI
241398(M+H)+FAB
2420,73-2,10 (17H, m), 3,20-was 4.02 (6H, usher.), 4,60-4,70 (1H, m), of 6.49-6,60 (3H, m), 7,17 (1H, t, J=8,3 Hz), of 8.09 (1H, usher.), 8,67 (1H, d, J=2.0 Hz), of 8.92 (1H, usher.), 13,40-13,80 (1H, usher.), DMSO: 469(M+H)+FAB
243370(M+H)+FAB
244524(M+H)+FAB
2451,60-to 1.77 (2H, m), 1,92 e 2.06 (2H, m), 3,35-of 3.96 (4H, m), 4,48-4,56 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), 7,63-7,71 (1H, m), 8.07-a 8,10 (1H, m), 8,14 -8,23 (1H, m), 8,58 (1H, d, J=2.4 Hz), of 8.90 (1H, d, J=1.9 Hz), DMSO: 466(M+H)+FAB
2461,59-of 1.78 (2H, m), 1.91 a-2,05 (2H, m), 3,25 is 3.57 (2H, m), 3,68-of 3.96 (2H, m), 4,47-4,56 (1H, m), 5,04 (2H, s), to 6.95 (4H, s), 7,29-7,46 (5H, m), of 7.64-of 7.70 (1H, m), of 8.04 (1H, DD, J=1.9 Hz, 2.4 Hz), 8,15-8,21 (1H, m), 8,58 (1H, d, J=2.4 Hz), 8,89 (1H, d, J=1.9 Hz), DMSO: 448(M+H)+FAB
247397(M+H)+FAB
248451(M+H)+FAB
249523(M+H)+FAB
250579(M+H)+ESI
251524(M+H)+FAB
252577(M+H)+FAB
253537(M+H)+FAB
254577(M+H)+FAB
2551,58-of 1.78 (2H, usher.), 1,93 e 2.06 (2H, usher.), 3,32-of 3.42 (3H, m), 3,48-to 3.58 (3H, m), 3,70-of 3.80 (1H, usher.), 3,85-of 3.95 (1H, usher.), 4,48-4,58 (1H, m)to 4.92 (1H, usher.), 5,07 (2H, s), to 6.95 (4H, s), to 7.15 (1H, dt, J=2,4, an 8.8 Hz), 7.24 to 7,30 (2H, m), 7,41-7,47 (1H, m), 8,14 (1H, t, J=2.0 Hz), 8,63 (1H, d, J=2.4 Hz), the rate of 8.75 (1H, t, J=5.3 Hz), 8,93 (1H, d, J=1.4 Hz), DMSO: 510(M+H)+FAB

Table is CA 51
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
256586(M+H)+FAB
257549(M+H)+FAB
258of 1.13 and 1.33 (2H, usher.), of 1.66 (2H, d, J=a 12.7 Hz), 1,73-of 1.85 (1H, m), 2.57 m (2H, d, J=6.8 Hz), 2,86 (1H, t, J=and 12.2 Hz), to 3.02 (1H, t, J=and 12.2 Hz), a 4.03 (1H, d, J=and 12.2 Hz), 4,20 (1H, d, J=and 12.2 Hz), 7.18 in-of 7.23 (3H, m), 7,27-to 7.32 (2H, m), of 7.48 (1H, s), 7,60 (1H, t, J=7.8 Hz), to 7.93 (2H, d, J=7,3 Hz), 8,01 (1H, t, J=2.4 Hz), 8,13 (1H, s)8,23 (1H, s), 8,44 (1H, d, J=2.4 Hz), 8,84 (1H, d, J=2.0 Hz), DMSO: 416(M+H)+FAB
259374(M+H)+FAB
2601,60-1,75 (2H, m), 1,92-2,04 (2H, m), 3,30-3,91 (4H, m), 4,49-4,56 (1H, m), 5,07 (2H, s), of 6.96 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,39-7,47 (2H, m), 7,92 (1H, d, J=2.0 Hz), 8,02 (1H, d, J=2.0 Hz), DMSO: 438(M+H)+FAB
261550(M+H)+FAB
2621,58 is 1.75 (2H, m), 1,90-of 2.05 (2H, m), 3,30 is 3.57 (2H, m), 3,67-of 3.95 (2H, m), of 4.13 (2H, s), 4,48-4,55 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), to 7.61-to 7.64 (1H, m,), 8,35-8,39 (1H, m), 8,40-8,44 (1H, m), DMSO: 510(M+)FAB
2631,58-of 1.74 (2H, m), 1.91 a-2,04 (2H, m)of 2.50 (3H, s), 3,30-of 3.95 (4H, m), 4,48-4,58 (3H, m), 5,07(2H, C)of 5.40 (1H, t, J=5,9 Hz), to 6.95 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), 7,53-7,56 (1H, m), 8,28-8,31 (1H, m), at 8.36-8,39 (1H, m), DMSO: 453(M+H)+FAB
2641,59-of 1.74 (2H, m), 1,96-2,03 (2H, m), 3.27 to is 3.57 (2H, m), 3,70-the 3.65 (2H, m), 4,48-4,58 (3H, m), to 5.08 (2H, s), 6,72 (1H, d, J=16.1 Hz), of 6.96 (4H, s), 7,12-to 7.18 (1H, m), 7.24 to 7,30 (2H, m), 7,40-7,47 (1H, m), of 7.64 (1H, d, J=16.1 Hz), 8,07 (1H, DD, J=2.0 Hz, 2.0 Hz), to 8.45 (1H, d, J=2.5 Hz), 8,71 (1H, d, J=1.4 Hz), 12,40-12,74 (1H, usher.), DMSO: 493(M+H)+FAB
265445(M+H)+FAB
2661,10-of 1.33 (2H, m), 1,45-to 1.61 (3H, m), a 1.75-to 1.87 (2H, usher.), of 2.64 (2H, t, J=7,6 Hz), 2,81-3,10 (2H, usher.), 3,92-4,27 (2H, usher.), 7,14-to 7.32 (5H, m), 7,43-7,52 (1H, m), 7,60 (1H, d, J=8.0 Hz), of 7.90-7,98 (2H, m), 8,05-8,17 (2H, m), 8,21-of 8.27 (1H, m), 8,48 (1H, d, J=2.4 Hz), 8,87 (1H, d, J=2.4 Hz), DMSO
267380(M+H)+FAB
2681,33-of 1.56 (2H, m), 1.77 in-a 1.88 (2H, m), 2,37-2,48 (1H, m), 2,93 totaling 3.04 (1H, m), 3,09-is 3.21 (1H, m), 3,98-of 4.12 (1H, m), 4,14-to 4.28 (1H, m), of 6.31 (1H, DD,J=16,1, 6,8 Hz), of 6.45 (1H, d,J=16.1 Hz), 7.18 in-7,24 (1H, m), 7,28-to 7.35 (2H, m), 7,38-of 7.48 (3H, m), 7,63 (1H, DDD,J=8,3, of 2.5, 1.5 Hz), to 8.41-to 8.45 (2H, m), DMSO-d6: 309(M+H)+FAB
2691,33-of 1.56 (2H, m), 1,67-to 1.79 (2H, m), 2,73-is 2.88 (1H, m), 2,88-to 3.02 (1H, m), 2,88-to 3.02 (1H, m), 3.04 from-3,18 (1H, m), 3.95 to 4,07 (1H, m), 4,10-to 4.23 (1H, m)5,54 (1H, DD,J=11,8, 9.7 Hz), 6.42 per (1H, d,J=11.8 Hz), 7.23 percent-7,34 (3H, m), 7,35-7,42 (2H, m), 7,44 (1H, DD,J=8,3, 4,8 Hz), 7,63 1H, DDD,J=8,3, 2,4, 1.5 Hz), 8,40-to 8.45 (2H, m), DMSO: 309(M+H)+FAB
2701,08-of 1.30 (2H, m), 1,43 is 1.60 (3H, m), 1,73-1,82 (2H, usher.), 2,63 (2H, t, J=7.8 Hz), 2.77-to is 3.08 (2H, usher.), 3,92-4,20 (2H, usher.), 7,13-to 7.32 (5H, m), of 8.04 (1H, DD, J=2.0 a, 2,4 Hz), to 8.45 (1H, d, J=2.4 Hz), 8,58 (1H, d, J=2.0 Hz), DMSO: 389(M+)FAB

274
Table 52
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
2710,78-0,94 (2H, m), and 1.00-to 1.24 (10H, m), 1,37 of 1.50 (1H, m)of 1.57 to 1.76 (7H, m), 2,80 of 2.92 (1H, usher.), 2,96-is 3.08 (1H, usher.), 3,93-of 4.05 (1H, usher.), 4,08-is 4.21 (1H, usher.), to 7.68 (1H, DD, J=4,8 and 7.6 Hz), 7,93-8,00 (1H, m), 8,58 (1H, d, J=7,6 Hz), 8,62-8,69 (1H, m), DMSO: 317(M+H)+FAB
272of 0.79 to 0.92 (2H, m), 1.04 million-of 1.29 (10H, m), 1,36-1,49 (1H, m)of 1.57 to 1.76 (7H, m), 2,80 of 2.92 (1H, usher.), 2,95-is 3.08 (1H, usher.), are 3.90 (3H, s), 3,92-of 4.05 (1H, usher.), 4,08-is 4.21 (1H, usher.), of 8.09 (1H, DD, J=2.0 a, 2,4 Hz), 8,68 (1H, d, J=2.4 Hz), 8,93 (1H, d, J=2.0 Hz), DMSO: 375(M+H)+FAB
273the 1.44-of 1.59 (2H, m), 1.77 in-a 1.88 (2H, m), 2,37-2,48 (1H, m), 2,93-of 3.07 (1H, m), 3,07 is 3.23 (1H, m), 3,98-to 4.14 (1H, m), 4,14-the 4.29 (1H, m), of 6.31 (1H, DD,J=16,1, 6.9 Hz), of 6.45 (1H, d,J=16.1 Hz), 7,17-of 7.25 (1H, m), 7,27 was 7.36 (2H, m), 7,38-7,44 (2H, m), 8,05-of 8.09 (1H, m), 8,67 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=1.5 Hz), 13,60 (1H, user. C), DMSO: 353(M+H)+FAB
1,10-1,30 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m), 2.63 in (2H, t,J=8,3 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,16-7,34 (4H, m), of 8.04 (1H, DD,Jor =1.5, 2.0 Hz), 8,64 (1H, d,J=2,4 Hz), 8,91 (1H, d,J=1.9 Hz), 13,60 (1H, s), DMSO: 389(M+H)+FAB
275380(M+H)+FAB
2761,10-1,30 (2H, m), 1,44 is 1.60 (3H, m), 1,73-to 1.82 (2H, m)2,60 (2H, t,J=7,3 Hz), 2,80-3,10 (2H, m), 3,74 (3H, s), 3.95 to 4,24 (2H, m), 6,72-for 6.81 (3H, m), 7,19 (1H, t,J=8,3 Hz), of 8.04 (1H, t,J=1.9 Hz), 8,64 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=1.5 Hz), 13,60 (1H, s)DMSO: 385(M+H)+FAB
2771,10-1,30 (2H, m), 1,44 is 1.60 (3H, m), 1,73-to 1.82 (2H, m)2,60 (2H, t,J=7,4 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 6,95-7,10 (3H, m), 7.29 trend and 7.36 (1H, m), of 8.04 (1H, t,J=2.0 Hz), 8,65 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=1.9 Hz), 13,60 (1H, s), DMSO: 373(M+H)+FAB
278380(M+H)+FAB
279396(M-H)-FAB
280426(M+H)+FAB
2811,10-of 1.33 (2H, m), 1,46-to 1.59 (1H, m), 1,54-of 1.66 (2H, m), a 1.75-to 1.87 (2H, m), 2,68 (2H, DD,J=to 7.6 and 7.6 Hz), 2,79-to 2.94 (1H, m), 2.95 and-3,10 (1H, m), 3.95 to 4.09 to (1H, m), 4,11-of 4.25 (1H, m), 7,29-7,38 (3H, m), 7,41-7,49 (2H, m), 7,58 (2H, d,J=8,3 Hz), 7,62-to 7.68 (2H, m), 7,78-7,81 (1H, m), of 8.28 (1H, d,J=2,5 Hz), 8,78 (1H, d,J=1.4 Hz), DMSO: 431(M+H)+FAB
2821,07-of 1.33 (2H, m), 1,42-and 1.54 (1H, m), 1,47-to 1.59 (2H, m), 1,72 of-1.83 (2H, m), 2,62 (2H, DD,J=to 7.6 and 7.6 Hz), 2,78-of 2.93 (1H, m), 2,93-3,10 (1H, m), 3,92-4,08 (1H, m), 4,08-4,24 (1H, m), 7,05-7,13 (2H, m), 7,20-7,28 (2H, m), of 8.04 (1H, DD,J=2,5, and 2.1 Hz), 8,64 (1H, d,J=2,5 Hz), of 8.92 (1H, d,J=2.1 Hz), 13,62 (1H, user. C), DMSO: 373(M+H)+FAB
2831,10-of 1.35 (2H, m), 1,46-of 1.62 (3H, m), 1,74-of 1.88 (2H, m), is 2.74 (2H, DD,J=7,8, and 7.8 Hz), 2,80-2,96 (1H, m), 2,96-of 3.12 (1H, m), 3,94-4,08 (1H, m), 4,11-4.26 deaths (1H, m), 7.18 in-to 7.32 (2H, m), 7,32-the 7.43 (2H, m), with 8.05 (1H, DD,J=2,1, 1,6 Hz), 8,65 (1H, d,J=2.1 Hz), 8,91 (1H, d,J=1,6 Hz), 13,62 (1H, user. C), DMSO: 387(M-H)-FAB
2841,08-1,32 (2H, m), 1.41 to 1.55V (1H, m), 1,48 is 1.60 (2H, m), 1,71 of-1.83 (2H, m), 2,62 (2H, DD,J=7,8, and 7.8 Hz), 2,78-of 2.93 (1H, m), 2,93-to 3.09 (1H, m), 3,94-4,08 (1H, m), 4,10-to 4.23 (1H, m), 7,25 (2H, d,J=8.6 Hz), 7,33 (2H, d,J=8.0 Hz), of 8.04 (1H, DD,J=2,2, 1,6 Hz)8,64 (1H, d,J=2.2 Hz), 8,91 (1H, d,J=1,6 Hz), 13,61 (1H, user. C), DMSO: 389(M+H)+FAB
2851,06-1,32 (2H, m), 1,40-and 1.54 (1H, m), 1,47 is 1.60 (2H, m), 1.70 to of 1.84 (2H, m), 2,61 (2H, DD,J=to 7.6 and 7.6 Hz), 2,79-to 2.94 (1H, m), 2,94-to 3.09 (1H, m), 3,92-4,08 (1H, m), 4,08-of 4.25 (1H, m), 7,19 (2H, d,J=8,4 Hz), 7,46 (2H, d,J=8,4 Hz), of 8.04 (1H, DD,J=2,4, 1.2 Hz), 8,64 (1H, d,J=2,4 Hz), 8,91 (1H, d,J=1.2 Hz), 13,60 (1H, user. C), DMSO: 431(M-H)-FAB
2861,08-1,32 (2H, m), 1,42 is 1.58 (3H, m), 1.70 to of 1.84 (2H, m), of 2.56 (2H, DD,J=to 7.4, 7.4 Hz), 2,78-of 2.93 (1H,m), 2,93-of 3.07 (1H, m), and 3.72 (3H, s), 3,94-4,08 (1H, m), 4,08-to 4.23 (1H, m), at 6.84 (2H, d,J=8.0 Hz), 7,12 (2H, d,J=8.0 Hz), of 8.04 (1H, DD,J=2,8, and 1.6 Hz), 8,64 (1H, d,J=2,8 Hz), 8,91 (1H, d,J=1,6 Hz), 13,60 (1H, user. C), DMSO: 385(M+H)+FAB

Table 53
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MS m/z
2871,01-1,74 (11H, m), 2,58 (2H, t, J=7.2 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,14-7,31 (5H, m), of 8.04 (1H, t, J=2.4 Hz), 8,64 (1H, d, J=2.4 Hz), 8,91 (1H, d, J=1.6 Hz), 13,60 (1H, s), DMSO: 383(M+H)+FAB
288of 1.08 to 1.34 (2H, m), 1,44 is 1.60 (3H, m), 1,73 is 1.86 (2H, m)to 2.66 (2H, DD, J=7,4, 7,4 Hz), 2,78-2,95 (1H, m), 2.95 and-of 3.12 (1H, m), 3,93-4.09 to (1H, m), 4,10-4.26 deaths (1H, m), 7,08-to 7.18 (2H, m), 7,20-7,27 (1H, m), 7,27 and 7.36 (1H, m), with 8.05 (1H, DD, J=2,4, and 1.6 Hz), 8,65 (1H, d, J=2.4 Hz), 8,91 (1H, d, J=1.6 Hz), 13,60 (1H, user. C), DMSO: 373(M+H)+FAB
2890,79 with 0.93 (2H, m), 1.00 m of 1.28 (10H, m), of 1.35 to 1.48 (1H, m)of 1.57 to 1.76 (7H, m), 2,80-is 3.08 (2H, usher.), 3,96-4,22 (2H, usher.), 8,02-with 8.05 (1H, m), 8,62-8,66 (1H, m), 8,89-8,93 (1H, m), 13,53-13,64 (1H, usher.), DMSO: 361(M+H)+FAB
2901,13-1,32 (2H, m), 1,46-to 1.59 (1H, m), 1,54-of 1.62 (2H, m), a 1.75-to 1.87 (2H, m), 2,69 (2H, DD, J=7,8, and 7.8 Hz), 2,81-to 2.94 (1H, m), 2,94-3,10 (1H, m), 3,94-4,10 (1H, m), 4,10-4,27 (1H, m), 7,29-7,38 (3H, m), 7,86 (1H, DDD, J=7,4, 7,4, and 1.6 Hz), to 7.93 (1H, d, J=8.0 Hz), 8,01 (2H, d, J=8.0 Hz), with 8.05 (1H, DD, J=2,8, and 1.6 Hz, 8,62-8,68 (2H, m), of 8.92 (1H, d, J=1.6 Hz), 13,60 (1H, user. C), DMSO: 432(M+H)+ESI
2911,08-1,32 (2H, m), 1,44-to 1.61 (3H, m), 1,77 of-1.83 (2H, usher.), 2,63 (2H, t, J=7,6 Hz), 2,79-is 3.08 (2H, usher.), 3,95-to 4.23 (2H, usher.), of 6.73 (1H, d, J=16.0 Hz), 7,14-7,22 (3H, m), 7,25-to 7.32 (2H, m), of 7.64 (1H, d, J=16.0 Hz), 8,02-of 8.06 (1H, m), 8,40-8,44 (1H, m), 8,68-8,73 (1H, m), 12,55-12,63 (1H, usher.), DMSO: 381(M+H)+FAB
2921,10-1,32 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m), 2.63 in (2H, t, J=8,4 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,20-7,28 (2H, m), of 7.36-7,40 (1H, m), 7,44 (1H, usher.), of 8.04 (1H, t, J=2.0 Hz), 8,64 (1H, d, J=2.4 Hz), 8,91 (1H, d, J=1.6 Hz), 13,60 (1H, s), DMSO: 435,433(M+H)+ESI
2931,10-1,32 (2H, m), 1,45-to 1.67 (3H, m), a 1.75-to 1.87 (2H, m), a 2.71 (2H, t, J=7,6 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,22 (1H, d, J=7,2 Hz), 7,33-7,52 (6H, m), of 7.64-7.68 per (1H, m), of 8.04 (1H, DD, J=1,2, 2,4 Hz), 8,64 (1H, d, J=2.4 Hz), 8,91 (1H, d, J=2.0 Hz), 13,60 (1H, s), DMSO: 431(M+H)+ESI
2941,10-1,32 (2H, m), 1,45-to 1.67 (3H, m), a 1.75-to 1.87 (2H, m), a 2.71 (2H, t, J=7,6 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,29 (1H, d, J=7,6 Hz), 7,41 (1H, t, J=8.0 Hz), 7,55 (1H, d, J=7,6 Hz), a 7.62 (1H, s), to 7.67 (1H, t, J=8.0 Hz), 7,82 (1H, d, J=8.0 Hz), 8,00-8,08 (2H, m), 8,16 (1H, s), 8,65 (1H, usher.), 8,91 (1H, usher.), 13,60 (1H, s), DMSO: 456(M+H)+FAB
295of 1.07 to 1.34 (2H, m), 1.41 to was 1.58 (1H, m), 1,50-to 1.63 (2H, m), 1.70 to of 1.85 (2H, m), 2,65 (2H, DD, J=7,6, 7,6 Hz), 2,78-to 2.94 (1H, m), 2,93-is 3.21 (1H, m), 3,92-4.09 to (1H, m), 4,06-4.26 deaths (1H, m), 7,26 (2H, d, J=6.0 Hz), 8,04 (1H, DD, J=2,8, 2.0 Hz), to 8.45 (2H, userd, J=4.4 Hz), 8,64 (1H, d, J=2,8 Hz), 8,91 (1H, d, J=2.0 Hz), DM is About: 356(M+H) +FAB
296of 1.08 and 1.35 (2H, m), 1,43 is 1.58 (1H, m), 1,50-to 1.63 (2H, m), 1,71 is 1.86 (2H, m), 2,65 (2H, DD, J=7,2, 7,2 Hz), 2.77-to 2,96 (1H, m), 2,90-3,11 (1H, m), 3,90-4,08 (1H, m), 4,10-4.26 deaths (1H, m), 7,31 (1H, DD, J=8.0 a, 4,8 Hz), the 7.65 (1H, d, J=8.0 Hz), of 8.04 (1H, DD, J=2,4, 2.0 Hz), 8,40 (1H, userd, J=3.2 Hz), 8,46 (1H, user. C), 8,65 (1H, d, J=2.4 Hz), 8,91 (1H, d, J=2.0 Hz), DMSO: 354(M-H)-FAB
297of 1.08 and 1.35 (2H, m), 1,43 is 1.60 (1H, m), 1.60-to 1,72 (2H, m), 1,74-of 1.85 (2H, m), 2,78 (2H, DD, J=7,2, 7,2 Hz), 2,81-of 2.93 (1H, m), 2,94-is 3.08 (1H, m), 3.95 to 4,07 (1H, m), 4,11-4,24 (1H, m), 7,16-7,22 (1H, m), 7,27 (1H, d, J=8.0 Hz), 7,69 (1H, DDD, J=8,0, to 8.0, 2.0 Hz), of 8.04 (1H, DD, J=2,4, 2.0 Hz), 8,48 (1H, d, J=4.4 Hz), 8,64 (1H, d, J=2.4 Hz), 8,91 (1H, d, J=2.0 Hz), DMSO: 354(M-H)-FAB
2981,10-1,32 (2H, m), 1,45-to 1.67 (3H, m), a 1.75-to 1.87 (2H, m), 2,69 is 2.75 (2H, m), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,27-7,46 (3H, m), 7,80-7,99 (5H, m), 8,30 (1H, d, J=2,8 Hz), 8,66 (1H, d, J=4.4 Hz), 8,80 (1H, d, J=1.6 Hz), DMSO: 432(M+H)+FAB

Table 54
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
2991,10-of 1.36 (2H, m), 1,45-to 1.60 (1H, m), 1,54-of 1.66 (2H, m), 1,74-to 1.87 (2H, m)to 2.67 (2H, DD,J=to 7.2, 7.2 Hz), 2,80-2,95 (1H, m), 2.95 and-3,10 (1H, m), 3,92-4,10 (1H, m), 4,10-of 4.25 (1H, m), 7,26 (2H, d,J=8,8 Hz), 7,30 (2H, d,J=8,8 Hz), 7,56 (2H, d,J=8,8 Hz), to 7.68 (2H, DD,<> J=8,8, 5,2 Hz), with 8.05 (1H, DD,Jvalue of 3.2, 1.6 Hz), 8,65 (1H, d,J=3.2 Hz), of 8.92 (1H, d,J=1,6 Hz), 13,60 (1H, user. C), DMSO: 449(M+H)+FAB
3001,11-of 1.36 (2H, m), 1,46-to 1.59 (1H, m), 1,54-of 1.64 (2H, m), 1,74 is 1.86 (2H, m)to 2.66 (2H, DD,J=to 7.6 and 7.6 Hz), 2,81-2,95 (1H, m), 2.95 and-3,10 (1H, m), with 3.79 (3H, s), 3.95 to 4,07 (1H, m), 4,12-of 4.25 (1H, m), 7,01 (2H, d,J=8,8 Hz), 7,27 (2H, d,J=8.0 Hz), 7,53 (2H, d,J=8.0 Hz), 7,58 (2H, d,J=8,8 Hz), with 8.05 (1H, DD,J=2,8, 2.0 Hz), 8,65 (1H, d,J=2,8 Hz), of 8.92 (1H, d,J=2.0 Hz), 13,60 (1H, user. C), DMSO: 461(M+H)+FAB
3011,10-of 1.36 (2H, m), 1,45-to 1.59 (1H, m), 1,55-of 1.66 (2H, m), a 1.75-to 1.87 (2H, m), 2,69 (2H, DD,J=to 7.2, 7.2 Hz), 2,80-to 2.94 (1H, m), 2,96-of 3.12 (1H, m), 3,93-4,10 (1H, m), 4,10-4,27 (1H, m), of 7.36 (2H, d,J=8,4 Hz), to 7.68 (2H, d,J=8,4 Hz), 7,87 (2H, d,J=8,8 Hz), to $ 7.91 (2H, d,J=8,8 Hz), with 8.05 (1H, DD,J=2,4, and 1.6 Hz), 8,65 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=1,6 Hz), 13,61 (1H, user. C), DMSO: 456(M+H)+FAB
3021,10-of 1.36 (2H, m), 1,45 is 1.58 (1H, m), 1,55-1,65 (2H, m), 1,71-of 1.88 (2H, m), 2,68 (2H, DD,J=to 7.6 and 7.6 Hz), 2,78-2,95 (1H, m), 2.95 and-of 3.12 (1H, m), 3,92-4,10 (1H, m), 4,10-4.26 deaths (1H, m), 7,10-7,22 (1H, m), 7,32 (2H, d,J=8.0 Hz), 7,42-rate of 7.54 (3H, m), 7,63 (2H, d,J=8.0 Hz), with 8.05 (1H, DD,J=2,4, 2.0 Hz), 8,65 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=2.0 Hz), 13,61 (1H, user. C), DMSO: 449(M+H)+FAB
3031,11-of 1.35 (2H, m), 1,46 is 1.58 (1H, m), 1,54-of 1.64 (2H, m), a 1.75-to 1.86 (2H, m)to 2.67 (2H, DD,J=to 7.6 and 7.6 Hz), 2,80-2,95 (1H, m), 2.95 and-of 3.12 (1H, m), 3,82 (3H, s), 3,94-4,10 1H, m), 4,10-of 4.25 (1H, m)6,91 (1H, DDD,J=8,4, the 2.4, 0.8 Hz),7,14-to 7.18 (1H, m), 7.18 in-of 7.23 (1H, m), 7,30 (2H, d,J=8,4 Hz), was 7.36 (1H, DD,J=8,0, 8.0 Hz), to 7.59 (2H, d,J=8,4 Hz), with 8.05 (1H, DD,J=2,4, 2.0 Hz), 8,65 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=2.0 Hz), 13,60 (1H, user. C), DMSO: 459(M-H)-ESI
3041,10-of 1.36 (2H, m), 1,47 is 1.58 (1H, m), 1,55-of 1.66 (2H, m), 1,74-of 1.88 (2H, m), 2,87 (2H, DD,J=to 7.6 and 7.6 Hz), 2,82-2,96 (1H, m), 2,96-3,13 (1H, m), 3.95 to-4,10 (1H, m), 4,10-4.26 deaths (1H, m), 7.24 to to 7.32 (2H, m), 7,33 (2H, d,J=8,4 Hz), of 7.36-7,44 (1H, m), 7,44 is 7.50 (2H, m), of 7.48-of 7.55 (1H, m), with 8.05 (1H, DD,J=2,4, and 1.6 Hz), 8,65 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=1,6 Hz), 13,61 (1H, user. C), DMSO: 449(M+H)+FAB
305480(M+H)+FAB
306488(M+Na)+ESI
307490(M+Na)+ESI
3081,12-of 1.29 (2H, m), 1,50-to 1.63 (9H, m), 1,78-of 1.81 (2H, usher.), 2,64-2,69 (2H, m), 2,86 (1H, usher.), to 3.02 (1H, usher.), 3,23-to 3.38 (2H, m), 3,51-of 3.64 (2H, m)to 4.01 (1H, m), 4,17 (1H, m), 7,25-7,31 (4H, m), 7,80 (1H, m), of 8.28 (1H, m), 8,80 (1H, m), DMSO: 464(M-H)-FAB
3091,15 of 1.28 (2H, m), 1,47 is 1.60 (3H, m), 1,78-of 1.81 (2H, usher.), 2,65-2,69 (2H, usher.), of 2.86 (1H, m), to 3.02 (1H, m), 3,40-3,63 (8H, usher.), to 4.01 (1H, m), 4,18 (1H, m), 7,28-7,34 (4H, m), 7,80 (1H, m), of 8.28 (1H, m), 8,80 (1H, m), DMSO: 468(M+H)+FAB
310452(M+H)+FAB
311544(M+H)+ESI
312454(M+H)+ESI
3131,10-of 1.80 (16H, m), and 2.27 (3H, s), 2,65-to 2.74 (2H, m), 2,80-3,10 (2H, m), 3.95 to 4,32 (4H, m), 6.42 per (1H, d,J=7,6 Hz), 6,56 (1H, d,J=8,8 Hz), was 7.36 (1H, t,J=8.0 Hz), 7,80 (1H, usher.), of 8.27 (1H, d,J=3.2 Hz), 8,79 (1H, usher.), DMSO: 467(M+H)+FAB
3141,07-to 1.21 (2H, m), 1,27-1,51 (10H, m), 1,73-to 1.77 (2H, usher.), 1,81-of 1.84 (2H, user.) 2,83-2,89 (3H, usher.), totaling 3.04 (1H, usher.), 3,72 is 3.76 (2H, usher.), as 4.02 (1H, usher.), 4,18 (1H, usher.), 7,33 (1H, m), 7,58 (1H, m), 7,68 (1H, m), 7,80 (1H, m), 7,86 (1H, m), of 8.04 (1H, m), 8,08 (1H, m), of 8.28 (1H, m), 8,79 (1H, m), DMSO: 503(M+H)+FAB

Table 55
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
3151,00-to 1.82 (16H, m), 2.77-to is 3.08 (4H, m), 3.95 to to 4.23 (2H, m), a 4.53 (2H, d,J=12.0 Hz), 7,10-of 7.23 (2H, m), 7,42-7,58 (2H, m), 7,66 (1H, d,J=7.5 Hz), 7,81 (1H, s), to 7.99 (1H, d,J=8,5 Hz), 8,29 (1H, d,J=2.2 Hz), 8,80 (1H, s), DMSO: 503(M+H)+FAB
3161,08 is 1.23 (2H, m), 1,26-1,32 (2H, m), 1,47-of 1.57 (3H, m), 1,73-to 1.77 (2H, m), 2,37-to 2.41 (2H, m) 2,61-to 2.67 (4H, usher.), 2,87 (1H, m), 2,03 (1H, m), 3.27 to to 3.33 (4H, usher.), as 4.02 (1H, usher.), 4,18 (1H, the Shire.), 7,37 (1H, m), to 7.59 (1H, m), of 7.70 (1H, m), 7,81 (1H, m), 7,87 (1H, m), 8,06-8,11 (2H, m), 8,29 (1H, m), 8,80 (1H, m), DMSO: 526(M+Na)+ESI
3171,07-to 1.21 (2H, m), 1,27-1,51 (10H, m), 1,73-to 1.77 (2H, usher.), 1,82-of 1.85 (2H, user.) 2,67-by 2.73 (2H, usher.), 2,87 (1H, m), to 3.02 (1H, usher.), 3,28-3,39 (2H, usher.), as 4.02 (1H, usher.), 4,18 (1H, usher.), to 7.09 (1H, m), 7,41 (1H, m), 7,46-7,52 (2H, m), 7,55 (1H, m), 7,82 (1H, m), 7,86 (1H, m), 8,08 (1H, m), 8,29 (1H, m), 8,80 (1H, m), DMSO: 524(M+Na)+FAB
3181,10-1,30 (2H, m), 1,44-of 1.62 (3H, m), a 1.75 of-1.83 (2H, m), 2,70 (2H, t,J=7,3 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,47-7,74 (5H, m), 8,02 (1H, t,J=2,5 Hz), 8,17 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 379(M+H)+FAB
3191,10-1,30 (2H, m), 1,45-to 1.59 (3H, m)1,80 (2H, d,J=and 12.2 Hz), 2,63 (2H, t,J=7,4 Hz), is 2.88 (1H, t,J=and 12.2 Hz), 3,03 (1H, t,J=and 12.2 Hz), 3,31-to 3.38 (2H, m), 3,50-3,55 (2H, m), was 4.02 (1H, d,J=and 12.2 Hz), 4,18 (1H, d,J=and 12.2 Hz), 7,15-7,31 (5H, m), 8,01 (1H, t,J=2,4 Hz), 8,55 (1H, s), 8,69 (1H, t,J=5.6 Hz), 8,88 (1H, s), DMSO: 398(M+H)+FAB
3201,10-1,30 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m), 2.63 in (2H, t,J=7,4 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,15-7,31 (5H, m), to 7.67 (1H, s), 8,01 (1H, t,J=1.9 Hz), 8,17 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 354(M+H)+FAB
3211,10-1,30 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m)2,60 (2H, t,J=7,3 Hz), 2,80-3,10 (2H, m), 3,74 (3H, s), 3.95 to 4,24 (2H, m), 6,70-6,84 (3H, what), 7,13 -7,24 (1H, m), 7,66 (1H, s), 8,01 (1H, usher.), 8,18 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, usher.), DMSO: 384(M+H)+FAB
3221,10-1,30 (2H, m), 1,44 is 1.60 (3H, m), a 1.75 of-1.83 (2H, m)to 2.65 (2H, t,J=7,3 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), of 6.96-7,10 (3H, m), 7.29 trend and 7.36 (1H, m), 7,66 (1H, s), 8,01 (1H, t,J=2,5 Hz), 8,17 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=1.9 Hz), DMSO: 372(M+H)+FAB
323of 1.10 to 1.34 (2H, m), 1,50-of 1.64 (3H, m), 1,75-of 1.88 (2H, m), 2,80-3,10 (4H, m), 3.95 to 4,24 (2H, m), 7,41 (1H, dt,J=1,0, 7,4 Hz), 7,51 (1H, d,J=7,8 Hz), 7,62-of 7.70 (2H, m), 7,79 (1H, DD,Jor =1.5, 7.8 Hz), 8,02 (1H, t,J=2.0 Hz), 8,17 (1H, s), 8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 379(M+H)+FAB
324of 1.10 to 1.34 (2H, m), 1,45-of 1.64 (3H, m), 1,75-of 1.88 (2H, m)to 2.66 (2H, t,J=7,8 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,26-7,40 (3H, m), of 7.64 to 7.75 (3H, m), 7,92 (1H, s), 8,01(1H, usher.), 8,17 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2,4 Hz), DMSO: 397(M+H)+FAB
325of 1.10 to 1.34 (2H, m), 1,45-of 1.64 (3H, m), 1,75-of 1.85 (2H, m)to 2.66 (2H, t,J=7,3 Hz), 2,80-3,10 (8H, m), 3.95 to 4,24 (2H, m), 7,16-7,37 (4H, m), 7,66 (1H, s), 8,01 (1H, usher.), 8,17 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=1.4 Hz), DMSO: 425(M+H)+FAB
3260,79 with 0.93 (2H, m), 1,02-of 1.30 (10H, m), 1,37-1,49 (1H, m) of 1.57-1.77 in (7H, m), 2,81 of 2.92 (1H, usher.), 2,96-is 3.08 (1H, usher.), 3,94-of 4.05 (1H, usher.), 4,10-is 4.21 (1H, usher.), 7,63-of 7.70 (1H, usher.), of 8.00 (1H, DD, J=3.0 Hz, 2.4 Hz), 8,13-8,21 (1H, m), 8,55(1H, d, J=3.0 Hz), 8,88 (1H, d, J=2.4 Hz), DMSO: 360(M+H)+FAB
3271,10-1,30 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m), 2.63 in (2H, t,J=7,2 Hz), 2,80-3,10 (2H, m), 3,30-to 3.38 (2H, m), 3,49-3,55 (2H, m), 3.95 to 4,24 (2H, m), 7,16-7,34 (4H, m), 8,02 (1H, t,J=2,4 Hz), 8,55 (1H, usher.), 8,69 (1H, t,J=5.6 Hz), 8,87 (1H, s), DMSO: 432(M+H)+FAB

Table 56
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
3281,10-1,30 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m)2,60 (2H, t,J=7,6 Hz), 2,80-3,10 (2H, m), 3,30-to 3.38 (2H, m), 3,49-3,55 (2H, m), 3,74 (3H, s), 3.95 to 4,24 (2H, m), of 6.71 -6,82 (3H, m), 7,19 (1H, t,J=7,2 Hz), 8,01 (1H, usher.), 8,55 (1H, usher.), 8,68 (1H, t,J=6,0 Hz), 8,87 (1H, usher.), DMSO: 428(M+H)+FAB
3291,10-1,30 (2H, m), 1,45-to 1.60 (3H, m), 1,75-of 1.85 (2H, m)to 2.65 (2H, t,J=8,4 Hz), 2,80-3,10 (2H, m), 3,30-to 3.38 (2H, m), 3,49-3,55 (2H, m), 3.95 to 4,24 (2H, m), 7,05 -7,10 (3H, m), 7,30-to 7.35 (1H, m), 8,00 (1H, t,J=2,4 Hz), 8,55 (1H, usher.), 8,68 (1H, t,J=5.6 Hz), 8,87 (1H, usher.), DMSO: 416(M+H)+FAB
3301,10-1,30 (2H, m), 1,45-of 1.62 (3H, m), 1,75-of 1.85 (2H, m), 2,70 (2H, t,J=7,2 Hz), 2,80-3,10 (2H, m), 3,30-to 3.38 (2H, m), 3,49-3,55 (2H, m), 3.95 to 4,24 (2H, m)to 7.50 (1H, t,J=8.0 Hz), 7,56-7,74 (3H, m), 8,02 (1H, t,J=2.0 Hz), 8,55 (1H, d,J=2.0 Hz), 8,69 (1H, t,J=6,0 Hz), 8,87 (1H, usher.), DMSO: 423(M+H)+FAB
331of 1.10 to 1.34 (2H, m), 1,50-of 1.64 (3H, m), 1,75-1,89 (2H, m), 2,84 (2H, t,J=8.0 Hz), 2,84-3,11 (2H, m), 3,31-to 3.38 (2H, m), 3,49-3,55 (2H, m), 3.95 to of 4.25 (2H, m), 7,40 (1H, dt,J=to 0.8 and 7.6 Hz), 7,52 (1H, d,J=7,2 Hz), the 7.65 (1H, dt,J=to 1.6 and 7.6 Hz), 7,79 (1H, DD,J=1,2, 8.0 Hz), of 8.04 (1H, t,J=2.0 Hz), 8,55 (1H, d,J=2,4 Hz), 8,69 (1H, t,J=5.6 Hz), 8,87 (1H, d,J=1,6 Hz), DMSO: 423(M+H)+FAB
332462(M+H)+FAB
3331,10-1,30 (2H, m), 1,45-to 1.60 (3H, m)1,80 (2H, d,J=12.0 Hz), is 2.37 (2H, t,J=7,2 Hz), 2,63 (2H, t,J=7,2 Hz), 2,87 (1H, t,J=and 12.2 Hz), 3,03 (1H, t,J=and 12.2 Hz), 3,41-to 3.49 (2H, m)to 4.01 (1H, d,J=and 12.2 Hz), 4,18 (1H, d,J=and 12.2 Hz), 6,83 (1H, s), 7,15-7,31 (5H, m), of 7.36 (1H, s), to 7.99 (1H, t,J=2,4 Hz), 8,55 (1H, d,J=3.2 Hz), 8,76 (1H, t,J=5.6 Hz), cent to 8.85 (1H, t,J=2.0 Hz), DMSO: 425(M+H)+FAB
3341,08-1,32 (2H, m), 1,45-to 1.60 (3H, m), 1,74 is 1.86 (2H, m)to 2.66 (2H, DD,J=to 7.2, 7.2 Hz), 2,80-2,95 (1H, m), 2.95 and-3,11 (1H, m), 3.95 to 4,08 (1H, m), 4,11-of 4.25 (1H, m), 7,09-7,17 (2H, m), 7,20-7,28 (1H, m), 7,28 and 7.36 (1H, m), to 7.67 (1H, user. C)8,02 (1H, DD,J=2,4, 2.0 Hz), 8,18 (1H, user. C), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 372(M+H)+FAB
3351,08-1,32 (2H, m), 1,44-to 1.61 (3H, m), 1,77 of-1.83 (2H, usher.), 2,63 (2H, t, J=7,6 Hz), 2,79-is 3.08 (2H, usher.), 3,95-to 4.23 (2H, usher.), of 6.73 (1H, d, J=16.0 Hz), 7,14-7,22 (3H, m), 7,25-to 7.32 (2H, m), of 7.64 (1H, d, J=16.0 Hz),8,02-of 8.06 (1H, m), 8,40-8,44 (1H, m), 8,68-8,73 (1H, m), 12,55-12,63 (1H, usher.), DMSO: 380(M+H)+FAB
336of 1.09 to 1.31 (2H, m), USD 1.43-of 1.56 (1H, m), 1,53-of 1.64 (2H, m), 1,71 is 1.86 (2H, m)to 2.67 (2H, DD,J=8,0, 8.0 Hz), 2,79-2,96 (1H, m), 2,92-3,11 (1H, m), 3,93-4,10 (1H, m), 4,08-4,24 (1H, m), 7,31 (2H, d,J=5,2 Hz), to 7.67 (1H, s), 8,01 (1H, DD,J=2,4, and 1.6 Hz), 8,19 (1H, s), 8,49 (2H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=1,6 Hz), DMSO: 355(M+H)+ESI
3371,08-1,32 (2H, m), USD 1.43-of 1.57 (1H, m), 1,52-to 1.63 (2H, m), 1,72 is 1.86 (2H, m)to 2.66 (2H, DD,J=to 7.2, 7.2 Hz), 2,80-2,95 (1H, m), 2.95 and-3,11 (1H, m), 3,93-4,08 (1H, m), 4,10-of 4.25 (1H, m), 7,33 (1H, DD,J=to 7.6, 4.8 Hz), 7,62-7,72 (2H, m), 8,01 (1H, DD,J=2,4, and 1.6 Hz), 8,19 (1H, user. C)to 8.41 (1H, user. C)of 8.47 (1H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=1,6 Hz), DMSO: 355(M+H)+ESI
3381,10-of 1.33 (2H, m), 1,45-to 1.59 (1H, m), 1,54-of 1.65 (2H, m), a 1.75-to 1.87 (2H, m)to 2.67 (2H, DD,J=to 7.6 and 7.6 Hz), 2,81-2,95 (1H, m), 2,96-3,10 (1H, m), 3,92-4,08 (1H, m), 4,11-of 4.25 (1H, m), 7,27 (2H, t,J=8,8 Hz), 7,31 (2H, d,J=8,4 Hz), 7,56 (2H, d,J=8,4 Hz), 7,63-7,72 (3H, m), 8,02 (1H, DD,J=2,4, 2.0 Hz), 8,19 (1H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 448(M+H)+FAB
3391,10-of 1.33 (2H, m), 1,47-to 1.63 (1H, m), 1,53-of 1.65 (2H, m), 1,76-of 1.88 (2H, m)to 2.66 (2H, DD,J=to 7.2, 7.2 Hz), 2,80-2,96 (1H, m), 2,96-3,11 (1H, m), with 3.79 (3H, s), 3.96 points-4,07 (1H, m), 4,12-of 4.25 (1H, m), 7,01 (2H, d,J=8,4 Hz), 7,28 (2H, d,J=8,4 Hz), 7,53 (2H, d,J=8,4 Hz), 7,58 (2H, d,J=8,4 Hz), to 7.67 (1H, user. C)to 8.0 (1H, DD,J=2,4, 2.0 Hz), 8,19 (1H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 458(M+H)+FAB

Table 57
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
3401,10-1,32 (2H, m), 1,45-to 1.67 (3H, m), a 1.75-to 1.87 (2H, m), a 2.71 (2H, t,J=8.0 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7.23 percent (1H, d,J=7,2 Hz), 7,33-7,52 (6H, m), of 7.64-7,71 (2H, m), 8,02 (1H, t,J=2.0 Hz), 8,19 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=1,6 Hz), DMSO: 430(M+H)+FAB
3411,10-1,32 (2H, m), 1,45-to 1.67 (3H, m), a 1.75-to 1.87 (2H, m), a 2.71 (2H, t,J=7,6 Hz), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,29 (1H, d,J=7,6 Hz), 7,41 (1H, t,J=7,6 Hz), 7,55 (1H, d,J=7,2 Hz), 7,60-7,73 (3H, m), 7,82 (1H, d,J=7,2 Hz), 8,00-8,08 (2H, m), 8,16 (1H, s), to 8.20 (1H, s), 8,65 (1H, usher.), 8,91 (1H, usher.), DMSO: 455(M+H)+FAB
3421,06-of 1.30 (2H, m), USD 1.43-of 1.56 (1H, m)and 1.51-of 1.61 (2H, m), 1.69 in (2H, square,J=6,4 Hz), 1,74-of 1.85 (2H, m), 2.63 in (2H, DD,J=to 7.6 and 7.6 Hz), 2,80-to 2.94 (1H, m), 2,94-3,10 (2H, m)to 3.33 (2H, dt,J=to 6.4, 6.4 Hz), 3,47 (2H, t,J=6,4 Hz), 3,93-4.09 to (1H, m), 4.09 to-4,24 (1H, m), 7,13-7,24 (3H, m), 7.24 to 7,31 (2H, m), to 7.99 (1H, DD,J=2,4, and 1.6 Hz), 8,54 (1H, d,J=2,4 Hz), 8,67 (1H, user. t,J=5,2 Hz), cent to 8.85 (1H, d,J=1,6 Hz), DMSO: 412(M+H)+FAB
343 of 1.08 to 1.31 (2H, m), 1,44-of 1.56 (1H, m), 1,52-to 1.61 (2H, m), 1,74 is 1.86 (2H, m), 1,82-of 1.93 (2H, m), 2.63 in (2H, DD,J=to 7.2, 7.2 Hz), of 2.72 (6H, s), 2,80-of 2.93 (1H, m), 2,98-to 3.09 (3H, m)to 3.34 (2H, dt,J=to 6.4, 6.4 Hz), 3,94-4,07 (1H, m), 4,10-4,24 (1H, m), 7,13-7,24 (3H, m), 7.24 to to 7.32 (2H, m), 8,00 (1H, DD,J=2,4, and 1.6 Hz), to 8.57 (1H, d,J=2,4 Hz), cent to 8.85 (1H, user. t,J=5.6 Hz), 8,88 (1H, d,J=1,6 Hz), DMSO: 439(M+H)+FAB
344of 1.09 to 1.34 (2H, m), 1,45-to 1.60 (1H, m), 1,55-of 1.66 (2H, m), a 1.75-to 1.87 (2H, m), 2,70 (2H, DD,J=to 7.6 and 7.6 Hz), 2,80-2,96 (1H, m), 2,96-3,11 (1H, m), of 3.94-4.09 to (1H, m), 4,10-4.26 deaths (1H, m), 7,37 (2H, d,J=8,4 Hz), 7,68 (1H, user. C)of 7.69 (2H, d,J=8,4 Hz), 7,87 (2H, d,J=8,4 Hz), to $ 7.91 (2H, d,J=8,4 Hz), 8,02 (1H, DD,J=2,4, 2.0 Hz), 8,19 (1H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 455(M+H)+FAB
345of 1.10 to 1.34 (2H, m), 1,46 is 1.60 (1H, m), 1,54-of 1.66 (2H, m), 1,75-1,89 (2H, m), 2,68 (2H, DD,J=to 7.6 and 7.6 Hz), 2,80-2,96 (1H, m), 2,96-of 3.12 (1H, m), 3.95 to 4.09 to (1H, m), 4,11-4.26 deaths (1H, m), 7,13-7,21 (1H, m), 7,33 (2H, d,J=8.0 Hz), 7,45-7,52 (3H, m), 7,63 (2H, d,J=8.0 Hz), to 7.67 (1H, user. C)8,02 (1H, DD,J=2,4, 2.0 Hz), 8,19 (1H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 448(M+H)+FAB
3461,10-of 1.35 (2H, m), 1,48-to 1.61 (1H, m), 1.56 to of 1.66 (2H, m), 1,76-1,90 (2H, m), 2,69 (2H, DD,J=8,0, 8.0 Hz), 2,81-of 2.97 (1H, m), 2,97-3,13 (1H, m), 3.95 to-4,10 (1H, m), 4,10-4.26 deaths (1H, m), 7,25-to 7.32 (2H, m), 7,33 (2H, d,J=8.0 Hz), of 7.36-7,44 (1H, m), 7,44 is 7.50 (2H, m), of 7.48-7,56 (1H, m), to 7.67 (1H, user. C)8,02 (1H, DD,J=2,8, 2.0 Hz), 8,19 (1H, user. C)8,56 (1H, d,J=2,8 Hz), 8,89 (1H, d,J=2,0 Hz), DMSO: 448(M+H)+FAB
347of 1.08 to 1.31 (2H, m), USD 1.43-of 1.55 (1H, m), 1,50-to 1.61 (2H, m), 1,72-of 1.85 (2H, m), 2.63 in (2H, DD,J=7,8, and 7.8 Hz), 2,80-of 2.93 (1H, m), 2,90 (2H, t,J=6,8 Hz), 2,96-to 3.09 (1H, m), of 3.56 (2H, dt,J=to 6.8, 6.8 Hz), 3,93-4,08 (1H, m), 4,08-to 4.23 (1H, m), 7,14-7,24 (3H, m), 7.24 to 7,31 (2H, m), 7,33 (2H, d,J=5.6 Hz), 7,95 (1H, DD,J=2,8, 1,6 Hz)and 8.50 (2H, user. C), 8,55 (1H, d,J=2,8 Hz), 8,81 (1H, d,J=1,6 Hz), 8,81 (1H, t,J=6,0 Hz), DMSO: 459(M+H)+FAB
348of 1.08 to 1.31 (2H, m), USD 1.43-of 1.57 (1H, m), 1,50-of 1.62 (2H, m), 1,73 is 1.86 (2H, m), 2.63 in (2H, DD,J=7,8, and 7.8 Hz), 2,80-of 2.93 (1H, m), 2,89 (2H, t,J=6,8 Hz), 2,96-to 3.09 (1H, m), of 3.54 (2H, dt,J=to 6.8, 6.8 Hz), of 3.94-4.09 to (1H, m), 4.09 to of 4.25 (1H, m), 7,13-of 7.25 (3H, m), 7,25-to 7.32 (2H, m), 7,35 (1H, DD,J=to 7.6, 4.8 Hz), 7,71 (1H, d,J=7,6 Hz), 7,92-of 7.97 (1H, m), 8,44 (1H, user. C)8,49 (1H, user. C)charged 8.52-8,59 (1H, m), 8,77 cent to 8.85 (2H, m), DMSO: 459(M+H)+FAB
3491,10-1,32 (2H, m), 1,45-to 1.67 (3H, m), a 1.75-to 1.87 (2H, m), 2,69-2,78 (2H, m), 2,80-3,10 (2H, m), 3.95 to 4,24 (2H, m), 7,27-7,46 (3H, m), 7,66 (1H, s), 7,83-8,03 (5H, m), 8,18 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,66 (1H, usher.), 8,89 (1H, d,J=1.2 Hz), DMSO: 431(M+H)+FAB
350425(M+H)+FAB
3511,05-1,85 (17H, m)to 2.67 (2H, t,J=7,6 Hz), 2,80-3,10 (2H, m), 3,70-of 3.80 (1H, m), 3.95 to 4,24 (2H, m), 7,33-7,37 (2H, m), 7,62-of 7.70 (3H, m), 8,01 (1H, t,J=2.0 Hz), 8,13 (1H, d,J=7,6 Hz), 8,17 (1H, s), 8,55 (1H, d,J=2,8 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 479(M+H) FAB

Table 58
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MS m/z
352411(M+H)+FAB
3531,08-1,32 (2H, m), 1,43 is 1.58 (1H, m), 1,52-of 1.64 (2H, m), 1,72-to 1.87 (2H, m), 2,68 (2H, DD, J=7,8, and 7.8 Hz), 2,78-2,95 (1H, m), 2,97-of 3.12 (1H, m), 3,93-4.09 to (1H, m), 4,10-of 4.25 (1H, m), 7,26 (1H, user. C), 7,29 (2H, d, J=8.0 Hz), to 7.67 (1H, user. C)7,79 (2H, d, J=8.0 Hz), 7,89 (1H, user. C)8,01 (1H, DD, J=2,4, 1.2 Hz), 8,18 (1H, user. C), 8,55 (1H, d, J=2.4 Hz), 8,89 (1H, d, J=1.2 Hz), DMSO: 397(M+H)+FAB
354of 1.08 and 1.33 (2H, m), 1,44 is 1.58 (1H, m), 1,52-of 1.64 (2H, m), 1,73-of 1.88 (2H, m)to 2.67 (2H, DD,J=7,8, and 7.8 Hz), 2,80-2,96 (1H, m), of 2.92 (3H, s), 2,95 (3H, s), 2,96-of 3.12 (1H, m), 3,92-4,08 (1H, m), 4.09 to of 4.25 (1H, m), 7,27 (2H, d,J=7,6 Hz), 7,32 (2H, d,J=7,6 Hz), to 7.67 (1H, user. C)8,01 (1H, DD,J=2,4, and 1.6 Hz), 8,18 (1H, user. C)8,56 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=1,6 Hz), DMSO: 425(M+H)+FAB
355of 1.11 to 1.31 (2H, m), 1,40-of 1.66 (9H, m), 1,74 is 1.86 (2H, usher.), 2,64-2,69 (2H, m), 2,86 (1H, usher.), to 3.02 (1H, usher.), 3,23-to 3.38 (2H, m), 3,51-of 3.64 (2H, m)to 4.01 (1H, m), 4,17 (1H, m), 7,15-7,20 (2H, m), 7,30-7,37 (2H, m), to 7.67 (1H, s), 8,01 (1H, m), 8,18 (1H, s), 8,55 (1H, m), 8,89 (1H, m), DMSO: 465(M+H)+ESI
3561,21-of 1.36 (2H, m), 1,54-to 1.59 (3H, m), 1,78-1,82(2H, user.), 2,64-2,69 (2H, usher.), 2,87 (1H, m), 3,03 (1H, m), 3,37 at 3.69 (8H, usher.), to 3.99 (1H, m)to 4.16 (1H, m), 7,15-7,20 (2H, m), 7,30-7,37 (2H, m), to 7.67 (1H, s), 8,01 (1H, m), 8,18 (1H, s), 8,55 (1H, m), 8,89 (1H, m), DMSO: 467(M+H)+ESI
3571,15 of 1.28 (2H, m), 1,44-of 1.62 (9H, m), 1,79 of-1.83 (2H, usher.), 2,65 of 2.68 (2H, m), is 2.88 (1H, usher.), 3,03 (1H, usher.), 3,24-3,37 (2H, usher.), 3,47-3,62 (2H, m)to 4.01(1H, m), 4,18 (1H, m), 7,26-7,30 (4H, m), to 7.67 (1H, s), 8,02 (1H, m), 8,18 (1H, s), 8,55 (1H, m), 8,89 (1H, m), DMSO: 465(M+H)+FAB
3581,13 of 1.28 (2H, m), 1,48-to 1.61 (3H, m), 1,79-1,82 (2H, usher.), 2,65-2,69 (2H, usher.), is 2.88 (1H, m), 3.04 from (1H, m), 3,34-the 3.65 (8H, usher.), to 4.01 (1H, m), 4,18 (1H, m), 7,15-7,20 (2H, m), 7,28-7,34 (4H, m), 7,66 (1H, s), 8,01 (1H, m), 8,17 (1H, s), 8,55 (1H, m), 8,89 (1H, m), DMSO: 467(M+H)+FAB
3591,16-1,25 (2H, m)and 1.51-of 1.61 (3H, m), 1,79-of 1.88 (6H, usher.), 2,65-2,69 (2H, m), 2,87 (1H, usher.), 3,03 (1H, usher.), 3,31-to 3.38 (2H, usher.), 3,44-3,47 (2H, m)to 4.01 (1H, m), 4,18 (1H, m), 7.29 trend was 7.36 (4H, m), 7,68 (1H, s), 8,01 (1H, m), 8,19 (1H, s), 8,55 (1H, m), 8,89 (1H, m), DMSO: 451(M+H)+ESI
360of 1.03 to 1.31 (8H, m), 1,46-of 1.66 (3H, m), 1,78 of-1.83 (2H, usher.), 2,64-2,69 (2H, m), 2,87 (1H, usher.), 3,03 (1H, usher.), 3,14-3,24 (2H, usher.), 3,35-to 3.49 (2H, m), a 4.03(1H, m), 4,18 (1H, m), 7,12-to 7.18 (2H, m), 7,27-7,37 (2H, m), 7,68 (1H, s), 8,02 (1H, m), 8,19 (1H, s), 8,56 (1H, m), 8,89 (1H, m), DMSO: 453(M+H)+ESI
3611,13-of 1.30 (2H, m), 1,48-to 1.61 (3H, m), 1,78 of-1.83 (2H, usher.), 2,65-a 2.71 (2H, m), 2,87 (1H, usher.), 3,03 (1H, usher.), 3,92-3,98 (2H, m)4,00 (1H, m), 4,18 (1H, m), 4,37-,43 (2H, m), 7,38-7,41 (2H, m), 7,66-of 7.70 (2H, m), 7,73 (1H, s), 8,01 (1H, m), 8,19 (1H, s), 8,56 (1H, m), 8,89 (1H, m), DMSO: 423(M+H)+API
362the 1.04 to 1.37 (8H, m), 1,45 by 1.68 (3H, m)and 1.83 (2H, d, J=12,8 Hz), 2,69 (2H, t, J=7,3 Hz), 2,86 (1H, t, J=12.1 Hz), 2,99 (1H, t, J=12.1 Hz), or 3.28 (2H, usher.), of 3.53 (2H, usher.), 4,15-4,34 (2H, m), 7,20 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=8.1 Hz), 8,01 (1H, s), 8,59 (1H, s)8,89 (1H, s)CDCl3: 453(M+H)+ESI
3631,18-of 1.36 (2H, m), 1,44 by 1.68 (3H, m), 1,76-2,12 (6H, m), 2,69 (2H, t, J=7.5 Hz), 2,84 (2H, t, J=11,9 Hz), 2,98 (2H, t, J=11,9 Hz), 4,25 (4H, usher.), of 6.02 (1H, usher.), of 6.73 (1H, usher.), then 7.20 (2H, d, J=7.9 Hz), was 7.45 (2H, d, J=7.9 Hz), 7,98 (1H, s), to 8.57 (1H, s), cent to 8.85 (1H, s)CDCl3: 451(M+H)+ESI

Table 59
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
3641,18-of 1.36 (2H, m), 1,44 is 1.70 (3H, m), 1.77 in-of 1.92 (2H, m), of 2.72 (2H, t, J=7.5 Hz), 2,85 (2H, t, J=11,4 Hz)to 2.99 (2H, t, J=11,4 Hz), 4,08 (2H, t, J=9.6 Hz), 4.26 deaths (2H, usher.), 4,47 (2H, t, J=9.6 Hz), 7,25 (2H, d, J=7.8 Hz), to $ 7.91 (2H, d, J=7.8 Hz), 7,94-to 7.99 (1H, m), 8,58 (1H, d, J=2.4 Hz), 8,83 (1H, d, J=2.4 Hz)CDCl3: 423(M+H)+ESI
365of 1.03 (2H, d, J=6.2 Hz), 1,12-of 1.30 (2H, m), 1,48-of 1.62 (3H, m)1,80 (2H, d, J=12,8 Hz), 2,68 (2H, t, J=7.4 Hz), 2,87 (1H, t, J=12,8 Hz), 3,03 (1H, t, J=12,8 Hz), 3,38-of 3.80 (6H, m)to 4.01 (1H, d, J=12,8 Hz), 4,17 (1H, d, J=12,8 Hz), 6,65 of 6.68 (1H, is), at 6.84 (1H, d, J=8,4 Hz), 7.23 percent-7,39 (4H, m), 7,53-EUR 7.57 (1H, m), 7,66 (1H, s), 8,00-8,02 (1H, m), 8,11-8,13 (1H, m), 8,18 (1H, s), 8,55 (1H, d, J=2.4 Hz), 8,88 (1H, d, J=2.0 Hz), DMSO: 543(M+H)+FAB
366of 1.03 (2H, d, J=6.2 Hz), 1,12-of 1.30 (2H, m), 1,48-of 1.62 (3H, m)1,80 (2H, d, J=12,4 Hz), 2,68 (2H, t, J=7.4 Hz), 2,87 (1H, t, J=12,4 Hz), 3,03 (1H, t, J=12,4 Hz), 3,10-of 3.28 (3H, m), 3,40-a 3.83 (3H, m), was 4.02 (1H, d, J=12,4 Hz), 4,18 (1H, d, J=12,4 Hz), to 6.80 (1H, t, J=7,6 Hz), to 6.95 (2H, d, J=7,6 Hz), 7,20-740 (6H, m), 7,66 (1H, s), 8,00 (1H, t, J=2.4 Hz), 8,18 (1H, s), 8,55 (1H, d, J=2.4 Hz), 8,88 (1H, d, J=2,0 Hz), DMSO: 542(M+H)+FAB
3671,12-1,32 (2H, m), 1,48-and 1.63 (3H, m), equal to 1.82 (2H, d, J=12,4 Hz), 2,68 (2H, t, J=7.2 Hz), is 2.88 (1H, t, J=12,4 Hz), 3.04 from (1H, t, J=12,4 Hz), 3,40 of 3.75 (8H, m), was 4.02 (1H, d, J=12,4 Hz), 4,18 (1H, d, J=12,4 Hz), 6,65 of 6.68 (1H, m), at 6.84 (1H, d, J=8,8 Hz), 7,31 (2H, d, J=8.0 Hz), was 7.36 (2H, d, J=8.0 Hz), 7,53-EUR 7.57 (1H, m), 7,66 (1H, s), 8,01 (1H, d, J=2.4 Hz), 8,11-8,13 (1H, m), 8,18 (1H, s), 8,55 (1H, d, J=2,8 Hz), 8,89 (1H, d, J=2.0 Hz), DMSO: 543(M+H)+FAB
368of 1.11 to 1.31 (2H, m), 1,48-and 1.63 (3H, m), is 1.81 (2H, d, J=and 12.2 Hz), 2,68 (2H, t, J=7.2 Hz), is 2.88 (1H, t, J=12,8 Hz), 3.04 from (1H, t, J=12,8 Hz), 3,10-of 3.25 (4H, m), 3,42-3,81 (4H, m), was 4.02 (1H, d, J=12,8 Hz), 4,18 (1H, d, J=12,8 Hz), for 6.81 (1H, t, J=7.2 Hz), to 6.95 (2H, d, J=8,4 Hz), 7,21-7,37 (6H, m), 7,66 (1H, s), 8,01 (1H, s), 8,18 (1H, s), 8,55 (1H, d, J=2.4 Hz), 8,88 (1H, s), DMSO: 542(M+H)+FAB
3691,19 is 1.23 (2H, m), 1,52-of 1.62 (3H, m), 1,78-of 1.85 (2H, m), 2,70 (2H, d,J=7,8 Hz), is 2.88 (1H, t,J=to 11.9 Hz), 3,03 (1H, t,J=to 10.7 Hz), 3,52 (2H, DD,J=5,4, 5,2 Hz)and 3.59 (1H, DD,J=to 5.3, 5.3 Hz), was 4.02 (1H, m) 4,18 (1H, m), 4,48 (1H, t,J=5,2 Hz), 4,60 (1H, t,J=5,2 Hz), 7,35-7,38 (2H, m), 7.68 per-of 7.69 (2H, m), 7,72 to 7.75 (1H, m), 8,02-8,07 (1H, m), 8,18-8,23 (1H, m), 8,56-8,59 (1H, m), 8,63-8,68 (1H, m), 8,89-8,91 (1H, m), DMSO: 443(M+H)+FAB
370of 1.13 and 1.33 (2H, m), 1,52-and 1.63 (3H, m), 1,75-of 1.85 (2H, m), 2,68 (2H, d,J=7,8 Hz), is 2.88 (1H, t,J=10.0 Hz), 3,03 (1H, t,J=10.0 Hz), 3,30-to 3.35 (2H, m), 3.46 in-3,54 (2H, m), 4,15 (1H, d,J=and 17.2 Hz), 4,18 (1H, d,J=16.0 Hz), 7,33-7,39 (2H, m), 7,62-7,72 (3H, m), 8,00 shed 8.01 (1H, m), 8,16-8,18 (1H, m), 8,35-8,29 (1H, m), 8,55 (1H, d,J=3,4 Hz), 8,89 (1H, d,J=2.2 Hz), DMSO: 441(M+H)+ESI
371to 1.21 and 1.35 (2H, m)to 1.48 (9H, s), 1,48 is 1.60 (1H, m), 1,61 was 1.69 (2H, m), 1,79-to 1.87 (2H, m), a 2.71 (2H, DD, J=6,0,6,0 Hz), 2,86 (1H, t, J=9.6 Hz), of 3.00 (1H, t, J=9.6 Hz), 4,18-to 4.33 (2H, m), USD 5.76 (1H, usher.), to 5.93 (1H, s), 6,28 (1H, usher.), 7,27-to 7.35 (2H, m), 7,45 is 7.50 (1H, m), to 7.61 (1H, s), of 7.96 (1H, s), 8,58 (1H, s), 8,84 (1H, s)CDCl3: 454(M+H)+ESI
372of 1.27 (6H, d, J=4,8 Hz), 1,61 was 1.69 (2H, m), 1,72-of 1.88 (5H, m), a 2.71 (2H, t, J=6,0,6,0 Hz), 2,86 (1H, t, J=9,0 Hz)of 3.00 (1H, t, J=9.0 Hz), 4,17 is 4.36 (3H, m), of 5.81 (1H, usher.), 5,95 (1H, usher.), is 6.54 (1H, usher.), 7,21-7,39 (2H, m), 7,52 (1H, d, J=6.0 Hz), 7,63 (1H, s), of 7.97 (1H, s), 8,61 (1H, s)8,89 (1H, s)CDCl3: 439(M+H)+ESI
373of 1.10 to 1.31 (2H, m), 1,47-of 1.62 (3H, m), 1,78 of-1.83 (2H, m), 2,39 is 2.51 (2H, m), 2,66-2,69 (2H, m), 2,82 of 2.92 (1H, usher.), 2,98-3,10 (1H, usher.), the 3.65-to 3.73 (2H, usher.), the 3.89 (2H, t,J=13.1 Hz), 3,98-4,22 (2H, m), 7,31 (2H, d,J=8,2 Hz), of 7.48 (2H, d,J=8,2 Hz), 7,63-of 7.69 (1H, usher.), 8,00-8,02 (1H, m), 8,15-8,21 (1H, usher.), 8,55-8,56 (1H, m), 8,88-8,89 (1H, m) DMSO: 487(M+H) +FAB

Table 60
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
374of 1.10 to 1.31 (2H, m), 1,47-to 1.59 (3H, m), 1,77 of-1.83 (2H, m), of 2.56 (2H, t,J=7.5 Hz), 2,82-is 3.08 (2H, m), 3,99-is 4.21 (2H, m), 5,77-of 5.82 (2H, usher.), to 6.75 (1H, d,J=7.5 Hz), 7,11 (1H, t,J=7.5 Hz), 7,17-7,20 (1H, m), 7,25-7,27 (1H, usher.), the 7.65 of 7.70 (1H, usher.), 8,00-8,03 (1H, m), 8,15-8,21 (1H, usher.), 8,40-to 8.45 (1H, usher.), 8,54-8,56 (1H, m), 8,88-of 8.90 (1H, m), DMSO: 412(M+H)+FAB
3751,10-1,30 (2H, m), 1,46 is 1.60 (3H, m), 1,76-1,90 (6H, m), to 2.57 (2H, t,J=7,4 Hz), 2,82-3,10 (2H, m), 3,32-3,39 (4H, m), 3,97-to 4.23 (2H, m), 6,77 (1H, d,J=7,8), 7,12 (1H, t,J=7,8 Hz), 7,30-7,38 (2H, m), of 7.64-to 7.68 (1H, usher.), 7,99-8,02 (2H, m), 8,16-8,21 (1H, usher.), 8,54-8,56 (1H, m), 8,88-of 8.90 (1H, m) , DMSO: 466(M+H)+FAB
3761,12-of 1.30 (2H, m), 1,47-and 1.63 (3H, m), 1.77 in-of 1.85 (2H, m), 2,39-2,52 (2H, m), 2,69 (2H, t,J=7,8 Hz), 2,83-is 3.08 (2H, m), 3,63 of 3.75 (2H, m), 3,83-of 3.94 (2H, m), 3,97-4,24 (2H, m), 7,33-7,41 (4H, m), 7,66-of 7.70 (1H, usher.), 8,03-with 8.05 (1H, m), 8,18 is 8.22 (1H, usher.), to 8.57 (1H, d,J=2,4 Hz), of 8.90 (1H, d,J=1.7 Hz), DMSO: 487(M+H)+FAB
3771,18-to 1.38 (2H, m), 1,48-1,71 (3H, m), 1,78-1,89 (2H, m), 2,14 of-2.32 (2H, m), a 2.71 (2H, t, J=7.5 Hz), 2,80-3,24 (6H, m), 3,57-a 3.83 (2H, m), 4.26 deaths (2H, DD, J=7,0 Hz), 5,80 (1H, usher.), 6,51 (1H, usher.), to 7.09 (1H, d, J7,5 Hz), 7,22-7,53 (7H, m), 7,60 (1H, d, J=8,2 Hz), 7,80-7,87 (1H, m), with 8.05 (1H, DD, J=2,0,2,0 Hz), 8,16 is 8.25 (1H, m), at 8.60 (1H, s), 8,96 (1H, s), DMSO: 593(M+H)+ESI
3781,00-1,80 (16H, m), and 2.27 (3H, s), 2,65-to 2.74 (2H, m), 2,80-3,10 (2H, m), 3.95 to 4,32 (4H, m), 6.42 per (1H, d,J=7,6 Hz), 6,56 (1H, d,J=8,8 Hz), was 7.36 (1H, t,J=7,6 Hz), to 7.67 (1H, s), 8,00 (1H, t,J=2,4 Hz), 8,19 (1H, s), 8,55 (1H, d,J=2,4 Hz), 8,89 (1H, d,J=2.0 Hz), DMSO: 466(M+H)+FAB
3791,11-to 1.21 (2H, m), 1,27-1,49 (10H, m), 1,74-of 1.84 (4H, usher.), 2,83 of 2.92 (3H, usher.), 3,05 (1H, usher.), 3,71 of 3.75 (2H, usher.), as 4.02 (1H, usher.), 4,18 (1H, usher.), 7,34 (1H, m), 7,58 (1H, m), 7,66-7,71 (2H, m), 7,86 (1H, m), 8,00-8,03 (2H, m), 8,07 (1H, m), 8,19 (1H, s), 8,55 (1H, m), 8,89 (1H, m), DMSO: 502(M+H)+FAB
3801,00-to 1.82 (16H, m), 2.77-to 3,10 (4H, m), 3.95 to to 4.23 (2H, m), a 4.53 (2H, d,J=12.0 Hz), 7,15-7,26 (2H, m), 7,45-of 7.55 (2H, m), 7,62-of 7.70 (2H, m), 7.95 is-with 8.05 (2H, m), to 8.20 (1H, s), 8,46 (1H, d,J=2,8 Hz), 8,89 (1H, d,J=1.7 Hz), DMSO: 502(M+H)+FAB
3811,11-1,20 (2H, m), 1,27-1,32 (2H, m), 1,47-to 1.61 (3H, m), 1,75-of 1.78 (2H, m), 2,34 is 2.44 (2H, m), 2,56-to 2.74 (4H, m), is 2.88 (1H, t,J=12.1 Hz), 3.04 from (1H, t,J=12,5 Hz), 3,23-to 3.41 (4H, m)to 4.01 (1H, d,J=13,0 Hz), 4,18 (1H, d,J=and 12.4 Hz), 7,37 (1H, d,J=5.6 Hz), EUR 7.57-to 7.61 (1H, m), 7.68 per-7,71 (2H, m), 7,87 (1H, d,J=8.1 Hz), 8,01 (1H, t,J=2.2 Hz), 8,06-8,10 (2H, m), 8,18 (1H, usher.), 8,55 (1H, d,J=2,4 Hz), 8,88 (1H, d,J=1,8 Hz), DMSO: 503(M+H)+FAB
3821,15-1,19 (2H, m), 1,27-1,4 (10H, m), 1,74-of 1.85 (4H, m), 2,70 (2H, m), 2,89 (1H, t,J=and 12.4 Hz), 3.04 from (1H, t,J=12.1 Hz), 3,26-and 3.31 (2H, m), was 4.02 (1H, m), 4,18 (1H, d,J=and 12.4 Hz), to 7.09 (1H, d,J=14,8 Hz), 7,40 (1H, t,J=7,8 Hz), 7,46-7,51 (2H, m), 7,55 (1H, d,J=8,3 Hz), of 7.64-of 7.70 (1H, usher.), the 7.85-7,87 (1H, m), 8,17 (1H, t,J=2.2 Hz), 8.07-a of 8.09 (1H, m), 8,15-8,21 (1H, usher.), 8,55 (1H, d,J=2,8 Hz), 8,89 (1H, d,J=1.7 Hz), DMSO: 501(M+H)+FAB

Table 61
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
383of 0.87 (3H, t,J=6,4 Hz), 1,20-of 1.46 (8H, m), 1,54-1,72 (2H, m)to 1.70 (2H, square,J=6,4 Hz), 1,81-of 1.94 (2H, m), 2,54-of 2.64 (1H, m), 2,85 was 3.05 (1H, m), 3,05-of 3.25 (1H, m), 3,91 (2H, t,J=6,4 Hz), 4,00-4,16 (1H, m), 4,15-or 4.31 (1H, m), 6,56-6,63 (1H, m), 7,07-7,13 (1H, m), 7,17 (1H, DD,J=8,0, 8.0 Hz), 7.29 trend and 7.36 (1H, m), 7,45 (1H, DD,J=7,8, 5,2 Hz), to 7.59-to 7.67 (1H, m), 8,40-8,46 (2H, m), for 9.90 (1H, s),DMSO:440(M+H)+FAB
384of 0.87 (3H, t,J=6,4 Hz), 1,20-of 1.45 (8H, m), 1,55-to 1.77 (4H, m), 1,80-of 1.93 (2H, m), 2,52-2,62 (1H, m), 2,88 totaling 3.04 (1H, m), 3.04 from-3,19 (1H, m), 3,90 (2H, t,J=6,4 Hz), 4,00-to 4.14 (1H, m), 4,16-4,30 (1H, m), 6,85 (2H, d,J=8,8 Hz), was 7.45 (1H, DD,J=8,3, a 4.9 Hz), 7,49 (2H, d,J=9,2 Hz), to 7.61-7,66 (1H, m), 8,40-to 8.45 (2H, m), 9,78 (1H, s),DMSO:440(M+H)+FAB
385369(M+H)+FAB
386 480(M+H)+FAB
387424(M+H)+FAB
388of 0.85 (3H, t,J=7,2 Hz), 1,20-of 1.32 (6H, m), 1,45 is 1.58 (2H, m), 1.56 to of 1.78 (2H, m), 1,81-of 1.94 (2H, m), 2,48-of 2.54 (2H, m), 2,55-of 2.66 (1H, m), 2,90 was 3.05 (1H, m), 3,07-is 3.21 (1H, m), 4,00-to 4.15 (1H, m), 4,17-4,32 (1H, m), 7,10 (2H, d,J=8.0 Hz), to 7.50 (2H, d,J=8.0 Hz), 7,68 (1H, user. C)of 8.04 (1H, DD,J=2,8, 2.0 Hz), 8,19 (1H, usher.), 8,58 (1H, d,J=2,8 Hz), of 8.90 (1H, d,J=2.0 Hz), 9,86 (1H, usher.),DMSO:453(M+H)+FAB
3891,56-of 1.74 (2H, usher.), 1,88-2,04 (2H, usher.), 2,48 of $ 2.53 (3H, m), 3.25 to 3,55 (2H, usher.), the 3.65-to 3.92 (2H, usher.), 4,46-4,55 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,01 (1H, s), to 7.15 (1H, dt,J=2,9, 8,8 Hz), 7.23 percent-7,30 (2H, m), 7,40-7,47 (1H, m), 7,70-8,30 (2H, usher.),DMSO
3901,55-of 1.74 (2H, usher.), 1,88-2,04 (2H, usher.), 3,25-3,55 (2H, usher.), the 3.65-to 3.92 (2H, usher.), 4,46-of 4.54 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,01 (1H, s), to 7.15 (1H, dt,J=2,9, 8,8 Hz), 7.23 percent-7,30 (2H, m), 7,40-7,47 (2H, m), 7,86-7,94 (1H, usher.), 7,97-with 8.05 (1H, usher.), 10,19 (1H, s),DMSO:
439(M+H)+FAB
3911,58-to 1.77 (2H, usher.), 1,91 e 2.06 (2H, usher.), 3,28-to 3.41 (1H, usher.), 3,45 is 3.57 (1H, usher.), the 3.65-of 3.78 (1H, usher.), 3,82-of 3.94 (1H, usher.), 4,48-of 4.57 (1H, m), 5,07 (2H, s), to 6.95 (4H, s), 7,11-to 7.18 (1H, m), 7.23 percent-7,30 (2H, m), 7,40-7,47 (1H, m), 8,29-8,32 (1H, m), 8,78 (1H, d,J=2,5 Hz), 8,91 (1H, d,J=2.0 Hz),DMSO:448(M+H)+FAB
3920,78 with 0.93 (2H, m), 1.04 million-of 1.26 (6H, m), 1,35-1,45 (2H, m), 1,54-174 (9H, m), 1,90-2,04 (2H, usher.), 3,28-3,55 (2H, m), 3,66-of 3.95 (4H, m), 4,46-of 4.54 (1H, m), at 6.84 (2H, d,J=8,8 Hz), 6,93 (2H, d,J=8,8 Hz), was 7.45 (1H, DD,J=4,8, and 8.4 Hz), 7,60-7,66 (1H, m), to 8.41-to 8.45 (2H, m),DMSO:453(M+H)+FAB
393415(M+H)+FAB
394387(M+H)+FAB
3951,06-1,20 (2H, m), USD 1.43-1,82 (10H, m), 1,86-2,05 (3H, m), 3,24 is 3.57 (2H, usher.), 3,68-of 3.94 (4H, m) 4,51-4,55 (1H, m), 6,85 (2H, d,J=9,2 Hz), 6,93 (2H, d,J=9,2 Hz), 8,08 (1H, DD,J=1,6, 2.4 Hz), 8,66 (1H, d,J=2,4 Hz), of 8.92 (1H, d,J=1,6 Hz) , 13,38-at 13.84 (1H, usher.),
DMSO:455(M+H)+FAB
3961,21-of 1.42 (2H, m), of 1.78-1.90 (2H, usher.), 1,93 e 2.06 (1H, m), 2,85-2,99 (1H, usher.), 3,01 is 3.15 (1H, usher.), 3,81 (2H, d,J=8.0 Hz), 3,99-4,12 (1H, usher.), 4,15-4,27 (1H, usher.), 5,07 (2H, s), to 6.88 (2H, d,J=9,2 Hz), 6,94 (2H, d,J=9,2 Hz), 7,11-to 7.18 (1H, m), 7.23 percent-7,29 (2H, m), 7,39-7,47 (2H, m), a 7.62 (1H, DDD,J=1,2, 2,4, 8.0 Hz), 8,40-to 8.45 (1H, m),DMSO:
437(M+H)+FAB
397414(M+H)+FAB
398386(M+H)+FAB
3991,10-of 1.33 (2H, m), 1,45-to 1.61 (3H, m), a 1.75-to 1.87 (2H, usher.), of 2.64 (2H, t,J=7,6 Hz), 2,80-3,10 (2H, usher.), 3,95-4,24 (2H, usher.), 7,12-to 7.32 (5H, m), of 7.90 (2H, d,J=8,4 Hz), 7,98-8,08 (3H, m), 8,43-8,49 (1H, m), 8,80-8,86 (1H, m), 12,80-13,30 (1H, m),DMSO:
431(M+H)+FAB

Table 62Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z4001,06-of 1.30 (2H, m), 1.56 to of 1.80 (3H, m), 2,47-2,52 (2H, m), was 2.76-2.91 in (1H, usher.), 2,93-of 3.07 (1H, usher.), 3,92-of 4.05 (1H, usher.), 4,08-is 4.21 (1H, usher.), at 5.10 (2H, s)6,94 (2H, d,J=8.0 Hz), 7,08-to 7.18 (3H, m), 7.24 to 7,31 (2H, m), 7,40-of 7.48 (1H, m), 7,71 (1H, DD,J=4,8, and 8.4 Hz), 7,93-to 7.99 (1H, m), 8,58 (1H, d,J=4.4 Hz), 8,62-8,78 (1H, m),DMSO:421(M+H)+FAB401of 1.08 to 1.31 (2H, m), 1,58-to 1.79 (3H, m), 2,47-2,52 (2H, m), was 2.76 was 3.05 (2H, usher.), 3,92-4,22 (2H, usher.), at 5.10 (2H, s)6,94 (2H, d,J=8,4 Hz), 7,08-7,19 (3H, m), 7.24 to 7,31 (2H, m), 7,40-of 7.48 (1H, m), 7,98-8,03 (1H, m), 8,56-to 8.62 (1H, m), 8,87-8,93 (1H, usher.),DMSO:
465(M+H)+FAB4021,07 of 1.28 (2H, usher.), 1,43 is 1.60 (3H, m), 1,73-1,82 (2H, usher.), 2,62 (2H, t,J=7,8 Hz), 2.77-to 3,05 (2H, usher.), 3,92-4,20 (2H, usher.), of 7.00 (1H, DD,J=2,0, 2.4 Hz), 7,14-7,31 (5H, m), of 8.04 (1H, DD,J=2,0, 2.4 Hz), 7,86-7,94 (1H, usher.), 7,97-8,03 (1H, usher.), 10,06-10,26 (1H, usher.),
DMSO:327(M+H)+FAB403351(M+H)+FAB404395(M+H)+FAB405503(M+H)+FAB406453(M+H)+ FAB4071,02-is 1.51 (6H, m), 1,68 and 1.80 (4H, m), of 2.28 (3H, s), 2,66-to 2.74 (2H, m), 2,82-to 3.09 (2H, m), 3.95 to or 4.31 (4H, m), to 6.43 (1H, d,J=7,1 Hz), 6,56 (1H, d,J=8,5 Hz), 7,34-7,39 (1H, m), 7,65-of 7.69 (1H, usher.), 7,99 shed 8.01 (1H, m), 8,16-8,19 (1H, usher.), 8,55 (1H, d,J=2,5 Hz), 8,88 (1H, d,J=1.9 Hz),DMSO:452(M+H)+FAB408502(M+H)+FAB409369(M+H)+FAB410327(M+H)+FAB411441(M+H)+ESI4121,25-of 1.65 (6H, m), 2,25-2,48 (6H, m), to 2.57 (2H, t,J=7,8 Hz), 3,36-of 3.64 (4H, m), 7,12-7,30 (5H, m), 7,68 (1H, s), 8,03 (1H, t,J=2,4 Hz), 8,19 (1H, s), 8,56 (1H, d,J=2,4 Hz), of 8.90 (1H, d,J=1.5 Hz),DMSO:397(M+H)+FAB4133,00-of 3.75 (6H, m), 4,01-to 4.38 (4H, m)to 5.17 (2H, s), 7,10 (2H, d,J=8,8 Hz), 7,13-7,21 (1H, m), 7,27-7,33 (2H, m), 7,42-7,49 (1H, m), to 7.59 (2H, d,J=8,8 Hz), of 7.75 (1H, DD,Jvalue of 5.2 and 7.6 Hz), 7,97-8,02 (1H, m), to 8.62 (1H, d,J=4.4 Hz), to 8.70 (1H, d,J=2,4 Hz),DMSO:
422(M+H)+FAB414432(M+H)+FAB415431(M+H)+FAB416299(M+H)+FAB 417of 1.33 (3H, t,J=6,8 Hz), 1,60 to 1.76 (2H, usher.), 1,91-2,07 (2H, usher.), 3,30-of 3.43 (1H, usher.), of 3.46-of 3.60 (1H, usher.), 3,67 of 3.75 (1H, usher.), 3,83-of 3.96 (1H, usher.), of 4.35 (2H, square,J=6,8 Hz), 4,47-of 4.57 (1H, m), 5,07 (2H, s), of 6.96 (4H, s), 7,11-7,19 (1H, m), 7.23 percent-7,30 (2H, m), 7,40-7,47 (1H, m), to 7.84 (1H, DD,J=2,4, 8,8 Hz)to 8.12 (1H, d,J=8,8 Hz), 8,58 (1H, d,J=2,4 Hz),DMSO:
495(M+H)+FAB4181,58 - to 1.77 (2H, usher.), 1,90 - of 2.08 (2H, usher.), 3,28 of-3.60 (2H, usher.), 3,66 -3,98 (2H, usher.), 4,47 - of 4.54 (1H, m), 5,07 (2H, s), of 6.96 (4H, s), 7,10 - 7,19 (1H, m), 7,21 - to 7.32 (2H, m), 7,38 - 7,49 (1H, m), 7,69 - to 7.77 (1H, m), of 8.04 (1H, d,J=8.6 Hz), 8,60 - to 8.70 (1H, m),DMSO:467(M+H)+FAB419327(M+H)+FAB420354(M+H)+FAB421437(M+H)+FAB422437(M+H)+FAB423368(M+H)+FAB

Table 63
Example No.Physico-chemical properties
1H-NMR δ (ppm)solvent: MSm/z
424369(M+H)+ESI
425 370(M+H)+FAB
426383(M+H)+ESI
427412(M+H)+FAB
428483(M+H)+FAB
429384(M+H)+FAB
430483(M+H)+ESI
431493(M+H)+ESI
432522(M+H)+ESI
433466(M+H)+FAB
434480(M+H)+ESI
435438(M+H)+ESI
436427(M+H)+ESI
437481(M+H)+FAB

Table 64
No. AvecellNo. AvecellNo. Avecell
FAAH IC50(nm) FAAH IC50(nm)FAAH IC50(nm)
0020,111080,0522930,24
0030,0731130,0562940,60
0090,671150,0523000,43
0100,101160,0783010,40
0130,271220,153020,17
0140,201240,353030,12
0150,0331260,58304 0,24
0170,181380,0783130,89
0180,351440,0933150,51
0190,0721470,283180,062
0210,231490,453190,24
0230,0401510,17320of 0.081
0300,191520,183210,040
0330,0771540,173220,058
03 0,0461550,0613230,085
0360,0441590,233240,50
0370,691600,513250,54
0380,0281730,693260,13
0390,301740,603270,12
0420,431750,373280,42
0430,211760,843290,39
0440,095 179to 0.0603300,53
0460,411970,113330,43
0470,131990,583340,048
0490,102000,303350,075
0510,262060,173380,034
0530,0632070,313390,12
0550,442080,133400,052
0610,352180,44 3410,078
0630,122250,893420,33
0650,412280,223440,13
0660,0572610,543450,18
0690,095263being 0.0363460,27
0700,0992660,313490,054
0770,0712680,153510,13
078of 0.081269of 0.0813590,52
0800,0442700,173620,42
0810,0122720,483640,14
0880,372740,373710,21
0850,442810,0823720,49
0980,262830,433730,49
0990,0992840,363760,21
1000,0352850,473780,20
101 0,0782870,0313800,35
1030,0922890,16
104of 0.0662920,65

Table 65
Conn.No.R1R4Conn.No.R1R4
1HO2C(CH2)3H32cPen(CH2)2CONH2
2Mo4(CH2)2NHCO(CH2)3H 33cHexCH2H
34-HexOPh(CH2)2NHCOCO2H34cHexCH2CO2Me
44-OctPhNHCOCO2H35cHexCH2CO2H
5Ph(CH2)2CONHCO2Me36cHexCH2CONH2
6Ph(CH2)2CONHH37cHex(CH2)3H
7Ph(CH2)2CONHCO2H38cHex(CH2)3 CO2Me
8Ph(CH2)4NHCOCO2H39cHex(CH2)3CO2H
94-BuPhNHCOCO2H40cHex(CH2)3CONH2
104-HexPhNHCOCO2H41Ph(CH2)3H
11Py2(CH2)2NHCOH42Ph(CH2)3CONH2
12Py3(CH2)2NHCOH433-FPh(CH2)3H
13Ph(CH2 4NHCOCONH2443-FPh(CH2)3CO2Me
144-BuPhNHCOCONH2453-FPh(CH2)3CO2H
15Ph(CH2)3O(CH2)2CO2H463-FPh(CH2)3CONH2
162-H2NCOPhO(CH2)3CO2H473-ClPh(CH2)3H
174-(3-FPhCH2O)PhO483-ClPh(CH2)3CO2Me
18Ph(CH2) 2493-ClPh(CH2)3CO2H
191-MeBenzIM (CH2)3CO2H503-ClPh(CH2)3CONH2
20Ph(CH2)2CO2Me513-NCPh(CH2)3H
213-PIPE1Ph(CH2)2CO2H523-NCPh(CH2)3CO2Me
22CO2H533-NCPh(CH2)3CO2H
23Mo4CH2 H543-NCPh(CH2)3CONH2
24Mo4(CH2)2CO2Me553-MeOPh(CH2)3H
254-(3-FPhCH2)PIPERA1(CH2)2CO2Me563-MeOPh(CH2)3CO2Me
26Mo4(CH2)3CO2Me573-MeOPh(CH2)3CO2H
274-(3-FPhCH2PIPERA1(CH2)2H583-MeOPh(CH2)3CONH2
28Mo(CH2)3 H594-FPh(CH2)3H
29cPen(CH2)2H604-FPh(CH2)3CO2Me
30cPen(CH2)2CO2Me614-FPh(CH2)3CO2H
31cPen(CH2)2CO2H624-FPh(CH2)3CONH2

Table 66
Conn.No.R1R4Conn.No.R1 R4
634-ClPh(CH2)3H953,5-diFPh(CH2)3H
644-ClPh(CH2)3CO2Me963,5-diFPh(CH2)3CO2Me
654-ClPh(CH2)3CO2H973,5-diFPh(CH2)3CO2H
664-ClPh(CH2)3CONH2983,5-diFPh(CH2)3CONH2
674-NCPh(CH2)3H992,5-diFPh(CH2)3H
684-NCPh(CH2)3CO2Me1002,5-diFPh(CH2)3CO2Me
694-NCPh(CH2)3CO2H1012,5-diFPh(CH2)3CO2H
704-NCPh(CH2)3CONH21022,5-diFPh(CH2)3CONH2
714-MeOPh(CH2)3H1033-NC-5-FPh(CH2)3H
724-MeOPh(CH2)3CO2Me1043-NC-5-FPh(CH2)3CO2Me
73 4-MeOPh(CH2)3CO2H1053-NC-5-FPh(CH2)3CO2H
744-MeOPh(CH2)3CONH21063-NC-5-FPh(CH2)3CONH2
752-FPh(CH2)3H1073-FPh(CH2)2H
762-FPh(CH2)3CO2Me1083-ClPh(CH2)2H
772-FPh(CH2)3CO2H1093-NCPh(CH2)2H
782-FPh(CH2)3 CONH21103-MeOPh(CH2)2H
792-ClPh(CH2)3H1113-H2NCOPh(CH2)2H
802-ClPh(CH2)3CO2Me1123-Me2NCOPh(CH2)2H
812-ClPh(CH2)3CO2H1133-PIPE1COPh(CH2)2H
822-ClPh(CH2)3CONH21143-PYRR1COPh(CH2)2H
832-NCPh(CH2)3H 1153-EtNHCOPh(CH2)2H
842-NCPh(CH2)3CO2Me1163-Et2NCOPh(CH2)2H
852-NCPh(CH2)3CO2H1173-cHexNHCOPh(CH2)2H
862-NCPh(CH2)3CONH21184-FPh(CH2)2H
872-MeOPh(CH2)3H1194-ClPh(CH2)2H
882-MeOPh(CH2)3CO2Me1204-NCPh(CH2) 2H
892-MeOPh(CH2)3CO2H1214-MeOPh(CH2)2H
902-MeOPh(CH2)3CONH21224-Me2NCOPh(CH2)2H
913,4-diFPh(CH2)3H1234-PIPE1COPh(CH2)2H
923,4-diFPh(CH2)3CO2Me1244-PYRR1COPh(CH2)2H
933,4-diFPh(CH2)3CO2H1254-EtNHCOPh(CH2)2H
943,4-diFPh(CH2)3CONH21264-Et2NCOPh(CH2)2H

Table 67
Conn.No.R1R4Conn.No.R1R4
1274-cHexNHCOPh(CH2)2H1603-F-5-MeOPh(CH2)2H
1282-FPh(CH2)2H1613-F-5-MeOPh(CH2)2CO2Me
1292-ClPh(CH2)2H 1623-F-5-MeOPh(CH2)2CO2H
1302-NCPh(CH2)2H1633-F-5-MeOPh(CH2)2CONH2
1312-MeOPh(CH2)2H1642-F-5-MeOPh(CH2)2H
1323,4-diFPh(CH2)2H1652-F-5-MeOPh(CH2)2CO2Me
1333,4-diFPh(CH2)2CO2Me1662-F-5-MeOPh(CH2)2CO2H
1343,4-diFPh(CH2)2CO2H 1672-F-5-MeOPh(CH2)2CONH2
1353,4-diFPh(CH2)2CONH21682,4-diFPh(CH2)2H
1363,5-diFPh(CH2)2H1692,4-diFPh(CH2)2CO2Me
1373,5-diFPh(CH2)2CO2Me1702,4-diFPh(CH2)2CO2H
1383,5-diFPh(CH2)2CO2H1712,4-diFPh(CH2)2CONH2
1393,5-diFPh(CH2)2CONH2172 2-F-4-ClPh(CH2)2H
1402,5-diFPh(CH2)2H1732-F-4-ClPh(CH2)2CO2Me
1412,5-diFPh(CH2)2CO2Me1742-F-4-ClPh(CH2)2CO2H
1422,5-diFPh(CH2)2CO2H1752-F-4-ClPh(CH2)2CONH2
1432,5-diFPh(CH2)2CONH21762-F-4-NCPh(CH2)2H
1443-Cl-4-FPh(CH2)2H177 2-F-4-NCPh(CH2)2CO2Me
1453-Cl-4-FPh(CH2)2CO2Me1782-F-4-NCPh(CH2)2CO2H
1463-Cl-4-FPh(CH2)2CO2H1792-F-4-NCPh(CH2)2CONH2
1473-Cl-4-FPh(CH2)2CONH21802-F-4-MeOPh(CH2)2H
1483-Cl-5-FPh(CH2)2H1812-F-4-MeOPh(CH2)2CO2Me
1493-Cl-5-FPh(CH2)2CO2Me182 2-F-4-MeOPh(CH2)2CO2H
1503-Cl-5-FPh(CH2)2CO2H1832-F-4-MeOPh(CH2)2CONH2
1513-Cl-5-FPh(CH2)2CONH2184BIP3(CH2)2H
1522-F-5-ClPh(CH2)2H1853'-FBIP3(CH2)2H
1532-F-5-ClPh(CH2)2CO2Me1863'-NCBIP3(CH2)2H
1542-F-5-ClPh(CH2)2CO2H1873'-MeOBIP3(CH2)2 H
1552-F-5-ClPh(CH2)2CONH21883',4'-diFBIP3(CH2)2H
1563-MeO-4-FPh(CH2)2H1893'-MeO-4'-FBIP3(CH2)2H
1573-MeO-4-FPh(CH2)2CO2Me190BIP4(CH2)2H
1583-MeO-4-FPh(CH2)2CO2H1913'-FBIP4(CH2)2H
1593-MeO-4-FPh(CH2)2CONH21923'-NCBIP4(CH2)2H

Table 68
Conn.No.R1R4
1933'-MeOBIP4(CH2)2H
1943',4'-diFBIP4(CH2)2H
1953'-MeO-4'-FBIP4(CH2)2H
1963-Py2Ph(CH2)2H
1973-MeOPhNHCOH
1984-MeOPhNHCOH
1993-MeO-4-FPhNHCOH
2003-F-5-MeOPhNHCOH
2012-F-5-MeOPhNHCOH
2023-F-4-MeOPhNHCO2032-F-4-MeOPhNHCOH
2041-(6-MePy2)PIPE4(CH2)3H
2051-(6-MePy2)PIPE4CH2H
2061-PhCOPIPE4(CH2)3H
2071-(6-MePy2)PIPE4(CH2)2H
2081-(6-MePy2)PIPERA4(CH2)3H
2091-QUI2PIPE4(CH2)3H
2101-ISOQUI1PIPE4(CH2)3H
2111-ISOQUI1PIPERA4(CH2)3H
2121-NAPH1PIPE4(CH2)3H
213H
214 CONH2

4-(3-MeOPhCH2O)PhCO
Table 69
Conn.No.R1R4Conn.No.R1R4
215Ph(CH2)4CO2H2493-cHex(CH2)2OPhCOCONH2
216PhCO2H2503-cHepCH2OPhCOCONH2
217Ph(CH2)3CONH(CH2)2OH2513-PhCH2OPhCOCONH2
218Ph(CH2)5 CO2H2524-PhCH2OPhCOCONH2
219cHex(CH2)2H2533-cOctCH2OPhCOCONH2
220Ph(CH2)4H2544-cHexCH2N(Me)PhCOCONH2
221Ph(CH2)3H2554-(3-ClPhCH2O)PhCOCONH2
2223-MePh(CH2)2H2564-(3-F3CPhCH2O)PhCOCONH2
2233-MeOPh(CH2)2H257CONH2
2243-FPh(CH2)2H2584-(3-NCPhCH2O)PhCOCONH2
2253-NCPh(CH2)2H2594-(3,5-diFPhCH2O)PhCOCONH2
2264-MePh(CH2)2H2604-cHexCH2OPhCOCONH2
2274-MeOPh(CH2)2H261PhCH2OCOCONH2
2284-FPh(CH2)2H2624-tBuOPhCOCONH2
2294-NCPh(CH2)2H2634-PhCH2OPhCH2CONH2
2302-MePh(CH2)2H2644-H2NCOPhOCH2COCONH2
2312-MeOPh(CH2)2H265Ph(CH2)2OCOCONH2
2322-FPh(CH2)2H2663-MePh(CH2)2CONH2
2332-NCPh(CH2)2H2673-MeOPh(CH2)2CONH2
2343-Me-4-FPh(CH2)sub> 2H2683-FPh(CH2)2CONH2
2353-F-5-MePh(CH2)2H2693-NCPh(CH2)2CONH2
2362-F-5-MePh(CH2)2H2704-MePh(CH2)2CONH2
2373-MeO-4-FPh(CH2)2H2714-MeOPh(CH2)2CONH2
2383-F-5-MeOPh(CH2)2H2724-FPh(CH2)2CONH2
2392-F-5-MeOPh(CH2)2H 2734-NCPh(CH2)2CONH2
2403,4-diFPh(CH2)2H2742-MePh(CH2)2CONH2
2413,5-diFPh(CH2)2H2752-MeOPh(CH2)2CONH2
2422,5-diFPh(CH2)2H2762-FPh(CH2)2CONH2
2433-iPrOPh(CH2)2H2772-NCPh(CH2)2CONH2
2443-NC 4-FPh(CH2)2H278 3-MeO-4-FPh(CH2)2CONH2
2454-tBucHex(CH2)2H2792-F-3-MeOPh(CH2)2CONH2
2463-H2NCOPh(CH2)2H2802-F-5-MeOPh(CH2)2CONH2
2471-(6-MePy2)PIPE4(CH2)3H2813-Me-4-FPh(CH2)2CONH2
2483-cHexCH2OPhCOCONH22823-F-5-MePh(CH2)2CONH2

Table 70
Conn.No.R1R4Conn.No.R1R4
2832-F-5-MePh(CH2)2CONH23173-MePh(CH2)2CO2Me
2843,4-diFPh(CH2)2CONH23183-MeOPh(CH2)2CO2Me
2853,5-diFPh(CH2)2CONH23193-FPh(CH2)2CO2Me
2862,5-diFPh(CH2)2CONH23203-NCPh(CH2)2CO2Me
287 4-tBucHex(CH2)2CONH23214-MePh(CH2)2CO2Me
2883-cHexCH2OPhCOCO2Me3224-MeOPh(CH2)2CO2Me
2893-cHex(CH2)2OPhCOCO2Me3234-FPh(CH2)2CO2Me
2903-cHepCH2OPhCOCO2Me3244-NCPh(CH2)2CO2Me
2913-PhCH2OPhCOCO2Me3252-MePh(CH2)2CO2Me
2924-PhCH2OPhCO CO2Me3262-MeOPh(CH2)2CO2Me
2933-cOctCH2OPhCOCO2Me3272-FPh(CH2)2CO2Me
2944-[3-FPhCH2N(Me)]PhCOCO2Me3282-NCPh(CH2)2CO2Me
2954-[3,4-diFPhCH2N(Me)]PhCOCO2Me3293-Me-4-FPh(CH2)2CO2Me
2964-[3,5-diFPhCH2N(Me)]PhCOCO2Me3302-F-5-MePh(CH2)2CO2Me
2974-[2,5-diFPhCH2N(Me)]PhCO CO2Me3313-F-5-MePh(CH2)2CO2Me
2984-cHexCH2N(Me)PhCOCO2Me3323-MeO-4-FPh(CH2)2CO2Me
2994-(3-ClPhCH2O)PhCOCO2Me3332-F-5-MeOPh(CH2)2CO2Me
3004-(3-F3CPhCH2O)PhCOCO2Me3343-F-5-MeOPh(CH2)2CO2Me
3014-(3-MeOPhCH2O)PhCOCO2Me3353,4-diFPh(CH2)2CO2Me
3024-(3-MeO-4-FPhCH2O)PhCO CO2Me3362,5-diFPh(CH2)2CO2Me
3034-(3-F-5-MeOPhCH2O)PhCOCO2Me3373,5-diFPh(CH2)2CO2Me
3044-(3-NCPhCH2O)PhCOCO2Me3384-tBucHex(CH2)2CO2Me
3054-(3,5-diFPhCH2O)PhCOCO2Me3393-cHexCH2OPhCOCO2H
3064-cHexCH2OPhCOCO2Me3403-cHex(CH2)2OPhCOCO2H
307PhCH2OCOCO2Me 3413-cHepCH2OPhCOCO2H
3084-tBuOPhCOCO2Me3423-PhCH2OPhCOCO2H
3094-PhCH2OPhCH2CO2Me3434-PhCH2OPhCOCO2H
3104-H2NCOPhOCH2COCO2Me3443-cOctCH2OPhCOCO2H
311Ph(CH2)2OCOCO2Me3454-(3-F3CPhCH2O)PhCOCO2H
3123-Cl-4-(3-NCPhCH2O)PhCOCO2Me346 4-(3-MeOPhCH2O)PhCOCO2H
3132-Cl-4-(3-NCPhCH2O)PhCOCO2Me3474-(3-NCPhCH2O)PhCOCO2H
3144-[3-FPhCH2N(Me)]PhCOCO2H3484-(3,5-diFPhCH2O)PhCOCO2H
3154-cHexCH2N(Me)PhCOCO2H3494-cHexCH2OPhCOCO2H
3164-(3-ClPhCH2O)PhCOCO2H350PhCH2OCOCO2H

CO2H
Table 71
Conn.No. R1R4
3514-tBuOPhCOCO2H
3524-PhCH2OPhCH2CO2H
3534-H2NCOPhOCH2COCO2H
354Ph(CH2)2OCOCO2H
3553-Cl-4-(3-NCPhCH2O)PhCOCO2H
3562-Cl-4-(3-NCPhCH2O)PhCOCO2H
3573-MePh(CH2)2CO2H
3583-MeOPh(CH2)2CO2H
3593-FPh(CH2)2CO2H
3603-NCPh(CH2)2CO2H
3614-tBucHex(CH2)2
3624-(4-FPhCH2O)PhCOCONH2
3634-(4-FPhCH2O)PhCOCO2Me
3644-(4-FPhCH2O)PhCOCO2H
3654-(3,4-diFPhCH2O)PhCOCONH2
3664-(3,4-diFPhCH2O)PhCOCO2Me
3674-(2,4-diFPhCH2O)PhCOCONH2
3684-(2,4-diFPhCH2O)PhCOCO2Me
369Ph(CH2)2CONH2
370Ph(CH2)4CONH2
3714-[3-FPhCH2N(Me)]PhCOCONH2
3724-[3,4-diFPhCH2N(Me)]PhCOCONH2
3734-[3,5-diFPhCH2N(Me)]PhCOCONH2
3744-[3-MeO-4-FPhCH2N(Me)]PhCOCONH2
3754-[3-F-5-MeOPhCH2N(Me)]PhCOCONH2
3763-Cl-4-(3-NCPhCH2O)PhCOCONH2
3772-Cl-4-(3-NCPhCH2O)PhCOCONH2

Table 72
Conn.No.The structural formulaConn.No.The structural formula
378389
379390
380 391
381392
382393
383394
384395
385396
386397
387398
388399

Table 73
Conn.No.The structural formula
400
401
402
403
404
405
406

Industrial applicability

Connect the ment of the present invention have excellent activity of inhibiting FAAH and are useful for the treatment associated with FAAH disorders, in particular, frequent urination and urinary incontinence, increased activity of the bladder and/or pain.

Separate sequence listing

The author of the invention is indicated in the column that has the number <223> SEQ ID NO:1 below the list of sequences.

1. Peregrinae non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (I) or its pharmaceutically acceptable salt

where NO1represents a 5-7 membered non-aromatic nitrogen-containing heterokonta,
R1, R2and R3are the same or different from each other, and each represents a
(1) H,
(2) HE,
(3) BUT-CO-, lower alkyl-O -, aryl-lower alkyl-O-CO - or H2N-CO-aryl-lower alkyl-O-CO-,
(4) cyano,
(5) lower alkyl-CO-,
(6) oxo (=O),
(7) the formula [R101-(O)m1]m2-[ALK1not necessarily replaced IT]-(O)n1-,
(m1 and n1 are the same or different from each other, where each has a value of 0 or 1,
m2 has a value of from 1 to 5,
ALK1represents the lowest alkylene, lower albaniles or lower akinyan,
R101represents a
(i) H,
(ii) Ar1a, optionally substituted by at least one Deputy, selected from the group including:
(a) H2N-,
(b) halogen,
(c) cyano,
(d) optional acerifolia the p carboxyl,
(e) the group of R1011aR1012aN-CO-,
(f) NO2,
(g) Ar1a, optionally substituted with halogen, cyano, HE, lower alkyl or lower alkyl,
Ar1arepresents aryl,
(h) lower alkyl,
(j) OH,
(k) lower alkyl-O-, optionally substituted by a group Ar1aor halogen-Ar1a,
(l) NO2-CO-, optionally substituted with halogen, Ar1aor HETAr1a,
NO2represents a nitrogen-containing heterokonta,
HETAr1arepresents a nitrogen containing heteroaryl,
(s) HET2-CONR1011a-,
(t) H2NCONH - and
(u) optionally esterified carboxyl-ALK2a,
ALK2arepresents a lower alkyl or lower alkenyl,
(iii) ALK2a, optionally substituted by a group R1011aR1012aNorAr1a,
R1011aand R1012aare the same or different from each other, and
each is a
(a) H,
(b) cALK,
cALK is cycloalkyl,
(c) ALK2a, optionally substituted with halogen, cALK, HE, lower alkyl or Ar1aor
(d) Ar1a-SO2-, optionally substituted with halogen,
(iv) NO2, optionally substituted by at least one Deputy, selected from the group including
(a) ALK2a, optionally substituted by a group Ar1aor halogen-Ar1a,
(b) Ar1a,
(c) HETAr1a , optionally substituted lower alkyl,
(d) Ar1a-CO - or halogen-Ar1aWITH,
(v) cALK, optionally substituted ALK2aor
(vi) optionally esterified carboxyl,
(when m2 has a value from 2 to 5, then the group [R101-(O)m1] may be the same or different from each other),
(8) the group of R102-ALK1-N(R103)-CO-,
(R102represents a
(i) H,
(ii) cALK,
(iii) HETAr1aor
(iv) Ar1a, optionally substituted by at least one Deputy, selected from the group including
(a) BUT,
(b) ALK2a-O-,
(c) cALK-ALK1-O,
(d) cALK-Arla-ALK1-O-, and
(e) Ar1a-ALK1-O,
R103represents a
(i) H,
(ii) cALK,
(iii) ALK2a, optionally substituted by at least one Deputy, selected from the group including
(a) NO2,
(b) Ar1aand
(C) halogen-Ar1a,
(iv) HETAr1aor
(v) Ar1a-[CO]m1, optionally substituted by at least one Deputy, selected from the group including
(a) cALK,
(b) H2N
(c) the group of R1011aR1012aN-CO - or
(d) ALK2a),
(9) the group of R104aR105aN-[CO]m1-ALK1-,
(R104aand R105aare the same or different from each other, and each represents a group R103),
(10) a group of 11106-ALK3-L1-,
(R106is the th
(i) a group R101-(O)m1-,
(ii) the group R104aR105aN-,
(iii) a group ALK2a-CONH - or
(iv) a group Ar1a-CONH-,
ALK3represents the lowest alkylene, lower albaniles or cycloalkyl,
L1- represents-C(=O)- or-SO2-),
(11) ALK2a-CONH-, optionally substituted by a group Ar1a,
(12) Ar1asubstituted by halogen,
(13) group [R107-(O)m1]m2-Ar2-(O)n1-,
(Ar2represents arisen,
R107represents a
(i) H,
(ii) halogen,
(iii) ALK2a, optionally substituted by at least one Deputy, selected from the group including
(a) BUT,
(b) cALK,
(c) NO2,
(d) Ar1a, optionally substituted with halogen, lower alkyl, lower alkyl-O-group, R1011aR1012aN-[CO]p-, cyano or optionally esterified by carboxyla,
(e) optionally esterified carboxyl,
(f) HET2-[CO]p-, optionally substituted by a group R1011aR1012aN-[CO]p-, and
(g) the group of R1011aR1012aN-[CO]p-,
p is 0 or 1,
(iv) the group R1011aR1012aN-[CO]p -, or
(v) the group of R1011aR1012aN-[CO]p-Ar1a,
in this case, when m2 has a value from 2 to 5, then the group [R107-(O)m1] may be the same or different from each other, and, in addition, the group [R107-(O)m1]m2 can represent methylenedioxy education to which ICA),
(14) group [R107-(O)m1]m2-Ar2-N(R103)-CO-,
(when m2 has a value from 2 to 5, then the group [R107-(O)m1] may be the same or different from each other),
(15) group [R1011aR1012aN-[CO]m1]m2-Ar2-(O)n1-,
(when m2 has a value from 2 to 5, then the group [R1011aR1012aN-[CO]m1] may be the same or different from each other),
(16) group [R108]m2-Ar2-L2-,
[R108represents a
(i) H,
(ii) halogen,
(iii) BUT,
(iv) cALK-O,
(v) the group of R109-ALK1-(O)m1-,
(R109represents a
(a) H,
(b) cALK,
(c) Ar1a, optionally substituted by at least one Deputy, selected from the group including
(1') halogen,
(2') cyano,
(3') NO2,
(4') ALK2a, optionally substituted with halogen,
(5') BUT,
(6') ALK2a-O-, optionally substituted with halogen,
(7') optionally esterified carboxyl or
(8') group R104aR105aN
(d)HETAr1aor
(e) the group of R104aR105aN-[CO]m1),
(vi) the group R1013R1014N-,
R1013and R1014are the same or different from each other and each represents a
(i) H,
(ii) ALK2a,
(iii) cALK-ALK1or
(iv) Ar1a-ALK1-, optionally substituted by at least one Deputy, selected from the group including
(1') halogen,
(2 is) cyano,
(3') ALK2a, optionally substituted with halogen,
(4') ALK2a-O, optionally substituted with halogen,
(vii) HET2-(O)m1-, optionally substituted lower alkyl,
L2represents-CO - or-S(O)q-,
q is 0, 1 or 2,
in this case, when m2 has a value from 2 to 5, then the group [R108] may be the same or different from each other],
(17) group [R101]m2-Ar2-CONH-,
(when m2 has a value from 2 to 5, then the group [R101] may be the same or different from each other),
(18) group [R111]m2-HETAr2-(O)m1-,
(R111represents a
(i) H,
(ii) halogen,
(iii) oxo (=O) or
(iv) the group R103a-(O)n1-,
R103arepresents a
(i) H,
(ii) cALK,
(iii) ALKa, optionally substituted by at least one Deputy, selected from the group including
(a) NO2,
(b) Ar1a,
(c) cALK and
(d) a halogen-Ar1a,
(iv) HETAr1aor
(v) Ar1a, optionally substituted by at least one Deputy, selected from the group comprising (a) cALK, (b) H2N and (C) the group of R1011aR1012aN-CO-,
HETAr2represents a nitrogen-containing heteroaryl,
(when m2 has a value from 2 to 5, then the group [R111] may be the same or different from each other),
(19) the formula [R112]m2-HETAr2-N(R103)-CO-,
(R112 (i) H,
(ii) cALK,
(iii) ALK2aor
(iv) Ar1a, optionally substituted by at least one Deputy, selected from the group including
(a) halogen,
(b) BUT,
(c) ALK2a-O - and
(d) Ar1a-ALK1-O,
(when m2 has a value from 2 to 5, then the group [R112] may be the same or different from each other),
(20) the formula [R108]m2-HETAr2-L2-,
(when m2 has a value from 2 to 5, then the group [R108] may be the same or different from each other),
provided that, when any of the groups R1, R2and R3is a group [R111]m2-HETAr2-(O)m1 -, and when m1 is 0, then the rest of the group R1, R2and R3represent H;
one of R4, R5R and R7represents an optionally esterified carboxyl, while others are N.

2. The compound according to claim 1 represented by General formula (II), or its pharmaceutically acceptable salt:

where R1- R7have the meanings defined in claim 1,
T represents CH2, NH, NHCH2or,
and also includes the case where the hydrogen in T replaced by R1- R3.

3. The compound according to claim 2, where R1- R3are the same or different from each other and each represents H, a group [R101 -(O)m1]m2-
[ALK1, optionally substituted by OH]-(O)n1-, R102-ALK1-N(R103)-CO-group, R106-ALK3-L1group [R107-(O)m1]m2-Ar2-(O)n1 -, [R107-(O)m1]m2-Ar2-N(R103)-CO - or a group [R108]m2-Ar2-L2or its pharmaceutically acceptable salt.

4. Peregrinae non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (III) and its pharmaceutically acceptable salt:

where ring a is a benzene ring, cyclopentane ring, cyclohexane ring, Cycloheptane ring or a 5-7 membered nitrogen-containing heterokonta;
L represents a simple bond, a lower alkylene, lower albaniles, -N(R15)-C(=O)-, -C(=O)-N(R15)-, -(lower albaniles)-C(=O)-, -O - or-S(=O)-,
R15represents H or lower alkyl,
X represents CH or N,
R8-R10are the same or different from each other, and each represents a
group selected from the following group G,
aryl, optionally substituted by the same or different from each groups selected from the following group G,
the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G,
R16 -(lower alkylene)-O-,
R16-(lower alkylene)-N(R15)- or
R17R18N-C(=O)-,
R16represents a
aryl, optionally substituted by the same or different from each groups selected from the following group G,
the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G, or
3-8-membered cycloalkyl,
R17and R18are the same or different from each other and each represents H, lower alkyl or 3-8-membered cycloalkyl,
(in addition, R17and R18may form, together with the N atom associated with them, 3-8-membered nitrogen-containing heterokonta),
group G includes H, halogen, -CN, -CF3, lower alkyl or-O-lower alkyl,
R11represents H, lower alkyl or oxo (=O),
one of R12, R13, R14represents-C(=O)-O-(lower alkyl) or-CO2N and the other represents N.

5. The compound according to claim 4 in which the ring a represents a benzene ring, cyclohexane ring, piperidine ring or pieperazinove ring, or its pharmaceutically acceptable salt.

6. The compound according to claim 5, where R9, R10, R11, R12and R13represent H, or its pharmaceutically acceptable salt.

7. Peridinin the e non-aromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (IV) and its pharmaceutically acceptable salt:

where the ring And1represents a benzene ring, piperidine ring or pieperazinove ring;
L1represents the lowest alkylene, lower albaniles, -N(R15)-C(=O)- or-O-;
R15represents H or lower alkyl,
R19represents a
group selected from the following group G,
the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G,
R16-(lower alkylene)-O - or R17R18N-C(=O)-,
R16represents a
aryl, optionally substituted by the same or different from each groups selected from the following group G,
the nitrogen-containing heteroaryl, optionally substituted by the same or different from each groups selected from the following group G, or
3-8-membered cycloalkyl,
R17and R18are the same or different from each other and each represents H or lower alkyl,
(in addition, R17and R18may form, together with the N atom associated with them, a 5 - or 6-membered nitrogen-containing heterokonta),
group G includes H, halogen, -CN, -CF3, lower alkyl or-O-lower alkyl,
R20represents-C(=O)-O-(lower alkyl) or-CO2N./p>

8. Peregrinae nonaromatic nitrogen-containing heterocycle-1-carboxylate derivative of General formula (V) and its pharmaceutically acceptable salt:

where L2represents the lowest alkylene, lower albaniles or -(lower albaniles)-C(=O)-,
R21represents H, halogen, -CN, -CF3, lower alkyl or-O-lower alkyl,
R22represents-C(=O)-O-(lower alkyl) or-CO2N.

9. The compound according to claim 1, selected from the following groups:
5-{[(4-{4-[(3-terbisil)oxy]phenoxy}piperidine-1-yl)carbonyl]oxy}nicotinic acid,
5-({[4-(2-phenylethyl)piperidine-1-yl]carbonyl}oxy)-nicotinic acid,
5-[({4-[4-(2-cyclohexylmethoxy)phenoxy]piperidine-1-yl}carbonyl)oxy]nicotinic acid,
5-[({4-[(E)-2-phenylphenyl]piperidine-1-yl}carbonyl)-oxy]nicotinic acid,
5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidine-4-yl]propyl}piperidine-1-yl)carbonyl]oxy}nicotinic acid,
5-(methoxycarbonyl)pyridine-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate, or its pharmaceutically acceptable salt.

10. Pharmaceutical composition having FAAH inhibitory activity containing a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt as the active ingredient.

11. The pharmaceutical composition of claim 10, which is a drug for Leche is of frequent urination, urinary incontinence and/or increased activity of the bladder.

12. The pharmaceutical composition of claim 10, which is a drug for the treatment of pain.

13. The use of compounds according to any one of claims 1 to 9, or its pharmaceutically acceptable salt for a FAAH inhibitor or a medicinal product for the treatment of frequent urination, urinary incontinence and/or increased activity of the bladder.

14. The use of compounds according to any one of claims 1 to 9, or its pharmaceutically acceptable salt for a FAAH inhibitor or a medicinal product for the treatment of pain.

15. A method of treating frequent urination, urinary incontinence and/or increased activity of the bladder, including the introduction to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt.

16. A method of treating pain comprising the administration to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3-diiminoisoindoline, and more specifically to N1,N3-bis(5-amino-3-pentyl-1,3,4-thiadiazol-2-ylidene)-2H-isoindole-1,3-diamine. This compound is soluble in organic solvents and can be used for colouring hydrocarbons, synthetic fibre, fats, wax, alcohols, polymers of plastics, rubber.

EFFECT: wider assortment of fat-soluble light tone dyes.

1 cl, 2 dwg, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with formula (I): (I) A is absent or represents (CH2)2; L is CH or N; M is NR1, O, S, S(O) or S(O)2; R1 is C1-6alkyl, substituted with phenyl {which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3}; phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3, C1-4alkylthio}, S(O)2R, S(O)2NR6R7, C(O)R8; R2 is phenyl (which is possibly substituted with halogen, CN or C1-4halogenalkyl), thienyl or halogenthienyl; R3 is hydrogen or methyl; Rb is hydrogen or C1-3alkyl; R4 is a five- or six-member heterocycle, containing at least one carbon atom, one to four nitrogen atoms and, possibly, one oxygen or sulphur atom, where the carbon atom in the said heterocycle R4 is possibly substituted with oxo, C1-6alkyl [which is possibly substituted with halogen, OH, C1-4alkoxy, S(C1-4alkyl) group or piperidinyl {which it self is possibly substituted with benzene [which is possibly substituted with a S(O)2(C1-4alkyl) group], C(O)(C1-4alkoxy) group, C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) [where alkyl is possibly substituted with fluoro]}], C3-6cycloalkyl, CN, C(O)NH2, C(O)NH(phenylC1-2alkyl) group, phenyl [which is possibly substituted with a S(O)2(C1-4alkyl) group] or benzyl [which is possibly substituted with a S(O)2(C1-4alkyl) group]; if possible, the nitrogen atom in the said heterocycle R4 is substituted with C1-6alkyl [which is possibly substituted with C1-4alkoxy, S(O)(C1-4alkyl) group, S(O)2(C1-4alkyl), C(O)(C1-4alkoxy), CONH2, CONH(C1-4alkyl), CON(C1-4alkyl)2, phenyl{which is possibly substituted with C1-4alkyl, C1-4alkoxy, S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}, piperidinyl {which is possibly substituted with a S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}], C3-6cycloalkyl, CO(C1-4alkyl) group [which is possibly substituted with a halogen], S(O)2(C1-4alkyl) group [which is possibly substituted with fluorine], COO(C1-6alkyl) group, phenyl [which is possibly substituted with a S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group]; - under the condition that the nitrogen atom in the said heterocycle R4 is substituted with an alky group, the said alkyl does not have C1-4alkoxy, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) substitute on the carbon atom, bonded to the nitrogen atom in the said heterocycle R4; - five- or six-member heterocyle R4 is possibly condensed with cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring; ring carbon atoms in the said condensed cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring are possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy, CF3, S(C1-4alkyl), S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group; and the nitrogen atom of the condensed piperidine ring is possibly substituted with C1-4alkyl [which is possibly substituted with oxo, halogen, OH, C1-4alkoxy, C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl) group, C(O)N(C1-4alkyl)2 group, C(O)(C1-4alkyl)group [where alkyl is possibly substituted with C1-4alkoxy or halogen], benzene [which is possibly substituted with S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)], C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) group [where alkyl is possibly substituted with fluoro]; R5 is C1-6alkyl [which is possibly substituted with a halogen (for example fluoro), C1-4alkoxy, phenyl {which itself is possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with a halogen or C1-6alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with a S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R8 is hydrogen, C1-4alkyl [which is possibly substituted with halogen (for example fluro), C1-4alkoxy, phenyl{which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with halogen or C1-4alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R6 and R7 are bonded, forming a 5- or 6-member ring which is possibly substituted with C1-4alkyl; R9 and R10 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts. The invention also relates to a method of obtaining compounds in paragraph 1, to a method of modulating activity of CCR5 receptor, as well as to a pharmaceutical composition.

EFFECT: obtaining new biologically active compounds with modulating effect towards CCR5 receptor.

15 cl, 29 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I: , their optical isomers or optical isomer mix, and pharmaceutically acceptable salts, where: R1 is independently selected out of group including: aryl, heteroaryl, arylcarboxyamido, heteroarylcarboxyamido, aryloxy, arylalcoxy or arylamino, and where indicated groups of aryl, aryalkyl or heteroaryl can be substituted by 0-3 substitutes R1a, where R1a is independently selected out of group including: halogen, alkyl, alkenyl, alcoxy, alcoxyalkyl, hydroxyalkyl, mono-, di- or trihalogenoalkyl, mono-, di- or trihalogenoalcoxy, mono- or disubstituted aminoalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, etherified carboxylic acid residue, arylcarbonylamino, carbamate, R1b-aryl or R1b-heteroaryl where R1b is H, halogen, OH, amino, mono- or disubstituted amino, mono-, di- or trihalogenoalkyl, alkcoxy, mono-, di- or trihalogenoalcoxy, hydroxyalkyl; R2 is independently selected out of group including: H, OH, cyano, halogen or aryl; optionally R1 and R2 can be linked to form spirocyclyl; R3, R4, R5 and R6 are H; optionally R1 and R3 can be cyclised to form carbocycle; optionally R3 and R4 or R5 and R6 are cyclised to form bicyclic bridge system including ethylene bridge; optionally R3 and R6 are cyclised to form bicyclic bridge system including methylene or ethylene group; R7 and R8 are independently selected out of group including hydrogen, OH, C1-C8alkyl, arylalcoxy, heteroarylalcoxy; optionally R7 and R9 can be cyclised to form spirocarbocycle or spiroheterocycle; and m=0-5; where "aryl" term denotes aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, and aromatic groups condensed with heterocycles; where "heterocycle" term denotes aromatic and non-aromatic rings including 3 to 10 atoms in the ring, 1-4 of which are heteroatom selected out of oxygen, sulfur or nitrogen; where "alkyl" term, when used separately or as suffix, denotes branched or non-branched alkyl group including 1 to 8 carbon atoms in chain; where "alkenyl" term denotes non-saturated branched or non-branched alkyl group including 2 to 12 carbon atoms in chain.

EFFECT: compounds applicable as chemokine receptor activity modulators.

15 cl, 1 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound of the formula (I) , where R1 is a group of the formula and, in which R2, R3, R4, R5, R6, R7 and R8, each one independently represents a hydrogen atom or C1-6alkyl or its salt, to the method of its producing, to the method of antagonist effect on angiotensin II in the mammal, to the application of compounds of formula (I) as well as to methods of diseases prevention or treatment.

EFFECT: there are produced and provided new compounds that can be applied for prevention or treatment of disturbed circulation.

16 cl, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

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